The Bone and Mineral Manual, Second Edition: A Practical Guide

Contents ~, Conf'ibulO" Prr:facr: ~ I'i ; Part 0 "" Diagnostic Pr~ du .tz"a Part Th ree 165 Patient and Family...

Author: Michael Kleerekoper | Ethel S. Siris | Michael McClung

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Contents ~,

Conf'ibulO"

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Part 0 ""

Diagnostic

Pr~ du .tz"a

Part Th ree

165

Patient and Family Education and Support

3 4 Princirleso( Park nt and Famil)· Educaliun and Support lklsy McC/lmg 35 Resources (or Education Ilnd Support Bt'1Sy McC/u"g (nd~x

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Contributors Carolyn Becker Toni Stabile Osteoporosis Center Columbia University Medical Center New York, New York 10032 John P. Bilezikian Department of Medicine Columbia University College of P and S New York, New York 10032 Albert C. Clairmont Department of Physical Medicine and Rehabilitation The Ohio State University Columbus, OH 43210 Bess Dawson–Hughes Jean Mayer USDA Human Nutrition Research Center on Aging Tufts University Boston, Massachusetts 02111 Marc K. Drezner Endocrinology, Diabetes and Metabolism Section University of Wisconsin, Madison Madison, Wisconsin 53792 Murray J. Favus Department of Medicine University of Chicago Medical Center Chicago, Illinois 60637 Ignac Fogelman Department of Nuclear Medicine Guy’s Hospital London, UK SE1 9RT Harry K. Genant University of California, San Francisco San Francisco, California 94143 xi

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Contributors

David Goltzman Division of Endocrinology McGill University and McGill University Health Center Montreal, Canada H3A 1A1 Susan L. Greenspan Osteoporosis Prevention and Treatment Center University of Pittsburgh Pittsburgh, Pennsylvania 15213 Sari Halpert Columbia University New York, New York 10032 Hunter Heath III Lilly Research Laboratories Eli Lilly and Company Indianapolis, Indiana 46285 Frederick S. Kaplan Division of Metabolic Bone Diseases and Molecular Orthopaedics The University of Pennsylvania School of Medicine Philadelphia, Pennsylvania 19104 Michael Kleerekoper Division of Endocrinology Wayne State University School of Medicine Detroit, Michigan 48201 Winston Koo Wayne State University Detroit Medical Center Detroit, Michigan 48201 Craig B. Langman Feinberg School of Medicine, Northwestern University Head, Kidney Diseases, Children’s Memorial Medical Center Chicago, Illinois 60614 Edgar V. Lerma Department of Medicine/Section of Nephrology University of Illinois at Chicago College of Medicine Chicago, Illinois 60612 Marjorie Luckey Saint Barnabas Osteoporosis and Metabolic Bone Disease Center Livingston, New Jersey 07039

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Contributors

Barbara P. Lukert Division of Endocrinology University of Kansas Medical Center Kansas City, Kansas 66103 Velimir Matkovic Department of Phys Med and Med Nutr Ohio State University Davis Medical Center Columbus, Ohio 43210 Betsy McClung Oregon Osteoporosis Center Portland, Oregon 97213 Michael McClung Oregon Osteoporosis Center Portland, Oregon 97213 Paul D. Miller Colorado Center for Bone Research Lakewood, Colorado 80227 Dorothy A. Nelson Division of Rheumatology Wayne State University School of Medicine Detroit, Michigan 48201 Eric Orwoll Department of Medicine Oregon Health & Sciences University Portland, Oregon 97201 Socrates E. Papapoulos Department of Endocrinology and Metabolic Diseases Leiden University Medical Center Leiden, The Netherlands John M. Pettifor Department of Pediatrics Chris Hani Baragwanath Hospital University of Witwatersrand Johannesburg, South Africa S. Abbas Raza Department of Medicine University of Wisconsin, Madison Madison, Wisconsin 53792

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Contributors

Elizabeth Shane Columbia Univ Col P and S New York, New York 10032 Jay R. Shapiro Osteogenesis Imperfecta Program Kennedy Krieger Institute 707 North Broadway Baltimore, Maryland 20215 Frederick R. Singer John Wayne Cancer Institute Endocrinology and Bone Disease Program Santa Monica, California 90404 Ethel S. Siris Department of Medicine Columbia University College of Physicians and Surgeons New York, New York 10032 Paul D. Sponseller Department of Orthopedics-Pediatrics Johns Hopkins Hospital 720 Rutland Ave Baltimore, Maryland 21205 Line Vautour Division of Endocrinology McGill University and McGill University Health Centre Montreal, Québec, Canada H3A 1A1 Michelle P. Warren Department of Obstetrics and Gynecology Columbia University New York, New York 10032 Nelson Watts University of Cincinnati Bone Health and Osteoporosis Center Cincinnati, Ohio 45219

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Contributors

Michael P. Whyte Division of Bone and Mineral Diseases Washington University School of Medicine St. Louis, Missouri, 63110 and Center for Metabolic Bone Disease and Molecular Research Shriners Hospitals for Children St. Louis, Missouri 63131

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Preface The United States Surgeon General recently issued a landmark and comprehensive report on bone health and osteoporosis*. In the introduction, the Surgeon General made three important observations. First, the state of America’s bone health is not good. Second, recent advances in bone biology, diagnosis, and therapeutics have provided the knowledge and the tools to make America’s bone health much better. His third point, however, was that there are still major gaps between what is now known about bone and mineral disorders and what is actually applied in clinical practice, emphasizing the need for physicians and other health care providers to make bone health assessment and management a standard of care. Clinicians are faced with issues pertaining to osteoporosis and other common bone and mineral disorders on a daily basis, whether it involves advice for parents of growing children, diet and lifestyle considerations in young adults, concerns regarding bone loss and fracture risk in postmenopausal women and older men, or problems with falls and recurrent fractures in the elderly. Many relatively common non-skeletal medical conditions and their management also have an impact on bone health, and patients of all ages with less common bone and mineral disorders present themselves from time to time in the office exam room or in the hospital setting. Guidance for the clinician is available from many excellent text books, especially the Primer on the Metabolic Bone Diseases and Disorders of Mineral Metabolism published by the American Society for Bone and Mineral Research. However, such texts are voluminous and somewhat unwieldy in the office or inpatient setting where an initial review of the key diagnostic and treatment issues is what is needed at the moment of the patient encounter, to help the clinician quickly and correctly set to work. The second edition of The Bone and Mineral Manual, updated from the successful first edition with the latest knowledge and provision of practical information, is a “how-to” manual that aids in clarifying the diagnostic and management decisions that need to be made during the patient visit. In many instances, more in-depth reading from textbooks or journals will need to follow at a later point. However, this manual serves as an initial assessment guide and planning tool for subsequent monitoring and management of patients with or at risk for a diverse array of bone and mineral disorders. The editors are very grateful to the outstanding group of authors who have shared our vision for a concise and eminently practical guide to both simple and complex skeletal and mineral problems and who have written the chapters that comprise this work. We hope that *Bone Health and Osteoporosis: A Report of the Surgeon General, released in October, 2004, available at www.surgeongeneral.gov xvii

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Preface

primary care physicians and specialists alike, caring for patients at all stages of life, will find this manual to be a help to them. We also hope that this accessible body of useful clinical information will play its part in meeting the Surgeon General’s challenge to all of us—that we must effectively apply the knowledge that now exists so that America’s bone health will quickly and meaningfully begin to improve.

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Indications for Bone Mass Measurement

1

Dorothy A. Nelson Michael Kleerekoper

Children and Adolescents • History of recurrent fragility fractures that might suggest osteogenesis imperfecta (OI) or other in-born errors of collagen metabolism – Diagnosis made by history and physical examination, not by BMD (bone mineral density) measurement, because therapies are available, pretreatment study appropriate – No consensus on best measurement to perform; given the changing size of growing skeleton and impact on serial BMD measurements, appropriate to measure total-body bone mineral content (BMC) and follow serially until skeletal maturity reached • Adolescents with hypothalamic amenorrhea – Anorexia/bulimia – Athletic amenorrhea • Growth failure – Resulting from a defined hormonal or other chronic medical condition or therapy – Unexplained growth retardation

The Bone and Mineral Manual Copyright © 2005 by Elsevier Inc. All rights of reproduction in any form reserved.

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The Bone and Mineral Manual

Premenopausal Women and Young Adult Men • • • • • • • • •

Secondary amenorrhea Male hypogonadism Unexplained fragility fractures Malabsorption Primary hyperparathyroidism Hyperthyroidism (particularly if unrecognized for months to years before diagnosis) Chronic renal failure Hemoglobinopathies Chronic therapy with – Corticosteroids – Cyclosporine – Anticonvulsants – Anticoagulants – Thyroxine – GnRH agonists • Gastric or intestinal resection • Organ transplantation

Early Menopause (0–5 years postmenopause) • Any of the previous indications • Positive family history of osteoporosis with fractures

Postmenopause But Younger Than 65 Years • • • • •

Any of the previous conditions Positive family history of osteoporosis with fracture Personal history of fracture postmenopause Current cigarette smoker Low body mass index (BMI)

Postmenopause Age 65 Years or Older • All women

Men Age 65 Years or Older • Any of the previous medical, surgical, or therapeutic causes of accelerated bone loss • Hypogonadism

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Indications for Bone Mass Measurement

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Note • All patients being initiated on corticosteroid therapy (even if the initial plan is short-term therapy) should have a BMD study as soon as practical after therapy has started. • All patients on chronic steroid therapy who have never had a BMD study should have one as soon as possible. • All patients with unexplained fragility fractures should be evaluated for primary or secondary osteoporosis, and should be considered for therapy for osteoporosis. BMD may or may not be obtained as a baseline before initiating therapy. • Many fragility fractures occur in persons in whom the BMD T-score is not -2.5 or less. This should not dissuade you from the diagnosis. • Metastases to the spine may present with a vertebral compression fracture and the higher the spine BMD T-score, the more carefully this diagnosis should be considered.

Suggested Readings Many organizations publish physician- and patient-related osteoporosis material on their Web sites. These may include guidelines for BMD testing.

• • • •

www.nof.org www.aace.com www.rheumatology.org www.aafp.org

U.S. Preventive Services Task Force. Screening for osteoporosis in postmenopausal women: recommendations and rationale. Ann Intern Med 2002;137:526–528.

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A Practical Guide to Bone Densitometry

2

Dorothy A. Nelson Michael Kleerekoper

Purpose of Bone Densitometry • To assess fracture risk – Continuum of risk between BMD and risk of fracture: the lower the BMD, the greater the risk of fracture – No “fracture threshold” – Fracture risk only assessed in terms of relative risk, not absolute risk – All technologies assess fracture risk • To make intervention decisions – BMD in conjunction with clinical (fracture risk) history and physical examination • To monitor progression/regression of bone loss – Change in BMD (increase or decrease) statistically significant, depends on precision of measurement – In forearm and anteroposterior (AP) spine, change of 2% or more usually significant; in proximal femur, change of 5% or more usually significant (These values are only provided as a guide. It is incumbent on each program performing and reporting BMD to determine what change at each site represents a true change and not simply method imprecision. The techniques for obtaining these data can be found at the Web site of the International Society for Clinical Densitometry [www.iscd.org].) – Precision dependent on many factors; most important, skill and expertise of the operator • To diagnose osteoporosis – World Health Organization (WHO) criteria applicable to dual energy X-ray absorptiometry (DXA) of forearm, PA spine, proximal femur – Based on number of standard deviations (SDs) below mean value for peak bone mass in healthy, premenopausal non-Hispanic white women – Unit of measure for SD, T-score T-score ≥1.0, normal BMD T-score between -1.0 and -2.49, low bone mass (osteopenia) T-score £-2.5, osteoporosis Osteoporosis + fracture = severe osteoporosis


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Note: Fragility fractures often occur in patients with T-scores not as low as -2.5. Such patients (with radiographically confirmed fractures resulting from minimal trauma) should be diagnosed as having osteoporosis even though numeric criteria are not met. Note: There is no consensus about the correct (“best”) reference population for determining T-score in men and in women of other ethnicities.

Methods and Measurement Sites • DXA – The current “gold standard” and most widely used – Measures BMD in grams per square centimeter–spine (L1–L4 in AP projection) and proximal femur (femoral neck and total hip) the most common sites measured in clinical practice – Forearm (mid radius and ultradistal) also measured in most patients – Spine in lateral projection possible with many DXA instruments, but clinical utility uncertain – Phalangeal DXA instrument available, but not widely used – Total-body measurements (particularly BMC, not BMD) a useful measurement during growth • Quantitative computed tomography (QCT) and peripheral QCT (pQCT) – Measure true three-dimensional (3D) BMD in grams per cubic centimeters – QCT used at spine, pQCT used at forearm – Measure total BMD, cortical bone BMD, or cancellous bone BMD • Quantitative ultrasound (QUS) – Measures broadband ultrasound attenuation (BUA), speed of sound (SOS), and “stiffness index” at many peripheral skeletal sites (phalanges, heel, tibia) • Single energy X-ray absorptiometry (SXA) – Measures BMD in grams per square centimeters at peripheral skeletal sites (forearm, heel)

Who Should Have BMD Measured? • All women 65 years or older, independent of risk factors • Postmenopausal women younger than age 65 if historical risk factors for fracture are present • All patients already receiving corticosteroid therapy or about to start such therapy • Patients with primary hyperparathyroidism (forearm site should be included) • Men receiving androgen deprivation therapy for treatment of prostate cancer – Hypogonadism of any etiology • Patients awaiting organ transplantation or recent transplant recipients Note: It is not necessary to measure BMD to establish the diagnosis of osteoporosis in persons who have already sustained one or more fragility fractures, but it is helpful to have a baseline measurement before initiating therapy.

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A Practical Guide to Bone Densitometry

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Who Should Not Have BMD Measured? • Most children and adolescents • Healthy premenopausal women • Most healthy men

How Often Should BMD Be Repeated? • Every 6 months on patients on corticosteroid therapy • Every 3 to 5 years in patients in whom the initial measurement did not result in a decision to begin therapy for osteoporosis • Every 2 years in patients receiving therapy to prevent or treat osteoporosis

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Laboratory Analyses Useful in the Diagnosis of Bone and Calcium Metabolic Disorders

3

Hunter Heath III

Serum Calcium • • • •

• • •

•

Measured to detect hypercalcemia or hypocalcemia Not directly related to bone turnover rates Check normal range for lab, which should be about 8.9 to 10.2 mg/dL (2.22–2.55 mmol/L) Total calcium elevated by hyperproteinemia, lowered by hypoproteinemia (Rule of thumb: a change in serum albumin of 1.0 g/dL yields a corresponding change in serum total calcium [tCa] of 0.8 mg/dL [0.2 mmol/L].) Tourniquet venous stasis a very common cause of factitious hypercalcemia; resolved by redrawing blood without a tourniquet Serum ionized calcium (iCa) not altered by changes in serum proteins, but assay technically difficult and not always available Most common cause of persistent hypercalcemia, primary hyperparathyroidism; second most common, secretion of parathyroid hormone (PTH)-related protein by malignant tumors Most common cause of persistent hypocalcemia, vitamin D deficiency and/or intestinal malabsorption; also common, postsurgical and other forms of hypoparathyroidism

Serum Phosphorus • Measured to detect effects of poor phosphorus intake, PTH excess or deficiency, phosphate retention in renal failure • Rapid drop in levels with lack of oral intake • Decreased with PTH excess by enhancing renal excretion (decreasing renal tubular reabsorption) • Consistently elevated concentrations in hypoparathyroid states (increased renal tubular reabsorption) • Falsely elevated by hemolysis • Normal ranges laboratory specific and dependent on age


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Serum Parathyroid Hormone • Method of choice: two-site immunometric assays – Immunoradiometric assays (IRMAs), radioactive tracers in test tube – Immunochemiluminometric assays (ICMAs), no radioactivity • Two-site assays exquisitely sensitive and specific for intact, biologically active PTH-1-84 • Two-site assays can detect not only elevated but subnormal serum PTH levels • Newer generation two-site assays not clearly established to be substantial improvements for clinical diagnosis • Older “carboxy-terminal” and “mid-region” assays no longer indicated • Measured to detect hyper- or hyposecretion of PTH for pathophysiologic diagnosis of hypercalcemia and hypocalcemia • Normal ranges similar among assays but laboratory specific; approximate normal adult range, 10 to 65 pg/mL (1.06–6.90 pmol/L) • Serum calcium and PTH levels positively correlated in primary hyperparathyroidism • Ten to 15% of patients with primary hyperparathyroidism: serum PTH within normal range, but abnormally elevated for degree of hypercalcemia • In persistent hypercalcemia, serum PTH values below middle of normal range a strong suggestion for something other than primary hyperparathyroidism, such as humoral hypercalcemia of malignancy, familial benign hypocalciuric hypercalcemia, or vitamin D intoxication • No clinically meaningful diurnal variation or effect of fasting or feeding • Serum PTH values only interpretable with concurrent measurement of serum calcium

Serum Vitamin D Metabolites 25-Hydroxyvitamin D or Calcidiol • Most useful measurement: 25-hydroxyvitamin D (25OHD), predominant circulating metabolite and best reflection of either nutritional vitamin D deficiency or vitamin D excess • Normal range, approximately 5 to 80 ng/mL; recent evidence suggests optimum value for bone health, more than 30 ng/mL • Pronounced circannual variation in serum 25OHD because of seasonal changes in sun exposure and dermal generation of vitamin D; serum 25OHD levels higher in warm, sunny climates than in northern latitudes • Hypercalcemia from vitamin D intoxication associated mostly with markedly elevated serum 25OHD values (>200 ng/mL) • In vitamin D deficiency, serum 25OHD levels generally less than 5 to 8 ng/mL, may be undetectable; vitamin D insufficiency, 5 to 30 ng/mL

1,25-Dihydroxyvitamin D or Calcitriol • Calcitriol: vitamin D metabolite with greatest biologic activity; produced from 25OHD in kidney, by 25-hydroxyvitamin D 1-a hydroxylase • Level raised by actions of PTH, hypocalcemia, and hypophosphatemia on the hydroxylase enzyme

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Laboratory Analyses Useful in the Diagnosis of Bone and Calcium Metabolic Disorders

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• Normal range, approximately 20 to 60 pg/mL (50–150 pmol/L) • Measurement rarely indicated in clinical practice • Measured in hypercalcemia only if serum PTH, PTH-related protein, and 25OHD not elevated: to diagnose hypercalcemia resulting from ingestion of calcitriol, sarcoidosis and other granulomatoses, or from rare hypersecretion of calcitriol by tumors • Levels not accurate representations of nutritional vitamin D status; levels may be normal in vitamin D deficiency and vitamin D intoxication

Serum Parathyroid Hormone-Related Protein (PTHrP) • Normal product of skin, placenta, lactating mammary tissue, and certain neural tissues; severe skeletal dysplasias in mice lacking PTHrP • Best assay: two-site immunometric assays • Marked variation of normal ranges among assays; verification of correct range with laboratory required • Levels in normal plasma very low or undetectable • Measured to diagnose humoral hypercalcemia of malignancy (HHM) resulting from hypersecretion of PTHrP by neoplasm, only after determining serum PTH suppressed • Typical biochemical picture in HHM: severe hypercalcemia (often >12.0 mg/dL or >4.0 mmol/L), hypophosphatemia (unless in renal failure), suppressed PTH, normal serum 25OHD, low-to-normal serum calcitriol, and elevated PTHrP • Very rarely, primary hyperparathyroidism and HHM coexist: both PTHrP and PTH concentrations elevated

Excretion of Calcium and Phosphorus in Urine • Excretion of calcium in urine: varies somewhat with diet, but relatively stable day to day • Both calcium and creatinine measured in 24-hour collection; creatinine used to assess completeness of collection (should be 15–25 mg creatinine/kg body weight) • Urinary calcium low with vitamin D deficiency, intestinal malabsorption, very low dietary calcium intakes, familial benign hypocalciuric hypercalcemia • Urinary calcium elevated with idiopathic hypercalciuria, primary hyperparathyroidism (50% of cases); often strikingly elevated in humoral hypercalcemia of malignancy, vitamin D intoxication (>500 mg/24 hour) • Urinary calcium excretion measured to evaluate calcium urolithiasis, hypercalcemia, suspected renal calcium leak in osteoporosis, and suspected intestinal malabsorption • Urinary phosphorus excretion: reflects dietary phosphorus intake; measurement seldom of diagnostic value • Urinary phosphorus clearance assessed in chronic hypophosphatemic states to verify that hypophosphatemia results from renal losses rather than low dietary intake or malabsorption

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Strategy for Pathophysiologic Diagnosis of Hypercalcemia • Verify that hypercalcemia is persistent and not an artifact resulting from hyperproteinemia. • Determine by history and physicial any obvious causes (e.g., vitamin D ingestion, immobilization, symptoms of cancer, familial hypercalcemia). • Measure serum PTH and calcium, 24-hour urine calcium, and creatinine. • If serum PTH is high normal or elevated, and urinary calcium is normal or elevated, the diagnosis is primary hyperparathyroidism (>90% certainty), and management depends on severity. • If serum PTH is suppressed to below normal and urinary calcium is high, this is “parathyroid-suppressed hypercalcemia.” Measure serum PTHrP and 25OHD, which may confirm diagnosis of HHM or vitamin D intoxication. • If PTHrP is elevated, determine the location of the tumor and treat appropriately. • If 25OHD is elevated, remove the source of exogenous vitamin D. If hypercalcemia is severe, treat it with glucocorticoids and low calcium intake. • If serum PTH is suppressed, urinary calcium is high, and PTHrP and 25OHD are normal, measure serum 1,25OH2D (calcitriol) to detect rare hypersecretion of calcitriol by tumor or granulomas (e.g., sarcoidosis). • If serum calcium is high, urine calcium is low (generally 3.0–3.25 mmol/L) should suggest HHM. Minimal hypercalcemia often remits without intervention. Severe hypocalcemia suggests classic hypoparathyroidism if renal function is normal. Phosphorus: Hypophosphatemia is only found in half of primary hyperparathyroid cases, but hyperphosphatemia is much more common in hypoparathyroidism. It should be determined in a fasting sample to avoid dietary effects. Creatinine: Renal failure is common with sarcoidosis, vitamin D intoxication, and HHM, and is rare with primary hyperparathyroidism. Serum calcitriol levels are often low with severe, chronic renal insufficiency. Albumin: Albumin is often low in patients with HHM, chronic renal insufficiency, intestinal malabsorption, and malnutrition. Globulins: Globulins may be elevated in multiple myeloma. Chloride: The chloride level is generally more than 103 mEq/L in primary hyperparathyroidism. Cholesterol: Cholesterol is generally low in malabsorption, which causes hypocalcemia.

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4 Biochemical Markers of Bone Remodeling Michael Kleerekoper

Bone Remodeling • Bone remodeling is the process of removing old bone (resorption—a function of osteoclasts) and replacing it with new bone (formation—a function of osteoclasts). • During growth, remodeling rates are high and formation exceeds resorption, resulting in a net increase in bone mass. • During the third to fifth decade in healthy individuals, remodeling is in balance, so there is no net gain or loss of bone. • Beginning in the sixth decade of life there is the universal phenomenon of age-related bone loss, during which resorption exceeds formation, and this appears to continue at a slow rate for many years. • Menopause results in a brief period (5 years or so) of accelerated remodeling, with resorption far exceeding formation and resultant rapid bone loss. • Many illnesses (gonadal steroid deficiency in women and men, primary and secondary hyperparathyroidism, endogenous or exogenous hyperthyroidism, malabsorption/malnutrition, vitamin D insufficiency, immobilization) accelerate remodeling and subsequent bone loss. • Many drugs accelerate remodeling and bone loss (anticonvulsants, anticoagulants, antimetabolites). • Corticosteroids increase bone resorption and inhibit bone formation, resulting in greater rates of bone loss than most other circumstances. • In general, once peak bone mass is obtained, the rate of remodeling dictates the rate of bone loss. – High rates of remodeling—rapid bone loss – Low rates of remodeling—slower bone loss • High rates of bone remodeling predict fracture risk independent of BMD, and the combination of high remodeling and low BMD are additive predictors of fracture risk


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Clinical Utility of Biochemical Markers • Biochemical markers project the rate of bone loss, but cannot quantitate the anticipated amount of bone loss. • Biochemical markers are used to assess the response to therapy for osteoporosis. – Effective treatment with an antiresorptive drug (bisphosphonates, calcitonin, estrogen, SERMs) results in a reduction of markers of resorption and formation. – Resorption markers decrease within 6 to 8 weeks of initiation of therapy and reach a nadir by 3 months. The levels during adequate therapy are generally in the lower half of the normal range (reference interval) seen in healthy premenopausal women. – Formation markers decrease within 12 to 18 weeks and reach a nadir by 6 months of therapy. With adequate therapy, the nadir is usually in the lower half of the premenopausal reference interval. – During clinical trials, the rate of change in biochemical markers appears to be an earlier and more robust predictor of antifracture effectiveness of therapy than BMD. (A change in markers or BMD has not been demonstrated to be a reliable predictor of fracture prevention in individual patients.) – Effective treatment with a formation–stimulation drug (teriparatide) increases markers of formation and resorption. There are no data yet that relate these changes to antifracture effectiveness of formation–stimulation therapy. • Biochemical markers of bone remodeling are adjunctive tests to BMD in the evaluation and management of patients with low bone mass or osteoporosis. The markers correlate poorly with BMD and are not surrogates for BMD in the diagnosis of low bone mass or osteoporosis, or other metabolic bone diseases.

Resorption Markers • Breakdown products of type I collagen of bone – Pyridinium cross-links Pyridinoline (free and bound) - Pyrilinks: specimen can be 24-hour urine or second morning void Deoxypyridinoline (free and bound) - PYRILINKS-D: specimen as for Pyrilinks – Telopeptides of collagen cross-links Amino-terminal (NTX) - OSTEOMARK: specimen as for Pyrilinks, but serum assays can be ordered and are preferred when available because of lower assay variability Carboxy-terminal - CROSSLAPS: specimen as for NTX, again with serum assays preferred (not yet available commercially in the United States) – Considerable diurnal variation; for serial studies, essential to make sure that the time of collection and the specimen collected (24-hour urine, second-void urine, serum) are the same on each occasion

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Biochemical Markers of Bone Remodeling

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Formation Markers • Secretory products of the osteoblast – Total serum alkaline phosphatase Limited sensitivity and specificity, but inexpensive and widely available Of most value in metabolic bone diseases when total alkaline phosphatase is more than two to three times the upper limit of normal (Paget disease of bone, osteomalacia, renal osteodystrophy) Of little value in low bone mass or osteoporosis – Bone-specific alkaline phosphatase (BAP/BSAP) Tandem OSTASE: an immunoradiometric assay with results expressed in mass units Alkphase-B: an enzyme immunoassay with results expressed in enzyme activity units Both assays reliable; for serial studies, same assay should be used each time – Osteocalcin (OCN) Several immunoassays available commercially Circulates as the intact molecule or several smaller fragments; different assays detect different moieties No clear indication one assay is superior to others Same assay used for serial studies

When to Order a Biochemical Marker of Bone Remodeling • No firmly established guidelines have been published. • During early menopause, when most women have normal or low bone mass (but not osteoporosis), there are good 4-year prospective data that suggest a marker value above the premenopausal reference interval predicts rapid bone loss, whereas a marker value that is within the normal range suggests that there will be minimal bone loss during the next few years. • Order as a baseline before initiating therapy. – There are no data yet to suggest that patients with high bone turnover will respond best to therapy with an antiresorptive drug whereas those with low bone turnover will respond best to a formation–stimulation agent. This concept seems intuitively obvious but should not yet be applied to clinical care. • Order to monitor response to therapy. – Resorption markers should be within the bottom half of the premenopausal reference interval by 3 months of therapy with antiresorptive therapy and should remain “constant” at that level while therapy is continued. – Formation markers should reach a nadir after about 6 months of therapy with an anti-resorptive drug and should remain constant while therapy is continued. – If therapy is interrupted, the markers will revert toward baseline at a rate seemingly determined by the half-life in bone of the respective therapy. For example, when estrogen is discontinued, the markers revert back to baseline within a few weeks to months, whereas with alendronate the markers may remain low for as long as 12 months.

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• Order as a guide to an additional skeletal insult on seemingly adequate therapy. – Most patients do not lose bone mass with any of the available antiresorptive therapies and most demonstrate a reduction in markers of bone remodeling. In a patient who appears to be compliant with therapy but in whom there is significant reduction in BMD, an elevated marker level should trigger a search for a previously unrecognized, secondary cause of accelerated bone loss.

How Often Should Markers be Measured? • If the patient is not recommended to start therapy after the initial bone evaluation, there is little value in serial measurement of biochemical markers of bone remodeling. Serial BMD is preferred. • If the patient is recommended to begin therapy, the first follow-up bone marker should be measured after 3 months. If the value is in the lower half of the premenopausal reference interval, there is little need for further measurements. If the expected value is not attained, a repeat measurement should be made 3 months later. If there has been no further reduction in the marker, a search for a secondary cause of bone disease should be undertaken.

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Skeletal Imaging: Radiography, Computed Tomography (CT), and Magnetic Resonance Imaging (MRI)

5

Harry K. Genant

Techniques and Applications • • • •

Conventional radiography (all bone disorders) (3D) CT (trauma, neoplasms, infection) Ultrasound (joints and tendon disease) MRI (neoplasms, inflammation, infection, joint and tendon disease, bone marrow disorders) • Arthrography (joint disease) • Nuclear medicine (inflammation, neoplasm, trauma)

Bone and Mineral Disorders: Radiographic Features • Osteoporosis (bone loss) – Decrease in bone density – Cortical thinning – Trabecular stress line accentuation – Vertebral deformities, wrist and hip fractures • Osteomalacia (bone mineral loss) – Decrease in bone density – “Fuzzy” trabeculae – “Bowing, buckling” bones • Osteopenia (decrease in bone density) – Regional decrease in bone density Disuse, Sudecks atrophy, transient osteoporosis of the hip, regional migratory osteoporosis – Generalized decrease in bone density Osteoporosis, osteomalacia, hyperparathyroidism, bone marrow disorders


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• Increase in bone density – Regional Developmental (dysplasia, osteopoikilosis, tuberous sclerosis) Neoplastic (myeloma, lymphoma, mastocytosis, metastases) Paget disease Bone infarcts Posttrauma – Generalized Renal osteodystrophy Fluorosis, lead poisoning, hypervitaminosis A or D Paget disease Neoplasms (lymphoma, mastocytosis, metastases) Dysplasias and hyperostoses

Uses • • • • • • •

Confirming clinically suspected diagnosis Providing differential diagnosis Screening for disease and disorders Monitoring disease regression/progression Monitoring therapeutic interventions Providing imaging-guided biopsies Providing imaging-guided interventions

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6 Scintigraphy Ignac Fogelman

Advantages • Provides a functional display of skeletal metabolism • Highly sensitive for lesion detection • Rapid evaluation of the total skeleton

Disadvantage • Appearances nonspecific

In Osteoporosis • Identifies fracture • Assists in assessing whether a fracture detected by radiographs is new or old • Bone scan after fracture stays “hot” for 3 to 9 months in most cases and rarely longer than 18 months • Identifies other causes of pain (e.g., facetal joint disease) • Identifies coexistent pathology (e.g., metastases or infection)

In Osteomalacia • Detects pseudofractures • Suggested by often symmetric lesions involving multiple ribs (most common site) or pubic ramus, proximal femur/humerus, and scapula


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In Hyperparathyroidism • Assessment of severity of skeletal involvement by subjective evaluation of metabolic features – Increased tracer uptake in axial skeleton – Increased tracer uptake in long bones – Increased tracer uptake in periarticular areas – Faint or absent kidney images – Prominent calvaria and mandible – Beading of the costochondral junctions – “Tie sternum” • Identification of brown tumors

In Paget Disease • Bone scan features – Intense uptake of tracer – Diffuse involvement of bone – Anatomic outlines emphasized (e.g., transverse processes in spine) – Bone appears expanded (e.g., spine, tibia, humerus) – Ends of long bone affected • Earliest evidence of active disease • Documentation of extent of disease • May not identify coexistent fracture or sarcomatous change

In Primary Hyperparathyroidism • Sestamibi scanning has improved to the point where it is a very useful preoperative investigation in patients in whom a decision to correct primary hyperparathyroidism (PHPT) surgically has already been made. • Sestamibi scanning is not an appropriate procedure for diagnosing PHPT because a negative scan does not exclude the diagnosis and a positive scan does not confirm the diagnosis. The purpose of the scan is to assist the surgeon in planning the surgical approach. • In some centers, patients are administered sestamibi a few hours before surgery and intraperative probes are used to guide the surgeon in finding abnormal parathyroid tissue. • The cost-effectiveness of preoperative localization of abnormal parathyroid tissue in PHPT has not been fully evaluated.

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7 Hypocalcemia and Hypercalcemia in Neonates Winston Koo

Neonatal Hypocalcemia Definition • Serum or plasma tCa – Term: 2.75 mmol/L (11 mg/dL) • Serum or plasma iCa > 1.4 mmol/L (5.6 mg/dL)

Pathophysiology • Phosphate deficiency – Low or no phosphate, but calcium-containing parenteral nutrition – Very low-birthweight infants fed unfortified human milk or standard infant formula

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• Parathyroid related – Hereditary primary hyperparathyroidism Calcium-sensing receptor inactivating mutations: familial hypocalciuric hypercalcemia, neonatal severe hyperparathyroidism PTH receptor activating mutation – Secondary hyperparathyroidism Maternal: hypocalcemia, renal tubular acidosis Neonatal: renal tubular acidosis • PTH-related protein-secreting tumors • Vitamin D – Excessive intake in Mother: increases milk vitamin D Neonate: high-dose vitamin D prophylaxis, overfortification of milk – Subcutaneous fat necrosis (increase 1,25 dihydroxyvitamin D) • Calcitonin response impairment (?) in congenital hypothyroidism • Vitamin A excess • Uncertain pathophysiologic mechanism – Idiopathic infantile hypercalcemia/Williams syndrome – Extracorporeal membrane oxygenation therapy – Severe infantile hypophosphatasia – Blue diaper syndrome

Diagnostic Workup History • Familial or maternal disturbances in calcium or phosphorus metabolism • Gestational age, difficult labor, extracorporeal membrane oxygenation (ECMO) and preECMO therapy • Intake of calcium, phosphorus, vitamins D and A: mother and infant • Symptomatology often nonspecific, including vomiting, refusal to feed, or seizures; or asymptomatic

Physical Examination • General examination with focus on growth parameters; may be poor, hydration status from polyuria ± vomiting, heart rate, blood pressure • Associated features (e.g., subcutaneous fat necrosis, elfin facies, congenital heart disease, developmental delay)

Investigations • Serum tCa and iCa, magnesium, phosophorus, creatinine, total protein and albumin, alkaline phosphatase (total and bone specific), simultaneous “intact” or “whole” PTH, 25 hydroxyvitamin D and 1,25 dihydroxyvitamin D • Acid–base status • Urine calcium, phosphorus, creatinine, and amino acids • Radiograph of chest, hands, and long bones

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• Ultrasound of kidneys and abdomen, ophthalmologic examination, EKG (shorten QT interval, bradycardia) for complications • Other tests if previous do not yield diagnosis – Parental (both parents) serum and urine calcium, phosphorus, creatinine – Serum PTH-related protein – Serum vitamin A – Molecular studies – Family screening depends on primary diagnosis

Management Acute • Remove the etiologic factor if possible (e.g., discontinue vitamin D and calcium supplement). • Administer intravenous normal saline (20 mL/kg) and loop diuretic (furosemide 2 mg/kg). Reassess and repeat every 4 to 6 hours as necessary. Monitor fluid balance and serum calcium, magnesium, sodium, potassium, phosphorus, and osmolality every 6 to 12 hours. Prolonged diuresis may require magnesium and potassium replacement. • Use lower calcium content milk or parenteral nutrition if possible to maintain nutrition. • In neonates with low serum phosphorus levels ( 0.62 mmol/mmol) – No progressive effect on renal function in a limited series – Renal calculi in all age groups; no relationship to hypercalciuria – Hypercalciuria uncommon in adults

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Osteogenesis Imperfecta

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• Hyperplastic callus – Familial association, occurs after fracture – Occurs independently of OI severity – Associated with types IV and V OI – May simulate bone cancer on radiologic examination

Diagnostic Procedures • Serum bone biomarkers are variably altered in children and adults, depending on the rates of bone turnover. Bone turnover rates are relatively higher in children and in severe cases of adult OI, but are low in mild OI. • Alkaline phosphatase levels are usually normal for the patient’s age, but are increased with fracture healing. • Osteocalcin is increased if the bone turnover is elevated. • Procollagen C-1 propeptide is decreased in all OI types. • Urine collagen N-telopeptide excretion is frequently elevated for age and gender. It is increased in types III and IV OI in children. • The deoxypyridinoline cross-link excretion is similarly increased.

Bone Biopsy • • • • • •

Iliac crest bone biopsy with tetracycline/demeclochlorotetracycline dual labeling Altered trabecular pattern in different OI types (Rauch et al., 2002) Decreased bone volume, thin cortices, defect in cortical bone remodeling In children, activity of cancellous bone remodeling elevated In adults, trabecular bone remodeling activity depressed Increased number of osteocytes

Skin Biopsy Performed to Determine Fibroblast Type I Collagen Synthesis • Ninety percent demonstration of altered type I collagen synthesis – Type I OI: null allele effect, 50% less collagen with normal electrophoretic protein bands – Types II, III, IV: mutant collagen bands observed in gels – Less specific than gene sequencing

DNA Analysis of Collagen Type I Pro-a1 and Pro-a2 Genes • • • •

Mutations in pro-a1(I) or pro-a2(I) demonstrated in 85% cases When identified, defines genetic defect accurately Cystine substitution for glycine observed most often More than 300 different mutations reported to date – Most common: glycine-to-cystine point substitutions – Deletions, insertions, and exon skip mutations also recognized

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Genetics of OI • • • •

Most result from dominant mutations affecting collagen a chains Estimated 60% new mutations Incidence of mosaicism unknown, may represent 6% of OI cases Fibroblast collagen synthesis patterns on electrophoresis – Type I OI: mutated RNA degraded intracellularly, resulting in cell production of half expected amount of otherwise normal type I collagen (null allele effect) – Types II, III, IV: mutations permit synthesis of abnormal a chains, assembled extracellularly and incorporated into bone matrix

Medical Treatment • Dietary calcium supplementation depending on age and size – Urine screening for hypercalciuria after increasing calcium intake • Vitamin D supplementation: 400 to 600 IU/day depending on body size • Bisphosphonates: use of intravenous or oral bisphosphonate in children with OI limited to centers where dose and results of therapy are carefully monitored – In children (see reference) Oral bisphosphonate: results of clinical trials with alendronate and risedronate under investigation Intravenous pamidronate: administered according to age, dose varies from 0.5 to 3.0 mg/kg body weight – In adults Oral bisphosphonate: 70 mg alendronate and 35 mg risedronate) administered weekly Intravenous pamidronate: administered to adults as 1.5 mg/kg every 3 months Intravenous zoledronate: under investigation; no clinical trial results available Oral bisphosphonate: clinical trials with alendronate in progress Follow bone density and fracture incidence

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Orthopedic Treatment • Proper limb and joint alignment are essential for normal function and to decrease fracture risk. • Multiple osteotomies and realignment of a deformed bone over intramedullary rods is an option for many children with severe bowing. • A variety of intramedullary rods are available for individual cases. Replacement of rods is frequently required because of migration of the rod, bending or breakage, and growth of the bone. • Indications include frequent fractures at the apex of the bow, impaired standing, or limb length inequality resulting from bowing. • The ideal age for orthopedic intervention is after the age of 3 to 4 years, as the child increases weight-bearing activities. • Patients should be monitored for scoliosis, and it can be braced in type 1 OI. Surgery is an option for severe curves in those with reasonable bone density. • Patients should be monitored for basilar invagination using serial neurologic examinations. MRI should be obtained if abnormalities are found. • Rehabilitation therapy (see Engelbert et al.) – Goal: improved function, improved quality of life – Improved gross motor development – Strength assessment: increased muscle strength – Improved gait – Selective bracing and joint support important

Suggested Readings Cole WG. Advances in osteogenesis imperfecta. Clin Orthop 2002;401:6–16. Engelbert RH, Pruijs HE, Beemer FA, et al. Osteogenesis imperfecta in childhood: treatment strategies. Arch Phys Med Rehabil 1998;79:1590–1594. Glorieux F. Cyclic administration of pamidronate in children with severe osteogenesis imperfecta. N Engl J Med 1998;339:947–952. Rauch F, Travers R, Plotkin H, et al. The effects of intravenous pamidronate on the bone tissue of children and adolescents with osteogenesis imperfecta J Clin Invest 2002;110:1293–1299. Shapiro JR. Osteogenesis imperfecta and other defects of bone development as occasional causes of osteoporosis. In: Marcus R, Feldman D, Kelsey J, eds. Osteoporosis. San Diego: Academic Press; 2001:271–295.

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11 Juvenile Osteoporosis Craig B. Langman

Juvenile Osteoporosis • Juvenile osteoporosis (JOP) may occur in an idiopathic manner, termed idiopathic JOP (IJOP), or may be secondary to one of numerous diseases (as listed at the end of this chapter). Osteoporosis is a problematic diagnosis in children, because the disease process of bone fragility associated with reduced bone mass has not been rigorously defined either by densitometric or clinical criteria, unlike the disease in adults.

Bone Density Measurements in Children • Bone density measurements should be interpreted with caution in growing children, because of the variability in machines for measuring bone density, the lack of a uniform or complete database to define normal bone density for a given ethnicity or between ethnicities, and the large variation in body size, body mass index, and bone architecture in the growing child, all of which may confound the expression of BMD. • Although QCT may be a superior modality to measure bone density in growing children, it is not widely available and it currently remains a research tool. Therefore, dual-energy absorptiometry remains the most frequent bone density assessment tool for children and adolescents. • The clinician should use a Z-score, not the more commonly supplied T-score, for interpretation of BMD values in children and adolescents. The Z-score may be determined for chronologic and height ages, or for pubertal stage. The T-score reflects a deviation from bone mass that has reached its peak height, and is therefore inappropriate to apply to the growing skeleton of children and adolescents.

Clinical Symptoms of JOP • • • • • •

Bone pain, often in the mid to lower back; bilateral foot or leg pain Decreased ability to perform usual activities, including athletic endeavors Mild myopathy Bimodal onset of symptoms before 10 years of age, and during mid adolescence Fragility fractures in excess of age-specific rates Symptoms referable to the primary disease process if not idiopathic (see list at the end of the chapter for specific disease categories that may generate symptoms)


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Clinical Signs of JOP • • • •

Upper to lower body segment ratio less than 1 May have associated kyphosis or lordosis Associated scoliosis Signs referable to the primary disease process if not idiopathic (see list at the end of the chapter for specific disease categories that may generate signs)

Radiographic Findings in the Skeleton • • • •

IJOP: atraumatic vertebral compression fractures: metaphyseal fractures Absence of wormian bones in the skull Absence of gracile long bones, characteristic of OI Radiographic findings of primary disease processes if not idiopathic (see list at the end of the chapter for specific disease categories that may generate radiographic signs) • Reduced spinal bone density (Z-score more negative than -2).

Biochemical Findings of IJOP • Normal blood calcium, phosphorus, parathyroid hormone levels • No evidence of vitamin D deficiency (normal levels of 25OHD) • Insulin-like growth factor-1 (IGF-1) in the low-normal range, with normal IGF-binding protein-3 levels. • Exaggerated levels of urinary biochemical markers of bone resorption (collagen crosslinks, cross-laps, or deoxypyridinolines) in some • Normal type I collagen

Biochemical Findings of JOP as Part of Another Primary Disease Process • Such findings would relate to the primary disease process or use of therapeutic pharmacologic agents, by which the bone is affected (see the list at the end of the chapter for specific disease categories that may generate such findings). The review of such abnormalities is beyond the scope of this chapter.

Histomorphometric Findings of Bone in IJOP • Marked reduction in trabecular bone resulting from a decrease in both trabecular thickness and in trabecular numbers • Reduced bone formation rates with a lowered activation frequency of remodeling units, suggesting a primary defect in the osteoblast • Inconsistent findings of increased osteoclastic resorption, causing one to question whether bone resorption rates are above normal • No defect in cortical bone biology demonstrated in the few patients undergoing biopsy

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Natural History of IJOP • Inconsistent diagnostic criteria have limited our knowledge of the outcome of such cases. It appears that there is a tendency for reduction in fractures with increasing age, but there is no clear evidence that bone density normalizes. Wide variability makes it uncertain for individual cases that such a course will ensue.

Treatment Approach to IJOP • Given the variability in fracture recurrence, once the disease has come to medical attention, it is not surprising that there are no series of specific therapy in more than a handful of patients. • Attention to normal dietary intake of calcium for age is suggested in all patients with JOP. • Bisphosphonate therapy, parenteral or oral, has been reported to decrease fracture recurrence rates and to increase bone density. It is unclear whether the natural history of the disease allows for the effect of pharmacologic therapy to be noted. At this time, bisphosphonates have not been approved for use in children or adolescents. There are case reports of overdoses of bisphosphonates producing other bone disease as well. For these reasons, consultation with a specialist in pediatric metabolic bone disease is suggested if IJOP is suspected or diagnosed. • Orthopedic procedures, including orthotics, may be important in stabilizing the bone in a growing child. Consultation with a specialist in pediatric orthopedics is suggested.

Causes of Osteoporosis in Children and Adolescents • IJOP • Developmental disorders of bone and cartilage – OI – Chondrodysplasias • Metabolic bone diseases [primary] – Fibrous dysplasia – Hypophosphatasias • Metabolic bone diseases [secondary] – Anorexia nervosa – Anticoagulants – Antiepileptic agents – Antiretroviral agents – Celiac diseases – Cerebral palsy, paraplegia – Corticosteroids (endogenous, exogenous) – Cystic fibrosis – Gaucher – Growth hormone deficiency – Hypogonadism – Idiopathic hypercalciuria, kidney stones – Immobilization

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Inflammatory bowel disease Liver disease, inherited or acquired Malabsorption syndromes (sprue, tropical sprue, others) Malignancy and active; in remission; cured Methotrexate Muscular dystrophies Solid organ (and bone marrow) transplantation Renal osteodystrophy Renal tubular acidosis Thalassemias

Suggested Readings Campos LMA, Liphans BL, Silva CAA, et al. Osteoporosis in childhood and adolescence. Jornal de Pediatria 2003;79:481–488. Chebna–Sokol D, Loba–Jakubowska E, Sikora A. Clinical evaluation of patients with idiopathic juvenile osteoporosis. J Pediatr Orthoped B 2001;10:259–263. Chebna–Sokol D, Rusinska A. Serum IGF-1, bone mineral density and biochemical markers of bone metabolism in children with idiopathic osteoporosis. Endocr Regul 2001;35:201–208. Chebna–Sokol D, Rusinska A. The bone formation defect in idiopathic juvenile osteoporosis is surface-specific. Bone 2002;31:85–89. Khosla S, Melton LJ III, Dekutoski MB, et al. Incidence of childhood distal forearm fractures over 30 years: a population-based study. JAMA 2003;290:1479–1485. Lorenc R. Idiopathic juvenile osteoporosis. Calcif Tissue Int 2002;70:395–397. Rauchm F, Travers R, Norman ME, et al. Deficient bone formation in idiopathic juvenile osteoporosis: a histomorphometric study of cancellous iliac bone. J Bone Miner Res 2000;15:957–963. Tayback SP. Osteoporosis in children: 2002 guidelines do not apply [letter]. Can Med Assoc J 2003;168:675–676.

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12 Fibrous Dysplasia Frederick S. Kaplan

Fibrous Dysplasia Fibrous dysplasia is a sporadic skeletal disorder caused by somatic activating mutations in the gene for the a subunit of the stimulatory G-protein of adenylyl cyclase (GNAS-1). The disorder causes focal expansion of one or more bones as a result of the developmental arrest of normal osteogenesis and the pathologic development of osteogenic fibrous tissue within the bone marrow space. Fibrous dysplasia leads to skeletal deformity, pain, and pathologic fractures. • Usually diagnosed in children during the first decade of life on the basis of bone pain, deformity, pathologic fracture, headache, or cranial neuropathy • A prominent cause of morbidity but not mortality • Monostotic, polyostotic, or associated focal hyperpigmentation of skin (café-au-lait), endocrinopathies, growth disturbance, and precocious puberty in males and females (McCune–Albright syndrome)

Most Common Symptoms • Bone pain • Skeletal deformity • Pathologic fracture

Radiographic Appearance • Unicameral or multicameral expansile radiolucent lesions (“ground glass”) • Lesions in metaphysis or diaphysis • Lesions causing focal osteoporosis of the cortex of the bone with a scalloped appearance of the endosteal surface

Histologic Appearance • Primitive-appearing chaotic whirls of fibrous stroma • Arrested osteogenesis with woven bone and ill-defined, irregular-shaped trabecular (“Chinese letters”) appearance arising directly out of the fibrous stroma The Bone and Mineral Manual Copyright © 2005 by Elsevier Inc. All rights of reproduction in any form reserved.

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Skeletal Complications • Pathologic fracture with normal healing of the subperiosteal bone and abnormal healing of endosteal bone • Skeletal deformity resulting from focal proliferation of fibrous tissue in marrow cavity and imperfect osteogenesis; may cause visual disturbances, headaches, and other cranial neuropathies if the skull is involved • Limb length discrepancy with limp • Bone pain • Rarely undergoes malignant degeneration

Indications for Surgery • • • • • •

To prevent pathologic fractures of long bones To limit progressive deformity To treat nonunion of fractures and facilitate fracture healing To relieve intractable bone pain To improve mobility To relieve focal pressure on affected nerves

Surgical Procedures • Prophylactic intramedullary rodding of long bones with impending pathologic fractures • Curettage of affected bone followed by grafting with normal autologous bone or with banked bone; bone affected with fibrous dysplasia should not be used for bone graft • Corrective osteotomies with internal fixation and bone grafting

Medical Treatment • Increased bone resorption at the periphery of fibrous dysplasia lesions suggests that antiresorptive medications may be helpful in controlling disease symptoms and in limiting disease activity. • Intermittent treatment with cyclic intravenous pamidronate has been effective in some patients and can alleviate bone pain through a reduction of bone turnover. • The aromatase inhibitor testolactone may be used to decrease estrogen levels in females with precocious puberty and McCune–Albright syndrome.

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McCune–Albright Syndrome (1937) • • • • • • •

Polyostotic fibrous dysplasia (often unilateral) Multiple café-au-lait lesions (coast of Maine) Precocious puberty Other endocrine hyperactivity Not genetically inherited in the Mendelian manner Postzygotic somatic-activating mutations in the a subunit of GNAS-1 Localized increased production of cAMP in somatic tissues leading to increased activation of the cAMP-responsive element in the cFos gene in those cells • Sustained elevations of the Fos protein in target tissues of skin, bone, and endocrine organs leading to disease phenotype • Similar molecular findings with more restricted disease activity in isolated monostotic and polystotic fibrous dysplasia without skin or endocrine manifestations

Endocrine Overactivity That May Be Associated with McCune–Albright Syndrome • • • • •

Precious puberty Hyperthyroidism Hyperparathyroidism Acromegaly Cushing disease

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Suggested Readings Candeliere GA, Glorieux FH, Prud’homme J, et al. Increased expression of the c-fos protooncogene in bone from patients with fibrous dysplasia. N Engl J Med 1995;332:1546–1551. Chapurlat RD, Delmas PD, Liens D, et al. Long-term effects of intravenous pamidronate in fibrous dysplasia of bone. J Bone Miner Res 1997;12:1746–1752. Edgerton MT, Persing JA, Jane JA. The surgical treatment of fibrous dysplasia. With emphasis in recent contributions from cranio-maxillofacial surgery. Ann Surg 1985;202:459–479. Liens D, Delmas PD, Meunier PJ. Long-term effects of intravenous pamidronate in fibrous dysplasia of bone. Lancet 1994;343:953–954. Matarazzo P, Lala R, Masi G, et al. Pamidronate treatment in bone fibrous dysplasia in children and adolescents with McCune–Albright syndrome. J Pediatr Endocrinol Metab 2002;15(suppl 3):929–937. Shenker A, Weinstein LS, Moran A, et al. Severe endocrine and non-endocrine manifestations of the McCune–Albright syndrome associated with activating mutations of stimulating Gprotein GS-alpha. J Pediatr 1993;123:509–518. Stanton RP, Montgomery BE. Fibrous dysplasia [review]. Orthopaedics 1996;19:679–685. Stephenson RB, London MD, Hankin FM, et al. Fibrous dysplasia—an analysis of options of treatment. J Bone Joint Surg Am 1987;69A:400–409. Weinstein LS, Shenker A, Gejman PV, et al. Activating mutations of the stimulatory G protein in the McCune–Albright syndrome. N Engl J Med 1991;325:1688–1695.

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13 Optimizing Peak Bone Mass John M. Pettifor

Definition Peak bone mass (PBM) is the amount of bone tissue achieved in an individual at the end of skeletal maturation. From that time onward, it remains relatively constant until the perimenopausal period in women and a little later in men, when bone mass decreases progressively. • PBM is important because it influences fracture rates in later life, particularly in women. A 1-SD increase in PBM may reduce fracture rates by 50% in postmenopausal women. • PBM is achieved at different times in males and females. In females, there is little gain in bone mass after menarche. In males, it continues to increase until the beginning of the third decade. • Some 60% of bone mass is gained during the adolescent growth spurt. • About 80% of PBM is genetically determined.

Factors Influencing PBM • The genetic influence of parents, independent of body size of the subject • Intrauterine factors: There are some suggestions that intrauterine and early infant growth may influence PBM; thus, low-birthweight babies resulting from intrauterine growth retardation may have decreased PBM. This effect may be indirect through effects on body size. • Body size: The greater the stature, the greater the bone size and thus the higher the PBM. Lean tissue mass also influences PBM because bone mass is proportional to muscle mass. • Nutritional factors – Calcium intake may influence PBM. Intake of 1300 mg/day (AI) is recommended between the ages of 9 and 18 years. Calcium supplementation may increase bone mass by reducing the remodeling space. Adequate calcium intake during the prepubertal period may be more important than during puberty itself. – Protein intake may also influence PBM, through its effect on IGF-1 production. – Vitamin D status


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– Eating disorders: Bulimia and anorexia nervosa are associated with reduced bone mass. Anorexic patients are more severely affected. Mechanisms are thought to be the result of not only nutritional deficiencies, but also elevated corticosteroids and reduced sex steroids associated with delayed puberty or secondary amenorrhea. • Physical activity: Exercise inducing high strains (such as soccer, gymnastics, etc.) is associated with an increase in bone mass. • Endocrine factors – Reduced sex steroids, as in delayed puberty or Turner syndrome – Glucocorticoid therapy – Hyperthyroidism – Growth hormone deficiency – Hyperparathyroidism

Optimizing PBM • Although the major determinant of PBM is genetic inheritance, there are several lifestyle and nutritional factors that might optimize PBM. – Nutrition: Ensure good eating habits with adequate protein and calcium intake, and prevent vitamin D deficiency. – Exercise: Physical exercise has been shown to improve bone mass; however, bone loss does occur if exercise is not maintained. Excessive exercise and training, which may be associated with excessive thinness and menstrual disturbances, should be avoided. – Prevent eating disorders or treat them appropriately if they occur. Inappropriate and repeated dieting should be discouraged. – Smoking and excessive alcohol ingestion have been shown to reduce bone mass.

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Bone Disorders Associated with Primary or Secondary Amenorrhea

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Michelle P. Warren Sari Halpert

Definition • Amenorrhea, or lack of menses, is classified into primary and secondary types. – Primary amenorrhea is defined as the absence of menarche by age 16 in girls with no breast development or other secondary sex characteristics, or by age 18 in girls who have had secondary sex characteristics for 2 years. – Secondary amenorrhea is the absence of menstruation for at least three cycles in women with regular past menstruation. Some experts use a 6-month interval to make the diagnosis, 12 months if the patient has a history of oligomenorrhea.

Causes • Primary amenorrhea – Chromosomal disorders – Disturbances of the hypothalamic–pituitary–ovarian system – Systemic, nutritional or psychological disorders • Secondary amenorrhea – Physiologic changes such as pregnancy or menopause – Pituitary, hypothalamic, or ovarian disorders such as premature ovarian failure or tumors – Adrenal disease including Cushing’s disease and Addison’s disease – Thyroid disease – Nutritional disorders such as severe malnutrition or marked obesity – Excessive exercise – Psychosomatic and neurogenic disorders such as anorexia nervosa, pseudocyesis, or psychosis – Stress


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Amenorrhea and Bone • • • • •

Decrease in bone mass Compromised BMD, particularly in the spinal region Greater risk of fracture (even at a young age) Greater risk of developing osteoporosis later in life Hypothalamic amenorrhea resulting from anorexia nervosa particularly damaging to the skeletal system because osteopenia may persist even after long-term recovery • Amenorrhea especially harmful in adolescents; critical time period for bone accretion. If peak bone mass is not achieved during this time, future bone health is severely compromised.

Mediators of Bone Loss • The precise mechanism is not completely understood. • Estrogen deprivation: Estrogen receptors have been found on osteoblastlike cells and seem to increase bone resorption. There is debate regarding the extent to which estrogen can be implicated in decreased BMD because estrogen replacement therapy in amenorrheic young women has proved largely ineffective. • Nutritional factors: Caloric restriction results in a slower metabolic rate, which could affect bone turnover. In addition, malnutrition lowers bone formation markers triiodothyronine (T3) and IGF-1. • Leptin: An adipocyte hormone, leptin, has been shown to be an independent regulator of metabolic rate. Moreover, leptin receptors have been found in bone. Leptin may have a role in integrating the metabolic and reproductive pathways, and thus is a critical link between amenorrhea and osteopenia. • For women with anorexia nervosa, weight gain has shown to improve osteoblastic function, but osteoclastic function remains impaired until the return of menses.

Evaluation • Clinicians should assess stress levels, signs of androgen excess such as hirsutism, symptoms of hypothyroidism, acne, obesity, or excessive thinness. • Women presenting with amenorrhea and excessive dieting or exercise, particularly adolescents and women in their early 20s, must be screened for eating disorders. • Hormonal analyses are necessary to determine the cause of amenorrhea: LH, FSH, estradiol, prolactin, and, in rare cases, testosterone and DHEA-S (to rule out adrenal disease). • Bone density tests are necessary to determine the status of the skeleton, particularly in athletes and in those with anorexia nervosa.

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Treatment • Return of menses is the immediate goal of treatment because there is a strong correlation between duration of amenorrhea and loss of BMD. • The underlying cause of amenorrhea is treated: weight recovery in anorexia nervosa, decreased exercise or stress in hypothalamic amenorrhea, dopamine agonists in hyperprolactinemia, and surgery to cure Cushing disease. • Patient education is crucial. Women must be made aware of the harmful effects of excessive exercise and/or extreme caloric restriction. In addition, patients should be warned about the ill effects of cigarettes and alcohol on bone density. • Anorexic women with amenorrhea must be informed that weight gain alone will not suffice to rectify previous insults to the skeletal system. They must alter their eating habits, because weight-restored anorexics with continued disordered eating are still at risk for bone loss. • For amenorrheic women who are not anorexic, moderate muscle-building activity may improve bone health. • A diet rich in calcium and vitamin D is encouraged. • Estrogen may be useful for treating patients with premature ovarian failure, but it has not been successful for women with anorexia nervosa. In addition, this therapy is not indicated in young women who have not completed their growth, because it can cause epiphyseal closure.

Suggested Readings Dawood MY, Ravnikar VA, Schneider GT, et al. A practical approach to amenorrhea. Patient Care 1992(suppl):12–28. Grinspoon S, Miller K, Coyle C, et al. Severity of osteopenia in estrogen-deficient women with anorexia nervosa and hypothalamic amenorrhea. J Clin Endocrinol Metab 1999;84:2049–2055. Jonnavithula S, Warren MP, Fox RP, et al. Bone density is compromised in amenorrheic women despite return of menses: a 2-year study. Obstet Gynecol 1993;81:669–674. Locke RJ, Warren MP. How to prevent bone loss in women with hypothalamic amenorrhea. Womens Health Primary Care 2000;3:270–278. Warren MP, Brooks–Gunn J, Fox RP, et al. Osteopenia in exercise-associated amenorrhea using ballet dancers as a model: a longitudinal study. J Clin Endocrinol Metab 2002;87:3162–3168.

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15 Nephrolithiasis Murray J. Favus

Composition and Frequency of Kidney Stones • Calcium oxalate, or calcium phosphate crystals in 75 to 85% of all stones • Calcium oxalate crystals are either monohydrate (dumbbell shaped) or dihydrate (bipyramidal) • Calcium phosphate (elongated, narrow crystals) occurring alone (5–15% of calcium stones) or, more common, with calcium oxalate (30–45% of calcium stones) • Infection stones (20% of all stones) composed of struvite (magnesium ammonium phosphate); crystals are rectangular prisms • Uric acid stones (2–10% of all stones), crystals are flat, rhomboidal shaped • Cystine stones (1–3% of all stones), crystals are hexagonal plates

Clinical Manifestations of Stones by Stone Composition • Spontaneous stone passage occurs with calcium, uric acid, and cystine, but rarely with struvite. • Small, separate stones suggest calcium and uric acid, and occasionally cystine, not struvite. • On radiography, calcium and struvite are radiodense whereas cystine is less dense. • Uric acid stones are radiolucent and appear as a filling defect on IVP. • Staghorn stones fill the renal pelvis and may be struvite, uric acid, or cystine. • Formation of sludge with obstruction occurs with either uric acid or cystine stones. • All stones may cause infection, bleeding, and obstruction of the urinary tract.

Active Stone Disease • Adults with recurrent stones, multiple new stones within 1 year, or growing stones • All children with kidney stones


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Diagnostic Evaluation of Stone Formers • • • •

Every effort should be made to identify the composition of each stone. All patients should have a plain radiograph of the abdomen and an IVP. A microscopic inspection of freshly voided urine for crystalluria should be conducted. Note the radiographic changes (lucent, opaque) and the shape of the crystals in urine (see the preceding section on stone composition). • A helical CT scan of the abdomen should be obtained to identify small stones and to monitor for new stone formation.

Laboratory Evaluation of Stone Formers After the First Stone • • • • •

Only a basic evaluation if just one stone is formed Urinalysis Urine culture if infection is considered Blood calcium, phosphate, uric acid, creatinine Urine aliquot for cystine

Active Stone Disease (two or more stones formed) • Medication that may interfere with calcium or uric acid metabolism discontinued for at least 14 days (vitamin D, vitamin C, multivitamins, diuretics, calcium supplements, steroids, and acetazolamide [Diamox]) • Twenty-four-hour urine collection for volume, pH, concentration of calcium, phosphate, uric acid, sodium, oxalate, citrate, and creatinine; measurement of cystine if stone opaque on radiograph • Urine collection while patients eat their usual diet • Fasting blood sample for calcium, phosphate, uric acid, creatinine, sodium, potassium

Pathogenesis of Stone • Interstitial papillary apatite plaque formation has been found in kidneys of idiopathic hypercalciuric (IH) stone formers. The plaque may serve as a site of attachment for calcium oxalate crystals. – Urine supersaturation with respect to stone crystals may occur by increasing urine excretion, decreasing urine volume, or reduction in other ligands (such as citrate) that normally form soluble calcium complexes rather than permitting formation of an insoluble complex of calcium oxalate. – Urine pH is important in the supersaturation of calcium phosphate (high urine pH favors crystal formation) and uric acid (low pH favors insoluble uric acid crystals), but not calcium oxalate. – Nucleation of crystals may occur in supersaturated urine with binding of crystals onto the surface of preformed crystals or particles in urine. Calcium stones anchor at sites on the surface of the calyceal system.

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– Urine inhibitors of crystal growth such as citrate, pyrophosphate, and proteins (uropontin, Tamm–Horsfall protein) reduce supersaturation, nucleation, adsorption, or crystal growth. Their absence (e.g., low urine citrate) may promote stone formation.

Causes of Calcium Oxalate Stones • • • •

Hypercalciuria Low urine citrate Hyperoxaluria Hyperuricosuria

Causes of Hypercalciuric Calcium Oxalate Stone Formation1 • Definition of hypercalciuria: 24-hour urine greater than 250 mg for women, more than 300 mg for men, or more than 4 mg/kg body weight either sex; more than 140 mg/g urine creatinine • Hypercalciuria with hypercalcemia – Primary hyperparathyroidism – Granulomatous disease – Vitamin D intoxication – Sarcoidosis – Lithium carbonate • Hypercalciuria with normocalcemia – Idiopathic (familial, IH) – Sarcoidosis – Renal tubular acidosis – Hyperthyroidism – Immobilization – Paget disease of bone – Rapidly progressive osteoporosis

Causes of Low Urine Citrate (45mg)1 • Metabolic overproduction – Hereditary types I and II – Ethylene glycol ingestion – Methoxyflurane anesthesia • Gastrointestinal overabsorption – Resection of the distal ileum – Small bowel bypass surgery – Pancreatic insufficiency – Celiac sprue – Selected dietary overingestion – Cellulose phosphate or low calcium diet

Causes of Hyperuricosuria (24-hour urine uric acid >800mg in men, >750mg in women) • • • •

Increased purine ingestion (meat, fish, poultry) Overproduction of uric acid Low urine pH Dehydration with low urine volumes and low urine pH

Pathogenesis of IH • Familial, with evidence of genetic basis consistent with autosomal dominant inheritance • Hypercalciuria life-long, same frequency in children as in adults (about 5–10% of general population) • Stones, calcium oxalate alone, or with minor amounts of either calcium phosphate or uric acid crystals • Serum calcium normal; PTH elevated in 5% of patients • Intestinal calcium hyperabsorption in most patients • Source of excess urine calcium, intestinal hyperabsorption when calcium intake normal; when calcium intake low, urine calcium may decrease to low levels (like nonstone formers) or may remain excessive (indicates bone resorption) • No conservation of urine calcium during low-calcium diet, development of negative calcium balance; serum 1,25-dihydroxyvitamin D [1,25(OH)2D3] levels elevated in 50 to 65% of patients; no metabolic differences between those with normal or elevated serum 1,25(OH)2D3 • BMD reduced in men and women; evidence suggesting increased fracture risk

1

Adapted from Coe FL, Parks JH. Clinical approach. In: Nephrolithiasis: pathogenesis and treatment. 2nd ed. St. Louis: Mosby; 1988:1–37.

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Four Models of Hypercalciuria in IH • All models, normal serum calcium and increased intestinal calcium absorption • Primary intestinal overabsorption – Normal serum 1,25(OH)2D3 and PTH – Maintenance of calcium balance during low-calcium diet • Primary overproduction of 1,25(OH)2D3 – Elevated serum 1,25(OH)2D3 and normal PTH – May have fasting hypercalciuria – Negative calcium balance during low-calcium diet • Renal hypercalciuria – Fasting hypercalciuria – Elevated PTH and 1,25(OH)2D3 – Intestinal calcium hyperabsorption secondary to increased 1,25(OH)2D3 – Negative calcium balance during low-calcium diet • Elevated vitamin D receptor (VDR) – Found in genetic, hypercalciuric, stone-forming rats, an animal model of IH – Elevated VDR found in peripheral blood monocytes from men with IH – Normal serum 1,25(OH)2D3 and PTH in most men

Treatment of IH to Prevent Stones • Reduce 24-hour urine calcium to 200 mg or less using a thiazide diuretic. • Administer chlorthalidone or indapamide once daily or hydrochlorothiazide twice daily. • Monitor serum potassium and replace it if it is low using KCl, potassium citrate, or potassium–citrate–acetate–bicarbonate (Urocit-K). – If urine citrate is also low, add potassium citrate or Urocit-K with each meal. – Ensure adequate hydration to maintain urine output of 1.5 L daily. – Avoid dehydration. – Measure 24-hour urine calcium excretion 6 to 8 weeks after initiating therapy and yearly. – Dietary calcium restriction does not reduce stone recurrence and may create a negative calcium balance and low bone density. – Maintain an adequate calcium diet of about 800 mg/day. – If 24-hour urine calcium remains more than 200 mg/24 hour, then evaluate dietary calcium intake and compliance with medication, increase the patient’s dose of thiazide, measure urine sodium excretion, and limit sodium intake if excessive.

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Treatment of Hyperoxaluric States • Enteric hyperoxalurias – Increased colon oxalate absorption resulting from a variety of factors, may reach 100 mg/24 hr • Colon oxalate absorption decrease by – Low-fat diet – Low-oxalate diet – Oral calcium carbonate 250 to 1000 mg with each meal to bind dietary oxalate – Cholestyramine resin 4 to 16 g/day in divided doses to bind luminal oxalate, and fatty acids and bile salts that increase colon permeability to oxalate – Oral citrate to bind and solubilize urine calcium • Treatment of genetic hyperoxaluric states I and II – Pyridoxine 400 mg/day – Urine volume 3 L/day – Oral citrate – Combined liver and renal transplantation before systemic oxalosis develops • Dietary hyperoxaluria from excessive consumption of foods high in oxalate – Oxalate-rich foods: spinach, rhubarb, parsley, pepper, nuts, chocolate, cocoa, tea – Limitation of intake of oxalate-rich foods

Treatment of Hyperuricosuric Calcium Oxalate Stone Formation • • • • •

Dietary overingestion of purine-rich foods is major source of urine uric acid. Overproduction of uric acid is seen in a minority of patients. Avoid dehydration. Maintain urine pH above 6.0 to improve uric acid solubility. Administer allopurinol 200 mg/day when hyperuricosuria is the result of uric acid overproduction. • Allopurinol reduces new calcium oxalate stone formation and the growth of preexisting stones.

Stone Removal • Surgical removal of stones if they cause obstruction, severe pain, bleeding, serious infection • Stones less than 5 mm passed spontaneously; more than 7 mm tend not to pass • Extracorporeal shock wave lithotripsy – Stones less than 2 cm – Presence of a single stone in renal parenchyma – Location in upper two thirds of ureter • Other procedures – Ureterolithotomy for stones more than 2 cm, stones in lower one third of ureter, large infected stones, stones in the ureteropelvic junction or in calyceal diverticula

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Suggested Readings Asplin JR, Coe FL, Favus MJ. Nephrolithiasis. In: Harrison’s principles of internal medicine, 16th Edition Eds. Kasper DL, Fauci AS, Longo DL, Braunwald E, Hauser SL, Jameson JL. New York: McGraw-Hill; 2005:1710–1714. Coe FL, Favus MJ, Pak CYC, et al., eds. Kidney stones: medical and surgical management. Philadelphia: Lippincott-Raven; 1996. Lemann J Jr. Idiopathic hypercalciuria. In: Coe FL, Favus MJ, eds. Disorders of bone and mineral metabolism. Philadelphia: Lippincott Williams and Wilkins; 2002:673–697. Lingeman JE, Patterson RF. Mechanism of stone disruption and dissolution. In: Coe FL, Favus MJ, eds. Disorders of bone and mineral metabolism. Philadelphia: Lippincott Williams and Wilkins; 2002:629–672.

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Acute Spinal Cord Injury and Traumatic Brain Injury

16

Albert C. Clairmont VeIimir Matkovic

Acute Spinal Cord Injury (SCI) Definition Acute SCI is characterized by sustained damage to neural elements in the spinal canal, resulting in impairment or loss of motor and or sensory function. This is described as tetraplegia if the cervical segments are involved and paraplegia if thoracic, lumbar, or sacral segments are involved.

Epidemiology The incidence rate in the United States is 30 to 40 cases per million population. Prevalence in the United States is between 183,000 and 230,000 people.

Causes • • • • •

Motor vehicle accidents, 44.5% Falls, 18.1% Acts of violence, 16.6% Sports, 12.7% Other, 8.1% – Incomplete tetraplegia, 29.6% – Complete paraplegia, 27.3% – Incomplete paraplegia, 20.6% – Complete tetraplegia, 18.6%

Complications at the Bone Tissue Level Disuse Osteoporosis • Increased bone resorption, decreased bone formation • Rapid bone loss primarily in the paralyzed limbs (22% in distal femur during the first 3 months, 27% at 4 months, 40—45% in pelvic bones after 1 year; lower limb bone loss of 25% at the end of first year; long-term bone loss of 50%; see the Figure) • Biochemical markers of bone resorption increased, peaks 6 weeks after acute SCI • Resorptive hypercalciuria The Bone and Mineral Manual Copyright © 2005 by Elsevier Inc. All rights of reproduction in any form reserved.

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Trabecular bone density at the distal end of the tibia in a group of SCI patients plotted against the time since injury. The data show a considerable amount of variability, which is to be expected in these patients. A regression line based on an exponential function, however, can provide the pattern of bone loss to be expected in patients with SCI. (Adapted from Hangartner TN. Osteoporosis due to disuse. In: Matkovic V, ed. Physical medicine and rehabilitation clinics of North America. Philadelphia: WB Saunders; 1995:579–593.

• Possible presence of hypercalcemia, particularly in young individuals • Significant difference in BMC in the upper limbs between tetraplegics and paraplegics, higher in paraplegics • No loss of BMD in lumbar spine in paraplegics • Increased incidence of long-bone fractures with trivial trauma • Fractures occurring during normal events in rehabilitation (e.g., transfer activity and range of motion) Diagnosis • Plain radiograph, DXA, pQCT Treatment • Generally not satisfactory • Calcitonin, bisphosphonates • Functional electrical stimulation

Renal Calculi • Overall incidence of urinary tract stones, 17.7%; renal stones, 14.8% • Type of stones: magnesium ammonium phosphate (struvite), calcium phosphate, calcium oxalate

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• Contributing factors: hypercalcemia, vesicoureteral reflex, and urinary tract infection with urea-splitting bacteria; Foley or suprapubic catheters • Calcium and magnesium ammonium phosphate precipitate in the alkaline medium; nidus formation on which more crystals deposit, eventually forming staghorn calculi Prevention • Intermittent catheterization, appropriate diuresis, effective treatment of infections Treatment • Easy fragmentation of renal and bladder calculi usually found in SCI population • Lithotripsy treatment of choice for partial staghorn calculi • For complete staghorn calculi, percutaneous nephrolithotomy followed by lithotripsy treatment of choice

Heterotopic Ossification (HO) • Incidence, 10 to 53% • Etiology unclear, central and local mechanisms may be involved; hormonal, genetic, and metabolic causes postulated • Microtrauma around the affected joint implicated; aggressive rehabilitation, including range of motion, thought to be contributory. • Association with pressure sores, immobilization, infection, and vasomotor disturbances Common Clinical Findings • Decreased range of motion • Periarticular swelling • Pain (in those with sensory sparing) Diagnosis • Triple-phase bone scan positive during early stage; may not be positive during first few days of inflammatory process • Disadvantages of bone scan: use of ionizing radiation, expensive, not portable to bedside • Ultrasound positive during early stages of HO; least expensive method of detection; usually positive at the time of first clinical symptoms; characteristic appearance depending on age and stage of mineralization of lesion; early findings, zone phenomena, which disappear and ultrasound beam reflected in characteristic fashion with bone maturation • Increased serum alkaline phosphatase, increased excretion of urinary prostaglandins (PGE2) • Plain radiographs positive, but only 4 to 6 weeks after first clinical symptoms of HO Treatment • Various regimens, including bisphosphonates alone, nonsteroidal antiinflammatory drugs (NSAIDS; indomethacin) alone, or bisphosphonates in combination with NSAIDS (intravenous disodium etidronate 300 mg/day for 3 days, followed by oral dose of 20 mg/kg/day for 6 months); newer bisphosphonates considered • Warfarin potentially useful in prophylaxis against HO • Radiation therapy an effective modality

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• Surgical resection results in recrudescence; prophylactic presurgical and postsurgical treatment recommended; disodium etidronate alone or in combination with NSAIDS, effective prophylaxis for surgery

Hypercalcemia • Occurs mostly in young SCI patients (growing skeleton with increased number of bone remodeling units); caused by excessive bone resorption acutely during the disease (first 3–6 months) Treatment • Hydration, forced diuresis, calcitonin, bisphosphonates

Traumatic Brain Injury (TBI) Epidemiology • One and a half million Americans survive TBI each year and more than 80,000 are left with a permanent disability. • Children and the elderly are more likely to present with head injury than other age groups. • The leading causes of TBI are motor vehicle accidents and violence-related injuries. • Falls are important in the elderly.

Pathophysiology • • • • •

Acceleration/deceleration and rotational forces Contusion caused by shearing forces applied to the brain Both focal and diffuse axonal injury Abnormal cerebral perfusion Most important complication related to bone tissue in persons who have sustained TBI, heterotopic bone formation; most likely explanation: a certain growth factor released by neurotrauma triggers osteogenic potential of mesenchymal stem cell locally in the soft tissue – Reported incidence of HO in TBI, 11 to 76% – Coma or vegetative state lasting 1 month or more associated with significantly increased risk of HO; spasticity a contributory factor – Onset of HO, 4 to 12 weeks after TBI – Treatment same as for HO occurring in SCI

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Suggested Readings Banovac K, Gonzalez F, Wade N, et al. Intravenous disodium etidronate therapy in spinal cord injury patients with heterotopic ossification. Paraplegia 1993;31:660–666. Bienng–Sorensen F, Bohr HH, Schaadt OP. Longitudinal study of bone mineral content in the lumbar spine, the forearm, and the lower extremities after spinal cord injury. Eur J Clin Invest 1990;20:330–335. Cassar–Pulhcino VN, McClelland M, Badwan DA, et al. Sonographic diagnosis of heterotopic bone formation in spinal injury patients. Paraplegia 1993;31:40–50. Go BK, DeVivo MJ, Richards S. The epidemiology of spinal cord injury. In: Stover SL, DeLisa JA, Whiteneck GG, eds. Spinal cord injury: clinical outcomes from the model systems. Gaithersburg: Aspen; 1995:21–55. Hall MK, Hackler RH, Zampieri TA, et al. Renal calculi in spinal cord injured patient: association with reflux, bladder stones, and Foley catheter drainage. Urology 1989;34:126–128. Schurch B, Capaul M, Vallotton MB, et al. Prostaglandin E2 measurements: their value in the early diagnosis of heterotopic ossification in spinal cord injury patients. Arch Phys Med Rehabil 1997;78:687–691. van Kuijk AA, Geurts AC, van Kuppevelt HJ. Neurogenic heterotopic ossification in spinal cord injury. Spinal Cord 2002;40:313–326.

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17 Reflex Sympathetic Dystrophy Albert C. Clairmont Velimir Matkovic

Definition • Reflex sympathetic dystrophy (RSD) is a syndrome characterized by diffuse limb pain, swelling, vasomotor and sudomotor phenomena, hyperalgesia, allodynia, and trophic changes. The exact pathophysiology of RSD is still unclear. An inciting traumatic event is usually but not always identifiable. Trauma may be major or trivial. Fractures or ankle sprains frequently precede RSD. Several other events have been associated with RSD, including stroke, myocardial infarction, cancer, surgery, and even the use of antituberculous medications. Transient regional osteoporosis is a form of RSD. • The International Association for the Study of Pain issued a consensus statement redefining RSD in 1993. RSD is now grouped as a member of the complex regional pain syndromes (CRPS). It is designated CRPS-I. The terms RSD and CRPS-I are used interchangeably in this chapter. Causalgia is designated CRPS-II. • The clinical features of causalgia are very similar to RSD (CRPS-I). • A major differentiating point between RSD (CRPS-I) and causalgia (CRPS-II) is that causalgia is usually associated with a partial nerve injury. In RSD (CRPS-I), injury to a named nerve is not usually present.

Diagnosis • The diagnosis is made based on clinical signs and symptoms (dolor, calor, rubor, tumor, functio laesa). • There is spontaneous pain beyond the territory of a single peripheral nerve. The pain is disproportionate to the noxious event. • Abnormal sudomotor and/or vasomotor activity, and swelling of the skin and subcutaneous tissues usually follow. There is dysregulation of blood flow and sweating. • Spontaneous pain, allodynia, hyperalgesia, and hyperpathia are present. • Trophic changes of skin, appendages of skin, subcutaneous tissues, and bone atrophy develop at a later stage. • A single limb is usually affected initially, with maximal expression in the distal limb. Movement disorders, including increased physiologic tremor, spasm, and dystonia, may occur. • The number of symptoms and the extent to which each is expressed is variable. • Plain radiographs show patchy osteoporosis. The Bone and Mineral Manual Copyright © 2005 by Elsevier Inc. All rights of reproduction in any form reserved.

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Diagnostic Procedures • No single test is diagnostic of RSD (CRPS-I), but a number of laboratory tests, in conjunction with clinical criteria mentioned earlier, help clinch the diagnosis. – Skin surface temperature measurement is helpful. Digital pad surfaces are used. The normal and affected extremities are compared. Measurements are made symmetrically using infrared thermography. Environmental temperature should be well controlled and stable before measurement. A temperature difference of more than 2°C is suggestive of unilateral sympathetic dysfunction. – Sympathetic blocks: Successful response to sympathetic blockade (pain relief) indicates that a component of, if not all of, the person’s pain is mediated by the sympathetic nervous system. This is defined as sympathetically maintained pain. A positive response to sympathetic blockade supports treatment directed to the sympathetic nervous system. A negative response to sympathetic blockade indicates sympathetically independent pain (SIP). In SIP, treatment directed to the sympathetic nervous system is unlikely to be rewarding. The quantitative sudomotor axon reflex test measures the evoked sweat response. It measures resting cholinergic sympathetic tone and sudomotor activity stimulated by 10% acetylcholine per iontophoresis. A positive result for sympathetic overactivity shows increased sweat output and changes in latency and duration. – Bone scans usually show increased periarticular uptake. – Quantitative bone mineral analysis by DXA shows decreased BMC secondary to osteoporosis. – Radiographs may show bone demineralization similar to atrophy associated with immobilization or disuse. At first, there is soft tissue swelling, and then diffuse periarticular osteopenia is noted. Cortical bone resorption, subperiosteal, endosteal and intracortical. Articular erosions; metacarpophalangeal, metatarsophalangeal. Proximal interphalangeal and distal interphalangeal. X-ray findings proceed in stages.

Treatment • No single method is guaranteed to succeed in treating RSD (CRPS-I). Widely different pharmacologic approaches may succeed in individual cases. The wider range of successful treatments reported suggest different pathophysiologic mechanisms for RSD (CRPSI). Restoration of function using principles of physical medicine and rehabilitation is essential to a successful outcome. • The mainstay of treatment is sympathetic blockade (usually with a local anesthetic)—a series of one to six blocks one or more weeks apart, depending on the patient’s response. For RSD (CRPS-I) involving the upper limb, the stellate ganglion is the usual target. For RSD (CRPS-I) involving the lower limb, the lumbar sympathetic chain is targeted. Sympathetic blockade should continue only if there is a demonstrated response to the first block and subsequent blocks. • A different approach is to use pulse steroid therapy (e.g., with prednisone at a high dose [100 mg orally/day], and decreasing by 10 mg each day until 0 mg is reached). Patients with the shoulder/hand variety of RSD (CRPS-I) respond well to steroids, especially if treated early during the course of the disease.

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• Physical and occupational therapy techniques and modalities are indispensable to increase functional use of the affected limb. Maximal functional gain is anticipated when the person afflicted with RSD (CRPS-I) is engaged in an active physical medicine and rehabilitation program. Therapy should be initiated immediately after pain-relieving measures have been successfully used (sympathetic blocks, steroids, etc.). – Stress loading of the affected limb – Range of motion of the limb – Contrast baths applied to limb – Isotoner glove – Transcutaneous neurostimulation – Dorsal column stimulation • The most important consideration is adequate pain relief to allow the afflicted person the ability to engage in functional therapeutic exercise. If pain is not adequately managed, there is little hope of restoring functional activity or reversing RSD (CRPS-I). – Pharmacology – a-Adrenergic blockers – Gabapentin – Bisphosphonates – Tricyclic antidepressants – Mexiletine – Lidocaine – Carbamazepine – Calcitonin – Nonsteroidal analgesics – Opioid analgesics – Intrathecal morphine and others

Suggested Readings Baron R, Blumberg H, Janig W. Clinical characteristics of patients with complex regional pain syndrome in Germany with special emphasis on vasomotor function. In: Stanton–Hicks M, Janig W, eds. Reflex sympathetic dystrophy: a reappraisal. Seattle: IASP Press; 1996:25–48. Genant HK, Kozin F, Bekerman C, et al. The reflex sympathetic dystrophy syndrome. A comprehensive analysis using fine-detail radiography, photon absorptiometry, and bone and joint scintigraphy. Radiology 1975;117:21–32. Janig W. CRPS-I and CRPS-II: a strategic view. In: Harden NH, Baron R, Janig W, eds. Complex regional pain syndrome. Seattle: IASP Press; 2001:3–15. Low PA, Wilson PR, Sandroni P, et al. Clinical characteristics of patients with reflex sympathetic dystrophy (sympathetically maintained pain) in the USA. In: Stanton–Hicks M, Janig W, eds. Reflex sympathetic dystrophy: a reappraisal. Seattle: IASP Press; 1996:49–66.

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18 Evaluation of the Patient with Low Bone Density Marjorie Luckey

Densitometry Densitometry detects low bone density, but does not identify its etiology, nor does it indicate whether bone loss has occurred or is ongoing. • Further evaluation of the patient is necessary to establish the correct diagnosis and to assess fracture risk. • Failure to identify underlying disorders may lead to inappropriate and/or ineffective therapy.

Differential Diagnosis of Low Bone Density • Low peak bone mass (PBM) attained during childhood and adolescence – Frequent cause of low bone density in premenopausal or early menopausal women – Characterized by low bone density, but not the microarchitectural abnormalities caused by bone loss – Fracture risk not comparable with that of older postmenopausal women who have experienced bone loss • Osteoporosis – Primary (resulting from postmenopausal or age-related bone loss) – Secondary (caused, at least in part by other diseases or medications) – Idiopathic (osteoporosis in premenopausal women or young men without identifiable cause) • Other bone diseases – Osteomalacia – OI or other disorders of collagen – Renal osteodystrophy


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Secondary Osteoporosis • Many disorders and medications affect the skeleton and can lead to low BMD. – Onset during childhood and/or adolescence interferes with attainment of PBM. – Onset during adulthood leads to excessive bone loss that is superimposed on loss due to aging and menopause. • The prevalence of secondary osteoporosis is high. – Fifty one percent of men and 41% of women older than 50 years of age with osteoporosis reported to have secondary causes (Canadian Database of Osteoporosis and Osteopenia). – Forty-four to 90% of young men and young women with osteoporosis are found to have secondary causes. • Because some of these disorders may be occult, they should be considered in the differential diagnosis of osteoporosis in every patient.

High Prevalence of Unsuspected Secondary Osteoporosis in Otherwise Healthy Postmenopausal Women and Men with Osteoporosis • More than 40% of 173 otherwise healthy postmenopausal women with osteoporosis found to have occult secondary causes by laboratory testing – Vitamin D deficiency (3 times, bone disease probable

Normal to increased

Increased

Variable, 15%

Increased

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