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Mohammad Masud Iqbal, MD, MPH, MSPH, Department of Epidemiology and International Health, School of Public Health, University of Alabama at Birmingham
Abstract Osteoporosis is an important health problem in the United States affecting approximately 24 million Americans, 15 to 20 million of whom are women over 45 years of age. Bone fractures are the major cause of morbidity and mortality associated with osteoporosis. The most common fractures are those of the forearm, hip, and vertebral body, as well as the humerus, tibia, pelvis, and ribs. Osteoporosis-related injuries result in complications leading to prolonged hospitalization, decreased independence, increased incidence of depression, and a reduced quality of life. The disease takes an enormous personal and economic toll, with estimated costs in excess of $13.8 billion annually for direct medical treatment. The incidence of osteoporosis-related fractures is increasing and constitutes a major public health problem in the United States. With a few preventive measures such as identification of risk factors, careful examination, and a few simple diagnostic tests, prevention of osteoporosis during the teen and early adult years is far superior to any treatment for older individuals. Osteoporosis can be identified and an appropriate treatment strategy can be determined. Introduction Osteoporosis is a systemic disorder characterized by decreased bone mass and microarchitectural deterioration of bone tissue leading to bone fragility and increased susceptibility to fractures of hip, spine, and wrist. Osteopenia has been defined as the appearance of decreased bone mineral content on radiography, but the term more appropriately refers to a phase in the continuum from decreased bone mass to fractures and infirmity. By the time the diagnosis of osteopenia is made radiographically, significant and irreversible bone loss has already occurred. The most common cause of osteopenia is osteoporosis; other causes include osteomalacia and the bone disease of hyperparathyroidism. Epidemiology As the average age of the world's population shifts upward, the incidence and prevalence of osteoporosis and its economic burden on society will increase further. Surveys based on data from developed countries show that the number of individuals aged 45 years and older increased from about 155 million in 1960 to 206 million in 1980. This number can be expected to rise to 257 million by the year
2000. This trend is true not only for industrialized countries, but also in the developing countries. The world population of women older than 45 is therefore set to more than double in this time. More than 200 million women worldwide have osteoporosis. Estimates indicate that the number of osteoporotic hip fractures occurring in the world each year will rise from 1.66 million to 6.26 million by the year 2050, thereby implying an urgent need for preventive strategies. In the United States, osteoporosis is a major public health threat for 24 million Americans, 80% of whom are women. Ten million individuals already have osteoporosis, and 14 million more have low bone mass, placing them at increased risk for this disease. Osteoporosis is responsible for more than 1.5 million fractures annually, among them more than half a million vertebral fractures, 300,000 hip fractures, 200,000 wrist fractures, and 300,000 fractures of other sites. Approximately 37,500 people die each year after complications related to osteoporotic fracture. Osteoporosis also caused more than 44 million patient-days in nursing homes and an estimated $13.8 billion in annual health care expenditures in 1995.[4,5] The direct medical costs associated with hip fractures among men and women have been estimated to be between $5.4 billion and $7.4 billion. Costs will escalate as the proportion of elderly in the population increases; costs of hip fractures are projected to reach $62 billion in the United States by the year 2020. According to one projection, demographic changes alone could lead to an increase in the number of hip fractures annually to 840,000 by the year 2040.
In the United States, roughly 1 in 4 women more than age 50 has osteoporosis. The overall prevalence of osteoporotic fractures rises dramatically in menopausal women. Bone loss is more abrupt for the first decade after the onset of menopause, followed by more gradual loss thereafter. With increasing age, fracture incidence increases. The frequency of hip fractures increases
exponentially with age, particularly after age 70, and is more commonly seen in white women. About 32% of women who live to age 80 have hip fractures.[7,8] A woman's risk of a hip fracture equals the combined risk of breast, uterine, and ovarian cancer, and the risk of dying of hip fracture is equal to breast cancer mortality. The prevalence of vertebral fractures is 42% in women of advanced age and/or who have decreased bone mass. In women, a rapid rise of vertebral fractures, which is initially associated with the onset of menopause, is followed by an increase in the frequency of wrist and hip fractures due to age-related bone loss. Osteoporosis develops less often in men than women because bone loss starts later and progresses more slowly in men, and there is no period of rapid hormonal change and accompanying rapid bone loss. Differences in bone geometry and remodeling also contribute to the lower rate of fractures in men. However, in the past few years, the problem of osteoporosis in men has become recognized as an important public health issue, particularly in light of estimates that the number of men older than 70 will double between 1993 and 2050 according to the US National Osteoporosis Foundation.
Roughly 1 in 8 men more than 50 years old has osteoporosis. Presently, more than 2 million men in the United States are affected by osteoporosis, and another 3 million are at risk for this disease. Each year, men have one third of all hip fractures that occur, and one third of these men will not survive more than a year. The frequency of hip fracture increases exponentially with age, particularly after age 70, and 17% of men who live to age 80 have hip fractures.[7,8] In addition to hip fracture, men also have painful and debilitating fractures of the spine, wrist, and other bones due to osteoporosis.
In the elderly, use of psychotropic agents, the high rate of orthostatic hypotension (frequently due to antihypertensive drug therapy), and the wide use of polypharmacy contribute to the increasing incidence of falls and consequent fractures. In 90% of hip fractures with falling involved, only 5% or less of these falls resulted in subsequent fractures. Types of Osteoporosis Osteoporosis may be either a primary or a secondary form. Primary osteoporosis is the more common form and is due to the typical age-related loss of bone from skeleton. It is classified as type 1 and type 2. Secondary osteoporosis results from the presence of other diseases or conditions that predispose to bone loss and is classified as type 3. Type 1 Type 1 or postmenopausal osteoporosis occurs in 5% to 20% of women, affecting those within 15 to 20 years of menopause, with a peak incidence in the 60s and early 70s. The incidence in women is eight times higher than that in men. The frequency of postmenopausal osteoporosis accounts for the overall female-male ratio of 2:1 to 3:1.
Estrogen deficiency is thought to underlie this form of osteoporosis, rendering the skeleton more sensitive to parathyroid hormone (PTH), resulting in increased calcium resorption from bone. This in turn decreases PTH secretion, 1,25dihydroxyvitamin D production, and calcium absorption and ultimately causes loss of trabecular bone, leading to vertebral crush fractures and Colles' fractures. Women can lose around 2% to 3% of their bone per year for the first 5 years after menopause. Because of the drop in estrogen production, women lose nearly 50%
of their trabecular bone and 35% of their cortical bone throughout their lifetime, whereas men lose only 25% of both types of bone. At least 75% of the bone loss that occurs in women during the first two decades after menopause can be attributed to lack of estrogen rather than to aging. Bone loss associated with menopause does not begin with the onset of amenorrhea but may occur 1 to 3 years before the actual cessation of menstrual periods. Type 2 Type 2 or senile osteoporosis occurs in women or men more than 70 years of age and usually is associated with decreased bone formation along with decreased ability of the kidney to produce 1,25(OH)2D3. The vitamin D deficiency results in decreased calcium absorption, which increases the PTH level and therefore bone resorption. In type 2 osteoporosis, cortical and trabecular bone is lost, primarily leading to increased risk of hip, long bone, and vertebral fractures. Type 3 Type 3 or secondary osteoporosis occurs equally in men and women and at any age. In men, most cases are due to disease or to drug therapy, but in 30% to 45% of affected individuals no cause can be identified. In various series of osteoporotic patients, secondary osteoporosis accounts for about 40% of the total number of osteoporotic fractures seen by a physician.
This type of osteoporosis is associated with a variety of conditions, including hormonal imbalances (eg, Cushing's syndrome); cancer (notably multiple myeloma); gastrointestinal disorders (especially inflammatory bowel disease causing malabsorption); drug use (eg, corticosteroids, cancer chemotherapy, anticonvulsants, heparin, barbiturates, valporic acid, gonadotropin-releasing hormone [GnRH], excessive use of aluminum-containing antacids); chronic renal
failure; hyperthyroidism; hypogonadism in men; immobilization; osteogenesis imperfecta and related disorders; inflammatory arthritis (particularly rheumatoid arthritis); and poor nutrition (including malnutrition due to eating disorders).[17-19] Risk Factors The two major determinants of risk in the development of osteoporosis are peak bone mass and rate of bone loss. These two determinants are influenced by a number of genetic and environmental factors. Roughly 70% of cases of osteoporosis are probably the result of genetic predisposition, including the role of genetics in dictating how an individual will respond to various exogenous stressors. The remaining 30% of cases are probably triggered by environmental influences.
Ethnic or racial origin is an important risk factor for decreased bone mass. Women are more likely to have osteoporosis than men because of a lower peak bone mass and greater rate of bone loss, especially after menopause. White and Asian women are at greatest risk, whereas blacks and Hispanics are relatively protected because of greater peak bone mass. Increasing age is an important risk factor in both men and women, since bones become less dense and weaker with age. Any factor that results in estrogen deficiency, especially before natural menopause, increases the risk of bone loss. At particular risk are women who have early menopause or late menarche, or those who have premenopausal oophorectomy or amenorrhea. In men, low testosterone due to hypogonadism has been associated with the development of osteoporosis.
Certain medications can cause osteoporosis. Glucocorticoid excess, either intrinsic or iatrogenic, causes osteoporosis. Steroid therapy in doses >5 mg of prednisone or 25 mg of hydrocortisone daily for prolonged periods (more than 6 months) contributes to bone loss by increasing bone resorption and decreasing bone
formation. Other forms of drug therapy that can cause bone loss include longterm treatment with certain antiseizure drugs, such as phenytoin, barbiturates, and valporic acid; GnRH analogs used to treat endometriosis; excessive use of aluminum-containing antacids; thyroxine; heparin; and certain drugs used in cancer treatment. The occurrence of heparin-induced osteoporosis appeared to be strictly related to the length of treatment (longer than 4 or 5 months) and the dosage (15,000 U or more daily), but the pathogenesis is poorly understood. It has been suggested that heparin could cause an increase in bone resorption by increasing the number of differentiated osteoclasts and by enhancing the activity of individual osteoclasts. Prolonged bed rest and a sedentary lifestyle are also important risk factors for osteoporosis.
Less well established risk factors include a positive family history (particularly in a mother) and a short-thin stature. Indeed, evidence suggests that obesity may be a protective factor against osteoporosis because of the conversion of adrenal androgens to estrogens in peripheral adipose tissue. High alcohol consumption is considered a risk factor. The habitual consumption of even moderate quantities of alcohol (1 to 2 drinks per day) on a chronic basis has been clearly identified as a risk factor for the development of osteoporosis even in young women and men. Those who drink heavily are more prone to bone loss and fractures, both because of poor nutrition and the increased risk of falling. Although the exact mechanism by which alcohol influences bone metabolism is not clear, it is likely a combination of both direct effects of alcohol on bone cells and indirect or modulating effect through mineral regulating hormones such as vitamin D metabolites, parathyroid hormone, and calcitonin.[23-25] Alcoholics have also been found to have high levels of corticosteroids in their blood. These hormones, produced by the adrenal glands, can induce bone loss.
Recent studies have shown that women who are smokers have low levels of estrogen and thus have menopause significantly earlier than nonsmokers. Smokers, therefore, should be considered to be at increased risk for osteoporosis. The role of caffeine is extremely controversial. It has been argued that tea drinkers are less likely to have osteoporosis than coffee drinkers. Caffeine is a diuretic and causes hypercalciuria, and current evidence indicates that aging individuals are less able to compensate for the diuretic effect of caffeine by increasing serum concentrations of 1,25-dihydroxyvitamin D. Elderly persons who are heavy consumers of coffee may have a negative calcium balance, which in turn aggravates age-related bone loss.
Malnutrition due to eating disorders such as anorexia nervosa is considered one of the risk factors for osteoporosis, which is present in more than half of all patients with anorexia nervosa. Bone loss often occurs at a young age and may persist even after recovery, predisposing patients to debilitating spinal crush fractures. The pathogenesis of bone loss in anorexia nervosa is not completely understood and may result from a number of mechanisms, including estrogen deficiency, inadequate vitamin and calcium intake, and nutritional effects on bone formation. Recent studies show that estrogen itself is inadequate to increase bone density in a majority of patients with anorexia nervosa and suggest that nutritionally dependent factors such as insulin-like growth factor I, a potent bone trophic hormone, may be important in maintaining bone mass Diagnosis No exact clinical chemical tests on blood or urine are abnormal in osteoporosis, but biochemical markers, radiography, and measurement of bone mineral density (BMD) are helpful in diagnosing osteoporosis. Bone density testing is used to diagnose osteoporosis, and x-ray films are used to rule out other bone or arthritic conditions. Thin bones may be detected on an x-ray film, but bone density testing is more accurate. Bone Densitometry
Considerable progress in the development of methods for assessing the skeleton now makes it possible to detect osteoporosis noninvasively and early. Generally, osteoporosis may be detected after fractures that occur with minimal trauma, as an incidental finding on an x-ray film, or by measurement of BMD by bone densitometry, which is also known as bone density scans. Bone density scans are considered by many as an instant snapshot of bone status. These scans, also known collectively as BMD tests, are used to detect the amounts of bone mass in the spine, hip, wrist, hand, heel, or the entire body and to evaluate its density. Some studies have indicated that information regarding bone-mineral content at any anatomic site is equally valuable for predicting the risk of fracture in general,[29,30] but other studies have suggested that measurements obtained at a particular site of interest may provide the most important information for the prediction of fracture at that site. Bone mineral density tests are the most sensitive and specific tests for osteopenia and predict the risk of fracture. Anyone with a condition that might reduce bone mass or accelerate bone loss should be tested, as should postmenopausal women and perimenopausal women who are undecided about starting estrogen replacement therapy. Almost all patients with BMD in the osteoporotic range on densitometry should be considered for pharmacologic therapy, and so should many of those with values in the osteopenic range. Periodic retesting with bone densitometry is appropriate to monitor the progress of age-related bone loss and response to therapy. There are differences among skeletal sites used in BMD measurement, particularly regarding response to therapy. In addition, there are differences in calibration among densitometry machines, so whenever possible, serial studies should be done on the same machine and by the same technologist. Many factors that can lead to a decrease in bone mass have been identified. As a result, numerous potential indications for bone densitometry have been proposed. However, data are insufficient to justify routine screening with this technique. Recently, the Health Care Financing Administration defined five important diagnostic categories that it considers to be major indications for the use of bone densitometry. These categories include estrogen deficiency in women at clinical risk for osteoporosis, evidence of vertebral abnormalities, long-term glucocorticoid therapy, a diagnosis of primary hyperparathyroidism, and the need for monitoring to assess the response to or the efficacy of an approved drug therapy for the treatment of osteoporosis. Besides these five major categories, other indications for which bone densitometry can be ordered are listed in Table 1 . Several techniques are available to measure BMD noninvasively. All of today's xray-based measurement systems are precise and deliver extremely low, effective radiation doses. The main advantages of an x-ray system over a radionuclide system are safe, shortened examination time, greater accuracy and precision limited to high resolution, and removal of errors due to source decay correction. The variety of bone scan techniques that are most widely used today include single x-ray absorptiometry, dual energy x-ray absortiometry (DEXA), quantitative
computed tomography, peripheral quantitative computed tomography, radiographic absortiometry, quantitative ultrasound, simple photon absorptiometry, and dual photon absortiometry. Their development has been driven by the need to overcome the inherent shortcomings of plain radiography for this purpose. Although single and dual photon absorptiometry are still available, these older techniques are rapidly being replaced by single x-ray absorptiometry and DEXA, their modern counterparts. Of the several techniques available, DEXA has become the most widely used technique for measuring BMD because of its low radiation, availability, capacity to evaluate multiple sites, and ease of use. Dual energy x-ray absortiometry can measure soft-tissue composition (lean and fat mass) and bone mass or bone density at the lumbar spine, hip, and forearm, as well as total-body BMD, with greater precision and faster scanning times than the dual-photon absortiometry. As a screening procedure, DEXA is limited by its relatively high equipment cost. The accuracy of this technique has not been fully documented for all the skeletal sites that can be measured. Interpretation of Bone Densitometry A standard bone mineral report consists of measurements expressed as bone mineral content (the amount of hydroxyapatite, in grams) and converted to area density (grams per square centimeter) within the region of interest. In addition, normal values are provided according to sex and race and are plotted according to age. Demographic data, including the clinical indications and the patient's age, sex, race, weight, and height, are also considered. To interpret a standard bone mineral report, a region of interest must be selected. To compare individuals, the sites of measurement should be constant because the bone mineral content varies between different bones and between different regions of the same bone. The results are compared with normative values, and standard curves of normative values are provided for individuals of both sexes and several races. Comparison of measured values with mean values for normal young or age-matched individuals permits an assessment of the risk of fracture. The World Health Organization (WHO)* recently published a document that attempted to clarify definitions and to assist clinicians in their interpretation of bone densitometry results. According to that report, a normal value for bone mineral content is within 1 standard deviation (SD) of the mean value for young adults of the same age and sex (that is, the t score is more than -1). Osteopenia is considered to be present when the value for bone mineral content is more than 1 SD but not more than 2.5 SDs below the mean for young adults (that is, the t score is less than -1 and more than -2.5). Osteoporosis is considered to be present when the value is more than 2.5 SDs below the mean bone mineral content for young adults (that is, the t score is less than -2.5). Severe osteoporosis is considered to be present when the value for bone mineral content is more than 2.5 SDs below the mean for young adults and there is at least one so-called fragility fracture (a
fracture assumed to be associated with osteoporosis because it occurred as a result of slight trauma). Generally, the t score is used for the diagnosis of low bone mass or osteoporosis. Physicians should initiate therapy to reduce the patient's risk of fracture on the basis of the presence or absence of risk factors for osteoporosis. Therapy should be initiated to reduce the risk of fracture in women who have a bone mineral density t score of less than -2 in the absence of risk factors and in those who have a t score of less than -1.5 if other risk factors are present. Biochemical Markers of Bone Turnover A combination of markers of bone turnover can be used in a variety of ways in the clinical investigation of osteoporosis. Growing evidence suggests that the rate of postmenopausal bone loss may be determined by biochemical markers, such that a single biochemical assessment shortly after menopause, in conjunction with a bone mass measurement, may be used to identify women with high bone turnover and who are therefore likely to sustain a high rate of bone loss. In osteoporotic patients, markers may be used to identify the subgroup of patients with high bone turnover who may benefit from a different therapeutic strategy from that used in patients with low bone turnover. Finally, markers can be used in the clinical investigation of new therapeutic agents to monitor their effect and mechanism of action. Osteocalcin is a bone-specific protein secreted by osteoblasts, the bone-forming cells, and its serum level is a sensitive marker of the rate of bone formation. Other markers of bone formation include serum levels of total and bone-specific alkaline phosphatase and serum type 1 collagen propeptide. Pyridinoline and deoxypyridinoline are collagen cross-links that are released into the blood and urine during the degeneration of type 1 collagen in the process of osteoclastic bone resorption. Urinary excretion of pyridinoline such as hydroxylysylpyridinoline and lysylpyridinoline has been shown to be a more sensitive and specific marker of bone resorption than conventional markers such as urinary hydroxyproline. Its use should be valuable in the clinical investigation of metabolic bone diseases, especially osteoporosis. Plasma tartrate-resistant acid phosphatase is another marker of bone resorption. Radiographic Findings It has been reported that a reduction in bone calcium content must exceed 30% to be observed with certainty on conventional radiographs. Radiographically evident thinning of the cortices of long bones or vertebral bodies may be noted, with a loss of trabecular pattern and bulging of the disks into the vertebral end plates. Plain radiographs are notoriously inaccurate in the diagnosis of osteoporosis, since the demonstration of bone density is strongly dependent on radiographic technique. However, accurate densitometric measurements have
become widely available using quantitative computed tomography scans of the spine or DEXA, which can measure the density of any bone. Prevention and Treatment Treatment of symptomatic osteoporosis has had limited success. Prevention is preferable to treatment, since no therapy fully restores lost bone mass. Prevention is a more useful approach, and ideally, women at high risk should be identified before menopause when preventive measures can be instituted. Whether single measurements of bone density in women who are at risk can identify those who should be treated is a point of controversy.
Treatment for osteoporotic men is poorly researched and remains largely unsupported by experimental evidence, though clinical experience suggests a useful role for low-dose estrogen, calcitonin, selective estrogen receptor modulators, biphosphonates, and perhaps fluorides. Although its effect in men has not been studied, evidence suggests that these drugs may work the same in men as in women. Testosterone replacement therapy may be prescribed for a man with a low testosterone level. However, none of the osteoporosis medications that have been approved by the US Food and Drug Administration (FDA) for postmenopausal women have yet been approved for men. Symptom control by preventive measures and explanation remain the most important therapeutic interventions.
Preventive measures include regular exercise against gravity to make bone stronger; walking, hiking, jogging, stair-climbing, dancing, tennis, exercise classes, or other weight-bearing exercise protects bone mass when accompanied by an adequate daily intake of calcium and vitamin D. Exercise not only improves bone health, but also increases muscle strength, coordination, and balance and leads to better overall health. Although exercise is good for someone with osteoporosis, it should not put any sudden or excessive strain on bones. In addition, a simple
modification of diet and life-style can reduce the risk of osteoporosis in many patients. Appropriate dietary changes include a reduction of alcohol and caffeine intake and an increase in calcium intake through diet or supplementation. Life-style adjustments such as smoking cessation also may decrease the risk of osteoporosis. Prevention should begin early in life, and teenagers should be taught the importance of exercise and of diets rich in calcium, which is contained in yogurt, cheese, milk, nuts, and green leafy vegetables.
Prevention of falls is also a special concern for men and women with osteoporosis. Falls increase the likelihood of fracturing a bone in the hip, wrist, spine, or other parts of the skeleton. Thus, it is important that individuals with osteoporosis be aware of any physical changes that may affect their balance and gait, and that they discuss these changes with their health care providers.
Various medications are available for prevention and treatment of osteoporosis. Pharmacologic interventions for the prevention of fractures in patients with osteoporosis aim at correcting the bone remodeling imbalance by either reducing bone resorption and bone turnover or stimulating bone formation. Pharmacologic treatment should be offered to all individuals, especially women more than 70 years old with risk factors or a fracture of the proximal aspect of the femur or a vertebral fracture. A number of agents are currently available, but only a few have been evaluated under controlled conditions in clinical trials in which the primary efficacy end-point was the prevention of fractures. The therapeutic options for patients who have osteoporosis include hormonal replacement therapy (HRT) such as estrogen and nonhormonal replacement therapy such as biphosphonates (alendronate), calcitonin, selective estrogenreceptor modulators (raloxifene), and fluoride ( Table 2 ). Besides these drugs, other drugs such as testosterone, human parathyroid hormone, and growth
hormone have been used to treat osteoporosis, but the results are not promising. Currently, estrogen, calcitonin, and alendronate are approved by the FDA for the treatment of postmenopausal osteoporosis, and estrogen, raloxifene, and alendronate are approved for prevention of the disease. Nonhormonal agents have been shown to be more effective than hormonal agents in treating and managing postmenopausal osteoporotic women. Calcium Supplementation Retrospective, cross-sectional, and prospective studies suggest that increasing calcium intake during the premenopausal period would allow women to enter menopause with greater bone density. Increasing calcium intake in the immediate postmenopausal period does not appear to affect the rapid bone loss that occurs during early menopause. The recommended daily calcium intake is 1,500 mg for postmenopausal women and 1,000 mg for pre-menopausal women. However, recent study has shown that supplementation of 800 mg of calcium daily may prevent bone loss in post-menopausal women, and the results of clinical trials also suggest that such supplementation may prevent hip and vertebral fractures in the elderly. Most if not all postmenopausal women should take calcium supplements to achieve this intake. The benefits of calcium on bone mass are also supported by epidemiologic data, which suggest that a lifetime of adequate calcium intake decreases fracture risk. The more soluble calcium salts appear to be the most effective. Apart from the possible increased risk of renal caliculi, tolerability is not a concern with these agents. The combination of calcium (1.2 g/day) with vitamin D3 (800 IU/day) has been reported to prevent fractures in elderly women. Daniel found that the number of hip fractures was 43% lower and the total number of nonvertebral fractures was 32% lower among women treated with vitamin D3 and calcium than among those
who received placebo. Increased intake of calcium from natural sources, particularly low-fat dairy products, such as milk, yogurt, cheese, and ice cream, may also help prevent or slow the progress of osteoporosis, although the effects are not great. Vitamin D Supplementation Vitamin D3 plays an important role in calcium absorption and in normal mineralization of new bone. It increases intestinal calcium absorption, enhances renal tubular calcium reabsorption, stimulates osteoblast synthesis of osteocalcin but decreases osteoblast synthesis of collagen, and augments bone resorption. Because of decreased calcium absorption and reduced circulating levels of 1,25(OH)2D3 in patients with postmenopausal osteoporosis, the hormone has been used in the treatment of disease. The value of 1-alpha-OHD and 1,25(OH)2D3 (the two most potent vitamin D analogues) in the treatment of osteoporosis is controversial. Some but not all studies have shown that low-dose 1,25(OH)2D3 or its analogues increase bone mass and/or reduce fracture frequency in patients with established osteoporosis.
Vitamin D supplementation may be particularly useful in vitamin D-deficient elderly. In many Western countries, elderly persons, particularly those living in institutions, are prone to vitamin D deficiency, often associated with secondary hyperparathyroidism, which is one of the major causes of osteoporosis. Lowdose vitamin D3, with or without calcium supplementation, reduces the secondary hyperparathyroidism in the elderly and may improve bone strength in the femur. Because it is well tolerated, low-dose vitamin D supplementation should be recommended in this sub-group of the population.
Daily intake of low doses of vitamin D between 400 and 800 IU should be taken but should not exceed 800 IU. The major difficulty with the use of 1,25(OH)2D3 in the treatment of postmenopausal osteoporosis is the narrow window between therapeutic efficacy and side effects, eg, hypercalciuria, hypercalcemia, and kidney stone formation. This significant risk of hypercalciuria and hypercalcemia necessitates close monitoring. Hormonal Replacement Therapy Estrogen replacement therapy (ERT) is the most effective HRT and a treatment of choice for prevention and treatment of osteoporosis by decreasing fracture rates in women immediately after menopause. Estrogen reduces bone turnover and thus conserves bone mass. It can be administered orally, by injection, or transdermally. The most potent natural estrogen is estradiol-17-beta, which is largely oxidized to estrone and then hydrated to estriol. Estradiol is metabolized in the liver. Normally, estrogen receptors are present on osteoblasts. When estrogen binds to these receptors, chemical mediators are secreted that inhibit the activity of osteoclasts. Initial therapy with estrogen has been shown to reduce bone loss, increase bone density in both the spine and hip, and reduce the risk of hip and spinal fractures in postmenopausal women. Large epidemiologic studies have indicated that the risk of hip and Colles' fractures may be reduced by as much as 50%, with an even greater reduction in the risk for vertebral fracture. Numerous studies also have shown that women treated with estrogen within 3 years of natural or induced menopause have a reduced rate of bone loss and significantly lower rates of fractures of vertebrae, wrists, and hips.[48,49] Considerable observational evidence indicates that the benefits of estrogen replacement outweigh the risks in most women. Cohort studies have
shown that women receiving estrogen after menopause have a lower risk of myocardial infarction, stroke, and cardiovascular death, and lower death rates from all causes. Estrogen can also alleviate other bothersome symptoms associated with menopause, such as hot flashes, vaginal dryness, headaches, aching joints, and bladder problems. Estrogen replacement therapy is indicated for all women with premature or surgical menopause in the absence of contraindications. Lindsay et al found that women given ERT shortly after oophorectomy maintained metacarpal bone density over a 16-year follow-up. In this same study, women who began ERT 3 to 6 years after oophorectomy maintained their bone density at the level that had existed upon initiation of therapy, whereas placebo recipients steadily lost bone density. In another study, Christiansen et al showed that women who began ERT shortly after oophorectomy maintained bone density at the radius for 2 years, whereas a placebo group steadily lost bone density. At the end of 2 years, women initially taking placebo were given estrogen, and those who had been taking estrogen were switched to placebo. After the cross-over, bone loss ceased in the new ERT patients and commenced in the new placebo group. The optimal duration of ERT is unknown, but at least 10 years of treatment is needed to augment bone mass by age 75, when most hip fractures occur. It is also clear that the preservation of bone mass from estrogen replacement does not persist after estrogen is withdrawn. Women who take estrogen for 10 years after menopause and then stop begin to lose bone density, and after age 75, it is the same as if they had not had ERT. Thus, the greatest benefit is seen when ERT is begun as soon as possible after menopause and continued throughout the remainder of life. Therefore, ERT prophylaxis is most properly viewed as a lifelong commitment. If estrogen must be withdrawn for any reason, and if continued
skeletal protection is still necessary, the clinician should institute another pharmacologic intervention.
Conjugated estrogen in doses of 0.625 to 1.25 mg is administered most commonly in the forms of pill, skin patch, or gel. All forms, in the proper dose, have equivalent effects on bone. The adverse side effects of long-term daily estrogen administration, including breast cancer, endometrial cancer, vaginal bleeding, formation of blood clots, elevated blood pressure, and throboembolism, can be virtually negated by administering estrogen cyclically balanced by progestins. Breast cancer is currently the most controversial issue concerning the use of ERT. Numerous studies have been conducted, but no conclusive evidence has yet shown the exact relationship between ERT and breast cancer. A clearly documented and established risk exists, however, for development of endometrial cancer with ERT. This risk can be reduced with the addition of pregesterone, another natural female hormone. Also, studies conducted during the past decade show that combination of estrogen and progesterone or any HRT can also help to reduce the relative risk of heart disease by 50%.[53,54] In addition, progesterone might provide less cardiovascular protection than estrogen alone. The risks and benefits of HRT should always be presented to women so they can make an informed decision.
For women with an intact uterus, progesterone should be given with the estrogen to prevent continuous stimulation of the endometrium. The estrogen and progesterone may be administered cyclically, resulting in a monthly period, or in a continuous daily fashion, resulting in an atrophic uterus. The most common progestin used in North America to oppose the estrogen effect on the uterus is medroxyprogesterone acetate (Provera), either 2.5 or 5.0 mg daily. For the continuous regimen, the 2.5 mg dose appears to be effective in preventing hyperplasia of the endometrium when the progestin is used on a continuous
basis. The other main type of progestin used is norethindrone, which is not commonly used in North America because of its propensity to reduce high-density lipoprotein cholesterol levels, but it is widely used in Europe. Unfortunately, progesterone causes side effects such as headaches, breast tenderness, bloating, anxiety, and mood swing. Also, since the body's premenopausal hormone is being mimicked, vaginal bleeding will frequently occur with combination estrogen and progesterone therapy. Such bleeding does not indicate any significant health problem, nor does it indicate a return of fertility.
Transdermal estradiol-17beta patch (Estraderm) has proved useful for treatment of osteoporosis. Lufkin et al studied a group of women (average age, 64 years) who had at least one preexisting spinal fracture and lumbar spine and proximal femur bone densities below the 10th percenile for premenopausal women. One year of transdermal estrogen therapy produced a 5.5% gain in bone density at the spine and a 7.6% gain in bone density at the trochanter, which were significantly superior to the gains experienced by the placebo group. Of greater importance was a 61% reduction in the risk of a new spinal fracture in the estrogen-treated group. The authors also described a 1-year double-blind placebo-controlled study involving 75 osteoporotic women (ages, 47 to 75 years) with vertebral fractures. Treatment with 0.1 mg of transdermal estradiol-17beta sequentially combined with 10 mg of oral medroxyprogesterone acetate significantly increased bone mineral content in the lumbar spine, mid-radius, and trochanter, and new vertebral fractures were reduced significantly.
The first and only estrogen gel (Estrogel) that has been safely used as an ERT in Europe for more than 20 years is currently the most prescribed estrogen in France and Canada for naturally or surgically induced estrogen deficiency and the relief of menopausal symptoms. It has not yet been approved in the United States. Estrogel has a much lower incidence of skin irritation than transdermal estrogen patches.
Biphosphonates Biphosphonates are potent agents that inhibit bone resorption and increase BMD, acting via a mechanism not yet fully understood. It has been postulated that these drugs alter both osteoclast activation and function. Therefore, biphosphonate compound inhibits osteoclastic activity, increases the mineral content of bone in both spine and hip when administered in a cyclic fashion (with or without a calcium supplement), and decreases the risk of fractures. History of previous fracture is an especially important prognostic feature because it not only shows propensity to fracture, but also manifests fragility. In such high-risk individuals, biphosphonates protect against further bone loss and significantly reduce fracture risk. Biphosphonates have been used successfully to inhibit bone resorption in a variety of metabolic disorders, such as osteoporosis, malignancy-induced hypercalcemia, tumor-induced osteolysis, and Paget's disease of bone. Included in this drug class are alendronate (Fosamax), etidronate (Didronel), and clodronate. These drugs differ widely in their antiresorptive potencies and of those currently available, alendronate is the first most potent of the biphosphonates approved by the FDA for the management of osteoporosis. Cummings et al described a new finding from the Randomized Fracture Intervention Trial study of 4 years involving a total of 4,432 women (aged 54 to 81 years), 2,214 of whom received alendronate and 2,218 placebo. Alendronate decreased the risk of all clinical fractures, hip fractures, and vertebral deformity in women with low BMD but without vertebral fractures. All participants were asked to take a daily supplement containing 500 mg of elemental calcium and 250 IU of cholecalciferol (vitamin D). On the other hand, this same group also previously showed that alendronate decreased the risk of vertebral, hip, and wrist fractures by about 50% and all clinical fractures by 28% among women with vertebral
fractures. On the basis of these studies, alendronate (5 mg/day) appears to be effective in preventing bone loss in postmenopausal women who have either vertebral fractures or osteoporosis confirmed by bone densitometry. Garnero et al also described the long-term effects of alendronate as assessed by biochemical markers of bone turnover in osteoporosis in 84 latepostmenopausal women. In this double-blind, placebo-controlled study, placebo or alendronate (5 or 10 mg) was administered for 24 months. Certain markers of bone resorption decreased to normal premenopausal levels as soon as 1 month after initiation of alendronate therapy, and this was maintained through month 15. These changes in markers of bone turnover were highly correlated with increased BMD at month 24. These findings are consistent with the mechanism of action of alendronate, ie, direct inhibition of bone resorption followed by an indirect decrease in bone formation so that bone turnover is reduced to the normal premenopausal range. The minimal effective dose of alendronate for the prevention and treatment of osteoporosis in postmenopausal bone loss is 5 mg/day orally, and the drug has been approved at this dose by the FDA. For older women, the minimal effective dose of alendronate that prevents bone loss is 10 mg. The ideal management of glucocorticoid-induced osteoporosis has yet to be defined. However, alendronate (in conjunction with calcium supplementation and vitamin D) offers well-tolerated and successful prevention and treatment of chronic steroid-induced osteoporosis in men and women. Whenever possible, the daily dose of glucocorticoids should be the lowest effective dose, and topical steroids should be used where possible. Early intervention to prevent bone loss is critical because glucocorticoid users can lose large amounts of bone rapidly -- as much as 20% in the first year of treatment alone. Bone loss from glucocorticoid therapy ultimately leads to osteoporosis and a high incidence of fractures in an estimated 11% to 20% of patients, depending on the dose and duration of treatment.
Side effects of alendronate are uncommon but may include irritation of the esophagus, abdominal or musculoskeletal pain, nausea, and heartburn. To derive the most benefit from alendronate, patients should take alendronate on an empty stomach with a full glass of water first thing in the morning, remain upright for at least 30 minutes after taking it, and have nothing to eat or drink during this time. Since alendronate is excreted unchanged by the kidneys, it also is not recommended in persons with a creatinine clearance of less than 35 mL/min.
Etidronate, a first-generation biphosphonate, was initially used in clinical medicine in a desperate attempt to save a child with respiratory paralysis due to myositis ossificans. Early research with etidronate suggested a role for biphosphonates in the treatment of osteoporosis, and the drug has been approved for the treatment of osteoporosis in several countries, including Canada. It has not been approved in the United States because a pivotal trial of 400 osteoporotic patients showed that althought etidronate effectively increased BMD of the spine by 5% and of the femoral neck by 3%, it failed to reduce fracture incidence significantly. Other biphosphonates that are undergoing investigation at present are tiludronate, risedronate, and ibandronate. Calcitonin Because of the concerns regarding prolonged estrogen use in postmenopausal women, pharmacologic doses of calcitonin may become an alternative treatment to prevent bone loss in perimenopausal women who cannot tolerate estrogen or for whom estrogen is contraindicated. Calcitonin's main effect in the body, the one that makes it useful in osteoporosis therapy, is to inhibit the activity of specialized bone cells called osteoclasts. This effect enables bone to "hold on" to more calcium and thus keeps bone from becoming more brittle. Calcitonin does not build bone, but rather, in women who are at least 5 years beyond menopause, calcitonin slows
bone loss, increases spinal bone density, and according to anecdotal reports, relieves the pain associated with bone fractures. Therefore, calcitonin is not recommended in osteoporotic women during the first 5 years after menopause, since few data support its efficacy during this period. Of the several types of calcitonin available, salmon calcitonin appears to be the most potent form of calcitonin, as measured by its effect on serum calcium, parathyroid hormone, and urinary cyclic adenosine monophosphate. Calcimar, Miacalcin, and Cibacalcin are the only agents from this class that are available in the United States at this time. Since calcitonin is a protein, it cannot be taken orally since it would be digested before it could work. Therefore, calcitonin is available as injection or in a nasal spray form.
The recommended dosage of parenteral calcitonin is 100 IU/day or every other day subcutaneously/intramuscularly for the prevention of bone loss and fractures in established osteoporosis, and this dosage appears to be effective for both the primary and secondary prevention of glucocorticoid-induced bone loss in osteoporosis. With parenteral injection, benefits may have diminished after 20 months of treatment. Potential side effects of the parenteral formulations of these agents include gastrointestinal (nausea, vomiting, diarrhea, anorexia), vascular (facial flushing, tingling), skin rash, edema of the feet, and pain at the injection site. Nausea occurs in about 10% of people who take the drug. The more convenient intranasal formulation of salmon calcitonin (Miacalcin nasal spray) was approved by the FDA in 1995 for the management of osteoporosis. The recommended dosage of intranasal calcitonin is one nasal spray per day (200 IU/activation) is effective in the prevention and treatment of established osteoporosis, as well as glucocorticoid-induced osteoporosis. With use of the intranasal nasal spray, it is also recommended that at least 1,000 mg of elemental
calcium and 400 IU of vitamin D be taken daily. Studies using intranasal salmon calcitonin have shown preservation of or small gains in BMD of the spine with this dosage,[64,65] as well as an analgetic effect.
The most common side effect reported with nasal calcitonin spray is a runny nose. Other symptoms that occur in a minority of patients studied include nasal crust, dryness, redness, irritation, sinusitis, nose bleeds, and headache. Because calcitonin is a protein, a large number of people taking the drug have resistance or allergic reactions after long-term use (longer than 1 year). These are generally not serious enough to necessitate discontinuing the medication. These effects, however, are likely to occur when spraying anything in the nostrils and are not necessarily due to calcitonin. Another drawback of nasal spray is that it comes in only one strength so the dose cannot be adjusted. Selective Estrogen Receptor Modulators Selective estrogen receptor modulators (SERMs), a new class of drugs with selective activity in various organ systems, act as weak estrogen in some systems and as an estrogen antagonist in others. The potential benefits of these drugs include protection against four important hormone-dependent diseases: osteoporosis, coronary artery disease, endometrial cancer, and breast cancer. One of the first SERMs to be developed was tamoxifen, which has been clinically used to prevent recurrent breast cancer because it appears to block the effect of estrogen in breast tissue (antagonist). However, studies conducted on breast cancer patients have suggested that tamoxifen also preserves bone density in the spine.
Raloxifene is a newer SERM that like tamoxifen was originally developed in an effort to find a treatment for breast cancer. Raloxifene became the first SERM
drug approved by the FDA for the prevention of postmenopausal osteoporosis. It is a nonsteroidal benzothiophene that is being developed in an effort to find a treatment that will stimulate bone and cardiovascular tissue the way estrogen does (agonistic effect) while not stimulating breast and uterine tissue (antagonistic effects). Raloxifene's biologic actions are mediated through binding to estrogen receptors. This binding results in differential expression of multiple estrogenregulated genes in various tissues. An increase in BMD at the spine, total hip, and total body has been reported with raloxifene but seems to be less than that seen with estrogen or alendronate therapy. Raloxifene has been shown to reduce total and low-density lipoprotein cholesterol concentrations similar to decreases produced by estrogen therapy, but high-density lipoprotein cholesterol and triglyceride concentrations do not increase during raloxifene therapy. Raloxifene has proved most beneficial in women who are at moderate risk for osteoporosis; are unwilling or unable to use conventional forms of estrogen replacement; have infrequent hot flashes; are at low risk for cardiovascular disease; and are at moderate to high risk for breast cancer.
Clinical studies with raloxifene in post-menopausal women are limited. One randomized, double-blind, placebo-controlled trial examined the effects of raloxifene, placebo, and conjugated equine estrogens on aspects of bone metabolism, endometrial histologic features, and lipid profiles in 251 postmenopausal women during an 8-week period. Raloxifene was found to reduce cholesterol by between 5% and 10% and to have no stimulatory effect on the endometrium after 8 weeks of therapy. Bone turnover markers (serum osteocalcin and alkaline phosphatase, urinary pyridinoline cross-links) were reduced in both the estrogen-treated and raloxifene-treated groups, which implies a potentially beneficial effect on the skeleton. Between 12% and 20% of women in the raloxifene group had classic symptoms associated with antiestrogens such as hot flushes; this seemed to be dose-dependent, though 11% of the placebo group
of women also had hot flushes. As would be expected, mastalgia was more common in the estrogen-treated group. In a more recent 2-year randomized, placebo-controlled study, raloxifene was found to increase bone density at the hip and spine by 2%, in addition to reducing total cholesterol by 6.4% and low-density lipoprotein cholesterol by 10%, similar to the changes induced by estrogen therapy. Serum triglycerides and high-density lipoprotein cholesterol levels were unchanged with raloxifene therapy. This study had a dropout rate of 25%, but the reasons for this were not clear. None of the women in the study had uterine bleeding, and the treatment groups had equal numbers of dropouts. The incidences of hot flushes were reported to be similar in treatment and placebo groups, and no relationship between flushes and raloxifene dosage was found. Endometrial effects of raloxifene were measured by transvaginal ultrasonography, which showed no evidence of stimulatory activity. Although these results are favorable, the authors gave little information about the 25% dropout rate and made no comment concerning the lack of dose-related raloxifene-induced hot flushes. In clinical studies of postmenopausal women, raloxifene at a dose of 60 mg/day for 2 years significantly increased BMD as compared with placebo. In comparative clinical studies, raloxifene (60 mg/day) had more modest effects than conjugated estrogens (0.625 mg/day) on bone resorption and formation parameters and appeared to be less effective in increasing BMD. In older post-menopausal women with existing bone fractures, raloxifene at 60 or 120 mg/day for 1 year produced modest increases in BMD. As with most drugs, raloxifene is associated with some side effects, the majority of which were reported as mild. The most commonly reported side effects are hot flushes and leg cramps. The first occurrence of hot flushes was most commonly reported during the first 6 months of treatment. A rare but serious side effect is deep vein thrombosis, which is also
associated with estrogen or HRT. The recommended dosage for raloxifene is 60 mg per day without regard to food, beverage, or other medications. Supplemental calcium should be added to the diet if daily intake is inadequate.
Short-term data on the use of raloxifene suggest that bone is preserved and lipid profiles are less atherogenic. However, data on long-term efficacy and safety regarding raloxifene are limited. Effects on fracture incidence, cardiovascular events, cognitive function, incidence of breast, ovarian, and endometrial cancer, and mortality rates associated with raloxifene therapy are not yet firmly established. Sodium Fluoride Fluoride has been used in the treatment of osteoporosis for more than 30 years, and its anabolic action on trabecular bone is well documented. However, research has failed to solve the controversy about use of fluoride in the treatment of osteoporosis. Fluoride is a potent mitogenic for osteoblasts, stimulating the production of DNA and new osteoblasts and leading to a progressive increase in BMD of the skeleton and thus in turn to a significant increase in bone formation. However, the new bone has an abnormal texture and is less mineralized and relatively fragile. The effects of fluoride therapy on fracture frequency are controversial. In an open study (N = 257) comparing low-dose sodium fluoride (50 mg enteric coated tablets plus 1 g of calcium per day plus vitamin D2, 800 IU per day) with other treatment modalities, a significant (P = .05) decrease in vertebral fracture rate in the fluoridetreated group was reported after 2 years of treatment, whereas no significant change was observed in the frequency of nonvertebral fractures. In a 4-year, double-blind, placebo-controlled study (N = 202), however, no significant difference
in the vertebral fracture rate was observed between the group receiving sodium fluoride, given at a higher dose (75 mg plain tablets), plus 1.5 g of calcium per day, and the group receiving placebo. In addition, the incidence of nonvertebral fractures was increased in the fluoride group. These studies suggest that higher doses of fluoride should be avoided in the treatment of osteoporosis, since it causes nonveretebral fractures, and that the beneficial effect of low doses on vertebral and non-vertebral fracture rates must be confirmed in placebo-controlled studies.
In other studies, fluoride has been shown to decrease the rate of bone fractures in patients with osteoporosis. However, it is not effective in all patients, and it is not possible to predict who will respond. The recommended dose is 15 to 25 mg per day, which is 33 to 55 mg of sodium fluoride or 140 to 190 of Na2FPo3. Calcium and vitamin D should be prescribed to all patients concurrently. When fluoride is given in large doses without the concurrent administration of calcium, mineralization becomes markedly impaired, leading to osteomalacia. The major side effects associated with fluoride therapy are upper gastrointestinal complaints (nausea and gastric irritation) and lower extremity pain associated with stress fractures. Hematologic and rheumatologic problems are also associated with the long-term use of fluoride. The therapeutic window for fluoride therapy in osteoporosis is narrow, and further investigation is needed to determine alternative formulations and dose responses. Testosterone Therapy Testosterone has been given to men with osteoporosis due to hypogonadism. One small study has shown that testosterone increases BMD 3% to 5% in the spine over a period of 2 years. Testosterone probably works like estrogen, mainly as an antiresorptive agent, and on theoretical grounds should be a suitable drug for
men with osteoporosis, though more controlled studies need to be conducted. The recommended dose of testosterone is 200 mg IM every 2 weeks. The problems with testosterone therapy are well known: an increase in prostate size and hyperplasia, increased libido, sleep apnea, polycythemia, and (rarely) priapism with initial dose have been reported. Human Parathyroid Hormone Parathyroid hormone (PTH) is an agent that is under investigation for the treatment of osteoporosis. It stimulates bone turnover and causes an increase in bone formation. Studies have shown that the intermittent administration of human parathyroid hormone (hPTH) administered subcutaneously at a dose of 400 to 500 IU per day is beneficial for restoration of vertebral bone mass in osteoporotic patients.[80,81] This was done, however, by a decrease in cortical bone mass, compared with the control group, suggesting that PTH may be deleterious to cortical bone. Thus, PTH has profound effects on bone metabolism, though the most effective way in which to use it in the treatment of osteoporosis remains to be defined. Growth Hormone (Somatotropin) The various components of the growth hormone-insulin-like growth factor I axis and their binding proteins have many peripheral effects, mainly on bone, growth, activation of main cellular functions, energy metabolism, and protein anabolism. However, limited clinical trials have failed to show efficacy of growth hormone in increasing bone density or reducing fracture incidence. Its efficacy must be evaluated through double-blind, placebo-controlled clinical trials. A fairly high incidence of side effects has been reported with growth hormone therapy. Combination Therapy
Two studies have been conducted to determine whether the combined use of two antiresorptive agents from different classes might be more beneficial than either agent alone. In a 4-year study, postmenopausal women who received estrogen/etidronate had significantly greater increases in BMD of the spine and femoral neck than women who received either agent alone. In a 2-year study, 95 postmenopausal women were randomized to receive placebo, carbocalcitonin, estrogen, or carbocalcitonin/estrogen. Those who received the combination had greater gains in BMD than did those receiving either agent alone. Although research is now under way to evaluate the use of estrogen/alendronate, this combination cannot be recommended at this time. In addition, none of the approved agents, either alone or in combination, is recommended for use in premenopausal women. Conclusion Osteoporosis results in significant use of healthcare resources. It is a common disease and has become a major public health problem, especially in the United States and Europe, as the number of elderly people in the population has increased. Despite the profound effect of osteoporosis on the quality of life of millions of people, preventive measures and the various treatment options can be strategically used to minimize both the morbidity of the disease and its burden on society. The primary goal should be to ensure that optimum peak bone mass is achieved by early adulthood. Adequate dietary calcium intake, good nutrition, exercise and hormone sufficiency all contribute to this goal. The secondary goal is to maintain bone mass by these measures as well as by avoiding tobacco and excessive alcohol consumption. Effective management of diseases and certain drugs that can cause bone loss should also be considered. Osteoporosis and its consequent fractures cause significant morbidity and mortality among both men and women. A number of risk factors can help to broadly identify persons at risk for osteoporosis and fractures; however, risk factors need to be further defined to differentiate persons at high risk from those at negligible risk. The assessment of bone mineral density is the single best predictor of risk for osteoporotic fractures and contributes to clinical decision-making. Periodic measurements of bone mass in a given individual, using modern techniques (eg, bone densitometry) may alert the physician to a progressive bone loss before clinical or x-ray evidence of osteoporosis occurs. Measures to prevent progressive
loss of bone mass may be more effective than treatment of the clinical disease, which at present is costing $13.8 billion in medical care annually in the United States
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