COVER ARTICLE PROBLEM-ORIENTED DIAGNOSIS

Osteoporosis: Part I. Evaluation and Assessment JEANNETTE E. SOUTH-PAUL, COL, MC, USA Uniformed Services University of the Sciences, Bethesda, Maryland

Osteoporosis afflicts 75 million persons in the United States, Europe and Japan and results in more than 1.3 million fractures annually in the United States. Because osteo- O A patient informa- porosis is usually asymptomatic until a fracture occurs, family physicians must identify tion handout on the appropriate timing and methods for screening those at risk. Prevention is the most osteoporosis, written by the author of this important step, and women of all ages should be encouraged to take 1,000 to 1,500 mg article, is provided on of supplemental calcium daily, participate in regular weight-bearing , avoid page 908. medications known to compromise bone density, institute hormone replacement ther- apy at menopause unless contraindicated and avoid tobacco and excessive alcohol intake. All postmenopausal women who present with fractures as well as younger women who have risk factors should be evaluated for the . Physicians should recommend bone mineral density testing to younger women at risk and post- menopausal women younger than 65 years who have risk factors for osteoporosis This is Part I of a two-part other than being postmenopausal. Bone mineral density testing should be recom- article on osteoporosis. mended to all women 65 years and older regardless of additional risk factors. Bone Part II, “Nonpharmacologic mineral density screening should be used as an adjunct to clinical judgment only if the and Pharmacologic Treat- results would influence the choice of therapy or convince the patient to take appro- ment,” will appear in the priate preventive measures. (Am Fam Physician 2001;63:897-904,908.) next issue.

steoporosis is a public persons during the sixth decade (the peri- health problem affecting menopausal period in women). 75 million persons in the Both processes are regulated by genetic United States, Europe and and environmental factors. Reduced Japan, including one third bone mass is the result of varying combi- Oof postmenopausal women and most of nations of hormone deficiencies, inade- the elderly in the United States, Europe quate nutrition, decreased physical activ- and Japan. Osteoporosis results in more ity, comorbidity and the effects of than 1.3 million fractures annually in the medications used to treat various unre- United States.1 Family physicians and lated medical conditions.3,4 other primary care professionals should Of the approximately 25 million Amer- recognize the implications involved when ican women who have osteoporosis, patients present with fractures, identify 8 million have had a documented frac- patients with subclinical osteoporosis and ture.1 The female-to-male fracture ratios know when to implement preventive are 7:1 for vertebral fractures, 1.5:1 for Members of various family prac- strategies in younger patients. An algo- distal forearm fractures and 2:1 for hip tice departments develop articles rithm (Figure 1) is presented to assist in fractures.5,6 The lifetime risk of a 50-year- for “Problem-Oriented Diagno- sis.” This article is one in a series the evaluation of osteoporosis. old white woman having an osteoporotic coordinated by the Department Osteoporosis is a condition character- fracture is 40 percent. Osteoporotic frac- of Family Medicine at the Uni- ized by microarchitectural deterioration tures are more common in whites and formed Services University of the of bone tissue leading to decreased bone Asians than in blacks and Hispanics, and Health Sciences, Bethesda, Md. mass and bone fragility.2 The major are more common in women than in Guest editors of the series are Francis G. O’Connor, LTC, MC, processes responsible for osteoporosis men. One possible reason is that blacks USA, and Jeannette E. South- are poor bone mass acquisition during and men achieve higher peak bone densi- Paul, COL, MC, USA. adolescence and accelerated bone loss in ties than whites and women. With respect

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Patient Asymptomatic woman Man or woman with pain or fracture

Risk factor assessment: Background (age, family history, habits) Ongoing conditions/medicines Nutrition Exercise Surgical history

Physical examination: Physical examination: No signs of Signs of secondary chronic disease osteoporosis (see Table 2)

No risks Risks (see Table 1) (see Table 1)

BMD Positive Laboratory evaluation and BMD (see Tables 3 and 4)

Negative

Positive Negative Prevention: Habits (no tobacco or alcohol) Exercise Treat specific diagnosis Select treatment: Calcium supplementation and osteoporosis HRT (in postmenopausal HRT (in postmenopausal women) women) Alendronate (Fosamax) Calcium plus vitamin D Raloxifene (Evista) in Exercise postmenopausal women Alendronate, +/- HRT BMD after age 65 Calcitonin (Calcimar) No tobacco or alcohol

BMD every 12 to 24 months to monitor medication effectiveness

FIGURE 1. Algorithmic approach to osteoporosis. (BMD = bone mineral density determination; HRT = hormone replacement therapy)

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to women, age-related bone loss accelerates during menopause as estrogen levels decrease.5 Of approximately 25 million American women who have osteoporosis, 8 million have had a documented fracture. Primary vs. Secondary Osteoporosis Primary osteoporosis—deterioration of bone mass that is unassociated with other chronic illness—is related to aging and extrapolations from what is known about decreased gonadal function. Therefore, early osteoporosis in women. Approximately menopause or premenopausal estrogen defi- 30 percent of hip fractures in persons older ciency states may hasten the development of than 65 years occur in men. Osteoporosis- primary osteoporosis. Prolonged periods of related fracture in older men is associated with inadequate calcium intake, sedentary lifestyle lower femoral neck bone mineral density, and tobacco and alcohol abuse also con- quadriceps weakness, higher body sway, lower tribute to this condition. body weight and decreased stature.10 Secondary osteoporosis results from Osteoporosis is much more common in chronic conditions that contribute signifi- older persons and in the ethnic groups previ- cantly to accelerated bone loss. These chronic ously mentioned. Furthermore, family history conditions include endogenous and exoge- of osteoporosis increases the risk. One example nous thyroxine excess, hyperparathyroidism, malignancies, gastrointestinal , med- ications, renal failure and connective tissue TABLE 1 7 diseases. Osteoporosis is a common compli- Secondary Forms of Osteoporosis cation of long-term glucocorticoid therapy and is responsive to bisphosphonates in this Endocrine or metabolic causes Medications setting. Secondary forms of osteoporosis are Acromegaly Cyclosporine (Sandimmune) 8 listed in Table 1. If secondary osteoporosis is Anorexia nervosa Excess thyroid hormone suspected, appropriate diagnostic work-up Athletic amenorrhea Glucocorticoids could identify a different management mellitus (type 1—formerly known GnRH agonists course. For example, if a pituitary tumor is as insulin-dependent diabetes mellitus) Methotrexate (Rheumatrex) identified, surgical removal could prevent Hemochromatosis Phenobarbital ongoing accelerated bone loss. The bone loss Hyperadrenocorticism Phenothiazines already sustained can be treated. The sec- Hyperparathyroidism Phenytoin (Dilantin) ondary hyperparathyroidism of renal failure Hyperprolactinemia Heparin, prolonged treatment Thyrotoxicosis can be ameliorated through dietary modifi- Nutritional cation and calcium supplementation. Collagen/genetic disorders Alcoholism Ehlers-Danlos syndrome Calcium deficiency Risk Factors Glycogen storage diseases Chronic liver disease Homocystinuria GENETIC Gastric operations Hypophosphatasia Malabsorption syndromes Because osteoporosis is usually asympto- Marfan syndrome Vitamin D deficiency matic until a fracture occurs, it is crucial to Osteogenesis imperfecta recognize who is at risk and identify the appropriate timing and methods for screen- GnRH = gonadotropin-releasing hormone. ing. Women are more susceptible to osteo- Adapted with permission from Tresolini CP, Gold DT, Lee LS, eds. Working with porosis than men. However, osteoporosis in patients to prevent, treat and manage osteoporosis: a curriculum guide for men is now recognized as an important health health professions. 2d ed. San Francisco: National Fund for Medical Education, problem, particularly in the aged.9 Many clin- 1998. ical decisions involving men must be based on

MARCH 1, 2001 / VOLUME 63, NUMBER 5 www.aafp.org/afp AMERICAN FAMILY PHYSICIAN 899 TABLE 2 NUTRITIONAL Risk Factors for Osteoporosis Increasing the milk intake of adolescents has been shown to improve bone mineraliza- Female gender Lifelong low calcium intake tion.11 However, because other nutrients Petite body frame Smoking besides calcium are essential for bone health, White or Asian ancestry Excessive alcohol use calcium alone may be insufficient to combat Sedentary lifestyle/immobilization Long-term use of certain drugs osteoporosis. Unquestionably, adolescents Nulliparity Postmenopausal status must maintain a dietary balance among cal- Increasing age Low body weight cium, protein, other calorie sources and High caffeine intake Impaired calcium absorption phosphorus. For example, phosphorus is a Renal disease substantial component of carbonated drinks, and high phosphorus intake compromises calcium uptake by bone, thereby promoting of genetically determined osteoporosis is seen decreased bone mass. in patients with Turner’s syndrome (45XO Eating disorders also affect bone mineral gonadal dysgenesis). Osteoporosis commonly density. Inability to maintain normal body complicates this syndrome and its genetic mass promotes bone loss. The body weight variants. Women with this syndrome have low history of women with anorexia nervosa is plasma estradiol levels and elevated gonado- the most important predictor of the presence tropin concentration.7 Another genetic dis- of osteoporosis.12 The bone mineral density ease in which osteoporosis occurs is osteogen- of these patients does not increase to the nor- esis imperfecta. mal range even several years after recovery from the disorder, and all persons with a his- tory of an eating disorder remain at high risk TABLE 3 for osteoporosis in the future. Evaluation of Secondary Osteoporosis Major demands are placed on the mother by the fetus for calcium during pregnancy Abnormal study result Suggested pathology and by the infant during lactation. The axial Increased creatinine level Renal disease spine and hip show losses of bone mineral Increased hepatic transaminase Hepatic disease density during the first six months of lacta- levels tion, but these losses appear to be completely Increased calcium level Primary hyperparathyroidism or malignancy restored six to 12 months after weaning.13 Decreased calcium level Malabsorption, vitamin D deficiency A summary of risk factors is presented in Decreased phosphorus level Osteomalacia Table 2. Increased alkaline phosphatase Liver disease, Paget’s disease, fracture, other level bone pathology BEHAVIORAL Decreased albumin level Malnutrition Decreased TSH level Hyperthyroidism Sedentary lifestyle and immobility (con- Increased ESR Myeloma finement to bed or wheelchair) increase the Anemia Myeloma incidence of osteoporosis. Low body weight Decreased 24-hour calcium Malabsorption, vitamin D deficiency and cigarette smoking negatively influence excretion level bone mass. Excessive alcohol consumption has been shown to depress osteoblast function TSH = thyroid stimulating hormone; ESR = erythrocyte sedimentation rate. and, thus, to decrease bone formation. Adapted with permission from Harper KD, Weber TJ. Secondary osteoporosis. Because certain medications negatively affect Diagnostic considerations. Endocrinol Metab Clin North Am 1998;27(2):325-48. bone mineral density, these drugs should be avoided, if possible, in those at risk (Table 1).8

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clues to serious illnesses that may otherwise Diagnosis and Assessment have gone undetected and which, if treated, HISTORY AND PHYSICAL EXAMINATION could result in resolution or modification of The history and physical examination are the bone loss. Specific biochemical markers neither sensitive enough nor sufficient for (human osteocalcin, bone alkaline phos- diagnosing primary osteoporosis. However, phatase, immunoassays for pyrinoline cross- they are important in screening for secondary links and type 1 collagen-related peptides in forms of osteoporosis and directing the eval- urine) that reflect the overall rate of bone for- uation. A medical history provides valuable mation and bone resorption are now avail- clues to the presence of chronic conditions, able. These markers are primarily of research behaviors, and the long-term interest and are not recommended as part of use of medications that could influence bone the basic work-up for osteoporosis.14 They density. have a high degree of biologic variability and Those already affected by complications of diurnal variation and do not differentiate osteoporosis may complain of upper- or midthoracic back pain associated with activ- ity, aggravated by long periods of or TABLE 4 standing, and easily relieved by rest in the Directed Laboratory Assessment for Secondary Osteoporosis recumbent position. The history should also assess the likelihood of fracture. Low bone Cause Finding/test density, a propensity to fall, greater height and Hypogonadism Increased testosterone level in men prior fractures are indications of increased Decreased estrogen level in women fracture risk. Increased gonadotropin levels (LH and FSH) The physical examination should be thor- ough for the same reasons. For example, lid Hyperthyroidism Decreased TSH level Increased T lag, and enlargement or nodularity of the 4 thyroid suggest hyperthyroidism. Moon Hyperparathyroidism Increased parathyroid hormone level facies, thin skin and a buffalo hump suggest Increased serum calcium level Cushing’s syndrome. Cachexia mandates Increased 1,25 hydroxyvitamin D level screening for an eating disorder or malig- Vitamin D deficiency Decreased 25-hydroxycalciferol level nancy. A pelvic examination is necessary for Hemochromatosis Increased serum iron level the complete evaluation of women. Osteo- Increased ferritin level porotic fractures are a late physical manifes- Cushing’s syndrome 24-hour urine free cortisol excretion tation. Common fracture sites are the verte- Overnight dexamethasone suppression test brae, forearm, femoral neck and proximal Multiple myeloma Serum protein electrophoresis—M spike and Bence humerus. The presence of a dowager’s hump Jones proteinuria (spinal curvature) in elderly patients indi- Increased ESR cates multiple vertebral fractures and de- Anemia creased bone volume. Hypercalcemia Decreased parathyroid hormone LABORATORY TESTS

Basic chemical analysis of serum is indi- LH = luteinizing hormone; FSH = follicle-stimulating hormone; TSH = thyroid- cated when the history suggests other clinical stimulating hormone; T4 = thyroxine; ESR = erythrocyte sedimentation rate. conditions influencing the bone density. The Adapted with permission from National Osteoporotic Foundation, 1996 and tests presented in Tables 37 and 45 are appro- 2015 osteoporosis prevalence figures: state-by-state report. January 1997. priate for excluding secondary causes of Women’s Health Matters 1998;2(3):1. osteoporosis.7 These tests provide specific

MARCH 1, 2001 / VOLUME 63, NUMBER 5 www.aafp.org/afp AMERICAN FAMILY PHYSICIAN 901 menopause.17 The presence of multiple risk TABLE 5 factors (i.e., older than 80 years, poor health, Indications for Screening for Loss of Bone Mineral Density limited , poor vision, previous postmenopausal fracture, psychotropic drug Concerned perimenopausal woman willing to start drug therapy use) seems to be a stronger predictor of hip Radiographic evidence of bone loss fracture than low bone density.17 Indications Patient on long-term glucocorticoid therapy (more than one month of therapy for bone mineral density screening are out- at a dosage of 7.5 mg [or higher] of prednisone per day) lined in Table 5.18 Asymptomatic hyperparathyroidism where osteoporosis would suggest Plain radiographs are not sensitive enough parathyroidectomy to diagnose osteoporosis until total bone den- Monitoring therapeutic response in women undergoing treatment for sity has decreased by 50 percent, but bone osteoporosis if the result of the test would affect the clinical decision densitometry is useful for measuring bone density and monitoring the course of ther- Information from AACE Clinical practice guidelines for the prevention and treat- apy19 (Table 5).18 Single- and dual-photon ment of postmenopausal osteoporosis. Endocrin Pract 1996;2(2):157-71. absorptiometry have been used in the past but provide poorer resolution, less accurate analysis and more radiation exposure than x- causes of altered bone metabolism.14-16 For ray absorptiometry. example, measures of bone turnover increase The most widely used techniques of assess- and remain elevated after menopause but do ing bone mineral density are dual-energy not necessarily provide information that can x-ray absorptiometry (DXA) and quantita- direct management. tive computerized tomography (CT).20 These methods have precision error rates of 0.5 to BONE DENSITY MEASUREMENT 2 percent. Of these methods, DXA is the most Controlled trials have yet to prove that precise and the diagnostic measure of women who receive bone density screening choice.21 Quantitative CT is the most sensitive have better outcomes (i.e., improved bone method but results in substantially greater density or fewer falls) than women who are radiation exposure than DXA. not screened. The U.S. Preventive Services Smaller, less expensive systems for assessing Task Force suggests that the primary argu- the peripheral skeleton are now available. ment for screening is that postmenopausal These include DXA scans of the distal fore- women with low bone density are at arm and the middle phalanx of the nondom- increased risk for subsequent fractures of the inant hand, and a variety of devices for hip, vertebrae and wrist, and that interven- obtaining quantitative ultrasound measure- tion can slow the decline in bone density after ments on bone. The predictive value of these peripheral measures in assessing fracture risk at the hip or vertebrae is not clear. Ideally, baseline measurements should be taken at a The Author central and a peripheral site. If follow-up measurements are needed to monitor ther- JEANNETTE E. SOUTH-PAUL, COL, MC, USA, is professor and chair of the Department of Family Medicine at the Uniformed Services University of the Health Sciences, F. apy, the peripheral scans can be compared Edward Hébert School of Medicine, Bethesda, Md. She graduated from the University with the original measurements. Follow-up of Pittsburgh (Pa.) School of Medicine and completed a family practice residency at the measures must be obtained using the same Eisenhower Army Medical Center, Ft. Gordon, Ga., and a fellowship in faculty devel- opment at the University of North Carolina at Chapel Hill. instruments to ensure reliability of data. Bone densitometry reports provide a T score Address correspondence to Jeannette E. South-Paul, M.D., Uniformed Services Uni- versity of the Health Sciences, 4301 Jones Bridge Rd., Bethesda, MD 20814-4799. (the number of standard deviations above or Reprints are not available from the author. below the mean bone mineral density for sex

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and race matched to young controls) or a Z score (comparing the patient with a population Dual energy x-ray absorptiometry is the diagnostic measure adjusted for age, sex and race). The bone min- of choice for osteoporosis. eral density result enables the classification of patients into three categories: normal, osteo- penic and osteoporotic. Normal patients need no further therapy; osteopenic patients should ing to postmenopausal women younger than be counseled, treated and followed so that no 65 years who have one or more risk factors for further bone loss develops; osteoporotic osteoporosis in addition to menopause. patients should receive active therapy aimed at 4. Recommend bone mineral density test- increasing bone density and decreasing fracture ing to all women 65 years and older regardless risk. Osteoporosis is the classification for a T of additional risk factors. score of more than 2.5 standard deviations 5. Advise all patients to obtain an adequate below the sex-adjusted mean for normal dietary intake of calcium (at least 1,200 mg young adults at peak bone mass.2 Z scores are per day), including supplements if necessary. of little value to the practicing clinician. 6. Recommend regular weight-bearing and Decisions to intervene in patients with muscle-strengthening exercise to reduce the osteoporosis reflect a desire to prevent early risk of falls and fractures. or continuing bone loss, a belief that there 7. Advise patients to avoid smoking and to can be an immediate impact on the patient’s keep alcohol intake at a moderate level (i.e., well-being and a willingness to comply with one drink or less per day for women and two the patient’s desires. Bone densitometry can drinks or less per day for men). assist in the decision-making process if the 8. Consider all postmenopausal women patient’s age confers risk, there are no mani- who present with vertebral or hip fractures to festations of disease and the decision point is be candidates for osteoporosis treatment. prevention versus treatment. Medicare cur- 9. Initiate therapy to reduce fracture risk in rently reimburses costs of bone densitome- women with bone mineral density T scores try when the conditions outlined in Table 6 21 below –2 in the absence of risk factors and in are met.

RECOMMENDATIONS FOR PREVENTION TABLE 6 Recognizing the variety of conditions con- Conditions Qualifying Patients for ferring risk of osteoporosis, the National Medicare Coverage of Densitometry Osteoporosis Foundation makes the follow- ing recommendations to physicians: Estrogen deficiency in a woman at clinical risk for 1. Counsel all women on the risk factors for osteoporosis osteoporosis. Osteoporosis is a “silent” risk Vertebral abnormalities (e.g., osteopenia, vertebral factor for fracture, just as is for fractures, osteoporosis) stroke; one out of two white women will have Long-term (more than 3 months’ duration) glucocorticoid therapy an osteoporotic fracture at some point in her Primary hyperparathyroidism lifetime. Monitoring to assess response to osteoporosis drug 2. Perform an evaluation for osteoporosis therapy on all postmenopausal women who present with fractures, using bone mineral density Adapted with permission from the National Osteo- (testing to confirm the diagnosis and deter- porosis Foundation. Retrieved October 2000, from mine the disease severity. http://www.nof.org. 3. Recommend bone mineral density test-

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8. Tresolini CP, Gold DT, Lee LS, eds. Working with patients to prevent, treat and manage osteoporo- Bone mineral density testing should be considered in sis: a curriculum guide for health professions. 2d women younger than 65 years who are at risk for ed. San Francisco: National Fund for Medical Edu- cation, 1998. osteoporosis and in all women older than 65. 9. Orwoll ES. Osteoporosis in men. Endocrinol Metab Clin North Am 1998;27:349-67. 10. Taxel P. Osteoporosis: detection, prevention, and treatment in primary care. Geriatrics 1998;53(8): women with T scores below –1.5 if other risk 22-33. 11. Cadogan J, Eastell R, Jones N, Barker ME. Milk factors are present. intake and bone mineral acquisition in adolescent 10. Pharmacologic options for osteoporosis girls: randomised, controlled intervention trial. BMJ prevention and treatment are hormone 1997;315:1255-60. 12. Hotta M, Shibasaki T, Sato K, Demura H. The impor- replacement therapy, alendronate (Fosamax) tance of body weight history in the occurrence and and raloxifene (Evista) for prevention; and recovery of osteoporosis in patients with anorexia calcitonin (Calcimar) for treatment.22 nervosa: evaluation by dual x-ray absorptiometry and bone metabolic markers. Eur J Endocrinol 1998;139:276-83. The opinions and assertions contained herein are the 13. Eisman J. Relevance of pregnancy and lactation to private views of the author and are not to be con- osteoporosis? Lancet 1998;352:504-5. strued as official or as reflecting the views of the Army 14. Kroger H, Reeve J. Diagnosis of osteoporosis in Medical Department or the Army Service at large. clinical practice. Ann Med 1998;30:278-87. 15. Assessment of fracture risk and its application to REFERENCES screening for postmenopausal osteoporosis. Re- port of a WHO study group. World Health Organ 1. Melton LJ 3d, Chrischilles EA, Cooper C, Lane AW, Tech Rep Ser 1994;843:1-129. Riggs BL. Perspective. How many women have 16. Arnaud CD. Osteoporosis: using ‘bone markers’ for osteoporosis? J Bone Miner Res 1992;7:1005-10. diagnosis and monitoring. Geriatrics 1996;51 2. Scientific Advisory Board, Osteoporosis Society of (4):24-30. Canada. Clinical practice guidelines for the diag- 17. U.S. Preventive Services Task Force. Guide to clini- nosis and management of osteoporosis. CMAJ cal preventive services. 2d ed. Baltimore: Williams 1996;155:1113-33. & Wilkins, 1996. 3. Rosen CJ, Donahue LR. Insulin-like growth factors 18. AACE Clinical practice guidelines for the preven- and bone: the osteoporosis connection revisited. tion and treatment of postmenopausal osteoporo- Proc Soc Exp Biol Med 1998;219:1-7. sis. Endocrin Pract 1996;2(2):157-71. 4. Heaney RP. Pathophysiology of osteoporosis. 19. Genant HK. Current state of bone densitometry for Endocrinol Metab Clin North Am 1998;27:255-65. osteoporosis. Radiographics 1998;18:913-8. 5. National Osteoporotic Foundation, 1996 and 2015 20. Blake GM, Fogelman I. Applications of bone den- osteoporosis prevalence figures: state-by-state sitometry for osteoporosis. Endocrinol Metab Clin report. January 1997. Women’s Health Matters North Am 1998;27:267-88. 1998;2(3):1. 21. The National Osteoporosis Foundation. Retrieved 6. Cooper C. Melton LJ 3d. Epidemiology of osteo- October 2000, from http://www.nof.org. porosis. Trends Endocrinol Metab 1992;3:224-9. 22. National Osteoporosis Foundation. Physician’s 7. Harper KD, Weber TJ. Secondary osteoporosis. guide to prevention and treatment of osteoporosis. Diagnostic considerations. Endocrinol Metab Clin Washington, D.C.: the Foundation, 1998:1-2. North Am 1998;27(2):325-48.

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