Chapter 30: Osteoporosis

Osteoporosis is a public health problem affecting more than 40 million people, one-third of postmenopausal women and a substantial portion of the elderly in the United States and almost as many in Europe and Japan. An additional 54% of postmenopausal women have low bone density measured at the hip, spine, or wrist. Osteoporosis results in approximately 1,500,000 fractures annually in women in the United States alone, as well as in men. At least 90% of all hip and spine fractures among elderly women are a consequence of osteoporosis. The direct expenditures for osteoporotic fractures have increased during the past decade from $5 billion to almost $15 billion per year. The number of women experiencing osteoporotic fractures annually exceeds the number diagnosed with heart attack, stroke, and breast cancer combined. Thus, family physicians and other primary care providers will (1) frequently care for patients with subclinical osteoporosis, (2) recognize the implications of those who present with osteoporosis-related fractures, and (3) determine when to implement prevention for younger people.

The female-to-male fracture ratios are reported to be 7:1 for vertebral fractures, 1.5:1 for distal forearm fractures, and 2:1 for hip fractures. Approximately 30% of hip fractures in persons aged ≥65 years occur in men. Osteoporosis-related fractures in older men are associated with lower femoral neck bone mineral density (BMD), quadriceps weakness, higher body sway, lower body weight, and decreased stature. Osteoporotic fractures are more common in whites and Asians than in African Americans and Hispanics, and more common in women than in men. Little is known regarding the influence of ethnicity on bone turnover as a possible cause of the variance in bone density and fracture rates among different ethnic groups. Significant differences in bone turnover in premenopausal and early perimenopausal women can be documented. The bone turnover differences do not appear to parallel the patterns of BMD. Other factors, such as differences in bone accretion, are likely responsible for much of the ethnic variation in adult BMD.

Osteoporosis is characterized by microarchitectural deterioration of bone tissue that leads to decreased bone mass and bone fragility. The major processes responsible for osteoporosis are accelerated bone loss during the perimenopausal period (mid-50s to the sixth decade in women and the seventh decade in men) and beyond and, to a lesser extent, poor bone mass acquisition during adolescence. Both processes are regulated by genetic and environmental factors. Reduced bone mass, in turn, is the result of varying combinations of hormone deficiencies, inadequate nutrition, decreased physical activity, comorbidity, and the effects of drugs used to treat various medical conditions.

The term primary osteoporosis is now used less frequently than in the past and signifies deterioration of bone mass not associated with other chronic illness—usually related to increasing age and decreasing gonadal function. Therefore, early menopause or premenopausal estrogen deficiency states may hasten its development. Prolonged periods of inadequate calcium intake, a sedentary lifestyle, and tobacco and alcohol abuse also contribute to primary osteoporosis.

Secondary osteoporosis results from chronic conditions that contribute significantly to accelerated bone loss. These include endogenous and exogenous thyroxine excess, hyperparathyroidism, cancer, gastrointestinal diseases, medications, renal failure, and connective tissue diseases. Secondary forms of osteoporosis are listed in Table 30-1. If secondary osteoporosis is suspected, appropriate diagnostic workup may identify a different management course.

A. Nutrition

Bone mineralization is dependent on adequate nutritional status in childhood and adolescence. Therefore, measures to prevent osteoporosis should begin with increasing the milk intake of adolescents to improve bone mineralization. Nutrients other than calcium are also essential for bone health. Adolescents must, therefore, maintain a balance in calcium intake, protein intake, other calorie sources, and phosphorus. Substituting phosphorus-laden soft drinks for calcium-rich dairy products and juices compromises calcium uptake by bone and promotes decreased bone mass.

Eating disorders are nutritional conditions that affect BMD. Inability to maintain normal body mass promotes bone loss. The body weight history of women with anorexia nervosa has been found to be an important predictor of the presence of osteoporosis as well as the likelihood of recovery. The BMD of these patients does not increase to a normal range, even several years after recovery from the disorder, and all persons with a history of an eating disorder remain at high risk for osteoporosis in the future.

Major demands for calcium are placed on the mother by the fetus during pregnancy and lactation. The axial spine and hip show losses of BMD during the first 6 months of lactation, but this bone mineral loss appears to be completely restored 6–12 months after weaning. Risk factors for osteoporosis are summarized in Table 30-2.

B. Lifestyle

Sedentary lifestyle or immobility (confinement to bed or a wheelchair) increases the incidence of osteoporosis. Low body weight and cigarette smoking negatively influence bone mass. Excessive alcohol consumption has been shown to depress osteoblast function and, thus, to decrease bone formation. Those at risk for low BMD should avoid drugs that negatively affect BMD (see Table 30-1).

C. Behavioral Measures

Behavioral measures that decrease the risk of bone loss include eliminating tobacco use and excessive consumption of alcohol and caffeine. A balanced diet with adequate calcium and vitamin D intake and a regular exercise program (see discussion below) retard bone loss. Medications, such as glucocorticoids, that decrease bone mass should be avoided if possible. The importance of maintaining estrogen levels in women should be emphasized. Measurement of bone density should be considered in the patient who presents with risk factors, but additional evidence is needed before instituting preventive measures.

D. Exercise

Regular physical exercise can reduce the risk of osteoporosis and delay the physiologic decrease of BMD. Short- and long-term exercise training (measured up to 12 months; eg, walking, jogging, stair climbing) in healthy, sedentary, postmenopausal women results in improved bone mineral content. Bone mineral content increases more than 5% above baseline after short-term, weight-bearing exercise training. With reduced weight-bearing exercise, bone mass reverts to baseline levels. Similar increases in BMD have been seen in women who participate in strength training. In the elderly, progressive strength training has been demonstrated to be a safe and effective form of exercise that reduces risk factors for falling and may also enhance BMD.

Estrogen deficiency results in diminished bone density in younger women as well as in older women. Athletes who exercise much more intensely and consistently than the average person usually have above-average bone mass. However, the positive effect of exercise on the bones of young women is dependent on normal levels of endogenous estrogen. The low estrogen state of exercise-induced amenorrhea outweighs the positive effects of exercise and results in diminished bone density. When mechanical stress or gravitational force on the skeleton is removed, as in bed rest, space flight, immobilization of limbs, or paralysis, bone loss is rapid and extensive. Weight-bearing exercise can significantly increase the BMD of menopausal women. Furthermore, weight-bearing exercise and estrogen replacement therapy have independent and additive effects on the BMD of the limb, spine, and Ward triangle (hip).

There have been no randomized prospective studies systematically comparing the effect of various activities on bone mass. Recommended activities include walking and jogging, weight training, aerobics, stair climbing, field sports, racquet sports, court sports, and dancing. Swimming is of questionable value to bone density (because it is not a weight-bearing activity), and there are no data on cycling, skating, or skiing. It should be kept in mind that any increase in physical activity may have a positive effect on bone mass for women who have been very sedentary. To be beneficial, the duration of exercise should be between 30 and 60 minutes and the frequency should be 3–4 times per week.

A. Symptoms and Signs

The history and physical examination are neither sensitive enough nor sufficient for diagnosing primary osteoporosis. However, they are important in screening for secondary forms of osteoporosis and directing the evaluation. The goals of the evaluation should be to: (1) establish the diagnosis of osteoporosis by assessing bone mass, (2) determine fracture risk, and (3) determine whether intervention is needed. A medical history provides valuable clues to the presence of chronic conditions, behaviors, physical fitness, and the use of long-term medications that could influence bone density. Those already affected by complications of osteoporosis may complain of upper or midthoracic back pain associated with activity, aggravated by long periods of sitting or standing, and easily relieved by rest in a recumbent position. The history should also assess the likelihood of fracture. Other indicators of increased fracture risk are low bone density, a propensity to fall, taller stature, and the presence of prior fractures.

The physical examination should be thorough for the same reasons. For example, lid lag and enlargement or nodularity of the thyroid suggests hyperthyroidism. Moon facies, thin skin, and a “buffalo hump” (dorsocervical fat pad) suggest hypercortisolism. Cachexia mandates screening for an eating disorder or cancer. A pelvic examination is one aspect of the total evaluation of hormonal status in women and a necessary part of the physical examination in women. Osteoporotic fractures are a late physical manifestation. Common fracture sites are the vertebrae, forearm, femoral neck, and proximal humerus. The presence of a “dowager hump” in elderly patients suggests multiple vertebral fractures and decreased bone volume.

Studies completed under the auspices of the World Health Organization Collaborating Centre for Metabolic Bone Diseases were used to create a 10-year probability model for a more accurate assessment of fracture risk. The fracture risk assessment tool (FRAX) that was developed identifies and accounts for clinical risk factors for fracture—age, low body mass index, parental history of hip fracture, current smoking, alcohol intake of >3 units daily, rheumatoid arthritis or other secondary causes of osteoporosis, oral glucocorticoids, and previous fragility fracture. Primary data were used from nine large patient cohorts in North America, Europe, Asia, and Australia representing over 1 million patient-years. The primary data are used to accurately evaluate the interaction of each risk factor, rather than being limited to the potential bias of published data. Additional secondary causes of osteoporosis include untreated hypogonadism, inflammatory bowel disease, prolonged immobility, organ transplantation, type 1 diabetes, thyroid disorders, and chronic obstructive pulmonary disease. This tool estimates the 10-year, patient-specific absolute risk of hip or major osteoporotic fracture (hip, spine, shoulder, or wrist), taking account of death from all causes and death hazards (eg, smoking). The tool may be used alone employing individual clinical risk factors, with or without BMD, and is easily accessed online.

B. Laboratory Findings

Basic chemical analysis of serum is indicated when the history suggests other clinical conditions influencing bone density. The tests presented in Tables 30-3 and 30-4 are appropriate for excluding secondary causes of osteoporosis. These tests provide clues to serious illnesses that may otherwise have gone undetected and that, if treated, could result in resolution or modification of the bone loss. Specific biochemical markers (human osteocalcin, bone alkaline phosphatase, immunoassays for pyridinoline crosslinks and type 1 collagen–related peptides in urine) that reflect the overall rate of bone formation and bone resorption are now available. These markers are primarily of research interest and are not recommended as part of the basic workup for osteoporosis. They suffer from substantial biological variability and diurnal variation and do not differentiate causes of altered bone metabolism. For example, measures of bone turnover increase and remain elevated after menopause but do not necessarily provide information that can direct management.

C. Imaging Studies

Plain radiographs are not sensitive enough to diagnose osteoporosis until total bone density has decreased by 50%, but bone densitometry is useful for measuring bone density and monitoring the course of therapy (Table 30-5). Single- or dual-photon absorptiometry (SPA, DPA) has been used in the past but provides poorer resolution, less accurate analysis, and more radiation exposure than x-ray absorptiometry. The most widely used techniques for assessing BMD are dual-energy x-ray absorptiometry (DXA) and quantitative computerized tomography (CT). These methods have errors in precision of 0.5–2%. Quantitative CT is most sensitive, but results in substantially greater radiation exposure than DXA. For this reason, DXA is the diagnostic measure of choice. Vertebral fracture assessment is now available through imaging completed with the DXA assessment and provides more accurate assessment of the patient’s bone density.

Smaller, less expensive systems for assessing the peripheral skeleton are now available. These include DXA scans of the distal forearm and the middle phalanx of the nondominant hand and a variety of devices for performing quantitative ultrasound (QUS) measurements on bone. Prospective studies using QUS of the heel have predicted hip fracture and all nonvertebral fractures nearly as well as DXA at the femoral neck. Both of these methods provide information regarding fracture risk and predict hip fracture better than DXA at the lumbar spine. Clinical trials of pharmacologic agents have used DXA rather than QUS, so it is unclear whether the results of these trials can be generalized to patients identified by QUS to have high risk of fracture.

Bone densitometry reports provide a T score (the number of standard deviations above or below the mean BMD for sex and race matched to young controls) or Z score (comparing the patient with a population adjusted for age as well as for sex and race). The BMD result enables the classification of patients into three categories: normal, osteopenic, and osteoporotic. Normal patients receive no further therapy; osteopenic patients are counseled, treated, and followed so that no further bone loss develops; osteoporotic patients receive active therapy aimed at increasing bone density and decreasing fracture risk. Osteoporosis is indicated by a T score of >2.5 standard deviations below the sex-adjusted mean for normal young adults at peak bone mass. Z scores are of little value to the practicing clinician.

There is little evidence from controlled trials that women who receive bone density screening have better outcomes (improved bone density or fewer falls) than women who are not screened. The US Preventive Services Task Force (USPSTF) suggests that the primary argument for screening is that postmenopausal women with low bone density are at increased risk for subsequent fractures of the hip, vertebrae, and wrist, and that interventions can slow the decline in bone density after menopause. The presence of multiple risk factors (eg, age ≥80 years, poor health, limited physical activity, poor vision, prior postmenopausal fracture, psychotropic drug use) seems to be a stronger predictor of hip fracture than low bone density. The patient who is not asymptomatic but may have only one or two risk factors can benefit from BMD screening. Indications for BMD screening are outlined in Table 30-5.

The approach to the patient is governed by the presentation. The greatest challenge for clinicians is to identify which asymptomatic patients would benefit from screening for osteoporosis, rather than determining a treatment regimen for those with known disease (see Table 30-2). All women and girls should be counseled about appropriate calcium intake and physical activity. Assessment of osteoporosis risk is also important when following a patient for a chronic disease known to cause secondary osteoporosis (see Table 30-1). Figure 30-1 presents an algorithm to assist in the evaluation. Preventive measures are always the first step in therapy.

Should there be a suspicion of osteoporosis in a man or evidence of a pathologic fracture in a man or a woman, assessment of risk via medical history and determination of BMD should be completed. BMD measurement and laboratory evaluation are necessary to document the extent of bone loss and to rule out secondary causes of osteoporosis. Should there be clinical evidence of a particular condition, the evaluation can focus on the suspected condition when the basic laboratory work has been completed as described in Table 30-3 and Figure 30-1.

Recognizing the variety of conditions conferring risk of osteoporosis, the National Osteoporosis Foundation makes the following recommendations to physicians:

Universal recommendations:

• Counsel on the risk of osteoporosis and related fractures.

• Advise on a diet rich in fruits and vegetables and that includes adequate amounts of total calcium intake (1000 mg per day for men aged 50–70 years; 1200 mg per day for women aged ≥51 years and men ≥71 years).

• Advise on vitamin D intake (800-1000 IU per day), including supplements if necessary for individuals aged ≥50 years.

• Recommend regular weight-bearing and muscle-strengthening exercise to improve agility, strength, posture, and balance and reduce the risk of falls and fractures.

• Assess risk factors for falls and offer appropriate modifications (eg, home safety assessment, balance training exercises, correction of vitamin D insufficiency, avoidance of certain medications, and bifocals use when appropriate).

• Advise on cessation of tobacco smoking and avoidance of excessive alcohol intake.

• Measure height annually, preferably with a wall-mounted stadiometer.

Diagnostic assessment:

• In women aged ≥65 years and men aged ≥70, recommend bone mineral density (BMD) testing.

• In postmenopausal women and men aged 50–69 years, recommend BMD testing based on risk factor profile.

  • Recommend BMD testing and vertebral imaging to those who have had a fracture, to determine degree of disease severity.

  • BMD testing should be performed at DXA facilities using accepted quality assurance measures.

• Vertebral imaging should be performed

  • In all women aged ≥70 years and all men aged ≥80 years.

  • In women aged 65–69 and men aged 75–79 years if BMD T, score is ≤1.5.

  • In postmenopausal women aged 50-64 and men aged 50-69 years with specific risk factors:

    • Low trauma fracture

    • Historical height loss of ≥1.5 inches (4 cm)

    • Prospective height loss of ≥0.8 inch (2 cm)

    • Recent or ongoing long-term glucocorticoid treatment

• Check for causes of secondary osteoporosis.

When monitoring patients who have the diagnosis of osteoporosis, perform BMD testing 1–2 years after initiating therapy to reduce fracture risk and every 2 years thereafter. In certain clinical situations more frequent testing may be indicated. Likewise, the interval for repeat screening may be longer if the initial T score is in the normal or upper low bone mass range or the patient is without major risk factors.

Decisions to intervene when osteoporosis is diagnosed reflect a desire to prevent early or continuing bone loss, a belief that there can be an immediate impact on the patient’s well-being, and a willingness to comply with the patient’s desires. Bone densitometry can assist in the decision-making process if the patient’s age confers risk, there are no manifestations of disease, and if the decision point is prevention rather than treatment. BMD measurements can also assist in therapy when there are relative contraindications to a specific agent, and demonstrating efficacy could encourage continuation of therapy. Medicare currently reimburses costs of bone densitometry according to the conditions outlined in Table 30-6. The decision to intervene with pharmacologic therapy involves clinical judgment based on a global assessment, rather than BMD measurement alone. All currently approved therapeutic agents for the prevention and treatment of osteoporosis work by inhibiting or decreasing bone resorption.

A. Estrogen

Adequate estrogen levels remain the single most important therapy for maintaining adequate bone density in women. Prior to 2003, estrogen replacement therapy was considered for all women with decreased bone density, absent contraindications. However, in July 2002, the Women’s Health Initiative randomized controlled primary prevention trial was stopped at a mean 5.2 years of follow-up by the Data and Safety Monitoring Board because the test statistic for invasive breast cancer exceeded the stopping boundary for the adverse effect of estrogen and progesterone versus placebo. Estimated hazard ratios were excessive for coronary heart disease, breast cancer, and strokes, but were <1.0 for colorectal cancer, endometrial cancer, and hip fracture. Therefore, careful risk assessment is needed for each patient to determine whether the improvement of risk for hip fracture (0.66) balances the risk for cardiovascular and breast disease. Contraindications to estrogen replacement therapy are listed in Table 30-7.

Studies have been done to determine the effect of the timing of initiation and the duration of postmenopausal estrogen therapy on BMD. Current users who started estrogen therapy at menopause had the highest BMD levels, which were significantly higher than those of women who never used estrogen therapy or past users who started at menopause (with a duration of use of ≥10 years). BMD was similar for women using unopposed estrogen or estrogen plus progestin, and for current smokers or nonsmokers. Current users who started estrogen within 5 years of menopause had a decreased risk of hip, wrist, and all nonspinal fractures compared with those who never used estrogen. Long-term users who initiated therapy 5 years after menopause had no significant reduction in risk for all nonspinal fractures, despite an average duration of use of 16 years. Therefore, early initiation of estrogen with respect to menopause may be more important than the total duration of use. Estrogen initiated early in the menopausal period and continued into late life appears to be associated with the highest bone density.

As more and more women utilize estrogen therapy, there has been increasing concern regarding its impact on breast cancer risk. The relation between the use of hormones and the risk of breast cancer in postmenopausal women was assessed in a follow-up survey of participants in the Nurses’ Health Study in 1992. The risk of breast cancer was significantly increased among women who were currently using estrogen alone or estrogen plus progestin, as compared with postmenopausal women who had never used hormones. Women currently taking hormones who had used such therapy for 5-9 years had an adjusted relative risk (RR) of breast cancer of 1.46, as did those currently using hormones who had done so for a total of 10 or more years (RR = 1.46). The addition of progestins to estrogen therapy does not reduce the risk of breast cancer among postmenopausal women.

The only randomized trial of estrogen-progesterone therapy describes secondary prevention of coronary heart disease in postmenopausal women [Heart and Estrogen/progestin Replacement Study (HERS)] and included only women who had a prior history of cardiovascular disease. Women received either estrogen alone or estrogen plus progesterone. There was an excessive number of deaths from coronary heart disease and a threefold excess risk of venous thrombosis during the first year of the trial in women on estrogen and a small risk of stroke in women on estrogen and progesterone. Recommendations at the conclusion of the trial included not starting women who already have clinical cardiovascular disease on estrogen and progesterone therapy (ie, secondary prevention).

B. Calcium and Vitamin D

Calcium supplementation produces small beneficial effects on bone mass throughout postmenopausal life and may reduce fracture rates by more than the change in BMD would predict—possibly as much as 50%. Postmenopausal women receiving supplemental calcium over a 3-year period in a placebo-controlled, randomized clinical trial had stable total body calcium and BMD in the lumbar spine, femoral neck, and trochanter compared with the placebo group.

Vitamin D increases calcium absorption in the gastrointestinal tract, so that more calcium is available in the circulation and is subsequently reabsorbed in the renal proximal tubules. There is now evidence of significant reductions in nonvertebral fracture rates from physiologic replacement of vitamin D in the elderly. Vitamin D supplementation is important in those of all ages with limited exposure to sunlight.

Dietary calcium augmentation should be recommended to maintain lifetime calcium levels and to help prevent early postmenopausal bone loss (Table 30-8). Adults should ingest 1200 mg of elemental calcium per day for optimal bone health. Teenagers, pregnant or lactating women, women aged >50 years taking estrogen replacement therapy, and everyone aged >65 years should ingest 1500 mg of elemental calcium per day for optimal bone health. If this cannot be achieved by diet alone, calcium supplementation is recommended. Calcium preparations should be compared relative to elemental calcium content. Therefore, attention to which form the patient is ingesting is important.

C. Calcitonin

Calcitonin, a hormone directly inhibiting osteoclastic bone resorption, is an alternative for patients with established osteoporosis in whom estrogen replacement therapy is not recommended. A unique characteristic of calcitonin is that it produces an analgesic effect with respect to bone pain and, thus, is often prescribed for patients who have suffered an acute osteoporotic fracture. The American College of Rheumatology recommends treatment until the pain is controlled, followed by tapering of medication over 4—6 weeks. Calcitonin decreases further bone loss at vertebral and femoral sites in patients with documented osteoporosis but has a questionable effect on fracture frequency. Calcitonin has been shown to prevent trabecular bone loss during the first few years of menopause, but it is unclear whether it has any impact on cortical bone. Calcitonin is also thought to be effective in decreasing the fracture rate of vertebrae and peripheral bones.

For reasons that are poorly understood, the increase in BMD associated with administration of calcitonin may be transient, or there may be the development of resistance. Therefore, calcitonin should be prescribed more acutely and other medications used for chronic management. Calcitonin can be provided in two forms. Nasal congestion and rhinitis are the most significant side effects of the nasal form. The injectable formulation has gastrointestinal side effects and is less convenient than the nasal preparation. The increase in bone density observed by this therapy is significantly less than that achieved by bisphosphonates or estrogen and may be limited to the spine, but it still has recognized value in reducing risk of fracture.

The FDA is currently reviewing prescribing recommendations for calcitonin and new guidelines are forthcoming in the near future.

D. Bisphosphonates

Bisphosphonates are antiresorptive agents and effective for preventing bone loss associated with estrogen deficiency, glucocorticoid treatment, and immobilization. Antiresorptive agents improve the quality of bone by preserving trabecular architecture. They may increase bone strength by methods other than by increasing BMD. All bisphosphonates act similarly on bone in binding permanently to mineralized bone surfaces and inhibiting osteoclastic activity. Thus, less bone is degraded during the remodeling cycle. First-, second-, and third-generation bisphosphonates are now available (alendronate, risedronate, and ibandronate). Because food and liquids can reduce the absorption of bisphosphonates, they should be given with a glass of plain water 30 minutes before the first meal or beverage of the day. Patients should not lie down for at least 30 minutes to lessen the chance of esophageal irritation. In addition, patients should consider taking supplemental calcium and vitamin D if their dietary intake is inadequate.

Bisphosphonates are of comparable efficacy to hormone replacement therapy in preventing bone loss and have a demonstrated positive effect on symptomatic and asymptomatic vertebral fracture rate as well as on nonvertebral fracture rate (forearm and hip). More than 4 years of treatment would be needed in women with low bone density (T score ≥ −2.0), but without preexisting fractures, to substantially reduce the risk of clinical fracture.

In clinical trials, alendronate was generally well tolerated and no significant clinical or biological adverse experiences were observed. Alendronate appears to be effective at doses of 5 mg daily in preventing osteoporosis induced by long-term glucocorticoid therapy. In placebo-controlled studies of men and women (aged 17–83) who were receiving glucocorticoid therapy, femoral neck bone density and the bone density of the trochanter and total body increased significantly in patients treated with alendronate.

Alendronate appears to be a safe, well-tolerated, and lower-cost agent for the osteoporosis and is a good first-line treatment. Some small-scale studies suggest an additional benefit of adding alendronate to hormone replacement therapy, and ongoing studies should provide additional information. However, all of the bisphosphonates accumulate over time in bone, and further research is needed to determine their long-term impact as well as their potential for use in premenopausal women and men.

Risedronate is a pyridinyl bisphosphonate approved as treatment for several metabolic bone diseases in 2000. In doses of 5 mg daily, risedronate reduces the incidence of vertebral fractures in women with two or more fractures by rapidly increasing BMD at sites of cortical and trabecular bone. In a randomized trial of 2458 postmenopausal women with diagnosed osteoporosis, participants were treated with either 2.5 mg or 5 mg of risedronate or placebo as well as calcium supplementation and cholecalciferol if they had low baseline 25-hydroxyvitamin D levels. The 2.5-mg dose was found to be ineffective in other trials and was discontinued. After 3 years of treatment, the 5-mg risedronate group showed a 41% reduction in risk of new vertebral fractures and a 39% reduction in incidence of nonvertebral fractures.

In a large, prospective, hip fracture prevention trial of elderly women, risedronate was shown to significantly reduce the risk of hip fracture in women with osteoporosis. Bisphosphonates should be prescribed for 3–4 years in women with osteoporosis and low bone density.

Ibandronate is currently approved by the Food and Drug Administration (FDA) for the treatment and prevention of osteoporosis in postmenopausal women. Over a 3-year period, ibandronate was shown to decrease the incidence of new vertebral fractures by 52% and to increase BMD at the spine by 5%. It can be administered daily or once a month.

Zoledronic acid was approved by the FDA in 2011 and is marketed as Reclast. A single annual intramuscular dose of 5 mg was studied in 1367 patients. Femoral neck BMD increasedby 3.7% above placebo 3 years after a single dose of zoledronic acid. Clinical fracture rates were reduced by 32% in patients receiving single infusions and 34% in those receiving three infusions over a 3-year period. There is no general agreement regarding how long to wait before repeating the injection.

Strontium ranelate is approved and used in the European Union and is effective in treating osteoporosis in both men and women.

More than 150 million bisphosphonate scripts were dispensed between 2005 and 2009. Postmarketing surveillance reports atypical femoral fracture, jaw osteonecrosis, and esophageal cancer. FDA reviews of alendronate, residronate, and zoledronic acid reveal rare side effects of 1 in 1000 to 10,000 users. Little additional benefit in fracture prevention is seen after 3–5 years of use, except for vertebral fractures.

E. Selective Estrogen Receptor Modulators

Raloxifene was the first drug to be studied from a new class of drugs termed selective estrogen receptor modulators. This drug has a mixed agonist-antagonist action on estrogen receptors: specifically, estrogen agonist effects on bone and antagonist effects on breast and endometrium. Its discovery evolved from a structural rearrangement of the antiestrogen tamoxifen, although it is structurally very different. It blocks estrogen in a manner similar to tamoxifen, while also binding and stimulating other tissue receptors to act like estrogen. Raloxifene inhibits trabecular and vertebral bone loss in a manner similar, but not identical, to estrogen (ie, by blocking the activity of cytokines that stimulate bone resorption).

Raloxifene therapy results in decreased serum total and low-density lipoprotein (LDL) cholesterol without any beneficial effects on serum total high-density lipoprotein (HDL) cholesterol or triglycerides. Reported side effects of raloxifene are vaginitis and hot flashes. Investigators in the Multiple Outcomes of Raloxifene (MORE) trial of >7000 postmenopausal, osteoporotic women over 3 years showed a decreased risk of breast cancer in those already at low risk for the disease. The study results were analyzed separately for women presenting with preexisting fracture. Although treatment effectiveness was similar in both groups, the absolute risk of fractures in the group with preexisting fractures was 4.5 times greater than in the group with osteoporosis, but no preexisting fracture (21% vs 4.5%). Thus, it is important to identify and treat patients at higher risk. Studies of women at higher risk for breast cancer are currently under way.

A summary of overall treatment strategies is given in Table 30-9, and guidelines for dosing the pharmacologic agents are given in Table 30-10. Table 30-11 summarizes the risks and benefits of osteoporosis therapy.

F. Other Modalities

Fluoride increases bone formation by stimulating osteoblasts and increasing cancellous bone formation in patients with osteoporosis. However, the bone is formed only in the spine and is abnormal—irregularly fibrous and woven with lacunae of low mineral density. Cessation of therapy resulted in rapid loss of much of the bone formed during treatment. The major side effect of fluoride therapy is gastric distress, an effect that is thought to be related to the direct effect of hydrofluoric acid on the gastric mucosa. Fluoride is also associated with joint pain and swelling. For these reasons, sodium fluoride is not routinely used for treatment of osteoporosis and does not have FDA labeling for this indication.

Anabolic therapy produces some increase in bone mass. Teriparatide (PTH 1-34), marketed under the trade name Forteo, or recombinant parathyroid hormone, is FDA-approved for the treatment of osteoporosis in perimenopausal women who are at high risk for fracture. Teriparatide also has FDA labeling for increasing bone mass in men with primary or hypogonadal osteoporosis who are at high risk for fracture. Unlike antiresorptive agents, teriparatide stimulates new bone formation. There are some concerns regarding extended use of teriparatide because of the long-term effects on multiple organ systems (ie, significant hepatotoxicity, reduced HDL, and elevated LDL cholesterol).

Teriparatide is the first approved agent for the treatment of osteoporosis that stimulates new bone formation. It is administered once a day by injection (20 μg/d) in the thigh or abdomen. Patients treated with 20 μg/d of teriparatide, along with calcium and vitamin D supplementation, had statistically significant increases in BMD at the spine and hip when compared with patients receiving only calcium and vitamin D supplementation. Clinical trials also demonstrated that teriparatide reduced the risk of vertebral and nonvertebral fractures in postmenopausal women. The effects of teriparatide on fracture risk have not been studied in men.

Of note, osteosarcoma developed in animals in early studies, and the possibility that humans treated with teriparatide may face an increased risk of developing this cancer cannot be ruled out. This safety issue is highlighted in a black box warning in the drug label for health professionals and explained in a brochure for patients. Children and adolescents with growing bones and patients with Paget disease of the bone have a higher risk for developing osteosarcoma and should not be treated with this agent. Because the effects of long-term treatment with teriparatide are not known, therapy for >2 years is not recommended.

Testosterone replacement is acceptable therapy for many of the causes of hypogonadism in men [eg, Klinefelter syndrome, isolated gonadotropin deficiency (Kallmann syndrome)].

Denosumab, a fully human, monoclonal antibody that inhibits Rank Ligand—a key modulator of osteoclast formation, function, and survival—was approved by the FDA in 2012. The FREEDOM study of 7808 postmenopausal women with osteoporosis compared 60 mg of denosumab with placebo given every 6 months for 36 months. DXA and quantitative CT scans were used for monitoring. Denosumab significantly increased BMD (bone mineral content) and does not appear to delay fracture healing. Denosumab usage warrants caution in the presence of hypocalcemia; serious side effects include skin infections, osteonecrosis of the jaw, and suppression of bone turnover, which could include atypical femoral fracture after long-term use.

G. Complementary and Alternative Therapies

Nutraceuticals are now being used more frequently by patients to promote bone health. There is a paucity of data confirming the benefit of these products, but likewise no evidence of harm. The most common nutraceuticals used for bone health are phytoestrogens (isoflavones, lignins, and coumestans), vitamin A, the B vitamins [B₂ (folate) and B₁₂], vitamin K, magnesium, and omega-3 fatty acids.

Evidence from animal studies suggests a beneficial effect of phytoestrogens on bone, but long-term human studies are lacking. Epidemiologic evidence that Asian women have a lower fracture rate than white women, even though the bone density of Asian women is less than that of African-American women, promotes consideration of the impact of nutrition. It is possible that high soy intake contributes to improved bone quality in Asian women. A comparison study of a soy protein and high isoflavone diet versus a milk protein diet or medium isoflavone and soy protein diet demonstrated that only those receiving the higher isoflavone preparation were protected against trabecular (vertebral) bone loss.

A topical form of natural progesterone derived from diosgenin in either soybeans or Mexican wild yam has been promoted as a treatment for osteoporosis, hot flashes, and premenstrual syndrome, and a prophylactic against breast cancer. However, eating or applying wild yam extract or diosgenin does not produce increased progesterone levels in humans because humans cannot convert diosgenin to progesterone.

All patients should be encouraged to maintain a bone-healthy diet. This includes reducing soft drink and sodium consumption, eating potassium-rich foods, encouraging iron and folate supplementation in adolescent females and women of childbearing age, and vitamin B₁₂ supplementation in persons aged 50 years and vitamin D supplementation in the elderly, in dark-skinned people, and in those with low UVB exposure.

H. Glucocorticoid-Induced Osteoporosis

Glucocorticoids are widely used in the treatment of many chronic diseases, particularly asthma, chronic lung disease, and inflammatory and rheumatologic disorders, and in those who have undergone organ transplantation. The risk that oral steroid therapy poses to bone mineral density, among other side effects, has been known for some time. As a result, clinicians have eagerly substituted inhaled steroids in an endeavor to protect the patient from unwanted negative steroid effects. Recent evaluations of the effects of inhaled glucocorticoids on bone density in premenopausal women demonstrated a dose-related decline in bone density at both the total hip and the trochanter. Women with asthma were enrolled and were divided into three groups: those using no inhaled steroids, those using four to eight puffs per day, and those using more than eight puffs per day at 100 μg per puff. No dose-related effect was noted at the femoral neck or the spine. Serum and urinary markers of bone turnover or adrenal function did not predict the degree of bone loss. To achieve the best possible outcome for the patient, given the potentially devastating effects of systemic steroids, therapy to combat the steroids should begin as soon as the steroids are begun. See Table 30-9 for specific guidelines.

American College of Rheumatology recommendations are to initiate bisphosphonate use in glucocorticoid-induced osteoporosis and to initiate therapy if: (1) the glucocorticoid use will equal or exceed 3 months, (2) if the patient has a T score of less than –1, or (3) if the patients receiving long-term glucocorticoid therapy have had fractures on, or cannot tolerate hormone replacement therapy.

Summary recommendations for postmenopausal women and men aged ≥50 years are to: (1) counsel on the risk of osteoporosis and fractures, (2) check for secondary causes, (3) advise on adequate calcium and vitamin D, (4) recommend regular exercise, and (5) advise on avoidance of tobacco and alcohol intake. In women aged ≥65 years and men aged ≥70 years, recommend BMD testing. In postmenopausal women between the ages of 50 and 69, recommend BMD testing based on the risk factor profile. Furthermore, when a patient has already experienced a fracture, recommend BMD to determine the severity of the disease.