Primary Care Reports January 13, 1997

Osteoporosis: Prevention and Treatment in the Primary Care Setting

Authors: Jany Moussa, MD, Post-Doctoral Research Fellow, Loma Linda University, Loma Linda, CA; Yvonne Elias, PharmD, Pharmacy Practice Resident, Loma Linda University, Loma Linda, CA; and Cesar Libanati, MD, Associate Professor of Medicine, Loma Linda University, Loma Linda, CA.

Peer Reviewer: Susan H. Allen, MD, Director, Kettering Osteoporosis Center, Kettering, OH.

Editor’s Note—Osteoporosis is a silent epidemic, affecting millions of men and women in the United States alone. Its cost to the health care system and negative effect on patient quality of life make it an important health care issue. Because of this, primary care physicians should be aware of proper screening techniques, in order to diagnose the problem before fractures occur, as well as therapeutic choices available. The following article presents an overview of both diagnostic and treatment options available for osteoporosis.

Introduction

Osteoporosis is a systemic progressive disease characterized by a decrease in the density (mass/unit volume) of normal bone. In osteoporosis, normal bone becomes increasingly porous and thin. This leads to a decrease in bone strength and subsequently an increased susceptibility to fracture with little or no trauma.1

Primary osteoporosis refers to that which occurs as a consequence of age-related bone loss in men or women or as a consequence of estrogen deficiency in post-menopausal women.2 Secondary osteoporosis may occur as the result of various endocrine diseases, metabolic causes, drugs, nutritional conditions, or collagen disorders. (See Table 1.)

Epidemiology

In the United States alone conservative estimates place the burden of osteoporosis at 25 million women, of which at least 8 million have documented osteoporosis with fracture.3 The annual incidence of osteoporotic fractures is 1.5 million (700,000 vertebral fractures; 250,000 fractures of the distal forearm; 250,000 hip fractures; and 300,000 fractures of other sites combined).4 A 50-year-old Caucasian women has a 40% lifetime risk of suffering an osteoporotic fracture.3 Osteoporotic fractures are more prevalent in whites than in blacks, and in women than in men, probably due to the fact that blacks and males achieve higher peak bone densities than whites and females, respectively, and that age related bone loss accelerates in females during menopause due to the decrease in estrogen levels. The female-to-male fracture ratios are reported as 7:1 for vertebral fractures; 1.5:1 for distal forearm fractures; and 2:1 for hip fractures.5

Estimating the financial burden of osteoporosis is difficult because expenses include acute hospital care related to fracture occurrence as well as chronic care associated with long-term care facility costs. The total cost of treating osteoporosis annually in the United States is calculated in the order of $7-10 billion, undoubtedly making osteoporosis a serious and costly public health issue.

Pathophysiology

Osteoporosis denotes an increased likelihood for fractures due to decreased bone density. Bone density at any time during adult life is the result of peak bone density minus accumulated bone loss. By the end of the second decade of life, almost 98% of peak bone density has been achieved.6,7 Bone loss at a rate of 0.5-1.0% per year develops after the third decade of life. Age-related bone loss is associated with calcium malabsorption leading to secondary hyperparathyroidism and with a decline in growth factors at both the endocrine and the local tissue levels.8 This decline in systemic and local growth factors potentially leads to a decrease in bone formation and an imbalance between bone accretion and bone resorption. Resorptive processes can be further influenced by deficiencies in hormones including estrogen, androgens, and growth hormone; deficiency of calcium or weight-bearing exercise; and an excess of glucocorticoid.

In females, bone loss accelerates during the menopause due to declining estrogen levels.9,10 Estrogen exerts its effect on bone partly via estrogen receptors located on osteoblasts. Stimulation of these receptors results in the inhibition of the production of several cytokines including interleukin-1 (IL-1), TNF alpha, GM-CSF, and IL-6, from peripheral monocytes or from osteoblasts.11 There is accumulating evidence that these cytokines mediate both normal and abnormal bone remodeling and thus are implicated in the pathways leading to increased bone resorption. Thus, during a state of estrogen deficiency, such as the menopause, cytokines may increase leading to increased osteoclastic activity and subsequent bone loss.

Risk Factors

Female gender, petite body frame, Caucasian or Asian race, sedentarism, nulliparity, post-menopausal status, lifelong history of low calcium intake, smoking, excessive alcohol consumption, and long-term use of certain medications (i.e., corticosteroids, phenytoin, high-dose thyroid replacement) have long been accepted as major risk factors for developing osteoporosis. A recent study reported the sensitivity and specificity of variables obtained by a questionnaire to determine the likelihood of predicting a true positive or a true negative densitometric diagnosis of osteoporosis in women. Of the large number of variables assessed, only six variables (age, weight, race, prior fracture history, coexisting rheumatoid arthritis and history of estrogen replacement therapy) were modeled into a screening tool, the "Score" questionnaire, to help identify patients most likely to benefit from bone density evaluation. (See Table 2.) The use of this tool for screening for indication of bone density testing resulted in a 90% sensitivity and a 40% specificity when patients with a score above 6 are referred for densitometry.12 This simple tool can be modified to meet different sensitivity and specificity thresholds in order to help reduce the potential large cost of screening massive number of subjects.Although low bone density is the major determinant for fracture risk other factors such as propensity to fall, greater height, and presence of prior fractures also influence the likelihood of a fracture.

Clinical Manifestations

Osteoporosis is often referred to as the "silent epidemic" because bone loss may not be associated with any clinical symptoms until a fracture develops. The only "early" symptom of osteoporosis may be the development of upper or mid-thoracic back pain associated with activity, aggravated by long periods of sitting or standing, and easily relieved by rest in the recumbent position. This pain may be due to microfractures from trabecular discontinuation leading to microarchitectural damage in the vertebral bodies. Accumulated microdamage may lead to the development of clinical fractures at the spine. Common osteoporotic fracture sites include: the vertebrae, the forearm, the femoral neck, and the proximal humerus.

When a vertebral compression fracture occurs, usually in the mid-thoracic or the high lumbar regions, the patient can commonly pinpoint the exact area of fracture and onset of pain. The course of back pain usually begins as intense and severe, persisting for 2-3 weeks, followed by a period of gradual regression over 3-4 months. Pain may evolve into a chronic condition limiting the patient’s ability to function or may resolve completely.13 Unfortunately, once a vertebral fracture has occurred the risk for further fractures increases irrespective of the bone density.

Dorsal kyphosis (dowager’s hump) is the result of multiple anterior compression fractures of the thoracic spine. Thus, the presence of dorsal kyphosis, and its associated loss of height, denotes severe osteoporosis irrespective of the bone density level.

Hip fractures are a serious complication of osteoporosis. In the first six months following a hip fracture, the mortality rate may be as high as 20%. Furthermore, up to 50% of patients suffering a hip fracture will be unable to walk or perform activities of daily living without assistance, as a consequence of the fracture, and 25% will require long-term care adding to the cost of this disease and underscoring its morbidity.14-16

Diagnosis

The strategy for the diagnosis and therapeutic intervention of osteoporosis is based on the assessment of the type and degree of bone loss and in ruling out secondary forms of osteoporosis. With the advent and availability of bone density testing, we can now determine the risk for fracture in an individual patient much like we can determine the risk for stroke or heart disease from blood pressure or cholesterol measurements. In fact, the relationship between bone density and fracture risk is stronger than the widely accepted relationship between cholesterol and coronary artery disease.17 Today, patients at risk for fracture (i.e., low bone density) can be identified, and treatment instituted, before fractures occur. Bone density can be assessed by a number of different techniques such as single X-ray absorptiometry, radiogrametry, dual X-ray absorptiometry, and quantitative computed tomography. Dual X-ray absorptiometry (DXA) has rapidly become the standard for clinical testing largely due to the fact that this technique is highly reproducible and allows measurements of bone density at both the spine and the hip, the sites of clinical relevance in osteoporosis.18

In addition to bone density testing, which will be further discussed below, physical evaluation, laboratory testing, and plain radiography are part of the tools available for the evaluation of osteoporosis.

The initial step in the evaluation of patients for osteoporosis is obtaining a complete medical history, physical, and gynecological examinations. The disease states and drugs listed in Table 1 may give rise to secondary osteoporosis and must be ruled out before a diagnosis of primary osteoporosis is made. This can be accomplished by a thorough medical history and a few basic laboratory tests including a complete blood count, serum chemistry group (chem 20), urinalysis, and thyrotropin. If suggested by the findings in the history or the physical examination, the following diagnostic tests may be indicated as well: erythrocyte sedimentation rate, serum parathyroid hormone concentration, serum 25-hydroxyvitamin D concentration, 24-hour urinary calcium excretion, serum/urine protein electrophoresis, or bone marrow examination/biopsy.

Radiographic studies of the thoracic and lumbar spine may show the presence of one or more compression fractures (a fracture is defined as a ³ 20% difference between anterior and posterior vertebral heights or between adjacent vertebral body measurements) or significant osteopenia. While it is true that the presence of a vertebral fracture in an x-ray will correctly identify the patient as suffering from osteoporosis, plain radiography is not sensitive enough for osteoporosis screening since bone loss is only apparent in an x-ray after 30% bone loss or more has occurred.19

The use of biochemical markers of bone formation (i.e., alkaline phosphatase, osteocalcin) or bone resorption (urinary hydroxyproline or collagen cross links such as pyridinoline and deoxypyridinoline) outside of research studies is still limited by the large diurnal variation or the poor reproducibility (15-20%) of most markers. The lack of predictive value of these markers to assess present skeletal status or determine prospective bone loss further questions their utility in the individual patient. Consequently, no established guidelines exist for the use of these biochemical markers in the diagnosis or monitoring of osteoporotic patients.20

The pivotal test for the diagnosis of osteoporosis is a measurement of bone density. Because bone loss can be asymptomatic and since no risk factor(s) can accurately identify all patients at risk for developing the disease, bone density should be considered for all females during their peri-menopausal years. When this general approach cannot be accomplished, the following indications for bone density should be adhered to: a) screening concerned peri- or post-menopausal women who are willing to start therapy based on the result of the test; b) women with bone loss suggested by plain radiographic studies; c) patients beginning or receiving long-term glucocorticoid therapy (defined as more than 1 month at a dose of ³ 7.5 mg of prednisone per day); d) patients with asymptomatic primary hyperparathyroidism in whom evidence of osteoporosis would lead to recommendation for parathyroidectomy; and e) for monitoring therapeutic response in women undergoing treatment for osteoporosis if the result of the test would affect the clinical decision (i.e., stopping therapy, changing dosage, or switching agents).21

The density test result enables the classification of patients in three categories: normal, osteopenic, and osteoporotic patients. (See Table 3.) Bone density is commonly expressed in terms of T-score units. The T-score can be calculated for any measured bone density and is the distance of the measured density from the peak young adult bone density expressed in terms of units of standard deviation for the same young population. T-scores not only allow for direct comparison of bone densities between different densitometers but, more importantly, provide a rapid assessment of fracture risk. Roughly, fracture risk doubles for each unit decrease in the T-score. Patients with normal density may not need to worry about osteoporotic fractures and may not require any form of pharmacological intervention (estrogen replacement therapy after menopause may still be advisable based on cardiovascular risk profile).

Subjects with osteopenia should be carefully counseled, treated, and followed such that no further bone loss develops. Finally, patients with osteoporosis require active therapy aimed at increasing bone density and decreasing fracture risk.

Treatment Strategies

The main objective in the treatment of osteoporosis is the prevention of fractures. This goal can be accomplished by achieving the highest possible peak bone density at maturity and by preventing bone loss afterwards. The two major factors affecting peak bone density are genetic and environmental. While our understanding of the genetic contribution to peak bone density is still limited and not yet amenable to manipulation, environmental influences can be modified to attempt to maximize skeletal density and minimize bone loss. A well-balanced diet including sufficient intake of calcium should be encouraged, particularly during the adolescent years. Weight-bearing exercise and avoidance of alcohol, tobacco products, and drugs not only benefits bone development but the body as a whole. Clearly, the above lifestyle modifications can be described in two words: healthy lifestyle. Unfortunately, although this "healthy lifestyle" should be adhered to, its exact contribution to maximizing peak bone density has not been established but is probably modest.

As previously mentioned, the pathophysiology of primary osteoporosis is bone loss that begins after peak bone density is achieved and accelerates during menopause, with the greatest bone loss occurring in the first 5-7 menopausal years. Estrogen is the only agent currently approved by the Food and Drug Administration for the prevention of postmenopausal osteoporosis. In addition to estrogen, alendronate (FOSAMAX), and calcitonins are available for the treatment of this disease once it has been established by densitometry or by the presence of fractures. Nutritional supplements including calcium and vitamin D are also approved to use in osteoporotic patients. Recently, the American Associateion for Clinical Endocrinologists published clinical guidelines for the treatment of osteoporosis.22 Similarly, guidelines from the National Osteoporotic Foundation are expected soon.

Estrogen. Post-menopausal osteoporosis occurs as a result of increased bone resorption due to estrogen deficiency. Accordingly, estrogen replacement therapy (ERT) has logically been the standard of practice for the prevention and treatment of osteoporosis. ERT should be considered for all women with estrogen deficiency who have no contraindications. Contraindications to estrogen administration include: family or individual history of breast cancer, estrogen dependent neoplasia, undiagnosed abnormal genital bleeding, and a history of or active thromboembolic disorder.

The greatest benefit from estrogen is derived if ERT is begun early because the greatest rate of bone loss occurs in the first years after cessation of ovarian function.23,24 When therapy is begun after the age of 75, the observed benefits of estrogen on bone may be decreased because a significant degree of bone loss may have already accumulated from aging and from the years of estrogen deficiency. Several small studies show a lower incidence of fractures in osteoporotic women treated with estrogen.25-28 The estimated reduction in fracture risk, derived mainly from epidemiological data, varies between 20% and 60%. The greatest benefit from estrogen therapy may occur if estrogen is used for 10 years or longer.28 Because the few placebo-controlled studies with estrogen have shown only modest (£ 3%) increases in bone density, it is not clear if the decrease in fracture risk associated with estrogen replacement therapy is entirely due to the effect on bone density alone. It is also not clear if the protective effect is maintained after estrogen discontinuation.

A very important characteristic of estrogen replacement therapy is that the clinical benefits extend beyond the skeletal system. Estrogen replacement results in a favorable effect on the lipid profile by causing a significant increase in serum high-density lipoprotein and significant decreases in serum total cholesterol and low density lipoproteins.29,30 Accordingly, estrogen replacement therapy is associated with a decreased incidence of cardiovascular disease, reducing the mortality from cardiovascular causes by one-third to one-half.31,32 Finally, estrogen benefits post-menopausal women by reducing the symptoms of menopause.

ERT is not, however, without side effects. Unopposed estrogen therapy is associated with increased risk of endometrial hyperplasia and cancer. In all women with an intact uterus, estrogen therapy must be accompanied by a progestin since combined estrogen/progestin regimens reduce the risk of endometrial hyperplasia to that of women not taking estrogen. From a clinical standpoint, we find that two other side effects associated with estrogen replacement limit the patient’s acceptance of this form of therapy: irregular vaginal bleeding in women with an intact uterus receiving combination cyclic estrogen/progestin therapy and mastalgia. Vaginal bleeding diminishes over time, and most women will become amenorrheic within one year on continuous combination therapy. Mastalgia, like fluid retention, may be controlled by a reduction in dosage. Unfortunately, the protective effect on bone density may not be maintained when the estrogen dose is reduced, and, too commonly, these side effects lead to poor compliance or discontinuation of therapy.

The greatest controversy with the use of estrogen replacement therapy is the potential increased risk of breast cancer. Prolonged use of estrogen (10-15 years) along with aging may increase the risks of breast cancer by 10-30%.33 A recent prospective study further demonstrates the potential link between estrogen levels, breast cancer risk, and skeletal status. Subjects with bone density at the top quartile had more than a two-fold greater risk of breast cancer than matched females who had bone density at the lowest quartile. These data suggest that a higher lifetime estrogen exposure, beneficial to bone, would be detrimental to breast cancer risk. This interesting and logical observation raises the concern that the protective effect on breast cancer associated with poor bone density could be lost if long-term ERT is administered to women with severe osteoporosis and that the risk for breast cancer derived from studies of osteoporotic patients receiving estrogens may have underestimated the actual risk for patients with normal or near normal bone density receiving estrogen therapy. Although the addition of a progestin does not appear to influence breast cancer risk, long-term data on breast cancer and the use of estrogen and progesterone, in general or in the subset of patients with severe osteoporosis, are not available.

Several protocols exist for the dosage and administration of estrogen replacement therapy for the prevention or the treatment of osteoporosis. For the prevention of post-menopausal osteoporosis, the estrogen dose should be sufficient to halt bone loss. The usually prescribed dose of 0.625 mg of conjugated estrogens may not be sufficient to accomplish that goal in many post-menopausal women. For the treatment of post-menopausal osteoporosis doses of 0.625-1.25 mg/d of conjugated estrogens are most commonly recommended. As stated above, patients with an intact uterus should receive 2.5-5.0 mg medroxyprogesterone in conjunction with estrogen. Continuous daily estrogen therapy decreases the symptoms of estrogen deficiency and also promotes patient compliance, but intermittent regimens provide similar effect on bone. Several preparations are marketed including tablets, depo-injection, and transdermal delivery systems. The route of administration does not seem to affect the efficacy of estrogen. The recommended duration of hormonal replacement therapy is at least 10 years, but preferably lifelong since bone loss rapidly resumes after estrogen discontinuation.

Follow-up of patients on estrogen should include regular gynecological and breast exams. Follow-up of bone density in patients receiving ERT needs to be individualized. The recommendation to repeat the bone density measurement 1-2 years after starting therapy depends on the baseline bone density: females with significant osteopenia at baseline should be closely followed to prevent further bone loss. In this subgroup of women, a repeat bone density would identify the subset of patients who continue to lose bone at the commonly prescribed 0.625 mg conjugated estrogen dosage. A higher estrogen dose or switching to alendronate therapy should be considered in these patients.

Alendronate (FOSAMAX). Alendronate is an oral bisphosphanate recently approved for the treatment of primary osteoporosis in postmenopausal women. Alendronate exerts its effect on bone by inhibiting osteoclast mediated bone resorption. It preferentially deposits in sites of high bone turnover. Because of its chemical structure, alendronate is 200-1000 times more potent than etidronate (occasionally used "off-label" for osteoporosis in the United States) in inhibiting bone resorption; therefore, lower doses inhibit bone resorption without affecting bone mineralization.

Alendronate therapy, given continuously for three years, has been shown to be effective in achieving bone stabilization and in increasing bone density and decreasing fracture risk in women 35 Contrary to what would be expected, the increase in bone density due to alendronate does not appear to be affected by age, the pretreatment bone turnover level, or the baseline bone density.

The results of the Fracture Intervention Trial, a prospective, randomized, placebo-controlled study designed to determine the efficacy of alendronate in reducing fracture risk in almost 6000 women 55-80 were recently released. This large study confirmed the effect of alendronate therapy as an effective agent to reduce the incidence of new vertebral and hip fractures by about 50% in osteoporosis.36 The importance of these data is underscored by the fact that this is the first prospective, placebo-controlled study designed with enough power to detect statistically significant differences in fracture rate at the hip between treatment groups.

In the treatment of postmenopausal osteoporosis, alendronate is administered orally at a dose of 10 mg/d. Patients should be instructed to take the pill in the morning with 1-2 glasses of water, at least half an hour before food or beverages. Because the absorption of bisphosphonates is very small and because this group of drugs binds very tightly to other compounds, it is very important that no other medication be taken at the same time, particularly not any calcium preparation. Patients should also be instructed against lying down for a 30-minute period after taking alendronate to avoid gastro-esophageal reflux and consequent esophagitis.

Because alendronate exerts its action in the skeletal system exclusively, the side effect profile is low and limited to the gastrointestinal tract. Until an enteric coated formulation becomes available, alendronate should be given with extreme caution to patients with a history of dysphasia, esophageal problems, gastritis, duodenitis, or ulcers since adverse effects such as esophageal or gastric ulcers and gastrointestinal bleeding could develop. Alendronate is not recommended for use in patients with severe renal insufficiency or hypocalcemia. No dose adjustment is required for patients with mild renal insufficiency. Alendronate has no known drug interactions since it is not metabolized by the liver and is not protein bound.

No guidelines exist yet for the follow-up of bone density in patients receiving alendronate, but the fact that the majority of patients respond to therapy with an increase in bone density supports the concept that follow-up of bone density may not be routinely required for all patients. Careful determination of the patient’s height at baseline and during therapy provide an alternative economic and fairly precise estimate of clinical response. Patients responding to therapy typically maintain their standing height.

Finally, alendronate, at half the dose recommended for the treatment of osteoporosis, was recently shown to have similar efficacy to estrogen for the prevention of bone loss and may soon become an available alternative for the prevention of osteoporosis in postmenopausal women.37 Studies evaluating the efficacy of alendronate for male osteoporosis and for secondary forms of osteoporosis such as glucocorticoid-induced osteoporosis are currently being performed.

Calcitonin. Calcitonin is a hormone produced by the parafollicular cells of the thyroid gland in humans. Analogous hormones are produced by birds and fish. The observation that calcitonin functions in calcium homeostasis by directly inhibiting osteoclastic bone resorption led to the development of this hormone for the treatment of osteoporosis. Commercially available calcitonins include salmon calcitonin (injectable and nasal spray) and human calcitonin (injectable only). A unique characteristic of calcitonin is that it produces an analgesic effect with respect to bone pain. This is among the reasons why it is often prescribed for patients who have suffered an acute osteoporotic fracture.38-40

In the treatment of osteoporosis, salmon calcitonin may be given as either 50 IU or 100 IU intramuscularly or subcutaneously daily or every other day,41 or as 200 IU intranasally every day.42 For reasons still poorly understood, the increase in bone density associated with calcitonin administration may be transient.43,44 This led to the concept that resistance to calcitonin may develop over time. In an attempt to prevent the development of resistance, several investigators administer calcitonin in a cyclic manner (i.e., 3 months on, 1 month off). These regimens are based on theoretical, not yet proven, strategies. Calcium supplementation at a dose of 1000 mg/d, and vitamin D (400 IU/d) should be given during calcitonin treatment.

Regardless of the treatment regimen, the effect of calcitonin to increase bone density appears to be significantly less than that achieved by alendronate or even estrogen and may be limited to the spine. Additionally, despite 20 years of experience, the efficacy of calcitonin to decrease fracture risk has not been clearly established. Ongoing prospective studies will hopefully answer this important question about calcitonin efficacy in the months to come.

Currently, calcitonin is an alternative to estrogen and alendronate therapy in women who cannot tolerate or refuse these therapies. It is generally well-tolerated with minimal adverse effects. Common side effects experienced in up to 50% of patients receiving parenteral therapy include: transient vasomotor symptoms (i.e., flushing of face and hands), dizziness, nausea and vomiting, and injection site reactions. Side effects seen in patients receiving nasal therapy are limited to nasal irritation and congestion. Because of the possible, albeit rare, allergic reaction to salmon calcitonin, a skin test should be done before initiation of parenteral therapy.

Calcium and Vitamin D Supplementation. Calcium supplementation 1000-1500 mg/d along with 400 IU vitamin D daily have been shown to reduce the rate of bone loss in women greater than five years post-menopause and should be given concomitantly with estrogen, alendronate, or calcitonin. Calcium and vitamin D are nevertheless inadequate, when given alone, to prevent the development of clinically significant bone loss in the majority of postmenopausal women.

Because secondary hyperparathyroidism from calcium malabsorption may contribute to the pathogenesis of senile bone loss, calcium and vitamin D supplementation in the elderly may proven more beneficial. A study in elderly women, 75 years of age or older, documented a reduction in the incidence of vertebral and hip fractures when calcium and 800 IU of vitamin D were administered daily.45 This combination therapy was not associated with major side effects and may be cost-effective, particularly in the institutionalized elderly patient.

The most common side effects encountered with calcium supplementation are constipation and gastrointestinal upset. These side effects can be minimized, and calcium absorption increased, by taking calcium with food.

Exercise. Weight-bearing exercise is recommended for the maintenance of bone mineral density in the prevention and treatment of osteoporosis. Weight-bearing stress helps not only in maintaining the quality and quantity of bone, but also increases muscle mass and tone which, in turn, improves balance and thus prevents falls. We routinely recommended that our patients engage in daily weight-bearing exercises such as low impact aerobics or weightlifting exercises. Back extension and isometric abdominal exercises are beneficial. Exercise routines that involve flexion of the thoraco-lumbar spine should be avoided because they could precipitate a fracture event, particularly in the very osteoporotic individual. The addition of a daily 30-minute walk has the added benefit of exposing the body to sunlight and increasing production of vitamin D. The input and help from a physical therapist may be beneficial to patients with severe osteoporosis.

Conclusion

While osteoporosis is a silent epidemic, often not diagnosed until the time of fracture, its cost to the healthcare system and its negative effect on patient quality of life make it a significant health care issue. Screening is justified for those reasons and because therapies are now available to increase bone density and reduce fracture risk. Diagnosis is established by the presence of fragility fractures or, ideally, by a low bone density before fractures occur. The dual energy x-ray absorptiometry scan has rapidly become the standard by which to measure bone density at the spine and at the hip, assess fracture risk and determine the need for pharmacological intervention. With respect to pharmacological therapy, estrogen remains the first-line treatment and standard of practice. However, a significant number of patients may continue to lose bone while receiving estrogen. For these patients, as well as for those patients who refuse or have contraindications to ERT, alendronate and calcitonin are therapeutic options now available. Because of its proven reduction in fracture risk, alendronate may be favored over estrogen in the patient with severe bone loss or once fractures have already developed.

References

1. Consensus Development Conference. Prophylaxis and treatment of osteoporosis. Am J Med 1991;90:107-110.

2. Riggs BL, et al. Changes in bone mineral density of the proximal femur and spine with aging. Differences between the postmenopausal and senile osteoporosis syndromes. J Clin Invest 1982;70:716-723.

3. Melton LJ, et al. How many women have osteoporosis? J Bone Miner Res 1992;7:1005-1010.

4. Kelsey JL. Prevalence and incidence, in Osteoporosis. Proceedings of the NIH Consensus Development Conference, April 2-4, 1984; pp 25-28.

5. Cooper C, Melton LJ, III. Epidemiology of osteoporosis. Trends Endocrinol Metab 1992;3:224-229.

6. Bonjour JP, et al. Critical years and stages of puberty for spinal and femoral bone mass accumulation during adolescence. J Clin Endocrinol Metab 1991;73:555-563.

7. Matkovic V, et al. Timing of peak bone mass in Caucasian females and its implication for the prevention of osteoporosis. J Clin Invest 1994;93:799-808.

8. Hilliker S, et al. The pathogenesis of primary osteoporosis. In: Slavkin H, Price P (eds). Chemistry and Biology of Mineralized Tissues. Elsevier Science Publishers; 1992:455-463.

9. Hui SL, et al. Effects of age and menopause on vertebral bone density. Bone Miner 1987;2:141-146.

10. Richelson LS, et al. Relative contributions of aging and estrogen deficiency to postmenopausal bone loss. N Engl J Med 1984;311:1273-1275.

11. Mudny GR, et al. Cytokines and bone remodeling. In: Marcus R, Feldman D, Kelsey J (eds). Osteoporosis Academic Press; 1996:301-313.

12. Lydick E, et al. Development and validation of a simple questionnaire to facilitate identification of women with low bone density. J Bone Mineral Res 1996;11:M746.

13. Ross PD, et al. Pain and disability associated with new vertebral fractures and other spinal conditions. J Clin Epidemiol 1994; 47:231-239.

14. Miller CW. Survival and ambulation following hip fracture. J Bone Joint Surg 1978;60A:930-934.

15. Jensen JS, Bagger J. Long-term social prognosis after hip fractures. Acta Orthop Scand 1982;53:97-101.

16. Konar SK, et al. Factors associated with short- vs. long-term skilled nursing facility placement among community-living hip fracture patients. J Am Geriatr Soc 1990;38:1139-1144.

17. Ettinger B, et al. Reduced mortality associated with long-term postmenopausal estrogen therapy. Obstet Gynecol 1996;87:6-12.

18. Wahner HW. Use of densitometry in management of osteoporosis. In: Marcus F, Feldman D, Kelsey J (eds). Osteoporosis Academic Press; 1996:1055-1074.

19. Finsen V, Anda S. Accuracy of visually estimated bone mineralization in routine radiographs of the lower extremity. Skeletal Radiol 1988;17:270-275.

20. Delmas PD, Garnero P. Utility of biochemical markers of bone turnover in osteoporosis. In: Marcus F, Feldman D, Kelsey J (eds). Osteoporosis Academic Press; 1996:1075-1088.

21. Johnston CC, et al. Clinical indications for bone mass measurements. A report from the Scientific Advisory Board of the National Osteoporososis Foundation. J Bone Miner Res 1989;4:1-28.

22. American Association of Clinical Endocrinologists. Clinical practice guidelines for prevention and treatment of postmenopausal osteoporosis. Endocrine Practice, Vol. 2 No. 2; March-April 1996.

23. Lindsey R, et al. Prevention of spinal osteoporosis in oophorectomized women. Lancet 1980;2:1151-1153.

24. Natchigall LE, et al. Estrogen replacement therapy. I. A 10-year prospective study in the relationship to osteoporosis. Obstet Gynecol 1979;53:277-281.

25. Weiss NS, et al. Decreased risk of fractures of the hip and lower forearm with postmenopausal use of estrogens. N Engl J Med 1980;303:1195-1198.

26. Williams AR, et al. Effect of weight, smoking, and estrogen use on the risk of hip and forearm fractures in postmenopausal women. Obstet Gynecol 1982;60:695-699.

27. Ettinger B, et al. Long-term estrogen replacement therapy prevents bone loss and fractures. Ann Intern Med 1985;102:319-324.

28. Cauely JA, et al. Estrogen replacement therapy and fractures in older women. Ann Intern Med 1994;122:9-16.

29. Lobo RA, et al. Metabolic impact of adding medroxyprogesterone acetate to conjugated estrogen therapy in postmenopausal women. Obstet Gynecol 1994;84:987-995.

30. The Postmenopausal Estrogen/Progestins Interventions (PEPI) Trial. Effects of estrogen or estrogen/progestin regimens on heart disease risk factors in postmenopausal women. JAMA 1995; 273:199-208.

31. Stampfer MJ, et al. Postmenopausal estrogen therapy and cardiovascular disease: Ten-year follow-up from the Nurses’ Health Study. N Engl J Med 1991;325:756-762.

32. Hunt K, et al. Mortality in a cohort of long-term users of hormone replacement therapy: An updated analysis. Br J Obstet Gynaecol 1990;97:1080-1086.

33. Hulka BS. Hormone-replacement therapy and the risk of breast cancer. Cancer 1990;40:289-296.

34. Boonekamp PM, et al. Two modes of action of biphosphonates on osteoclastic resorption of mineralized matrix. Bone Miner 1986;1:27-39.

35. Liberman U, et al. Effect of oral alendronate on bone mineral densty and the incidence of fractures in postmenopausal osteoporosis. N Engl J Med 1995;333:1437-1443.

36. Black DM, et al. Alendronate reduces risk of vertebral and clinical fractures: Results of the fracture intervention trial. J Bone Mineral Res 1996;11:P242.

37. Hosking DJ, et al. J Bone Mineral Res 1996;11:153.

38. Gennari C, et al. Use of calcitonin in the treatment of bone pain associated with osteoporosis. Calcif Tissue Int 1991;49:S9-S13.

39. Lyritis GP, et al. Analgesic effect of salmon calcitonin in osteoporotic vertebral fractures: A double-blind placebo-controlled clinical study. Calcif Tissue Int 1991;49:369-372.

40. Pun KK, Chan LW. Analgesic effect of intranasal salmon calcitonin in the treatment of osteoporotic vertebral fractures. Clin Ther 1989;11:205-209.

41. Civitelli R, et al. Bone turnover in postmenopausal osteoporosis: Effect of calcitonin treatment. J Cin Invest 1988;82:1268-1274.

42. Overgard K, et al. Nasal calcitonin for treatment of established osteoporosis. Clin Endocrinol 1989;30:435-442.

43. Gruber HE, et al. Long-term calcitonin therapy in postmenopausal osteoporosis. Metabolism 1984;33:295-303.

44. Overgaard K, et al. Effect of salcatonin given intranasally on bone mass and fracture rates in established osteoporosis. A dose-response study. BMJ 1992;305:556-561.

45. Chapuy MC, et al. Vitamin D3 and calcium to prevent hip fractures in elderly women. N Engl J Med 1992;327:1637-1642.

Physician CMEQuestions

1. The main objective in the treatment of osteoporosis is:

a. to ease the spinal pain.

b. to prevent fracture.

c. to increase exercise tolerance.

d. to increase bone density.

e. cosmetic improvement.

2. Which of the following statements is not correct?

a. Patients should be instructed to take alendronate in the morning with breakfast.

b. Calcitonin has an analgesic effect on spinal osteoporotic pain.

c. A common side effect associated with calcium supplementation is constipation.

d. Estrogen replacement therapy is associated with a decreased incidence of cardiovascular disease.

e. Alendronate therapy was shown to reduce fracture risk at the spine and at the hip.

3. Which of the following is not a risk factor for osteoporosis?

a. Female gender

b. Petite body frame

c. Postmenopausal status

d. Multiparity

e. Caucasian race

4. Which bone densitometry statement is/are most appropriate?

a. Bone density studies are research tools used only to evaluate new drugs for osteoporosis.

b. Bone density testing can accurately identify subjects at risk for osteoporotic fractures.

c. Only patients who have suffered a fracture should be referred for bone density testing.

d. The majority of patients require a follow-up bone density within one year of starting therapy.

e. All of the above

5. Which of the following is/are true?

a. Normal bone density is defined by a T-score equal to or greater than -1.

b. Osteopenia is defined by a T-score between -1 and -2.5.

c. Osteoporosis is defined by the presence of fractures or by a T-score below -2.5.

d. Osteoporotic fractures are more common in whites than blacks and in women than men.

e. All of the above