Hip Fracture - A Medical Dictionary, Bibliography, and Annotated Research Guide to Internet References

HIP

FRACTURE A 3-IN-1 MEDICAL REFERENCE Medical Dictionary Bibliography & Annotated Research Guide TO I NTERNET

R EFERENCES

HIP

FRACTURE A M EDICAL D ICTIONARY , B IBLIOGRAPHY , AND A NNOTATED R ESEARCH G UIDE TO I NTERNET R E FERENCES

J AMES N. P ARKER , M.D. AND P HILIP M. P ARKER , P H .D., E DITORS

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ICON Health Publications ICON Group International, Inc. 4370 La Jolla Village Drive, 4th Floor San Diego, CA 92122 USA Copyright 2004 by ICON Group International, Inc. Copyright 2004 by ICON Group International, Inc. All rights reserved. This book is protected by copyright. No part of it may be reproduced, stored in a retrieval system, or transmitted in any form or by any means, electronic, mechanical, photocopying, recording, or otherwise, without written permission from the publisher. Printed in the United States of America. Last digit indicates print number: 10 9 8 7 6 4 5 3 2 1

Publisher, Health Care: Philip Parker, Ph.D. Editor(s): James Parker, M.D., Philip Parker, Ph.D. Publisher's note: The ideas, procedures, and suggestions contained in this book are not intended for the diagnosis or treatment of a health problem. As new medical or scientific information becomes available from academic and clinical research, recommended treatments and drug therapies may undergo changes. The authors, editors, and publisher have attempted to make the information in this book up to date and accurate in accord with accepted standards at the time of publication. The authors, editors, and publisher are not responsible for errors or omissions or for consequences from application of the book, and make no warranty, expressed or implied, in regard to the contents of this book. Any practice described in this book should be applied by the reader in accordance with professional standards of care used in regard to the unique circumstances that may apply in each situation. The reader is advised to always check product information (package inserts) for changes and new information regarding dosage and contraindications before prescribing any drug or pharmacological product. Caution is especially urged when using new or infrequently ordered drugs, herbal remedies, vitamins and supplements, alternative therapies, complementary therapies and medicines, and integrative medical treatments. Cataloging-in-Publication Data Parker, James N., 1961Parker, Philip M., 1960Hip Fracture: A Medical Dictionary, Bibliography, and Annotated Research Guide to Internet References / James N. Parker and Philip M. Parker, editors p. cm. Includes bibliographical references, glossary, and index. ISBN: 0-497-00544-1 1. Hip Fracture-Popular works. I. Title.

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Disclaimer This publication is not intended to be used for the diagnosis or treatment of a health problem. It is sold with the understanding that the publisher, editors, and authors are not engaging in the rendering of medical, psychological, financial, legal, or other professional services. References to any entity, product, service, or source of information that may be contained in this publication should not be considered an endorsement, either direct or implied, by the publisher, editors, or authors. ICON Group International, Inc., the editors, and the authors are not responsible for the content of any Web pages or publications referenced in this publication.

Copyright Notice If a physician wishes to copy limited passages from this book for patient use, this right is automatically granted without written permission from ICON Group International, Inc. (ICON Group). However, all of ICON Group publications have copyrights. With exception to the above, copying our publications in whole or in part, for whatever reason, is a violation of copyright laws and can lead to penalties and fines. Should you want to copy tables, graphs, or other materials, please contact us to request permission (E-mail: [email protected]). ICON Group often grants permission for very limited reproduction of our publications for internal use, press releases, and academic research. Such reproduction requires confirmed permission from ICON Group International, Inc. The disclaimer above must accompany all reproductions, in whole or in part, of this book.

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Acknowledgements The collective knowledge generated from academic and applied research summarized in various references has been critical in the creation of this book which is best viewed as a comprehensive compilation and collection of information prepared by various official agencies which produce publications on hip fracture. Books in this series draw from various agencies and institutions associated with the United States Department of Health and Human Services, and in particular, the Office of the Secretary of Health and Human Services (OS), the Administration for Children and Families (ACF), the Administration on Aging (AOA), the Agency for Healthcare Research and Quality (AHRQ), the Agency for Toxic Substances and Disease Registry (ATSDR), the Centers for Disease Control and Prevention (CDC), the Food and Drug Administration (FDA), the Healthcare Financing Administration (HCFA), the Health Resources and Services Administration (HRSA), the Indian Health Service (IHS), the institutions of the National Institutes of Health (NIH), the Program Support Center (PSC), and the Substance Abuse and Mental Health Services Administration (SAMHSA). In addition to these sources, information gathered from the National Library of Medicine, the United States Patent Office, the European Union, and their related organizations has been invaluable in the creation of this book. Some of the work represented was financially supported by the Research and Development Committee at INSEAD. This support is gratefully acknowledged. Finally, special thanks are owed to Tiffany Freeman for her excellent editorial support.

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About the Editors James N. Parker, M.D. Dr. James N. Parker received his Bachelor of Science degree in Psychobiology from the University of California, Riverside and his M.D. from the University of California, San Diego. In addition to authoring numerous research publications, he has lectured at various academic institutions. Dr. Parker is the medical editor for health books by ICON Health Publications. Philip M. Parker, Ph.D. Philip M. Parker is the Eli Lilly Chair Professor of Innovation, Business and Society at INSEAD (Fontainebleau, France and Singapore). Dr. Parker has also been Professor at the University of California, San Diego and has taught courses at Harvard University, the Hong Kong University of Science and Technology, the Massachusetts Institute of Technology, Stanford University, and UCLA. Dr. Parker is the associate editor for ICON Health Publications.

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About ICON Health Publications To discover more about ICON Health Publications, simply check with your preferred online booksellers, including Barnes&Noble.com and Amazon.com which currently carry all of our titles. Or, feel free to contact us directly for bulk purchases or institutional discounts: ICON Group International, Inc. 4370 La Jolla Village Drive, Fourth Floor San Diego, CA 92122 USA Fax: 858-546-4341 Web site: www.icongrouponline.com/health

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Table of Contents FORWARD .......................................................................................................................................... 1 CHAPTER 1. STUDIES ON HIP FRACTURE .......................................................................................... 3 Overview........................................................................................................................................ 3 The Combined Health Information Database................................................................................. 3 Federally Funded Research on Hip Fracture.................................................................................. 5 E-Journals: PubMed Central ....................................................................................................... 57 The National Library of Medicine: PubMed ................................................................................ 58 CHAPTER 2. NUTRITION AND HIP FRACTURE .............................................................................. 103 Overview.................................................................................................................................... 103 Finding Nutrition Studies on Hip Fracture .............................................................................. 103 Federal Resources on Nutrition ................................................................................................. 106 Additional Web Resources ......................................................................................................... 107 CHAPTER 3. ALTERNATIVE MEDICINE AND HIP FRACTURE ........................................................ 109 Overview.................................................................................................................................... 109 National Center for Complementary and Alternative Medicine................................................ 109 Additional Web Resources ......................................................................................................... 115 General References ..................................................................................................................... 116 CHAPTER 4. DISSERTATIONS ON HIP FRACTURE .......................................................................... 117 Overview.................................................................................................................................... 117 Dissertations on Hip Fracture ................................................................................................... 117 Keeping Current ........................................................................................................................ 117 CHAPTER 5. PATENTS ON HIP FRACTURE..................................................................................... 119 Overview.................................................................................................................................... 119 Patents on Hip Fracture............................................................................................................. 119 Patent Applications on Hip Fracture......................................................................................... 124 Keeping Current ........................................................................................................................ 128 CHAPTER 6. BOOKS ON HIP FRACTURE ........................................................................................ 131 Overview.................................................................................................................................... 131 Book Summaries: Online Booksellers......................................................................................... 131 CHAPTER 7. PERIODICALS AND NEWS ON HIP FRACTURE .......................................................... 133 Overview.................................................................................................................................... 133 News Services and Press Releases.............................................................................................. 133 Newsletters on Hip Fracture...................................................................................................... 136 Newsletter Articles .................................................................................................................... 137 Academic Periodicals covering Hip Fracture............................................................................. 137 CHAPTER 8. RESEARCHING MEDICATIONS .................................................................................. 139 Overview.................................................................................................................................... 139 U.S. Pharmacopeia..................................................................................................................... 139 Commercial Databases ............................................................................................................... 140 APPENDIX A. PHYSICIAN RESOURCES .......................................................................................... 143 Overview.................................................................................................................................... 143 NIH Guidelines.......................................................................................................................... 143 NIH Databases........................................................................................................................... 145 Other Commercial Databases..................................................................................................... 147 APPENDIX B. PATIENT RESOURCES ............................................................................................... 149 Overview.................................................................................................................................... 149 Patient Guideline Sources.......................................................................................................... 149 Finding Associations.................................................................................................................. 152 APPENDIX C. FINDING MEDICAL LIBRARIES ................................................................................ 155 Overview.................................................................................................................................... 155 Preparation................................................................................................................................. 155

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Finding a Local Medical Library................................................................................................ 155 Medical Libraries in the U.S. and Canada ................................................................................. 155 ONLINE GLOSSARIES................................................................................................................ 161 Online Dictionary Directories ................................................................................................... 161 HIP FRACTURE DICTIONARY ................................................................................................. 163 INDEX .............................................................................................................................................. 211

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FORWARD In March 2001, the National Institutes of Health issued the following warning: "The number of Web sites offering health-related resources grows every day. Many sites provide valuable information, while others may have information that is unreliable or misleading."1 Furthermore, because of the rapid increase in Internet-based information, many hours can be wasted searching, selecting, and printing. Since only the smallest fraction of information dealing with hip fracture is indexed in search engines, such as www.google.com or others, a non-systematic approach to Internet research can be not only time consuming, but also incomplete. This book was created for medical professionals, students, and members of the general public who want to know as much as possible about hip fracture, using the most advanced research tools available and spending the least amount of time doing so. In addition to offering a structured and comprehensive bibliography, the pages that follow will tell you where and how to find reliable information covering virtually all topics related to hip fracture, from the essentials to the most advanced areas of research. Public, academic, government, and peer-reviewed research studies are emphasized. Various abstracts are reproduced to give you some of the latest official information available to date on hip fracture. Abundant guidance is given on how to obtain free-of-charge primary research results via the Internet. While this book focuses on the field of medicine, when some sources provide access to non-medical information relating to hip fracture, these are noted in the text. E-book and electronic versions of this book are fully interactive with each of the Internet sites mentioned (clicking on a hyperlink automatically opens your browser to the site indicated). If you are using the hard copy version of this book, you can access a cited Web site by typing the provided Web address directly into your Internet browser. You may find it useful to refer to synonyms or related terms when accessing these Internet databases. NOTE: At the time of publication, the Web addresses were functional. However, some links may fail due to URL address changes, which is a common occurrence on the Internet. For readers unfamiliar with the Internet, detailed instructions are offered on how to access electronic resources. For readers unfamiliar with medical terminology, a comprehensive glossary is provided. For readers without access to Internet resources, a directory of medical libraries, that have or can locate references cited here, is given. We hope these resources will prove useful to the widest possible audience seeking information on hip fracture. The Editors

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From the NIH, National Cancer Institute (NCI): http://www.cancer.gov/cancerinfo/ten-things-to-know.

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CHAPTER 1. STUDIES ON HIP FRACTURE Overview In this chapter, we will show you how to locate peer-reviewed references and studies on hip fracture.

The Combined Health Information Database The Combined Health Information Database summarizes studies across numerous federal agencies. To limit your investigation to research studies and hip fracture, you will need to use the advanced search options. First, go to http://chid.nih.gov/index.html. From there, select the “Detailed Search” option (or go directly to that page with the following hyperlink: http://chid.nih.gov/detail/detail.html). The trick in extracting studies is found in the drop boxes at the bottom of the search page where “You may refine your search by.” Select the dates and language you prefer, and the format option “Journal Article.” At the top of the search form, select the number of records you would like to see (we recommend 100) and check the box to display “whole records.” We recommend that you type “hip fracture” (or synonyms) into the “For these words:” box. Consider using the option “anywhere in record” to make your search as broad as possible. If you want to limit the search to only a particular field, such as the title of the journal, then select this option in the “Search in these fields” drop box. The following is what you can expect from this type of search: •

Risk of Hip Fracture Among Dialysis and Renal Transplant Recipients Source: JAMA. Journal of the American Medical Association. 288(23): 3014-3018. December 18, 2002. Summary: Renal failure places people at particularly high risk of hip fracture. However, the possible differential impact of dialysis and renal (kidney) transplantation on this risk is not well understood. This article reports on a study undertaken to determine if patients who receive kidney transplants are at greater risk of hip fracture compared with those who continue to undergo dialysis. The data is from a cohort study of 101,039 patients with end stage renal disease (ESRD) placed on the renal transplant waiting list in the United States between January 1990 and December 1999. Among the patients included in this analysis, 971 hip fractures were observed during the followup period of 314,767 person-years. The incidence rate of hip fracture in patients receiving dialysis

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was 2.9 per 1000 patients per year compared with 3.3 hip fractures per 1000 patients per year in those who had previously received a renal transplant. Initially, the relative risk of hip fracture associated with transplantation was 1.34 fold greater when compared with dialysis, but then decreased by 1 percent per month until the estimated risk became equal for dialysis and transplant recipients approximately 630 days after transplantation. Among transplant recipients, risk of fracture was relatively higher in persons with a prolonged period of dialysis before transplantation. 1 figure. 3 tables. 26 references. •

Type 1 and Type 2 Diabetes and Incident Hip Fractures in Postmenopausal Women Source: Diabetes Care. 24(7): 1192-1197. July 2001. Contact: Available from American Diabetes Association. 1701 North Beauregard Street, Alexandria, VA 22311. (800) 232-3472. Website: www.diabetes.org. Summary: This article describes a study that examined whether postmenopausal women with diabetes experienced a higher incidence of hip fracture than women without diabetes. The study sample consisted of 32,089 postmenopausal women residing in Iowa who were surveyed by mail in 1986 and followed for 11 years. Diabetes status and other potential risk factors were assessed by questionnaire at baseline. Incidence of hip fracture was ascertained by follow up questionnaires. Over 306,900 person years of follow up, 490 hip fractures were identified, for an incidence rate of 1.6 per 1,000 person years. After adjustment for age, smoking status, estrogen use, body mass index, and waist to hip ratio, women with type 1 diabetes were 12.25 times more likely to report an incident hip fracture than women without diabetes. Women with type 2 diabetes had a 1.70 fold higher risk of incident hip fracture than women without diabetes. Longer duration of type 2 diabetes was associated with higher incidence, as was use of insulin or oral diabetes medications in women with type 2 diabetes. Furthermore, women who were initially free of diabetes but in whom diabetes developed had a relative risk of hip fracture of 1.60 compared with women who never had diabetes. The article concludes that postmenopausal women who have diabetes or in whom diabetes develops are at higher risk for hip fracture than postmenopausal women without diabetes. Strategies to prevent osteoporosis or falling may be especially warranted in women with diabetes. 2 tables. 31 references. (AA-M).

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Risk Factors for Hospital-Acquired Incontinence in Elderly Female Hip Fracture Patients Source: Journal of Gerontology. 57A(10): M672-M677. 2002. Summary: This article reports on a study undertaken to estimate the incidence of, and identify risk factors for, urinary incontinence in female hip fracture patients. The study was a secondary analysis of data abstracted from medical records in hospitals in Pennsylvania, Texas, New Jersey, and Virginia. The study included women aged 60 years and older who were admitted to one of the study hospitals with hip fracture. Data from 6,516 women were analyzed. Of these, 21 percent (n = 1,365) became incontinent during hospitalization. After adjusting for confounders (i.e., age, race, malnutrition, comorbidity, and severity of illness), admission from a nursing home or other long-term care facility, confusion, use of a wheelchair or device for walking, and prefracture dependence on others for ambulation significantly increased the odds of developing incontinence during hospitalization. The authors conclude that certain easilyidentifiable patient characteristics place female hip fracture patients at high risk of incontinence. Interventions to increase staff awareness of this vulnerable population

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need to be tested to minimize the incidence of hospital-acquired incontinence. 1 figure. 3 tables. 26 references. •

Randomised, Clinically Controlled Trial of Intensive Geriatric Rehabilitation in Patients With Hip Fracture: Subgroup Analysis of Patients With Dementia Source: BMJ. British Medical Journal. 321: 1107-1111. November 4, 2000. Summary: This journal article describes a study that investigated the effectiveness of intensive geriatric rehabilitation in people with mild to moderate dementia who had surgery for hip fracture. Participants were 243 people over age 64 years who lived independently and were admitted to the hospital with a hip fracture. Patients were evaluated to determine cognitive status. Following surgery, patients in the intervention group were referred to the geriatric ward, while the remaining patients were discharged to local hospitals. The study measured their length of hospital stay, place of residence at three months and one year after surgery, and mortality. The median length of hospital stays was significantly shorter in the intervention group. Three months following surgery, patients with mild dementia in the intervention group were as successful as people without dementia in returning to independent living. Severity of cognitive impairment related to less successful return to independent living and higher mortality. The researchers concluded that older people with mild to moderate dementia and hip fracture can return to community living if they receive active geriatric rehabilitation. 3 tables, 34 references.

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Rehabilitation Following Hip Fracture in Patients With Alzheimer's Disease and Related Disorders Source: American Journal of Alzheimers Disease. p. 209-211. September-October 1997. Summary: This journal article describes the rehabilitation outcomes of 19 patients with hip fractures admitted to a long-term care facility dedicated to caring for people with Alzheimer's disease and related disorders (ADRD). The patients ranged in age from 80 to 90 years, and most were female; all but one had surgery. The patients received physical therapy for 1 to 24 weeks. The physical therapy program included upper and lower extremity strengthening, balance training, transfer training, and gait training with and without assistive devices. At discharge, all 17 patients who survived were able to ambulate at least 100 feet with or without assistive devices. Some required assistance for safety due to decreased judgment and cognition, four were able to ambulate totally independently ad lib, and five needed supervision only. At followup several months later, most of the patients were still ambulatory at the same level as that at discharge. The authors conclude that people with ADRD who sustain hip fractures can be successfully rehabilitated with sufficient time and effort. 16 references. (AA-M).

Federally Funded Research on Hip Fracture The U.S. Government supports a variety of research studies relating to hip fracture. These studies are tracked by the Office of Extramural Research at the National Institutes of Health.2 CRISP (Computerized Retrieval of Information on Scientific Projects) is a searchable 2

Healthcare projects are funded by the National Institutes of Health (NIH), Substance Abuse and Mental Health Services (SAMHSA), Health Resources and Services Administration (HRSA), Food and Drug Administration (FDA), Centers for Disease Control and Prevention (CDCP), Agency for Healthcare Research and Quality (AHRQ), and Office of Assistant Secretary of Health (OASH).

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database of federally funded biomedical research projects conducted at universities, hospitals, and other institutions. Search the CRISP Web site at http://crisp.cit.nih.gov/crisp/crisp_query.generate_screen. You will have the option to perform targeted searches by various criteria, including geography, date, and topics related to hip fracture. For most of the studies, the agencies reporting into CRISP provide summaries or abstracts. As opposed to clinical trial research using patients, many federally funded studies use animals or simulated models to explore hip fracture. The following is typical of the type of information found when searching the CRISP database for hip fracture: •

Project Title: A LOW-COST FALL MONITOR FOR GERIATRIC SUBJECTS Principal Investigator & Institution: Parker, B Eugene.; Barron Associates, Inc. 1410 Sachem Place Charlottesville, Va 22901 Timing: Fiscal Year 2003; Project Start 01-OCT-2000; Project End 31-AUG-2005 Summary: (provided by applicant): Falls are a leading cause of disability and even death in the elderly. A method is needed by which to identify elderly persons who frequently experience falls or near falls (e.g., slips, stumbles, etc.). There are presently no tools to objectively record such events and their characteristics (e.g., kinematics) in independentliving, assisted-living, or nursing-home environments. A device that could be used to discreetly count fall frequency and record the characteristics of fall events - while still permitting free and unrestricted body movement - would be invaluable in understanding why elderly people fall. Such a device could also serve as a research tool, enabling a better understanding of risk factors associated with falls and near falls. A method for characterizing fall dynamics (e.g., impact velocity and orientation, fall direction, impact energy) would assist in identifying elderly persons at high risk for hip fracture. Hip fractures, for example, have been associated with high impact energy sideways falls in which the subject lands on their hip. Under the proposed Phase II SBIR effort, Barron Associates, Inc. and its subcontractors, the University of Kansas Center for Research and the University of Virginia Division of General Medicine, Geriatrics & Palliative Care, propose to develop and demonstrate the Wear And Forget Ambulatory Recorder for Elderly Residents (WAFARER), a wireless system to detect, archive, characterize, and "reconstruct," through PC-based graphical reenactment, fall and nearfall events in the elderly with the goals of understanding and preventing fall-related injuries and their sequelae. Three-dimensional animation of pelvic motions during fall and near-fall events will facilitate their interpretation by senior-care facility physicians, nurses, and others. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: A NEW SYSTEM FOR ULTRASONIC BONE ASSESSMENT Principal Investigator & Institution: Kaufman, Jonathan J.; President & Ceo; Cyberlogic, Inc. 611 Broadway, Ste 707 New York, Ny 10012 Timing: Fiscal Year 2002; Project Start 01-NOV-1997; Project End 31-AUG-2004 Summary: (provided by applicant): The long-term objective of this research is to establish ultrasound as a safe, effective, and non-invasive method for assessing fracture risk, an important component in clinical management of osteoporosis. Osteoporosis afflicts over 20 million people in the U.S., responsible for more than 275,000 hip fractures annually. Currently, the primary means for assessment relies on densitometric

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techniques. These methods subject the patient to ionizing radiation, are relatively expensive, and do not always provide good estimates of bone strength. Ultrasound offers several potential advantages. It is non-ionizing and relatively inexpensive. Moreover, since ultrasound is a mechanical wave and interacts with bone in a fundamentally different manner than electromagnetic radiation, it may be able to provide more accurate estimates of bone strength compared with current densitometric methods. The goal of this research is to significantly improve the effectiveness of current ultrasonic bone assessment techniques by demonstrating the feasibility of a new ultrasonic system to assess bone. The system employs a novel parametric signal processing approach which is ideally suited for analog and real-time implementation. Thus this research may enable less expensive and easier to use ultrasound devices, which are also less sensitive to various experimental artifacts. The specific aims are to measure a set of new ultrasonic parameters and compare them with presently used features, namely BUA and ultrasound velocity, in calcaneal bone samples. A comparison will be made of their respective capabilities to estimate bone density and bone strength. This comparison will include cost, ease of use, and accuracy and precision of the bone density and bone strength estimates. PROPOSED COMMERCIAL APPLICATION: Osteoporosis is a major health concern in the United States, afflicting over 20 million people, and whose incidence is increasing as the average age of the U.S. population increases. An effective, relatively inexpensive and safe technique such as ultrasound for assessing osteoporosis would be an extremely emportant benefit to the patient population, and represents an enormous commercial opportunity. Ultrasound's importance will grow as various new pharmacologic agents are approved for treatment, thus requiring periodic assessments of efficacy. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: ACTIVITY GAIT AND EFFICACY (AGE) IN ORDER WOMEN Principal Investigator & Institution: Mcauley, Edward; Professor; Kinesiology; University of Illinois Urbana-Champaign Henry Administration Bldg Champaign, Il 61820 Timing: Fiscal Year 2004; Project Start 01-SEP-2001; Project End 31-JUL-2006 Summary: (provided by applicant): Osteoporosis is a major public health issue. Being African-American affords some protection from osteoporotic fracture primarily due to bone dependent factors such as a higher bone mass, density and shorter hip axis length; however, pilot data from our laboratory also suggests a racial difference in bone independent fracture risk factors including gait, balance and social cognitive factors such as fear of falling. However, to our knowledge, no research has studied the interrelationship between bone dependent and independent fracture risk factors in an older racially diverse sample of postmenopausal women. Additionally, little research has prospectively examined the relation between and among bone dependent and independent risk factors in black and white postmenopausal women. This is important work because black women are among the fastest growing segment of the population and alarming evidence suggests that although fewer black women sustain osteoporotic fractures, they have nearly a three-times greater likelihood of death due to complications from hip fracture. Thus, the primary purpose of this prospective study is to combine physiological bone health outcomes (bone mass, density and ultrasound attenuation), physical activity patterns, and balance and gait abilities with social cognitive outcomes including self-efficacy and expectations, to further elucidate the causes of this racial discrepancy in fracture rate. Secondarily, racial differences in body composition determinants (i.e. fat and fat-free mass) of bone health will be explored at

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baseline and in a prospective fashion. Per the parent grant design (1R01AG02011801A1), a large sample of older (60 - 80 yrs) white (N = 150) and black (N = 150) women will be recruited with outcomes assessed at baseline, 1 year and 2 years. Bone and body composition will be assessed by dual energy X-ray absorptiometry (DXA). Additionally, quantitative ultrasound (QUS) will be used as an index of bone quality. This research has high public health priority because bone dependent and independent factors that influence the risk of osteoporotic fracture risk must be understood to implement effective programs for public health agendas and programs, specifically with regards to racial differences thereby optimizing programming for all individuals. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: ADVANCE REHABILITATION RESEARCH TRAINING PROJECT Principal Investigator & Institution: Rodgers, Mary M.; Professor and Chair; Physical Therapy; University of Maryland Balt Prof School Baltimore, Md 21201 Timing: Fiscal Year 2003; Project Start 20-JUN-2003; Project End 30-APR-2008 Summary: (provided by applicant): Societal demand for high quality rehabilitationrelated research relevant to chronic diseases and disabilities is increasing with the aging of the population in the United States. The objective of the proposed Advanced Rehabilitation Research Training Program (ARRTP) is to provide trainees with academic and research preparation in fields pertinent to the emerging discipline of physical rehabilitation science (PRS). The existing UMB-PRS program, which will be augmented by this ARRTP, offers predoctoral students and post-doctoral fellows an educational curriculum and laboratory experiences with an emphasis in one of five academic subdisciplines or concentration areas: applied anatomy and cell biology, rehabilitation biomechanics, epidemiology, neuromotor control/plasticity, and rehabilitation physiology. Trainees are subsequently afforded research development opportunities in areas where participating faculty have ongoing externally funded collaborations. These areas include stroke, spinal cord injury, hip fracture, rheumatological/immunological diseases and developmental disorders. The training program features rigorous academic and research requirements that are individually tailored to develop scientists that are capable of becoming independent investigators. It is expected that graduates and fellows will be capable of drawing on the skills and informational bases of their chosen sub-discipline to expand overall knowledge related to the mechanisms and epidemiology of physical disability and rehabilitation. Additional opportunities for collaborative research across campus are available through established training programs in neurology, geriatrics, pediatrics, epidemiology and rheumatology. The strengths of the proposed ARRTP are (1) strong institutional and school support, (2) an interdisciplinary faculty, (3) ongoing interdisciplinary research in suitable fields, and (4) well-equipped laboratories. The didactic portion of the program includes course work designed to develop competence in foundational sciences, analytical methodologies, and a substantive concentration area through formal lectures, independent study, research seminars, journal clubs, and regular training in the ethical conduct of research. The training program is designed to enable trainees to (1) master a core curriculum in foundational biophysical sciences and scientific methodologies, (2) become knowledgeable about fundamental rehabilitative and psychosocial processes related to disability, (3) become expert in at least one substantive area relevant to the reversal of impairment and functional decline in a disabled population, (4) learn to contribute to a research team under the supervision of a primary mentor expert in a disability-specific field with appropriate mentorship by secondary and associate experts in rehabilitation

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research, and (5) demonstrate the capacity to conduct independent, original research related to rehabilitation. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: ANALYSIS OF INJURY AVOIDANCE STRATEGIES DURING FALLS Principal Investigator & Institution: Lotz, Jeffrey Charles.; Professor; Orthopaedic Surgery; University of California San Francisco 500 Parnassus Ave San Francisco, Ca 941222747 Timing: Fiscal Year 2002; Project Start 20-SEP-2000; Project End 31-AUG-2004 Summary: At least 280,000 hip fractures occur annually in the U.S., at an estimated cost of $9 billion. While over 90% of these are caused by falls, only about 2% of all falls result in hip fracture. Considerable evidence now exists that the most important determinants of hip fracture risk during a fall are the body's impact velocity and configuration (and in particular, whether contact occurs to the hip region). Accordingly, protective responses for reducing impact velocity, and the likelihood for direct impact to the hip, strongly influence fracture risk. Improved understanding of the nature of such responses, and how these are affected by age-related declines in neuromuscular variables, would enhance our ability to develop exercise- based strategies for hip fracture prevention. Based on the results of epidemiological and biomechanical studies, we hypothesize that two protective responses central to safe landing during a fall are (a) absorbing energy in the lower extremity muscles during the descent phase of the fall, and (b) braking the fall with the outstretched hands. We also hypothesize, based on epidemiological evidence, that the efficacy of these responses associate with strength, flexibility, and reaction time. To test these hypotheses, we will address four aims. Aim 1 is to test whether use of the above protective responses influences young females' ability to avoid impact to the hip, and reduce the impact velocity of the body during falls onto a soft gymnasium mat. Aim 2 is to test whether ancillary measures of balance and lower extremity flexibility and reaction time associate with young and elderly subjects' ability to absorb energy in their lower extremity muscles, and reduce impact velocity when descending from standing to sitting. Aim 3 is to test whether balance and upper extremity strength, flexibility, and reaction time associate with young and elderly subjects' ability to quickly contact an impact surface with the outstretched hands, and absorb energy in the upper extremity muscles during simulated falls. Finally, Aim 4 is to develop and validate complementary mathematical models of falling, and use these to determine how specific impairments (or exercise-induced enhancements) in muscle strength, joint flexibility. Finally, Aim 4 is to develop and validate complementary mathematical models of falling, and use these to determine how specific impairments (or exercise-induced enhancements) in muscle strength, joint flexibility, and reaction time affect fall protective responses and fall severity. By identifying the biomechanical and neuromuscular variables which govern safe landing during a fall, these studies should lead to novel and effective interventions for reducing hip fractures in the elderly. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: BBA EFFECTS ON GEOGRAPHIC VARIATION IN POST-ACUTE CARE Principal Investigator & Institution: Lin, Wen-Chieh; Family and Community Medicine; University of Missouri Columbia 310 Jesse Hall Columbia, Mo 65211 Timing: Fiscal Year 2003; Project Start 01-SEP-2003; Project End 31-AUG-2004

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Summary: (Provided by Applicant): In response to the rapid growth in payments for post-acute care (PAC) services, Congress enacted Medicare reforms as part of the Balanced Budget Act of 1997 (BBA) for each PAC service. The reforms mandated a series of separate case-mix adjusted prospective payment systems, each with its own implementation timeline. In addition to the overall effects, the BBA's effects on PAC use varied substantially across geographic areas. For example, in the case of skilled nursing facility use from 1998 to 2000, the average change relative to 1996 for stroke patients was 2.7%.at the national level, but it ranged from -12% to 24% across regions (the nine United States Census Bureau divisions). This varied response raises concerns that the hospital discharge process may be driven by payment policy rather than by clinical needs and individual preferences. Furthermore, varied changes in PAC use across regions might lead to untoward consequences, such as early hospital readmission. As efforts continue to reform PAC services and payment systems, it is essential that policymakers understand how different payment mechanisms associate with geographic variation in PAC use. The proposed study seeks to: 1) analyze geographic variation in PAC use before and after the BBA changes; 2) explore whether utilization and cost have shifted among PAC settings and whether early hospital readmission has increased; and 3) investigate how the contributions of patient, hospital, and market area characteristics in explaining PAC use differ between pre- and post-BBA periods. We will analyze the Center for Medicare & Medicaid Services' 5% sample of Medicare claims data from 1996 to 2000 to study the initial effect of the BBA changes on geographic variation in PAC use. We will focus on six diseases associated with high PAC use: stroke, hip procedure, hip fracture, chronic obstructive pulmonary disease, pneumonia, and congestive heart failure. The selected diseases provide a contrast between rehabilitative and medical conditions. The stability, the degree, and the association of geographic variation in PAC use before and after the BBA changes will be examined. Shifts in utilization and costs will be presented as correlations between changes in PAC use, hospital length of stay, and early hospital readmission. Finally, we will estimate multinomial logit models to explore changes in contribution to explain PAC use by patient, hospital, and market area characteristics after the BBA changes. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: CHARACTERISTICS OF T CELL RECEPTORS Principal Investigator & Institution: Marrack, Philippa C.; Investigator; National Jewish Medical & Res Ctr and Research Center Denver, Co 80206 Timing: Fiscal Year 2003; Project Start 01-MAY-1982; Project End 30-APR-2006 Summary: T cells bearing alphabeta T cell receptors react with antigen in the form of peptides bound to major histocompatibility complex proteins (MHC). This reaction is crucial to the ability of T cells to orchestrate destruction of invading organisms. It is also involved in graft rejection and in T cell attacks on the tissues of their own host in autoimmune disease. Several aspects of T cell reaction with MHC are not understood. The projects in this application will study two of these aspects. The first set of experiments will study the ways in which T cells are selected to react with peptides bond to MHC in the thymus. A major focus of these experiments will be the role of the peptides bound to MHC. Mice will be created in which a single peptide is firmly bound to an MHC protein, and the ability of this MHC/single peptide combination to select T cells studied. The second set of experiments will investigate the relationship between T cell receptors and MHC. It is thought that the two sets of proteins may have an intrinsic affinity for each other. Experiments proposed here will try to find out if this is so. T cells

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from the MHV/single peptide mice, which are very reactive with MHC proteins, will be used to study the phenomenon. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: CLAUDE D. PEPPER OLDER AMERICANS INDEPENDENCE CENTER (O* Principal Investigator & Institution: Goldberg, Andrew P.; Professor; Medicine; University of Maryland Balt Prof School Baltimore, Md 21201 Timing: Fiscal Year 2002; Project Start 15-JUL-1994; Project End 30-JUN-2006 Summary: (provided by the applicant): The mission of the University of Maryland, Baltimore (UM)-OAIC is to conduct mechanistic and outcome-based research in exercise rehabilitation and provide research training in gerontology and geriatrics that will improve lifestyle and functionality for millions of older disabled Americans. The research focus is on older patients who are chronically disabled by hemiparetic stroke, a major complication of arteriosclerotic cardiovascular disease (CVD) which affects greater than 750,000 Americans annually. These patients have reduced ambulatory capacity and functionality, impaired IADL performance, gait dysfunction and a multitude of comorbidities, which worsen their quality of life and increase their utilization of the healthcare system. While our focus is on hemiparetic stroke, the UMOAIC also collaborates with and provides infrastructure support for research on peripheral arterial occlusive disease, hip fracture and other disabling conditions where there are institutional strengths. Exercise rehabilitation is the consistent theme in the UM-OAIC that provides cohesiveness for the research training, the research resources cores, education, dissemination, and clinical care. The intervention development studies (IDS) examine the effects of task-oriented treadmill exercise in patients with lower extremity hemiparesis (IDS-1) and upper extremity training with auditory cueing in patients with upper extremity paresis (IDS-2) on: 1) functional mobility and ambulation, motor control and strength, V02 peak, and free living daily activity; 2) central (neural) and peripheral (muscle) mechanisms underlying these functional responses using functional magnetic resonance imaging (fMRI) and transcranial magnetic stimulation (TMS) to assess neural plasticity; 3) muscle biopsies with histochemical and biochemical analyses to determine conditioning; and 4) long-term functionality and psychosocial status in hemiparetic stroke patients. These and other studies of disabling conditions utilize RRCs in 1) epidemiology research and recruitment; 2) neuromuscular mechanisms and function performance; and 3) physiology that are blinded to patient randomization for measuring outcomes. The biostatistics RRC provides data management and analysis, and maintains confidentiality and records for the safety monitoring board. OAIC leadership and advisory committees 1) guide and review accomplishments of the RCT?s on hemiparetic stroke, 2) train young investigators in mechanistic, functional, and psychosocial research examining physiologic as well as cellular adaptations to exercise and outcomes research, 3) promote collaboration of UMB and Johns Hopkins faculty in interdisciplinary aging research and research training, and 4) disseminate OAIC findings to the public and health professionals. OAIC leaders have institutional support for interdisciplinary aging research that supports a cadre of gerontologists to achieve the interdisciplinary research goals of the OAIC. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: CORE--CLINICAL/APPLIED PHYSIOLOGY Principal Investigator & Institution: Katzel, Leslie I.; Associate Professor; University of Maryland Balt Prof School Baltimore, Md 21201

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Timing: Fiscal Year 2002 Summary: (provided by the applicant) The clinical/applied physiology core (RRC-C) will be directed by Leslie l. Katzel, MD, Ph.D. with Andrew R. Coggan, Ph.D., Andrew W. Gardner, Ph.D. and Alice Ryan Ph.D. as core investigators. The specific aims of RRCC are: 1) to perform cardiovascular screening (treadmill exercise testing) of research patients entering IDS 1 and 2, and in the pilot and junior faculty projects that require these measurements; 2) to provide standardized and quality controlled measures of: A) peak aerobic capacity (V02 peak); B) walking economy; C) functional performance; D) physical activity; and E) body composition in patients enrolled in IDS1 and 2, and in other OAIC projects; 3) To determine the effects of exercise training on skeletal muscle histochemistry in stroke patients (IDS1), and in other OAIC patients undergoing exercise rehabilitation; 4) To provide standardized and quality controlled measures of fibrinolysis and other CAD risk factors;5) To train young investigators in geriatrics and gerontology in the performance of applied exercise physiology and metabolism research relevant to the mission of the Pepper Center (collaborative project with RDC); 6) To provide an educational and consultative resource for all investigators interested in aging and exercise at UMB; and 7)To assist other funded NIH and VA investigators in the evaluation of the cardiovascular and metabolic effects of exercise rehabilitation in older patients with CAD risk factors, hip fracture and peripheral arterial disease. The RRC-C will provide a framework to evaluate patients during their exercise rehabilitation interventions of the OAIC. The performance of standardized measures of cardiovascular function, muscle characteristics, body composition, physical activity, and cardiac risk factors in the RRC-C, rather than in the individuals studies improves the accuracy and efficiency of the measurements through the use of personnel trained in the performance of these procedures, and allows the strict maintenance of blinding as critical outcomes measurers are tested. It also eliminates duplicate equipment. Centralization of these measurements should increase the intraclass correlation coefficients of the measurements, decrease the coefficient of variation, enhance data entry, data management and oversight to assure the integrity of the data, and its subsequent analysis by the biostatistics core (RRC-D). The collection of physiologic data and its integration with data collected in the projects and other cores enable comprehensive, multidisciplinary examinations of physiologic factors associated with exercise-induced changes in functional performance, gait biomechanics and quality of life in stroke. The RRC-C will also collaborate with RDC to develop the research skills of junior faculty interested in clinical research and gerontology. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: CORE--FUNCTIONAL PERFORMANCE AND NEUROMUSCULAR MECHANISM Principal Investigator & Institution: Smith, Gerald V.; University of Maryland Balt Prof School Baltimore, Md 21201 Timing: Fiscal Year 2002 Summary: (provided by the applicant) The Functional Performance and Neuromuscular Mechanisms Core (RRC-B) provides support for research conducted in University of Maryland, Baltimore (UMB) OAIC studies. The RRC-B enhances Pepper Center goals by applying: 1) instrumented and standardized measures of gait, balance and motor control to measure functional performance changes, and 2) non-invasive brain stimulation and functional imaging methodologies to measure central nervous system (CNS) adaptations to exercise in patients with chronic stroke. RRC-B aims are to: 1. Support the research in the IDSs, selected RDC junior faculty pilot studies, and promote other aging-

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related research at UMB by providing quantitative and standardized measures of gait, balance, strength and motor control; 2. Investigate the effects of repetitive bilateral UE and LE task-oriented training on CNS motor control in hemiparetic stroke patients using novel non-invasive transcranial magnetic stimulation (TMS) and functional magnetic resonance imaging (fMRI). In collaboration with RRC-C studies of muscle mass and metabolism, this will identify the central and peripheral neuromuscular adaptations with treadmill training in IDS-1; 3. Train young investigators, RDC-OAIC awardees, and clinicians in the conduct of human performance and applied neurophysiological research relevant to the mission of the Pepper Center, and the fields of gerontology, neurology, and physical rehabilitation sciences; 4. Provide an educational and consultative resource for UMB investigators interested in pursuing research in aging and neurological rehabilitation; 5. Assist NIH and/or VA-funded investigators at UMB in the performance of rehabilitation research, particularly exercise rehabilitation studies in hip fracture and cortical excitability (RDC pilots, NSA and VA-CDA, NIH R37 MERIT), revascularized PAOD (R01), personal status monitoring of physical activity (VA MERIT) and other relevant rehabilitation research; and 6. Further inter-institutional collaborations in stroke and other rehabilitation research among investigators at UMB, Johns Hopkins University (JHU), the Human Cortical Physiology Section at the National Institutes of Health, Sinai Hospitals and other Pepper Centers. Conduct of laboratorybased and standardized measures of functional performance, cortical and peripheral neuromuscular adaptations in the RRC-B improves the accuracy of these assessments, allows strict maintenance of blinding as critical mechanistic outcomes are determined. and eliminates duplication of expensive testing equipment. Centralization of major mechanistic questions relevant to the IDS-1, IDS-2 and the RDC pilot studies into one core ensures the integrity of the methodologies and analysis. Collection of functional and neurophysiologic data by RRC-B investigators, and subsequent integration with data collected in IDS projects and research resources cores enables a comprehensive, multi-disciplinary examination of mechanistic factors associated with exercise rehabilitation in stroke. The RRC-B provides goal directed organization to precisely identify neuromuscular and cortical mechanisms of functional performance leading to adaptive modes of recovery after stroke and other disabling medical conditions in older populations. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: CORE--MEDICAL Principal Investigator & Institution: Williams-Russo, Pamela; Weill Medical College of Cornell Univ New York, Ny 10021 Timing: Fiscal Year 2002 Summary: Geriatric depression is rarely found without at least some medical comorbidity and/or impatient in physical functioning. Not only do these conditions complicate the study of geriatric depression, but evidence from the Developing CRC suggests that they are important indicators of heterogeneity in late life mood disorders and contribute to their outcomes; for example in depressed CRC subjects, medical burden predicts chronicity of depression and delayed recovery is associated with increased mortality. The Medical Core is newly added to the CRC and developed from collaborative relationships between investigators in the Departments of Psychiatry and Internal Medicine at Cornell. Addition of the Medical Core uniquely contributes to the CRC's investigation of heterogeneity of late life mood disorders by rigorous and extensive study of medical illness, functional impairment and depression course and outcome. The Medical Core expands the CRC's resource by providing: 1. funded

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medical investigators with extensive experience conducting longitudinal studies of comorbidity in medical setting patients and having central roles in the CRC; 2. access to a large population of elderly medical patients accustomed to receiving care in a research environment; 3. training and supervision in the administration of carefully selected instruments to assess longitudinal variation in medical morbidity and functional performance; (4) investigations of depression in post-operative depression in subjects enrolled in funded longitudinal studies of coronary bypass surgery and hip fracture repair. The Medical Core will work with the Clinical Core in screening and recruiting elderly patients from primary care settings for assessments and longitudinal follow-up, including subjects with major depression (N=50), minor depression (N=50) and nondepressed. These patients will contribute to the overall CRC database, yielding a sample of depressed elderly subjects ranging widely in severity and type of medical comorbidity and functional status, and followed longitudinally with extensive clinical, neuropsychological and psychosocial ratings. As part of its mission, the Medical Core will take advantage of these data to test cross-core hypotheses concerning the reciprocal relationships of depression and medical illness over time. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: CORE--RECRUITMENT AND EPIDEMIOLOGY Principal Investigator & Institution: Kittner, Steven J.; Professor; University of Maryland Balt Prof School Baltimore, Md 21201 Timing: Fiscal Year 2002 Summary: (provided by the applicant) The potential impact of the IDS-1 and IDS-2 stroke interventions and disability among Americans is enormous, and large-scale trials will be needed to test methods designed to maximize independence. The implementation of these trials will require information regarding the generalizability of findings and the potential personal and societal effects of those interventions. RRC-A is designed both to meet the needs of current UM-OAIC projects and to lay the groundwork for future trials. The specific aims of RRC-A are: 1. Support centralized recruitment and evaluation of factors affecting recruitment. 2. Implement interviewbased measures of outcomes, including basic and instrumental activities of daily living, quality of life, and caregiver burden, as well as potential modifiers of that outcome, including comorbidities, mood, cognitive function, social support, and exercise perception. 3.Develop an innovative approach to modeling the potential health care cost savings of interventions that lead to changes in functional status. There is a compelling rationale for including these services in a core rather than in individual projects. Centralized recruitment of stroke patients for both IDS studies is more efficient, allows study of the determinants of recruitment, and can provide strategic consultation regarding recruitment to other studies of chronic disease in older Americans. Centralized performance of interview-based measures will facilitate training, quality control, standardization, and precision of measurements. The inclusion of a healthservices component in this core makes this expertise available not only to the IDS studies, but also to R01 -funded studies of exercise interventions in peripheral vascular disease and hip fracture patients. The RRC-A will also contribute actively to training young geriatrics and gerontology investigators in epidemiology and health-services research, and will provide resources for the conduct of junior-faculty and pilot studies. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: CALCITONIN

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Principal Investigator & Institution: Kopecek, Jindrich N.; Distinguished Professor and Chairman; Pharmaceutics and Pharmaceutl Chem; University of Utah Salt Lake City, Ut 84102 Timing: Fiscal Year 2002; Project Start 01-APR-1995; Project End 31-DEC-2003 Summary: Osteoporosis is a major cause of morbidity and mortality in postmenopausal women. In an United States, an estimated 13% to 18% of women have osteoporosis. The financial burden is substantial, with an estimated yearly cost of $10 billion in the United States alone. The lifetime risk for osteoporotic fractures in Caucasian women 50 years of age is about 30-40%. Between 13-19% of postmenopausal women who have a hip fracture die within the following year. We propose to use a combination of human calcitonin (hCT) and polymer-bound cathepsin K inhibitor (CKI) as a novel treatment of osteoporosis. The rationales for hCT use in osteoporosis therapy are the stimulation of osteoblasts, specific inhibition of bone resorption by osteoclasts, and prevention of fusion of osteoclast precursors. Clinical studies have shown that a significant gain in bone mass can be achieved by administration of CT. An osteoclast-specific cysteine proteinase, cathepsin K, plays a specialized role in the resorption of organic bone matrix. It was shown that cathepsin K inhibitors (CKI) are effective in reducing osteoclastmediated bone resorption both in vitro and in vivo. The binding of CKI to a macromolecular carrier will change the mechanism of CKI internalization by osteoclasts from diffusion (CKI) to endocytosis (polymer-bound CKI). Consequently, the polymerbound CKI will localize in the sealed zones of the ruffled border (resorption lacuna), i.e. exactly in the place where bone resorption mediated by cathepsin K occurs. We hypothesize that the combination of the actions of hCT and CKI will produce cures which cannot be achieved with hCT or CKI alone. Establishing an oral delivery system for hCT and CKI is of great importance because it is expected that for treatment of chronic disorders in non-life threatening situations, such as postmenopausal osteoporosis, parenteral administration will lead to poor patient compliance and thus restricted utility. hCT is an excellent candidate for the development of alternate delivery routes due to its size and wide therapeutic index. The size of CKIs will be modified with semitelechelic poly[(N-2- hydroxypropyl)methacrylamide] (ST-PHPMA) chains to achieve comparable hydrodynamic volumes of CT and of the ST-PHPMA-CK conjugate, which will simplify the design of the delivery system and have beneficial biological consequences. Novel hydrogels were designed in the first period of research; they contain azoaromatic crosslinks, susceptible to degradation by bacterial enzymes in the colon and hydrolyzable side-chains, which control the kinetics of swelling in the small intestine. The structure and properties of biodegradable hydrogels will be optimized. A new macromolecular CKI will be synthesized. Its efficacy will be evaluated in an osteoclast culture in vitro as well as on an animal model in vivo. The effect of combination therapy will be compared with individual therapies. The bioavailability of hCT and ST-PHPMA-CKI conjugates in rabbits and dogs using hydrogel based delivery devices and a penetration enhancer will be determined. The efficacy and biocompatibility of an hCT and CKI delivery device in an animal model of osteoporosis will be studied. Based on in vivo animal data criteria will be studied. Based on in vivo animal data criteria will be established for the design of an oral hCT and CKI delivery system for the treatment of postmenopausal osteoporosis. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: DEPRESSION TREATMENT IN MEDICALLY REHABILITATING ELDERLY Principal Investigator & Institution: Lenze, Eric J.; Psychiatry; University of Pittsburgh at Pittsburgh 350 Thackeray Hall Pittsburgh, Pa 15260 Timing: Fiscal Year 2002; Project Start 01-SEP-2001; Project End 31-AUG-2006 Summary: (provided by applicant): This application requests a Mentored PatientOriented Research Career Development Award (K23). The candidate is a geriatric psychiatrist and postdoctoral research fellow at the University of Pittsburgh who proposes to develop research skills for geriatric psychiatry research in medical rehabilitation settings. Funding of this award would provide time and resources necessary for him to develop into an independent investigator capable of conducting depression intervention studies in elderly patients undergoing rehabilitation after disabling medical events such as hip fracture. Studies of elders undergoing rehabilitation suggest that depression is associated with poorer outcomes and an increased likelihood of permanent disability and institutionalization. Therefore, it would be of tremendous public health benefit to determine the most efficacious interventions for late-life depression in the medical rehabilitation setting. However, little such intervention research has been done, in part because not enough is known about depression in this setting, and in part due the difficulty of carrying out psychiatric Intervention studies in this setting. To perform such research, the candidate will develop skills in the areas of psychiatric assessment of patients in medical settings, design of intervention trials, measurement of rehabilitation outcomes, and data management and biostatistical analysis. Proposed research consists of a longitudinal descriptive study characterizing late-life depression in medical rehabilitation settings, leading to a pilot intervention study assessing effects of depression treatment on rehabilitation outcomes. The proposed activities will take place in the NIMH-funded Intervention Research Center for Late Life Mood Disorders, directed by the candidate's sponsor, in the Department of Psychiatry at the University of Pittsburgh. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: DETERMINANTS OF RECOVERY FOLLOWING HIP FRACTURE Principal Investigator & Institution: Magaziner, Jay S.; Professor; Epidemiology and Prev Medicine; University of Maryland Balt Prof School Baltimore, Md 21201 Timing: Fiscal Year 2002; Project Start 01-SEP-2001; Project End 31-AUG-2005 Summary: Hip fracture is a major public health problem. Results from our previous work demonstrate a 4.6 percent loss of femoral neck bone mineral density (BMD) during the year following a hip fracture; this dramatic loss in BMD is accompanied by notable changes in markers of bone metabolism. The parent project to the proposed ancillary study is a randomized controlled trial of a home-based exercise program intended to minimize losses in BMD, muscle and function following a hip fracture. The proposed ancillary study will evaluate markers of bone metabolism and selected regulating hormones in hip fracture patients who are participating in this intervention study in order to gain a better understanding of the mechanism by which exercise affects bone health during the year following a hip fracture. These markers and hormones also will be evaluated over a one year period in a matched group of non-fracture controls to establish expected levels and changes in markers of bone metabolism among a frail group of older persons who also have low BMD. The primary aims of the proposed study are: 1) to evaluate the role of exercise on bone metabolism following hip fracture by comparing bone metabolism during the year after hip fracture in patients

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randomized to a home-based exercise intervention with patients assigned to usual care, and 2) to separate the effects of hip fracture on bone metabolism from those of aging in similar persons with low BMD by comparing bone metabolism in hip fracture patients receiving usual care with bone metabolism in a matched group of non-fracture controls. These issues will be addressed using data from 170 female hip fracture patients age 65 plus (100 enrolled in the parent study, and an additional 70 hip fracture patients to be recruited for this ancillary study), and 85 age- and mobility-matched non- fracture controls with BMD Less than 0.82g/cm2. Patients are randomized to a year-long, homebased exercise program to begin when post-acute therapy ends, or usual care. As part of the parent study, 100 patients are having BMD measured during their hospital stay, and again at 2, 6, and 12 months, and blood samples for these 100 patients are being taken, processed, and stored. For the ancillary study, this protocol will be extended to include 70 additional hip fracture patients and 85 non- fracture controls, the latter of which will be measured at point of enrollment and 12 months later. For this ancillary study, all blood samples (i.e., those collected on 100 patients in the parent study and those collected on 70 patients and 85 non- fracture controls in the ancillary study) will be assayed to determine levels of four markers of bone metabolism and three regulating hormones. Information of this type will be useful developing interventions to improve bone health and maximize recovery. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: EARLY DETECTION OF FALLS WITH MULTIDIMENSIONAL SENSORS Principal Investigator & Institution: Xue, Shuwan; Integrated Biomedical Systems 17 Lida Dr Essex Junction, Vt 05452 Timing: Fiscal Year 2003; Project Start 01-JUL-2003; Project End 29-FEB-2004 Summary: (provided by applicant): The long-term objective of the project is to develop and commercialize an intelligent fall detector which can detect a fall in its early phase, well before the individual's hip, arm or head hit the ground Unlike any existing fall detectors which detect the fall after the impact, the new detector will be able to trigger a protective mechanism, e g and inflatable hip pads (and/or wrist pads, head pad) to protect the person from injuries due to the fall. The first application of the intelligent fall detection technology will be the Smart HipSaver This device includes the fall detector and the airbag-like inflatable hip pads which are concealed in comfortable and aesthetically appealing underpants The system will provide the elderly and others who are at the risk of falls with the protection against hip fracture, while affording them the freedom to extend their daily activities outside the specially designed hospital or nursing home rooms, such as the smart room, or rooms with dually stiff floor. The system will be expected to receive much higher user acceptance than the existing hip protectors because the inflatable underpants can be made to look and feel much like regular underpants when not inflated. The key to this system is the intelligent fall detector The goals for the fall detector are 1) The detector must be highly reliable in detecting actual falls, 2) the detector must detect a fall in its early phase, and leave sufficient time for any protective mechanisms to be put in place, 3) the detector should not give false alarms during the user's normal activities. In this proposed study (SBIR Phase I) the feasibility of the fall detector will be investigated with an integrated multidimensional sensor, which includes three linear accelerometers, and three angular rate sensors The fundamental requirements of the sensor, data acquisition and computational hardware and software, and most importantly the multi-dimensional event space discrimination algorithms of fall detection will be determined

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Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: EFFECT OF LEG STRENGTHENING EXERCISE AFTER HIP FRACTURE Principal Investigator & Institution: Mangione, Kathleen K.; Physical Therapy; Arcadia University 450 S Easton Rd Glenside, Pa 19038 Timing: Fiscal Year 2003; Project Start 01-JAN-2003; Project End 31-DEC-2004 Summary: (provided by applicant): Hip fracture is a common medical problem that can drastically change the quality of life for the elderly person. More than 300,000 older people are expected to fracture a hip each year at an estimated cost of 5 billion dollars. Interventions have not been identified that successfully return a majority of persons to their prefracture level of function following hip fracture. Muscle weakness, loss of balance and decreased physical endurance remain. These impairments are associated with slowed gait speed, decreased independence in ambulation, and inability to perform simple activities of daily living. Therefore, despite the improvements in medical care, functional recovery has not occurred. The purpose of this study is to examine the effectiveness of high intensity strengthening exercise used in the home setting for patients who sustain hip fracture. Intervention will begin six months after fracture to ensure healing of bone and soft tissue. Strengthening exercises will be performed twice a week for ten weeks and will be directed to the lower extremity muscles because of their role in gait and transfers. A control group will receive placebo intervention to the same muscle groups. Outcomes will be compared between groups after the intervention and one year after fracture. Effectiveness will be assessed using an impairment measure (quadriceps muscle force production), a functional limitation measure (gait speed), and a disability measure (self-reported physical function). Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: EFFECT OF THEAPEUTIC TOUCH ON BONE FORMATION IN POSTMENOPAUSAL WOMEN AFTER WRIST Principal Investigator & Institution: Prestwood, Karen M.; Assistant Professor and Associate Direct; University of Connecticut Sch of Med/Dnt Bb20, Mc 2806 Farmington, Ct 060302806 Timing: Fiscal Year 2002; Project Start 01-JUL-2001; Project End 30-JUN-2002 Summary: (provided by applicant): Therapeutic touch is a contemporary interpretation of several ancient healing arts developed in the 1970?s by Dolores Krieger, PhD, RN and Dora Kunz, a well known healer. Therapeutic touch is the probably the best researched form of biofield or energy medicine and has been shown to be effective in a wide variety of diseases. Osteoporosis is a common disease in older adults that may result in increased disability or mortality, especially in women or men with spine or hip fractures. Over 50% of women who fracture a hip do not return to pre-fracture function and those with vertebral fractures frequently suffer from chronic pain and associated disability. Anecdotal experiences and unpublished data suggest that therapeutic touch may speed fracture healing and functional recovery after fracture, although this has not been well studied. If therapeutic touch is beneficial to fracture recovery then its use might become an important part of fracture treatment. Serum and urine biochemical markers have been used in the diagnosis and to monitor treatment in metabolic bone disease for many years. Individual markers reflect bone resorption and bone formation and these measures have been shown to be associated with more invasive and cumbersome measures of bone remodeling. Although studies evaluating the use of

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markers after fracture are not well controlled, they suggest that bone formation decreases immediately after fracture then gradually increases and finally returns to the normal range at 6 months to 1 year after fracture. Persons with slower healing fractures have a more gradual rise and more prolonged increase in bone formation markers over time. To begin to examine the overall hypothesis that therapeutic touch may affect fracture healing, we propose to first look at the effect of therapeutic touch on markers of bone formation (and resorption) over time in women who have suffered a recent wrist fracture. We hypothesize that therapeutic touch will prevent the immediate decrease and will result in a more rapid rise and a faster return to normal values of markers of bone formation after fracture, compared to sham therapeutic touch. We will examine the effect of 3 different therapeutic touch treatment courses (or doses) on bone formation and hypothesize that any of the doses of therapeutic touch that we are testing will alter bone formation after fracture, compared to sham therapeutic touch, but that women who receive the highest dose will have the greatest response. We also hypothesize that stimulation of bone formation by therapeutic touch will be associated with altered levels of insulin-like growth factor I and binding protein 3. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: EFFECTS OF SOMATOKINE IN MYOTONIC DYSTROPHY TYPE 1 Principal Investigator & Institution: Moxley, Richard T.; Professor; University of Rochester Orpa - Rc Box 270140 Rochester, Ny 14627 Timing: Fiscal Year 2003; Project Start 30-SEP-2003; Project End 31-MAY-2008 Summary: These phase 1 studies examine a possible new treatment for myotonic dystrophy type1 (DM1), the most common form of adult muscular dystrophy. At present no treatment exists to reverse its progressive wasting and weakness. Low levels of testosterone and growth hormone, as well as insulin resistance, appear to contribute to the muscle loss, but therapeutic trials to reverse these hormonal abnormalities have failed to produce significant improvement. A previous trial of insulin-like growth factor1 [IGF1] has offered promise. Treatment with rhlGF1 increased strength, protein synthesis, and insulin action in 7 patients but side effects caused 2 to drop out. A new, better tolerated, longer acting, preparation of rhlGF1, is now available from INSMED. It is SomatoKine, rhlGF1 in complex with recombinant human IGF binding protein 3, and it will be used in this proposal. Preliminary studies show it is safe and well tolerated in healthy adults, diabetics, and older women treated after hip fracture. We will evaluate SomatoKine in DM1. The aim of this proposal is to evaluate the safety and feasibility of daily subcutaneous injections of SomatoKine for treatment of muscle wasting and weakness by performing two sequential studies, each involving 15 patients with DM1: 1st) An initial 24-Week Dose Escalation Study of SomatoKine [0.5, 1.0, and 2.0 mg/kg, with each dose given daily for 8 weeks] to identify an "optimal dose" based upon the side effects, drug levels, and efficacy [dual energy x-ray absorptiometry (DEXA); quantitative myometry; manual muscle strength testing] observed at each dose; 2nd) A subsequent 24-Week study of SomatoKine using an "Optimal Dose" to demonstrate its safety and feasibility as a daily treatment for a six month period. In addition, we will search for evidence of altered signaling along the intracellular pathway for IGF1 by measuring phosphorylation of p70S6K in needle muscle biopsy specimens obtained from 10 DM1 patients in the 24-Week "Optimal Dose" SomatoKine Study and from 10 age-gender matched normal volunteers who will receive SomatoKine for only two days. Specimens will be obtained from vastus lateralis muscle before and after two days of "optimal dose" treatment. These studies will test our hypothesis that supraphysiologic levels of IGF1 are safe and well tolerated and provide preliminary data regarding

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efficacy (reversal of muscle wasting and weakness.) If the results of this project prove promising, we plan to carry out a larger, multi-center, phase 2, controlled trial of SomatoKine. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: ENDOSTEAL BONE VOLUME REGULATION AND OSTEOPOROSIS Principal Investigator & Institution: Mohan, Subburaman; Research Professor; Loma Linda Veterans Assn/Research Educ C/O Research Service (151) Loma Linda, Ca 92357 Timing: Fiscal Year 2002; Project Start 01-AUG-1981; Project End 30-JUN-2007 Summary: (provided by applicant): The long-term goal of this project is to identify the molecular mechanisms responsible fur the pathogenesis of senile osteoporosis. Because impaired bone formation (BF) is a major contributor to this disease, and because of the importance of the IGF system in the regulation of BF, our studies have focused towards identifying the role of individual IGF system components in the regulation of BE. In this regard, studies during the past grant period have revealed that: (1) IGF binding protein5 (BP-5) could increase BE via a mechanism independent of IGFs (i.e. BP-5 is a growth factor); and (2) BP-5 could function as a physiologic regulator of BF, and that low serum BP-5 could play a pathogenic role in hip fracture patients. In order to define the role of BP-5 as a BE regulator, we need to understand the molecular mechanisms controlling the level of BP-5 and the molecular pathways involved in BP-5 action in bone. To this end, we have made two exciting and pivotal discoveries which form the basis for the continuation studies proposed in this application: (1) ADAM-9 (A Disintegrin And Metalloprotease) is an BP-5 protease in osteoblasts (OBs); and (2) FHL2 (Four and a Half LIM Domain) interacts with BP-5 in OBs. ADAM-9 and FHL2 are newly discovered proteins and relatively little is known about any aspects of these proteins in bone. Studies proposed in Specific Aim 1 deal with the role of ADAM-9 in OBs and these studies are based on the hypothesis that degradation of BP-5 by ADAM-9 is a key control mechanism in regulating BP-5 concentrations in the conditioned medium (and perhaps serum) and, thereby, osteoblast proliferation/differentiation. To this end, we will express recombinant ADAM-9 and test whether purified recombinant ADAM-9 cleaves BP-5 but not other IGFBPs. To evaluate if ADAM-9 is the predominant BP-5 protease, we will perform immunodepletion experiments with antibodies specific to ADAM-9 in the conditioned medium of human OBs. To determine if ADAM-9 is regulated, we will test the effect of osteoregulatory agents, known to modulate BP-5 proteolysis, on synthesis and activity of ADAM-9. To evaluate the functional role of ADAM-9, we will modulate expression of ADAM-9 in human OBs by transgenic approaches using MLV vectors and determine the consequence of changes in ADAM-9 expression on BP-5 proteolysis and BF parameters in vitro. Studies proposed in Specific Aim 2 deal with the role of FHL2 in OBs, and these studies are based on the hypothesis that FHL2 interacts with BP-5 and mediates IGF-independent actions of BP-5 in OBs. To test if BP-5 binds to FHL2 and shuttles it to the nucleus, we will over-express wildtype/nuclear localization sequence mutated BP-5 along with FHL2 fused to different fluorescent proteins and use a fluorescent energy transfer technique to monitor interactions between FHL2 and BP-5. To evaluate the significance of BP-5 interaction with FHL2, we will test the effects of BP-5 on bone formation parameters in mice lacking functional FHL2. We will also evaluate the BP-5 functional pathway by applying the ProteinChip Arrayer to determine if the complex of BP-5/FHL2 binds to other proteins in the nucleus of OBs. Successful completion of the proposed studies will provide information on the molecular pathways involved in the regulation of the BF process, which will eventually lead to better understanding the pathogenesis of why some

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people have impaired BF during aging, and suggest treatment options to correct BF deficiency in those patients. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: ESTROGEN REGULATION OF OSTEOCLASTOGENESIS IN OLDER MEN Principal Investigator & Institution: Taxel, Pamela; Medicine; University of Connecticut Sch of Med/Dnt Bb20, Mc 2806 Farmington, Ct 060302806 Timing: Fiscal Year 2003; Project Start 01-JUL-2003; Project End 30-JUN-2005 Summary: This R03 proposal is in response to Research Objective #17, entitled Basic Underlying Mechanisms of Musculoskeletal Aging. Male osteoporosis and hip fractures, primarily diseases of older men, have been poorly studied until recently. While there are numerous factors that cause osteoporosis and determine fracture risk, decreases in gonadal steroids with aging are known to influence bone metabolism in both men and women. Recent evidence has demonstrated the importance of estrogen (E2) in male bone health. E2 exerts a variety of important physiological effects, which are mediated via two estrogen receptors found in adult bone, although the mechanisms by which they interact is not well understood. In preliminary work we have found that ovariectomy in mice is rapidly followed by an increase in the ability of bone marrow cells to differentiate into osteoclasts, the cells that mediate bone resorption. This finding suggests that E2 regulates the ability of hematopoietic precursor cells to differentiate into osteoclasts, a process that has not been adequately examined. The studies of this proposal represents a collaboration between basic and clinical researchers who wish to determine if human bone marrow cells from older men respond to E2 in a manner similar to that which we have demonstrated in our murine model. Since increased rates of bone resorption appear to be the earliest known effects of estrogen withdrawal on the human skeleton, a better understanding of this process may lead to more effective therapies for the treatment of osteoporosis in both men and women. A unique model in which to better understand the role of E2 in men is that of men undergoing hormonal suppression with LHRH agonists for locally advanced prostate cancer. This therapy leads to hypogonadism, with both low testosterone (T) and E2 levels within a few weeks. Since E2 therapy has been previously used to achieve medical castration, adding back E2 in these men is acceptable and allows the study of the mechanisms of E2 action on bone without the simultaneous influence of T. As the mechanisms of E2 action on male bone metabolism are better understood, it should be possible to analyze these interactions more precisely and develop more specific interventions based on a better understanding of these interactions. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: EVALUATION OF OSTEOPOROSIS PREVENTION IN THE ELDERLY Principal Investigator & Institution: Tosteson, Anna N A.; Associate Professor; Community and Family Medicine; Dartmouth College 11 Rope Ferry Rd. #6210 Hanover, Nh 03755 Timing: Fiscal Year 2002; Project Start 05-JAN-1995; Project End 31-AUG-2007 Summary: (provided by applicant): The broad objective of this research proposal is to improve the health of elderly men and women by identifying more effective osteoporosis prevention and treatment strategies. Osteoporosis disproportionately affects the elderly and is associated with fractures that result in disability, death, and a large expenditure of health care resources. A growing number of interventions are

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available to prevent, diagnose, and treat osteoporosis. Cost-effective use of most such interventions requires selective targeting of high-risk populations, yet our previous research documents significant variation in clinical outcomes, cost, and intervention acceptance even among those at highest risk. Thus, the public health benefit of these interventions has yet to be fully realized. We hypothesize that this shortfall stems from multiple patient, provider and health system factors whose contribution to treatment and outcome variation is not yet understood. The proposed extension of AG 12262 entails four aims that will provide new information concerning variation in osteoporosis treatment and outcome. First, through surveys of patients and their healthcare providers, we will identify opportunities to improve intervention among elderly persons who have sustained a fracture; and will characterize correlates of long-term treatment continuation. Second, we will extend our study of fracture outcomes to a national sample to identify the patient, provider and health system attributes that contribute to variation in cost and adverse health outcomes. Third, we will develop a discrete state/event microsimulation model incorporating data from the first two aims to assess the cost-effectiveness of alternative osteoporosis interventions. This aim will also provide guidance to those planning future osteoporosis outcome studies through analyses addressing the correspondence between preference-based health outcomes measures and an osteoporosis-targeted health status instrument. Fourth, we will study the use of the microsimulation model as a tool for synthesizing evidence in patientcentered osteoporosis decision aids. Our proposed research will provide results useful in guiding both osteoporosis-related health policy and patient-centered decision making. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: EXERCISE--ADJUNCT THERAPY TO ESTROGEN IN OLDER WOMEN Principal Investigator & Institution: Dalsky, Gail; University of Connecticut Sch of Med/Dnt Bb20, Mc 2806 Farmington, Ct 060302806 Timing: Fiscal Year 2002 Summary: The central theme of this intervention development study is that regular exercise should be an adjunct therapy for older women to reduce the incidence of hip fracture. One out of every three white women 85 years and older are likely to experience a hip fracture, which leads to a loss of independence and a lower functional capacity. The primary approach for hip fracture prevention has been replacement estrogen. The long- range goal of implementing exercise as an adjunct therapy is to extend the time of first hip fracture by 5-10 years, resulting in a potential 30-50% reduction in hip fracture. The purpose of this intervention development study is to study the effects of participation in a three- year home-based exercise regimen for 105 women 65-78 years of age on risk factors related to bone and falling. An unique aspect of this study is that the volunteers will be long-term users of estrogen replacement therapy who have femoral neck bone mass >1 SD below the young adult level. The primary hypothesis to be tested is that women aged 65-78 years who are current users of estrogen replacement therapy and have low femoral neck bone mineral density will maintain sufficient compliance and retention in a 3 year home-based aerobic exercise and resistance training program to reduce risk factors regarding bone quantity and quality for osteoporosis, and falls. The specific aims to test this hypothesis are: 1) To evaluate the effectiveness of 3 year homebased exercise intervention on bone mass and geometric properties of the proximal femur. 2) To evaluate the effectiveness of home-based exercise intervention to improve formation relative to resorption, as evaluated by biochemical markers of bone

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metabolism. 3) To evaluate the effectiveness of home-based exercise intervention on risk factors for falls (balance, muscular strength and endurance, gait, lean body mass). A multivariate repeated measures factorial analyses of variance will be done to determine changes in the outcome measures as influenced by the determinants of bone mass. This proposal will establish an exercise regimen that may be implemented as an adjunct therapy to estrogen in older women to preserve or improve bone strength to delay the onset of first hip fracture. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: FALL BIOMECHANICS AND HIP FRACTURE RISK Principal Investigator & Institution: Hayes, Wilson C.; Professor; Exercise and Sport Sciences; Oregon State University Corvallis, or 973391086 Timing: Fiscal Year 2002; Project Start 01-FEB-1994; Project End 31-MAY-2005 Summary: (Verbatim from the application) Falls and fall-related injuries are the most serious, common costly medical problems facing the elderly. In the US each year there are about 30 millions falls, or about 1 per second, among 10 million fallers. In addition, of the approximately 300,000 hip fractures that occur each year, over 90% are associated with falls. We have shown previously that falls to the side with impact on the hip are associated with more than 20-fold increase in the risk of hip fractures (compared to a 3fold increase in risk associated with reduced bone density). Thus, when screening for interventions and fracture prevention programs (pharmaceutical agents, trochanter padding or exercise), it is far less cost effective and efficient from a public health perspective to attempt to identify the 10 million elderly who will fall each year (which can now be done using relatively simple field tests) than it is to focus on the 500,000 to 600,000 elderly subjects who will fall to the side (for which comparable validated tests are not yet available). The aims of this competitive renewal application are focused on this goal. During the previous funding period, we completed the goals of Aim 1: Dynamics of Side Falls, demonstrating that slow gait speed and the postural disturbances of slipping or fainting are associated with falls to the side and impact on the hip. We have also developed the first available multi‑segment, whole body model for falling and showed it to be a powerful tool for studying the biodynamics of falling to the side. For our previous Aim 2: Side Fall Risk Index, we completed both the development and refinement phases of the proposed index, demonstrating that a linear combination of tandem gait, hip abduction strength, step velocity asymmetry from the quick-step test, and sway variables while standing in a semi-tandem position could be used to distinguish elderly subjects who fell to the side from those who fell in all other directions. Under our new proposed Aim 1: Validation of Side Fall Risk Index (SFRI), we will determine whether the Side Fall Risk Index we have developed during the previous funding period can be used prospectively to identify elderly subjects who will fall to the side. As an extension of our previous work on the dynamics of side falls, under Aim 2: Gait Variability as a Predictor of Side Falls we will analyze the ground pressure time histories of elderly fallers ambulating on an instrumented mat. We will apply modern signal analysis theory to the ground pressure time histories. Using chaos theory and fractal analysis and noting that cardiovascular and neuromuscular pathologies are characterized by increased regularity of heartbeat and gait, respectively, we will determine if gait parameters determined from ground pressure time histories can be used to identify frail elderly subjects who fall to the side. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: FOCUS Principal Investigator & Institution: Carson, Jeffrey L.; Richard C. Reynolds Professor of Medicin; Medicine; Univ of Med/Dent Nj-R W Johnson Med Sch Robert Wood Johnson Medical Sch Piscataway, Nj 088545635 Timing: Fiscal Year 2003; Project Start 01-SEP-2003; Project End 31-AUG-2008 Summary: (provided by applicant); Red blood cell transfusions are an extremely common medical intervention in both the United States and worldwide; over 11 million units are transfused in the United States. Between 60% and 70% of all blood is transfused in the surgical setting. Despite the common use of red blood cell transfusions, the threshold for transfusion has not been adequately evaluated and is very controversial. A decade ago the standard of care was to administer a peri-operative transfusion whenever the hemoglobin (Hgb) level fell below 10 g/dl (the "10/30 rule"). Concerns about the safety of blood, especially with respect to HIV and hepatitis, and the absence of data to support a 10 g/dl threshold led to current standard of care today to administer blood transfusions based on the presence of symptoms and not a specific Hgb/hematocrit level. However, there are no randomized clinical trials in surgical patients that have tested the efficacy and safety of withholding blood until the patient develops symptoms or the "10/30" approach to transfusion. Patients with underlying cardiovascular disease are at greatest risk of adverse effects from reduced Hgb levels. We propose to conduct a multi-center randomized trial to test if a more aggressive transfusion strategy that maintains postoperative Hgb levels above 10 g/dl improves patient outcome as compared to a more conservative strategy that withholds blood transfusion until the patient develops symptoms of anemia. Eligible patients for the trial will have undergone surgical repair for a hip fracture and have a postoperative Hgb level below 10 g/dl within three days of surgery. Only patients with cardiovascular disease will be entered into the study. Patients will be randomized to one of the two transfusion strategies. The 10 g/dl threshold strategy will use enough red blood cell units to maintain Hgb levels at or above 10 g/dl through hospital discharge. Symptomatic transfusion strategy patients will receive red blood cell transfusions for symptoms of anemia, although transfusion is also permitted but not required if the Hgb level falls below 8 g/dl. Outcomes will include functional recovery (primary outcome: ability to walk ten feet across a room without human assistance at 60-days postrandomization), long-term survival, nursing home placement, and postoperative complications (death in hospital or within 30 days, pneumonia, myocardial infarction, thromboembolism, stroke, delirium). We will randomize 2,600 patients from 25 centers over a 3.5-year period. This will allow us to detect a 16% relative risk reduction in the loss of ability to walk independently with power about 0.90. A pilot study in 84 patients demonstrated the feasibility of the study. Ambulation at 60 days is known to be highly predictive of ultimate functional outcome as well as of mortality at one year. Because inability to walk again has such important implications for quality office, and because, unfortunately, it is a common problem, it far outweighs the remote chance of viral infection or other complications from transfusion in these elderly patients. Also, this study will measure the frequency and 95% confidence intervals of the medical errors that are important in this patient population and are poorly documented in the literature. The medical errors that will be measured are: transfusion errors (blood transfusion to the wrong patient, mislabeling of samples for type and cross match, use of whole blood instead of packed red cells), failure to use thromboembolism prophylaxis, incorrect antibiotic prophylaxis, wrong site surgery and femoral shaft fracture. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: FOCUS DATA COORDINATING CENTER Principal Investigator & Institution: Terrin, Michael L.; President; Maryland Medical Research Institute, Inc 600 Wyndhurst Ave Baltimore, Md 21210 Timing: Fiscal Year 2003; Project Start 10-JUL-2003; Project End 30-JUN-2008 Summary: (FROM THE APPLICATION): Over 11 million units are transfused in the United States. Despite the common use of red blood cell transfusions, the threshold for transfusion has not been adequately evaluated. A decade ago the standard of care was to administer a peri-operative transfusion whenever the hemoglobin level fell below 10 g/dl (the "10/30 rule"). Concerns about the safety of blood, especially with respect to HIV and hepatitis, and the absence of data to support a 10 g/dl threshold led to current standard of care to administer blood transfusions based on the presence of symptoms and not a specific hemoglobin/hematocrit level. However, there are no randomized clinical trials in surgical patients that have tested the efficacy and safety of withholding blood until the patient develops symptoms or the 10/30 approach to transfusion and limited evidence for patients with underlying cardiovascular disease are at greatest risk of adverse effects from reduced hemoglobin levels. We propose to conduct a multicenter randomized trial to test if a more aggressive transfusion strategy that maintains postoperative hemoglobin levels above 10 g/dl improves patient outcome as compared to a more conservative strategy that withholds blood transfusion until the patient develops symptoms of anemia. Patients eligible for the trial will have undergone surgical repair for a hip fracture and have a postoperative hemoglobin level below 10 g/dl within three days of surgery. Only patients with cardiovascular disease will be entered into the study. Symptomatic transfusion strategy patients will receive red blood cell transfusions for symptoms of anemia, although transfusion is also permitted but not required if the hemoglobin level falls below 8 g/dl. Outcomes will include functional recovery (primary outcome: ability to walk ten feet across a room without human assistance at 60-days post-randomization), long-term survival, nursing home placement, and postoperative complications (death in hospital or within 30 days, pneumonia, myocardial infarction, thromboembolism, stroke). We will randomize 2,600 patients over a 3.5-year period to detect a reduction in the loss of ability to walk independently from 43% to 36% (16% relative risk reduction) with power about 0.90. Also, this study will measure the frequency and 95% confidence intervals of the medical errors that are important in this patient population. The medical errors that will be measured are: transfusion errors (blood transfusion to the wrong patient, mislabeling of samples for type and cross match, use of whole blood instead of packed red cells), failure to use thromboembolism prophylaxis, incorrect antibiotic prophylaxis, wrong site surgery, and femoral shaft fracture. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: GENETIC ANALYSIS OF HIP FRAGILITY Principal Investigator & Institution: Turner, Charles H.; Professor; Orthopaedic Surgery; Indiana Univ-Purdue Univ at Indianapolis 620 Union Drive, Room 618 Indianapolis, in 462025167 Timing: Fiscal Year 2003; Project Start 04-APR-2003; Project End 31-MAR-2008 Summary: (provided by applicant): Genetic influences account for the majority of the population variance in bone mineral density and bone fragility. Considering that hip fracture is the most expensive of osteoporotic fractures, both in terms of health care cost and in human costs (i.e., morbidity and mortality), there should be considerable interest in an animal model for studying genetic influences on hip fragility. We recently

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identified two strains of rats, Copenhagen 2331 (COP) and DA, which have considerable variation in the biomechanical properties of their femoral necks. We propose to use these rat strains to identify genes responsible for the variation in hip fragility. We will test three hypotheses: (1) COP and DA rats reach peak femoral neck strength and bone mass at six months of age. Our goal is to determine genetic influences on the biomechanical properties and bone structure at an age when femoral neck strength is at its peak. Sprague-Dawley rats achieve peak bone mass and strength within a window of 5-9 months of age. Presumably, COP and DA strains follow similar skeletal growth curves. We will measure femoral biomechanical properties, geometry and microstructure in rats ranging from 2 to 10 months of age to determine the age associated with peak values; (2) chromosomal regions harboring genes that regulate femoral neck strength and microstructure can be determined for rats. COP and DA progenitor rats will be mated and their F1 hybrid offspring intercrossed to create an F2 population containing 500-600 individuals. These rats will be phenotyped based upon femoral neck biomechanical, geometrical and microstructural measurements. Quantitative trait loci (QTL) analyses will be performed to identify the genetic loci influencing variation phenotypes. We anticipate that these analyses will identify several QTLs containing genes that influence femoral neck fragility; and (3) femoral shaft and neck fragility are regulated, at least in part, by different genetic loci. The COP x DA F2 population will be further characterized for bone fragility at the femoral midshaft QTL analyses will be performed to identify the genetic loci contributing to the variation in the phenotypes. We anticipate that these analyses will identify some QTLs previously linked to femoral neck fragility in Aim 2, as well as novel QTLs specifically influencing femoral shaft phenotypes. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: GENETIC REGULATION OF IGF-I IN PEAK BONE DENSITY OF MICE Principal Investigator & Institution: Rosen, Clifford J.; Director; Jackson Laboratory 600 Main St Bar Harbor, Me 04609 Timing: Fiscal Year 2002; Project Start 22-JUL-1998; Project End 31-MAY-2005 Summary: Insulin-like growth factor- I (IGF-I) is a ubiquitously expressed 7.5 kDa polypedtide that circulate in relatively high concentrations. In bone, IGF-I is secreted by osteoblasts, and is stored in the matrix bound to IGF binding proteins (IGFBPs). Skeletal IGF-I promotes osteoblast differentiation, increasing collagen biosynthesis and mildly enhancing bone cell mitogenesis. Reduced serum IGF-I concentrations have been linked to lower skeletal levels of this peptide, future risk of hip fracture, histomorphometric indices of bone formation, bone mineral density, and a poly-morphism in the IGF-I gene. Hence serum IGF-I has been considered an intermediate skeletal phenotype. In the first three years of our proposal, using inbred strains of mice have established: 1) serum IGF-I is a heritable polygenic train; 2) three major non-growth hormone dependent quantitative trait loci (QTLs) and one interactive QTL influence the serum IGF-I phenotype; 3) two IGF-I QTLs associate with major skeletal phenotypes (BMD and femoral length); 4) one QTL contains the IGF-I gene and the interactive QTL maps in close proximity to the IGFBP-3 gene; 5) congenic mice carrying one of these major QTLs exhibit reduced serum IGF-I and a major skeletal phenotype; and 6) osteoblasts from high serum IGF-I mice (C3H/HeJ) show a sixfold up-regulation in IGF-I exon 1 promoter mRNA compared to the low serum IGF-I mice (C57BL/6). These data suggest that IGF-I is important for the acquisition of BMD and optimal strength. In this proposal we hypothesize that serum IGF-I genes are also major determinants of skeletal IGF-I

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expression. Our goals are to fine map these IGF-I regulatory genes and to understand how these genes affect osteoblast function and bone morphology. We propose three specific aims: 1) to delineate the genes for serum IGF-I by fine mapping and assessing nested congenics for changes in BMD and strength; 2) to determine the role of IGFBPs in modulating skeletal IGF-I by studying osteoblast expression and secretion of IGFBPs and by phenotype 'rescue' of newly developed congenics through targeted over expression of skeletal IGF-I; and 3) to determine the molecular mechanisms responsible for interstrain differences in skeletal IGF-I expression. These experiments will provide tremendous insight into the cellular regulation of the IGFs and IGFBPs, an important first stem towards understanding the role of IGF-I in osteoporosis and other chronic disease wherein tissue specific IGF-I activity may have a major pathophysiologic component. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: GENETICS OF BONE LOSS AND BONE STRENGTH IN MEN AND WOMEN Principal Investigator & Institution: Peacock, Munro; Professor; Indiana Univ-Purdue Univ at Indianapolis 620 Union Drive, Room 618 Indianapolis, in 462025167 Timing: Fiscal Year 2002 Summary: Osteoporotic fracture is due to age-related reduction in bone strength. Bone strength comprises bone mineral density, structure, quality and turnover, all of which are highly heritable. The most serious osteoporotic fracture occurs at the hip. Reduction in hip bone strength is due to a combination of low peak bone mass and age-related bone loss. Heritability of bone mass at the hip is high, but heritability of bone loss at the hip has not been studied. Women have lower bone strength and higher incidence of hip fracture than men. In men, heritability of bone strength has not been firmly established. Heritability of bone strength has been measured in 760 pairs of sisters, and a 10 cM genome screen has identified several chromosomal loci influencing bone strength. Two hypotheses will now be tested: 1. The rate of bone loss at the hip in women is genetically determined. This will be tested by remeasuring hip bone mass in 500 pairs of sisters in our current study and, if heritable, perform linkage analysis using genotypic already generated. 2. The genetic effect on bone strength in men is similar to that in women, but certain loci are sex specific. This will be tested by measuring bone strength in 700 pairs of brothers, comparing heritabilities to those in our 760 of sisters, and performing a genome screen to identify loci influencing bone strength in men. Three major goals in understanding the genetic basis of bone strength will be achieved: 1) establish if the rate of bone loss at the hip in women has a genetic component, and if so, localize the genes that underlie the loss; 2) establish heritabilities of bone strength in men and compare these with those established in women; 3) enrich our database for fine mapping bonestrength genes and establish if certain loci are sex specific. This information will lead to a much better understanding of the causes of osteoporotic hip fracture and of the difference in incidence between men and women and, ultimately, to new therapeutic and preventative treatments. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: GROWTH HORMONE W EXERCISE STRENGTH IN 60+ YR OLD MEN & WOMEN?

INCREASE

MUSCLE

Principal Investigator & Institution: Zachwieja, Jj; Washington University Lindell and Skinker Blvd St. Louis, Mo 63130

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Timing: Fiscal Year 2002 Summary: Advancing age is associated with a reduction in skeletal muscle protein and muscle force production capabilities; a syndrome referred to as sarcopenia. This process occurs in healthy, normal aging, but is accelerated by physical inactivity, degenerative or other disease conditions. Incorporation of 13C-leucine into skeletal muscle protein, as measured by isotope dilution mass spectrometry, provides a measure of muscle protein synthesis. Decreased muscle mass and strength are associated with an increased risk of falling, and therefore, increased risk for hip fracture. Reduced muscle strength with aging can also result in physical disability and frailty, a loss of independent function, and contributes to escalating health care costs. The biological consequences of advancing age and the progressive decline in physical activity with age contribute to sarcopenia. Exercise training programs have the potential to improve overall fitness, muscle force generation, and imp rove quali ty of life. The physiological and functional benefits of increased muscular activity have been reported, even into the 9th decade of life (1). Thus, human skeletal muscle protein maintains the ability to respond to an exercise-induced increase in contractile activity throughout. The ability to adapt may be limited by other biological processes. Circulating concentrations and the pulsatile release patterns of several hormones that regulate metabolism are reduced with age. By virtue of their anabolic actions on body proteins, low serum growth hormone (GH), testosterone, dehydroepiandrosterone (DHEA), and perhaps estrogen, along with reduced insulin action, have all been implicated as mediators of the muscle protein wasting aging. We review the efficacy of recombinant human growth hormone (rhGH) replacement therapy and resistance exercise training to enhance muscle protein mass and contractile force output in elderly (62+ yr old) men and women. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: HEALTH CONCORDANCE IN OLDER MEXICAN AMERICAN COUPLES Principal Investigator & Institution: Peek, Mary K.; Preventive Medicine and Community Health; University of Texas Medical Br Galveston 301 University Blvd Galveston, Tx 77555 Timing: Fiscal Year 2003; Project Start 01-JUL-2003; Project End 30-JUN-2006 Summary: (provided by applicant): Individuals who are married tend to have lower mortality, morbidity, and better mental health. The potential protective effect of marriage on both physical and mental health is of particular importance to older couples as the number of older married adults rises and mortality rates continue to decrease. However, there is very little information on the connection between the health statuses of older married couples. The similarity between health of spouses, or "concordance" can be of particular importance if the deterioration in the health of one spouse is associated with the deterioration in the health of the other spouse. One way to address concordance is to examine the connection between one spouse's health events and the other spouse's health outcomes. To address the association between spouses' health more extensively, we intend to examine the potential influence of physical functioning and health events in one spouse on the health of the other spouse over a 2-5 year time period in older Mexican American adults. The specific aims of the study are: (1) to examine the relationship between the presence of major health events (myocardial infarction, stroke, cancer, and hip fracture) in one spouse and depressive symptoms and lower body mobility of the other spouse; (2) to assess the connection between physical functioning (e.g., I/ADL disability) in one spouse and depressive symptoms and lower body mobility of the other spouse; and (3) to investigate the association of mortality of

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one spouse with depressive symptoms and lower body mobility of the other spouse. As a secondary aim, we will explore the possibility that social support and acculturation modify the relationship between spouses' health statuses in older Mexican Americans. We will be examining these specific aims in 553 married couples from the ongoing Hispanic Established Populations for Epidemiologic Studies of the Elderly (H-EPESE). One of the benefits of examining concordance in spouses' health in older Mexican Americans lies in their health profiles (mortality rates similar to older White adults but higher rates of certain diseases and disability). Structural equation modeling will be used for model estimation on three waves of data (1993-94 -1998/9.) Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: HIP OSTEOPOROSIS

RADIOGRAPHS:

NOVEL

METHOD

TO

DIAGNOSE

Principal Investigator & Institution: Arnaud, Claude D.; Professor Emeritus; Imaging Therapeutics, Inc. 1720 S Amphlett Blvd, St 240 San Mateo, Ca 94402 Timing: Fiscal Year 2003; Project Start 01-SEP-2003; Project End 28-FEB-2004 Summary: (provided by applicant): This Small Business Innovation Research Phase I project is designed to develop techniques for the diagnosis of osteoporosis and for assessing fracture risk by quantifying trabecular structural elements in hip x-rays. Osteoporosis is a public health threat for 44 million women in the United States alone. The inability to identify persons at risk for the disease is a major impediment in dealing with this epidemic. In fact, less than 30% of persons with osteoporosis are aware that they have it. This is due to the high cost and resulting small installed base of commercially available osteoporosis testing systems. Imaging Therapeutics Inc. proposes to develop technology for low-cost bone structural analyses by linking readily available x-ray equipment to novel image analysis algorithms. While measurements of bone mineral density (BMD) are easy to perform and are helpful in determining when to intervene therapeutically, low BMD accounts for only a portion of fracture risk. Progressive disruption of trabecular structure contributes the better part of the remainder of that risk. The aims of this proposal are: 1) To develop new image processing techniques for automated measurement of 2D-trabecular bone structural elements in hip radiographs. 2) To determine the influence of x-ray beam angulation, soft-tissue attenuation and radiographic technique on radiographic measurements of bone structure. 3) To determine the clinical validity of those 2 D measurements in vitro by a) comparing them, in cores of cadaver proximal femora, to similar measurements made using 3D micro CT and b) determining if they correlate significantly with biomechanical failure loads and stiffness. 4) To directly apply the technology developed in Phase I of this proposal to a series of clinical trials that will be developed for Phase II to prove the clinical utility of that technology in the diagnosis of osteoporosis and prediction of osteoporotic fracture. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: HOSPTIAL STAFFING, PHYSICAL RESTRAINT & PATIENT OUTCOMES Principal Investigator & Institution: Sullivan-Marx, Eileen; None; University of Pennsylvania 3451 Walnut Street Philadelphia, Pa 19104 Timing: Fiscal Year 2002; Project Start 01-SEP-2000; Project End 31-AUG-2004 Summary: The use of physical restraints with frail older adults is associated with increased risk for serious injuries and accidental death, as well as contributing to

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Hip Fracture

negative patient outcomes. Yet, the use of physical restraints with frail older adults in hospitals persists. This study examines the impact of hospital organizational context and nurse staffing on restraint use and associated patient outcomes. Data on restraint use for hip fracture patients in hospital will be merged with American Hospital Association Annual Hospital Survey data on hospital characteristics and nurse staffing and extensive organizational data from surveys collected in several NINR-funded studies by Penn's Center for Health Outcomes and Policy Research. It is hypothesized that hospital nurse staffing and organization affect the rate of physical restraint use, and that such use is associated with poorer outcomes at discharge. My research to date has focused on patient characteristics associated with physical restraint. In order to achieve my long term goal to be an independent investigator in outcomes research regarding care of frail older adults. I need advanced training and mentoring in the requisite methodologies and analytic techniques used in the emerging field of outcomes research. With targeted training and conduct of this proposed study, I will gain a new research skill set in the design and analysis required to investigate the organization of nursing, manage large date sets, and analyze interactive effects of multiple variables on outcomes employing such methods as hierarchical linear modeling, censoring, and multiple imputation techniques. This proposed study is consistent with my goals to expand my clinical research into a new field of inquiry, nursing outcomes research, in which I have had no previous training or experience. My goal for this research career award are to: 1) gain a new research skill set in outcomes research, 2) extend my research program by examining the effects of hospital factors on physical restraint and other outcomes, 3) publish findings in peer- reviewed journals, 4) develop a proposal for extramural funding extending the scope of the study proposed here, and 5) establish interdisciplinary/collaborative relationships with experts in the field of outcomes research. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: IMPACT OF MEDICARE POLICIES ON UTILIZATION AND OUTCOMES. Principal Investigator & Institution: Fitzgerald, John D.; Medicine; University of California Los Angeles 10920 Wilshire Blvd., Suite 1200 Los Angeles, Ca 90024 Timing: Fiscal Year 2002; Project Start 16-JUL-2002; Project End 30-JUN-2006 Summary: (provided by applicant): The candidate is a board-certified rheumatologist interested in applying the methodology of health economics to study fiscal policies that impact the care of patients suffering from arthritis and other rheumatic diseases. He is seeking external funding support so that he might have the protected time to avail himself of formal course studies, research time on the proposed project, and access to his mentors. He has a business background and is currently enrolled in the UCLA School of Public Health, Health Services Ph.D. degree program, with an emphasis on Health Economics. UCLA provides an excellent environment for the development of his career. The Department of Medicine provides formal support for its young investigators through the Scientific Training and Advanced Research program. UCLA has excellent health service researchers and health economists in the Schools of Public Health and Medicine. UCLA has a close working relationship with RAND and the RAND Graduate School. During the award, the candidate will take classes required to complete his Ph.D. degree. A portion of the proposed research will serve as his dissertation. He has enlisted a team of health economists, health service researchers, a rheumatologist and a statistician to teach him the skills he needs to complete the proposed research and to develop his career as an independent researcher with health economic and arthritis

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expertise. He has proposed to study the impact of the Balanced Budget Act expenditure cuts on post-acute care utilization and clinical outcomes on a 100% sample of Medicare patients who have undergone elective joint replacement surgery or surgical management of hip fracture. He has also proposed to examine managed care costshifting to the fee for service sector by studying managed care disenrollment prior to planned surgery (elective joint replacement) and disenrollment prior to unplanned surgery (hip fracture). Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: INCIDENCE OF LATE MACULAR DEGENERATION IN OLDER WOMEN Principal Investigator & Institution: Coleman, Anne L.; Assistant Professor; Jules Stein Eye Institute; University of California Los Angeles 10920 Wilshire Blvd., Suite 1200 Los Angeles, Ca 90024 Timing: Fiscal Year 2002; Project Start 15-AUG-2002; Project End 31-JUL-2007 Summary: (Applicant's Abstract) Age-related macular degeneration is the number one cause of irreversible blindness in the United States and is more prevalent in older, Caucasian women. Although there have been several studies on the incidence of ARM, none of these studies has been able to provide accurate estimates on the incidence of late ARM and/or the progression of ARM in the oldest old, those individuals over 80 years of age, because of the limited sample sizes in these studies in this age group. The population in the Study of Osteoporotic Fractures (SOF) is an appropriate cohort in which to evaluate the incidence of late ARM and the progression of ARM, because the mean age of the women at the re-examination will be 84.4 years of age and the sample is mainly Caucasian. The proposed research study aims to determine the incidence of late ARM, the rate of progression of ARM, and the association of specific risk factors such as diabetes mellitus and prior cataract surgery with late ARM and the progression of ARM in elderly women. In addition, it aims to determine the trajectory of visual decline in older women over a 14- year period. Secondarily, it aims to determine the impact of late ARM on vision-targeted health-related quality of life and to determine whether or not an association exists between the progression of ARM and the risk of falling and hip/non-spine fractures. In 1997 to 1998 (Visit 6), 5482 women had an eye examination that consisted of a medical and ocular history, nine questions from the National Eye Institute Visual Function Questionnaire (NEI-VFQ), and measurements of visual acuity, contrast sensitivity, peripheral vision with automated perimetry, intraocular pressure, and uncorrected refractive error. These women also had a refraction and imaging of their lenses and fundi of both eyes through dilated pupils. Approximately 4.5% of these women have photographically validated late ARM, 41.5% have early ARM, and 54% have no ARM or hard drusen only. In the proposed re-examination, we will update their medical and ocular history and ask them the nine questions from the NEIVFQ. In addition, visual acuity and contrast sensitivity will be re-measured. Fundus photographs of both eyes through dilated pupils will be obtained. These photographs and the relevant photographs from 1997 to 1998 will be graded for ARM with the Wisconsin Age-Related Maculopathy Grading System (WARMGS) in a masked fashion so that the readers do not know which film is from which visit. The University of Wisconsin will also grade the fundus photographs on 30% of the eyes with ARM and 10% of the total sample. This will allow the identification of women in SOF who have had progression of their ARM and developed late ARM since 1997 and 1998. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Hip Fracture

Project Title: INDEPENDENT SCIENTIST AWARD Principal Investigator & Institution: Ottenbacher, Kenneth; Associate Director; Sealy Center on Aging; University of Texas Medical Br Galveston 301 University Blvd Galveston, Tx 77555 Timing: Fiscal Year 2003; Project Start 01-MAY-2003; Project End 30-APR-2008 Summary: (provided by applicant): The candidate (Kenneth J. Ottenbacher) holds a faculty position at the University of Texas Medical Branch (UTMB) in Galveston, Texas, that involves several administrative roles including: Vice Dean in the School of Allied Health Sciences, Director of the Division of Rehabilitation Sciences, and Associate Director of the Sealy Center on Aging. The K02-Award will allow Dr. Ottenbacher to reduce his administrative responsibilities and focus additional time on research. K02 funding will permit him to expand his examination of the disablement process in older adults. His current research is funded by grants from the National Institute on Aging and, more recently, the American Heart Association. Specifically, Dr. Ottenbacher will systematically explore the relationship between functional status and two components of the disablement process associated with quality of life - patient satisfaction and participation in community and social/personal activities (as defined in the World Health Organization's, International Classification of Functioning, Disability and Health). The immediate goals for the K02 include: 1) reduce administrative responsibilities to a less than 25% time commitment, 2) increase publication rate by 20% per year for the next four years, and 3) increase amount of externally funded grant dollars by 100% by end of K02-award. These goals will be accomplished by permanent resignation of his administrative role as Vice Dean in the School of Allied Health Sciences and reassignment of other responsibilities, including transferring management of a Health Services Resources Administration training grant, for which he is currently PI, to another faculty member. These changes will allow Dr. Ottenbacher to devote a minimum of 75% time to research and achieve his long term goals of establishing a program of externally funded research supported by multiple R01 type grants that contributes to the understanding of older adults with disabilities. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: MECHANISMS

INTESTINAL

CALCIUM

ABSORPTION:

MOLECULAR

Principal Investigator & Institution: Fleet, James C.; Associate Professor; Foods and Nutrition; Purdue University West Lafayette West Lafayette, in 479072040 Timing: Fiscal Year 2004; Project Start 15-SEP-1997; Project End 30-JUN-2008 Summary: (provided by applicant): The control of intestinal calcium absorption is important for human health in two ways. First, the risk of osteoporotic hip fracture is higher in women with low calcium absorption efficiency and this may be due to ageassociated calcium malabsorption or intestinal resistance to 1,25(OH)2 vitamin D3 (1,25(OH)2 D, the primary regulator of intestinal calcium absorption). Second, a significant barrier to the use of vitamin D analogs as pro-differentiating agents in cancer treatment is that they stimulate intestinal calcium absorption and cause hypercalcemia. Our long-term objective is to clarify the mechanisms used by 1,25(OH)2 D to promote calcium absorption and to utilize this information to improve calcium absorption in people with low fractional calcium absorption and to aid in the design of vitamin D analogs that can be used as non-calcemic cancer therapeutics. New research shows that 1,25(OH)2 D rapidly activates second messenger and kinases pathways including the MAP kinases and their upstream activators; inhibition of these kinases blunts 1,25(OH)2

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D-mediated gene transcription indicating the classical and non-classical vitamin D signaling pathways interact. The goal of the proposed research is to determine how the 1,25(OH)2 D-mediated transcriptional activation of intestinal calcium absorption is influenced by the basal or induced activity of the MAP kinases ERK1 and 2. The specific aims of this project are to: (1) Identify the nVDR-mediated genomic pathways controlling intestinal calcium absorption that are modulated by 1,25(OH)2-induced activation of ERK1 and 2, and (2) Establish the protein-protein interactions necessary for 1,25(OH)2 D-mediated gene expression that are promoted by 1,25(OH)2 D-induced ERK1 and 2 activity. We will accomplish these aims by studying the effect of 1,25(OH)2 D in a well-characterized cell culture model (Caco-2 cells) and in the small intestine of mice. Biological actions of 1,25(OH)2 D will be studied in the presence of activators and inhibitors of protein kinases (pharmacologic inhibitors, dominant negative kinases) and the rapid actions of vitamin D (vitamin D analogs), nVDR action and function will be studied with cellular imaging, reporter genes, multi-hybrid assays, and chromatin immunoprecipitation (CHIP) assays. Elucidating the mechanism of this vitamin D signal pathway cross-talk will provide the foundation for controlled modulation of intestinal calcium absorption, e.g. when vitamin D resistance associated with aging or estrogen deficiency is present. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: LEAD EFFECTS ON SKELETAL STEM CELLS AND FRAC Principal Investigator & Institution: Schwarz, Edward M.; Associate Professor; University of Rochester Orpa - Rc Box 270140 Rochester, Ny 14627 Timing: Fiscal Year 2002; Project Start 01-JUL-2002; Project End 30-JUN-2006 Summary: (provided by the applicant): The unifying hypothesis of this Program Project is that Pb exposure causes osteoporosis, which at the cellular level is known to be the result of an imbalance between bone resorption and bone formation. This condition is also associated with defective skeletal repair, which represents a significant component of the disease, as it has been shown that ~24% of osteoporosis patients that sustain a hip fracture die from associated complications. Critical data in support of this theory are that animals feed Pb in their diet become osteoporotic. At present the mechanism of this Pb-induced osteoporosis and the effects of Pb on fracture healing are unknown. This project will test the hypotheses that 1) Pb-induced osteoporosis is caused by preferential inhibitory effects on bone stem cells (osteoblast >>osteoclast progenitors) and 2) this inhibition has significant effects on skeletal repair (fracture healing). To test this the investigators will utilize two different Pb exposure regimens: Chronic Pb exposure (adult mice continually fed Pb in their drinking water) and osteoporosis-induced exposure (adolescent mice are exposed to Pb during development to incorporate Pb into their bones following 2 month of a Pb free diet, to clear the systemic Pb, the mice are overiectomized to commence the osteoporosis-induced exposure). Utilizing these exposures regimens with the dosing of 0,200 or 500ppm of Pb in their drinking water, to achieve a blood Pb concentration of (