Osteoporosis: Clinical Guidelines for Prevention, Diagnosis, and Management

Osteoporosis Clinical Guidelines for Prevention, Diagnosis, and Management Editors Sarah H. Gueldner, DSN, RN, FAAN, FGSA, FNAP, FAGHE Theresa N. Grabo, PhD, APRN, BC, CRNP Eric D. Newman, MD David R. Cooper, MD, AAOS

.EW9ORK

Osteoporosis

Sarah H. Gueldner, DSN, RN, FAAN, FGSA, FNAP, FAGHE, presently serves as the Garvin Visiting Professor of Nursing at Case Western Reserve University and is professor of nursing and fellow in the Institute of Primary and Preventative Health Care at Binghamton University, in Binghamton, New York, She holds a bachelor’s degree in nursing from the University of Tennessee College of Nursing in Memphis, a masters degree in nursing from Emory University, and a doctor of science in nursing from the University of Alabama in Birmingham, where she was named medical center graduate fellow. Dr. Gueldner served as senior research scientist at the University of Georgia Gerontology Center, and served as the principal investigator of a federally funded study that examined the benefits of exercise in nursing home residents. She presently heads a 5-year study profiling the prevalence of osteoporosis in rural women, and a doubleblind clinical trial to test interventions that support smoking cessation to improve bone health. She lists more than 100 publications, including 53 articles in referred journals, 7 books, and 39 chapters, and is a fellow in the American Academy of Nursing, the National Academies of Practice, the Gerontological Society of America, and the Association of Gerontology in Higher Education.

Theresa N. Grabo, PhD, APRN, BC, CRNP, is associate professor of nursing and director of graduate programs and fellow in the Institute of Primary and Preventative Health Care at Binghamton University, in Binghamton, New York. She holds a bachelor of science in nursing degree from the State University of New York at Buffalo, a master of nursing degree and family nurse practitioner certificate from Binghamton University, a master of public administration from Marywood University in Scranton, Pennsylvania, and a PhD from the University of Pennsylvania in Philadelphia, where she served as a fellow in the Summer Nursing Research Institute, International Center of Research for Women, Children, and Families at the University of Pennsylvania School of Nursing. She is presently co-investigator on a National Institute of Nursing Research grant investigating ways to improve heart healthy behaviors among rural women. She is an advanced practice registered nurse, board certified in family health nursing, with over 20 years experience as a certified nurse practitioner providing care to women and practices at Valley Gyn Specialists in Luzerne, Pennsylvania.

Eric D. Newman, MD, received his bachelor of arts degree in biology from Johns Hopkins University, and his medical degree from the Pennsylvania State University College of Medicine in Hershey, Pennsylvania, where he was the recipient of a National Institutes of Health (NIH) research grant. He completed an internal medicine residency at the University of North Carolina (Chapel Hill) and a rheumatology fellowship at Geisinger Medical Center in Danville, Pennsylvania. He has been on staff at Geisinger since 1988 and has served as director of rheumatology, vice-chairman of the Division of Medicine, and director of the Clinical Trials Office for the Geisinger Health Care System. He developed and maintains the Rheumatology Diagnosis, Treatment, and Outcomes Database, with information on 30,000 patients, encompassing over 220,000 clinic visits. He played an integral role in the design and implementation of the Geisinger Osteoporosis Disease Management Program, which has received three national awards and generated 12 peer-reviewed publications. In this role he developed and directs the Geisinger Mobile DXA Program, which performs 3,500 DXAs yearly in outlying areas of Pennsylvania.

David R. Cooper, MD, AAOS, received his Bachelor of Arts degree at Binghamton University in Binghamton, New York, and his medical degree at the Thomas Jefferson University Medical School, followed by an orthopedic residency in Philadelphia. He is the director of The Knee Center in Wilkes-Barre, Pennsylvania, and has personally performed over 6,000 arthroscopies and 500 knee replacements in his career. He is an adjunct professor at Kings College in Wilkes-Barre, and at the Decker School of Nursing at Binghamton University in Binghamton, New York. He is also the attending orthopedic surgeon at the Pocono Raceway for the NASCAR events each year. In addition to his clinical practice, Dr. Cooper lectures and teaches nationwide, including presentations at the national conference of the American Bar Association and the LRP Publications, national workers’ compensation program. He is the recipient of the Professional Education Seminars, Inc., Excellence in Teaching Award.

Copyright © 2008 Springer Publishing Company, LLC All rights reserved. No part of this publication may be reproduced, stored in a retrieval system, or transmitted in any form or by any means, electronic, mechanical, photocopying, recording, or otherwise, without the prior permission of Springer Publishing Company, LLC. Springer Publishing Company, LLC 11 West 42nd Street New York, NY 10036 www.springerpub.com Acquisitions Editor: Sally J. Barhydt Project Manager: Carol Cain Cover design: Joanne E. Honigman Composition: Apex Publishing, LLC 07  08  09  10/  5  4  3  2  1 Library of Congress Cataloging-in-Publication Data Osteoporosis : clinical guidelines for prevention, diagnosis, and management / [edited by] Sarah H. Gueldner . . . [et al.].     p. cm.   Includes bibliographical references and index.   ISBN-13: 978-0-8261-0276-8 (alk. paper)   ISBN-10: 0-8261-0276-X (alk. paper)   1.  Osteoporosis—Prevention.  2.  Osteoporosis—Diagnosis. 3. Osteoporosis—Treatment.  I.  Gueldner, Sarah Hall.   [DNLM:  1.  Osteoporosis—therapy.  2.  Fractures, Bone—prevention & control.  3.  Health Promotion.  4.  Osteoporosis—diagnosis.  WE 250 O851185 2008]   RC931.O73O7725 2008   616.7'16—dc22 2007022459 Printed in the United States of America by Malloy Incorporated.

This book is dedicated to the elimination of osteoporotic fractures within our own and future generations.

Contents

Contributors  xi Foreword  xiii Preface  xv Acknowledgments  xvii



1

Introduction and Overview  1

Sarah H. Gueldner, Theresa N. Grabo, Eric D. Newman, and David R. Cooper



The Problem  1





The Science  1





Transferring Knowledge to Practice  2





The Clinical Mandate  2





Children: An Overlooked At-Risk Group  2





The System Mandate  3





The Purpose of This Book  3





Summary  5

Part 1: Prevalence, Risk Factors, and Pathogenesis

2

Demographic Perspectives: The Magnitude of Concern  9

Janice Penrod, Annabelle M. Smith, Susan Terwilliger, and Sarah H. Gueldner



Introduction  9





Prevalence  10





Fractures  11





Lifetime Fracture Risks  11





Global Perspectives  12





Consequences of Osteoporosis  13

ix



Contents







3

Future Projections  16

The Pathogenesis of Osteoporosis  19

Sheri A. Stucke, Bernadette M. Lombardi, Sarah H. Gueldner, and Theresa N. Grabo



Introduction  19





Bone Physiology  20





Conclusion  28

Part 2: Clinical Management

4

Diagnostic Tests and Interpretation  33



William T. Ayoub





Introduction  33





Bone Mineral Density Testing  33





Guidelines for Interpretation  35





Clinical Utility  38





Markers of Bone Turnover  39





Secondary Cause Evaluation  40



5

Pharmacological Management  47



Theresa N. Grabo and Daniel S. Longyhore





Bisphosphonate Therapy  48





Parathyroid Hormone Therapy (PTH)  52





Estrogen Therapy  53





Bioidentical Hormones  57





Selective Estrogen Receptor Modulators (SERMs)  59





Calcitonin (Salmon) Therapy  64





Combination Antiresorptive Therapy  66





Calcium and Vitamin D  67





Vitamin D  69





Integrative Therapies  72





Pain Management  73





Conclusion  76



6

Surgical Management of Fractures  83

Eric Seybold, Heather Hazlett, and David R. Cooper



Complications of Osteoporosis  83

Contents

xi





Hip Fractures  84





Vertebral Compression Fractures  88





Wrist Fractures  97





Prevention  99





Conclusion  99

Part 3: Nonpharmacological Management

7

Diet and Bone Health  103



Helen Smiciklas-Wright and Catherine E. Wright





The Effect of Calcium on Peak Bone Mass  104





Does Calcium Intake Minimize Bone Loss and Reduce Fractures?  104





Recommended Calcium Intakes  105





The Calcium Paradox  106





Food Sources of Calcium  106





Vitamin D  107





Sources of Vitamin D  108





Recommended Vitamin D Intakes  109





How Much Calcium and Vitamin D Is Available in Foods and Supplements?  109





Is It Possible to Consume Too Much Calcium and Vitamin D?   109





Total Diet  110





Nutritional Recommendations  112





Summary  113



8

Exercise Mandate: Preventative and Restorative  117



Renée M. Hakim and Janet Ramos Grabo





Preventative  118





Restorative  127





General Considerations  132





Summary  133



9

Osteoporosis and Fall Prevention  141



Roberta A. Newton





Elements of a Fall Prevention Program  143





HEROS© Fall Prevention Program for Community Dwelling Older Adults  148

xii

Contents

10

Maintaining Independence and Quality of Life  153



Marlene Joy Morgan





Client-Centered Approach  154





Setting Goals for Lifestyle Redesign  155





Integrating Interdisciplinary Assessments  155





Common Problems Affecting Independence and Quality of Life  159





Lifestyle Redesign for Living With Osteoporosis  161





Successful Lifestyle Redesign—Outcomes and Prognosis  164





Summary  164

Part 4: Prevention Strategies

11 Maximizing Peak Bone Mass in Children, Adolescents, and Young Adults: A Public Health Priority  169



Leann M. Lesperance





Nutrition  170





Physical Activity  173





Medications  174





Medical Conditions  175





Prevention Programs  177



12 A Model for Improving Access to Osteoporosis Care: The Geisinger Health System Mobile DXA Program  181



Eric D. Newman





Osteoporosis Testing  181





Heel Ultrasound—A Helpful but Incomplete Solution  182





Mobile DXA—Providing the Gold-Standard Test at the Convenience of the Patient’s Primary Care Physician’s Office  183





Mobile DXA—Conclusions and Future Directions  185



13 A Model for Community Outreach: Cooperative Extension Osteoporosis Prevention and Screening Programs  187



Marilyn A. Corbin, Jane Trainor, Chin-Fang Liu, and Sarah H. Gueldner





Introduction  187





About cooperative Extension  188





Creating Health: Osteoporosis  190





Other Program Examples  192





Summary  198

Contents



xiii 14

Health Policy and Insurance Reimbursement  201



Geraldine R. Avidano Britton, Katherine Kaby Anselmi, and Laura Pascucci





Policy Makers and Stakeholders  202





Reimbursement: Federal  208





Policy and Reimbursement: Individual States in the United States  209





Policy Development: Case Studies  214





Summary  216



15

Emerging Approaches in the Prevention of Osteoporosis  219



Carolyn S. Pierce, Guruprasad Madhavan, and Kenneth J. McLeod





Introduction  219





Bone Adaptation and Fluid Flow  220





Fluid Flow in Humans  221





Skeletal Muscle Pump Stimulation and Bone Health  224





Concluding Remarks  228





Acknowledgments  229

Appendix A Resources and Related Links  235





Federal Government  235





State Government  238





Nongovernment  239

Appendix B Diagnoses That Support Medical Necessity   for Bone Densitometry for Reimbursement  241 Index  247

Contributors

Katherine Kaby Anselmi, FNP, WHNP, PhD, Esquire

Assistant Professor College of Nursing and Health Professions Drexel University Philadelphia, Pennsylvania Former Staff Attorney, Barbara J. Hart Justice Center A project of the Women’s Resource Center Scranton, Pennsylvania William T. Ayoub, MD, FACP, FACR

Geisinger Health System State College, Pennsylvania Geraldine R. Avidano Britton, PhD, RN, FNP

Research Assistant Professor Decker School of Nursing Binghamton University Binghamton, New York Chin-Fang Liu, PhD, RN

Professional Registered Nurse Department of Nursing Kaohsiung Medical University Chung-Ho Memorial Hospital Kaohsiung City, Taiwan Marilyn A. Corbin, PhD

Associate Director, State Program Leader for Children, Youth, and Families, and Professor Penn State Cooperative Extension Pennsylvania State University University Park, Pennsylvania

Janet Ramos Grabo, MPT

Physical Therapist Center Manager for NovaCare Stratford, New Jersey Renée M. Hakim, PT, PhD, NCS

Certified Neurology Clinical Specialist Associate Professor and Director Department of Physical Therapy University of Scranton Scranton, Pennsylvania Heather Hazlett, RPA

Physician Assistant Orthopedic Associates PC Binghamton, New York Leann M. Lesperance, MD, PhD, FAAP

Research Assistant Professor Department of Bioengineering Thomas J. Watson School of Engineering and Applied Sciences Binghamton University Department of Pediatrics, Binghamton Clinical Campus Upstate Medical University Department of Pediatrics, United Health Services Hospitals Binghamton, New York Bernadette M. Lombardi, MS, RN

PhD Candidate, Decker School of Nursing Binghamton University Binghamton, New York

xv

xvi Daniel S. Longyhore, PharmD, BCPS

Nesbitt College of Pharmacy and Nursing Wilkes University Clinical Pharmacist Wyoming Valley Family Practice Residency Wilkes-Barre, Pennsylvania Guruprasad Madhavan, MS

Clinical Science and Engineering Research Center and Department of Bioengineering Thomas J. Watson School of Engineering and Applied Science State University of New York Binghamton, New York Kenneth J. McLeod, PhD

Professor and Chair Department of Bioengineering Thomas J. Watson School of Engineering and Applied Science Innovative Technologies Complex Binghamton University Binghamton, New York Marlene Joy Morgan, EdD, OTR/L

Assistant Professor Department of Occupational Therapy University of Scranton Scranton, Pennsylvania Roberta A. Newton, PhD, FGSA

Professor, Department of Physical Therapy College of Health Professions Associate Director, Institute on Aging Temple University Philadelphia, Pennsylvania Laura Pascucci, CC-P

Compliance Specialist Our Lady of Lourdes Memorial Hospital, Inc. Binghamton, New York Janice Penrod, PhD, RN

Professor in Charge of Graduate Programs and Assistant Professor of Nursing College of Health and Human Development Assistant Professor of Humanities College of Medicine

Contributors

Pennsylvania State University State College, Pennsylvania Carolyn S. Pierce, DSN, RN

Assistant Professor Decker School of Nursing Clinical Science and Engineering Research Center and Department of Bioengineering Binghamton University Binghamton, New York Eric Seybold, MD

Board Certified Orthopedic Surgeon Orthopedic Associates, PC Binghamton, New York Helen Smiciklas-Wright, PhD

Professor of Nutrition Pennsylvania State University State College, Pennsylvania Annabelle M. Smith, PhD(c), RN

School of Nursing Pennsylvania State University State College, Pennsylvania Sheri A. Stucke, PhD, RN, FNP

Assistant Professor Department of Physiologic Nursing University of Nevada at Las Vegas Las Vegas, Nevada Susan Terwilliger, EdD(c), RN, PNP

Clinical Lecturer Decker School of Nursing Binghamton University Binghamton, New York Jane Trainor, EdD, RN

Clinical Professor School of Nursing—Harrisburg Pennsylvania State University Harrisburg, Pennsylvania Catherine E. Wright, MPH

Epidemiologist Science Writing Consultant Pittsburgh, Pennsylvania

Foreword

T

his highly informative book fills a critical gap in the health care literature. Written by a team of key clinicians and researchers within the fields of medicine, nursing, nutrition, exercise physiology, physical therapy, and health care policy, the book is a comprehensive handbook of evidencebased clinical guidelines for the diagnosis and treatment of osteoporosis. It is specifically designed for frontline health care providers, who are in the best position to detect the presence of osteoporosis early and institute treatment in time to prevent its devastating fractures. The authors also acknowledge the disease and its sequelae as a global problem that will continue to exceed epidemic proportions in the rapidly aging population unless preventive measures are instituted now. The authors provide compelling statistics profiling the prevalence and impact of osteoporosis on individuals, their families, and society. The book also presents the most current information about the defining pathology of osteoporosis, including a detailed description of the complex process of bone remodeling and a discussion of risk factors that cue primary care providers to rule out osteoporosis. The diagnostic and treatment protocols are particularly thorough, providing exceptional ready-to-hand reference materials for busy clinicians; the appendixes point the reader to an extensive listing of additional relevant organizations and online resources. Given that the presenting symptom of osteoporosis is still most often a fracture, the chapter outlining the surgical repair of common fractures is a valuable resource for frontline health care providers as they prepare their clients with fractures for surgical referral and the ensuing period of postoperative rehabilitation. The vivid descriptions and illustrations of the specific surgical procedures are also instructive to those who provide rehabilitative follow-up care after the surgical procedure has been performed. The chapter on health care policy is authored collaboratively by a nurse attorney, a nurse practitioner, and a reimbursement specialist. It deals with the bottom line of how to document services within the codes of public payment systems so that preventive and treatment services are available to all who need them. But the book goes beyond the diagnosis and treatment of osteoporosis. It also includes a discussion of the national and global mandate for community-based educational programs that support lifestyle choices to prevent osteoporosis, starting with helping children achieve their maximum potential bone mass. A particularly innovative community outreach model featuring a mobile unit equipped with a full-body dual

xvii

xviii

Foreword

energy X-ray absorptiometry (DXA) machine is described in detail and presented for its use in facilitating early diagnosis for individuals who live in remote regions. The authors’ practical and in-depth insights challenge the complacency that has too long been the norm and offer new ways of confronting this silent but unwelcome intruder. Our research on osteoporosis is finally yielding the diagnostic and treatment options needed to eliminate osteoporosis in future generations. This book translates emerging findings in a way that will inform and mobilize the health care community toward this increasingly realistic goal. It provides a roadmap of detailed clinical protocols that will arm frontline clinicians from across disciplines with the information they need to significantly reduce the prevalence and impact of osteoporosis at the grassroots level. May L. Wykle, PhD, RN, FAAN, FGSA, FAGHE Dean and Cellar Professor of Nursing Frances Payne Bolton School of Nursing Director, University Center on Aging and Health Case Western Reserve University

Preface

O

steoporosis is a major global health problem that is increasing dramatically as the population ages. The World Health Organization (WHO) estimates that 70 million people worldwide have osteoporosis. Hip fractures are the most severe consequence of osteoporosis and are associated with lengthy hospital admissions, difficulty in performing activities of daily life, nursing home placement, and a high rate of mortality. The annual worldwide incidence of hip fracture is 1.5 million, a number projected to grow to 2.6 million by 2025 and to 4.5 million by 2050. The economic burden of osteoporotic fractures on society is immense. Each year in the United States, osteoporotic fractures result in more than 500,000 hospitalizations, 800,000 emergency room visits, 2.6 million physician’s office visits, and the placement of nearly 180,000 individuals in nursing homes. It is estimated that each hip fracture represents approximately $40,000 in total medical costs. But the impact of osteoporosis on the personal lives of the patients and their families is even greater. One in five persons who sustain hip fracture end up in a nursing home, and 20% of them die before a year has passed. Two-thirds of the individuals who sustain hip fracture never return to their prefracture level of function, and many lose their ability to walk, even if they were ambulatory before their fracture occurred. The primary purpose of this book is to address this now preventable health problem by giving busy clinicians the heightened awareness and knowledge they need to reduce osteoporotic fractures in present generations through early diagnosis and treatment and to prevent osteoporosis in future generations. The book is written as a handbook for frontline nurses, physicians, and other clinicians, who on a daily basis see individuals who have osteoporosis or are at risk for low bone density. They are in the best position to identify and teach those at risk early and to institute treatment in time to prevent fractures. The WHO has declared 2002–2011 as the Decade of the Bone and Joint, uniting nations throughout the world in the commitment of energy and resources to accelerate progress in bone health and prevention of fractures. Keeping in mind this global context, the chapters in this book offer quick reference information about the prevalence and impact of osteoporosis, its signature pathology, and factors that place individuals at risk for developing osteoporosis. Comprehensive but concise clinical protocols are provided, and state-of-the-art diagnostic measures, pharmacological and nonpharmaceutical

xix

xx

Preface

therapies, and prevention-based community education strategies are described. One chapter is devoted to surgical repair following vertebral and hip fractures, including the preparation and support of the patient and the family before and during surgery and during the ensuing lengthy rehabilitation process. Attention is also given to important related issues such as dietary requirements, exercise, fall prevention, quality of life, and independence issues. Encouraging information is also provided about emerging technological developments that may enhance our ability to detect and treat osteoporosis even earlier. But access and cost remain formidable issues in the detection of osteoporosis and the prevention of fractures, particularly for underserved and underinsured populations. Our policy and finance specialists address these issues, including Medicaid and insurance reimbursement, in their chapter. They have compiled a comprehensive list of reimbursement codes for diagnostic and treatment procedures to help practitioners apply for and obtain reimbursement for osteoporosis screening and management. Even more importantly, the editors and contributors hope that this book will have a significant impact on dispelling the insidious but still prevalent mind-set, even among clinicians, that osteoporosis and fractures are an inevitable part of aging. Specifically, we hope the book will raise the consciousness of health-related professionals about the mandate for widespread educational programs for the public, beginning with children of both genders and their parents, to eliminate osteoporosis as a public health problem in future generations. In summary, although osteoporosis is a devastating public health problem that affects all strata of the global community, there is a sound body of research findings indicating that osteoporotic fractures can be eliminated. And in recent years, pharmaceutical companies have stepped up to the challenge and are developing a sophisticated portfolio of new and improved products that can stop bone loss and build bone density. Data-based risk assessment protocols have proven to be reliable, and bone-scanning technologies are becoming increasingly portable and available to measure bone density with high accuracy, even among outlying populations. Simple but powerful bone healthy life choices are also well documented, and almost everyone in developed countries has now been exposed to the teachings that exercise, adequate calcium, and vitamin D are critical to building and maintaining strong bones. But we must not let up in our efforts. If together we apply what we already know in our practice, we can spare millions of elders in our country and around the world from the shattering experience of vertebral and hip fractures. We ask that you help us achieve this goal by applying the spirit of commitment and information provided in this book with those you see every day in your practice. Sarah H. Gueldner Theresa N. Grabo Eric D. Newman David R. Cooper

Acknowledgments

T

he editors would like to acknowledge and express appreciation to the many individuals and affiliating academic and practice institutions that have contributed to their vision and support to the development and completion of this book. In particular, we would like to thank the team of researchers and clinicians from across disciplines who have provided the high quality and relevant evidence-based information in the chapters. We would also express our deep appreciation to our respective institutional affiliations for their substantial support in terms of both their positive corporate energy and the technical assistance that they have made available to the project. Specifically, they include the Decker School of Nursing and the Bioengineering Department at Binghamton University, in Binghamton, New York; the Frances Payne Bolton School of Nursing at Case Western Reserve University in Cleveland, Ohio; The Knee Center in Wilkes-Barre, Pennsylvania; the Geisinger Health System based in Danville, Pennsylvania, and Valley GYN Specialists in Luzerne, Pennsylvania. Thanks also to artistic illustrators Stan Kaufman and Michael Cameron for their meticulous assistance in creating illustrations to clarify points made in the text, and to Guruprasad Madhavan, Ellen Madison, Jeffery Peake, Janice Pecen, Nick Plavac, Caron Baldwin, Ivy Ko, and Michael and Bernadette Lombardi for their unusually willing and capable technological support, often on short notice. Others who provided essential editorial assistance include Sally Barhydt and Katherine Tengco at Springer Publishing, Carol Cain and others at APEX Publishing, Dr. Marion Kennedy, Susan Forbush, and Meredith Lynn Cooper. We would also take this opportunity to express our appreciation to the Crane Fund for Widows and Children and the Binghamton University Research Foundation for their support of our community based research initiatives that provided the impetus for this book. Finally, we extend our utmost appreciation to the editors and support staff at Springer Publishing Company for their careful critique and polishing of our work, and for taking it to production. We believe they have once again brought out the best in us. And finally, we would like to thank the courageous individuals, including our own family members and friends, who have sustained fractures and grown stooped in their later years; it is they who have provided the personal inspiration for the book. We offer this quick reference guide to front line clinicians, who are in the best position to detect osteoporosis early and institute treatment measures in time to prevent its devastating fractures. Even more importantly, the editors and authors hope that this book will have a significant impact in dispelling the insidious but still prevalent mind set, even among clinicians, that osteoporosis and fractures are an inevitable part of aging. We hope the book will serve as an impetus to raise the awareness of health related professionals to the mandate for widespread educational programs, beginning with our children and their parents, to eliminate osteoporosis as a public health problem within future generations. Please help us achieve these goals. Sarah Gueldner, Theresa Grabo, Eric Newman, and David Cooper

xxi

Introduction and Overview

The incidence and prevalence of musculoskeletal pain and disability in older people in all parts of the world should be considered as a matter of urgency. (World Health Organization, The Burden of Musculoskeletal Conditions at the Start of the New Millennium: Report of a Scientific Group )

The Problem

O

1

Sarah H. Gueldner Theresa N. Grabo Eric D. Newman David R. Cooper

steoporosis, leaving behind its devastating wake of fractures, is a major global health concern. And like other chronic diseases that disproportionately affect the elderly, the prevalence of osteoporosis and associated fractures is projected to increase markedly as the population ages. The most devastating consequence of osteoporosis is fracture. In the United States, 1 in 2 two women and 1 in every 5 men over 50 years of age experience an osteoporotic fracture during their lives, and more women die from the aftereffects of osteoporotic fractures than from cancer of the ovaries, cervix, and uterus together. Likewise, the economic burden of osteoporosis on society is sobering.

The Science For years it was assumed that osteoporosis was an inevitable part of aging, and that little could be done. But the state of the art is improving. With recent advances in diagnostic and treatment modalities, it has become clear that it

2

Osteoporosis

should no longer be regarded as an untreatable disease. Research in the area of bone disorders has accelerated markedly, providing both the medical community and the public with a more detailed understanding of factors that promote bone health or cause bone disease and fractures. Advances in scientific knowledge have also revealed much about the pathology, prevention, diagnosis, and treatment of osteoporosis and have shown that osteoporosis can someday be prevented in the majority of individuals and identified early and treated effectively in those who do develop it.

Transferring Knowledge to Practice The next critical step in the quest to stop osteoporosis is to transfer the knowledge gained from prevalence data and research findings to the practice of clinicians and the lifestyles of the general public. By focusing on prevention and lifestyle changes as well as early diagnosis and appropriate treatment, Americans and their fellow global citizens can avoid much of the impact of osteoporosis. Health care professionals play a critical role in promoting and supporting these lifestyle choices, and in identifying and treating those at risk early enough to prevent fractures.

The Clinical Mandate Improved methods of routine screening now allow frontline clinicians to diagnose more patients and to diagnose them earlier, significantly slowing the progression of their osteoporosis. But preventing the disease in the first place is paramount to the ultimate management goals. Systematic national and global effort must be directed toward educating the world’s public about the importance of lifestyle habits from childhood through old age. It is imperative that an algorithm be developed and instituted worldwide to support lifestyle changes and early diagnosis of osteoporosis in time to prevent fractures if at all possible. It has been shown that low bone mass is a function of failing to achieve adequate peak bone mass during childhood and adolescence, and/or the occurrence of a high rate of bone loss during times of vulnerability, as seen during menopause and advancing age. Generic and lifestyle variables (i.e., nutrition, exercise, smoking), chronic disease, and exposure to drugs (such as steroids) known to be associated with rapid bone loss also affect rate of bone loss, superimposed on the influences of age, including menopause.

Children: An Overlooked At-Risk Group Until recently, little attention was given by the primary health care community to the achievement of maximum bone mass in children during their bone development years. Fortunately, that window of opportunity for prevention is gaining considerably more attention. The National Bone Health campaign, Powerful Bones, is a national campaign to promote optimal bone health in girls 9–12 years old to help reduce their risk of

Introduction and Overview

3

osteoporosis later in life, and healthy bone awareness programs that stress diet and physical activity are increasingly being implemented in elementary schools.

The System Mandate Individuals and health professionals acting alone cannot make enough of a difference. A coordinated public health approach is the most promising strategy for eliminating osteoporosis in coming generations. However, faced with other pressing health problems such as AIDS, tuberculosis, and malaria, osteoporosis has been relegated to a low priority in most countries. Thus, the persistent challenge is once and for all to erase the lingering misperception that osteoporosis and fractures are inevitable conditions of growing old, and that nothing can be done to prevent them. Toward that purpose, the World Health Organization (WHO), in collaboration with national and international organizations concerned with bone health, has taken the lead in uniting nations around the world in the commitment of effort and resources to improve bone health and prevent fractures. America’s response to that global charge is outlined in the surgeon general’s report of 2004 on bone health and osteoporosis, drafted by more than 100 experts in the field. The report provides state-of-the-science information about bone health and illustrates the large burden that osteoporosis places on our nation and its citizens. The report is intended to alert both the public and the medical community to the importance of bone health, including its impact on overall health and well-being, and the need to take action to prevent, assess, and treat bone disease throughout life. The primary message of the report is that the bone health status of Americans can be improved, and that prevention of bone disease, particularly osteoporosis, begins at birth and is a lifelong challenge.

The Purpose of This Book Addressing the rapidly increasing prevalence and global impact of osteoporosis, the purpose of this book is to translate research findings related to osteoporosis into concise clinical guidelines for frontline clinicians, who are in a position to make the biggest difference in the future trajectory of the disease. The book is organized around four content areas: (1) prevalence, risk factors, and pathogenesis; (2) clinical management; (3) nonpharmacologic considerations; and (4) prevention strategies. Part I of the book, composed of two chapters, profiles the prevalence, risk factors, and pathogenesis of osteoporosis. Chapter 2 provides an overview of the prevalence of osteoporosis, highlighting its exponentially growing impact on the aging global society. Chapter 3 describes the underlying pathogenesis of osteoporosis, with a detailed discussion of bone remodeling. Part II of the book, composed of three chapters, provides a detailed discussion of clinical topics germane to the diagnosis and clinical management of individuals with osteoporosis. Chapter 4, written by a physician-hematologist with many years of experience in osteoporosis, profiles diagnostic tests and interpretation, outlining the steps necessary to arrive at a confirmatory differential diagnosis. This chapter also discusses specific characteristics of clinical presentation across gender and

4

Osteoporosis

life span and offers data-based protocols for obtaining individual and family history. Chapter 5, contributed by faculty in pharmacology and practice, outlines treatment imperatives, including presently available and future pharmacologic prevention and treatment options. Chapter 6, coauthored collaboratively by two orthopedic surgeons and a physician’s assistant, features the latest information about surgical procedures and perioperative management for the best treatment and rehabilitation outcomes following hip, vertebral, or wrist fracture. Each of the four chapters in part III describes nonpharmacologic approaches important to the prevention or management of osteoporosis. Chapter 7, written by a professor of nutrition and a public health epidemiologist, provides an overview of nutritional considerations. Chapters 8 and 9, authored by experts in physical therapy, speak to the exercise mandate and the critical aspect of fall prevention. Chapter 10, authored by an occupational therapist, offers protocols that address the personal experience of living with osteoporosis, including maximum functional rehabilitation and psychological adjustment to characteristic body changes. All the chapters in part IV are directed specifically at steps that need to be taken if we are to eliminate osteoporosis in coming generations. Addressing the irretrievable opportunity to achieve maximum bone mass during childhood and young adult years, chapter 11 is devoted to ways of reaching young girls and boys who are presently building their peak bone mass. The chapter also highlights the potential of school-based health centers as a readily available venue for fostering bone healthy lifestyles in elementary and middle grade children. Chapters 12 and 13 feature two successful large-scale community osteoporosis education and screening programs designed to enable physician groups and other clinicians to reach even the most remote populations. Chapter 12, addressing the barrier to access, describes an innovative screening and diagnostic program using two DXAequipped mobile vans that are operated by the rural-based Geisinger Health System and travel throughout their outpost clinic network. Each year this mobile program screens more than 3,000 persons in outlying areas of Pennsylvania, and one-third of those screened are found to have low bone density. Remarkably, the program sustains itself financially. Chapter 13 describes Creating Health: Osteoporosis, an impressive statewide education and heel-screening program that is disseminated to every county in conjunction with the state-wide network of the Pennsylvania State University Extension Program. The public broadcasting system associated with the extension program enhances the production and delivery of appealing high-quality sound bites to a wide regional audience. Stand Tall Pennsylvania, a successful partnership model for the delivery of a screening and education program to people who live in remote areas of Pennsylvania, is also described. Chapter 14, written jointly by a nurse lawyer, a nurse practitioner, and a Medicare specialist, provides invaluable information about the role that health policy and insurance reimbursement play in the prevention and management of osteoporosis. The chapter provides detailed how-to information for obtaining reimbursement for procedures related to the diagnosis and management of osteoporosis. Finally, encouraging information is presented in chapter 15 about innovative nonpharmacological bioengineering theories and technologies under development that hold promise for increasing our ability to detect and treat osteoporosis in time to reduce

Introduction and Overview

5

and better manage its unwelcome sequelae. Perhaps the best-known such innovation is a vibrating platform device that resembles a bathroom scale that sits on the floor and delivers a high-frequency, low-magnitude (30Hz) mechanical signal (perceived as a gentle vibration) to the femur and spine of the standing human. It is thought by its developers to boost bone mass by increasing lower limb circulation, thus improving the delivery of essential nutrients and minerals to the bones. The device has been tested in children with disabling conditions, postmenopausal women, U.S. Army recruits, and most recently NASA astronauts, who are known to lose bone mass while in the weightless environment of space. In animal models, the intervention has been shown to inhibit disuse osteopenia. This chapter is written collaboratively by bioengineering and nursing faculty at Binghamton University, where the research project is based. The comprehensive appendix A provided at the back of the book includes access information for a number of important documents that have utility for clinicians as they incorporate best practices into their management of persons who have or are at risk for osteoporosis. The 2004 surgeon general’s report, Bone Health and Osteoporosis, prepared by the U.S. Department of Health and Human Services under the direction of the Office of the Surgeon General, represents perhaps the most definitive document available on this topic and served as a primary source for much of the information in this book. The full document is not provided in the appendix, but the NIH Resource Center provides free single copies of this publication to individuals who request it by faxing 1-202-293-2356. Appendix B is a listing of the diagnoses that support the medical necessity for bone densitometry studies, thus facilitating the reimbursement process.

Summary Osteoporosis is a severe public health problem that affects all strata of the global community. The good news is that healthy women and men 50–65 years of age still have time to engage in osteoporosis-preventing behaviors to reduce bone loss and eventual height loss. It is imperative that research efforts be continued and expanded to develop additional effective treatment measures with fewer unpleasant side effects, and that both professionals and the general public become better informed about lifestyles that support bone health. Professional and community education programs are beginning to have an impact in teaching primary care providers and the clients that they serve about the importance of early diagnosis of osteoporosis and the timely institution of treatment. But for best results, more awareness and education efforts need to also be directed toward the young girls and boys who are presently building their peak bone mass, for it is only through their generation and following generations that osteoporosis can be eliminated. Osteoporosis is a lifelong condition that manifests itself in old age, and the best treatment is to engage in bone healthy lifestyles from childhood on. Applying what is already known about prevention, assessment of risk factors, diagnosis, and treatment has led to marked improvements in bone health status. It is the intent of this book to place that stateof-the-science information at the fingertips of primary health care providers and other health-related professionals, to hasten the achievement of that goal.

1

Prevalence, Risk Factors, and Pathogenesis

Demographic Perspectives: The Magnitude of Concern

The silent epidemic of osteoporosis has been challenged. We are now beginning to appreciate the magnitude of this disorder in our world populations. (R. L. Wolf, “Epidemiology: The Magnitude of Concern” )

Introduction

T

2

Janice Penrod Annabelle M. Smith Susan Terwilliger Sarah H. Gueldner

he prevalence of osteoporosis is typically determined using a classification system suggested in 1994 by an expert panel of the World Health Organization (WHO) (Kanis, 1994; World Health Organization [WHO], 2003). The classification system is based on measurements of the bone mineral density (BMD) of women. A woman’s actual BMD is assessed and then compared to the average peak BMD of a healthy young adult White female reference group. The woman’s deviation from this average (statistical mean) is then calculated in standardized units (i.e., standard deviations or SDs). Women are considered to have a normal BMD if their score falls within 1 SD of the mean. Those whose BMD score falls within 1 to 2 SDs below the mean are classified as having osteopenia, a condition in which the bone loss is not severe enough to warrant classification as osteoporosis. The classification of osteoporosis is given to those whose BMD score is greater than (or equal to) 2.5 SDs below the mean. Women who have a history of fragility fractures and a BMD score greater than or equal to 2.5 SDs below the mean are classified as having severe or established osteoporosis. It is important to take into account the fact that this classification system, though commonly used, has significant limitations for estimating prevalence across diverse international populations. The applicability of the WHO criteria to groups other than White women is not exact. Current recommendations are to use a White female

10

Osteoporosis

reference population for all groups (Radiological Devices FDA Panel Meeting Summary, 1999), although the appropriate cutoff values for osteoporosis and osteopenia in men and other racial and ethnic groups are still under investigation. In addition, the prevalence of osteoporosis may be underestimated when only a single BMD site (e.g., the hip) is used, since an individual with normal BMD at one site may have low BMD at another site (e.g., the spine, wrist). The prevalence of osteoporosis is expected to be higher if a number of skeletal sites are assessed simultaneously (Melton, Atkinson, O’Connor, O’Fallon, & Riggs, 1998). These limitations are important when trying to estimate the prevalence rates of osteoporosis in a given population, especially from a global perspective. Since available estimates are based on these measurements, the authors acknowledge the possibility of variances in the prevalence statistics presented below. Likewise, despite advances in the accurate measurement and interpretation of BMD, it is recognized that the numbers of individuals tested for and diagnosed as having osteoporosis may be underestimated.

Prevalence Using the WHO definition based on bone density measurement, it is estimated that there are roughly 10 million Americans over the age of 50 with osteoporosis of the hip, and 34 million others with osteopenia of the hip (National Osteoporosis Foundation [NOF], 2002; U.S. Department of Health and Human Services [USDHHS], 2004). Using the WHO criteria for osteopenia and osteoporosis, Looker et al. (1997) reported the prevalence of low femoral bone density in a sample of 14,646 men and women who participated in the Third National Health and Nutritional Examination Survey (NHANES III). The reference population was 382 White men and 409 White women, 20 to 29 years of age. According to the WHO criteria, osteoporosis under age 50 was rare. However, 13% to 18% of women aged 50 or older had osteoporosis, and another 37% to 50% had osteopenia. At the time of this report, those figures translate to 4 to 6 million women with osteoporosis and 13 to 17 million with low bone mass (osteopenia). Further predictions based on the NHANES III study were made for the year 2002 and beyond (NOF, 2002), with a reported expectation that by the year 2002, 7.8 million women and 2.3 million men over age 50 would have osteoporosis, and 21.8 million women and 11.8 million men over age 50 would have osteopenia. The prevalence of osteoporosis in the United States is highest among White women (Hispanic or non-Hispanic). The NHANES III report estimated that 15% of White women met the criteria for osteoporosis (Mirza & Prestwood, 2004). Similar numbers were seen in the Hispanic population; however, the prevalence among African American women was only half as great as was seen in the White and Hispanic populations. The National Osteoporosis Foundation (NOF) estimates that 55% of all Americans aged 50 and older in the year 2002 had either osteoporosis or osteopenia (low bone mass). Based on the 2000 Census, prevalence estimates increased to 52 million women and men for the year 2010, and to 61 million in 2020 (NOF, 2002). In the United Kingdom, it is estimated that 23% of women aged 50 years or more are osteoporotic, with increases proportional to age (Upton, 2005). The percentages of Swedish women who have osteoporosis range from 7% of women 50–59 years of

Demographic Perspectives

11

age to 36% for those 80–89 years. The prevalence of osteoporosis is higher for women in Norway than anywhere else in Europe. Estimates of prevalence among African American women are that it is about half that of White women (Mirza & Prestwood, 2004). Asian and White non-Hispanic women have the lowest BMDs throughout life, and African American women have the highest. Mexican American women have bone densities that are intermediate between the two groups. Limited data suggest that Japanese and Native American women attain a peak BMD that is lower than for White non-Hispanic women (National Institutes of Health, 2000). In 2002, it was estimated that 44 million people in the United States have osteoporosis, with 68% being women and 32% being men (Gueldner, Britton, & Stucke, 2006; NOF, 2002), providing confirmatory evidence that osteoporosis affects both genders, and that the numbers of individuals with the disease are on the rise. It is estimated that the number of persons with osteoporosis/osteopenia will increase to 52 million by year 2010, and to 61 million by year 2020.

Fractures Fracture is the most significant consequence of osteoporosis. Although osteoporosis can affect any bone in the body, the most typical sites of fractures related to osteoporosis are the hip, spine, and wrist (NOF, 2006). Of the 1.5 million fractures that occur in the United States each year, 20% occur at the hip, 50% in the spine, and 30% at the wrist and other sites. The annual worldwide incidence of fracture was estimated to be 1.29 million in l990, and is projected to grow to 2.6 million by 2025 and to 4.5 million by 2050 (WHO, 2003). The highest fracture rates are reported from northern Europe, the northern part of the United States, and among Southeast Asian populations, with the lowest rate from African countries. The risk of hip fracture among Norwegians is four times that of southern Europeans and double that of Americans. It is of note that the differences in incidence of hip fractures between countries are greater than the differences between genders (Chang, Center, Nguyen, & Eisman, 2004; WHO, 2003). Fracture site is also age related. For individuals in their 50s, wrist fractures are most common. Individuals in their 60s are more likely to sustain fractures of the vertebrae of the spine, and by the time an individual reaches the 70s, the hip becomes the most common site of osteoporotic fracture (Cooper, Campion, & Melton, 1992). The rates of all three types of fracture increase with age, but the increased risk with aging is most pronounced for hip fractures (Kenny, Joseph, Taxel, & Prestwood, 2003; Melton, 1996).

Lifetime Fracture Risks Considering the lifetime fracture risk for each site, women have about an 18% chance of hip fracture, a 16% chance of vertebral fracture, and a 16% chance of wrist fracture (Melton, Chrischilles, Cooper, Lane, & Riggs, 1992). Again, age-related changes are prominent; by age 50, White women have about a 40% chance of fracturing their hip, spine, or wrist in their remaining lifetime (Cummings & Melton, 2002). This statistic equates to a 4 out

12

Table

2.1

Osteoporosis

2002 Prevalence of Osteoporosis and Low Bone Mass for the Top 10 States, With Estimated Prevalence for 2010 and 2020 State California Florida New York Texas Pennsylvania Ohio Michigan New Jersey North Carolina Virginia

2002

2010

2020

4,297,500 3,014,600 2,831,400 2,748,500 2,216,300 1,889,200 1,509,300 1,323,200 1,273,300 1,058,100

5,246,600 3,772,400 3,123,200 3,444,300 2,490,200 2,156,500 1,731,000 1,512,800 1,594,100 1,295,700

6,542,700 4,715,900 3,424,500 4,152,600 2,728,300 2,365,500 1,898,600 1,710,800 1,937,000 1,541,200

Note. From “Tables in National Osteoporosis Foundation,” 2002, in America’s Bone Health: The State of Osteoporosis and Low Bone Mass in Our Nation (Washington, DC: National Osteoporosis Foundation), pp. 17–25.

of 10 lifetime risk for significant fracture and a 1 out of 6 lifetime risk for hip fracture for every woman over the age of 50. These risks are equal to the combined risks of developing breast, uterine, and ovarian cancer in the remaining years of life (NOF, 2002). For men, the estimated lifetime fracture risk is about 13% after age 50 (Cauley, 2002; Cummings & Melton, 2002). The site-specific fracture risks are 6% for the hip, 5% for the spine, and 3% for the wrist. However, even though men age 50 and beyond have a lower lifetime risk for osteoporotic fracture than women, the risk for developing a fracture is almost as great as the risk of developing other conditions common to this age group, such as prostate cancer (Cauley, 2002). The lifetime risk for a White male, based on an age-adjusted incidence rate, is 16.3% (National Cancer Institute, 2006). The most abundant data available for non-Whites in the United States are related to fractures of the hip. Fang, Freeman, Jeganathan, and Alderman (2004) conducted a study in New York City from 1988 to 2002 in which hospitalization rates for male and female non-Hispanic Whites, Blacks, Hispanics, and Asians over age 50 were tracked. The results showed that the risk of a hip fracture in the three ethno-cultural subgroups was approximately one-third to one-half less than that of Whites. A listing of the top 10 states, by prevalence and estimate increase, is provided in Table 2.1.

Global Perspectives The WHO has reported that in 1990, 1.66 million hip fractures occurred around the world (WHO, 2003). Johnell and Kanis (2004) estimated slightly fewer fractures (1.3 million) for the same year, with the most fractures (52.5%) occurring in North America, Japan, Australia, and western Europe, and the least (0.5%) in sub-Saharan Africa. The highest rates of hip fracture have been found to occur in Scandinavia (Woolf & Pfleger,

Demographic Perspectives

13

2003), with 5-year mortality rates in Sweden following hip fracture reaching 59%, and 72% after fracture of the spine ( Johnell et al., 2004). When considering the geographic distribution of osteoporosis and related fractures, deficiencies in vitamin D cannot be ignored. Vitamin D deficiency may predispose individuals to developing osteoporosis and, subsequently, to suffering osteoporotic fracture. Individuals living north of 42 degrees north latitude (the established northern border for optimal ultraviolet B (UVB) synthesis of vitamin D; Higdon, 2004), such as those included in the Scandinavian region, are at risk for vitamin D deficiencies. Similarly, individuals who cover their bodies or are darker skinned are also at risk for vitamin D deficiencies. A study of Lebanese men and women (both people of dark pigmentation and people who practice veiling) reported a 68.1% vitamin deficiency in this population, with the deficiency being more prevalent in women than men (Ghassan et al., 2004).

Consequences of Osteoporosis Mortality Of the three most common sites of osteoporotic fractures, hip fracture poses the most significant insult to the health status of an individual. Increased mortality risk with hip fracture is related to comorbidities such as strokes or chronic lung diseases (Browner, Pressman, Nevitt, & Cummings, 1996), poor health prior to the fracture (Richmond, Aharonoff, Zuckerman, & Koval, 2003), and complications that arise secondary to medical/surgical treatment of the fracture. Excess mortality occurring after a hip fracture, compared with that expected in the population, is estimated to be 12% to 35% higher. A person’s age, race, gender (Center, Nguyen, Schneider, Sambrook, & Eisman, 1999; Ismail et al, 1998; Jacobsen et al., 1992), health, and functional status (Browner et al., 1996; Magaziner et al., 1997) contribute to the survival outcome following hip fractures. The greatest excess mortality typically occurs within the first year ( Jacobsen et al., 1992), with one study reporting a death rate of 20% in the first year following hip fracture (Leibson, Tosteson, Gabriel, Ransom, & Melton, 2002). In the same study it was shown that the risk of mortality was four times greater during the first 3 months following the fracture. Men appear to have a poorer prognosis postfracture than do women (Center et al., 1999). A large prospective study demonstrated that men had poorer survival outcomes than women for hip, vertebra, and other major (e.g., pelvic, rib) and minor (e.g., distal arm and leg) fractures (Center et al., 1999). In general, African Americans fare relatively worse than their White counterparts ( Jacobsen et al., 1992) in terms of mortality following hip fracture.

Morbidity Morbidity, the term used to denote living with the sustained effects of a health disturbance, is of great concern for persons who suffer a fracture. For most, the effects of the event are sustained. Reports from the Established Populations for Epidemiologic Studies of the Elderly (EPESE) confirm that 40%–79% do not regain their prefracture

14

Osteoporosis

walking status within a year after hip fracture, and fewer than 50% ever recover their prefracture ability to perform physical activities of daily living such as eating, dressing, grooming, or bathing (Greendale & Barrett-Connor, 2001). Further, nearly 1 in 5 persons who sustain a hip fracture will end up in a nursing home, and 20% will die before a year has passed (Leibson et al., 2002). One study showed that more than half of the men who suffer a hip fracture are discharged to a nursing home, and that 79% of these men who survive at 1 year will reside in nursing homes or intermediate care facilities (Poor, Atkinson, Lewallen, O’Fallon, & Melton, 1995). By comparison, 19% of women who suffer a hip fracture will require the services of a long-term care facility (Chrischilles, Butler, Davis, & Wallace, 1991). In a study of members of a fairly healthy population sustaining a new hip fracture and then being discharged to their own homes, gait and balance were assessed 2 months after the fracture and then patients were followed for the next 2 years (Fox et al., 1998). Both poor balance and poor gait were associated with more admissions to nursing homes (20% and 17% increases in odds, respectively); however, poor balance, but not gait, resulted in more hospitalizations and increased mortality rates (a 17% increase with each unit decrease in balance score) following the fracture. Another study found that after adjustments for possible confounders, including comorbid conditions, women with hip fractures were significantly more likely to report difficulty performing 11 out of 15 different tasks, including mobility tasks (e.g., walking two or three blocks), higherfunctioning tasks (e.g., light housework, preparing meals), and basic self-care tasks (e.g., bathing, dressing) (Hochberg et al., 1998). Thus, hip fracture presents long-term negative effects for those who survive the initial threat to health. In vertebral fractures, morbidity is a profound concern. Osteoporotic fractures of the spine result in an unnatural, pronounced curvature of the spine (i.e., kyphosis) and loss of height. These spinal fractures are often called crush fractures—a term that captures the collapse of the vertebral column onto itself. As the spine loses structural support, the rib cage moves downward. In some cases, the rib cage eventually comes to rest on the iliac crests. This downward shift of the body’s structural support pushes internal organs downward and forward from the thorax toward the abdomen, accentuating an abdominal protuberance. These structural changes produce concomitant morbidity: height loss, back pain, abdominal fullness, and inhibited breathing patterns. Nevitt et al. (1998) reported the results from a large prospective study of 7,223 older White women who had spine X-rays at baseline, and at a follow-up examination an average of 3.7 years later as part of their participation in the Study of Osteoporotic Fractures (SOF). Compared to women without a spine fracture at baseline, those with at least one new vertebral fracture were more likely to have increased back pain and back disability. Among women who already had a fracture at baseline, those with a new incident fracture had a substantial increase in back pain and functional limitations as well. Many of these problems subsequently affect other health patterns. For example, kyphosis is associated with diminished function, especially in mobility tasks like walking and climbing stairs (Ryan & Fried, 1997). Abdominal fullness is often related to early satiety (a term referring to early satisfaction and fullness upon eating), which over time may result in weight loss. Kyphotic changes in posture lead to more shallow respirations, which have implications should the person affected require surgery or anesthesia. Over time, severe kyphosis may even lead to chronic lung disease.

Demographic Perspectives

15

The impact of vertebral deformities may be worse for men than for women (Burger et al., 1997; Matthis, Weber, O’Neill, & Raspe, 1998). A large study of 15,570 European men and women showed that the associations between vertebral deformities and negative health outcomes (presence and intensity of back pain, functional capacity, and overall subjective health) were stronger in men than women (Matthis et al., 1998). Similarly, in another prospective study conducted in Rotterdam, the Netherlands, stronger associations were found between severe deformities and detrimental health outcomes in men than in women (Burger et al., 1997). Even wrist fracture poses morbidity concerns. Colles’ fractures can result in longterm inability to perform household tasks or personal hygiene. Though the impact on function tends to be underestimated, these fractures may have serious lasting effects on everyday life (USDHHS, 2004). It is also important to note that while the consequences of wrist fractures are generally not as serious as those of hip and spinal fractures on presentation, they have great clinical importance as a predictor of future hip fractures. The risk of hip fracture after a wrist fracture is increased 1.4-fold in U.S. women, 1.5-fold in Swedish women, and 1.8-fold in Danish women. Wrist fracture is an even stronger predictor of hip fracture in men; U.S. men who had a wrist fracture were found to be 2.3 times more likely to sustain a hip fracture, and Swedish men with a wrist fracture were 2.8 times more likely to sustain a hip fracture. From a psychological perspective, postfracture morbidity poses a threat to the overall quality of life. Several factors discussed above contribute to perceived losses in functional, social, and psychological well-being. For example, limited mobility and functional capabilities, pain, and loss of independence are often direct effects of fracture. Deformity, produced as osteoporotic changes invade the spine, is difficult for many to accept. Fear of falling and of subsequent fractures may also pose psychological concerns. In a survey conducted by the NOF, 89% of the women who had sustained an osteoporotic fracture said they were afraid of breaking another bone, 80% feared losing their independence, 80% feared they would not be able to perform their daily activities, and 68% were afraid that they would have to go to a nursing home if they had another fracture. As noted before, approximately half of the individuals who sustain hip fractures never walk independently again, even if they were ambulatory before their fracture (USDHHS, 2004). Such morbidities should not be underattended in the effort to reduce the toll of osteoporosis on the public’s health. Nor is the effect of postfracture morbidity limited to the individual—the effect ripples into the social structures of the adult with osteoporosis. Loss of independence leads to new family roles and responsibilities. Chronic care, offered informally within the family and coordinated with formal caregivers, has its own set of demands and burdens that extend into the network of family and community, and ultimately into society at large. The human and monetary costs of treatment and rehabilitation following fracture are often shared among family members and are partially assumed by public providers. Osteoporosis reaches into the lives and pockets of us all.

Costs The monetary costs associated with osteoporotic fractures are sobering. In l995, osteoporosis resulted in 423,000 hospital admissions, 800,000 emergency room visits, 180,000 nursing home admissions, and 2.5 million physician’s office visits. In the United States alone, the annual direct cost for medical care associated with osteoporotic fractures was

16

Osteoporosis

estimated to be between $12.2 and $17.9 billion in 2002, with each hip fracture costing $40,000 in medical costs (Tosteson, 1999). Spinal fractures are considerably less problematic in terms of cost, with only 10% requiring hospitalization and fewer than 2% being admitted to a nursing home. However, they account for 66,000 physician’s office visits and at least 45,000 hospital admissions each year (USDHHS, 2004). Since most of these fractures occur among older adults who are no longer employed, these figures are not heavily weighted by loss of wages. Rather, the costs are associated with direct care services: inpatient care (62%), nursing home care (28%), and outpatient service (10%). Hip fractures account for about 63% of these costs, while fractures at other sites consume the remaining 37% (Ray, Chan, & Thamer, 1997). Given that 75% of all hip, spine, and distal forearm fractures occur in persons 65 years and older, a large portion of the direct costs is borne by society, in the form of social reimbursement programs (Gueldner, Grabo, Britton, Pierce, & Lombardi, 2007). Even the group least susceptible to fracture, non-White men, required $174 million in osteoporosis care in 1995. The significant contribution of nonhip fractures in men and non-White groups to health care expenditures dispels any lingering misconceptions that the impact of osteoporosis is limited to hip fractures among older White women.

Future Projections Global graying has become a commonplace reality—the population is living longer, and the proportion of old people within the population is growing. The fastest-growing segment of the population is the oldest-old (i.e., those age 85 years or more). Consider the ramifications of these demographic trends on the incidence of osteoporosis and fracture (both highly associated with increasing age). Global demographic changes are expected to dramatically increase the prevalence of osteoporosis. By 2050, it is estimated, the number of individuals age 65 and older will be nearly 1.55 billion worldwide. The increase among this population could result in an almost 4-fold increase in the number of hip fractures worldwide (Cooper et al., 1992). That projection equates to a growth from 1.66 million fractures (worldwide) in 1990 to 6.26 million fractures in 2050. The most significant increase in hip fracture rates is expected to occur in third world countries, particularly in Asia ( Johnell & Kanis, 2004). Currently, Asia accounts for approximately 30% of global hip fractures. By 2050, it is expected to account for more than 50% of all hip fractures (Ellfors, 1998). It is imperative that due consideration be given to the collective impact of these fractures on the individual, the family, the community, and society. Osteoporotic fractures represent a phenomenal concern that demands our utmost attention if we are to avert the predicted rapidly increasing trend. Osteoporosis presents a major public health concern. Arresting this preventable disorder must be a major focus of global preventive efforts in this century.

REFERENCES Browner, W. S., Pressman, A. R., Nevitt, M. C., & Cummings, S. R. (1996). Mortality following fractures in older women: The study of osteoporotic fractures. Archives of Internal Medicine, 156, 1521–1525.

Demographic Perspectives

17

Burger, H., Van Daele, P. L., Grashuis, K., Hofman, A., Grobbee, D. E., Schutte, et al. (1997). Vertebral deformities and functional impairment in men and women. Journal of Bone and Mineral Research, 12, 152–157. Cauley, J. A. (2002). The determinants of fracture in men. Journal of Musculoskeletal and Neurological Interactions, 2(3), 220–221. Center, J. R., Nguyen, T. V., Schneider, D., Sambrook, P. N., & Eisman, J. A. (1999). Mortality after all major types of osteoporotic fracture in men and women: An observational study. Lancet, 353, 878–882. Chang, K., Center, J., Nguyen, T., & Eisman, J. (2004). Incidence of hip and other osteoporotic fractures in elderly men and women: Dubbo Osteoporosis Epidemiology Study. Journal of Bone and Mineral Research, 19(4), 532–536. Chrischilles, E. A., Butler, C. D., Davis, C. S., & Wallace, R. B. (1991). A model of lifetime osteoporosis impact. Archives of Internal Medicine, 151(10), 2026–2032. Cooper, C., Campion, G., & Melton, L. J., III. (1992). Hip fractures in the elderly: A world-wide projection. Osteoporosis International, 2(6), 285–289. Cummings, S. R., & Melton, L. J., III. (2002). Epidemiology and outcomes of osteoporotic fractures. Lancet, 18(359), 1761–1767. Ellfors, L. (1998). Are osteoporotic fractures due to osteoporosis? Impacts of a frailty pandemic in an aging world. Aging: Clinical and Experimental Research, 10, 191–204. Fang, J., Freeman, R., Jeganathan, R., & Alderman, M. H. (2004). Variations in hip fracture hospitalization rates among different race/ethnicity groups in New York City. Ethnicity and Disease, 14(2), 280–284. Fox, K. M., Hawkes, W. G., Hebel, J. R., Felsenthal, G., Clark, M., Zimmerman, S. E., et al. (1998). Mobility after hip fracture predicts health outcome. Journal of the American Geriatrics Society, 46, 169–173. Ghassan, M., Alexandre, N., Joseph, W., Fadj, H., Georges, F., Joseph, H., et al. (2004). Osteoporosis a disease for all; in Lebanon. Clinical Calcium, 14(9), 116–122. Greendale, G. A., & Barrett-Connor, E. (2001). Outcomes of osteoporotic fractures. In R. Marcus, D. Feldman, & J. Kelsey (Eds.), Osteoporosis (Vol. 1, 2nd ed., pp. 819–829). San Diego: Academic Press. Gueldner, S. H., Britton, G., & Stucke J. (2006). Osteoporosis. In J. Fitzpatrick & M. Wallace (Eds.), Encyclopedia of nursing research. New York: Springer Publishing. Gueldner, S. H., Grabo, T. N., Britton, G. A., Pierce, C., & Lombardi, B. (2007). Osteoporosis and aging related bone disorders. In J. Birren (Ed.), Encyclopedia of gerontology. Oxford, England: Elsevier. Higdon, J. The Linus Pauling Institute Micronutrient Information Center. (2004). Vitamin D. Retrieved October 17, 2005, from http://lpi.oregonstate.edu/infocenter/vitamins/vitaminD/ Hochberg, M. C., Williamson, J., Skinner, E. A., Guralnik, J., Kasper, J. D., & Fried, L. P. (1998). The prevalence and impact of self-reported hip fracture in elderly community-dwelling women: The Women’s Heath and Aging Study. Osteoporosis International, 8, 385–389. Ismail. A. A., O’Neill, T. W., Cooper, C., Finn, J. D., Bhalla, A. K., Cannata, J. B., et al. (1998). Mortality associated with vertebral deformity in men and women: Results from the European Prospective Osteoporosis Study (EPOS). Osteoporosis International, 8, 291–297. Jacobsen, S. J., Goldberg, J., Miles, T. P., Brody, J. A., Stiers, W., & Rimm, A. A. (1992). Race and sex differences in mortality following fracture of the hip. American Journal of Public Health, 82, 1147–1150. Johnell, O., & Kanis, J. A. (2004). An estimate of the worldwide prevalence, mortality and disability associated with hip fracture. Osteoporosis International, 15, 897–902. Johnell, O., Kanis, J. A., Oden, A., Sernbo, I., Redlund-Johnell, I., Petterson, C., et al. (2004). Mortality after osteoporotic fractures. Osteoporosis International, 15, 38–42. Kanis, J. A. (1994). Osteoporosis and its consequences. In R. Marcus (Ed.), Osteoporosis (pp. 1–20). Cambridge, MA: Blackwell Science. Kenny, A. M., Joseph, C., Taxel, P., & Prestwood, K. M. (2003). Osteoporosis in older men and women. Connecticut Medicine, 67(8), 481–486. Leibson, C. L., Tosteson, A. N., Gabriel, S. E., Ransom, J. E., & Melton L. J. (2002). Mortality, disability, and nursing home use for persons with and without hip fracture: A population-based study. Journal of the American Geriatrics Society, 50(10), 1644–1650. Looker, A. C., Orwoll, E. S., Johnston, C. C., Jr., Lindsay, R. L., Whaner, H. W., Dunn, W. L., et al. (1997). Prevalence of low femoral bone density in older US adults from NHANES III. Journal of Bone and Mineral Research, 12, 1761–1768.

18

Osteoporosis Magaziner, J., Lydick, E., Hawkes, W., Fox, K. M., Zimmerman, S. I., Epstein, R. S., et al. (1997). Excess mortality attributable to hip fracture in white women aged 70 years and older. American Journal of Public Health, 87, 1630–1636. Matthis, C., Weber, U., O’Neill, T. W., & Raspe, H. (1998). Health impact associated with vertebral deformities: Results from the European Vertebral Osteoporosis Study (EVOS). Osteoporosis International, 8, 364–372. Melton, L. J., III. (1996). Epidemiology of hip fractures: Implications of the exponential increase with age. Bone, 18, 121S–125S. Melton, L. J., III, Atkinson, E. J., O’Connor, M. K., O’Fallon, W. M., & Riggs, B. L. (1998). Bone density and fracture risk in men. Journal of Bone and Mineral Research, 13, 1915–1923. Melton, L. J., III, Chrischilles, E. A., Cooper, C., Lane, A. W., & Riggs, B. L. (1992). Perspective: How many women have osteoporosis? Journal of Bone and Mineral Research, 7, 1005–1010. Mirza, F. S., & Prestwood, K. M. (2004). Bone health and aging: implications for menopause. Endocrinology and Metabolism Clinics of North America, 33, 741–759. National Cancer Institute. (2006). SEER cancer statistics review 1975–2002. Retrieved June 28, 2006, from http://seer.cancer.gov/statfacts/html/prost.html National Institutes of Health. (2000). Osteoporosis prevention, diagnosis, and therapy. NIH Consensus Statement, 17(1), 1–52. National Osteoporosis Foundation. (2002). America’s bone health: The state of osteoporosis and low bone mass in our nation. Washington, DC: National Osteoporosis Foundation. National Osteoporosis Foundation. (2006). Osteoporosis: What is it? Retrieved June 28, 2006, from http://www.nof.org/osteoporosis/index.htm Nevitt, M. C., Ettinger, B., Black, D. M., Stone, K., Jamal, S. A., Ensrud, K., et al. (1998). The association of radiographically detected vertebral fractures with back pain and function: A prospective study. Annals of Internal Medicine, 128, 793–800. Poor, G., Atkinson, E. J., Lewallen, D. G., O’Fallon, W. M., & Melton, L. J., III. (1995). Age-related hip fractures in men: Clinical spectrum and short-term outcomes. Osteoporosis International, 5, 419–426. Radiological Devices Panel Meeting Summary. (1999, May 17). Retrieved from www.fda.gov/cdrh/ rdp.html Ray, N. F., Chan, J. K., & Thamer, M. (1997). Medical expenditures for the treatment of osteoporotic fractures in the US in 1995: Report from the National Osteoporosis Foundation. Journal of Bone and Mineral Research, 12, 24–35. Richmond, J., Aharonoff, G. B., Zuckerman, J. D., & Koval, K. J. (2003). Mortality risk after hip fracture. Journal of Orthopedic Trauma, 17(8)(Suppl.), S2–S5. Ryan, S. D., & Fried, L. P. (1997). The impact of kyphosis on daily functioning. Journal of the American Geriatrics Society, 45, 1479–1486. Tosteson, A.N.A. (1999). Economic impact of fractures. In E. S. Orwoll (Ed.), Osteoporosis in men: The effects of gender on skeletal health (pp. 15–27). San Diego: Academic Press. Upton, J. (2005). The osteoporosis nurse initiative: Past, present, and future. Retrieved July 1, 2005, from http://web4.epnet.com/DeliveryPrintSave.asp?tb=1&_ug=sid+C19B3F46–7D5F4E8A-B08 U.S. Department of Health and Human Services. (2004). Bone health and osteoporosis: A report of the surgeon general. Public Health Service, Office of the Surgeon General, Rockville, MD. Retrieved from http://www.surgeongeneral.gov/library/bonehealth/ Wolf, R. L., Penrod, J. & Cauley, J. A. (2000). Epidemiology: The magnitude of concern. In S. H. Gueldner, M. S. Burke, & H. Smiciklas-Wright (Eds.), Preventing and managing osteoporosis (p. 5). New York: Springer Publishing Company. Woolf, A. D., & Pfleger, B. (2003, September). Burden of major musculoskeletal conditions. Bulletin of the World Health Organization, 81(9), 646–656. World Health Organization. (2003). Prevention and management of osteoporosis. Technical Support Series, no. 921. Geneva, Switzerland: Author.

The Pathogenesis of Osteoporosis

Osteoporosis, regardless of etiology, always represents enhanced bone resorption, relative to formation. Thus, insights into the pathogenesis of this disease, and progress in its prevention and/or cure, depend upon understanding the mechanisms by which bone is degraded. (S. L. Teitelbaum, M. M. Tondravi, and P. Ross, “Osteoclast Biology” )

Introduction

F

3

Sheri A. Stucke Bernadette M. Lombardi Sarah H. Gueldner Theresa N. Grabo

or clinicians to be able to detect and treat this silent disease, an understanding of the pathophysiology of osteoporosis is critical. Osteoporosis is primarily a skeletal disorder, usually not diagnosed until an osteoporotic fracture occurs. But by the time a fracture occurs, the pathology has been in progress for a long time. We must learn how to recognize the pathology in time to institute treatment to prevent fractures. The human skeleton, comprised of approximately 206 bones, fulfills a variety of functions: Bones give shape and form to the body, support the body’s weight, protect vital organs, serve as a storage area for minerals such as calcium and phosphorus, provide stem cells from bone marrow for healing and cell growth, and work in concert with the muscular system to assist the body with movement (Black, Topping, Durham, Farquharson, & Fraser, 2000; Orthovita, 2006). Perhaps because of its hard texture, bone is commonly thought of as an inactive tissue. However, it is actually a dynamic tissue in which the cells are involved in extensive interactions with one another, and with hematopoietic (blood-forming) and stromal (connective-tissue) cells in the bone marrow. These interactions are particularly prominent in maintaining bone mass.

20

Osteoporosis

Bone Physiology There are two types of bone, cancellous (also called trabecular) bone, which accounts for approximately 20% of the total bone mass, and cortical bone, which accounts for the other 80% of bone mass (American Medical Association [AMA], 2006). Cancellous bone is formed by an interconnected structure of latticework and is the more delicate type of bone. It is porous and is often referred to as the spongy inner structure of the bone. Because it is more metabolically active and has a larger surface area, cancellous bone is more susceptible to bone loss and fracture. Cancellous bone is located primarily at the ends of the long bones (such as the head of the femur and distal end of the ulna and radius, where osteoporotic fractures often occur) and is the main type of bone, comprising the flat bones such as the sternum, the pelvis, and the 33 vertebrae (Rosen, Verault, Steffens, Cheleuitte, & Glowacki, 1997). Cortical bone is the more dense type of bone that surrounds the cancellous bone to form the outer, more durable layer bearing the majority of the body’s weight. Cortical bone is located primarily in the middle section of the long bones of the body, including the tibia, fibula, femur, radius, ulna, and humerus. In addition to providing strength, cortical bone provides sites for attachment of tendons and muscles (U.S. Department of Health and Human Services [USDHHS], 2004).

At the Cellular Level The distinctive firm fabric of the bone is a unique deposit of living cells embedded in a three-dimensional structure of extra-cellular matrix that has been stabilized by calcification (Marcus, Feldman, & Kelsey, l996). Invasion by blood vessels brings in nutrients and the cells that carry out the functions of the bone, including repair and maintenance of mass. At the cellular level, bone is made up of three types of specialized bone cells (osteoblasts, osteocytes, and osteoclasts) that interact with a variety of minerals, proteins, hormones, water, and other molecules to nourish the bone, and to continually remove old or worn bone tissue and replace it with new bone in a process called remodeling, which is described in the next section. Both the osteoblasts and the osteocytes are derived from not yet differentiated precursor cells that can also be stimulated to become muscle, fat, or cartilage but under the right conditions can differentiate to form new bone cells. During the remodeling process, osteoblasts lay down orderly layers of bone that add strength to the matrix. Some of the osteoblasts are buried in the matrix as it is being produced, becoming osteocytes (bone cells). Other osteoblasts remain as thin bone cells that cover the surface of the bone, called lining cells (Figure 3.1). Osteocytes are connected to each other and to the surface of osteoblasts by a network of small threadlike extensions, and are involved in conveying nutrition and information throughout the bone (USDHHS, 2004). Osteoclasts, on the other hand, are the cells that remove old or damaged bone by dissolving the mineral and breaking down the matrix in a process called bone resorption. Under normal conditions, the functions of the osteoblasts and osteoclasts are coupled, with signals from one affecting the other (Manalagas, Jilka, Bellido, O’Brian, & Parfitt, 1996), to maintain the balance between bone breakdown and new bone formation (Figure 3.2). Osteoporosis results from an imbalance between bone resorption and formation, in which case bone resorption significantly exceeds bone formation. The body begins to lose bone

The Pathogenesis of Osteoporosis

21

Figure

3.1

Bone remodeling. Note: The sequence of activation, resorption, reversal, and formation is illustrated here. The activation step depends on cells of the osteoblast lineage, either on the surface of the bone or in the marrow, acting on blood cell precursors (hematopoietic cells) to form bone-resorbing osteoclasts. The resorption process may take place under a layer of lining cells as shown here. After a brief reversal phase, the osteoblasts begin to lay down new bone. Some of the osteoblasts remain inside the bone and are converted to osteocytes, which are connected to each other and to the surface osteoblasts. The resorption phases last only a few weeks, but the formation phase is much slower, taking several months to complete, as multiple layers of new bone are formed by successive waves of osteoblasts.

more rapidly, leaving the bones weaker and more susceptible to fracture (Figure 3.3). Since osteoclasts are the principal resorptive cells of the bone, virtually all successful treatment to date targets osteoclastic bone resorption (Teitelbaum, Tondravi, & Ross, l996).

Remodeling The skeleton is continually being renovated and replaced through the process of remodeling (see Figure 3.1). This process occurs to maintain maximal bone mineral density, in addition to repairing any damage that has occurred to the bones, including micro “cracks” or outright fractures (National Institutes of Health [NIH] Consensus Development Panel on Osteoporosis Prevention, Diagnosis, and Therapy, 2001). Bone loss occurs when the osteoclasts produce an unusually deep resorption space, or when the osteoblasts fail to completely refill the cavity created during resorption (Oursler, Landers, Riggs, & Spelsberg, 1993). The remodeling process takes place at discrete locations near the surface of the bones, just underneath the thin lining cells (Figure 3.1). As described

22

Osteoporosis

Figure

3.2

How osteoclasts are formed. Note: The interaction between cells of the osteoblastic lineage and the osteoclast lineage is illustrated here. The osteoblastic cells produce several proteins that regulate osteoblast formation and activity. One is a macrophagecolony-stimulating factor (M-CSF), which acts on its receptor to increase the number of precursors available to form osteoclasts. The osteoclasts also produce a protein called a receptor activator of nuclear factor kappa B ligand (RANKL), which can bind to a receptor on the osteoclast precursors (RANK) and stimulate them to develop into fully differentiated osteoclasts. The RANKL/RANK interaction also increases osteoclast activity. Finally the osteoblastic cells can produce osteoprotegerin (OPG), a protein that can be secreted outside the cell and then bind RANKL and prevent it from interacting with RANK, thus blocking the formation and acitivation of osteoclasts. Hormones and local factors such as parathyroid hormone (PTH), calcitriol or 1,25 dihydroxy D (1,25D), prostaglandin F2 (PGF2) and Interleukin-1 (IL-1) are shown in this figure as acting on the osteoblastic cells to increase production of RANKL, and decrease production of OPG. The balance between RANKL and OPG production determines how fast bone breaks down.

earlier, two classes of cells participate in the remodeling process: osteoclasts, which break down and remove old bone matrix, and osteoblasts, which synthesize new bone matrix (Hughes & Boyce, 1997). The removal and replacement of bone in the remodeling cycle occurs in a carefully orchestrated sequence that involves four phases: activation, resorption, a period of reversal, and bone formation (Figure 3.1). Signaling the start of the activation stage, the cells of the osteoblast lineage act on blood cell precursors (i.e., hematopoietic cells) to produce more bone-resorbing osteoclasts. Then, during the resorption stage, the new army of osteoclasts removes worn or damaged bone by dissolving the mineral and breaking down the matrix, leaving small cavities in the surface of the bone (Simon, 2005). After a period of quiescence (called reversal), the osteoblasts then appear in increased numbers and repair the bone by filling the recently excavated cavities with new bone. During this process, some of the osteoblasts remain inside the bone tissue and are converted to actual bone cells (osteocytes). Once the new bone has been mineralized, the remodeling

The Pathogenesis of Osteoporosis

23

Figure

3.3

Normal vs. osteoporotic bone. Note: These pictures, called scanning electron micrographs, are from biopsies of a normal and an osteoporotic patient. The normal bone shows a pattern of strong interconnected plates of bone. Much of this bone is lost in osteoporosis and the remaining bone has a weaker rod-like structure. Moreover, some of the rods are completely disconnected. These bits of disconnected bone may be measured as bone mass but contribute nothing to bone strength. Source: Reproduced from the Journal of Bone and Mineral Research, 7, pp. 16–21, with permission from the American Society for Bone and Mineral Research.

process in that particular area of bone is complete. The resorption phase lasts only a few weeks, but the formation phase may take several months to complete, as layer after layer of new bone is created by the osteoblasts. Bone remodeling continues throughout adulthood, with each remodeling process lasting 6–9 months. During the adult lifetime, the bone is replaced about every 10 years. It is important to note that the bone is in a weakened state while it is undergoing the remodeling process and is more susceptible to fracture at that time (AMA, 2006; USDHHS, 2004). This remodeling process is necessary to maintain bone strength and occurs on all bone surfaces (Simon, 2005). Prior to adulthood, bone formation occurs at a higher rate than bone resorption, facilitating bone growth. The adult bone mass is thought to be genetically predetermined and when it is reached (by the late 20s to mid-30s), bone formation and resorption achieve an equal balance, so that the bone structure remains stable. Osteoporosis results from an imbalance between bone resorption and formation, in which bone resorption significantly exceeds bone formation. The body begins to lose bone tissue more rapidly, leaving the bones weaker and more susceptible to fracture. A dramatic period of bone loss occurs in some women around the time of menopause, and a similar pattern is seen in men at a slightly older age, linking the loss of bone to decreased androgens in both genders (USDHHS, 2004). The mechanism of resorption can also supply needed phosphorus and calcium when there is a deficiency in the diet, or for the extra needs of the developing fetus during pregnancy or the infant through lactation. Conversely, when the calcium and phosphorus supplies are sufficient, the formation phase of remodeling can absorb these minerals and replenish their storage in the bone (USDHHS, 2004).

24

Osteoporosis

Nutrition Bones need nutritional essentials such as calcium, vitamin D, and phosphorus to build tissue; these minerals are normally obtained from one’s diet. Under normal conditions, a portion of the dietary calcium ingested is absorbed into the blood, with the remaining calcium being excreted via the intestinal tract. When a person does not ingest enough calcium and/or phosphorus, the body’s regulating hormones respond by removing these minerals from the bones for use in other essential functions in the body. But when this process continues to occur again and again over time, the bones become weakened (USDHHS, 2004). A complex system of regulatory hormones helps to maintain adequate supplies of the needed minerals in a variety of situations. These hormones act not only on bone but also on other tissues, such as the intestine and the kidney, to regulate the supply of the needed elements (USDHHS, 2004). These mechanisms rely on an intricate network of biologic messenger molecules, which will be discussed in the following sections.

Effects of Estrogen and Testosterone on Bone Two hormones that are particularly important in the formation of bone are estrogen and testosterone. There is a consensus that the early and most pronounced effect of estrogen on bone remodeling is a decrease in the amount of bone resorption (USDHHS, 2004). Estrogen is also known to have a variety of effects on the proliferation and synthesis of enzymes and bone matrix proteins by osteoblast-like cells through a process mediated by complex biomolecular biologic signals and mechanisms. It is estimated that women lose about 50% of their cancellous bone and about 35% of their cortical bone over their lifetime (Riggs et al., 1981). It is still not clear how much of this bone loss is due to estrogen deficiency and how much is due to age and environmentally related processes, but it is estimated that 25% of cancellous bone loss and 15% of cortical bone loss is due to estrogen deficiency (Lindsay, 1990). Estrogen acts on both osteoclasts and osteoblasts to inhibit bone breakdown at all stages in life, but in some instances it may also stimulate bone formation (USDHHS, 2004, p. 28). At the time of menopause there is a decrease in estrogen associated with rapid bone loss. Testosterone stimulates muscle growth, which encourages bone formation by placing stress on the bone, and also produces estrogen as a by product of its action. There is now a consensus that testosterone is important to bone health in both men and women (USDHHS, 2004).

Estrogen Receptors Estrogens mediate their receptor-dependent effects by diffusing through the plasma membrane of the cells and then binding to specific high-affinity estrogen receptors (ERs) in the target cell. The activated complex then translocates to the nucleus of the target cell and binds to chromatin at a specific region of the DNA called the hormone response element. The hormone response element then stimulates or inhibits specific genes, resulting in the synthesis of specific proteins. This generation of intracellular proteins causes the activation of a cascade of events leading to cell growth and differentiation. The ERs play a key role in mediating the cellular effects of estradiol on cell

The Pathogenesis of Osteoporosis

25

growth and differentiation (Phillips, Chalbas, & Rochefort, 1993; Rosselli, Reinhart, Imthurn, Keller, & Dubey, 2000).

Biologic Messenger Molecules Oseoblastic and osteoclastic functions and bone metabolism are regulated by numerous systemic and local factors, including the following: Systemic factors involved in calcium homeostasis. Local factors influencing bone cell function. Cytokines and colony-stimulating factors associated with the regulation of osteoclast development. Growth regulator factors that stimulate osteoblastic proliferation and differentiation from progenitor cells. A summary of mediating molecules is provided in Table 3.1.

Calcium-Regulating Hormones Parathyroid hormone (PTH), calcitriol, and calcitonin are calcium-regulating hormones that play an important role in producing healthy bones. PTH helps maintain the level of calcium, in addition to stimulating both resorption and formation of bone. Specifically, PTH assists with the movement of calcium from the bones to the bloodstream, but when too much PTH production occurs, hyperparathyroidism develops, and this can lead to accelerated bone loss. Biologically active calcitriol (1,25-dihydroxy vitamin D3) is made from activated cholecalciferol. Its function is to stimulate the intestines to facilitate the absorption of calcium and phosphorus. Calcitonin is produced by the thyroid gland and blocks bone breakdown by inactivating osteoclasts. Calcitonin is also important in maintaining bone development and regulating blood calcium levels in early development (USDHHS, 2004). Growth factors and cytokines are thought to be the mediators of the complex intercellular chemical communication between osteoblasts and osteoclasts that regulates bone resorption. Likewise, the increased production of bone-forming osteoblasts is thought to be linked to bone resorption by the release of growth factors from the bone matrix during the resorptive process (Jilka, 1998). There is evidence that osteoblast and osteoclast formation is controlled by the same set of factors, such as Interleukin 6 (IL-6)-type cytokines.

Cytokine Regulation by Estrogen The cellular hallmark of osteopenia caused by estrogen deficiency is an increase in bone remodeling, and it is proposed that cytokines mediate the acceleration of bone loss following menopause. The mediating cytokines include the following: 1 . TRANCE/RANKL/OPGL: this term refers to a cytokine that was inde-

pendently cloned by several laboratories and named the tumor necrosis factor–related, activation-induced cytokine (TRANCE), receptor activator of NFkB ligand (RANKL), or osteoprotegerin ligand (OPGL) (Jilka, 1998);

Table

Hormones and Growth Factors Regulating Bone Formation

3.1

Factor

Target cells and tissue

Effect

Parathyroid hormone (PTH)

Kidney and bone

Calcitonin (Produced by thyroid gland) Calcitriol (1,25-dihydroxy vitamin D3)

Bone osteoclasts

Stimulates the production of vitamin D (1,25D) and helps move calcium from bones to bloodstream Inhibits resorptive action of osteoclasts; lowers circulating calcium concentrations Stimulates collagen, osteopontin, osteocalcin synthesis; stimulates differentiation; increases circulating calcium concentrations Stimulates activity of osteoclasts Stimulates calcium retention Stimulates calcium absorption

Bone osteoblasts

Bone osteoclasts Kidney Intestine

Estrogen

Bone

Testosterone

Muscle, bone

Prostaglandins

Osteoclasts

Bone morphogenic protein

Mesenchyme

Transforming growth factor (TGF-B) Interleukins (IL-1, IL-3, IL-6, IL-11) Tumor necrosis factor (TNF-a); granulocytemacrophage-stimulatingfactor (GMCSF)

Osteoblasts, chondrocytes Bone marrow, osteoclasts Osteoclasts

Leukemic inhibitory factor

Osteoblasts, osteoclasts

Stimulates formation of calcitonin receptors, inhibiting resorption; may also stimulate bone formation Stimulates muscle growth, placing stress on the bone, increasing bone formation Stimulate resorption and formation Stimulates cartilage protein and bone matrix formation; stimulates replication Stimulates differentiation Stimulate osteoclast formation Stimulates bone resorption

Stimulates osteoblast and osteoclast formation in marrow

The Pathogenesis of Osteoporosis

2. 3. 4. 5.

27

the macrophage-colony stimulating factor (M-CSF); the granulocyte/monocyte-colony stimulating factor (GM-CSF); Interleukin 1 (IL-1); and Interleukin 6 (IL6).

Interleukens IL-1, IL-6, and TNF (the tumor necrosis factor) mediate the effects of estrogen deficiency on osteoclast number IL-1 and TNF, produced by monocytes and macrophages as well as by the systemic hormones PTH and 1,25-dihydroxy vitamin D3 [1,25(OH)2D3], and stimulate osteoclast differentiation by increasing the synthesis of mediating cytokines.

Regulation of Bone Loss It has been shown that IL-6 is an essential mediator of bone loss caused by estrogen deficiency, and that inherited or acquired disorders of testicular function, as well as congenital male hypogonadism, are also associated with bone loss (Jilka, l998). In the case of congenital male hypogonadism, bone mass can be increased with the administration of testosterone. It has also been established that castration in men causes increased bone resorption and bone loss. Research findings suggest that the cellular and molecular mechanisms that progress to bone loss due to androgen deficiency in the male are similar and may be identical to the mechanisms that underlie the bone loss caused by estrogen deficiency in the female. It is of note that IL-6 is an essential pathogenic factor in bone loss caused by both androgen and estrogen deficiencies (Bellido et al., 1995).

Lifestyle Factors Affecting Bone Loss Lifestyle factors also have a significant impact on bone health. While the size and shape of bones are principally predetermined by genetics, other modifiable factors, including physical activity and diet, are also important to bone health. It is known that physical activity can increase bone mass by increasing muscle mass, thus placing additional stress on bones. Individuals who are obese and those with high muscle mass tend to have a higher bone mass, whereas individuals who develop osteoporosis are more likely to be thin with less muscle mass (Simon, 2005). Other lifestyle habits, such as smoking and excessive use of alcohol, also represent modifiable lifestyle risk factors.

Concerns Related to Environmental Toxins Research by Wang, Shen, Li, and Agrawal (2002) has shown that it is not just changes in mineral content or mineral density that are important in evaluating the propensity of bone to fracture; equally important are changes in the organic nature of the bony matrix. These findings raise questions about how toxic environmental chemicals such as antiestrogenic dioxins (TCDDs) and polychlorobiphenyls (PCBs) may affect bone. It is known that antiestrogen molecules bind to the estrogen receptor to block its action, by preventing it from being available for estrogen or by blocking the receptor sites for further action. Animal studies have confirmed that exposure to PCBs and TCDDs interferes with bone growth, and that it weakens the mechanical strength of bone (Jamsa, Viluksela, Tuomisto, Tuomisto, & Tuukkanen, 2001; Juberg, 2000; McLachlan, 2001). Because PCBs are particularly stable environmental pollutants that bio-accumulate, their widespread presence

28

Osteoporosis

in the environment and persistence in the body pose a serious and relevant concern in terms of bone health. Exposure to PCBs most often occurs by ingesting contaminated food, inhaling contaminated air, eating fish from PCB-contaminated waters, or coming in contact with other sources that we may not yet be aware of. Future studies are needed to address the effects of dioxins and other environmental contaminants on bone.

Conclusion In conclusion, our understanding of the pathology underlying osteoporosis is complex and still not fully known. But we already have the knowledge to detect its presence in time to institute treatment to prevent many devastating osteoporotic fractures. And in many cases, we know how to prevent osteoporosis. It is imperative that we apply the knowledge we already have, to reduce the impact of osteoporosis on global society.

REFERENCES American Medical Association. (2006). Osteoporosis management. Pathophysiology of osteoporosis. Retrieved July 2, 2006, from http://www.ama-cmeonline.com/osteo_mgmt/module03/ 01cme/02.htm Bellido, T., Jilka, R. L., Boyce, B. F., Girasole, G. G., Groxmeyer, H., Dalrymple, S. A., et al. (1995). Regulation of Interleukin-6, osteoclastogenesis and bone mass by androgens: The role of the androgen receptor. Journal of Clinical Investigation, 95, 2886–2895. Black, A., Topping, J., Durham, B., Farquharson, R., & Fraser, W. (2000). A detailed assessment of alterations in bone turnover, calcium homeostasis, and bone density in normal pregnancy. Journal of Bone and Mineral Research, 15, 557–563. Hughes, D. E., & Boyce, B. F. (1997). Apoptosis in bone physiology and disease. Journal of Clinical Pathology, 50, 132–137. Jamsa, T., Viluksela, M., Tuomisto, J. T., Tuomisto, J., & Tuukkanen, J. (2001). Effects of 2,3,7,8Tetrachlorodibenzo-p-Dioxin on bone in two rat strains with different aryl hydrocarbon receptor structures. Journal of Bone and Mineral Research, 16, 1812–1820. Jilka, R. L. (1998). Cytokine, bone, remodeling, and estrogen deficiency: A 1998 update. Bone, 23, 75–81. Juberg, R. J. (2000). An evaluation of endocrine modulators: implications for human health. Ecotoxicology and Environmental Safety, 45, 93–105. Lindsay, R. (1990). Overview of prevention strategies. In C. C. Overgaard (Ed.), Third international symposium on osteoporosis (pp. 945–947). Aalborg, Denmark: Handelstrykkeriet Aalgorg ApS. Manalagas, S. C., Jilka, R. L., Bellido, T., O’Brian, C. A., & Parfitt, A. M. (1996). Interleukin-6-type cytokines and their receptors. In J. P. Bilezikian, L. G. Raisz, & G. A. Rodan (Eds.), Principles of bone biology (pp. 701–713). San Diego: Academic Press. Marcus, R., Feldman, D., & Kelsey, J. (1996). Osteoporosis. New York: Academic Press. McLachlan, J. A. (2001). Environmental signaling: What embryos and evolution teach? us about endocrine disrupting chemicals. Endocrinology Review, 22, 319–341. National Institutes of Health Consensus Development Panel on Osteoporosis Prevention, Diagnosis, and Therapy. (2001). Osteoporosis prevention, diagnosis, and therapy. The Journal of the American Medical Association, 285, 785–795. Orthovita. 2006. Bone health and repair. Retrieved August 5, 2006, from http://www.orthovita.com/ patient_info/bonehealth.html Oursler, M. J., Landers, J. P., Riggs, B. L., & Spelsberg, T. C. (1993). Estrogen effects on osteoblasts and osteoclasts. Annals of Medicine, 25, 361–371. Phillips, A., Chalbos, D., & Rochefort, H. (1993). Estradiol increases and antiestrogens antagonize the growth factor induced activator protein –I activity in MCF-7 cells without affecting c-fos and c-fos synthesis. Journal of Biological Chemistry, 268, 14103–14108.

The Pathogenesis of Osteoporosis

29

Reinhart, K. C., Dubey, R. K., Keller, P. J., Imthurn, B., & Rosselli, M. (1999). Xenoestrogens and phytoestrogens induce the synthesis of leukemia inhibitory factor by human and bovine oviduct. Molecular Human Reproduction, 5, 899–907. Riggs, B. L., Wahner, H. W., Dunn, W. L., Mazess, R. B., Offord, K. P., & Melton, L. J., III. (1981). Differential changes in bone mineral density of the appendicular skeleton with aging: relationship to spinal osteoporosis. Journal of Clinical Investigation. 67, 328–335. Rosen, C. J., Verault, D., Steffens, C., Cheleuitte, D., & Glowacki, J. (1997). Effects of age and estrogen status on the skeletal IGF regulatory system: Studies with human marrow. Endocrine, 7, 77–80. Rosselli, M., Reinhart, K., Imthurn, B., Keller, P. J., & Dubey, R. K. (2000). Cellular and biochemical mechanisms by which environmental oestrogens influence reproductive function. Human Reproduction Update, 6, 332–350. Simon, L. S. (2005). Osteoporosis. Clinics in Geriatric Medicine, 21, 603–629. Teitelbaum, S. L., Tondravi, M. M., & Ross, P. (1996). Osteoclast biology. In R. Marcus, D. Feldman, & J. Kelsey (Eds.), Osteoporosis (p. 61). New York: Academic Press. U.S. Department of Health and Human Services. (2004). Bone health and osteoporosis: A report of the surgeon general. Public Health Service, Office of the Surgeon General, Rockville, MD. Retrieved August 22, 2006, from http://www.surgeongeneral.gov/library/bonehealth/ Wang, X., Shen, X., Li, X., & Agrawal, C. M. (2002). Age-related changes in the collagen network and the toughness of bone. Bone, 31, 961–967.

2

Clinical Management

Diagnostic Tests and Interpretation

Much of the burden of bone disease can potentially be avoided if at-risk individuals are identified and appropriate interventions (both preventive and therapeutic) are made in a timely manner. (U.S. Department of Health and Human Services, Bone Health and Osteoporosis )

Introduction

4

William T. Ayoub

steoporosis is our most common metabolic bone disease. It has been defined as “a skeletal disorder characterized by compromised bone strength predisposing to an increased risk of fracture” (NIH Consensus Development Panel on Osteoporosis Prevention, Diagnosis, and Therapy, 2001). Fractures produce significant morbidity and mortality, as well as a tremendous economic burden for our health care system (U.S. Department of Health and Human Services [USDHHS], 2004). Since osteoporosis is often clinically silent, it is imperative that we make a concerted effort to identify patients who are at risk for fracture. By doing this effectively, we can determine who should be treated with medication shown to decrease fracture risk and thus reduce morbidity and mortality. Studies have shown that effective screening of an at-risk population can result in a decreased incidence of fracture (Kern et al., 2005; Newman, Ayoub, Starkey, Diehl, & Wood, 2003).

O

Bone Mineral Density Testing Any individual patient’s risk of a fracture is dependent upon a variety of factors. First, the patient’s propensity to fall is an extremely important risk factor for

34

Osteoporosis

fracture (Tinetti, 2003). This issue will be discussed elsewhere in this text. Second, bone strength is another important determinant of fracture risk. Bone strength is related to bone mineral density (BMD) as well as other properties of bone that are often termed “bone quality” (Watts, 2002). Bone quality is a manifestation of the architecture (bone geometry, microarchitecture, trabecular thickness, trabecular connectivity, cortical thickness, and cortical porosity) and matrix and mineralization properties. In clinical practice, these various determinants of bone quality are not generally measurable and therefore cannot help the clinician predict fracture risk. Therefore, the cornerstone of evaluation is the measurement of BMD. BMD correlates highly with fracture risk and allows the clinician to determine the need for pharmacological interventions (Bates, Black, & Cummings, 2002; Bonnick, 2004; Cummings, Bates, & Black, 2002). Measurement of BMD can also help to monitor the response to therapy. Various techniques are used to measure BMD (Bonnick, 2004). Some of the earliest techniques to assess bone density included qualitative spinal morphometry and the Singh index. These studies utilized standard X-rays and attempted to grade the degree of bone loss by relying on the appearance of the trabecular patterns within the vertebral body or the proximal femur. These techniques proved to be highly subjective and did not necessarily correlate with dual photon absorptiometry. Photon absorptiometry techniques became available in the mid-1960s. Single photon absorptiometry was the first method employed. This involved passing a single energy photon beam from a radioactive source through a peripheral bone such as a radius or calcaneus. Bone density was estimated based on the degree of attenuation of this X-ray beam. Later, dual photon absorptiometry became available. This technique used photons with distinct photoelectric peaks from a radioactive source that were attenuated differently by soft tissue and bone. Bone density could therefore be more accurately estimated despite varying amounts of soft tissue. This allowed the study of axial sites such as the hip and spine. Dual energy X-ray absorptiometry (DXA) has become the most commonly used method to measure BMD (Bonnick, 2004). This technique involves an X-ray tube that generates photon beams of two different energy levels. The difference in attenuation of the two photon beams as they pass through the region of interest (ROI) allows this technology to differentiate bone from soft tissue. DXA measures both bone mineral content (BMC, in grams) and area (in cm2). By dividing bone mineral content by area, one obtains an “areal” BMD (g/cm2). This value can be converted to a T-score, which is calculated by subtracting the mean BMD of a young adult reference population from the patient’s BMD and then dividing by the standard deviation of the young adult population. Therefore, a T-score compares the patient to a gender-matched, young, healthy control population. This comparison is most often used for diagnostic purposes as noted later. Similarly, a Z-score can be derived by subtracting the mean BMD of an age- and sex-matched reference population from the patient’s BMD and dividing by the standard deviation of the reference population. Thus, a Z-score compares the patient to an age- and gender-matched population. This comparison is useful in certain situations. The Z-score is often reported in premenopausal women, men under the age of 50, and children. When the value is low, it is also a clue that a secondary cause of osteoporosis may be present. Central DXA units measure BMD at the lumbar spine, proximal femur, and distal forearm. These regions of interest correlate with the common areas affected by osteoporotic fracture.

Diagnostic Tests and Interpretation

35

Vertebra fracture assessment (VFA) has been an added feature to central DXA units (Ferrar, Jiang, Adams, & Eastell, 2005). VFA produces a lateral image of the thoracic and lumbar vertebrae. These images are reviewed visually and also measured in a morphometric fashion to determine if there are prevalent vertebral deformities. The presence and severity of vertebral fractures are determined by using the semiquantitative assessment criteria developed by Genant and colleagues (Genant, Wu, van Kuijk, & Nevitt, 1993). Vertebral fractures are common and are often not recognized clinically, with only about a third of vertebral fractures found on radiographs coming to clinical attention (Cooper, O’Neill, & Silman, 1993). VFA produces an image (taken at the time of the DXA scan) that is easy to obtain and adds very little radiation. The finding of a vertebral deformity allows the densitometrist to place the patient at a high risk for future fracture regardless of the BMD values. VFA is indicated when there is a documented height loss of greater than 2 cm, a historical height loss of greater than 4 cm, a history of a fracture after the age of 50, chronic use of glucocorticoids, or a history suggestive of vertebral fracture not documented by prior radiographic studies (Binkley et al., 2006). Quantitative computed tomography (QCT) is another method used to measure spinal bone density. It provides a three-dimensional, or volumetric, measurement with a spatial separation of trabecular from cortical bone. This technology is not as widely used as DXA because of the expense and higher radiation dosage. Quantitative ultrasonography (QUS) is another technique that has been used to predict fracture risk. QUS is commonly used at the calcaneus (heel). It does not measure bone mineral content or density directly but instead measures the transmission of ultrasound, including broadband ultrasound attenuation (BUA), speed of sound (SOS), and the combined quantitative ultrasound index (QUI). This technology is more portable and less expensive than central DXA units.

Guidelines for Interpretation The International Society for Clinical Densitometry (ISCD) has published official positions and guidelines for bone densitometry (Binkley et al., 2006; Hans et al., 2006; Leslie et al., 2006; Shepherd et al., 2006; Vokes et al., 2006). Since this is a rapidly evolving field, the ISCD has updated these positions on a yearly basis, and the reader should review the latest recommendations for the most updated version (International Society for Clinical Densitometry [ISCD], 2005). The 2005 official positions of the ISCD are available on the ISCD Web site (ISCD, 2005). Some of the important highlights in the official positions are as follows: 1. The reference data base for T-scores will now use a uniform White (non-race-

adjusted) normative database for men and women of all ethnic groups. This statement is limited to the United States. The rationale for this guideline stems from difficulties in defining ethnicity, along with multiethnic fracture data suggesting similar relative risks among various ethnic groups (Miller et al., 2002). 2 . Osteoporosis may be diagnosed in postmenopausal women and in men over the age of 50 if the T-score of the lumbar spine, total hip, or femoral neck is 2.5 or less. In patients with hyperparathyroidism, or if the above-mentioned

36

Osteoporosis

3.

4.

5.

6.

7.

sites cannot be measured or interpreted, the 33% radius site may be utilized to make the diagnosis. Other sites such as Ward’s area should not be used for diagnosis as they may significantly after the diagnostic category assigned to a patient without truly reflecting the known distribution of the disease. The spinal ROI should include L1 through L4. Vertebrae may be eliminated if there are structural changes or artifacts. If only one vertebra remains after excluding others, the diagnosis should be based on a different skeletal site. A distinction is made between diagnostic classification and the use of BMD for fracture risk assessment. Any well-validated technique can be used for fracture risk assessment. As seen below, combining BMD values with clinical risk factors allows for better determination of fracture risk. T-scores are reported in postmenopausal women and men age 50 and older. Z-scores are preferred in premenopausal women and men younger than the age of 50. This is particularly important in children. Serial BMD testing can be used to monitor the response to therapy. For those with an increased or stable bone density, it is felt that therapy is adequate, while a nonresponsive therapy would be suggested by finding a loss of bone density that exceeds the least significant change (LSC). Precision assessment should be calculated for each technologist.

Serial BMD testing allows one to determine changes in BMD over time. This may be important as the clinician monitors the response to therapy. When possible, it is recommended that the same unit be used for serial studies. The interpreting physician should compare BMD values as opposed to T-scores when performing serial studies. Each bone densitometry center should have the technologist perform a precision assessment (Shepherd et al., 2006). The precision assessment determines how well the technologist is able to replicate a study. This assessment produces an LSC, which would be expressed in an absolute value (g/cm2) with a 95% confidence level. This allows the interpreting physician to determine whether a repeat BMD has actually changed or whether the difference is merely within the range of the technologist’s and equipment’s error. Use of the LSC gives one the ability to determine when the next DXA scan should be performed. Most densitometry centers would have an LSC in the range of 3%–5%. One would consider repeating the DXA scan in a period of time in which a treatment would be expected to change BMD to an extent greater than the LSC. From a practical standpoint, initiating an antiresportive agent may allow an improvement of 2%–3% per year (depending on the ROI). Thus, repeating a DXA scan in 2 years after initiation of therapy may allow for proper interpretation of the results. Alternatively, in a situation such as treatment with high-dose corticosteroids, BMD could fall 5% or more within a year. In that situation, a DXA scan may be repeated in 1 year. The World Health Organization (WHO) has defined osteoporosis as a T-score below −2.5, while defining osteopenia as a T-score between −1.0 and −2.5, and normal as a T-score above −1.0 (World Health Organization [WHO], 1994; also Kanis, Melton, Christiansen, Johnston, & Khaltaev, 1994). This is an operational definition that allows researchers and clinicians to classify degrees of low bone density within populations. From a practical clinical standpoint, however, this definition lacks the ability to make decisions regarding fracture risk and treatment thresholds. The National Osteoporosis

Diagnostic Tests and Interpretation

37

Risk Assessment (NORA) study cohort of nearly 150,000 postmenopausal women showed that 82% of those with fractures had T-scores greater than −2.5 (Siris et al., 2004). Additionally, the Study of Osteoporotic Fractures showed that 54% of postmenopausal women with incident hip fractures did not have an osteoporotic T-score at the hip on the baseline DXA (Wainwright et al., 2005). Therefore, relying purely on WHO criteria to determine future fractures is inadequate. There have been attempts made to combine BMD values with clinical risk factors to allow clinicians to determine when to intervene with treatment modalities. The National Osteoporosis Foundation (NOF) has developed recommendations for treatment, which have been widely adopted by many physicians who interpret BMD studies (“Osteoporos: Review of the Evidence,” 1998). The NOF suggests that one should consider pharmacological treatment for individuals with a T-score below −2.0, regardless of risk factors, and below −1.5 in the presence of one or more of the major risk factors. The major risk factors are listed in Table 4.1. This guideline has been adopted and operationalized by many health care organizations and systems. Additionally, the American College of Rheumatology has recommended treatment in patients taking chronic oral corticosteroids if the T-score is less than -1.0 (“Recommendations for the Prevention and Treatment,” 2001). This recommendation is not based upon any controlled trial, but given the rapid loss of bone and the increased propensity to fracture at a higher BMD, this guideline seems quite appropriate. Fracture risk may be expressed in a variety of fashions. Absolute risk (AR) is the probability of a fracture over a specific period of time (for instance, 10 years). Meanwhile, relative risk (RR) is the ratio of absolute risks of two populations. RR tends to overestimate fracture risk in some populations and underestimate it in others. For example, a 50-year-old woman and an 80-year-old woman with identical T-scores will have the same RR for fracture compared to an age-matched population with a normal BMD. However, the AR over a 10-year period of time is much higher in the 80-year-old than in the 50-year-old. The WHO is presently attempting to define a cost utility analysis that will combine results from the BMD with clinical risk factors for fracture (Kanis, Borgstrom, et al., 2005; Kanis, Oden, et al., 2001). WHO is also attempting to use BMD and clinical risk factors to determine a 10-year absolute risk of fracture. This work may eventually set the standard for pharmacological therapy. Until that methodology is available and widely used, many suggest that the NOF approach should be used.

Table

4.1

National Osteoporosis Foundation Guidelines for Treatment • • •

T-score is less than –2.0 T-score is less than –1.5 with a major risk factor Major risk factors i. Personal history of fracture ii. Family history of fracture iii. Current cigarette smoker iv. Weight less than 127 pounds

38

Osteoporosis

Clinical Utility As with every piece of technology, we need to determine the most effective and efficient use of BMD testing. A number of organizations (the American Association of Clinical Endocrinologists [AACE], ISCD, National Institutes of Health [NIH], NOF, North American Menopause Society [NAMS], Institute for Clinical Systems Improvement [ICSI], and United States Preventive Services Task Force [USPSTF]) have recommended the need to screen certain high-risk groups (Binkley, Bilzikian, Kendler, Leib, Lewiecki, & Petak, 2006; Hodgson, Watts, Bilezikian, Clarke, Gray, Harris et al., 2003; ICSI, 2006; ISCD, 2005; Kern, Powe, Levine, Fitzpatrick, Harris, Robbins et al., 2005; NAMS, 2002; NOF, 2003; USDHHS, 2004).The published guidelines are slightly different among the various organizations but tend to agree on most recommendations. A listing of potential indications for BMD testing is found in Table 4.2. It is generally accepted that BMD testing is recommended for all women over the age of 65. In this age group, approximately 45% of screened patients are found to be at high risk according to NOF criteria. This group includes those patients who are not only at a higher absolute risk for fracture but also most likely to respond to pharmacological treatments (Newman et al., 2003). For younger postmenopausal women, BMD testing has been recommended in patients who have other major risk factors as noted above. Some organizations would limit this to women over the age of 60 (US Preventire Services Task Force, 2002). In younger postmenopausal women, a substantial number will be identified as at a high relative risk according to NOF criteria. Their 10-year absolute risk, however, will not be as high as that of the older postmenopausal group. Patients taking chronic corticosteroid therapy are another important group in which BMD testing can be quite useful. It is well established that chronic use of oral corticosteroids leads to decreased BMD and increased incidence of fractures (Haugeberg, Uhlig, Falch, Halse, & Kvien, 2000; Hooyman, Melton, Nelson, O’Fallon, & Riggs, 1984). Chronic use has been arbitrarily defined as taking the equivalent of 7.5mg of prednisone daily for 3 months. However, a number of studies have shown that lower doses of corticosteroids are associated with decreased bone density and increased fracture risk (Laan et al., 1993; Van Staa, Leufkens, Abenhaim, Zhang, & Cooper, 2000). Bone loss can occur rapidly after the initiation of oral glucocorticoids in a dose-dependent fashion. Within the first

Table

4.2

Groups That Should Be Tested With DXA • • • • • • •

All women over the age of 65 Postmenopausal women with major risk factors All individuals over the age of 50 who suffer an osteoporotic fracture All individuals who are taking long-term corticosteroids Men with hypogonadal conditions Men over the age of 70 Patients with diseases associated with bone loss and fracture

AQ3

Diagnostic Tests and Interpretation

Q3

39

6 months to 1 year, one can lose up to 20% of bone in patients taking high-dose corticosteroids. The rate of bone loss tends to lessen after 1 year and the bone loss effects can partially reverse after discontinuation of corticosteroids. The health care system tends to fall short in the evaluation and treatment of patients taking glucocorticoids (Solomon, Katz, La Tourette, & Coblyn, 2004). Other high-risk groups include any adult who presents with a fracture of the hip, vertebrae, or wrist (Cooper, Atkinson, O’Fallon, & Melton, 1992; Klotzbuecher, Ross, Landsman, Abbot, & Berger, 2000; Lindsay et al., 2001). There can be a 5-fold increase in vertebral fracture risk when a vertebral fracture is found at baseline (Klotzbuecher et al., 2000). This value may rise to a 12-fold increase when there are two vertebral fractures at baseline (Klotzbuecher et al., 2000). A number of investigators have shown that this high-risk group is infrequently evaluated for osteoporosis or treated with medication that could reduce future fractures (Andrade et al., 2003; Feldstein, Nichols, et al., 2003; Harrington, Broy, Derosa, Licata, & Shewman, 2002; Kamel, Hussain, Tariq, Perry, & Morley, 2000; Kiebzak et al., 2002; Smith, Ross, & Ahern, 2001; Solomon, Finkelstein, Katz, Morgun, & Avorn, 2003). A number of investigators have shown that less than 20% of patients hospitalized with hip fracture are ever evaluated for bone density. Additionally, less than 10% are ever treated with antiresorptive agents to prevent future fractures. A large health care system reviewed over 70,000 patients who had suffered over 2,800 fractures and found that only 8.4% of the women and 1.5% of the men had been BMD tested within 2 years of the fracture (Feldstein, Elmer, Orwell, Herson, & Hillier, 2003). The ISCD has also recommended DXA testing for men over the age of 70 (Shepherd et al., 2006). Although that recommendation has not been made by other organizations, it does appear clear that some men are at a much higher risk for future fracture. This includes men who are hypogonadal or taking chronic corticosteroid therapy. Those men that have been treated with orchiectomy or antiandrogen therapy for prostate cancer are at a particularly high risk for bone loss and subsequent fracture (Shahinian, Kuo, Freeman, & Goodwin, 2005).

Markers of Bone Turnover Bone is a dynamic organ that is constantly being remodeled (Eastell & Bainbridge, 2003; Fohr, Woitage, & Seibel, 2003). Bone resorption is initiated by osteoclasts. These cells attach to the bone surface and secrete hydrolytic enzymes that resorb bone. This releases a variety of bone minerals and fragments of collagen. Collagen is digested, and various fragments are excreted in the urine. This includes deoxypyridinoline (DPD) and peptide-bound alpha I to alpha II N-telopeptide (NTX) cross-links. The peptide-bound NTX can be measured in the urine and serum by an immunoassay termed Osteomark®. Bone formation is initiated by osteoblasts, which synthesize type I collagen and other proteins to form osteoid, which is the organic substrate upon which mineralization occurs. Osteoblasts express alkaline phosphatase on their cell membranes, and consequently bone-specific alkaline phosphatase (BSAP) reflects the cellular activity of osteoblasts. Osteoblasts also form osteocalcin, which can also be measured in the serum

40

Osteoporosis

Table

Bone Turnover Markers

4.3

•

Measures of osteoblast function i. Alkaline phosphatase (AP): a membrane-bound enzyme found in bone, liver, intestine, spleen, kidney, and placenta. The bone alkaline phosphatase (BAP) is more specific for bone and reflects cellular activity of osteoblasts. ii. Osteocalcin (OC): a hydroxyapatite binding protein synthesized by osteoblasts. A specific marker of osteoblast function, but heterogeneity of OC fragments in serum limits clinical usefulness. Significant diurnal variations.

•

Measures of osteoclast function i. Hydroxyproline (OHP): This reflects breakdown of collagen in bone, cartilage, and skin. It may also reflect dietary intake of collagen. ii. Collagen crosslinks: These reflect bone resorption but not dietary intake. They tend to be specific markers of bone resorption. These include the following: 1. N-telopeptide (NTX) measured in the urine and in serum by an immunoassay termed Osteomark 2. C-telopeptide (CTX) measured in serum by an immunoassay termed Crosslaps 3. Deoxypyridinoline (DPD)

and is a reflection of osteoblastic synthesis. A listing of some common markers of bone turnover are found in Table 4.3. In most cases of postmenopausal osteoporosis, bone loss is due to an increase in bone resorption with an inadequate increase in bone formation. This would result in elevated markers of bone resorption such as the urinary NTX. Some studies have shown a significant correlation of markers of bone turnover and subsequent rates of bone loss (Bauer et al., 1999; Chaki et al., 2000; Chestnut, Bell, & Clark, 1997; Ross & Knowlton, 1998). There have also been studies correlating bone turnover markers with an increased risk of hip fracture and a greater fracture reduction when taking antiresorptive agents (Bauer et al., 2004; Bauer et al., 2006; Seibel, Naganathan, Barton, & Grauer, 2004; Van Daele et al., 1996). Women with the highest bone turnover have been shown to gain the most BMD from antiresorptive therapy (Chestnut et al., 1997). The clinical utility of routine measurements of bone markers is unclear. Some have suggested that elevated bone turnover markers could predict which patients will respond to the initiation of antiresorptive therapy. Additionally, some have suggested that measurements of antiresorptive markers are useful to monitor the efficacy of and adherence to an antiresorptive agent. By measuring bone turnover markers 6 months after antiresorptive therapy, one could determine compliance and drug efficacy if urinary NTX or CTX decreased by 30%–50%. Alternatively, some have suggested that the routine measurement of bone turnover markers is not necessary.

Secondary Cause Evaluation As a diagnosis of osteoporosis is made, one needs to consider the possibility of secondary causes producing low bone density (Fitzpatrick, 2002). Primary osteoporosis is defined

Diagnostic Tests and Interpretation

41

as the bone loss that occurs during the normal aging process, while secondary osteoporosis reflects bone loss that is a result of another clinical problem. Obviously, it is important to determine secondary causes, since these conditions may be treated in a different manner. The numerous secondary causes of osteoporosis are reviewed elsewhere in this text, with some of the more common causes listed in Table 4.4. It is estimated that up to 20%–30% of postmenopausal women may have a secondary cause of osteoporosis, while the value may be 50% in men. A complete history and a physical examination are the first steps in the evaluation of potential secondary causes for osteoporosis. The history is especially important since

Table

Secondary Causes of Osteoporosis

4.4

•

Pharmacotherapy i. Glucocorticoids ii. Thyroid overreplacement iii. Anticonvulsants (phenytoin, phenobarbital) iv. Lithium, aluminum v. Heparin (long-term) vi. Drugs producing hypogonadism (aromatase inhibitors, antimetabolite chemotherapy, depo-medroxyprogesterone, gonadotropin-releasing hormone agonists)

•

Endocrine disorders i. Cushing syndrome ii. Hyperparathyroidism iii. Hypogonadism iv. Hyperthyroidism

•

Gastrointestinal disorders i. Alcohol-related diseases ii. Malabsorption syndromes iii. Eating disorders iv. Celiac disease v. Inflammatory bowel diseases vi. Chronic liver diseases vii. Gastrectomy

•

Genetic diseases i. Osteogenesis imperfecta ii. Hypophosphatasia

•

Miscellaneous causes i. Organ transplant ii. Rheumatoid arthritis iii. Neurological diseases iv. Spinal cord injury v. Multiple sclerosis vi. Prolonged bed rest vii. Multiple myeloma viii. Marrow infiltrative diseases

42

Osteoporosis

there are a number of clues that may help to explain low bone density. Obviously, one of the most common secondary causes of osteoporosis is the use of oral glucocorticoids. Other pharmacotherapy must also be considered, such as the use of thyroid hormone at high dosages, anticonvulsants (especially phenytoin and phenobarbital), lithium, longterm heparin, and drugs that produce hypogonadism (such as aromatase inhibitors, depo-medroxyprogesterone, and gonadotropin-releasing hormone agonists). Other items within the history that would be important to ascertain include a history of eating disorders, symptoms of hypogonadism in a male, gastrointestinal symptoms suggestive of malabsorption, alcohol excess, smoking, and the presence of a connective tissue disease. The physical examination might also assist in finding clues to a variety of endocrine, gastrointestinal, and inflammatory arthropathies. Several laboratory studies may also be useful in determining secondary causes of osteoporosis. Over the past several years, vitamin D deficiency has been shown to be a very common laboratory finding. Studies have shown that in patients with a vitamin D deficiency, supplementation is associated with improved bone density and a reduced risk of falls (Bischoff-Ferrari et al., 2004; Shea et al., 2002). It is felt that the serum 25-hydroxy vitamin D level should be at least 30ng/ml, since levels lower than this value are associated with elevated parathyroid hormone levels. Since vitamin D deficiency is so common, it appears wise to obtain a 25-hydroxy vitamin D level in any patient who is being considered for therapy with a pharmacological agent. Other appropriate laboratory studies would include a parathyroid hormone level, serum calcium, alkaline phosphatase, serum protein electrophoresis, a complete blood count, serum creatinine, and a testosterone level (in men). These studies would help to rule out the possibility of conditions such as hyperparathyroidism, hypogonadism, multiple myeloma, and renal insufficiency. Additional laboratory studies would be indicated if there are clues within the history and physical examination related to any of the secondary causes of osteoporosis. See Table 4.5 for a listing of common laboratory tests that may be used to evaluate secondary causes of osteoporosis. Secondary causes should be considered in all patients diagnosed with osteoporosis, and certainly the history and physical examination should always focus on the various possibilities. Complete laboratory testing in all patients is not likely a cost-effective

Table

4.5

Tests That Should Be Considered When Evaluating Secondary Causes of Osteoporosis • History and physical examination • 25-OH vitamin D • Serum calcium • Serum phosphorus, alkaline phosphatase, creatinine • Parathyroid hormone • Thyroid function tests • Serum protein electrophoresis • Serum testosterone (in men)

Diagnostic Tests and Interpretation

43

approach. Since vitamin D deficiency is quite common, this test is often recommended. Certainly, in all men or if the patient’s Z-score (age-matched control) is less than 1.0, one might have a higher index of suspicion for a secondary cause and, in those cases, a thorough laboratory evaluation should be considered.

REFERENCES American College of Rheumatology Ad Hoc Committee on Glucocorticoid-Induced Osteoporosis. (2001). Recommendations for the prevention and treatment of glucocorticoid-induced osteoporosis. Arthritis Rheum, 44, 1496-1503. Andrade, S. E., Majumdar, S. R., Chan, K. A., Buist, D. S., Go, A. S., Goodman, M., et al. (2003). Low frequency of treatment of osteoporosis among postmenopausal women following a fracture. Archives of Internal Medicine, 163(17), 2052–2057. Bates, D. W., Black, D. M., & Cummings, S. R. (2002). Clinical use of bone densitometry. Journal of the American Medical Association 288, 1898–1900. Bauer, D. C., Black, D. M., Garnero, P., Hochberg, M., Ott, S., Orloff, J., et al. (2004). Change in bone turnover and hip, non-spine, and vertebral fracture in alendronate-treated women: The fracture intervention trial. Journal of Bone Mineral Research, 19, 1250. Bauer, D. C., Garnero, P., Hochberg, M. C., Santora, A., Delmas, P., Ewing, S. K., et al. (2006). Pretreatment levels of bone turnover and the antifracture efficacy of alendronate: The fracture intervention trial. Journal of Bone Mineral Research, 21, 292. Bauer, D. C., Sklarin, P. M., Stone, K. L., Black, D. M., Nevitt, M. C., Ensrud, K. E., et al. (1999). Biochemical markers of bone turnover and prediction of hip bone loss in older women: The study of osteoporotic fractures. Journal of Bone Mineral Research, 14, 1404. Binkley, N., Bilezikian, J. P., Kendler, D. L., Leib, E. S., Lewiecki, E. M., & Petak, S. M. (2006). Official positions of the International Society for Clinical Densitometry. Journal of Clinical Densitometry, 9, 4–14. Bischoff-Ferrari, H. A., Dawson-Hughes, B., Willett, W. C., Staehelin, H. B., Bazemore, M. G., Zee, R. Y., et al. (2004). Effects of vitamin D on falls: A meta-analysis. Journal of the American Medical Association, 291, 1999–2006. Bonnick, S. L. (2004). Bone densitometry in clinical practice. Totowa, NJ: Humana Press. Chaki, O., Yoshikata, I., Kikuchi, R., Nakayama, M., Uchiyama, Y., Hirahara, F., et al. (2000). The predictive value of biochemical markers of bone turnover for bone mineral density in postmenopausal Japanese women. Journal of Bone Mineral Research, 15, 1537. Chestnut, C. H., III, Bell, N. H., & Clark, G. S. (1997). Hormone replacement therapy in postmenopausal women: Urinary N-telopeptide of type I collagen monitors therapeutic effect and predicts response of bone mineral density. American Journal of Medicine, 102, 29. Cooper, C., Atkinson, E. J., O’Fallon, W. M., & Melton, L. J, III. (1992). Incidence of clinically diagnosed vertebral fractures: a population-based study in Rochester, Minnesota, 1985–1989. Journal of Bone Mineral Research, 7, 221. Cooper, C., O’Neill, T., & Silman, A. (1993). The epidemiology of vertebral fractures. European Vertebral Osteoporosis Study Group. Bone, 14(Suppl. 2), S89–S97. Cummings, S. R., Bates, D., & Black, D. M. (2002). Clinical use of bone densitometry. Journal of the American Medical Association, 288, 1889–1897. Eastell, R., & Bainbridge, P. R. (2003). Bone turnover markers. In E. S. Orwell & M. Bliziotes (Eds.), Osteoporosis: Pathophysiology and clinical management (pp. 185–197). Totowa, NJ: Humana Press. Feldstein, A., Elmer, P. J., Orwell, E., Herson, M., & Hillier, T. (2003). Bone mineral density measurement and treatment for osteoporosis in older individuals with fractures. Archives of Internal Medicine, 163, 2165–2172. Feldstein, A. C., Nichols, G. A., Elmer, P. J., Smith, D. H., Aickin, M., & Herson, M. (2003). Older women with fractures: Patients falling through the cracks of guideline recommended osteoporosis screening and treatment. Journal of Bone Joint Surgery of America, 85A(12), 2294–2302. Ferrar, L., Jiang, G., Adams, J., & Eastell, R. (2005). Identification of vertebral fractures: An update. Osteoporosis International, 16, 717. Fitzpatrick, L. A. (2002). Secondary causes of osteoporosis. Mayo Clinical Proceedings, 77, 453–468.

44

Osteoporosis Fohr, B., Woitage, H. W., & Seibel, M. J. (2003). Molecular markers of bone turnover. In E. S. Orwell & M. Bliziotes (Eds.), Osteoporosis: Pathophysiology and clinical management (pp. 163–184). Totowa, NJ: Humana Press. Genant, H. K., Wu, C. Y., van Kuijk, C., & Nevitt, M. C. (1993). Vertebral fracture assessment using a semiquantitative technique. Journal of Bone Mineral Research, 8, 1137–1148. Hans, D. H., Downs, R. W., Jr., Duboeuf, F., Greenspan, S., Jankowski, L. G., Kiebzak, G. M., et al. (2006). Skeletal sites for osteoporosis diagnosis: The 2005 ISCD official positions. Journal of Clinical Densitometry, 9, 15–21. Harrington, J. T., Broy, S. B., Derosa, A. M., Licata, A. A., & Shewman, D. A. (2002). Hip fracture patients are not treated for osteoporosis: A call to action. Arthritis and Rheumatitis, 47, 651–654. Haugeberg, G., Uhlig, T., Falch, J. A., Halse, J. I., & Kvien, T. K. (2000). Bone mineral density and frequency of osteoporosis in female patients with rheumatoid arthritis. Arthritis and Rheumatitis, 43, 522–530. Hodgson, S. F., Watts, N. B., Bilezikian, J. P., Clarke, B. L., Gray, T. K., Harris, D. W., et al. (2003). American Association of Clinical Endocrinologists medical guidelines for clinical practice for the prevention and treatment of postmenopausal osteoporosis: 2001 edition, with selected updates for 2003. Endocrine Practice, 9, 544. Hooyman, J. R., Melton, L. J., III, Nelson, A. M., O’Fallon, W. M., & Riggs, B. L. (1984). Fractures after rheumatoid arthritis: A population based study. Arthritis and Rheumatitis, 27, 1353–1361. Retrieved July 27, 2006, from www.icsi.org Institute for Clinical Systems Improvement [ICSI] (2007). Diagnosis and treatment of osteoporosis. Retrieved July 9, 2007, from http://www.icsi.org/guidelines_and_more/guidelines__order_ sets__protocols/womens_health/osteoporosis/osteoporosis__diagnosis_and treatment_of.html International Society for Clinical Densitometry. (2005). Official positions. Retrieved July 17, 2006, from http://www.iscd.org/Visitors/positions/OfficialPositionsText.cfm Kamel, H. K., Hussain, M. S., Tariq, S., Perry, H. M., & Morley, J. E. (2000). Failure to diagnose and treat osteoporosis in elderly patients hospitalized with hip fracture. American Journal of Medicine, 109, 326–328. Kanis, J. A., Borgstrom, F., De Laet, C., Johansson, H., Johnell, O., Jonnson, B., et al. (2005). Assessment of fracture risk. Osteoporosis International, 16, 581. Kanis, J. A., Melton, L. J., III, Christiansen, C., Johnston, C. C., & Khaltaev, N. (1994). The diagnosis of osteoporosis. Journal of Bone Mineral Research, 9, 1137–1141. Kanis, J. A., Oden, A., Johnell, O., Jonsson, B., de Laet, C., & Dawson, A. (2001). The burden of osteoporotic fractures: A method for setting intervention thresholds. Osteoporosis International, 12, 417. Kern, L. M., Powe, N. R., Levine, M. A., Fitzpatrick, A. L., Harris, T. B., Robbins, J., et al. (2005). Association between screening for osteoporosis and the incidence of hip fracture. Annals of Internal Medicine, 142, 173–181. Kiebzak, G. M., Beinart, G. A., Perser, K., Ambrose, C. G., Siff, S. J., & Heggeness, M. H. (2002). Undertreatment of osteoporosis in men with hip fracture. Archives of Internal Medicine, 162, 2217–2222. Klotzbuecher, C. M., Ross, P. D., Landsman, P. B., Abbot, T. A., III, & Berger, M. (2000). Patients with prior fractures have an increased risk of future fractures: A summary of the literature and statistical synthesis. Journal of Bone Mineral Research, 15, 721. Laan, R.F.J., Van Riel, P.L.C.M., Van de Putte, L.B.A., van Erning, L. J., van’t Hof, M. A., & Lemmens, J. A. (1993). Low-dose prednisone induces rapid reversible axial bone loss in patients with rheumatoid arthritis: A randomized controlled trial. Annals of Internal Medicine, 119, 963–968. Leslie, W. D., Adler, R. A., El-Hajj Fuleihan, G., Hodsman, A. B., Kendler, D. L., McClung, M., et al. (2006). Application of the 1994 WHO classification to populations other than postmenopausal Caucasian women: The 2005 ISCD official positions. Journal of Clinical Densitometry, 9, 22–30. Lindsay, M. R., Silverman, S. L., Cooper, C., Hanley, D. A., Barton, I., Broy, S. B., et al. (2001). Risk of new vertebral fracture in the year following fracture. Journal of the American Medical Association, 285, 320–323. Miller, P. D., Siris, E. S., Barrett-Conner, E., Faulkner, K. G., Wehren, L. E., Abbott, T. A., et al. (2002). Prediction of fracture risk in postmenopausal White women with peripheral bone densitometry: Evidence from the National Osteoporosis Risk Assessment. Journal of Bone Mineral Research, 17, 2222–2230.

Diagnostic Tests and Interpretation

45

Newman, E. D., Ayoub, W. T., Starkey, R. H., Diehl, J. M., & Wood, G. C. (2003). Osteoporosis disease management in a rural health care population: Hip fracture reduction and reduced costs in postmenopausal women after 5 years. Osteoporosis International, 14, 146–151. National Institutes of Health Consensus Development Panel on Osteoporosis Prevention, Diagnosis, and Therapy. (2001). Osteoporsis prevention, diagnosis, and therapy. The Journal of the American Medical Association 285, 785–789. Osteoporosis: Review of the evidence for prevention, diagnosis and treatment and cost-effectiveness analysis. (1998). Osteoporosis International, 8(Suppl. 14), S7. Ross, P. D., & Knowlton, W. (2000). Rapid bone loss is associated with increased levels of biochemical markers. Journal of Bone Mineral Research, 13, 297. Seibel, M. J., Naganathan, V., Barton, I., & Grauer, A. (2004). Relationship between pretreatment bone resorption and vertebral fracture incidence in postmenopausal osteoporotic women treated with risedronate. Journal of Bone Mineral Research, 19, 323. Shahinian, V. B., Kuo, Y. F., Freeman, J. L., & Goodwin, J. S. (2005). Risk of fracture after androgen deprivation for prostate cancer. New England Journal of Medicine, 352, 154–164. Shea, B., Wells, G., Cranney, A., Zytaruk, N., Robinson, B., Griffith, L., et al. (2002). Meta-analysis of calcium supplementation for the prevention of postmenopausal osteoporosis. Endocrine Review, 23, 552–559. Shepherd, J. A., Lu, Y., Wilson, K., Fuerst, T., Genant, H., Hangartner, T. N., et al. (2006). Crosscalibration and minimum precision standards for Dual-Energy X-ray Absorptiometry: The 2005 ISCD official positions. Journal of Clinical Densitometry, 9, 31–36. Siris, E. S., Chen, Y. T., Abbott, T. A., Barrett-Connor, E., Miller, P. D., Wehren, L. E., et al. (2004). Bone mineral density thresholds for pharmacological intervention to prevent fractures. Archives of Internal Medicine, 164, 1108. Smith, M. D., Ross, W., & Ahern, M. J. (2001). Missing a therapeutic window of opportunity: An audit of patients attending a tertiary teaching hospital with potentially osteoporotic hip and wrist fractures. Journal of Rheumatology, 28, 2504–2508. Solomon, D. H., Finkelstein, J. S., Katz, J. N., Morgun, H., & Avorn, J. (2003). Underuse of osteoporosis medications in elderly patients with fractures. American Journal of Medicine, 115, 398–400. Solomon, D. H., Katz, J. N., La Tourette, A. M., & Coblyn, J. S. (2004). Multifaceted intervention to improve rheumatologists’ management of glucocorticoid-induced osteoporosis. Arthritis Care and Research, 51, 383–387. Tinetti, M. E. (2003). Preventing falls in elderly persons. New England Journal of Medicine, 348, 4249. U.S. Department of Health and Human Services. (2004). Bone health and osteoporosis: A report of the surgeon general. Public Health Service, Office of the Surgeon General, Rockville, MD. Retrieved on August 27, 2007 from http://www.surgeongeneral.gov/library/bonehealth/ U. S. Preventive Services Task Force [USPSTF] (2002). Screening for osteoporosis in postmenopausal women: Recommendations and rationale. Annals of Internal Medicine, 137, 526–528. Van Daele, P. L., Seibel, M. J., Burger, H., Hofman, A., Grobbee, D. E., van Leeuwen, J. P., et al. (1996). Case-control analysis of bone resorption markers, disability, and hip fracture risk: The Rotterdam study. Bone Mineral Journal, 312, 482. Van Staa, T. P., Leufkens, H.G.M., Abenhaim, L., Zhang, B., & Cooper, C. (2000). Use of oral corticosteroids and risk of fracture. Journal of Bone Mineral Research, 15, 993–1000. Vokes, T., Bachman, D., Baim, S., Binkley, N., Broy, S., Ferrar, L., et al. (2006). Vertebral fracture assessment: The 2005 ISCD official positions. Journal of Clinical Densitometry, 9, 37–46. Wainwright, S. A., Marshall, L. M., Ensrud, K. E., Cauleu, J. A., Black, D. M., Hillier, T. A., et al. (2005). Hip fracture in women without osteoporosis. Journal of Clinical Endocrinology Metabolism, 90, 2787. Watts, N. B. (2002). Bone quality: Getting closer to a definition. Journal of Bone Mineral Research, 17, 1148. World Health Organization. (1994). Assessment of fracture risk and its application to screening for postmenopausal women. Geneva, Switzerland: World Health Organization.

Pharmacological Management

Osteoporosis is not an inevitable part of ageing; it is preventable. So it is vital that all of us, of all ages, start taking care of our bones now, before it is too late. (Camilla, Duchess of Cornwall )

O

5

steoporosis is both a preventable and a treatable disease. Important advances have been made in the ability to prevent and treat fractures in the last decade, particularly in people with skeletal fragility (U.S. Department of Health and Human Services [USDHHS], 2004). There are a number of effective, well-tolerated therapies that may significantly reduce a person’s risk, in addition to lifestyle changes such as improved diet and increased exercise. The four major goals in the treatment of osteoporosis are (1) to prevent fracture, (2) to stabilize bone mass or achieve increased bone mass, (3) to relieve symptoms of fractures and skeletal deformity, and (4) to maximize physical function (Hodgson et al., 2003). The U.S. surgeon general has recommended a three-level pyramidal approach to treatment in order to achieve these goals (USDHHS, 2004):

Theresa N. Grabo Daniel S. Longyhore

Lifestyle changes form the base of the prevention and management pyramid, including adequate calcium and vitamin D intake, physical activity, and fall prevention. The second level includes assessing and treating secondary causes. The third level includes pharmacological interventions to improve bone density and reduce the risk of fracture (USDHHS, 2004). The purpose of this chapter is to present the current pharmacotherapeutic interventions used to prevent and treat osteoporosis. Pain management will also be addressed. A number of pharmacologic treatments are available for the prevention and/or treatment

48

Osteoporosis

of postmenopausal osteoporosis based on their capability to increase bone mineral density (BMD) and to decrease the risk of fracture (Delaney, 2006). Current U.S. Food and Drug Administration (FDA)-approved pharmacotherapeutics include bisphosphonates, calcitonin (salmon), parathyroid hormone, risedronate, estrogen plus progestin or estrogen alone, and calcium and vitamin D.

Bisphosphonate Therapy Bisphosphonates are a pyrophosphate analogue and much less susceptible to hydrolysis from stomach acids than their predecessors, the inorganic pyrophosphates (Crandall, 2001). Their primary mechanism of action is inhibition of osteoclast activity and resorption of bone, thereby slowing deterioration and allowing osteoblast activity to slightly increase BMD. Bisphosphonate therapy should be considered first-line therapy for the treatment of osteoporosis, in conjunction with lifestyle modifications and appropriate doses of calcium plus vitamin D. As well, bisphosphonates are effective, have convenient dosing schedules, and a relatively safe adverse event profile. Their limitation is only their strict dosing procedures, as patients must remain upright and avoid sustenance before and 30 minutes or more after dosing. Alendronate (Fosamax®), risedronate (Actonel®), and ibandronate (Boniva®) are second- and third-generation bisphosphonates and are currently approved by the FDA for the prevention and treatment of postmenopausal osteoporosis (Merck & Co., 2006; Procter & Gamble Pharmaceuticals, 2006; Roche Laboratories Inc., 2006). Alendronate is also approved for the treatment of corticosteroid-induced osteoporosis, Paget’s disease, malignant hypercalcemia, and osteoporosis in Crohn’s disease (Merck & Co., 2006). Risedronate is also approved for the treatment and prevention of corticosteroidinduced osteoporosis (Procter & Gamble Pharmaceuticals, 2006). As some of the pivotal clinical trials are followed out to 10 years or more, the use of bisphosphonates for extended periods of time is questioned. Recently, Black et al., evaluated the prolonged use of bisphosphonates (5 versus 10 years) in the Fosamax Intervention Trial Extension and found that continuing bisphosphonates out to 10 years provided only a minimal, but statistically significant beneficial effect on bone mineral density (BMD). Black, Schwartz, et al. 2007, Colón-Emeric, 2006).

Mechanism of Action/Kinetics Bisphosphonates’ primary mechanism of action is inhibition of osteoclast activity on the surface of the bone. The bisphosphonates also inhibit osteoclast activity on the surface of the bone as well as inhibit the recruitment of osteoclasts to bone, decrease osteoclast life span, cause osteoclast apoptosis (a genetically determined process of cell self-destruction), and alter bone to slow or delay its resorption (Friedman, 2006; Licata, 2005). The bisphosphonates have a high affinity for bone, specifically those sites being prepared for resorption. There is a relatively low systemic concentration and any drug that is not deposited in the bone tissue is excreted rapidly in the urine. Also, this medication class has very limited absorption and less than 1% of the oral dose is absorbed systemically due to its decreased oral bioavailability, drug absorption is further lowered

Pharmacological Management

49

beyond its already limited degree when taken with or around mealtimes. Therefore, bisphosphonate dosing is recommended first thing in the morning with 8 ounces of water. The patient must then wait 30 minutes (alendronate or risedronate) or 60 minutes (ibandronate) before any food or beverage consumption, to allow the drug to reach maximal systemic concentration (Licata, 2005; Merck & Co., 2006; Procter & Gamble Pharmaceuticals, 2006; Roche Laboratories Inc., 2006).

Efficacy Vertebral Fractures Several clinical investigations have evaluated the use of bisphosphonates for primary and secondary prevention of vertebral fractures in postmenopausal women. BMDS of patients treated with a bisphosphonate are consistently increased to greater than the densities of those not taking a bisphosphonate. Increases in the lumbar spine can range from 5% to 8%, with some investigators finding a sustained increase of 13.7% up to 10 years later with alendronate 10 mg daily (Bone et al., 2004; O’Connell & Seaton, 2005). Alendronate is the most established of the three available approved oral bisphosphonates for the treatment of postmenopausal osteoporosis. Approved in 1995, its clinical efficacy for primary and secondary prevention of vertebral fractures set the stage for current osteoporosis treatment. The first major investigation was conducted by Liberman et al. (1995) in 994 postmenopausal women with a T-score of –2.5 or lower, regardless of history of fracture. The findings concluded that there was an overall 48% relative risk reduction in patients taking alendronate. The relative risk reduction for patients with and without a history of vertebral fractures was 30% and 50%, respectively. These findings were later validated further with the Fracture Intervention Trials (FITs), which evaluated alendronate’s benefit in patients with (FIT1) and without (FIT2) a history of vertebral fractures. The results were similar, with relative risk reductions of 47% and 45%, respectively (Black et al., 1996; Cummings et al., 1998). Interestingly, when Cummings et al. (1998) evaluated the benefit of alendronate in patients with a history of osteopenia without a vertebral fracture (T-score –1.0 to –2.5) they did not find a significant difference in fractures between their pharmacologic intervention and placebo. The researchers did find a significant difference between BMDs, but this difference did not translate into difference in fractures. Later studies also discovered that a once-weekly dose of alendronate 70 mg was comparable in efficacy to alendronate 10 mg daily (Schnitzer et al., 2000). Given this finding and the above information, alendronate 10 mg daily or alendronate 70 mg weekly is an effective agent for primary and secondary prevention of fractures secondary to osteoporosis. Most patients with osteopenia will not need alendronate 5 mg daily or 35 mg weekly for prevention of fracture, as appropriate calcium plus vitamin D supplementation may be sufficient. Risedronate showed much of the same beneficial clinical data as its predecessor in its major clinical investigations (Harris et al., 1999; Reginster et al., 2000). These trials, deemed the Vertebral Efficacy with Risedronate Therapy (VERT) trials, showed a 65% and 61% relative risk reduction in new vertebral fractures at 1 year, and a 41% and 49% reduction at 3 years of follow-up. These numbers were essentially equal to those of alendronate, making risedronate an acceptable alternative. Risedronate is also available in a

50

Osteoporosis

once-weekly dosing of 35 mg that has proven just as efficacious as the 5 mg daily dose (Brown et al., 2002). The newest oral bisphosphonate, ibandronate, has been marketed in a 2.5 mg oncedaily dose as well as in a 150 mg once-monthly dose. Various monthly dosing regimens were compared to the original daily dose using multiple doses and dosing schemes. In the end, all monthly regimens were proven “noninferior” to daily dosing, with 150 mg monthly producing a significant increase in overall BMD over daily dosing (3.9% vs. 4.9%). However, the daily-dosing regimen of ibandronate is the only formulation with fracture prevention data (Chesnut et al., 2004; Felsenberg et al., 2005; Miller et al., 2005). Zoledronic acid (Zometa®, Reclast®) is a bisphosphonate originally prescribed for hyperclacemia of malignancy or Paget’s disease and is being studied for treatment of patients with osteoporosis. A 5mg annual infusion has been shown to reduce morphometric vertebral fractures by 70% (10.9 vs. 3.3%, HR 0.30, 95%CI 0.24–0.38) over a 36 month period. This new dosage form proves to be an interesting approach to osteoporosis therapy as it avoids the gastrointestinal adverse events reported with the oral formulations. However, in the major clinical study looking at zoledronic acid infusions for preventing fractures, patients were more likely to experience pyrexia, myalgias, influenza-like symptoms, headache, and arthralgias, occurring most often after the initial infusion. Surprisingly, the most concerning adverse event was “serious” atrial fibrillation, occurring in 2.4% of the zoledroninc acid population (versus 1.9% in placebo). (Black, Delmas, et al., 2007, Novartis Pharmaceuticals Corp., 2007).

Nonvertebral Fractures The bisphosphonate class is one of the few medications for decreasing nonvertebral fracture risks. Unlike the selective estrogen receptor modulators (SERMs) and intranasal calcitonin, the oral bisphosphonates alendronate and risedronate may be used effectively in patients for primary and secondary nonvertebral fracture prevention. Ibandronate has yet to prove its efficacy for preventing nonvertebral fractures (Rosen, 2005). It is this efficacy data that further supports the use of these agents as first-line therapy in postmenopausal osteoporosis, in conjunction with adequate calcium plus vitamin D supplementation. As discussed earlier, the FIT1 and FIT2 trials evaluated the use of alendronate in the primary and secondary prevention of fractures in postmenopausal women (Black et al., 1996; Cummings et al., 1998). The results for nonvertebral fractures in these trials were not as compelling as those for vertebral fractures, though a significant improvement was seen in the FIT1 trial. As well, Pols et al. (1999) found a significant difference in nonvertebral fracture rates in patients with a T-score of less than –2.0 who were taking alendronate 10 mg. Fracture relative risk reductions were reported by the FIT1 and Fosamax International Study Trial Group (FOSIT) (Pols et al., 1999) trials as 51% and 47% in the hip and nonvertebrae, respectively. Recently, a meta-analysis by Papapoulos et al. (2005) evaluated alendronate’s efficacy in hip fractures in postmenopausal women and found a 55% overall risk reduction in new fractures. Like alendronate, risedronate has proven its clinical efficacy for the prevention of primary and secondary nonvertebral fractures in postmenopausal women. In the Hip Intervention Program (HIP) trial, a relative risk reduction of 36% was found

Pharmacological Management

51

in women taking alendronate 5 mg when compared to women taking only placebo (McClung et al., 2001). The same efficacy for hip fractures can be seen with Deal’s work (2002), though some controversy exists over the results. Overall, patients experienced a significant 28% risk reduction for hip fractures, though a subgroup analysis showed that this benefit was not seen in patients aged 70 to 79 without a history of vertebral fractures. Currently, conclusive data is not available for ibandronate’s efficacy in nonvertebral fractures. Daily and intermittent dosing of ibandronate was compared to placebo for 3 years in order to evaluate its effect on nonvertebral fractures. At the trial’s end, there was a negligible, nonsignificant decrease in nonvertebral fracture rates (9.1%, 8.9%, and 8.2%, respectively) (Chesnut, Skag, et al., 2004). Given this information, ibandronate currently cannot be recommended for the prevention of nonvertebral fractures.

Administration and Adverse Events Bisphosphonates are highly polar compounds and have very limited gastrointestinal absorption after oral administration. Even under the best dosing conditions, on an empty stomach 2 hours before meals, the oral bioavailability of bisphosphonates is usually less than 1% and is drastically reduced when administered with a meal. Given this limited absorption, the oral bisphosphonates have specific dosing instructions that patients must follow. Patients should be instructed to take their dose first thing in the morning before eating or drinking anything for the day. They should take the tablet with 6–8 ounces of water and then refrain from eating and drinking for at least another 30 minutes for alendronate and risedronate, 60 minutes for ibandronate. The oral solution of alendronate (Fosamax®) should be followed by at least 2 ounces (a quarter of a cup) of water. Patients should also avoid taking any other medications. During this time, patients should also remain sitting or standing upright. They should avoid being in a supine position, for this may prolong esophageal exposure to the drug and increase changes of topical irritation and adverse reactions. In most cases, it is easy to counsel patients to take the dose immediately upon rising in the morning and then ready themselves for the day by performing hygienic activities and dressing. This procedure should be followed with each dose, be it daily, weekly, or monthly. As stated above, there is not a significant difference between dosing regimens, and patients should participate in the regimen that is most appropriate, given their propensity for medication adherence (and fracture risk). Many patients may prefer the onceweekly dosing schedule to the daily regimen, given the burden of the dosing rituals on a daily basis of taking the bisphosphonate with 8 ounces of plain water 30 minutes before any other medication, liquid, or food is consumed, and remaining upright. Less frequent dosing regimens may allow regeneration of drug-related damage of the stomach mucosa, though providers should evaluate for medication adherence problems due to forgotten doses. The side effect profiles of each oral bisphosphonate are comparable regardless of agent or dosing regimen. Abdominal pain, dyspepsia, and nausea appear to be the most prevalent gastrointestinal complaints of patients taking oral bisphosphonates, though these rates do not differ greatly from those of placebo. Back pain was also a highly reported adverse event among the bisphosphonates. Recently, bisphosphonate osteochemonecrosis has become the adverse event of attention for patients taking injectable

52

Osteoporosis

and perhaps rarely oral bisphosphonates (Hellstein & Marek, 2004, 2005). Patients with these complaints should be evaluated by their providers to discuss the risks versus benefits of continuing therapy. Patients should also avoid taking bisphosphonates with products containing aluminum, calcium, and magnesium, as these products will decrease the absorption of the bisphosphonate from the gastrointestinal tract. It is important to note that while calcium is a critical component to the effectiveness of osteoporosis therapy, it should not be taken at the same time as a bisphosphonate, since bisphosphonate effectiveness decreases if calcium is taken within 30 minutes.

Parathyroid Hormone Therapy (PTH) The parathyroid gland was one of the last major human organs to be discovered (Holick, 2005). Its role, to secrete parathyroid hormone and regulate calcium and 1,25-dihydroxy vitamin D, is one of the few that facilitate osteoblast activity rather than preventing osteoclast activity (O’Connell et al., 2005). The recombinant human parathyroid hormone, teriparatide (Forteo®), is currently the only available agent in this class of medication. It is administered as a once-daily injection and is approved for use for up to 24 months. The FDA issued a black box warning for the medication because of an increased incidence of osteosarcoma in rats receiving doses at 3 to 60 times higher exposure than humans (Eli Lilly & Company, 2004). Although its exact placement in the paradigm of osteoporosis treatment has not been fully worked out, teriparatide may be an agent to consider in patients at very high risk of future vertebral fracture or patients who have failed to benefit from bisphosphonate therapy. After a course of teriparatide for up to 24 months, consideration should be given to adding a bisphosphonate to reduce the loss of bone density that may follow its cessation.

Mechanism of Action/Kinetics Parathyroid hormone functions to regulate bone metabolism, facilitate resorption of calcium and phosphate in the renal tubule, and control gastrointestinal calcium absorption, and increase 1,25-dihydroxy vitamin D (Eli Lilly & Company, 2004). Recently, parathyroid hormone receptors have been found on osteoblasts, better describing its anabolic properties and ability to catabolize bone metabolism (Holick, 2005). After subcutaneous administration, the drug is 95% bioavailable and has a half-life of approximately 1 hour (Eli Lilly & Company, 2004).

Efficacy Vertebral Fractures Various clinical investigations support bone mineral density improvements when teriparatide is used with or without antiresorptive agents. Monotherapy or combining teriparatide with hormone replacement therapy or selective estrogen receptor reuptake modulators increased bone mineral densities in the spine from 6% to 15% (Deal et al., 2005; Orwoll et al., 2003; Ste-Marie, Schwartz, Hossain, Desaiah, & Gaich, 2006). These

Pharmacological Management

53

benefits have been reported to be sustained out to 30 months after discontinuation of treatment (Prince et al., 2005). The addition of bisphosphonate therapy after 12 months of teriparatide (consecutive therapy) increased BMD minimally, though the changes were still better than teriparatide alone. Also, combining teriparatide with a bisphosphonate for the duration of treatment was beneficial, but still less so than the consecutive therapy (Black et al., 2005; Ettinger, San, Crans, & Pavo, 2004; Finkelstein et al., 2003). Teriparatide also has beneficial data surrounding fracture prevention in both men and women. Men using teriparatide 20 mcg daily experienced a reported 83% reduction in moderate to severe fracture risk (Kaufman et al., 2005). Women using teriparatide 20 mcg daily experienced a reported 65% reduction in new vertebral fractures (Neer et al., 2001).

Nonvertebral Fractures Teriparatide’s benefits are also present in increasing hip bone mineral density and preventing fractures when used alone or in combination (as above). Total hip and femoral neck BMDs increased as much as 5% with its use (Deal et al., 2005; McClung et al., 2005; Ste-Marie et al., 2006). Nonvertebral fractures were not significantly increased and were decreased by 53% in patients using teriparatide as compared to those using a placebo (Gallagher, Genant, Crans, Vargas, & Krege, 2005; Neer et al., 2001).

Administration and Adverse Events Teriparatide is administered as a daily subcutaneous injection. It is available as a 28-day, prefilled pen delivery device. Each administration provides the patient with a 20 mcg dose. The manufacturer suggests that patients should receive their first dose of teriparatide sitting or lying down because the drug may cause orthostatic hypotension. Patients should rotate injection sites along the abdominal belt line and thighs. Adverse events associated with the medication previously mentioned include osteosarcoma in rats (in particular, baby rats). To date there are no published reports of osteosarcoma in humans receiving teriparatide, and osteosarcoma has never been associated with hyperparathyroidism (where there is chronic elevation of parathyroid hormone). Other adverse events include injection-site reactions such as injection pain, erythema, itching, and urticaria. Patients using teriparatide may also report an increased incidence of leg cramps, dizziness, or paresthesias. Metabolic changes may include hyper- or hypocalcemia, hyperuricemia, or hypoparathyroidism (Eli Lilly & Company, 2004). A major limiting factor with teriparatide is cost—approximately 10 times the cost of bisphosphonate therapy.

Estrogen Therapy Estrogen is an essential hormone that is important throughout life for bone development in both men and women. Unlike the bisphosphonate drugs discussed earlier, estrogen acts primarily on reproductive and nonreproductive tissues in the body. Consequently,

54

Osteoporosis

the use of exogenous estrogen hormone treatment for the prevention and treatment of osteoporosis must be weighed against the ways in which the form and dose of estrogen might affect other tissues in the body. Therefore, of particular importance is consideration of the risk: benefit ratio and whether there are risks that might restrict use (USDHHS, 2004).

Mechanism of Action/Kinetics Estrogens are available as naturally occurring hormones or as synthetic steroidal and nonsteroidal compounds with estrogenic action. Estrogens are secreted primarily by the ovaries, and also by the adrenals, corpus luteum, placenta, and testes. They regulate the growth and function of the female sex organs and the appearance of female secondary sex characteristics (McEvoy et al., 2006). Estrogen is effective in inhibiting bone resorption and increasing BMD by binding to estrogen receptors on bone and blocking the production of specific cytokines that increase the number of osteoclasts and prolong their life span (Ettinger, Pressman, & Silver, 1999). Estrogens are secreted at varying rates throughout the menstrual cycle, and during menopause, ovarian secretion of estrogens falls off at varying rates. The secretion of the ovarian hormones estradiol and progesterone is regulated by control mechanisms along the hypothalamic–pituitary– target organ axis. Rising levels of estrogen and progesterone stimulate the hypothalamus to secrete gonadotropin-releasing hormone (GnRH), which travels via the portal system to the anterior pituitary. GnRH regulates the synthesis, storage, and secretion of the gonadotropins, follicle-stimulating hormone (FSH), and luteinizing hormone (LH) from the anterior pituitary. FSH and LH are responsible for follicular development (ovarian cycle) and sequential changes in the endometrium (uterine cycle) as well as the production of estrogen (primarily in the form of estradiol) and progesterone by the corpus luteum (McEvoy et al., 2006). The human body produces three estrogens: estradiol E2, estrone E1, and estriol E3. Of these, estradiol is the most potent of the estrogens produced by the ovary. Estrone, a metabolite of estradiol, is considerably less potent, and estriol, a further metabolite of estradiol, is very weak. There are several types of estrogen prescribed in the United States and Europe. These pharmaceuticals are given in a variety of prescription strengths and forms. Of the three estrogens, estrone is the form of estrogen present in women after menopause and is available as tablets under the brand name Ogen®. Until the recent report of the Women’s Health Initiative (WHI), the most commonly prescribed estrogen in the United States was Premarin®, a conjugated estrogen that is a mixture of estrone and other estrogens. Estradiol is the form of estrogen naturally present in premenopausal women. It is available as tablets (Estrace®), as transdermal patches (Estraderm®), or as vaginal creams (Estrace®, Estring®, Femring®) and vaginal tablets (Vagifem®). Estriol is a weaker form of estrogen produced by the breakdown of other forms of estrogen; it is most commonly used in Europe under the brand name Estriol and thought not to cause cancer. In the United States, estriol can be made by a compounding pharmacist (Gulli, 2002). Table 5.1 lists the estrogens approved for the prevention of osteoporosis in postmenopausal women (Nurse Practitioners’ Prescribing Reference, 2006). Currently, hormone therapy is not approved by the FDA for the treatment of osteoporosis, presumably because the fracture data required for the approval

55

Pharmacological Management

Table

5.1

Approved Estrogens for the Prevention of Osteoporosis in Postmenopausal Women Product *Estrace® estradiol *Ogen (USDHHS, 2004) estrone sodium as estropipate *Ortho-est® estropipate *Premarin® conjugated equine estrogens *Alora® (transdermal) estradiol *Estroderm® (transdermal) estradiol *Vivelle® (transdermal) estradiol *Vivelle Dot ® (transdermal) estradiol *Climara® (transdermal) estradiol

*Menostar® (transdermal) estradiol Esclim® (transdermal) estradiol

Estrogel® (topical gel) estradiol Estrosorb® (emulsion) estradiol

Dosage 0.5 mg, 1 mg, or 2 mg; tabs daily 0.625 mg, 1.25 mg, 2.5 mg; tabs daily 0.75 mg, 1.5 mg; tabs; daily 0.3 mg, 0.45 mg, 0.625 mg, 0.9 mg, 1.25 mg, 2.5 mg daily 0.025 mg/d, 0.05 mg/d, 0.075 mg/d, 0.1 mg/d Patch applied biweekly 0.05 mg/d, 0.1 mg /d Patch applied biweekly 0.05 mg/d, 0.1 mg Patch applied biweekly 0.025 mg/d, 0.0375 mg/d, 0.05 mg/d, 0.075 mg/d, 0.1 mg/d Patch applied biweekly 0.025 mg/d, 0.0375 mg/d, 0.05 mg/d, 0.06 mg/d, 0.075 mg/d, 0.1 mg/d Patch applied weekly 0.014 mg/d patch applied Patch applied biweekly 0.025 mg/d, 0.0375 mg/d, 0.05 mg/d, 0.075 mg/d, 0.1 mg/d Patch applied biweekly 1.25 mg pump once qd

Cautions (all estrogens) Undiagnosed abnormal genital bleeding Known or suspected breast cancer Known or suspected estrogen-dependent neoplasia Venous thromboembolism or pulmonary embolism or past history Active or recent (within past year) arterial thrombolic disease (e.g., stroke, myocardial infarction) Porphyria Liver disease or impairment Hypersensitivity to estrogens or any ingredient in the formulation Suspected or known pregnancy

1.74 g/pouch; 2 pouches qd

*FDA-approved estrogens for the prevention of osteoporosis in postmenopausal women. From Nurse Practitioners’ Prescribing Reference,® NPPR, 2006; McEvoy et al., 2006. Note. Estrogen must be combined with a progestin/progesterone either cyclically or continuous in women with an intact uterus.

process were never submitted (Grass & Dawson-Hughes, 2006). Women with an intact uterus should use estrogen combined with a progestin or progesterone either cyclically or continuously to prevent endometrial hyperplasia, which can lead to endometrial cancer if atypical cells are present.

56

Osteoporosis

Efficacy Vertebral-Nonvertebral Fractures The favorable impact of hormone therapy (HT), including estrogen and combination therapy (estrogen + progestin), on BMD has been supported by the results of randomized, placebo-controlled trials, including the Postmenopausal Estrogen/Progestin Interventions (PEPI) trial (Writing Group for the Postmenopausal Estrogen/Progestin Interventions, 1996) and the Women’s Health, Osteoporosis, Progestin, Estrogen (HOPE) study (Lindsay, Gallagher, Kleerekoper, & Pickar, 2002). These studies and a meta-analysis conducted by Wells et al. (2002) found that postmenopausal HT had a consistent and positive result on BMD at the forearm (3%–4.5%), spine (3.5%–7%), and hip (2%–4%). According to these studies, BMD increased in the first year of HT. Different formulations of conjugated estrogen (CEE/Premarin®, as well as estradiol) and combination therapy were included in both the PEPI trial and the meta-analysis, and no significant differences were found in the effects of different formulations of estrogen on bone density (USDHHS, 2004). The effect of HT on fracture rates is more limited in the research literature. Kiel, Felson, Anderson, Wilson, and Moskowitz (1987) and Cauley et al. (1995) all found that there are fewer fractures in women who received HT over the long term. In order to fill the research gap, Torgerson and Bell-Syer conducted a systematic review of all randomized trials of HT that reported or collected vertebral fracture data. Their meta-analysis demonstrated that HT reduced nonvertebral fractures by 27% (Torgerson & Bell-Syer, 2001a) and produced an overall 33% reduction in vertebral factures (Torgerson & Bell-Syer, 2001b). The WHI conducted two separate randomized clinical trials to evaluate the effect of postmenopausal HT on decreasing the risk of cardiovascular disease. In addition, the results have provided information on other chronic diseases including fractures. In the first trial, women with an intact uterus received an estrogen-progestin combination, Prempro® 2.5 mg (E+P, 0.625 mg conjugated equine estrogen [CEE], and 2.5 mg medroxyprogesterone [MPA], daily) (Rossouw et al., 2002), and the second trial evaluated the effect of estrogen alone, Premarin® (CEE, 0.625 mg), in women who have undergone hysterectomies (Anderson et al., 2004). The WHI estrogen-plus-progestin study is the first large randomized clinical trial that confirmed that combined postmenopausal hormone therapy, specifically, Prempro® 2.5 mg, reduces the risk of fractures at the wrist, hip, and vertebrae (Cauley et al, 2003). Vertebral and hip and other fractures were decreased by at least one-third in both of the trials, and total fractures fell by 24%–30%. The results of these two large clinical trials are consistent with observational studies of postmenopausal women using HT and trials evaluating the outcome of HT on BMD (USDHHS, 2004). While the WHI set forth apparent benefits of HT in the prevention of postmenopausal bone loss and the reduction of bone turnover, these positive effects must be weighed against the higher rates of breast cancer, stroke, deep vein thrombosis, and cognitive impairment that were found among those receiving combined, continuous HT (E+P) for the 5.2 years of the study. Postmenopausal women receiving estrogen alone did not experience an increase in breast cancer risk based on 6.6 years of use (Anderson et al., 2004; Rossouw et al., 2002). In addition, no clear cardiovascular benefit of HT was demonstrated in the WHI trials (USDHHS, 2004).

Pharmacological Management

57

Based on the current evidence regarding the safety of the long-term use of HT, this treatment should be reserved for women unable to tolerate nonestrogen therapy. The FDA (U.S. Food and Drug Administration, 2004) recommends that HT only be used for the shortest amount of time at the lowest possible doses required to accomplish treatment goals. Research evidence has shown that lower doses of CEE alone, or CEE/MPA, 0.3 mg/1.5 mg daily, significantly increased spine and hip BMD from baseline within 2 years of therapy (Lindsay et al., 2002) and that low-dose estradiol also preserves bone (Prestwood, Kenny, Kleppinger, & Kulldorff, 2003). While HT is effective for the prevention of postmenopausal osteoporosis, there is general consensus that it should only be offered to women who are at increased risk for osteoporosis and are unable to tolerate nonestrogen medications (USDHHS, 2004). The current recommendations are that estrogens and progestins be used at the lowest doses for the shortest period of time needed to reach treatment goals (U.S. Food and Drug Administration, 2004). Estrogen or combination hormones (E+P) in lower doses can help to maintain bone density. The Women’s HOPE study, the first large, randomized placebo-controlled trial to evaluate BMD with lower doses of CEE and CEE/MPA, found that doses as low as 0.3 mg daily of CEE or the combination significantly increased spine and hip BMD from baseline within 2 years of therapy (Lindsay et al., 2002). Prestwood et al. (2003) also showed that low-dose estrogen preserved bone. They found that in postmenopausal women, taking a dosage of 0.25 mg daily of 17-estradiol for 3 years increased bone density of the hip, spine, and total body and reduced bone turnover. However, larger long-term trials are needed to support the lasting benefits of low-dose HT on bone health. Currently, the long-term effects of various doses, formulations (including estrogens or progesterone), and modes of administration (e.g., transdermal, vaginal administration) on bone and other tissues have been not been sufficiently studied to support their long-term effectiveness and safety (USDHHS, 2004).

Administration and Adverse Events Estrogens can be administered orally, intravaginally, transdermally, parenterally, and by topical application of a gel or emulsion to the skin. Estrogen is usually taken in a continuous daily dosage regimen or in a cyclic regimen. Cyclically administered estrogen is usually taken once daily for 3 weeks followed by 1 week off the drug, or once daily for 23 days followed by 5 days without the drug. Dosage is individualized according to the condition being treated, and the tolerance and therapeutic response of the patient (McEvoy et al., 2006).

Bioidentical Hormones In addition to conventional or traditional HT, discussed above, a brief discussion of bioidentical hormone therapy (BHRT), sometimes called natural hormone therapy (NHRT), is offered. These hormones are not the same as phytoestrogens, also referred to as natural estrogen-like products, which will be discussed under integrative therapies. Bioidentical hormones refer to hormones that have the same molecular structure as those made by the human body and are isomolecular and indistinguishable from each other.

58

Osteoporosis

By definition, bioidentical hormones are plant derived and bioidentical to endogenous hormones. The prescription for BHRT is written by a licensed health care provider and made up by a compounding pharmacist to treat symptoms of perimenopause, menopause, and hormonal imbalance. The dosage, formulation, and administration are individualized to balance each woman’s hormone profile to manage symptoms of menopause and maintain health (Ahlgrimm & Kells, 2003; Smith, 2003; Wright & Morgenthaler, 1997). Salivary and blood spot hormone tests, in addition to symptoms, are used to guide the provider in achieving hormone balance (Ahlgrimm & Kells, 2003). There has been an increased interest in bioidentical or natural hormones since the WHI clinical trial report was released in 2002, noting greater harm than benefit from the use of combined CEE plus a progestin. These findings resulted in a precipitous decrease in the use of estrogen and progestin and a critical reexamination of menopausal HT and triggered greater interest in other approaches to managing menopausal symptoms, including the use of bioidentical hormones (Stefanick, 2005). Bioidentical hormones include estrogens estrone (E1), estradiol (E2), and estriol (E3), progesterone, testosterone, dehydroepiandrosterone (DHEA), and pregnenolone. Bioidentical hormones are prepared from either beta sitosterol extracted from the soybean or from diosgenin extracted from the Mexican wild yam root. Bioidentical hormones can be administered in various forms, including oral (capsules, drops, sublingual), transdermal/topical, vaginal, rectal, and pellet implants. In addition, estradiol (Estrase®) and micronized progesterone (Prometrium®) are considered bioidentical hormones and are found in synthetically produced hormones. Examples of individually compounded estrogens include Biestrogen (Biest), which is made up of estriol 80%, a weaker estrogen, and estradiol 20%, a more potent estrogen, expressed on a milligram-per-milligram basis. A similar preparation, Triestrogen (Triest), contains the three estrogens, estriol 80%, estradiol 10%, and estrone 10%. These hormones are pharmaceutical grade and are not commercially marketed but must be compounded in a pharmacy. In the United States, estrone and estradiol are commercially marketed, but estriol is not. Micronized progesterone is also compounded and prescribed singly or in combination with estrogen and or testosterone (Ahlgrimm & Kells, 2003; Smith, 2003; Wright & Morgenthaler, 1997).

Table

5.2

International Names for Evista® Brand name Bonmax Celvista Evista® Loxar Loxifen Optruma

Raxeto

Country where approved for use India Thailand United States, Hong Kong, Indonesia, Israel, Korea, Malaysia, Philippines, Singapore, Taiwan Uruguay Paraguay Austria, Belgium, Bulgaria, Czech Republic, Denmark, England, Finland, France, Germany, Greece, Guatemala, Hungary, Ireland, Italy, Netherlands, Norway, Poland, Portugal, Russia, Slovenia, Spain, Sweden, Switzerland, Turkey Argentina

Note. From Mosby’s Drug Consult, 16th ed., 2006.

Pharmacological Management

59

Proponents of BHRT assert that these hormones are better tolerated and are safer alternatives than synthetic manufactured hormones. However, the FDA recommends that the labeling of bioidentical hormones include a statement that there is no evidence these hormones are safer than synthetic products. Regrettably, few observational studies or clinical trials have been conducted comparing synthetic HT with BHRT (Stefanick, 2005). BHRT has not been approved by the FDA for the prevention or treatment of osteoporosis. Currently participants are being recruited for a double-blind, placebocontrolled pilot study comparing bioidentical hormones to low-dose Prempro®. The purpose of this study is to try to gather information about safety when bioidentical hormones are used during early menopause.

Selective Estrogen Receptor Modulators (SERMs) Raloxifene hydrochloride (Evista®) is a nonsteroidal benzothiophene derivative with mixed estrogen agonist or antagonist activity in specific tissues. Raloxifene belongs to the class of compounds known as SERMs (McEvoy et al., 2006). The biological actions of SERMs are principally mediated via binding to estrogen receptors. This binding results in the activation of specific estrogenic pathways and the blockade of others (“Raloxifene Hydrochloride,” 2006). Thus, raloxifene acts like estrogen to prevent bone loss and improve lipid profiles but also has the potential to block some estrogen effects, such as those that lead to breast and endometrial cancer. It increases the risk of deep vein thrombosis (DVT) compared to placebo and does not block the vasomotor symptoms seen with menopause, which may limit compliance with therapy in postmenopausal women. The effects on bone seen with the administration of SERMs appear to be less than with the use of estrogen therapy (Lexi-Comp Online, 2006). Table 5.2 lists the international brand names for raloxifene where it is approved for use in various countries. Tamoxifen, another SERM, is primarily used for the prevention of breast cancer, but it is not approved for the prevention and treatment of osteoporosis. Limited data on the effects of tamoxifen on bone turnover have shown that it maintains or improves BMD in postmenopausal women but causes bone loss in premenopausal women (Powles, Hickish, Kanis, Tidy, & Ashley, 1996). Newer SERMs are under development and may provide more benefit to the bones, heart, and breast tissue. They may also decrease vasomotor symptoms and have a positive effect on cholesterol (USDHHS, 2004). These newer SERMs include lasofoxifen, under development by Ligand and Pfizer. Now in phase III trials, it provides an improved effect on BMD and fracture reduction, and has cardiovascular benefits as well. Wyeth and Ligand are developing a new SERM, known as TSE-424, a combination bazedoxifene and conjugated estrogen (Premarin). Phase III clinical trials comparing TSE-424 to placebo and to raloxifene for the treatment of osteoporosis in postmenopausal women are in progress. Phase II clinical trials of SERM 3339, developed by Aventis for the treatment of osteoporosis, are in progress (Liebman, 2002). Raloxifene is the only SERM that has been approved by the FDA for osteoporosis prevention (LexiComp Online, 2006).

60

Osteoporosis

A clinical trial that was designed to compare raloxifene with tamoxifen in reducing the incidence of breast cancer in postmenopausal women at increased risk for the disease demonstrated that both drugs reduced breast cancer risk by 50% for postmenopausal women. Additionally, the raloxifene group had 36% fewer uterine cancers and 29% fewer blood clots than the tamoxifen group (National Cancer Institute, 2006).

Mechanism of Action/Kinetics Raloxifene differs pharmacologically and chemically from naturally occurring estrogens, synthetic steroidal and nonsteroidal compounds with estrogenic activity, and antiestrogen agents (e.g., clomiphene, tamoxifen, toremifene). Raloxifene exhibits estrogen agonist activity on bone and circulating lipoproteins, but estrogen antagonist activity on breast and uterine tissue. As with estrogen replacement, the principal pharmacologic action of raloxifene is to decrease the rate of bone resorption, consequently slowing the rate of bone loss in postmenopausal women (McEvoy et al., 2006). In addition, raloxifene decreases total LDL cholesterol but usually does not affect HDL cholesterol or triglycerides (Mosby Drug Consult, 2006). Approximately 60% of raloxifene is rapidly absorbed from the gastrointestinal (GI) tract after an oral dose; however, its absolute bioavailability as an unchanged drug is only 2%, due to extensive first-pass effect metabolized to glucuronide conjugates. Taking it with a high-fat meal increases the absorption but does not substantially lead to clinically meaningful changes in systemic exposure; therefore, raloxifene can be taken without regard to meals and has a half-life of 27.7–32.5 hours. The usual dosage for the prevention of osteoporosis in postmenopausal women is 60 mg daily, but no additional benefit is gained from administering higher doses. The onset of action is 8 weeks from the commencement of taking the drug. Raloxifene’s use in invasive breast cancer risk reduction (investigational use) is 60 mg per day for 5 years (Lexi-Comp Online, 2006).

Efficacy Vertebral Data related to the fracture protection of raloxifene in postmenopausal women with osteoporosis come from the Multiple Outcomes of Raloxifene Evaluation (MORE) study, a large, 3-year, randomized, placebo-controlled, double-blind, multinational osteoporosis treatment trial (Ettinger, Black, et al., 1999). The incidence of new vertebral fracture was the primary end point in this trial. The results show that raloxifene increased spine BMD by 2.3% and hip BMD by approximately 2.5% after 3 years of use (Ettinger, Black, et al., 1999). About a 50% reduction in spine fractures was observed, but there was no effect on hip or other nonvertebral fractures (Cranney et al., 2002; Ettinger, Black, et al., 1999). A post hoc analysis of the MORE study found a 68% vertebral fracture reduction after 1 year of raloxifene 60 mg/d in the overall study population and a 66% reduction in women with known vertebral fracture at baseline (Maricic et al., 2002). In a 1-year extension of the MORE trial, women who remained on therapy for at least 4 years had a 36% vertebral fracture reduction in the overall study population,

Pharmacological Management

61

with a 34% reduction in women with at least 1 prevalent fracture at baseline (Delmas et al., 2002). The reduction in vertebral fracture in older postmenopausal women is raloxifene’s primary clinical benefit, particularly if some vertebral fractures are present at baseline; however, bone turnover can return to its prior condition, resulting in bone loss after raloxifene is stopped (USDHHS, 2004).

Nonvertebral Fractures Findings from the MORE study show that raloxifene did not significantly decrease the 3-year risk of hip or overall nonvertebral fractures in the overall population receiving raloxifene 60 mg per day and 120 mg per day (Ettinger, Black, et al., 1999).

Administration and Adverse Events Raloxifene is available in a 60 mg film-coated tablet for oral administration once daily at any time of day without regard to meals. It should be stopped around 72 hours prior to and during prolonged immobilization, such as surgery requiring restricted activity or extended travel by air or land, owing to serious adverse events due to venous thromboembolic disease (similar to the reported risk of HT) (Lexi-Comp Online, 2006). For prevention of thromboembolic events, antiembolism stockings and compression stockings are recommended. Raloxifene also causes significantly more mild to moderate adverse effects such as leg cramps and hot flashes compared with placebo, but considerably less vaginal bleeding than estrogen-progestin combination therapy. Contraindications: Prolonged immobilization (e.g., postoperative recovery, prolonged bed rest) or active thromboembolic condition. Side effects: Increased risk of thromboembolism, pulmonary embolism, and superficial thrombophlebitis, vasomotor symptoms (hot flashes), flu-like symptoms (these disappear with continued use), gastrointestinal upset, vaginitis, and urinary tract infection. Drug interactions: Cholestyramine (Questran®) and ampicillin decrease raloxifene absorption/blood levels. Raloxifene the potential to interact with other highly protein-bound drugs by increasing the effects of either drug. Caution is recommended with coadministration of highly protein-bound drugs, warfarin, clofibrate, indomethacin, naproxen, ibuprofen, diazepam, phenytoin, tamoxifen, or lidocaine (Lexi-Comp Online, 2006, Mosby’s Drug Consult, 2006). The MORE study reported that the majority of adverse events were mild or moderate. The most common serious event related to raloxifene treatment was venous thromboembolism. Women receiving raloxifene had an increased risk of venous thromboembolus as compared with women receiving a placebo (Ettinger, Black, et al., 1999). Raloxifene is administered in the geriatric population at the usual adult dose. There are no gender differences; however, the influence of race has not been conclusively determined. Studies in patients with renal insufficiency were not conducted, since only negligible amounts of raloxifene are excreted in urine. Raloxifene and metabolite concentrations in women enrolled in the osteoporosis treatment and prevention trials with

5.3

Ibandronate

Risedronate

Agent Bisphosphonates Alendronate

Boniva 2.5 mg, 150 mg, 1mg/mL (3 mL prefilled syringe)

Actonel + Calcium (35 mg/1250 mg)

Fosamax 7 0mg/75 ml solution Actonel 5 mg, 35 mg, 75 mg

Fosamax +D (70 mg/2,800 IU or 70 mg/5,000 IU)

Fosamax 5 mg, 10 mg, 35 mg, 70 mg

Brand name / Formulation

Gastrointestinal abdominal pain colitis diarrhea Musculoskeletal osteonecrosis of the jaw arthralgias (rare with oral bisphosphonates) Neurologic headache

Osteopenia Oral: 5 mg daily or 3 5 mg weekly

• Inhibit osteoclast activity on the surface of the bone • Inhibit recruitment of osteoclasts to bone • Alter bone to slow or delay its resorption Osteoporosis / Osteopenia Oral: 5 mg daily 35 mg weekly or 75 mg on 2 consecutive days monthly Osteoporosis Oral: 2.5 mg daily or 150 mg monthly Injection: 3 mg IV every 3 months

Osteoporosis Oral: 10 mg daily or 70 mg weekly

Adverse events

Dosing

Mechanism of action

Table Pharmacological Management of Osteoporosis

Forteo 750 mcg injection

Miacalcin 200 units/ activation

Various doses and formulations

Evista 60 mg

• Increased intestinal calcium absorption • Increased calcium and phosphate resorption by the bone • increased tubular calcium resorption in the presence of inhibited tubular phosphate resorption

• Excreted in response to serum hypercalcemia • Directly inhibits and depresses osteoclast function

• Inhibits bone resorption • Reduces biochemical markers of bone turnover to the premenopausal range • Inhibits bone resorption • Preserves or increases bone mass

Injection: 20 mg SC once daily for up to 2 years

Dizziness Leg cramps Osteosarcoma in rats

Rhinitis Back pain Nausea Vomiting

increased risk of venous thromboembolism Nausea Breast tenderness Menstrual flow

Dosing varies by product

Intranasal: 1 spray in alternating nostrils, daily Injection: 100 IU IM or SC every other day

increased risk of venous thromboembolism return of hot flashes

Oral: 60 mg daily

Note. From information in R. K. Klasco, ed., DRUGDEX® System, Internet database, Thomson Micromedex. Updated periodically. Retrieved August 28, 2006, from http://slhwebappsvr.slhn.org:81/hcs/librarian/PFPUI/Ms4kXLJ1XoHuvh

Parathyroid hormone Teriparatide

Calcitonin Calcitonin

Estrogen

SERM/Estrogen Raloxifene

64

Table

5.4

Osteoporosis

Pharmaceutical Agents: A Comparison of Their Efficacy in Vertebral and Nonvertebral Fractures Agent Alendronate

Risedronate Ibandronate Raloxifene

Estrogen

Vertebral fracture Primary Prevention 30%–47% relative risk reduction Secondary Prevention 45%–50% relative risk reduction 41%–49% relative risk reduction in new fractures 50%–62% relative risk reduction in new fractures

Nonvertebral fracture 47%–55% relative risk reduction in new fractures

64% relative risk reduction in new fractures, 60 mg daily; 57% 120 mg daily 33% reduction in new fractures

Not significantly affected

36% relative risk reduction in new fractures Not significantly affected

27% reduction in new fractures

Calcitonin

Primary Prevention 33% reduction in new fractures Secondary Prevention 36% reduction in recurrent fractures

Unable to report statistical significance

Teriparatide

65%–83% reduction in patients with a moderate to severe fracture risk

53% reduction in fracture

Note. Adapted with permission from Umland, E. M. (2006) Guidelines for pharmacists: Interpreting the medical evidence for bisphosphonates in postmenopausal osteoporosis U.S. Pharmacist. Retrieved July 9, 2007, from http://www.uspharmacist.com/index.asp?page=ce/105219/default.htm

an estimated creatinine clearance as low as 21 ml/min are similar to the concentrations in women with normal creatinine clearance. Raloxifene was examined following a single dose in Child-Pugh Class A patients with cirrhosis and total serum bilirubin ranging from 0.6–2.0 mg/dl, and plasma raloxifene concentrations were about 2.5 times higher than in controls and correlated with bilirubin concentrations. The safety and efficacy of raloxifene have not been further evaluated in patients with hepatic insufficiency. Table 5.3 provides a summary of the pharmaceutical agents used in the management of osteoporosis, and Table 5.4 presents a comparison of their efficacy in vertebral and nonvertebral fractures.

Calcitonin (Salmon) Therapy Calcitonin (Miacalcin®) is an endogenous hormone secreted by the thyroid’s parafollicular gland in mammals. In the treatment of osteoporosis, calcitonin derived from a salmon’s ultimobranchial gland is utilized, due to its greater potency and prolonged duration of action when compared to mammalian calcitonin (Novartis Pharmaceutical Corp., 2003). It was first formulated as an injection, to be administered on an everyother-day basis. Most recently, a daily nasal spray formulation was added as a dose

Pharmacological Management

65

delivery system. In clinical trials of women treated out to 5 years, intranasal calcitonin has demonstrated limited benefit in secondary vertebral fracture prevention (Chesnut et al., 2000). Calcitonin (salmon) is not an appropriate first-line agent for the treatment of osteoporosis. It should be considered as a second- or third-line agent in patients with intolerance to bisphosphonate therapy or patients who are unable to use bisphosphonates due to physiologic functional limitations. Calcitonin has reported analgesic effects in patients with Paget’s disease or bone metastases and provides minimal support to help with pain in patients with osteoporosis (Thomson Micromedex, 2006).

Mechanism of Action/Kinetics While the mechanism of action of calcitonin on bone has not been fully explicated, its use causes a decrease in bone resorption through direct osteoclastic inhibition and decreased life span of other circulating osteoclasts. Upon nasal administration, calcitonin is taken up rapidly into systemic circulation and approximately 3% of this dose is bioavailable (as compared to intravenous administration). It cannot be administered orally, as the product is destroyed by gastric acids. The peak concentration of the drug occurs in 20 (intravenous) to 35 (nasal) minutes, with an approximately 43-minute half-life (Novartis Pharmaceutical Corp., 2003; Thomson Micromedex, 2006).

Efficacy Vertebral Fractures There is sparse clinical evidence for the use of calcitonin (salmon) in vertebral fractures. Various clinical trials report an increase in lumbar spine BMD by 1% to 7% in patients using intranasal calcitonin for at least 12 months (Downs et al., 2000; Tiras, Noyan, Yildiz, & Biberoglu, 2000; Toth et al., 2005; Trovas, Lyritis, Galanos, Raptou, & Constantelou, 2002). Two clinical investigations provided evidence of calcitonin’s benefit in decreasing new vertebral fractures in patients with osteoporosis significantly over placebo (Dursun, Dursun, & Yalcin, 2001; Ishida & Kawai, 2004). In addition, the soundest evidence supporting calcitonin’s use in preventing fractures in osteoporosis was provided by the PROOF study (Chesnut et al., 2000). Researchers reported a 33% reduction in new vertebral fractures in patients using 200 IU calcitonin (salmon) daily over placebo. Patients with a previous history of fracture experienced a 36% reduction. This was the only effective dose in the trial for vertebral fracture, as both 100 IU and 400 IU yielded insignificant reductions in new vertebral fractures.

Nonvertebral Fractures Evidence for the use of calcitonin (salmon) in patients to prevent nonvertebral fractures is minimal. BMD in patients using calcitonin (salmon) increased by a maximum of 3% during the studies and did not show a significant change in risk of nonvertebral fractures (Chesnut et al., 2000; Downs et al., 2000; Huusko et al., 2002; Tiras et al., 2000; Toth et al., 2005; Trovas et al., 2002). Authors have reported a significant decrease in nonvertebral fractures in the group receiving 100 IU intranasally versus 200 IU and 400 IU doses.

66

Osteoporosis

However, authors also point out that the study did not meet its statistical power and the evidence-based conclusion is not as sound as was anticipated (Hamdy et al., 2005).

Analgesic Effect The use of calcitonin (salmon) for pain associated with osteoporotic fractures is a unique feature of the medicine. Several clinical investigations have evaluated calcitonin’s effect on perception of pain and functionality with positive results. While a majority of the data involves injectable or rectal administration, Pontiroli et al. (1994) showed similar efficacy between the injectable and intranasal dosages. Patients with vertebral crush fracture reported a significant decrease in spinal pain and experienced earlier mobilization and earlier ability to sit, stand, and walk when using 200 IU intranasal calcitonin (salmon) daily (Lyritis et al., 1997). Patients randomized to placebo remained bed bound for almost the entire duration of the study.

Administration and Adverse Events Patients using intranasal calcitonin (salmon) should be educated to alternate the nostril in which they administer the medication on a daily basis. The medication is generally well tolerated without significant reporting of adverse events.

Combination Antiresorptive Therapy Bisphosphonates, HT, and SERMs are all classified as antiresorptive drugs; however, they operate through different mechanisms of action, suggesting that if used in combination they could have an additive effect. Bone et al. (2000) compared the use of two antiresorptive therapies together to a similar use of estrogen and alendronate alone in postmenopausal women with a hysterectomy over a 2-year period. Women receiving combination therapy had around an 8% increase in BMD at the spine, compared to 6% in women taking alendronate or estrogen. Similar results were reported in BMD at the hip, while combination therapy demonstrated a 1%–2% greater increase in BMD than either therapy alone. No additional unexpected side effects were seen in women in the combination therapy group. A study by Greenspan, Resnick, and Parker (2003) of women age 65 and older also reported that using alendronate and HT together resulted in greater increases in BMD at the spine and hip than did treatment with either drug alone. However, a study by Eviö, Tiitinen, Laitinen, Ylikorkala, and Välimäki (2004) did not support the findings of earlier studies; rather, these investigators found that treating elderly osteoporotic women with combination therapy of alendronate and HRT did not provide any additional advantage over either treatment alone. The use of risedronate in combination with HT for 1 year has also been studied and has been shown to increase BMD at the hip but not the spine (Harris et al., 2001). Johnell et al. (2002), in another short-term study using combination therapy of alendronate and raloxifene, also found a greater increase in hip BMD than in women taking either drug alone. In this study, women taking alendronate alone had a considerably higher BMD

Pharmacological Management

67

of the spine and hip than those taking raloxifene alone. A study by Greenspan et al. (2003) also found that women who took combination therapy or alendronate alone maintained BMD of the spine and hip following discontinuation of therapy, while women who gained bone during 2 years on HT lost their BMD gains at the spine and hip during the year after therapy was stopped. Because of the economic burden of multiple drug therapies, because of the greater risk for more side effects, and because trials reported in the literature did not study fracture risk, combination therapy is not generally recommended as first-line therapy. It is generally reserved for individuals of the following types: (1) those who have suffered a fracture while on a single drug, (2) those who have an extremely low BMD and a history of multiple fractures, and (3) those with a very low BMD who continue to lose more bone mass while being treated with a single drug (USDHHS, 2004). Combining an antiresorptive agent with an anabolic agent is discussed under parathyroid hormone therapy.

Calcium and Vitamin D Calcium is a mineral that accounts for 1% to 2% of the adult human body weight and plays a vital role in the development and maintenance of a healthy skeleton. Most of the body calcium (99%) is found in bones and teeth, providing mechanical rigidity. The rest of the calcium in the body is found in blood, intracellular fluid, muscle, and other tissues where it plays a role in other body functions. Calcium mainly exists in bone in the form of hydroxyapatite (Ca)10 (PO4)6(OH)2, and bone mineral is approximately 40% of bone weight (Institute of Medicine [IOM], 1997). Vitamin D (calciferol) is vital for bone health because it assists in the absorption and utilization of calcium. The major source of vitamin D is sunlight, which the human body absorbs by exposure to sunlight through the conversion of precursors in the skin to active vitamin D. Consumption of adequate levels of calcium and vitamin D throughout life and appropriate physical activity are essential to bone health (USDHHS, 2004). The skeleton also serves as a calcium reserve, and bone tissue is resorbed from the skeleton when the exogenous supply is inadequate to maintain serum calcium at a constant level. However, using skeletal calcium over the long term to meet this need leads to

Table

Calcium Recommendations

5.5

800 mg daily: children ages 1 to 10 1,000 mg daily: males, premenopausal women, and postmenopausal women receiving estrogen 1,200 mg daily: teenagers and young adults ages 11 to 24 1,500 mg daily: postmenopausal women not receiving estrogen 1,200 mg to 1500 mg daily: pregnant and nursing mothers Total daily intake of calcium should not exceed 2,000 mg

Note. National Institutes of Health(NIH) Consensus Development Panel on Osteoporosis Prevention, Diagnosis, and Therapy. Osteoporosis prevention, diagnosis, and therapy. Journal of the American Medical Association, 285, 785–795, 2001.

68

Osteoporosis

osteoporosis (Nieves, 2003). National nutrition surveys have shown that most Americans are not getting adequate calcium in their diets; in fact, the average diet contains merely 600 mg of calcium daily. While several organizations have established appropriate intakes of calcium and vitamin D, most experts support the recommendations made by the National Institutes of Health (NIH) Consensus Development Panel on Optimal Calcium Intake (NIH, 1994). According to their recommendations, postmenopausal women desiring to reduce the risk of osteoporosis should consume 1,000–1,500 mg of elemental calcium and 400–800 IU of vitamin D daily. The recommended calcium intake for postmenopausal women is 1,000–1,500 mg per day in two or more doses (since it cannot be effectively

Table

Adverse Reactions to Calcium

5.6

Calcium Carbonate: generally well tolerated, 1–10% Central nervous system: headache Endocrine and metabolic: hypercalcemia (anorexia, nausea, vomiting, constipation, headache, drowsiness, lethargy, muscle weakness, coma, polyuria, thirst); metabolic alkalosis; milk-alkali syndrome with very high, chronic dosing and/or renal failure (nausea, vomiting, headache, disorientation); hypophosphatemia Gastrointestinal: constipation, diarrhea, nausea, vomiting, anorexia, rebound hyperacidity, abdominal pain, flatulence, dry mouth Genitourinary: renal stones, renal dysfunction, renal failure

Calcium Citrate: frequency not defined Central nervous system: headache Endocrine and metabolic: hypophosphatemia, hypercalcemia: mild (calcium >10.5 mg/dL) asymptomatic or cause in anorexia, nausea, vomiting, and constipation; more severe (calcium >12 mg/dL) is manifested in confusion, delirium, stupor, and coma Gastrointestinal: nausea, vomiting, anorexia, constipation, abdominal pain, thirst

Note. From Lexi-Comp Online, 2006; MD Consult Online 2006..

Table

Calcium Drug Interactions

5.7

Calcium carbonate and Calcium citrate Calcium channel blockers (eg., verapamil): Effects may be reduced; monitor response. Levothyroxine: Calcium carbonate (and maybe other calcium salts) may decrease T4 absorption; separate dose of calcium from levothyroxine by a minimum of 4 hours. Polystyrene sulfonate: Potassium-binding ability is lessened; do not use concurrently. Tetracycline, atenolol (and possibly other beta-blockers): Iron, quinolone antibiotics, alendronate, sodium fluoride, and zinc absorption is considerably reduced; administer at different times. Thiazide diuretics: Can produce hypercalcemia; monitor response. Could potentiate digoxin toxicity. Milk-alkali syndrome and hypercalcemia can result from high doses of calcium with thiazide diuretics.

Note. From Lexi-Comp Online, 2006; MD Consult Online, 2006.

Pharmacological Management

69

absorbed in larger doses) through dietary calcium sources and/or supplements (e.g., calcium carbonate, calcium citrate, other calcium salts) and vitamin D 400–800 IU per day (IOM, 1997; NIH, 1994; Physician’s Guide to Prevention, 2003; WHI, 2006). The total calcium intake should not exceed 2,500 mg per day. Exceeding the recommended daily calcium intake offers no health benefit and may be harmful because of the risk of hypocalcaemia and hypercalciuria. While the threshold for calcium toxicity is high, the National Academy of Sciences does not recommend regularly taking more than 2,500 mg per day (IOM, 1997). Table 5.5 reflects the current calcium recommendations. Table 5.6 lists the adverse reactions to commonly used calcium preparations, and Table 5.7 presents drug interactions with calcium. There are a number of calcium salts readily available on the market (e.g., calcium citrate, calcium carbonate, calcium gluconate, oyster shell, and others) and many more commercial formulations (e.g., Tums, Caltrate, Citracal, Os-Cal 500, etc.) (Levenson & Bockman 1994). Calcium supplements are recommended if the patient is unable to ingest adequate amounts of dietary calcium. The two most common calcium supplements are calcium citrate and calcium carbonate. The highest amount of elemental calcium available among calcium formulations is calcium carbonate, with 40% elemental calcium. Calcium carbonate requires an acidic environment to maximize absorption capacity and should be taken with food (NIH, 1994). Calcium citrate may be taken without regard to food, but contains less elemental calcium (21%) (Heller, Stewart, Haynes, & Pak, 1999). Calcium citrate may be useful for patients taking histamine H2-receptor antagonists or proton-pump inhibitors and those with achlorhydria (Follin & Hansen, 2003). For a discussion of dietary sources of calcium, see chapter 7.

Vitamin D Vitamin D is essential for calcium absorption and bone mineralization. Vitamin D is synthesized in the skin by exposure to sunlight, or it may be taken in the form of a supplement. However, vitamin D is not synthesized by the skin of older individuals as well as by younger individuals; also some areas of the country do not receive sufficient sunlight in the winter, thereby promoting vitamin D deficiency. Some food sources contain vitamin D, such as fortified milk that contains 100 international units (IU) per cup (USDHHS, 2004), and fatty fish and fish oils as in cod, tuna, and shark (Hamdy et al., 2005). Since many individuals do not get enough vitamin D through sunlight or diet, recommendations for supplementation are set at a level designed to be adequate for individuals lacking sun exposure or food sources. Measuring serum 25-hydroxy vitamin D(3) 25-OHD(3) assists in determining adequate levels of vitamin D. Populations such as nursing home residents, hospitalized patients, and adults with hip fractures have been shown to experience a high prevalence of vitamin D insufficiency, presumably due to lack of sunlight exposure (Thomas et al., 1998). Vitamin D levels commonly decline in older adults, and consequently the requirement for vitamin D increases with age. A metaanalysis by Bischoff-Ferrari et al. (2005) found that 700-800 IU/daily vitamin D reduced hip fracture risk in elderly individuals by 25%. These results point out the need for additional calcium supplementation in individuals receiving vitamin D for

70

Osteoporosis

the prevention of hip fractures. In a study designed to extend the findings of BischoffFerrari et al., found that oral vitamin D appears to decrease the risk of hip fractures only when calcium supplementation is added (Boonen, S., et al., 2007.) As with calcium, excessive amounts of vitamin D can be harmful to the skeleton. Vitamin D (400 IU/dose) is found in many calcium supplements and multiple vitamins; vitamin D can be taken in combination with these supplements or as a separate supplement (USDHHS, 2004). Vitamin D is a fat-soluble vitamin that can be stored in the body; therefore, excess vitamin D can be toxic, resulting in hypercalcemia, kidney failure, and calcification of soft tissue (IOM, 1997). As a result, a tolerable upper limit for the dietary intake of vitamin D of 2,000 IU per day has been established by the Institute of Medicine (IOM). Higher doses of vitamin D are required to treat individuals who are vitamin D insufficient (having low levels of vitamin D in the blood) or deficient (having very low levels of vitamin D in the blood). Secondary hyperparathyroidism can result from vitamin D deficiency with normal levels of blood calcium. Osteomalacia or rickets can result from severe cases. The optimal range for 25-OHD(3) is higher than the “normal” ranges established by clinical laboratories, because these ranges come from a population that includes individuals with suboptimal levels. The recommended treatment is vitamin D supplementation of 50,000 IU once a week for up to 3 months with follow-up blood tests of vitamin D, calcium, and PTH levels (Pettifor, 2003). Additional information about recommended requirements and dietary sources of vitamin D is provided in chapter 7.

Mechanism of Action/Kinetics Calcium functions as an antiresorptive agent like the bisphosphonates; however, its mechanism of action is not the same. On the cellular level, calcium is involved in several important processes such as blood clotting, nerve transmission, and muscle contraction. Calcium is also involved in the regulation of the release and storage of neurotransmitters and hormones, in the uptake and binding of amino acids, and in the absorption of vitamin B12 (cyanocobalamin) and gastrin secretion (Hospital Formulary Service [AHFS], 2006). A small amount of the total body calcium is also found in muscles, blood, extracellular fluid, and other tissues, where it plays a part in mediating vascular contraction and vasodilatation, muscular contraction, nerve transmission, and glandular secretion (Hospital Formulary Service [AHFS], 2006). The calcium level in the blood is protected via the PTH–vitamin D axis. Any drop in the blood level of calcium prompts an increase in PTH levels causing short-term bone remodeling, and vitamin D activation can result in an increase in calcium absorption in the gut and calcium resorption in the kidney (Morgan, 2001). Calcium is mobilized from the skeleton to maintain a normal blood calcium level if intake is insufficient. Along with being a substrate for bone mineralization, calcium also exerts an inhibitory effect on bone remodeling through suppression of circulating parathyroid hormone (Physician’s Guide to Prevention, 2003). Consuming adequate levels of calcium and vitamin D throughout life and engaging in appropriate physical activity are essential to bone health (USDHHS, 2004). In addition, calcium neutralizes gastric acidity.

Pharmacological Management

71

The absorption of calcium is from the GI tract by active transport and passive diffusion in the duodenum and proximal jejunum, and to a lesser extent in the more distal portions of the small intestine. Oral bioavailability from calcium supplements depends on intestinal pH, the presence or absence of food, and the dose. Calcium supplements are never completely absorbed from the small intestine. The degree of absorption depends on several factors, including (1) stable, ionized form; (2) acidic intestinal pH for ionization of calcium; (3) vitamin D in its activated form; and (4) estrogen (Hospital Formulary Service [AHFS], 2006). Studies indicate that in adults, only about 30% of calcium intake is actually absorbed by the body (IOM, 1997).) Some calcium is excreted from the body into the intestine, resulting in an even lower net absorption (Heaney & Abrams, 2004). The elderly actually absorb less dietary calcium because their intestines are no longer as responsive to the action of 25OHD(3) (Heaney, Recker, Stegman, & Moy, 1989). Increasing overall calcium intake and maintaining adequate levels of vitamin D can overcome poor absorption of calcium (USDHHS, 2004). Vitamin D is essential for calcium absorption, and recent studies have found that absorption effectiveness increases with improving vitamin D status up to serum 25OHD(3) levels of approximately 80 nmol/L (32 ng/mL) (Heaney, Dowell, Hale, & Bendich, 2003). Many studies report that postmenopausal women tend to have average serum 25-OHD(3) values of 50 to 55 nmol/L (20 to 22 ng/mL) and are consequently not absorbing the calcium they consume with the best efficiency. Osteoporotic fractures are reduced when serum 25-OHD(3) is raised to near 80 nmol/L (Heaney, 2005).

Efficacy Vertebral and Nonvertebral Fractures A study was conducted by the WHI (2006) to determine whether calcium/vitamin D supplements reduce the risk of colorectal cancer and the frequency of hip and other bone fractures in postmenopausal women. A sample of 36,282 postmenopausal women aged 50–79 who were enrolled in the WHI clinical trial was randomized into one of two study groups. One group received 1,000 mg of elemental calcium as calcium carbonate and 400 IU of vitamin D daily; the second group took a placebo for an average period of 7 years. Researchers found that calcium and vitamin D supplementation registered a modest but significant improvement on hip bone density but had no significant effect on the rate of hip fractures. The report indicates that calcium and vitamin D decrease the incidence of hip fracture more in older women than in younger women, which would be expected. Although calcium is usually not thought to be harmful, researchers found a 17% increase in nephrolithiasis in the women using the supplements (Jackson et al., 2006). In 1997, the IOM carried out a major review of the bone-related nutrients and developed evidence-based recommendations for calcium and vitamin D intake. Their purpose was to determine the level of nutrient intake for normal, healthy individuals that would prevent the development of a chronic state of deficiency related to that nutrient. Of the nutrients that affect bone health, calcium has been underscored as a major public health concern today, not only because it is an essential nutrient for bone, but also because national surveys show that individuals’ intake of calcium is significantly below the levels recommended for optimal bone health (USDHHS, 2004). Calcium supplements should

72

Osteoporosis

be taken with meals in divided doses, with only 500 mg of elemental calcium taken at a time, since only a small percentage of the oral calcium supplement is absorbed with higher doses. In addition, vitamin D is necessary for the intestinal absorption of calcium. As the majority of women age, serum concentrations of 25-OHD(3) decrease, requiring vitamin D supplementation (Dawson-Hughes, Harris, Krall, & Dallal, 1997; Grass & Dawson-Hughes, 2006).

Administration and Adverse Events Calcium carbonate (Caltrate) contains 600 mg of calcium and 200 IU of vitamin D per tablet, and is administered one tablet twice daily in divided doses with food. Calcium citrate (Citracal) contains calcium 630 mg per two caplets (315 mg each caplet) and vitamin D 400 IU per two caplets (200 IU each caplet), and is administered one to two caplets twice daily in divided doses with or without food. Calcium is usually well tolerated. Table 5.6 lists the adverse reactions to the two most common calcium formulations, and Table 5.7 presents common drug interactions.

Integrative Therapies In light of the research findings in 2002 from the Writing Group for the Women’s Health Initiative Investigators, alternatives to HT for preventing and treating osteoporosis have received increased attention. Discussed earlier are bioidentical hormones, which are different from phytoestrogens. It is important to mention that although phytoestrogens have actions similar to those of estrogen, they are not true estrogens as produced by the human body. Bioidentical hormones are also derived from plants, but they have the same chemical structure as the body’s natural hormones after conversion to the human form by chemical synthesis carried out in the laboratory, and they require a prescription by a licensed provider. Recently, phytoestrogens (promoted as “natural” estrogen-like products) have been gaining popularity, due to the health benefits they claim to offer, and because of their wide range of availability in both foods and supplements. Phytoestrogens are naturally occurring plant compounds that have properties similar to those of estradiol (National Institutes of Health [NIH], 2005). Phytoestrogens are made up of more than 20 compounds and can be found in more than 300 plants such as fruits, herbs, and grains. However, phytoestrogens are not stored in the body, can be easily broken down

Table

Dietary Sources of Phytoestrogens

5.8

Isoflavones (genistein, daidzein, glycitein, and equol) Lignans (enterolactone and enterodiol)

Coumestans (coumestrol)

Primarily found in soy beans and soy products, chickpeas, and other legumes Found in oilseeds (primarily flaxseed), cereal bran, legumes, and alcohol (beer and bourbon) Found in alfalfa and clover

Note. From National Institutes of Health Osteoporosis and Related Bone Diseases National Resource Center, 2005.

Pharmacological Management

73

and eliminated, and have weaker effects than most estrogens. Isoflavones, lignans, and coumestans make up the three main classes of dietary phytoestrogens. Dietary sources of phytoestrogens are listed in Table 5.8. The majority of food sources containing these compounds usually include more than one class of phytoestrogens (NIH, 2005b). Observational studies have discovered a lower prevalence of hip fracture, breast cancer, and heart disease rates among people living in places like Southeast Asia, where diets traditionally are high in phytoestrogens. Much interest has been generated in the United States regarding the health benefits of phytoestrogens as a result of these studies. A great deal of the evidence related to the potential role of phytoestrogens in bone health is based on animal studies. Actually, soybean protein, soy isoflavones, genistein, daidzein, and coumestrol have all been shown to have a protective effect on bone in animals whose ovaries had been surgically removed. However, the evidence is conflicting in humans. Studies demonstrate that persons who live in Hong Kong, China, and Japan, where dietary phytoestrogen intakes are high, experience lower rates of hip fracture when compared to White populations. A number of studies have examined the effects of soy isoflavones on bone health; however, the results have been mixed, ranging from a modest effect to no effect. It is difficult to fully evaluate the impact of these compounds on bone health, since most of these studies have serious limitations, including short duration and small sample size (NIH, 2005b). In postmenopausal women, ipriflavone, a synthetic isoflavone, has shown some promise in its ability to preserve bone. However, a 3-year study of over 400 postmenopausal women found that ipriflavone did not prevent bone loss. According to some studies, phytoestrogens, unlike estrogen, do not appear to increase the risk of breast or uterine cancer. This finding suggests that they may function more like SERMs such as raloxifene and tamoxifen than as actual estrogens. Conversely, other studies show that high isoflavone levels have been linked to an increased risk of breast cancer. Currently, the NIH is supporting research looking at the safety of phytoestrogens and their potential role in the skeletal health of postmenopausal women (NIH, 2005b). A 1-year, placebo-controlled, randomized trial examined the effect of isoflavoneenriched soy extracts on bone loss in 203 Chinese postmenopausal women within the first 10 years postmenopause. Researchers found a mild, but statistically significant, effect of daily supplementation of soy-derived isoflavones in attenuating bone mineral content (BMC) loss at the trochanter, intertrochanter, and total hip (Chen, Ho, Lam, Ho, & Woo, 2003). Since currently available evidence concerning phytoestrogens is contradictory and incomplete, additional studies are needed to further evaluate the safety and effects of phytoestrogens (NIH, 2005b).

Pain Management Pain has been reported in up to 62% of female patients with osteoporosis (Roberto, 2004). There are various pain origins for osteoporosis, including concurrent degenerative disk disease, osteoarthritis, and vertebral fracture. Before introducing measures for pain management, patients’ pain should be evaluated for a drug-induced cause as opposed to a physiologic cause. Bisphosphonates are the agent of choice for most individuals with osteoporosis, though as many as 26% of patients taking these agents experience some sort of back or bone pain (Merck & Co., 2006; Procter & Gamble Pharmaceuticals, 2006;

74

Table

5.9

Osteoporosis

Pain Management of Osteoporosis Agent Nonaspirin analgesic Acetaminophen

Daily dosing regimen

Maximum daily dose

500 mg every 4 hours as needed 1,000 mg every 6 hours as needed

4 grams daily

Nonsteroidal antiinflammatory drugs (NSAIDs) Ibuprofen 400 mg every 4 hours as needed Naproxen 500 mg every 12 hours Indomethacin 25 to 50 mg three times daily 75 mg (extended release) once to twice daily Opioid combinations Hydrocodone/APAP One 5/500 mg tablet every 4 hours as needed NOTE: There are varying dose combinations of hydrocodone/ APAP, and each should be evaluated for a maximum dose based on the daily maximum acetaminophen use. Hydrocodone/ibuprofen One 5/200 mg tablet every 4 hours as needed Oxycodone/APAP One 5/325 mg tablet every 4 hours as needed NOTE: There are varying dose combinations of oxycodone/ APAP, and each should be evaluated for a maximum dose based on the daily maximum acetaminophen use. Opiate analgesics Morphine Starting 15 mg every 12 hours scheduled Oxycodone Starting 10 mg every 12 hours scheduled Fentanyl Starting 25 mcg/hr every 72 hours in opiate-naïve patients

3,200 mg daily 1,500 mg daily 200 mg daily

Eight 5/500 tablets daily

Five 7.5/200 tablets daily 12 tablets daily

Patient tolerance Patient tolerance Patient tolerance

Note. Adapted from Thomson Micromedex, 2006.

Roche Laboratories Inc., 2006). If the bisphosphonate is the suspected cause of the pain, discontinuing it and evaluating for resolution of pain should be considered. If a patient’s pain does not subside, then analgesic and anti-inflammatory therapy may be warranted. Outside of oral and nonpharmacologic measures, surgical vertebroplasty or kyphoplasty procedures may also be considered, as outlined in this chapter (also see chapter 6).

75

Pharmacological Management

Table

International Names for Fosamax®

5.10

Brand name

Aldrox Alenato Alend Alnax Alovell Arendal Armol Bifemelan Bifosa Bonapex Defixal Endronax Eucalen Fixopan Fosalan Fosamax®

Fosmin Fosval Marvil MaxiBone MaxiBone 70 Neobon Osdron Osdronat Oseotenk Osficar Oslene Osteofar Osteofos Osteopor Osteosan Osteovan Osticalcin Porosal Tibolene Voroste

Country where approved for use

Chile Argentina Korea Paraguay Indonesia Peru Colombia Colombia India Egypt Costa Rica, Dominican Republic, El Salvador, Guatemala, Nicaragua, Panama Brazil Colombia Ecuador Israel United States, Argentina, Austria, Belgium, Brazil, Bulgaria, Canada, Chile, Costa Rica, Czech Republic, Denmark, Ecuador, Egypt, El Salvador, England, France, Germany, Guatemala, Honduras, Hong Kong, Hungary, Indonesia, Ireland, Italy, Korea, Malaysia, Mexico, Netherlands, Nicaragua, Norway, Panama, Peru, Philippines, Poland, Singapore, South Africa, Spain, Sweden, Switzerland, Taiwan, Thailand Peru Paraguay Peru, Paraguey Israel Israel Colombia Brazil Colombia Argentina Colombia Indonesia Indonesia Hong Kong Uruguay Chile Costa Rica Colombia Venezuela Colombia Indonesia Indonesia

Note. From Mosby’s Drug Consult, 16th ed., 2006 (St. Louis, MO: Mosby).

76

Osteoporosis

Analgesics and Nonsteroidal Anti-inflammatory Drugs (NSAIDs) Analgesics and nonsteroidal anti-inflammatory drugs (NSAIDs) have an important role in the treatment of pain associated with osteoporosis. However, these agents should be used cautiously in the postmenopausal (older) osteoporotic population. Patients using analgesics and NSAIDs regularly, or in higher than needed doses, may be more likely to develop gastrointestinal ulcers, renal insufficiency, or hepatotoxicity, or worsen cardiovascular status secondary to overuse. Table 5.9 lists available NSAIDs and analgesics for managing pain in patients with osteoporosis. Combination opioids (opiate plus NSAID or acetaminophen) may be considered in patients who do not respond to simple analgesics. These agents are beneficial in pain management but provide a potential for overuse of analgesic medication. In cases where patients require large doses of combination opioids to control osteoporotic pain, a switch to opioid alone should be considered. Patients will still receive the analgesic effect, but without the increased risk for gastrointestinal bleeding and other adverse side effects. Caution should be used, though, as some research suggests that patients using opioid analgesics may be at a higher risk for vertebral fractures, potentially secondary to falls related to opioids use (Vestergaard, Rejnmark, & Mosekilde, 2006). Patients should be continually assessed for fall risks as well, and for increased need for pain control and titration of maintenance medication.

Vertebroplasty and Kyphoplasty Vertebroplasty Recommendations from the National Osteoporosis Foundation (NOF) state that vertebroplasty should be reserved for those patients unable to achieve adequate pain control, after vertebral fracture, on traditional pharmacologic and nonpharmacologic therapies (Bonner et al., 2003). Emerging data regarding the use of vertebroplasty shows an initial benefit, especially in patients with pain due to a vertebral fracture, but long-term outcome data are still awaited (Muto, 2005).

Kyphoplasty The recommendations for vertebroplasty are generally applicable to kyphoplasty. Currently, there are no head-to-head trials for kyphoplasty in pain management versus vertebroplasty or medicinal therapies. Researchers state that this interventional therapy could lend to decreased hospital stays after a vertebral fracture as well, and more immediate pain relief in the patient (Masala, Fiori, Massari, & Simonetti, 2005). Further discussion of vertebroplasty and kyphoplasty is provided in chapter 6.

Conclusion The research supports proper nutrition and lifestyle as having a positive effect on bone health and shows that pharmacotherapy along with these can slow the rate of bone loss

Pharmacological Management

77

and also build new bone (USDHHS, 2004). The most thoroughly researched pharmaceutical treatments currently available for the prevention and treatment of osteoporosis are the bisphosphonates: alendronate, (Fosamax®), risedronate (Actonel®), and ibandronate (Boniva®). In planning intervention strategies, one needs to consider the unique features of each person, taking into account dosing and fracture risk. Table 5.10 lists the international brand names for Fosamax® where the drug is approved for use in various countries.

REFERENCES Ahlgrimm, M., & Kells, J. M. (2003). The HRT solution: Optimizing your hormonal potential. New York: Avery. Anderson, G. L., Limacher, M., Assaf, A. R., Bassford, T., Beresford, S. A., Black, H., et al. (2004). Women’s Health Initiative Steering Committee. Effects of conjugated equine estrogen in postmenopausal women with hysterectomy: The Women’s Health Initiative randomized controlled trial. Journal of the American Medical Association, 291(14), 1701–7012. Bischoff-Ferrari, H. A., Willett, W. C., Wong, J. B., Giovannucci, E., Dietrich, T., Dawson-Hughes, B. (2005). Fracture prevention with vitamin D supplementation: a meta-analysis of randomized controlled trials. Journal of the American Medical Association, 293, 2257–2264. Black, D. M., Bilezikian, J. P., Ensrud, K. E., Greenspan, S. L., Palermo, L., Hue, T., et al. (2005). One year of alendronate after one year of parathyroid hormone (1–84) for osteoporosis. New England Journal of Medicine, 353, 555–565. Black, D. M., Cummings, S. R., Karpf, D. B., Cauley, J. A., Thompson, D. E., Nevitt, M. C., et al. (1996). Randomised trial of effect of alendronate on risk of fracture in women with existing vertebral fractures. Fracture Intervention Trial Research Group. Lancet, 348, 1535–1541. Black, D. M., Delmas, P. D., Eastell R., Reid, I. R., Boonen, S., Cauley, J. A., et al. (2007). Once Yearly Zoledronic Acid for the Treatment of Postmenopausal Osteoporosis. HORIZON Pivotal Fracture Trial. New England Journal of Medicine, 356, 1809–1822. Bone, H. G., Greenspan, S. L., McKeever, C., Bell, N., Davidson, M., Downs, R. W., et al. (2000). Alendronate and estrogen effects in postmenopausal women with low bone mineral density. Alendronate/Estrogen Study Group. Journal of Clinical Endocrinology and Metabolism, 85(2), 720–726. Black, D. M., Schwartz, A.V., Esrund, K. E., Cauley, J. A. Levis, S., Quandt, S. A., et al. (2006). Effects of Continuing or Stopping Alendronate After 5 Years. The Fracture Intervention Trial Long Term Extension. Journal of the American Medical Associate, 296, 2927 – 2938. Bone, H. G., Hosking, D., Devogelaer, J. P., Tucci, J. R., Emkey, R. D., Tonino, R. P., et al. (2004). Ten years’ experience with alendronate for osteoporosis in postmenopausal women. New England Journal of Medicine, 350, 1189–1199. Bonner, F. J., Jr., Sinaki, M., Grabois, M., Shipp, K. M., Lane, J. M., Lindsay, R., et al. (2003). Health professional’s guide to rehabilitation of the patient with osteoporosis. Osteoporosis International, 14(Suppl 2), S1–22. Boonen, S., Lips, P., Bouillon, R., Bischoff-Ferrari, H. A., Vanderschueren, D. and Haentjens. P. (2007). Need for Additional Calcium to Reduce the Risk of Hip Fracture with Vitamin D Supplementation: Evidence from a Comparative Metaanalysis of Randomized Controlled Trials. Journal of Clinical Endocrinology and Metabolism 92, 1415–1423. Brown, J. P., Kendler, D. L., McClung, M. R., Emkey, R. D., Adachi, J. D., Bolognese, M. A., et al. (2002). The efficacy and tolerability of risedronate once a week for the treatment of postmenopausal osteoporosis. Calcified Tissue International, 71, 103–111. Cauley, J. A., Robbins, J., Chen, Z., Cummings, S. R., Jackson, R. D., LaCroix, A. Z., et al. (2003), Women’s Health Initiative Investigators. Effects of estrogen plus progestin on risk of fracture and bone mineral density: The Women’s Health Initiative randomized trial. Journal of the American Medical Association, 290(13), 1729–1738. Cauley, J. A., Seeley, D. G., Ensrud, K., Ettinger, B., Black, D., & Cummings, S. R. (1995). Estrogen replacement therapy and fractures in older women. Study of osteoporotic fractures research group. Annals of Internal Medicine, 122(1), 9–16.

78

Osteoporosis Chen, Y. M., Ho, S. C., Lam, S. S., Ho, S. S., & Woo, J. L. (2003). Soy isoflavones have a favorable effect on bone loss in Chinese postmenopausal women with lower bone mass: A double-blind, randomized, controlled trial. Journal of Clinical Endocrinology and Metabolism, 88(10), 4740–4747. Chesnut, C. H., III, Silverman, S., Andriano, K., Genant, H., Gimona, A., Harris, S., et al. (2000). A randomized trial of nasal spray salmon calcitonin in postmenopausal women with established osteoporosis: The prevent recurrence of osteoporotic fractures study. PROOF Study Group. American Journal of Medicine, 109, 267–276. Chesnut, C. H., III, Skag, A., Christiansen, C., Recker, R., Stakkestad, J. A., Hoiseth, A., et al. (2004). Effects of oral ibandronate administered daily or intermittently on fracture risk in postmenopausal osteoporosis. Journal of Bone and Mineral Research, 19, 1241–1249. Colón-Emeric, C. S. (2006). Ten vs Five Years of Bisphosphonate Treatment for Postmenopausal Osteoporosis. Journal of the American Medical Association, 296, 2968 – 2869. Crandall, C. (2001). Risedronate: A Clinical Review. Archives of Internal Medicine, 161, 353–360. Cranney, A., Tugwell, P., Zytaruk, N., Robinson, V., Weaver, B., & Adachi, J. (2002). Osteoporosis Methodology Group and the Osteoporosis Research Advisory Group. Meta-analyses of therapies for postmenopausal osteoporosis. IV. Meta-analysis of raloxifene for the prevention and treatment of postmenopausal osteoporosis. Endocrine Review, 4, 524–528. Cummings, S. R., Black, D. M., Thompson, D. E., Applegate, W. B., Barrett-Connor, E., Musliner, T. A., et al. (1998). Effect of alendronate on risk of fracture in women with low bone density but without vertebral fractures: Results from the Fracture Intervention Trial. Journal of the American Medical Association, 280, 2077–2082. Dawson-Hughes, B., Harris, S. S., Krall, E. A., & Dallal, G. E. (1997). Effect of calcium and vitamin D supplementation on bone density in men and women 65 years of age or older. New England Journal of Medicine, 337, 670–676. Deal, C. L. (2002). Risedronate prevents hip fractures, but who should get therapy? Cleveland Clinic Journal of Medicine, 69, 964, 968–6. Deal, C., Omizo, M., Schwartz, E. N., Eriksen, E. F., Cantor, P., Wang, J., et al. (2005). Combination teriparatide and raloxifene therapy for postmenopausal osteoporosis: Results from a 6-month double-blind placebo-controlled trial. Journal of Bone and Mineral Research, 20, 1905–1911. Delmas, P. D., Ensrud, K. E., Adachi, J. D., Harper, K. D., Sarkar, S., Gennari, C., et al. (2002). Multiple outcomes of raloxifene evaluation investigators. Efficacy of raloxifene on vertebral fracture risk reduction in postmenopausal women with osteoporosis: Four-year results from a randomized clinical trial. Journal of Clinical Endocrinology and Metabolism, 87(8), 3609–3617. Downs, R. W., Jr., Bell, N. H., Ettinger, M. P., Walsh, B. W., Favus, M. J., Mako, B., et al. (2000). Comparison of alendronate and intranasal calcitonin for treatment of osteoporosis in postmenopausal women. Journal of Clinical Endocrinology and Metabolism, 85, 1783–1788. Dursun, N., Dursun, E., & Yalcin, S. (2001). Comparison of alendronate, calcitonin and calcium treatments in postmenopausal osteoporosis. International Journal of Clinical Practice, 55, 505–509. Eli Lilly & Company. (2004). Forteo package insert. Pamphlet. Ettinger, B., Black, D. M., Mitlak, B. H., Knickerbocker, R. K., Nickelsen, T., Genant, H., et al. (1999). Reduction of vertebral fracture risk in postmenopausal women with osteoporosis treated with raloxifene: Results from a 3-year randomized clinical trial. Multiple outcomes of raloxifene evaluation (MORE) investigators. Journal of the American Medical Association, 282(7), 637–645. Ettinger, B., Pressman, A., & Silver, P. (1999). Effect of age on reasons for initiation and discontinuation of hormone therapy. Menopause, 6, 282–289. Ettinger, B., San, M. J., Crans, G., & Pavo, I. (2004). Differential effects of teriparatide on BMD after treatment with raloxifene or alendronate. Journal of Bone and Mineral Research, 19, 745–751. Eviö, S., Tiitinen, A., Laitinen, K. Ylikorkala, O., & Välimäki, M. J. (2004). Effects of alendronate and hormone replacement therapy, alone and in combination, on bone mass and markers of bone turnover in elderly women with osteoporosis. Journal of Clinical Endocrinology and Metabolism, 9(2), 626–631. Retrieved June 6, 2006, from http://home.mdconsult.com/das/journal/ view/60741976_2/N/14417862?sid=501437962&source=MI&SEQNO=1 Felsenberg, D., Miller, P., Armbrecht, G., Wilson, K., Schimmer, R. C., & Papapoulos, S. E. (2005). Oral ibandronate significantly reduces the risk of vertebral fractures of greater severity after 1, 2, and 3 years in postmenopausal women with osteoporosis. Bone, 37, 651–654. Finkelstein, J. S., Hayes, A., Hunzelman, J. L., Wyland, J. J., Lee, H., & Neer, R. M. (2003). The effects of parathyroid hormone, alendronate, or both in men with osteoporosis. New England Journal of Medicine, 349, 1216–1226.

Pharmacological Management

79

Follin, S. L., & Hansen, L. B. (2003). Current approaches to the prevention and treatment of postmenopausal osteoporosis. American Journal of Health-System Pharmacy, 60(9), 883, 901. Retrieved June 6, 2006, from http://www.medscape.com/viewarticle/453035 Friedman, P. A. (2006). Agents affecting mineral ion homeostasis and bone turnover. In L. L. Brunton, J. S. Lazo, & K. L. Parker (Eds.), The pharmacological basis of therapeutics (11th ed., pp. 1647– 1678). New York: McGraw-Hill Medical Publishing Division. Gallagher, J. C., Genant, H. K., Crans, G. G., Vargas, S. J., & Krege, J. H. (2005). Teriparatide reduces the fracture risk associated with increasing number and severity of osteoporotic fractures. Journal of Clinical Endocrinology and Metabolism, 90, 1583–1587. Grass, M., & Dawson-Hughes, B. (2006). Preventing osteoporosis-related fractures: An overview. American Journal of Medicine 119, S3–S11. Retrieved June 6, 2006, from http://home.mdconsult. com/das/journal/view/59590408–2/N/16114469?sid=491704938&source=MI&SEQNO=2 Greenspan, S. L., Resnick, N. M., & Parker, R. A. (2003). Combination therapy with hormone replacement and alendronate for prevention of bone loss in elderly women: A randomized controlled trial. Journal of the American Medical Association, 289(19), 2525–2533. Gulli, L. (2002). Hormone replacement therapy. In Jacqueline L. Longe (Ed.), Gale Encyclopedia of Medicine (Vol. 3, 2nd ed., pp. 1668–1673). Detroit: Gale. Retrieved June 6, 2006, from Gale Virtual Reference Library via Thomson Gale: 70 yrs.

Calcium (mg/day) 500 800 1300 1000 1200 1200

Vitamin D (μg/day [IU]) 5 (200) 5 (200) 5 (200) 5 (200) 10 (400) 15 (600)

Note. From Institute of Medicine, 1997.

Average calcium intake from food in the United States is approximately: 900 mg for adolescents 700 mg for adults 60 years and older Source: Ervin, Wang, Wright, & Kennedy-Stephenson, 2004. Average vitamin D intake from food in the United States is approximately as follows: 6–7 IU for children and adolescents 5.5–6 IU for men 19 years or older 4–4.5 IU for women 19 years and older Source: Moore et al., 2004.

106

Osteoporosis

Most people in the United States consume far less calcium than the recommended amounts. This is particularly true for adolescents and older adults, two age groups with high recommended intakes (Ervin, Wang, Wright, & Kennedy-Stephenson, 2004). Women generally consume lower energy diets than men and are more likely to be well below the recommended calcium intakes. People with poor appetites and those who reduce energy intake to achieve weight loss are at particular risk of inadequate calcium intake.

The Calcium Paradox Recommended intakes for calcium set for the United States and Canada are higher (Institute of Medicine, 1997) than recommendations in other countries (Stear, 2000). However, people in some geographical areas with low calcium intakes, such as Japan, have a low incidence of osteoporotic fractures. In contrast, some populations such as those in Scandinavian countries, where average calcium intakes are high, have a high incidence of osteoporosis. There are many possible explanations for this apparent paradox: Life expectancies—the longer life expectancies of people in developed countries may lead to a greater risk of osteoporosis; Differential reporting—osteoporosis rates may simply be underrepresented in some areas; Genetic differences; Physical activity patterns; Bone architecture; and Other dietary factors—calcium intake alone is not the only nutritional factor associated with bone health.

Food Sources of Calcium Calcium is found in varying amounts in a wide range of foods (Table 7.2). Dairy products generally contribute about half of the calcium to American diets (Moore, Murphy, Keast, & Holick, 2004; Weaver, 2001). Calcium in milk is readily absorbed because milk is fortified with vitamin D, which facilitates calcium absorption. Lower fat milks contain more calcium than regular milk because some nonfat milk products are added to replace the fat. Cottage cheese has traditionally been considered a relatively poor dairy source of calcium because calcium is lost during production. However, some cottage cheese products are fortified with calcium. Canned salmon with bones, sardines, and mackerel are excellent sources of calcium. There are good sources of calcium in some vegetables, such as kale and Chinese cabbage, with lesser amounts in broccoli, green beans, and acorn squash. Spinach is a good source but contains oxalic acid, which binds the calcium in spinach and interferes with its absorption. Phytic acid in dried peas and beans can also decrease calcium absorption.

107

Diet and Bone Health

Table

Approximate Amount of Calcium in Food

7.2

Amount

Nonfat milk Whole milk Milk, Ca fortified Yogurt Dry skim milk Cheddar, other hard cheeses Parmesan, grated Ice cream Cottage cheese Cottage cheese, Ca fortified

Calcium (mg)

Amount Nondairy ½ c. ½ c. ½ c. ½ c. ½ c. ½ c.

Calcium (mg)

Dairy 1 c. 1 c. 1 c. 1 c. ¼ c. 1 oz

415 315 500 300 210 150

Sardines, canned Salmon, canned Mackerel, canned Chinese cabbage Kale, cooked Broccoli

2 T. ½ c. ½ c. ½ c.

150 85 70 200

Beans, lima, kidney, navy Baked beans Orange Orange juice, Ca fortified

½ c. ½ c. 1 ½ c.

40 75 50 140

Almonds, blanched Tofu, firm processed with Ca Cereal, super-fortified Oatmeal, instant

1 oz ¼ c.

25 65

½ c. 1 pkg.

90 240 240 80 90 50

170 165

Note. For nutrient values in foods, refer to the U.S. Department of Agriculture’s Nutrient Database (2006), retrieved August 16, 2006 from http://www.nal.usda.gov/fnic/cgi-bin/nut_search.pl

As more and more calcium-fortified foods are produced, the number of good calcium sources increases. Currently, some manufacturers produce calcium-fortified rice, prune juice, pasta, waffles, and other foods.

Vitamin D Evidence is increasing for the many health benefits of vitamin D. Vitamin D deficiency increases the risk of some cancers, type 1 diabetes, cardiovascular disease, and autoimmune diseases, as well as osteoporosis (Calvo, Whiting, & Barton, 2005; Holick, 2004). While there is ongoing discussion about the recommended daily requirement for vitamin D, the Institute of Medicine (1997) recommends 5 micrograms (µg/day) for children and adults through 50 years of age, 10 µg for adults 51–70 years of age, and 15 µg for adults over 70 years of age (Table 7.1). Vitamin D is critical for bone health. It is necessary for the adequate absorption of both calcium and phosphorus, the bone-hardening minerals (Holick, 2004). Vitamin D has other functions that are essential for maintaining blood calcium levels and for bone health. It can act with bone-cell-building components to support bone status (Heaney, R. R., Carey, & Harkness, 2005). Vitamin D and calcium act as a team and function most effectively when the appropriate dose of vitamin D is coupled with calcium.

108

Osteoporosis

Vitamin D is a fat-soluble vitamin that is deposited in body fat stores. Many obese persons are vitamin D–deficient because the vitamin is held in the large body fat pool and is not available for metabolic activity.

Sources of Vitamin D Sunlight Vitamin D is not, in the true sense of the word, a vitamin; that is, it does not need to be supplied by dietary sources. It exists in the epidermis layer of the skin as a previtamin, which is converted to vitamin D(3) upon exposure to light (Holick, 2004). In northern latitudes, during the summer months, 10 to 15 minutes of sun exposure two or three times per week should be sufficient to ensure adequate production of vitamin D in children and young adults. The amount of vitamin D produced in the skin is affected by several factors including skin pigmentation, distance from the equator, use of sunscreens, and age (Heaney R. R., et al., 2005). Older adults produce less vitamin D than young adults exposed to the same amount of sunlight. Furthermore, older adults often spend less time outdoors and thus have less exposure to sunlight than children and young adults. Nursing home residents are at particular risk of vitamin D deficiency (Kinyamu, Gallagher, Balhorn, & Petranick, 1997). Additionally, fear of skin cancer may cause older adults to be particularly conscientious about applying sunscreen, which hinders vitamin D production. Sunscreen with a sun protection factor (SPF) of 8 or above almost completely blocks the production of vitamin D.

Diet Vitamin D can be obtained from food sources but is not widely present in the food supply. The major natural sources are some fatty fish (see Table 7.3) and fish oils. While

Table

7.3

*

Approximate Amount of Vitamin D in Food Food Milk, all types Salmon Sardines Tuna Cod liver oil Cereal + D Orange juice + D Egg

Amount 1 c. (8 oz) 3 oz 3 oz 3 oz 1 tsp 1 c. 6 oz 1 whole

40 International Units (IU) = 1 microgram (µg).

Vitamin D (IU*) 100 425 425 200 450 40 75 20

Diet and Bone Health

109

other animal foods, such as milk, eggs, and butter, contain some vitamin D, it is generally difficult to get the recommended amounts from unfortified foods. Some countries have mandatory fortification of milk. In the United States and Canada, milk is the only food that is routinely fortified with vitamin D. About half of the vitamin D intake from food is from dairy products. Most milk sold in North America is fortified to provide 100 IU per 8 ounces. Other products, such as breakfast cereals and orange juice, may also be vitamin D fortified.

Recommended Vitamin D Intakes The recommended intakes for vitamin D in the United States and Canada are shown in Table 7.1. The recommendations are expressed in two units: micrograms µg and IU. The higher recommendations for adults 50 to 70 years and for those 71 years or older are based on information about sunlight exposure, metabolism of vitamin D, and risk of skeletal fractures (Institute of Medicine, 1997). Higher vitamin D doses in combination with calcium have been shown to reduce fracture risk (Chapuy et al., 1992). Many teenagers and adults fail to consume adequate amounts of vitamin D from food. Less than 10% of adults 51 to 70 years old and 2% of those 71 years or older met the recommended intakes from food alone. Females, both teenagers and adults, reported the lowest vitamin D intakes in the Third National Health and Nutrition Examination Survey, 1994–1996 (Moore et al., 2004).

How Much Calcium and Vitamin D Is Available in Foods and Supplements? The amount of calcium and vitamin D is shown on the “Nutrition Facts” label for foods and the “Supplement Facts” label for supplements. However, interpreting the labels requires some information that is not on the label. The calcium content is listed as a percentage of daily value (DV). The DV for calcium is currently set at 1,000 mg; the DV for vitamin D is currently set at 400 IU. For example, a food product that provides 15% DV for calcium would contain 150 mg of calcium. A product that provides 25% DV for vitamin D would contain 100 IU of vitamin D.

Is It Possible to Consume Too Much Calcium and Vitamin D? Both calcium and vitamin D can cause health risks when consumed in very high amounts. The Institute of Medicine of the National Academy of Science (Institute of Medicine,

110

Osteoporosis

1997) recently set upper limits (ULs) for both calcium and vitamin D for persons 1 year old and older: UL for calcium = 2,500 mg/day; UL for vitamin D = 50 µg (2,000 IU)/day. The potential risks of a high calcium intake are decreased absorption of other minerals, such as iron and zinc, that can compete for absorption sites with calcium, and the formation of kidney stones. The potential risk of an excessive vitamin D intake is damage to target tissues such as those of the central nervous system, which can result in severe depression, nausea, and anorexia. It is unlikely that people would consume toxic levels of calcium and vitamin D from traditional food sources. However, with the increasing availability of supplements and fortified foods, it may be important to monitor intakes of these nutrients.

Total Diet Energy intake, many nutrients, and other dietary components can affect bone health. Several excellent reviews of total diet needs and bone health have been published (Dowd, 2001; Ilich & Kerstetter, 2000; Tucker, 2003). A few of the many dietary components that influence bone health are presented here.

Energy Very low energy intakes and low body weight are associated with higher osteoporotic risk. The 2004 surgeon general’s report on bone health reviewed studies reporting that very low body weight may limit peak bone mass. Low body weight and weight loss in older women are associated with reduced bone mass and increased fracture risk (U.S. Department of Health and Human Services [USDHHS], 2004). Persons with reduced appetites and those who diet frequently or have eating disorders are at risk for impaired bone health.

Protein Protein plays a paradoxical role in bone health. Both low and high protein intakes may have a detrimental effect on bone status (Kerstetter, O’Brien, & Insogna, 2003). Several epidemiological studies show that individuals with low-protein diets have lower bone mineral densities and greater losses in bone density. An increased risk of hip fracture has been reported for women consuming the lowest amounts of protein. Protein may function in several ways to reduce fracture risk. Protein deficiency alters muscle function as well as impairing bone health (Rizzoli, Ammann, Chevalley, & Bonjour, 2001). Hip fracture patients provided with protein supplements show improved clinical outcomes. Concern about high protein intakes comes from many studies, carried out over many years, that show that urinary calcium excretion increases as protein intake increases (Heaney, R. P., 1993), leading to inadequate calcium retention. There is no simple answer to the question, “Does high protein intake adversely affect bone?” It really does depend on the amount of calcium consumed and other dietary components that can buffer some of the consequences of a high protein diet. Meat, fish, and cheese produce high potential

111

Diet and Bone Health

renal acid loads (Tucker, 2003). However, vegetables, fruits, milk, and yogurts produce renal alkaline loads that buffer renal acid loads and promote calcium retention. This is one of many arguments for a varied diet with adequate servings from each of the food groups.

Other Nutrients Many nutrients are involved in bone health. Bone tissue is complex and dynamic with various hormones and enzymes regulating its metabolism. Therefore, it is not surprising that there are many possible roles for nutrients. Generally nutrients act in one of the following ways: Direct effect on bone structure and metabolism Effect on calcium absorption, metabolism, excretion Some nutrients directly affect bone structure (i.e., mineral matrix, collagen, and bone metabolism). These include phosphorus, zinc, magnesium, iron, vitamin K, vitamin B12, vitamin A, and fatty acids. Nutrients function indirectly in many ways to affect calcium status. Some, such as magnesium, potassium, and phytoestrogens, contribute to an alkaline environment promoting urinary calcium retention. Phytoestrogens are compounds that mimic the action of estrogen. They occur in many plant products, including cereals, seeds, vegetables, legumes, nuts, and fruits. Soy isoflavones are phytoestrogens that have been studied as potential adjuncts to or replacements for hormone replacement therapy. Higher intakes of soy isoflavones have been associated with increased bone mineral density and decreased bone loss. Relatively high doses (i.e., the consumption of several soy-containing foods per day) may be necessary to achieve bone effects (Setchell, 1998).

Caffeine High caffeine consumption has been suggested as a risk factor for osteoporosis. Various physiological mechanisms have been proposed to account for the risk. Unfortunately, studies of caffeine consumption as a potential risk factor have been contradictory. Overall, the evidence suggests that a daily caffeine intake equivalent to about two to three servings of brewed coffee may increase bone loss, particularly among postmenopausal women with low calcium intakes (Harris & Dawson-Hughes, 1994).

Alcohol A moderate alcohol intake appears to be positively associated with bone mineral density. There are likely several explanations for the protective effects, including the presence of antioxidants and other compounds in alcoholic drinks. However, heavy drinkers are at risk for bone loss and fractures. Poor nutrition, malabsorption of nutrients, and a direct “attack” on the bone-forming osteoblasts may contribute to bone loss. The North American Menopause Society (2002) recommends that postmenopausal women should not drink more than seven drinks a week (a drink is one beer, 4 oz of wine, or 1 oz of liquor).

112

Osteoporosis

Nutritional Recommendations Diet Some years ago, Heaney published a paper entitled “Food: What a Surprise!” (Heaney, R. P. 1996), which described how a diet with an appropriate energy intake and a variety of foods can provide nutrients for bone health. Key foods in the diet are low-fat dairy products and fruits and vegetables. Dairy products are the major source of calcium in Western diets. Milk provides a good source of many nutrients. Diets low in dairy products are often low in many nutrients. Per capita consumption of milk has declined in the past 25 years. Many people prefer the taste of other beverages to that of milk or choose noncaloric beverages for weight control. Lactose intolerance is a major reason why many people avoid dairy products. Lactose intolerance occurs in people who have insufficient levels of the intestinal enzyme lactase to break down lactose, the principal carbohydrate in milk. Lactose that is not well digested can undergo microbial fermentation. The consequent gastrointestinal symptoms (i.e., bloating, cramps, pain, and diarrhea) may be mild or severe. Many people who have symptoms of lactose intolerance can tolerate small amounts of dairy products without experiencing gastrointestinal discomfort ( Jarvis & Miller, 2002). Solid products, such as cheese, may be better tolerated because of delayed gastric emptying time. Yogurts with active cultures and hard cheeses have lower lactose contents. Drinking milk with other foods or adding chocolate to milk may also improve lactose tolerance. Lactose-reduced milks are also available but are more expensive than regular milk. A number of studies have demonstrated an association between fruit and vegetable intake and bone health (New, 2004; Prynne et al., 2006). Fruits and vegetables contain many nutrients and phytochemicals that contribute to bone health. They also reduce the acid load and increase an alkaline environment, thereby reducing urinary calcium excretion. Studies are underway to assess the role of fruits and vegetables on bone health. Encouraging an increased intake of fruits and vegetables is likely to have many health-related benefits (Lanham-New, 2006).

Supplements Calcium and vitamin D are available as single nutrient supplements, as components of multinutrient supplements, or as calcium plus vitamin D supplements, with or without other nutrients (e.g., vitamin K, phosphate).

Calcium supplements are not a sole alternative to food sources that also provide other nutrients.

Calcium supplements are available as a number of salt forms, which can differ in their elemental calcium content (ranging from 200 to 600 mg calcium) as well as their

Diet and Bone Health

113

solubility and cost (Kass-Wolff, 2004). The most common and generally least expensive form of calcium is calcium carbonate. Calcium carbonate contains the highest amount of calcium per tablet of any salt. Calcium carbonate supplements are best taken with meals to increase calcium absorption in an acid environment. Calcium citrate supplements have less calcium but may be better for older people with reduced stomach acidity (i.e., achlorhydia). They are also recommended for patients taking acid blockers. All calcium supplements should be taken in several small doses throughout the day for the most efficient calcium absorption. To maximize absorption, doses of less than 500 mg at a time are recommended. Some people complain that calcium supplements cause gas, constipation, bloating, or gastric irritation. Physicians may recommend trying another type of supplement to relieve the symptoms. Adequate fluid and fiber intake may help to alleviate symptoms. Vitamin D supplements also vary in doses from 100 to 400 IU. Supplements provide an added 2 to 3 µg (approximately 80 to 120 IU) to the vitamin D intakes of American adults (Calvo et al., 2005). Even with supplement use, total vitamin D intakes are generally below recommendations.

Summary There is a persuasive body of evidence that nutritional factors play significant roles in the development and maintenance of bone strength. Calcium and vitamin D have been the most extensively studied nutritional factors and appear to be important in bone health throughout life. Other dietary factors, energy, protein, micronutrients, and phytoestrogens can all have significant roles to play in reducing osteoporotic risk. Dietary recommendations encourage a varied diet with adequate intakes of low-fat dairy products and fruits and vegetables.

REFERENCES Anderson, J. J., & Rondano, P. A. (1996). Peak bone mass development of females: Can young adult women improve their peak bone mass? Journal of the American College of Nutrition, 15, 570–574. Calvo, M. S., Whiting, S. J., & Barton, C. N. (2005). Vitamin D intake: A global perspective of current status. Journal of Nutrition, 135, 310–316. Chapuy, M. C., Arlot, M. E., DuBoeuf, F., Brun, J., Crouzet, B., Arnaud, S. et al. (1992). Vitamin D3 and calcium to prevent hip fractures in elderly women. New England Journal of Medicine, 327, 1637–1642. Dawson-Hughes, B., Harris, S. S., Krall, E. A., & Dallal, G. E. (1997). Effect of calcium and vitamin D supplementation on bone density in men and women 65 years of age or older. New England Journal of Medicine, 337, 670–676. Dodiuk-Gad, R. P., Rozen, G. S., Rennert, G., Rennert, H. S., & Ish-Shalom, S. (2005). Sustained effect of short-term calcium supplementation on bone mass in adolescent girls with low calcium intake. American Journal of Clinical Nutrition, 81, 168–174. Dowd, R. (2001). Role of calcium, vitamin D, and other nutrients in the prevention and treatment of osteoporosis. Nursing Clinics of North America, 3, 417–431. Eastell, R., & Lambert, H. (2002). Diet and healthy bones. Calcified Tissue International, 70, 400–404. Ervin, R. B., Wang, C.-H., Wright, J. D., & Kennedy-Stephenson, W. (2004). Dietary intake of selected minerals for the United States population. Advance data, from vital and health statistics (No. 341). Hyattsville, MD: National Center for Health Statistics.

114

Osteoporosis Fiorita, L. M., Smiciklas-Wright, H., Mitchell, D. C., & Birch, L. L. (in press). Dairy intake and bone mineral content during middle childhood. Journal of Nutrition. Harris, S. S., & Dawson-Hughes, B. (1994). Caffeine and bone loss in healthy postmenopausal women. American Journal of Clinical Nutrition, 60, 573–578. Harvey, N., & Cooper, C. (2004). The developing origins of osteoporotic fractures. Journal of the British Menopause Society, 10, 14–15, 29. Heaney, R. P. (1993). Protein intake and the calcium economy. Journal of the American Dietetic Association, 93, 125–160. Heaney, R. P. (1996). Food: What a surprise! American Journal of Clinical Nutrition, 64, 791–792. Heaney, R. P. (2003). Long-latent deficiency disease: Insights from calcium and vitamin D. American Journal of Clinical Nutrition, 78, 912–919. Heaney, R. R., Carey, R., & Harkness, L. (2005). Roles of Vitamin D, n-3 polyunsaturated fatty acid, and soy isoflavones in bone health. Journal of the American Dietetic Association, 105, 1700–1702. Holick, M. F. (2004). Vitamin D: Importance in the prevention of cancers, type 1 diabetes, heart disease, and osteoporosis. American Journal of Clinical Nutrition, 79, 362–371. Ilich, J. Z., & Kerstetter, J. E. (2000). Nutrition in bone health revisited. Journal of the American College of Nutrition, 19, 715–737. Institute of Medicine. (1997). Dietary reference intakes for calcium, phosphorus, magnesium, vitamin D, and fluoride. Standing Committee on the Scientific Evaluation of Dietary Reference Intakes. Food and Nutrition Board. Washington, DC: National Academy Press. Jackson, R. D., LaCroix, A. Z., Gass, M., Wallace, R. B., Robbins, J., Lewis, C. F. et al. (2006). Calcium plus vitamin D supplementation and the risk of fractures. New England Journal of Medicine, 354, 669–683. Jarvis, J. K., & Miller, G. D. (2002). Overcoming the barrier of lactose intolerance to reduce health disparities. Journal of the National Medical Association, 94, 55–66. Kass-Wolff, J. H. (2004). Calcium in women: Healthy bones and much more. Journal of Obstetrical Gynecology of Neonatal Nursing, 33, 21–33. Kerstetter, J. E., O’Brien, K. O., & Insogna, K. L. (2003). Low protein intake: The impact on calcium and bone homeostasis in humans. Journal of Nutrition, 133, 855S–861S. Kinyamu, H. K., Gallagher, J. C., Balhorn, K. E., & Petranick, K. M. (1997). Serum vitamin D metabolism and calcium absorption in normal young and elderly free-living women and in women living in nursing homes. American Journal of Clinical Nutrition, 65, 790–797. Kitchin, B., & Morgan, S. (2003). Nutritional considerations in osteoporosis. Current Opinions in Rheumatology, 15, 476–480. Lanham-New, S. A. (2006). Fruit and vegetables: The unexpected natural answer to the question of osteoporosis prevention? American Journal of Clinical Nutrition, 83, 1254–1255. Matzko, M. (2002). Preventing osteoporosis: Lifelong nutrition and exercise habits are the most powerful weapons. ADVANCE for Nurse Practitioners, 10, 41–43, 76. Moore, C., Murphy, M. M., Keast, D. R., & Holick, M. F. (2004). Vitamin D intake in the United States. Journal of the American Dietetic Association, 104, 980–983. New, S. A. (2004). Intake of fruit and vegetables: Implications for bone health. Proceedings of the Nutrition Society, 62, 889–899. Nieves, J. W., Komar, L., Cosman, F., & Lindsay, R. (1998). Calcium potentiates the effect of estrogen and calcitonin on bone mass: Review and analysis. American Journal of Clinical Nutrition, 67, 18–24. North American Menopause Society. (2002). Management of postmenopausal osteoporosis: Position statement. Journal of the North American Menopause Society, 9, 84–101. Prynne, C. J., Mishra, G. D., O’Connell, M. A., Muniz, G., Laskey, M. A., Yan, L. et al. (2006). Fruit and vegetable intakes and bone mineral status: A cross-sectional study in 5 age and sex cohorts. American Journal of Clinical Nutrition, 83, 1420–1428. Rizzoli, R., Ammann, P., Chevalley, T., & Bonjour, J.-P. (2001). Protein intake and bone disorders in the elderly. Joint Bone Spine, 68, 383–392. Setchell, K. D. (1998). Phytoestrogens: The biochemistry, physiology, and implications for human health. American Journal of Clinical Nutrition, 68, 1333S–1346S. Stear, S. (2000). The role of diet in reducing the risk of osteoporosis. Community Nurse, 6(10), S7–S8. Tucker, K. L. (2003). Dietary intake and bone status with aging. Current Pharmaceutical Design, 9, 2687–2704.

Diet and Bone Health

115

U.S. Department of Health and Human Services. (2004). Bone health and osteoporosis: A report of the surgeon general. Public Health Service, Office of the Surgeon General, Rockville, MD. Retrieved August 17, 2005, from http://www.surgeongeneral.gov/library/bonehealth/ Weaver, C. (2006). Calcium. In B. A. Bowman & P. M. Russell (Eds.), Present knowledge in nutrition (9th ed.). Washington, DC: International Life Sciences Institute, pp. 273–282. Welten, D. C., Kemper, H. C., Post, G. B., & van Staveren, W. A. (1995). A meta-analysis of the effect of calcium intake on bone mass in young and middle aged females and males. Journal of Nutrition, 125, 2802–2813.

Exercise Mandate: Preventative and Restorative

Exercise—Giving up a half-hour (one sitcom) of TV every day is all it takes. (Rankin, “Exercise: A Prescription for Osteoporosis?”)

T

8

he importance of sustained exercise over time cannot be overemphasized in the prevention and management of osteoporosis. Based on a growing body of evidence over the past several years, exercise has been supported as a means of maintaining good health in individuals of all ages, as well as preventing many diseases of the maturing adult. It is now possible to detect bone disease early, as well as to predict those individuals who are at a higher risk for developing bone disease and fractures. Exercise as a means of prevention and treatment of osteoporosis is extensively documented (Bassey, Rothwell, Littlewood, & Pye, 1998; Beverly, Rider, Evans, & Smith, 1989; Cussler et al., 2003; Heinonen et al., 1996; Kerr, Ackland, Maslen, Morton, & Prince, 2001; Kohrt, Ehsani, & Birge 1997; Snow, Shaw, Winters, & Witzke, 2000; Warden, Fuchs, & Turner, 2004; Winter & Snow, 2000). The effects of immobilization, bed rest, and spinal cord injury, as well as other skeletal unloading, can increase bone loss (Beck & Snow, 2003). These results in terms of bone loss can be taken to reflect the likely results for an aging adult with a sedentary lifestyle. The ability of exercise to improve bone strength through bone loading has been analyzed primarily through the use of bone mineral density (BMD) scans. Dual energy X-ray absorptiometry (DXA) is the standard method of measuring BMD in clinical and research settings. BMD describes the amount of mineral measured per unit area or volume of bone tissue (Kahn et. al., 2001; Kohrt, Bloomfield, Little, Nelson, & Yingling, 2004). Many factors that may affect BMD, such as nutrition, hormonal effects, and medications, are discussed in other chapters. Highlighted in this chapter

Renée M. Hakim Janet Ramos Grabo

118

Osteoporosis

are recommendations relevant to exercise prescription in order to most greatly improve BMD across the lifespan, from both a preventative and a restorative perspective.

Preventative Risk Reduction for Fractures The goal of exercise should not only be to increase BMD but also to reduce the risk of fractures that occur with greater frequency in individuals with low bone mass. The mortality rate in the first year following hip fracture is 15%–20% (Schurch et al., 1996). It is estimated that the incidence of hip fractures will double to 2.6 million by the year 2025, with a greater increase in men than in women (Gullberg, Johnell, & Kanis, 1997). Because 90% of hip and 50% of spine fractures are associated with a fall, exercise should aim to improve peak bone mass, minimize bone loss in adulthood, and reduce the risk of falling (Beck & Snow, 2003). Exercise consideration should begin in childhood, because peak bone mineral accrual rate within a 2-year span of pubertal years is consistent with 26% of adult total body bone mineral (Bailey, 1997). The most commonly studied areas for changes in BMD are the hip, spine, forearm, and calcaneous (heel) (U.S. Department of Health and Human Services [USDHHS], 2004). Exercise may cause small gains in BMD and bone mineral content (BMC), while resulting in large improvements in bone strength because new bone formation is localized to the bone surfaces where there was the greatest mechanical stress (Robling, Burr, & Turner, 2001, 2002; Turner & Robling, 2005). The issue of how to overload a bone has been studied in varying forms. Breakthrough research by Hert, Liskova, and Landa (1971) established that bone tissue responds best to dynamic rather than static loading. Dynamic loading creates fluid movement in bone’s lacunar-canalicular network, which in turn generates shear stresses on the plasma membranes of resident osteocytes, bone lining cells, and osteoblasts. Bone cells are highly sensitive to fluid shear stresses. Therefore, high-impact exercises that produce high rates of deformation of the bone matrix are an effective application of mechanical forces (Turner & Robling, 2005). BMD is the most commonly used predictor for risk analysis of fractures (Beck & Snow, 2003); however, it should be noted that a general increase in strength, balance, and flexibility can be measures of decreased risk as well (USDHHS, 2004). A 12-week home-based trunk-strengthening exercise program developed by Chien, Yang, and Tsau (2005) was found to improve the quality of life of osteoporotic and osteopenic postmenopausal women. Twenty-eight postmenopausal women (mean age 60.3 ± 9.3 years) diagnosed with osteoporosis or osteopenia without fracture history were recruited and randomly assigned to exercise (n = 14) and control groups (n = 14). The study aimed to improve trunk strength, spinal range of motion, velocity, and quality of life (QOL), as well as to decrease disability (i.e., as measured by the Oswestry Disability Questionnaire [ ODQ ]). The 12-week exercise program included three sessions every day using an instructional booklet, after the initial instructional session. Exercises were selected by a physical therapist based on an individual’s abilities. The control

Exercise Mandate

119

group participants were asked to maintain their current lifestyle and diet. Statistically significant improvements were demonstrated in spinal range of motion (ROM) and motion velocity for the exercise group ( p < .05). Trunk flexor and extensor strength increased after exercise training ( p < .05) and the ODQ scores were improved ( p DXA T-score > –2.5 SD)

Participants 120 premenopausal women (age 35–40 years) randomized into exercise (n = 39) and control (n = 41) groups No baseline group differences in weight, height, calcium intake, menarcheal age, exercise frequency, and activity level

Home/Control Group: • 2 home training sessions per week, 25 minutes each

Exercise Group: • 2 group sessions per week 60–70 minutes each

Control Group: • Usual activities

Intensity Exercise Group: • Training sessions 3 times a week for 12 months with a physical therapist • 60 minutes total with 10 minutes warm-up and cool-down; 40 minutes high-impact training; Plus daily home program (10 minutes)

At 6 months: jumping phase introduced including: rope skipping, 4 sets of 15 simple multidirectional jumps;

Exercise Group: First 3 months: warm-up; gradually increased walking and running; running games added (at 70%–80% HRmax); increasing amount of high-impact aerobics concluded the sequence for 20 minutes

Control Group: No prescribed exercise

High-impact exercise: step patterns, stamping, jumping, running, walking 3 months later 10 cm step 6 months later 2–3 steps Progression: higher j umps & drops added; plus 10-minute daily home program of similar patterns of exercise

Intervention details Exercise Group: Warm-up: walking, running in place, with/without arm movements/knee bends

•

•

•

•

(Continued)

Significant decreases ( p < .001) in pain frequency and intensity in the spine in the exercise group and increased in the control group, while no betweengroup differences were detected in the main joints Low-volume/high-intensity exercise program successful in maintaining BMD at the spine ( p Acts, Chap. No. 554 N.C. Gen. Stat. § 58-3-174 & Sess. Laws, Chap. 443

N.H. Rev. Stat. § 126:I:1 et. seq. N.J. Stat. § 26:2R-1 et seq.; N.J. Senate Bill 1055, 1053 N.M. Laws, Chap. 116

Nev. Rev. Stat. § 236.065

Statute

(Continued)

Prevention, treatment education program; required insurance coverage for high risk osteo

Awareness programs

Prevention awareness; insured screening Prevention & treatment education Prevention, education; bone mineral density tests, medications Diagnostic tests; prevention & education

Prevention education & awareness Prevention & education

Comments

Yes

No Yes

Yes

No No

Yes Yes Yes

Yes No

South Dakota Tennessee

Texas

Utah Vermont

Virginia Washington

West Virginia

Wisconsin

Wyoming

No

Yes

Yes

No No

No No

Yes

No

Yes

South Carolina

No

Yes

Rhode Island

www.wdh.state.wy.us/

www.dhfs.wisconsin.gov/

www.wvdhhr.org/bph/ oehp/hp/osteo

www.health.utah.gov/ www.healthvermont.gov/ research/chronic/osteo porosis www.vdh.state.va.us www.doh.wa.gov

www.dshs.state.tx.us/osteo

www.state.tn.us/comaging/ www.State.tn.us/health/

www.health.state.ri.us/ disease/osteo/coalition www.scstatehouse.net/ CODE/titl44 www.scdhec.gov/ www.state.sd.us/DOH/

Wis. Stat. § 534, 592, & 3482

Va. Code § 32.1-11.3 Wash. Rev. Code § 28B.20.462 W. Va. Code §§ 16-5M-1, 3316-18. W. Va Senate Bill 125

Tex. Health & Safety Code Ann. § 90.001. Tex Insur. Code Ann. § 21.53C

Tenn. Code Ann. §§68-11501, 56-7-2506, 4-29-228. Tenn. Pub. Acts, H. Jt. Res. 431, 101, 433, 1071

R.I. Gen. Laws § 23-70-1, 42-66.2-3 S.C. Code Annotated § 44125-10

Prevention, education, & screening

Prevention, education, & screening

Early detection, prevention, bone mass measurement coverage

Prevention, treatment, & education programs; Bone Mass Measurement Coverage Act; Council on Osteoporosis

Prevention, treatment options; drug assistance Prevention, treatment, & education program

214

Osteoporosis

states have not enacted laws relating to osteoporosis (Weidenbener, 2006). Many states’ departments of health have osteoporosis programs, policy, and legislation under the rubric of women’s health or chronic disease/arthritis. Considering the morbidity and mortality of advanced osteoporosis and the health and economic sequelae of bone deterioration, it is surprising that legislators have not responded more aggressively to this disease. However, because of the variability of reliability of the BMD testing technology, Indiana, in June 2006, ended its 6-year diagnostic screening program (Weidenbener, 2006). For bone health by individual U.S. state, see Table 14.3.

Policy Development: Case Studies Anderson’s original sequential model (Anderson, Brady. Bullock, & Stewart, 1984) identifies six stages in the policy process: (1) problem identification, (2) agenda setting, (3) policy formulation, (4) policy adoption, (5) policy implementation, and (6) policy evaluation. The National Osteoporosis Society of the United Kingdom (2005) exemplifies the application of this model in its adoption of a policy framework easily accessed on its Web site (www.nos.org.uk/nos-policy-positions.htm). Formulated to develop policy papers and position statements on issues related to osteoporosis, it is depicted in the algorithm shown in Figure 14.1.

Public Funding for Osteoporosis Medications: Israel Many countries are utilizing the consensus conference as a tool to develop public policy on a national level. Originally developed by Perry (Perry, 1987; Perry & Kalbret, 1980) to discuss major health issues at the U.S. NIH, this type of conference has been adapted to the needs of different world regions. Shemer (2000) describes the use of the consensus conference by the National Health Services Basket in Israel to formulate a national policy on osteoporosis. This initiative was spurred by research findings related to new-generation medications for osteoporosis, and by pressure from physicians and patients. Coverage of medications by the government required accurate utilization prediction, a needs assessment of the population, information on pharmaco-epidemiology, and compliance and consensus on good medical practice (Shemer, 2000, p. 375). The conference brought together leading experts in the field and resulted in the “adoption of new drugs through public funding, and the acceptance of all the other recommendations for the prevention, detection and treatment of the disease” (Shemer, 2000, p. 376).

Calcium and Vitamin D: United States, Canada Calcium and vitamin D are essential nutrients for bone health, and intake recommendations have evolved over the years. Looker (2003) makes the case that calcium can serve as an exemplar of the interrelationships among research, consumer practices, and public policy. The same case can also be made for vitamin D (Calvo & Whiting, 2006). Data linking calcium to bone health have provided the scientific rationale for the calcium intake recommendations published by the U.S. Food and Nutrition Board of the

Figure

14.1

Practice policy formulation process of the National Osteoporosis Society, United Kingdom. Reprinted with permission from the Policy Framework Summary of the National Osteoporosis Society of the United Kingdom.

216

Osteoporosis

National Academy of Sciences dating back to the early 1940s. Increasingly, the evidence from randomized control trials, particularly calcium’s and vitamin D’s positive effect on the bone density of postmenopausal women and the reduction of fracture risk in women over 60, has supported higher intake allowances (Jackson et al., 2006). One exception has been the evidence that calcium intake during lactation does not influence bone status (Prentice, 2000). In addition, data on consumer consumption of the nutrients in question impact policy development and implementation. The National Health and Nutrition Examination (NHANES) III survey in the United States on calcium intake in the general population indicates that after childhood, female intake, even with supplementation, was below the recommended levels. NHANES III survey data also found little change in vitamin D intake over the last decade, with “few age, race and gender groups meeting dietary intake guidelines” (Calvo & Whiting, 2006, p. 1136). Likewise, studies in Canada found that even in young White women, vitamin D intake at the level of the dietary guidelines did not result in circulating 25-hydroxy vitamin D levels of 80 nmol. These studies did not only fuel changes in dietary recommendations but also in permitted health claims on food and supplement labels; they also led to the inclusion of objectives related to calcium in Healthy People 2010 and to promotional campaigns to increase calcium and vitamin D intake in the United States. The campaigns encouraged increased consumption of natural food sources, fortified foods, and dietary supplements. However, policies are fluid and ever subject to revisions. As new research into the calcium–vitamin D–bone health relationship is reported, policies are periodically reviewed and revised as warranted (Looker, 2003). Because of the lack of strong data regarding younger individuals, the sustained effects after discontinuance of supplementation, and other complexities in the calcium-bone connection, questions have been raised and changes regarding intake recommendations have been made. Examples of such policy changes include revisions with regard to dietary calcium intake during lactation. Emerging issues that may impact policy development include the relationship to bone health of exercise, vitamin D receptor genotype, and mandatory fortification of cereal grain products with vitamin D (Calvo & Whiting, 2006; Looker, 2003).

Summary Health policy that affects bone health is developed by international organizations, individual countries, and, in the United States, by individual states. In order to reduce the prevalence of osteoporosis and the number of fractures worldwide, several initiatives have been undertaken. These decisions made by governments and by private agencies influence the promotion of bone health in several diverse areas: how osteoporosis is defined, how whole populations are screened, and what preventive and treatment measures are the most cost-effective, to name a few. The United Nations’ WHO, the Bone and Joint Decade, and the IOF have spearheaded these efforts. In the United States, Healthy People 2010 and the surgeon general’s report, Bone Health and Osteoporosis (USDHSS, 2004), call for a national action plan to implement systems changes including dietary,

Health Policy and Insurance Reimbursement

217

physical activity, and financing recommendations. Such a plan, however, needs to recognize that policy development is a fluid process and involves a complex interrelationship with research, science, and public health awareness that demands a framework to address the ever-changing data.

REFERENCES Anderson, J. E., Brady, D. W., Bullock, C. S., & Stewart, J. (1984). Public policy and politics in America (2nd ed.). Monterey, CA: Brooks/Cole. BJDonline: Bone and Joint Decade’s Musculoskeletal Portal. (2006). The initiative; the structure; the supporting governments. Retrieved August 9, 2006, from http://www.boneandjointdecade.org Calvo, M. S., & Whiting, S. J. (2006). Public health strategies to overcome barriers to optimal vitamin D status in populations with special needs. Journal of Nutrition, 136, 1135–1139. Harrington, C., & Estes, C. (2004). Health policy: Crisis and reform in the US health care delivery system (4th ed.). Boston: Jones and Bartlett. International Osteoporosis Foundation. (2005). Advocacy and policy. Retrieved August 9, 2006, from http:///www.osteopfound.org/advocacy_policy/index.html Jackson, R. D., LaCroix, A. Z., Gass, M., Wallace, R. B., Robbins, J. C., Lewis, C. R. et al. (2006). Calcium plus vitamin D supplementation and the risk of fractures. New England Journal of Medicine, 354(7), 669–683. Johnell, O., & Hertzman, P. (2006). What evidence is there for the prevention and screening of osteoporosis? WHO Regional Office for Europe, Copenhagen. Retrieved May 18, 2006, from http://wwwleuro .who.int/document/e88668.pdf Longest, B. B. (1998). Health policy making in the United States (2nd ed.). Chicago: Health Administration Press. Looker, A. C. (2003). Interaction of science, consumer practices and policy: Calcium and bone health as a case study. Journal of Nutrition, 133, 1988S–1991S. Mason, D., Leavitt, J., & Chaffee, M. (2002). Policy and politics in nursing and health care (4th ed.). St. Louis: Saunders. National Institutes of Health. (2000). Osteoporosis prevention, diagnosis, and therapy. NIH Consensus Development Conference Statement Online, March 27–29, 2000 (pp. 1–36). Retrieved November 16, 2003 from http://consensus.nih.gov/cons/111/111–statement.htm. National Osteoporosis Foundation. National Osteoporosis Society of the United Kingdom. (2005, August). Policy framework summary. Retrieved August 23, 2006, from www.nos.org.uk/policy/nos-policy-positions.html National Osteoporosis Foundation. (2006). Summary of Osteoporosis Laws & Legislation in the United States. Retrieved July 23, 2006 from http://www.nof.org/advocacy/updates/ stateleg.htm National Osteoporosis Foundation (2007). About NOF: Mission and goals. Retrieved August 25, 2007 from http://www.nof.org/aboutnof/. NIH News Release (2000, March 29). NIH consensus panel addresses osteoporosis prevention, diagnosis, and therapy. Retrieved on August 27, 2006 from http://www.nih.gov/new/pr/mar2000/ od-29.htm. Perry, S. (1987). The NIH consensus development program and the assessment of health-care technologies. New England Journal of Medicine, 317(8), 485–488. Perry, S., & Kalbret, J. T. (1980). The NIH consensus development program and the assessment of health-care technologies. New England Journal of Medicine, 303(3), 169–172. Prentice, A. (2000). Maternal calcium metabolism and bone mineral status. American Journal of Clinical Nutrition, 71(Suppl.), 1312S–1316S. Shemer, J. (2000). Consensus conference as a tool for national health services policy: The case for osteoporosis. Israeli Medical Association Journal, 2, 375–376. Shi, L., & Singh, D. (2004). Delivering health care in America: A systems approach (3rd ed.). Gaithersburg, MD: Aspen. U.S. Department of Health and Human Services. (2000). Healthy People 2010. Washington, DC: Author.

218

Osteoporosis U.S. Department of Health and Human Services. (2004). Bone health and osteoporosis: A report of the surgeon general. Public Health Service, Office of the Surgeon General, Rockville, MD. Retrieved June 6, 2006 from http://www.surgeongeneral.gov/library/bonehealth/ U.S. Preventive Services Task Force (2002). Screening for osteoporosis in postmenopausal women: Recommendations and rationale. Annals of Internal Medicine, 137 (6), 526–528. Weidenbener, L. S. (2006, July 6). State dropping osteoporosis test: Questions raised about screenings. Courier-Journal.com. Retrieved July 24, 2006 from http://www.courier-journal.com/apps/pbcs. dll/article?AID=/20060706/NEWS02/6070604. World Health Organization. (1994). Assessment of fracture risk and its application to screening for postmenopausal osteoporosis: Report of WHO Study Group (WHO Technical Report Series, No. 843). Geneva, Switzerland: Author. World Health Organization. (2003a).The burden of musculoskeletal conditions at the start of the new millennium: Report of a WHO Scientific Group (WHO Technical Report Series, No. 919). Geneva, Switzerland: Author. World Health Organization. (2003b). Diet, nutrition and the prevention of chronic diseases: Report of a Joint WHO/FAO Expert Consultation (WHO Technical Report Series, No. 916). Geneva, Switzerland: Author. World Health Organization. (2003c). Prevention and management of osteoporosis: Report of a WHO Scientific Group (WHO Technical Report Series, No. 921). Geneva, Switzerland: Author. Writing Group for International Society for Clinical Densitometry Position Development Conference. (2004). Position Statement of 2003 Conference. Journal of Clinical Densitometry, 7(1), 7–12.

Emerging Approaches in the Prevention of Osteoporosis

Interstitial fluid flow is essential for maintaining bone integrity. Simple, non-invasive approaches which enhance skeletal muscle pumping and thereby ensure sustained interstitial flow through bone have the potential to prevent and treat osteoporosis. (K. J. McLeod)

Introduction

O

15 Carolyn S. Pierce Guruprasad Madhavan Kenneth J. McLeod

steoporosis is characterized by long-term loss of bone tissue. While the bone tissue that remains is normal and fully capable of repairing itself, the effective strength of the skeleton is reduced by the loss, leading to increased risk of fracture following even minor trauma. The most common sites of osteoporotic fractures are those composed principally of trabecular bone, namely, the distal radius, spine, and femoral neck. Osteoporosis is a common occurrence in the aged, usually resulting from slow progressive bone loss, but rapid bone loss can occur during menopause, extended bed rest, cast immobilization, or extended exposure to microgravity. While inhibitors of bone resorption are commercially available, as well as at least one anabolic agent, a pharmacologic approach is neither an appropriate nor a costeffective approach for young and otherwise healthy men and women, who are looking for an osteoporosis prevention strategy that can be utilized over extended time periods. Indeed, recent reports suggest that the extended use of bisphosphonates to prevent bone resorption may lead to serious long-term complications (Bamias et al., 2005; Migliorati et al., 2005; Woo, Hellstein, & Kalmar, 2006). In order to understand the new directions being pursued in the development of preventative strategies for osteoporosis, it is necessary to understand the driving forces behind bone adaptation. It has long been observed that larger animals have larger bones,

220

Osteoporosis

and so it was only natural to hypothesize that adaptation processes are directed toward placing bone mass appropriately within the skeleton to the mechanical loading forces placed on the skeleton during day-to-day activities (Wolff, 1892/1986). In this context, osteoporosis is primarily viewed as a physiologic adaptation to an altered environment, that is, an adaptation by changes in the pattern of mechanical loading of the bone tissue. Indeed, numerous animal studies, in which bone tissue can be loaded in a controlled manner, have shown that mechanical loading of the skeleton can lead to new bone formation. However, investigations specifically addressing the link between mechanical loading and bone mass have shown that there is actually little correlation between mechanical load distributions in bone tissue and bone mass distributions. These results indicate that the bone adaptation is probably not due to the direct influence of mechanical loading but to some phenomenon coupled to the mechanical loading process. Understanding this underlying process is critical, as increased mechanical loading of the skeleton in humans has very little effect on bone adaptation processes. Numerous clinical studies have shown that while high levels of physical activity may be capable of significantly affecting bone mass in the skeleton of children, exercise regimens can produce, at best, only modest increases in bone mass, either in young adults ( Jones, Priest, Hayes, Tichenor, & Nagel, 1977; Snow-Harter, Bouxsein, Lewis, Carter, & Marcus, 1992) or in the elderly (Hoshino et al., 1996; Smith, Gilligan, McAdam, Ensign, & Smith, 1989).

Bone Adaptation and Fluid Flow Though mechanical loading, per se, does not appear to significantly affect skeletal adaptation, the nutritional and hormonal support that is tenuously associated with mechanical loading does have a profound influence on the maintenance of bone tissue. While oxygen and low-mass nutrients can diffuse from the capillaries directly to the cell population of even sparsely vascularized tissues such as bone, large proteins are diffusion limited and so are reliant on fluid flow in the tissue for transport to the cells (Montgomery, Sutker, Bronk, Smith, & Kelly, 1988). These large proteins are being continuously extravasated from the capillaries along with interstitial fluid. The flow of this interstitial fluid through the bone tissue is therefore critical to the integrity of bone cells, and, correspondingly, to the maintenance of bone mass. The extravasation of interstitial fluid is primarily dependent on transmural pressures (i.e., the difference between capillary and tissue pressures), but it can also be influenced by pressure gradients developed by the mechanical deformation of bone tissue during exercise. It is this process that provides the link between mechanical loading and bone adaptation. However, as intensive exercise generally represents a small fraction of the daily activity of most individuals (Fritton, McLeod, & Rubin, 2000), the contributions of capillary pressures and tissue pressures can be expected to dominate interstitial fluid flow in bone. Studies performed over the last 4 decades have clearly demonstrated the importance of interstitial fluid flow in the formation and maintenance of bone mass. In the mid-1960s, Keck and Kelly (1965) first demonstrated that increased bone growth was associated with increased venous pressure. These observations led to investigations of interstitial flow in bone, and the demonstration of lymphatic vessels in bone directed

Approaches in the Prevention of Osteoporosis

221

from the marrow to the periosteal surfaces (Seliger, 1970). Subsequently, it was shown that high venous pressures encouraged bone formation in the absence of any change in blood flow (Kruse & Kelly, 1974), and also that high venous pressure was associated with increased venous filtration (Li, Bronk, An, & Kelly, 1987). The influence of increased venous pressure and increased filtration has been confirmed more recently using the rat hindlimb suspension model of microgravity (Bergula, Huang, & Frangos, 1999). Numerous additional studies have lent support to the theory that blood flow and interstitial fluid flow are critical to the maintenance of bone mass. Colleran and associates (Colleran et al., 2000) showed that decreased blood flow to the limbs results in decreased cancellous bone formation as well as reduced periosteal bone. McDonald and Pitt Ford (1993) demonstrated that an important effect of mechanical loading was the significant alteration of blood flow in bone. Perhaps one of the most important clinical observations regarding the role of venous pressure and filtration was made by Issekutz and colleagues (Issekutz, Blizzard, Birkhead, & Rodahl, 1966), who demonstrated in a population of young men that bed rest resulted in substantially elevated urinary calcium secretion and that no form of supine exercise regimen was capable of inhibiting this calcium loss. However, just six periods of quiet standing for 30 minutes per day returned urinary calcium to normal levels. These study results are consistent with the premise that the influence of gravity (hydrostatic pressure effects) on the fluid within bone is sufficient to increase capillary filtration and interstitial flow, allowing bone mass to be maintained. The proposition that interstitial flow may be a critical factor in the maintenance of bone mass is also consistent with the distribution of bone loss in disuse, whether due to aging, bed rest, or passive inactivity. Bone loss does not occur to any degree in the thorax or cranial regions of the skeleton, where blood pressure and/or gravity can sustain a normal filtration rate, and skeletal muscle pump activity combined with gravity can maintain interstitial fluid return via the lymphatic system. However, at sites where interstitial flow is limited, due to either a lack of adequate filtration or inadequate return, loss of bone mass is commonly observed. Maintenance of bone mass, in summary, requires adequate filtration and transport of nutrients and growth factors through the bone tissue. Adequate filtration, correspondingly, requires high capillary pressures, which are normally produced by the influence of gravity during upright stance. In addition, sustained fluid transport through bone requires effective venous and lymphatic return, which serves to maintain low tissue pressures. Venous and lymphatic return, at least in the periphery of the body, is mediated primarily by skeletal muscle pumping, an often ignored physiologic function. Developing strategies to prevent bone loss, therefore, requires an understanding of how gravity influences fluid flow in the human, and how effective circulation is maintained through skeletal muscle pump activity.

Fluid Flow in Humans Gravitational Effects on Circulation The pumping action of the heart is sufficient to sustain blood circulation for individuals in the supine (or prone) position, but it is not sufficient when an individual is upright.

222

Osteoporosis

When humans are in a supine posture, the peak blood pressure generated by the heart is approximately 100 mmHg throughout the large arteries. Conversely, venous pressures in the supine position range from slightly negative at the right atrium to no more than 15 to 20 mmHg in the peripheral veins. Therefore, the driving pressure from the lower limb vessels back to the heart is only about 20 to 25 mmHg. A pressure of 25 mmHg is equivalent to approximately 25 cm (10 inches) of water, meaning that venous pressure in the supine position is sufficient to raise blood about 25 cm above the lowest point in the body. For most individuals, this pressure is adequate to return blood to the heart when an individual is lying down. However, when humans assume an upright posture, the pressures in the circulatory system change dramatically. For example, when standing, the heart is about 1200 to 1500 cm above the feet. Venous pressures of 25 mmHg are clearly incapable of returning blood to the heart during standing; and indeed, even upright sitting would experience diminished venous return in the absence of a supplemental pump that is capable of significantly increasing venous pressures.

Role of Skeletal Muscle Pumping in Maintaining Fluid Flows Venous return from the extremities during upright posture is accomplished in humans by skeletal muscle activity. In the legs, this “muscle pumping” is predominantly the result of calf muscle contraction synergistically assisted by competent venous valves (Figure 15.1). The role the calf muscles play in driving blood back to the heart against the force of gravity has given rise to the term “second heart.” In returning this venous blood, the calf muscle pump (in particular, the soleus muscle) also serves to maintain arterial blood pressure during upright posture. In the absence of adequate calf muscle pump activity, blood sequestration into the lower extremities can be substantial. Even in healthy individuals, a shift to upright posture typically leads to a 10% blood volume shift of 7 ml/kg, or 300–600 ml, into the lower extremities (Sheperd, 1966). This “loss” of blood volume results in inadequate cardiac refilling and therefore decreased cardiac output per the Frank-Starling mechanism (Rowell, 1993). Additionally, skeletal muscle pumping is essential for lymphatic return from the lower limbs. Upper body lymphatics can drain back to the subclavian vein by gravitydriven flow, and the thoracic region drains during respiratory motion. But the lower limbs lack any explicit lymphatic pump, and so lymphatic fluid return is completely dependent on skeletal muscle activity. While it is widely believed that interstitial fluid extravasated from capillaries is reabsorbed at the venous end of the capillaries, it has been well established that, under normal conditions, capillary flow is unidirectional—from vessel lumen to interstitium—with lymphatic drainage removing filtered interstitial fluid (Zweifach & Intaglietta, 1966). This is not an insubstantial amount of fluid, as has been shown through studies of serum volume changes during a shift in posture. Lymphatic return amounts to approximately 3 liters per day when an individual is supine, or roughly an amount equal to the entire serum plasma volume in an adult. However, the volume of this flow is greatly influenced by the increased hydrostatic forces created by gravity when an individual is upright. For example, up to 20% of serum fluid leaves the vascular system through extravasation within 30 minutes of attaining an upright stance (Hagan, Diaz, & Harvath, 1978). This fluid largely pools in the interstitial

Approaches in the Prevention of Osteoporosis

223

Figure

15.1

Soleus muscle in synergy with unidirectional valves promotes venous and lymphatic fluid return. In the absence of soleus muscle contraction, blood tends to pool in the legs, resulting in increased venous pressure, while diminished lymphatic return results in peripheral edema and swelling. (Image developed from Gray, 2004.)

spaces of the lower limbs unless it is taken up by the lymphatic system. Inadequate lymphatic return, therefore, results in substantially increased interstitial fluid pressures. These high tissue pressures serve to inhibit extravasation from the vascular supply with a corresponding loss of nutrient delivery to the dependent tissues.

Role of Skeletal Muscle Activity in Maintaining Bone Mass From the above discussion, it should be evident that the maintenance of adequate interstitial fluid flow across the bone tissue is essential for preventing the loss of bone mass that leads to osteoporosis. In order to sustain this interstitial flow, two conditions must be met: 1 . An individual must spend a significant portion of the day upright, so as to

maximize the hydrostatic pressure on the circulatory system. The gravitational

224

Osteoporosis

force operating on the circulatory system ensures high capillary pressures, which lead to high levels of fluid extravasation from the blood supply, thereby providing the nutritional support necessary to maintain bone mass. 2 . The extravasated fluid must be cleared from the tissue surrounding the bone and returned to the circulatory system. If this fluid is not removed, increased tissue pressure (edema) will preclude further interstitial flow, resulting in loss of nutritional support to the tissue and in bone atrophy. For young, healthy individuals, maintaining an upright posture for a significant fraction of the day is not usually an issue, though this factor can be an insurmountable hurdle in the prevention of osteoporosis in the elderly or in bed rest patients. However, ensuring that an individual has sufficient calf muscle pump activity to maintain low tissue pressure and thereby permit sustained interstitial fluid flow through the bone tissue can be more problematic. Even for an individual in good health, age-related changes in the musculature can result in the conversion of the critical Type IIA (fast twitch oxidative) muscle fibers in the soleus into Type IIB (fast twitch glycolytic) muscle fibers, which are unable to sustain continual contraction. Osteoporosis preventative therapy, therefore, becomes a matter of training up the soleus to improve calf muscle pump function. Numerous approaches are currently being pursued for achieving effective calf muscle pump stimulation. These include training based on physical activity regimens, functional electrical stimulation, and reflex-mediated micro-mechanical stimulation of the calf muscles.

Skeletal Muscle Pump Stimulation and Bone Health Physical Activity Physical activity is widely accepted as a successful preventative strategy for a wide variety of conditions. Perhaps best documented are the beneficial influences of exercise on the cardiovascular system, and the ability of exercise to assist type II diabetics in regulating serum glucose levels. Both of these outcomes can be achieved by increasing the activity of any of the voluntary muscles, and so strenuous exercise of many forms has been found to be beneficial for these conditions. However, developing a physical activity regimen capable of enhancing calf muscle pump activity presents a somewhat greater challenge, in that the dominant muscle of the calf muscle pump, the soleus, is largely an involuntary muscle. While the soleus can be voluntarily contracted, this muscle typically fires autonomically when the individual is either sitting or standing in order to maintain balance and posture. Correspondingly, exercises focused on balance and postural control, such as T’ai Chi Chuan, have recently emerged as potential exercise modalities capable of inhibiting bone loss. T’ai Chi Chuan is a unique form of physical activity, characterized by a high demand for neuromuscular coordination, low velocity of muscle contraction, low impact, and minimal weight bearing (Figure 15.2). In a case-controlled study in postmenopausal women (n = 17), T’ai Chi exercise was found to significantly reduce the rate of trabecular bone loss in the tibia (Qin et al., 2002). More recently, the effectiveness of T’ai Chi Chuan in slowing

Approaches in the Prevention of Osteoporosis

225

Figure

15.2 An illustration of postural movements in T’ai Chi Chuan. T’ai Chi Chuan is an ancient Chinese martial art technique that involves deep diaphragmatic breathing and relaxation, with many fundamental postures that flow imperceptibly and smoothly from one to the other through slow, gentle, and graceful movements. The benefits of T’ai Chi Chuan are improved muscle strength, flexibility, postural balance, and neuromuscular coordination, reduced fall risks, and improved bone density.

bone loss has been demonstrated in a larger prospective study (Chan et al., 2004). In this controlled study of 132 women (mean age: 54±3.5 years), regular practitioners of T’ai Chi Chuan saw a three- to four-fold reduction in their rate of bone loss. In addition to preventing bone loss, T’ai Chi Chuan has the benefit of improving muscle strength, flexibility, and neuromuscular coordination, and thus of reducing fall-related fracture risks in the elderly population (Lane & Nydick, 1999). T’ai Chi Chuan is easily learned and can be practiced throughout one’s lifetime. However, like all exercise programs, it requires that an individual set aside significant time each day to perform the exercises. In Asian societies where T’ai Chi Chuan is linked to other cultural values and activities, high levels of compliance are observed, but it is unclear to what extent T’ai Chi Chuan could become broadly practiced by populations in Western cultures.

Functional Electrical Stimulation Electrical stimulation of muscle (Figure 15.3) is a widely used technique directed to both enhancing intrinsic muscle function and training up muscle so that it can function normally in the absence of external stimulation (Langzam, Nemirovsky, Isakov, & Mizrahi, 2006; Paillard, Noe, Passelergue, & Dupui, 2005). Common application areas include stroke rehabilitation, bladder stimulation, phrenic nerve pacing, and neuroprosthetics (Peckham & Knutson, 2005). In addition, a major focus of electrical muscle stimulation is in the treatment of patients with spinal cord injury (SCI), who commonly experience extensive muscle as well as bone atrophy below the site of injury. One objective of these studies has been to determine whether electrical muscle stimulation can assist in preventing further bone loss in these patients or even serve to augment bone mass. There is compelling physiologic evidence to suggest that direct electrical muscle stimulation should be effective in influencing bone mass. One complication of lower limb muscle atrophy is severe orthostatic hypotension, as the loss of lower limb muscle activity also eliminates any muscle-pumping activity (Claydon, Steeves, & Krassioukov, 2006). In a study of six chronic and acute SCI patients, electrical stimulation of muscles in the lower limbs was found to significantly improve diastolic and systolic pressure, indicative of the ability of such stimuli to activate the muscle pump (Sampson, Burnham, & Andrews, 2000). Consistent with this observation, several studies have demonstrated that electrical stimulation can prevent bone loss and even increase bone mass in the lower limbs in SCI patients. Belanger

226

Osteoporosis

Figure

15.3

Functional electrical stimulation of muscles employed to enhance and train intrinsic muscle function. Evidence supports the concept that electrical stimulation can be effective in maintaining bone mass, but this approach suffers from the discomfort and inconvenience of use. (Image used with permission from the Johns Hopkins University Arthritis Unit.)

and colleagues (Belanger, Stein, Wheeler, Gordon, & Leduc, 2000) reported that stimulation of the quadriceps muscle for 1 hour a day, 5 days a week, over 24 weeks, significantly increased bone mass in the proximal tibia and distal femur. Eser and colleagues (Eser et al., 2003) showed that electrical muscle stimulation for 30 minutes a day, starting immediately after the onset of muscle paralysis, slowed the rate of bone loss in the tibia by 50%. Similarly, in a crossover trial, electrically stimulated cycling activity was able to reverse bone loss in the distal femur and proximal tibia, demonstrating that sustained stimulation was necessary to maintain the bone mass (Chen et al., 2005). However, a more recent study indicates that these effects may be limited to the more distal aspects of the limbs. Clark and colleagues (Clark et al., 2006) addressed the effect of lower limb muscle stimulation on bone mass in the proximal femur and lumbar spine, and while they were able to show a beneficial effect of the stimulation on tibial bone mineral density, no effect was observed at the proximal femur or lumbar spine, where osteoporotic fractures most frequently occur. Clinical results for SCI patients suggest that, at least conceptually, direct electrical stimulation of the musculature may have potential as a means to prevent bone loss. However, electrical stimulation is not conveniently applied, can be painful, and often leads to rapid muscle fatigue, factors that may significantly limit its applicability as a long-term prevention strategy for osteoporosis.

Approaches in the Prevention of Osteoporosis

227

Mechanical Stimulation As a means of bypassing the complications of direct electrical stimulation of muscle contraction, investigators have recently begun pursuing the concept of using reflexmediated pathways to trigger muscle activity indirectly. Stimulation of a muscle such as the soleus can be readily achieved through such an approach, as it is fundamentally a postural muscle and hence receptive to a wide variety of somatosensory inputs. For example, mechanoreceptors on the plantar surface, such as the Meissner’s Corpuscles, provide feedback on body position when standing, and correspondingly, are linked to the soleus muscle through short-loop reflex arcs. Micromechanical stimulation of the plantar surface stimulates the cutaneous mechanoreceptors, which subsequently initiate calf muscle contraction. Stimulus amplitudes of no more than 20–30 microns are sufficient to stimulate the cutaneous receptors in young adults when applied in the optimal frequency range for these receptors (40–60 Hz), though receptor sensitivity does decrease with increasing age (Inglis, Kennedy, Wells, & Chua, 2002). This strategy has been implemented in a device that can be placed in front of a chair, or under a desk, so that the user can readily obtain calf muscle pump stimulation essentially continuously, in either the home or the workplace (Figure 15.4).

Figure

15.4

Reflex-mediated, calf muscle pump activation can be achieved through plantar stimulation in either the seated or standing position. A small electromagnetic actuator is sufficient to provide a 20-30 micrometer displacement to the plantar surface, which stimulates cutaneous mechanoreceptors and subsequently initiates calf muscle contraction. The lack of any direct attachment to the subject allows convenient use and therefore increases potential as a long-term bone loss preventative strategy.

228

Osteoporosis

Studies utilizing this technology have shown that calf muscle pump activation can be readily enhanced. Stewart, Karman, Montgomery, and McLeod (2004), using plethysmographic techniques, have shown that plantar stimulation can increase lower limb blood flow by close to 50% during upright tilt, while increasing pelvic flow by 35% and even thoracic flow by 20%. In addition, plantar stimulation was shown to almost double lymphatic return pressure. Using cardiovascular monitoring techniques, plantar stimulation has also been shown to significantly enhance venous return from the lower limbs, resulting in reversal of orthostatic hypotension and orthostatic tachycardia (Madhavan, Stewart, & McLeod, 2005). Consistent with these observed effects on lower limb muscle pump activity, sustained plantar stimulation has been shown to significantly increase lower limb muscle strength in postmenopausal women (Russo et al., 2003). Torvinen and colleagues (Torvinen et al., 2003) have shown a similar result for lower leg strength in an 8-month study of 56 young adult men and women in the 19–38 age group. Correspondingly, these effects on the musculature have been observed to affect bone density over the long term. In children, effects of plantar stimulation have been reported as early as 6 months after the start of use (Ward et al., 2004). In adults, a longer duration use appears to be necessary to observe a substantial effect on bone density. In a 1-year-long, randomized, controlled study of postmenopausal women, daily use of plantar stimulation was effective in preventing bone loss in a dose-dependent manner (Rubin et al., 2004). Women who utilized plantar stimulation for 18 minutes a day or more experienced no loss of bone density in the femoral neck, as compared to a 2.1% loss in the control group. Similarly, in the lumbar spine, highly compliant subjects experienced only a 0.1% loss of bone density over the year, versus a 1.6% loss in the control group. These preliminary results, combined with the ease of use of this technology, suggest that this technology may, in the near future, form the basis of a convenient, noninvasive, nonpharmacologic means to prevent or reduce age-related bone loss and osteoporosis.

Concluding Remarks Over the past several decades, physiologic studies have identified interstitial fluid flow as being a dominant factor in the regulation of bone mass. Ensuring adequate interstitial flow through bone tissue must be an essential goal in any long-term strategy for preventing osteoporosis. Sustaining high levels of interstitial fluid flow requires extended periods of upright posture in combination with effective skeletal muscle pumping activity. Because age-related changes in the postural musculature of people commonly result in degradation of skeletal muscle pumping activity, explicit techniques need to be developed to regain this lost function. Here, we have reviewed three techniques currently under development. Balanceoriented exercise programs, such as T’ai Chi Chuan, appear to be capable of preventing bone loss, but they require a commitment level from the individual that may be very difficult to achieve. Sustained electrical stimulation of the musculature has been shown to reverse bone loss, but it can be painful and may not find wide acceptance beyond subpopulations with a very high fracture risk. An alternative approach that has more recently been proposed is reflex-mediated muscle stimulation.

Approaches in the Prevention of Osteoporosis

229

Micromechanical stimulation of the plantar surface has been shown to significantly enhance calf muscle pump activity by activating mechanoreceptors on the surface of the foot, which trigger soleus (calf ) muscle contractions through a reflex arc. This technology has been shown to significantly increase venous and lymphatic return from the lower limbs, enhance blood flow to the lower limbs, and prevent bone loss in postmenopausal women. Convenience of use may lead to wide acceptance of this technology. More importantly, however, the success of this technology has served to refocus attention on the importance of maintaining skeletal muscle pump activity in the goal of preventing bone loss and osteoporosis.

Acknowledgments This work was supported in part by a grant from the New York State Office of Science, Technology, and Academic Research, Albany, New York.

REFERENCES Bamias, A., Kastritis, E., Bamia, C., Moulopoulos, L. A., Melakopoulos, I., Bozas, G., et al. (2005). Osteonecrosis of the jaw in cancer after treatment with bisphosphonates: Incidence and risk factors. Journal of Clinical Oncology, 23, 8580–8587. Belanger, M., Stein, R. B., Wheeler, G. D., Gordon, T., & Leduc, B. (2000). Electrical stimulation: Can it increase muscle strength and reverse osteopenia in spinal cord injured individuals? Archives of Physical Medicine and Rehabilitation, 81, 1090–1098. Bergula, A. P., Huang, W., & Frangos, J. A. (1999). Femoral vein ligation increases bone mass in the hindlimb suspended rat. Bone, 24, 161–162. Chan, K., Qin, L., Lau, M., Woo, J., Au, S., Choy, W., et al. (2004). A randomized, prospective study of the effects of Tai Chi Chun exercise on bone mineral density in postmenopausal women. Archives of Physical Medicine and Rehabilitation, 85, 717–722. Chen, S. C., Lai, C. H., Chan, W. P., Huang, M. H., Tsai, H. W., & Chen, J. J. (2005). Increases in bone mineral density after functional electrical stimulation cycling exercises in spinal cord injured patients. Disability and Rehabilitation, 27, 1337–1341. Clark, J. M., Jelbart, M., Rischbieth, H., Strayer, J., Chatterton, B., Schultz, C., et al. (2007). Physiological effects of lower extremity functional electrical stimulation in early spinal cord injury: Lack of efficacy to prevent bone loss. Spinal Cord, 45(1), 78–85. Claydon,V. E., Steeves, J. D., & Krassioukov, A. (2006). Orthostatic hypotension following spinal cord injury: Understanding clinical pathophysiology. Spinal Cord, 44, 341–351. Colleran, P. N., Wilkerson, M. K., Bloomfield, S. A., Suva, L. J., Turner, T. T., & Delp, M. (2000). Alterations in skeletal perfusion with simulated microgravity: A possible mechanism for bone remodeling. Journal of Applied Physiology, 89, 1046–1054. Eser, P., de Bruin, E. D., Telley, I., Lechner, H. E., Knecht, H., & Stussi, E. (2003). Effect of electrical stimulation-induced cycling on bone mineral density in spinal cord-injured patients. European Journal of Clinical Investigation, 33, 412–419. Fritton, S., McLeod, K., & Rubin, C. T. (2000). Quantifying the strain history of bone: Spatial uniformity and self-similarity of low-magnitude strains. Journal of Biomechanics, 33, 317–325. Gray, H. (2004). Gray’s anatomy: The anatomical basis of clinical practice (39th ed.). New York: C. V. Mosby and Company. Hagan, R. D., Diaz, F. J., & Harvath, S. (1978). Plasma volume changes with movement to supine and standing positions. Journal of Applied Physiology, 45, 414–417. Hoshino, H., Kushida, K., Yamazaki, K., Takahashi, M., Ogihara, H., Naitoh, K., et al. (1996). Effect of physical activity as a caddie on ultrasound measurements of the os calcis: A cross-sectional comparison. Journal of Bone and Mineral Research, 11, 412–418.

230

Osteoporosis Inglis, J. T., Kennedy, P. M., Wells, C., & Chua, R. (2002). The role of cutaneous receptors in the foot. Advances in Experimental Medicine and Biology, 508, 111–117. Issekutz, B., Jr., Blizzard, J. J., Birkhead, N. C., & Rodahl, K. (1966). Effect of prolonged bed rest on urinary calcium output. Applied Physiology, 21, 1013–1020. Jones, H., Priest, J., Hayes, W., Tichenor, C., & Nagel, D. (1977). Humeral hypertrophy in response to exercise. Journal of Bone and Joint Surgery, 59, 204–208. Keck, S. W., & Kelly, J. (1965). The effect of venous stasis on intraosseous pressure and longitudinal bone growth in the dog. Journal of Bone and Joint Surgery, 47A, 539–544. Kruse, R. L., & Kelly, P. J. (1974). Acceleration of fracture healing distal to a venous tourniquet. Journal of Bone and Joint Surgery, 56A, 730–739. Lane, J. M., & Nydick, M., (1999). Osteoporosis: Current modes of prevention and treatment. Journal of American Academy of Orthopaedic Surgeons, 7, 19–31. Langzam, E., Nemirovsky, Y., Isakov, E., & Mizrahi, J. (2007). Muscle enhancement using closedloop electrical stimulation: Volitional versus induced torque. Journal of Electromyography and Kinesiology, 17(3) 275–284. Li, G. P., Bronk, J. T., An, K. N., & Kelly, P. J. (1987). Permeability of cortical bone of canine tibiae. Microvascular Research, 34, 302–310. Madhavan, G., Stewart, J. M, & McLeod, K. J. (2005). Effect of plantar stimulation on the cardiovascular responses to immobility. American Journal of Physical Medicine and Rehabilitation, 84, 338–345. McDonald, F., & Pitt Ford, T. R. (1993). Blood flow changes in the tibia during external loading. Journal of Orthopaedic Research, 11, 36–48. Migliorati, C. A., Casiglia, J., Epstein, J., Jacobsen, P. L., Siegel, M. A., & Woo, S. B. (2005). Managing the care of patients with bisphosphonate-associated osteonecrosis: An American Academy of Oral Medicine position paper. Journal of the American Dental Association, 136, 1658–1668. Montgomery, R. J., Sutker, B. D., Bronk, J. T., Smith, S. R., & Kelly, P. J. (1988). Interstitial fluid flow in cortical bone. Microvascular Research, 35, 295–307. Paillard, T., Noe, F., Passelergue, P., & Dupui, P. (2005). Electrical stimulation superimposed onto voluntary muscular contraction. Sports Medicine, 35, 951–966. Peckham, P. H., & Knutson, J. S. (2005). Functional electrical stimulation for neuromuscular applications. Annual Review of Biomedical Engineering, 7, 327–360. Qin, L., Au, S., Choy, W., Leung, P., Neff, M., Lee, K., et al. (2002). Regular Tai Chi Chuan exercise may retard bone loss in postmenopausal women: A case-control study. Archives of Physical Medicine and Rehabilitation, 83, 1355–1359. Rowell, L. B. (1993). Human cardiovascular control. New York: Oxford University Press. Rubin, C., Recker, R., Cullen, D., Ryaby, J., McCabe, J., & McLeod, K. (2004). Prevention of postmenopausal bone loss by a low-magnitude, high-frequency mechanical stimuli: A clinical trial assessing compliance, efficacy, and safety. Journal of Bone and Mineral Research, 19, 343–351. Russo, C. R., Lauretani, F., Bandinelli, S., Bartali, B., Cavazzini, C., Guralnik, J. M., et al. (2003). High-frequency vibration training increases muscle power in postmenopausal women. Archives of Physical Medicine and Rehabilitation, 85, 1854–1857. Sampson, E. E., Burnham, R. S., & Andrews, B. J. (2000). Functional electrical stimulation effect on orthostatic hypotension after spinal cord injury. Archives of Physical Medicine and Rehabilitation, 81, 139–143. Seliger, W. G. (1970). Tissue fluid movement in compact bone. The Anatomical Record, 166, 247–256. Sheperd, J. T. (1966). Role of the veins in the circulation. Circulation, 33, 484–491. Smith, E., Gilligan, C., McAdam, M., Ensign, C., & Smith, P. (1989). Deterring bone loss by exercise intervention in premenopausal and postmenopausal women. Calcified Tissue International, 44, 312–321. Snow-Harter, C., Bouxsein, M., Lewis, B., Carter, D., & Marcus, R. (1992). Effects of resistance and endurance exercise on bone mineral status of young women. Journal of Bone and Mineral Research, 7, 761–769. Stewart, J. M., Karman, K., Montgomery, L. D., & McLeod, K. J. (2005). Plantar vibration improves leg fluid flow in perimenopausal women. American Journal of Physiology, Regulatory Integrative and Comparative Physiology, 288, 623–629. Torvinen, S., Kannus, P., Sievanen, H., Jarvinen, T. A., Pasanen, M., Kontulainen, S., et al. (2003). Effect of 8-month vertical whole body vibration on bone, muscle performance, and body balance: A randomized controlled study. Journal of Bone and Mineral Research, 18, 876–884.

Approaches in the Prevention of Osteoporosis

231

Ward, K., Alsop, C., Caulton, J., Rubin, C., Adams, J., & Mughal, Z. (2004). Low magnitude mechanical loading is osteogenic in children with disabling conditions. Journal of Bone and Mineral Research, 19, 360–369. Wolff, J. (1892). Das Gesetz der Transformation der Knochen (The law of bone remodeling). Originally published Berlin: Verlag von August Hirshwald; English translation by P. Maquet & R. Furlong, Berlin: Springer Verlag, 1986. Woo, S. B., Hellstein, J. W., & Kalmar, J. R. (2006). Systematic review: Bisphosphonates and osteonecrosis of the jaws. Annals of Internal Medicine, 144, 753–761. Zweifach, B. W., & Intaglietta, M. (1966). Fluid exchange across the blood capillary interface. Federation Proceedings, 25, 1784–1788.

Appendixes

Appendix A Resources and Related Links

This section provides the names of resources and links in government and the private sector related to bone health. Links to nonfederal organizations do not constitute an endorsement of any organization by the federal government, and none should be inferred.

Federal Government Agency for Healthcare Research and Quality (AHRQ) Osteoporosis publications and electronic information http://www.ahrq.gov/news/pubsix.htm

Centers for Disease Control and Prevention (CDC) Growing Stronger: Strength Training for Older Adults http://www.cdc.gov/nccdphp/dnpa/physical/growing_stronger PATCH—CDC’s Planned Approach to Community Health http://www.cdc.gov/nccdphp/patch/index.htm Physical Activity and Health: A Report of the Surgeon General http://www.cdc.gov/nccdphp/sgr/sgr.htm Powerful Bones, Powerful Girls Web Site http://www.cdc.gov/powerfulbones/ http://www.cdc.gov/powerfulbones/parents Powerful Girls Calendar http://www.cdc.gov/powerfulbones/games_fun/calendar_2004.pdf Promoting Better Health for Young People Through Physical Activity and Sports http://www.cdc.gov/nccdphp/dash/presphysactrpt/index.htm VERBTM. It’s What You Do. Youth Media Campaign http://www.cdc.gov/youthcampaign/ WISEWOMAN: Well-Integrated Screening and Evaluation for Women Across the Nation http://www.cdc.gov/wisewoman

236

Appendix A

Centers for Medicare and Medicaid Services (CMS) Bone Mass Measurement Health Promotion Initiative http://www.cms.hhs.gov/partnerships/tools/outreach/initiatives/default. asp#bonemass

National Heart, Lung, and Blood Institute (NHLBI) DASH (Dietary Approaches to Stop Hypertension) Eating Plan http://www.nhlbi.nih.gov/health/public/heart/hbp/dash/ Hearts N’ Parks http://www.nhlbi.nih.gov/health/prof/heart/obesity/hrt_n_pk/index.htm National Cholesterol Education Program http://www.nhlbi.nih.gov/about/ncep/

National Institute on Aging (NIA) Exercise: A Guide From the National Institute on Aging http://www.niapublications.org/exercisebook/index.asp Exercise: A Video From the National Institute on Aging http://www.niapublications.org/exercisevideo/index.asp

National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) Information Package—Ordering Information http://www.niams.nih.gov/hi/index.htm#ip Osteoporosis Prevention, Diagnosis, and Therapy http://www.odp.od.nih.gov/consensus/cons/111/111_intro.htm Osteoporosis: Progress and Promise http://www.niams.nih.gov/hi/topics/osteoporosis/opbkgr.htm

National Institute of Child Health and Human Development (NICHD) Milk Matters Educational Campaign http://www.156.40.88.3/milk/milk.cfm

National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) Sisters Together: Move More, Eat Better http://www.win.niddk.nih.gov/sisters/index.htm

National Institutes of Health (NIH) Clinical Trials http://www.ClinicalTrials.gov NIH Osteoporosis and Related Bone Disease—National Resource Center http://www.osteo.org/default.asp

237

Appendix A

President’s Council on Physical Fitness and Sports The President’s Challenge http://www.fitness.gov http://www.presidentschallenge.org U.S. Administration on Aging Aging Internet Information Notes: Osteoporosis http://www.aoa.gov/prof/notes/docs/osteoporosis.doc

U.S. Department of Agriculture (USDA) Dietary Guidelines for Americans http://www.usda.gov/cnpp/ School Meals http://www.fns.usda.gov/cnd USDA Food and Nutrition Service http://www.fns.usda.gov United States National Agricultural Library http://www.nal.usda.gov

U.S. Department of Education (USDOE) National Institute on Disability and Rehabilitation Research (NIDRR) http://www.ed.gov/about/offices/list/osers/nidrr/index.html?src =mr

U.S. Department of Health and Human Services (HHS) Dietary Guidelines for Americans http://www.health.gov/dietaryguidelines HealthierUS Initiative http://www.healthierus.gov Healthfinder® Gateway to Reliable Consumer Health Information on the Internet http://www.healthfinder.gov Healthy People in Healthy Communities: A Community Planning Guide Using Healthy People 2010 http://www.healthypeople.gov/publications/HealthyCommunities2001 Healthy People 2010 Toolkit http://www.healthypeople.gov/state/toolkit National Women’s Health Information Center http://www.4woman.gov STEPS to a HealthierUS Initiative http://www.healthierus.gov/steps/index.html

U.S. Food and Drug Administration (FDA) Guidance on How to Understand and Use the Nutrition Facts Panel on Food Labels http://www.cfsan.fda.gov/~dms/foodlab.html U.S. Food and Drug Administration—FDA Consumer Magazine (10/02) http://www.fda.gov/fdac/features/2002/502_men.html

238

Appendix A

State Government Association of State and Territorial Chronic Disease Program Directors Osteoporosis Council http://www.chronicdisease.org/Osteo_Council/osteo_about.htm Osteoporosis Council: Contact Information for State Osteoporosis Directors/ Coordinators http://www.chronicdisease.org/Osteo_Council/osteo_membership.htm Osteoporosis State Program Practices That Work http://www.chronicdisease.org/whc/Practices_that_Work.pdf Osteoporosis 2000: A Resource Guide for State Programs http://www.chronicdisease.org/Osteo_Council/publications/Resource_Guide.pdf

State Osteoporosis Web Sites Alabama Department of Public Health http://www.adph.org/NUTRITION/default.asp?DeptId=115&TemplateId=2022& TemplateNbr=0 Arizona Osteoporosis Coalition http://www.azoc.org http://www.fitbones.org California Department of Health Services, Arthritis and Osteoporosis Unit http://www.dhs.ca.gov/osteoporosis Colorado Department of Public Health and Environment: Osteoporosis Web Site http://www.cdphe.state.co.us/pp/Osteoporosis/osteohom.html Florida Osteoporosis Prevention and Education Program http://www.doh.state.fl.us/family/osteo/default.html Georgia Osteoporosis Initiative http://www.gabones.com Indiana Osteoporosis Prevention Initiative http://www.in.gov/isdh/programs/osteo Kentucky Office of Women’s Physical and Mental Health: Osteoporosis http://chs.ky.gov/womenshealth/resourcecenter/Resources/osteoporosis.htm Maryland Department of Health and Mental Hygiene http://www.strongerbones.org Michigan Department of Community Health http://www.michigan.gov/mdch/0,1607,7–132–2940_2955—-,00.html Mississippi State Department of Health http://www.msdh.state.ms.us/msdhsite/index.cfm/13,0,225,html Missouri Department of Health and Senior Services http://www.dhss.state.mo.us/maop New Jersey Department of Health and Senior Services http://www.state.nj.us/health/senior/osteo New York State Department of Health http://www.health.state.ny.us/nysdoh/osteo/index.htm

239

Appendix A

Ohio Department of Health http://www.odh.ohio.gov/resources/publications/osteo_guide.pdf Rhode Island Department of Health http://www.health.ri.gov/disease/osteo/index.php Tennessee Department of Health http://www2.state.tn.us/health/healthpromotion/osteoporosis.html Texas Department of Health: Osteoporosis Awareness and Education Program http://www.tdh.state.tx.us/osteo Virginia Department of Health http://www.vahealth.org/nutrition/bones.htm West Virginia Department of Health and Human Resources http://www.wvdhhr.org/bph/oehp/hp/osteo/default.htm

Nongovernment American Academy of Orthopaedic Surgeons (AAOS) http://www.aaos.org

American Academy of Pediatrics (AAP) Policy Statement on Calcium Requirements of Infants, Children, and Adolescents http://aappolicy.aappublications.org/policy_statement/index.dtl#C

American Council on Exercise http://www.acefitness.org

American College of Sports Medicine http://www.acsm.org

American Dietetic Association (ADA) http://www.eatright.org

American Society for Bone and Mineral Research (ASBMR) http://www.asbmr.org

ASBMR Bone Curriculum Web Site http://depts.washington.edu/bonebio/ASBMRed/ASBMRed.html

Bone Builders http://www.bonebuilders.org/

BoneKEy-Osteovision® http://`www.bonekey-ibms.org

240

Appendix A

Foundation for Osteoporosis Research and Education (FORE) http://www.fore.org/

Growing Stronger: Strength Training for Older Adults http://nutrition.tufts.edu/research/growingstronger

International Bone and Mineral Society (IBMS) http://www.ibmsonline.org/

International Osteoporosis Foundation (IOF) http://www.osteofound.org/

International Society for Clinical Densitometry (ISCD) http://www.iscd.org/visitors/osteoflash/index.cfm

National Dairy Council (NDC) http://www.nationaldairycouncil.org

National Osteoporosis Foundation (NOF) http://www.nof.org

National Strength and Conditioning Association http://www.nsca-lift.org

Osteoporosis and Bone Physiology, University of Washington http://courses.washington.edu/bonephys

Osteoporosis Education, University of Washington http://www.osteoed.org/faq/index.html#male http://www.osteoed.org

Osteogenesis Imperfecta Foundation (OIF) http://www.oif.org

The Paget Foundation (TPF) http://www.paget.org

Shape Up America! http://www.shapeup.org

U.S. Bone and Joint Decade http://www.usbjd.org

Appendix B Diagnoses That Support Medical Necessity for Bone Densitometry for Reimbursement

ICD-9 Code Hyperparathyroidism, unspecified Primary hyperparathyroidism Secondary hyperparathyroidism, nonrenal Other hyperparathyroidism Cushing’s syndrome (includes latrogenic cortisol excess) Ovarian dysfunction; postablative ovarian failure Ovarian dysfunction; other ovarian failure, premature menopause Ovarian dysfunction; other ovarian failure, other Other endocrine disorders; ectopic hormone secretion, not elsewhere classified Other endocrine disorders; ectopic hormone secretion, unspecified Disorders of menstruation and other abnormal bleeding from female genital tract; absence of menstruation Menopausal and postmenopausal disorders; postmenopausal bleeding Menopausal and postmenopausal disorders; symptomatic menopausal or female climacteric state Menopausal and postmenopausal disorders; postmenopausal atrophic vaginitis Menopausal and postmenopausal disorders; symptomatic states associated with artificial menopause Menopausal and postmenopausal disorders; other specified menopausal and postmenopausal disorders Menopausal and postmenopausal disorders; unspecified menopausal and postmenopausal disorders Other disorders of bone and cartilage; osteoporosis, unspecified Other disorders of bone and cartilage; osteoporosis, senile Other disorders of bone and cartilage; osteoporosis, idiopathic Other disorders of bone and cartilage; osteoporosis, disuse Other disorders of bone and cartilage; osteoporosis, other Other disorders of bone and cartilage; pathologic fracture, fracture of humerus Other disorders of bone and cartilage; pathologic fracture, distal radius and ulna Other disorders of bone and cartilage; pathologic fracture, fracture of vertebrae Other disorders of bone and cartilage; pathologic fracture, fracture of neck of femur Other disorders of bone and cartilage; pathologic fracture, fracture of tibia or fibula Pathologic fracture of other specified site

252.00 252.01 252.02 252.08 255.0 256.2 256.31 256.39 259.3 259.9 626.0 627.1 627.2 627.3 627.4 627.8 627.9 733.00 733.01 733.02 733.03 733.09 733.11 733.12 733.13 733.14 733.16 733.19

242

Appendix B

ICD-9 Code Other disorders of bone and cartilage; other and unspecified Other congenital musculoskeletal anomalies; osteodystrophies, osteogenesis imperfecta Other congenital musculoskeletal anomalies; other specified anomalies of muscle, tendon, fascia, and connective tissue, Ehler-Danlos syndrome Chromosomal anomalies; gonadal dysgenesis Nonspecific abnormal findings on radiological and other examination of body structure, musculoskeletal system Fracture of vertebral column without mention of spinal cord injury; cervical, closed, unspecified level Fracture of vertebral column without mention of spinal cord injury; cervical, closed, first vertebra Fracture of vertebral column without mention of spinal cord injury; cervical, closed, second vertebra Fracture of vertebral column without mention of spinal cord injury; cervical, closed, third vertebra Fracture of vertebral column without mention of spinal cord injury; cervical, closed, fourth vertebra Fracture of vertebral column without mention of spinal cord injury; cervical, closed, fifth vertebra Fracture of vertebral column without mention of spinal cord injury; cervical, closed, sixth vertebra Fracture of vertebral column without mention of spinal cord injury; cervical, closed, seventh vertebra Fracture of vertebral column without mention of spinal cord injury; cervical, closed, multiple vertebrae Fracture of vertebral column without mention of spinal cord injury; cervical open, unspecified level Fracture of vertebral column without mention of spinal cord injury; cervical, open, first vertebra Fracture of vertebral column without mention of spinal cord injury; cervical, open, second vertebra Fracture of vertebral column without mention of spinal cord injury; cervical, open, third vertebra Fracture of vertebral column without mention of spinal cord injury; cervical, open, fourth vertebra Fracture of vertebral column without mention of spinal cord injury; cervical, open, fifth vertebra Fracture of vertebral column without mention of spinal cord injury; cervical, open, sixth vertebra Fracture of vertebral column without mention of spinal cord injury; cervical, open, seventh vertebra Fracture of vertebral column without mention of spinal cord injury; cervical, open, multiple vertebrae Fracture of vertebral column without mention of spinal cord injury; dorsal (thoracic), closed Fracture of vertebral column without mention of spinal cord injury; dorsal (thoracic), open

733.90 756.51 756.83 758.6 793.7 805.00 805.01 805.02 805.03 805.04 805.05 805.06 805.07 805.08 805.10 805.11 805.12 805.13 805.14 805.15 805.16 805.17 805.18 805.2 805.3

243

Appendix B

ICD-9 Code Fracture of vertebral column without mention of spinal cord injury; lumbar, closed Fracture of vertebral column without mention of spinal cord injury; lumbar, open Fracture of vertebral column without mention of spinal cord injury; sacrum and coccyx, closed Fracture of vertebral column without mention of spinal cord injury; sacrum and coccyx, open Fracture of vertebral column without mention of spinal cord injury; unspecified, closed Fracture of vertebral column without mention of spinal cord injury; unspecified, open Fracture of vertebral column with spinal cord injury; cervical, closed, C1–C4 level with unspecified spinal cord injury Fracture of vertebral column with spinal cord injury; cervical, closed, C1–C4 level with complete lesion of cord Fracture of vertebral column with spinal cord injury; cervical, closed, C1–C4 level with anterior cord syndrome Fracture of vertebral column with spinal cord injury; cervical, closed, C1–C4 level with central cord syndrome Fracture of vertebral column with spinal cord injury; cervical, closed, C1–C4 level with other specified spinal cord injury Fracture of vertebral column with spinal cord injury; cervical, closed, C5–C7 level with unspecified spinal cord injury Fracture of vertebral column with spinal cord injury; cervical, closed, C5–C7 level with complete lesion of cord Fracture of vertebral column with spinal cord injury; cervical, closed, C5–C7 level with anterior cord syndrome Fracture of vertebral column with spinal cord injury; cervical, closed, C5–C7 level with central cord syndrome Fracture of vertebral column with spinal cord injury; cervical, closed, C5–C7 level with other specified spinal cord injury Fracture of vertebral column with spinal cord injury; cervical, open, C1–C4 level with unspecified spinal cord injury Fracture of vertebral column with spinal cord injury; cervical, open, C1–C4 level with complete lesion of cord Fracture of vertebral column with spinal cord injury; cervical, open, C1–C4 level with anterior cord syndrome Fracture of vertebral column with spinal cord injury; cervical, open, C1–C4 level with central cord syndrome Fracture of vertebral column with spinal cord injury; cervical, open, C1-C4 level with other specified spinal cord injury Fracture of vertebral column with spinal cord injury; cervical, open, C5–C7 level with unspecified cord injury Fracture of vertebral column with spinal cord injury; cervical, open, C5–C7 level with complete lesion of cord Fracture of vertebral column with spinal cord injury; cervical, open, C5–C7 level with anterior cord syndrome

805.4 805.5 805.6 805.7 805.8 805.9 806.00 806.01 806.02 806.03 806.04 806.05 806.06 806.07 806.08 806.09 806.10 806.11 806.12 806.13 806.14 806.15 806.16 806.17

244

Appendix B

ICD-9 Code Fracture of vertebral column with spinal cord injury; cervical, open, C5–C7 level with central cord syndrome Fracture of vertebral column with spinal cord injury; cervical, open, C5–C7 level with other specified spinal cord injury Fracture of vertebral column with spinal cord injury; dorsal, closed, T1–T6 level with unspecified spinal cord injury Fracture of vertebral column with spinal cord injury; dorsal, closed, T1–T6 level with complete lesion of cord Fracture of vertebral column with spinal cord injury; dorsal, closed, T1–T6 level with anterior syndrome Fracture of vertebral column with spinal cord injury; dorsal, closed, T1–T6 level with central cord syndrome Fracture of vertebral column with spinal cord injury; dorsal, closed,T1–T6 level with other specified spinal cord injury Fracture of vertebral column with spinal cord injury; dorsal, closed, T7–T12 level with unspecified spinal cord injury Fracture of vertebral column with spinal cord injury; dorsal, closed, T7–T12 level with complete lesion of cord Fracture of vertebral column with spinal cord injury; dorsal, closed,T7–T12 level with anterior cord syndrome Fracture of vertebral column with spinal cord injury; dorsal, closed, T7–T12 level with central cord syndrome Fracture of vertebral column with spinal cord injury; dorsal, closed, T7–T12 level with other specified spinal cord injury Fracture of vertebral column with spinal cord injury; dorsal, open, T7–T12 level with unspecified spinal cord injury Fracture of vertebral column with spinal cord injury; dorsal, open, T1–T6 level with complete lesion of cord Fracture of vertebral column with spinal cord injury; dorsal, open, T1–T6 level with anterior cord syndrome Fracture of vertebral column with spinal cord injury; dorsal, open, T1–T6 level with central cord syndrome Fracture of vertebral column with spinal cord injury; dorsal, open, T1–T6 level with other specified cord injury Fracture of vertebral column with spinal cord injury; dorsal, open, T7–T12 level with unspecified cord injury Fracture of vertebral column with spinal cord injury; dorsal, open, T7–T12 level with complete lesion of cord Fracture of vertebral column with spinal cord injury; dorsal, open, T7–T12 level with anterior cord syndrome Fracture of vertebral column with spinal cord injury; dorsal, open, T7–T12 level with central cord syndrome Fracture of vertebral column with spinal cord injury; dorsal, open, T7–T12 level with other specified spinal cord injury Fracture of vertebral column with spinal cord injury; lumbar, closed Fracture of vertebral column with spinal cord injury; lumbar, open Fracture of vertebral column with spinal cord injury; sacrum and coccyx, closed, with unspecified spinal cord injury

806.18 806.19 806.20 806.21 806.22 806.23 806.24 806.25 806.26 806.27 806.28 806.29 806.30 806.31 806.32 806.33 806.34 806.35 806.36 806.37 806.38 806.39 806.4 806.5 806.60

245

Appendix B

ICD-9 Code Fracture of vertebral column with spinal cord injury; sacrum and coccyx, closed, with complete cauda equina lesion Fracture of vertebral column with spinal cord injury; sacrum and coccyx, closed, with other cauda equina injury Fracture of vertebral column with spinal cord injury; sacrum and coccyx, closed, with other spinal cord injury Fracture of vertebral column with spinal cord injury; sacrum and coccyx, open, with unspecified spinal cord injury Fracture of vertebral column with spinal cord injury; sacrum and coccyx, open, with complete cauda equina lesion Fracture of vertebral column with spinal cord injury; sacrum and coccyx, open, with other cauda equina injury Fracture of vertebral column with spinal cord injury; sacrum and coccyx, open, with other spinal cord injury Fracture of vertebral column with spinal cord injury; unspecified, closed Fracture of vertebral column with spinal cord injury; unspecified, open Acquired absence of genital organs Other conditions influencing health status; asymptomatic postmenopausal status (age-related) (natural) Encounter for other and unspecified procedures and aftercare; long-term (current) use of steroids Follow-up examination; following completed treatment with high-risk medications, not elsewhere classified

806.61 806.62 806.69 806.70 806.71 806.72 806.79 806.8 806.9 V45.77 V49.81 V58.65 V67.51

Index

Abdominal fullness, 14 Absolute risk (AR) of fracture, 37 Access to care, 181–186 Acetaminophen, 74, 76 ACOVE Quality Indicators for Management of Osteoporosis in Vulnerable Elders, 207 Active range of motion (AROM), 156 Activities of daily living (ADLs) after hip fractures, 84 client-centered approach, 154 –155 common problems, 160 fear of falling and, 142 functional ability, 144 –145 post-fracture functioning, 13 –14 Activities-Specific Balance Confidence Scale, 144 Activity Index and Meaningfulness Scale, 154 –155 Actonel®. See Risedronate Adaptation. See Bone remodeling Adolescents calcium intake, 172 calcium supplementation in, 170 maximizing bone mass, 169 –179 soda consumption, 171–172 vitamin D intake, 172 –173 Aerobic exercise, 121 African American women, 10 Age/aging bone density and, 84 bone mass decrease and, 120 bone mineral density testing and, 38 fracture sites and, 11 of global populations, 16 Alcohol intake, 42, 111 Alendronate (Fosamax®), 48 administration, 51–52 adverse events, 51–52 characterization, 62 efficacy, 49 –50 Alkaline phosphatase, 39, 40 Amenorrhea, 174, 176 American College of Rheumatology, 37

American College of Sports Medicine (ACSM), 121 Ampicillin, drug interactions, 61 Analgesics, 74, 76 Anderson’s sequential model, 214, 215 Androgens, decrease in, 23 Annulus fibrosis, 88 Anorexia nervosa, 176 Antiandrogen therapy, 39 Anticoagulation therapy, 87 Anticonvulsants, 42, 174 –175 Antiepileptics, 174 –175 Aquatic exercise, restorative, 130 Arixtra, 87 Arizona Department of Health Services, 193 Arizona Osteoporosis Coalition, 193 Arthritis Foundation, 191 Arthropathies, low bone density and, 42 Aspirin, 87 Association of Retired and Senior Volunteer Program Directors, Inc. (RSVP), 194 Asthma, corticosteroid therapy, 174 Balance, measures of, 156 –157 Balance assessments, 144 –145, 149 Balance exercise, restorative, 129 Balance screening, 143 –145 Bazedoxifene, 59 Beck Depression Inventory, 159 Bed rest for hip fractures, 86 urinary calcium levels and, 221 Berg Balance Test, 145 Biestrogen (Biest), 58 Binghampton University Foundation, 198 Bioidentical hormone therapy (BHRT), 57–59, 72 Bisphosphonate therapy administration, 51–52 adverse events, 51–52, 219 description, 48 efficacy, 49 –51

247

248 mechanism of action, 48 – 49 pharmacokinetics, 48 – 49 Blood flow, 220 – 222 Bone causes of low density in, 40 – 43 cellular components, 20 – 21 diet and, 103 –115 formation of, 26, 118 loss, 27, 120 – 212 maintenance of, 221 maximization of mass, 169 –179 mechanical stimulation of, 227– 228 physiology of, 20 – 28 skeletal muscle and, 223 – 224 types of, 20 Bone and Joint Decade, 202 – 203 Bone Builders, 192 –193 Bone Estrogen Strength Training (BEST), 193 Bone Health and Osteoporosis (Surgeon General’s report), 5, 204, 205, 206 – 207 The Bone Mass Measurement Act, 209 Bone metastases, 65 Bone mineral content (BMC), 118 Bone mineral density (BMD) calculation of, 9 classification based on, 9 clinical utility of, 38 –39 electrical stimulation of muscle and, 225 – 226 exercise and, 117 femoral, 10 lifestyle issues, 99 Medicare coverage for, 209 osteopenia and, 9 osteoporosis and, 9 reference population for, 9 –10 serial testing, 36 testing of, 33 –35 Bone morphogenic proteins (BMPs), 26 Bone remodeling cycle of, 120 –121 description of, 20, 21– 24 fluid flow and, 220 – 221 phases of, 22 – 23 steps in, 21 Bone resorption calcium from, 23 description, 20 – 21 initiation of, 39 nutrition and, 24 osteoclasts and, 39 phosphorus from, 23 Bone-specific alkaline phosphatase (BSAP), 39 Bone strength, exercise and, 117

Index Bone turnover, markers of, 39 – 40 Bones: Don’t Wait Until You Break One to Find Out That You Have Osteoporosis, 193 Boniva®. See Ibandronate Bonmax, 58 Broadband ultrasound attenuation (BUA), 35 C-telopeptide (CTX), 40 Caffeine intake, 111 Calciferol. See Vitamin D (calcitriol) Calcitonin bone formation and, 26 bone health and, 25 characterization, 63 production of, 25 Calcitonin (salmon) therapy administation, 66 adverse events, 66 analgesic effects of, 66 efficacy, 65 – 66 mechanism of action, 65 pharmacokinetics, 65 Calcitriol (1,25-dihydroxy vitamin D3). See Vitamin D (calcitriol) Calcium, 67– 69. See also Calcium intake absorption of, 67, 71 adverse effects, 68 bone content of, 104 bone health and, 170 –172 from bone resorption, 23 drug interactions, 68 efficacy of therapy with, 71–72 excretion of, 221 food sources of, 106 –107 mechanism of action, 70 mobilization of, 71 peak bone mass and, 104 Calcium, Its Not Just Milk Program, 193 –194 Calcium carbonate (Caltrate) administration, 72 adverse events, 68 cost of, 113 drug interactions, 68 Calcium citrate (Citrical) administration, 72 adverse events, 68 drug interactions, 68 tolerability, 113 Calcium intake during childhood, 170 –172 excessive, 109 –110 formulations, 69 health policy and, 214, 216

249

Index increasing, 172 interfering foods, 106 nephrolithiasis and, 71 osteoporosis paradox, 106 recommendations, 67– 69, 105 –106, 171 risk reduction and, 47 supplementation in children, 170 supplements, 112 –113 Calf muscle activation, 227– 229 Caltrate. See Calcium carbonate Canada, policy development, 214 – 215 Canadian Occupational Performance Measure (COPM), 155 Cancellous bone estrogens and loss of, 24 sites of, 20 structure of, 20 Cancer, 65, 175, 176 Carbamazine, 174 Cefazolin, 87 Celiac disease, 175 Celvista, countries where approved, 58 Cerebral palsy, 175 Chartered Society of Physiotherapy (CSP), 128 Cheese, 112 Children calcium intake, 172 calcium supplementation in, 170 dietary calcium in, 104 exercises for, 121, 122 fractures in, 175 maximizing bone mass, 169 –179 osteoporosis prevention programs, 2 –3, 177 soda consumption, 171–172 vitamin D intake, 172 –173 Cholecalciferol. See Vitamin D Cholesterol, raloxifene and, 60 Cholestyramine (Questran®), 61 Chondrodysplasia, 175 Chronic illness depression and, 158 –159 impact on families, 15 quality of life and, 153 Chronic obstructive pulmonary disease (COPD), 91–92 Circulatory system gravity and, 221– 222 posture and, 223 – 224 Citrical. See Calcium citrate Clindamycin, 87 Collagen, digestion of, 39 Collagen cross-linking, 40 College of Public Health, University of Arizona, 192

Colles’ fractures, 15, 97, 98 Combination antiresorptive therapy, 66 – 67 Community health planning committees, 189 Community outreach programs, 187–199 Compensation strategies, 162 –163 Compression fractures, 88 –97, 90. See also Crush fractures; Spinal fractures; Vertebral fractures diagnosis of, 92 –94 treatment options, 94 –95 Computed tomography (CT), 92 –94 Connective tissue disease, 42 Cooperative Extension Programs, 187, 188 –190 Cooperative State Research, Education and Extension Service (CSREES) agency, 188 Coping skills, 158 Cortical bone estrogens and loss of, 24 sites of, 20 structure of, 20 Corticosteroid therapy, 38 –39, 174 –175 Cost utility analysis, of therapy, 37 Costs, of osteoporotic fractures, 15 –16 Coumadin, 87 Coumestans, 73 Coumestrol, 72, 73 County extension educators, 190 Crane Fund for Widows and Children, 198 Creating Health Initiative, 190 –192 Crosslaps immunoassay, 40 Crush fractures, 14. See also Compression fractures Cutaneous mechanoreceptors, 227 Cystic fibrosis, 175 Cytokine regulation, 25 – 27 Daidzein, 72, 73 Dairy products, 106, 112. See also Nutrition Dancers, bone mineral density, 173 Decker School of Nursing at Binghamton University, 198 Deep vein thrombosis (DVT), 59, 87 Dehydroepiandrosterone (DHEA), 58 Delayed puberty, 176 Demographics global changes, 16 for osteoporosis, 9 –18 Deoxypyridinoline (DPD), 39, 40 Depression, 158 –159 Diet. See Nutrition Dietary Reference Intake (DRI) values, 171 1,25 Dihydroxyvitamin D. See Vitamin D Dioxins (TCDDs), 27 Diphenylhydantoin, 174 Disordered eating, 176

250 Dual energy X-ray absorptiometry (DXA), 34 –35, 117 demographics for screening, 38 efficacy, 182 future directions, 185 mobile equipment, 183 –185 profitability, 185 Early supported discharge programs (ESDPs), 127 Eating disorders, 42 Elderly persons exercise programs for, 122 fall-related mortality, 141 Physical Activity for Inactive Seniors series, 193 Electronic medical records (EMR), 184 Emergency room visits, 15 Encyclopedia of Gerontology, 198 Encyclopedia of Nursing Research, 198 Energy conservation of, 163 diet and, 110 Enterodiol, 72 Enterolactone, 72 Environmental toxins, 27– 28 Erlangen Fitness Osteoporosis Prevention Study (EFOPS), 133 Established Populations for Epidemiologic Studies of the Elderly (EPESE), 13, 144 Estrace®. See Estradiol Estraderm®. See Estradiol Estradiol (Estrace®, Estraderm®, Estrace®, Estring®, Femring®, Vagifem®), 5, 54. See also Bioidentical hormone therapy (BHRT); Estrogen therapy; Estrogens; Hormone replacement therapy; Hormone therapy (HT) Estring®. See Estradiol Estriol, 54 Estriol®, 54 Estrogen receptors, 24 – 25 Estrogen therapy, 53 –57 administration, 57 adverse events, 57 description, 53 –54 efficacy, 56 –57 mechanism of action, 54 –55 pharmacokinetics, 54 –55 Estrogens. See also specific estrogens bone formation and, 26 calcium supplementation and, 105 characterization, 62 cytokine regulation by, 25 – 27 deficiency in, 175 effects on bone, 24 FDA-approved, 54

Index Estrone, 54 Europe, fracture incidence in, 11 Evista®. See Raloxifene Exercise. See also Physical activity amenorrhea and, 174 for children, 121 classes of, 121 fall prevention, 149 importance of, 117–139 lifespan and, 119 –120 long-term effects, 119 –120 Physical Activity for Inactive Seniors series, 193 preventative, 118 –126 program planning, 120 recommendations, 121–122, 127–128 restorative, 127–131 safety issues, 131–132 Exercise programs adherence to, 132 –133 description, 123 –126 efficacy, 123 –126 high-intensity, 132 home-based, 129 External fixation, of fractures, 98 Facet joints, 88, 89 Fall prevention environmental modifications, 146 exercise and, 122 follow-up, 146, 148, 149 –150 osteoporosis and, 141–151 program components, 143 –148 program development, 142 –143 resource identification, 146 strategies, 161–162 Falls causes of, 142 environmental factors in, 142 fear of falling index, 143 –144 getting up after, 146, 147 history of, 143 risk assessment, 148 Falls Efficacy Scale, 144 Family roles, 15 Fear of falling index, 143 –144, 148 Female athlete triad, 176 Femoral neck fractures, 84, 86. See also Hip fractures Femring®. See Estradiol Femur, bone mineral density, 10 Fentanyl, dosing regimens, 74 Fibrous dysplasia, 175 Fluid flow bone adaptation and, 220 – 221

Index in humans, 221– 224 skeletal muscle and, 222 – 223 Forearm fractures, 142 Forteo (teriparatide), 52, 63 Forward Reach test, 144 Fosamax®. See Alendronate Fosamax International Study Trial Group (FOSIT), 50 Fracture Intervention Trials (FITs), 49, 50 Fracture risk, expression of, 37 Fractures. See also specific fractures in childhood, 175 lifetime risks, 11–12 micro “cracks,” 21 monetary costs of, 15 –16 osteoporosis-related, 11 preventative exercise, 118 –126 risk in men, 12 risk of, 34 risk reduction, 118 –119 surgical management of, 83 –100 Fragility fractures, 83 Frank-Starling mechanism, 222 Fruit intake, 112 Furniture selection, 162 Gait Stability Ratio, 145 Geisinger Health System Mobile DXA Program, 181–186 Gender, hip fracture and, 83 Genistein, 72, 73 Geriatric Depression Scale, 159 Geriatric hip fracture programs (GHFPs), 127 Geriatric orthopaedic units (GORUs), 127 Girls, bone mineral density, 173 –174. See also Children Glucocorticoid therapy, 38, 42 Gonadotropin-releasing hormone (GnRH), 54 Goniometry, 156 Granulocyte macrophage colony-stimulating factor (GM-CSF), 26 Gravity, impact of, 221– 222 Ground reaction forces, 119 Growth factors, bone formation and, 26 Gymnasts, bone mineral density, 173 Health Belief Model, 132 Health Care Financing Administration (HCFA), 209 Health People 2010, 204 Health policy Anderson’s sequential model, 214, 215 case studies, 214 – 216 formulation of, 201– 202 international, 202 – 204 national, 204 – 205

251 policy makers, 202 – 208 stakeholders, 202 – 208 United States initiatives, 204 – 208 Health status, self-report of, 144 Healthy People 2010 initiatives, 205 Heat therapy, 130 HEDIS Performance Measure for Osteoporosis: Health Plan Employer Data and Information Set, 207 Heel ultrasound (HUS), 182 Height, loss of, 14. See also Compression fractures Hemiarthroplasty, 86 Heparin therpy, 87 HEROS© Fall Prevention Program for Community Dwelling Older Adults, 143, 144, 148 –150 Hip osteopenia of, 10 osteoporosis of, 10 Hip fractures. See also Femoral neck fractures age and, 11 bone loss and, 105 cost of, 141–142 global rates of, 12 –13 hospitalizations for, 84 incidence of, 118 intertrochanteric, 87 lifetime risk of, 11 medical costs of, 15 –16 morbidity rate, 83 mortality rate, 12, 83 nonsurgical treatment, 86 occult, 85 osteoporosis-related, 11 perioperative complications, 87 predictors of, 15 rehabilitation, 87– 89 restorative exercise, 127–128, 130 signs and symptoms of, 84 treatment of, 85 – 87 types of, 84 – 85 vertebral fracture risk and, 39 Hip hemiarthroplasty, 86 HIP Intervention Program (HIP) trial, 50 –51 Hispanic women, 10 Hologic Discovery—C Bone Densitometer, 183 –185 Home environment assessment, 159 Hormone replacement therapy (HRT), 105, 121 Hormone therapy (HT) alternatives to, 72 combination, 67 efficacy of, 54 –57 Hormones. See also specific hormones bone formation and, 26 in osteoclast formation, 22

252 Hospital admissions for hip fractures, 84, 142 osteoporosis-related, 15 Hydrocodone/APAP, 74 Hydrocodone/ibuprofen, 74 Hydroxyapatite, 67 Hydroxyproline (OHP), 40 Hypercalcaemia, 69 Hyperparathyroidism, 70 Hypocalcaemia, 69 Hypogonadism, 39, 42 Iasofoxifen, function of, 59 Ibandronate (Boniva®), 48, 49 –50, 62 Ibuprofen, dosing regimens, 74 Idiopathic juvenile osteoporosis, 175 Immunoassays, 39, 40 Immunosuppressive therapy, 174 –175 Incentive spirometry, 87 Independence common problems, 159 –161 loss of, 15 maintenance of, 153 –165 self-care and, 155 Indomethacin, 74 Inflammatory bowel disease, 175 Inflammatory diseases, 174 Instrumental activities of daily living (IADLs), 154, 160, 164 Interleukin 1 (IL-1), 22, 26, 27 Interleukin 3 (IL-3), 26 Interleukin 6 (IL-6), 26, 27 Interleukin 11 (IL-11), 26 International Osteoporosis Foundation (IOF), 202, 203 International Society for Clinical Densitometry (ISCD), 35 –39, 184, 203, 204 Internet, use of, 192 Interstitial fluid extravasation, 220, 222, 224 Interstitial fluid flow, 220 – 221 Intertrochanteric fractures, 84 Ipriflavone, 73 Isoflavones, 73, 111 Israel, public policy development, 214 Japanese women, osteoporosis in, 11 Joint protection techniques, 163 Jump Start Your Bones©, 194 Kidney stones. See Nephrolithiasis Klinefelter’s syndrome, 175 Knowles pinning, 86 Kyphex inflatable balloons, 95, 96

Index Kyphoplasty, 76, 95 –97 Kyphosis, 14, 142. See also Compression fractures Laboratory studies, 42 Lactation, bone loss in, 24 Lactose intolerance, 112 Least significant change (LSC), 36 Leisure interests, 160 Leukemic inhibitory factor, 26 Life expectancy, bone loss and, 120 Life roles, quality of life and, 154 Lifespan, exercise and, 119 –120 Lifestyles client-centered approach to, 154 –155 compensation strategies, 162 –163 fall prevention and, 146 fracture prevention and, 99 goals for redesign, 155 prevention strategies, 161–162 prognosis and, 164 redesign outcomes, 164 remediation strategies, 161 Lignans, 72, 73 Loading blood flow and, 221 bone loss and, 120 –121 Long-term care, 14, 84 Lovenox, 87 Loxar, countries where approved, 58 Loxifen, countries where approved, 58 Lung disease, 14, 91–92 Lymphatic drainage, 222, 223 Macrophage colony-stimulating factor (M-CSF), 22, 27 Magnetic resonance imaging (MRI), 92 Malabsorption syndromes, 42 Manual Muscle Test (MMT), 156 Mechanoreceptors, 227 Media, target audiences for, 189 Medical histories, fall prevention and, 144 Medicare coverage, 209 The Medicare Osteoporosis Measurement Act of 2005 (House Bill 2257), 208 Medications, effect on bone health, 174 –175. See also Pharmacotherapy Meissner’s corpuscles, 227 Men discharges to nursing homes, 14 DXA screening guidelines, 39 effect of exercise, 120 fracture risk, 12 mortality rates after hip fractures, 84 prognosis after fractures, 13

253

Index timing of bone loss in, 23 vertebral fractures in, 14 –15 Menarche, late, 176 Menopause, bone loss and, 23, 25 – 26, 104, 120 Merck SCORE risk assessment sheet, 196, 197 Methotrexate, 175 Miacalcin®, 63, 64 – 66 Michigan Department of Community Health, 192 Michigan Nutrition Network, 192 Michigan State University Extension, 192 Micro “cracks,” 21 Microgravity models, 221 Milk. See also Lactation allergies, 172 calcium from, 171 human, 173 per capita consumption, 112 vitamin D fortified, 106 Morbidity, postfracture, 13 –15, 83 Morphine, dosing regimens, 74 Mortality rates, 13 Motor control changes, 157 Multi-Directional Reach Test (MDRT), 144 Muscle mass, exercise and, 120 Muscle pumping, 222 – 223 Muscle spasms, 130 Muscle strength bone health and, 121 measures of, 156 N-telopeptide (NTX) cross-linking, 39, 40 Naproxen, dosing regimens, 74 National Dairy Council, 191 National Fluid Milk Processor Promotion Board, 191 National Institute of Health, 193 National Osteoporosis Foundation (NOF), 181, 191 initiatives, 208 reimbursement initiatives, 208 – 209 survey, 15 treatment recommendations, 37 National Osteoporosis Risk Assessment (NORA) study, 37 National Osteoporosis Society, U.K., 214 Native American women, 11 Natural hormone therapy (NHRT), 57–59 Nelson, Mirian E., 195 Nephrolithiasis, 71, 110 Nevada Nutrition Network, 194 New Jersey Department of Health and Senior Service, 194 Nonsteroidal anti-inflammatory drugs (NSAIDs), 76 Nonvertebral fractures bisophosphonate efficacy in, 50 –51

calcitonin efficacy in, 65 – 66 efficacy of hormonal therapy, 56 parathyroid hormone therapy in, 52 –53 raloxifene efficacy, 61 Norway, fracture incidence in, 10, 11 Nucleus pulposus, 88 Nursing homes after osteoporetic fractures, 14 fear of, 15 osteoporosis-related admissions, 15 vitamin D deficiency in residents of, 69 Nutrition bone health and, 103 –115, 170 –173 bone resorption and, 24 calcium content of foods, 107 calcium-fortified foods, 106 components of, 110 –111 dietary deficiencies, 23 – 24 health policy and, 214, 216 osteoporosis prevention and, 103 recommendations, 112 –113 vitamin D from, 108 Obesity, vitamin D deficiency and, 107–108 Ogen®. See Estrone Oligomenorrhea, 176 Open reduction internal fixation (ORIF), 87, 98 Opioids, pain management, 74, 76 Orchiectomy, 39 Osteoblasts bone formation and, 39 in bone remodeling, 21 celllular interactions, 22 derivation of, 20, 22 effect of estrogens on, 24 location of, 20 measures of function of, 40 parathyroid hormone receptors, 52 Osteocalcin (OC), 39 – 40, 40 Osteochemonecrosis, 51 Osteoclasts action of bisphosphonates, 48 – 49 bone resorption and, 39 cellular interactions, 22 effect of estrogens on, 24 function of, 20 – 21 measures of function of, 40 Osteocytes in bone remodeling, 21 cellular interactions, 20 derivation of, 20, 23 location of, 20 Osteogenesis imperfecta, 175

254 Osteomalacia, 70. See also Rickets Osteomark® immunoassay, 39 Osteopenia, 176 definition, 36, 202 in estrogen deficiency, 25 of hip, 10 Osteoporosis bone micrograph, 23 calcium paradox, 106 complications of, 83 – 84 consequences of, 13 –16 definition of, 33, 36, 202 demographics, 9 –18 incidence of fractures, 1 laboratory testing in, 42 pathogenesis of, 19 – 29 pharmacological management of, 47– 82 prevalence, 9 –10 secondary causes of, 40 – 43 testing, 181–182 top ten states, 12 Osteoporosis: Physical Performance Measurement, 206 The Osteoporosis Early Detection and Prevention Act of 2005 (House Bill 2946), 208 The Osteoporosis Education and Prevention Act of 2005 (House Bill 1081), 208 Osteoporosis Prevention, Diagnosis and Therapy, 204 Osteoporosis prevention programs, 177 Osteoprotegrerin (OPG), 22 Oswestry Disability Questionnaire (ODQ), 118 Oxycodone, dosing regimens, 74 Oxycodone/APAP, dosing regimens, 74 Paget’s disease, 65 Pain control, exercise and, 128 –129 Pain management, 73 –74, 76, 128 –129 Parathyroid hormone (PTH) bone formation and, 26 bone health and, 25 characterization, 63 low bone density and, 42 in osteoclast formation, 22 Parathyroid hormone (PTH) therapy, 52 –53 administration, 53 adverse events, 53 efficacy, 52 –53 mechanism of action, 52 overview, 52 pharmacokinetics, 52 Passive range of motion (PROM), 156 Patient education community-based programs, 190 –192 Cooperative Extension Programs, 188 –189

Index curriculum, 190 exercise adherence and, 132 –133 fall prevention, 146, 149 fracture prevention and, 99 getting up from falls, 147 learn-at-home lessons, 191 media formats, 190 Pennsylvania Geriatric Education Center, 195 Pennsylvania State University Cooperative Extension Programs, 187–192, 195, 196 Pennsylvania State University Public Broadcasting, 190 Pennsylvania State University School of Nursing, 195, 196 Percutaneous pinning, 86, 98 Performance Activities of Daily Living (PADL) battery, 144 Performance Oriented Mobility Assessment (POMA), 145 Pharmacotherapy drug characteristics, 62 – 63 low bone density and, 42 Phenobarbital, 174 Phosphorus, from bone resorption, 23 Photon absorptiometry techniques, 34 Physical activity. See also Exercise bone mass and, 27, 173 –174 electrical stimulation of muscle, 225 – 226 mechanical stimulation of bone, 227– 228 skeletal muscle pump and, 224 – 225 Physical Activity for Inactive Seniors, 193 Physical Disability Index, 144 Physical inactivity, 173 –174 Physical Performance and Mobility Examination, 144 Physical performance measures, 144 –145 Physical Performance Test, 144 Physical therapists, role of, 118 Physician office visits, osteoporosis-related, 15 Phytic acid, 106 Phytoestrogens, 72 –73, 111 Planned Approach to Community Health group, 193 Plantar stimulation, 227– 228 Policy-making, model of, 214, 215 Polychlorobiphenyls (PCBs), 27– 28 Polymethylmethacrylate (PMMA), 86, 95 Postfracture morbidity, 13 –15, 83 Postural control, measures of, 156 –157 Posture, circulatory system and, 223 – 224 A Practical Guide to Bone Health, 192 Pregnancy, bone loss in, 24 Premarin®, 54, 59 Prematurity, 175 Prempro®, 56 Preventing and Managing Osteoporosis, 198

255

Index Prevention programs for children, 177 community outreach and, 187–199 trends in, 219 – 231 Primary care physicians, 184 –185 Prioritization, 163 Productivity, measures of, 155 Progesterone, micronized (Prometrium®), 58 Progesterone, secretion of, 54 Project Healthy Bones, 194 –195 Prometrium®. See Progesterone PROOF study, 65 Prostaglandins, 22, 26 Protein intake, bone health and, 110 –111 Psychological well-being, 15 Psychosocial assessment, 157 Psychosocial problems, 153 Puberty, delayed, 176 Public health priorities, 169 –179 Quadriceps muscle, 226 Quality of life common problems, 159 –161 exercise and, 118 independence and, 153 –165 life roles and, 154 postfracture morbidity and, 13 –15, 83 productivity measures, 155 self-care and, 155 Quantitative computed tomography (QCT), 35 Quantitative ultrasonography (QUS), 35 Quantitative ultrasound index (QUI), 35 Questran® (cholestyramine), 61 Race osteoporosis and, 10 prognosis after fractures, 13 Raloxifene (Evista®), 59 – 64 administration, 61, 64 adverse events, 61, 64 characterization, 63 contraindications, 61 countries where approved, 58 drug interactions, 61 efficacy, 60 – 61 international names for, 59 mechanism of action, 60 pharmacokinetics, 60 Range of motion (ROM) exercise and, 118 measures of, 156 restorative exercises, 129 Raxeto, countries where approved, 58

Readiness for change, 158 Receptor activator of nuclear factor kappa B ligand (RANKL), 22 Receptor activator of nuclear factor kappa B (RANK), 22 Recommended Daily Allowance (RDA), 171 Reference population, 9 –10 Rehabilitation. See also Exercise; Physical activity; Physical therapists, role of after hip fractures, 87– 89 after wrist fractures, 99 costs of, 15 inpatient, 128 Reimbursement, 208 – 209, 214 – 216 Relative risk (RR) of fracture, 37 Relaxation techniques, 130, 163 Remediation strategies, 161 Research, advances in, 2 Resistance training, 120, 121, 129 Rickets, 70, 173 Risedronate (Actonel®), 48 characterization, 62 combination therapy, 66 efficacy, 49 –50 Rutgers Cooperative Extension, 194 Saint Barnabas Health Care System, 194 Scandinavia, hip fracture rates, 12 School health programs, 177, 189 School of Nutrition Science and Policy, Tufts University, Boston, 195 SCORE risk assessment sheet, 196, 197 Scottish Intercollegiate Guidelines Network (SIGN), 130 Screening programs, 38, 176, 195 –196 Selective estrogen reuptake modulators (SERMs), 50, 59 – 64 Self-care, measures of, 155 Self-concept, assessment of, 157–158 Self-help devices, 162, 163 Sequential compression devices (SCDs), 87 SERM 3339, 59 Singh index, 34 Skeletal loading, 120 – 212, 221 Skeletal muscle bone mass and, 223 – 224 electrical stimulation of, 225 – 226 fluid flow and, 222 – 223 Skeletal muscle pump, 224 – 228 Skeleton, human as calcium reserve, 67 calcium storage in, 104 function of, 19

256 number of bones in, 19 osteoporetic changes, 157 Smith’s fractures, 97, 98 Smoking, low bone density and, 42 Social Cognitive Theory, 132 Soda consumption, 171–172 Soleus muscle, function, 223 Southeast Asia, fracture incidence in, 11 Soybean protein, 73 Soy isoflavones, 111 Speed of sound (SOS), 35 Spinal column anatomy of, 88 –92 load distribution, 90, 91 mechanical stability, 88 – 89 Spinal cord injury, 225 – 226 Spinal fractures costs of, 16 functional decline and, 127 lifetime risk of, 11 mortality rates after, 12 osteoporosis-related, 11 rates of, 12 restorative exercise, 128 –131 Spine morphometry, qualitative, 34 Spinous processes, 88, 89 Squash players, 174 St. Luke’s Health Initiative, 192 –193 Stages of Change theory, 132, 189 Stand Tall Pennsylvania, 191, 195 –198 Strength, exercise and, 120 Strong Women,™ Strong Bones program, 195 Study of Orthoporotic Fractures (SOF), 14, 37 Sunlight, 108, 172 Sweden, fracture rates, 12 Swedish women, osteoporosis in, 10 T-scores calculation of, 34 guidelines for treatment, 37 heel ultrasound, 182 interpretation of, 35 –36 reference database, 35 screening programs and, 196 T’ai Chi, 122, 146, 224 – 225 Tamoxifen, use of, 59 Temple University, 195 Tennis players, 174 Teriparatide (Forteo®), 52 –53, 63 Testosterone, 24, 26, 175. See also Hormone therapy (HT) Third National Health and Nutritional Examination Survey (NHANES III), 10

Index Timed Up and Go (TUG) times, 144 Trabecular bone. See Cancellous bone Traction, for hip fractures, 86 TRANCE/RANK/OPGL, 25, 27 Transcutaneous electrical nerve stimulation (TENS), 130 Transforming growth factor β (TGF-β), 26 Transtheoretical model (TTM), 158, 189 Triest (Triestrogen), 58 Triestrogen (Triest), 58 TSE-424, 59 Tumor necrosis factor-α (TNF-α), 26 Turner's syndrome, 175 United Dairy Industry, 192 United Kingdom, osteoporosis in, 10 United States coverage by state, 210 – 213 fracture incidence in, 11 policies by state, 210 – 213 policy development, 214 – 215 University Cooperative Extension, Nevada, 194 University of Arizona Cooperative Extension, 192 –193, 193 University of Pittsburgh, 195 U.S. Department of Health and Human Services (DHHS), 204 Vagifem®. See Estradiol Valproate, 174 Vegan diets, 172 Vegetable intake, bone health and, 112 Vertebrae, load distribution, 90 Vertebral bodies composition of, 89, 91 shape of, 91, 92 Vertebral deformities, 14 –15 Vertebral Efficacy with Risdronate Therapy (VERT), 49 Vertebral fracture assessment (VFA), 35, 184 –185 Vertebral fractures. See also Compression fractures bisphosphonate therapy, 49 –50 calcitonin efficacy in, 65 efficacy of hormonal therapy, 56 hip fractures and risk of, 39 morbidity after, 14 –15 parathyroid hormone therapy in, 52 raloxifene efficacy, 60 – 61 rate of, 83 Vertebroplasty, 76, 95 –97 Vitamin D (calcitriol) bone formation and, 26, 27 bone health and, 25, 107–108 calcium and, 67– 69

257

Index deficiency, 12, 42, 70 efficacy of therapy using, 71–72 function of, 25 mechanism of action, 70 –71 pharmacokinetics, 70 –71 sources of, 108 synthesis of, 69 therapy using, 69 –72 Vitamin D intake calcium metabolism and, 172 –173 excessive, 109 –110 health policy and, 214, 216 recommendations, 67– 68, 70, 105 –106, 109, 171 risk reduction and, 47 sources of, 69 supplements, 105, 109, 112 –113 Walking, bone health and, 121, 133 Weight-bearing exercise, 121, 122 Weight lifting, 119 Weight loss, kyphosis and, 14 White women, 10, 11 WISEWOMAN Expansion Act of 2005 (House Bill 3086), 208 Women. See also Girls; Menopause; specific issues lifetime risk of hip fracture, 83 vertebral fractures in, 14 –15

Women’s Health Initiative (WHI), 54, 56, 105 Work problems, 160 –161 World Health Organization (WHO) classification of osteoporosis, 9 cost utility analysis, 37 global osteoporosis mandates, 3 initiatives and reports, 203 osteopenia definition, 36 osteoporosis definition, 36 policy making, 202 reports of hip fractures, 12 Wrist fractures description, 97 hip fractures following, 15 lifetime risk of, 11 morbidity following, 15 osteoporosis-related, 11 rehabilitation after, 99 restorative, 129 –130 restorative exercise, 131 treatment of, 97–99 X-ray evaluation, 92 Yogurt, 112 Z-scores, 34, 36