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Osteoporosis is a major public health problem. There are an estimated 1.5 million fractures each year including 700,000 spine fractures, 300,000 hip fractures, and 250,000 wrist fractures (1;2). Although only about one-quarter to one-third of vertebral fractures are clinically evident, they can lead to loss of height, kyphosis, restrictive lung disease, abdominal distension, and increased mortality. Most hip fractures (90% in women and 80% in men) are associated with osteoporosis. Approximately 50% of patients who sustain a hip fracture lose the ability to walk independently; up to 24% of women and 30% of men die within the first year (2-4).

Unfortunately, osteoporosis is underdiagnosed and undertreated. In a recent retrospective study of patients with hip fractures, fewer than 15% of subjects were diagnosed and fewer than 13% were treated with medications for osteoporosis (including calcium and vitamin D) (5). Fracture patients require treatment of osteoporosis to help prevent subsequent fractures. Effective therapies to prevent and treat osteoporosis are available, but underutilized.

The preceding chapters by Dr. Clifford Rosen and Dr. Sundeep Khosla summarize the pathogenesis and the clinical evaluation of osteoporosis. This chapter will review established therapeutic options and new approaches for the prevention and treatment of osteoporosis. Strategies include both lifestyle and medical approaches to enhance bone strength. A regular weight-bearing program that includes exercise against gravity and weight training may lead to a modest increase in bone mass, muscle mass, and strength and reduce risk of falls that are often associated with the development of fractures (6).

CALCIUM

Adequate calcium intake is necessary to prevent calcium mobilization from the bone where 99% of calcium is stored. The effects of calcium supplementation on bone depend on age, menopausal status, calcium intake, and vitamin D sufficiency. Increased calcium intake is necessary during acquisition of peak bone mass and with advancing age. Calcium supplementation is ineffective or minimally effective for prevention of bone loss in women within 5 years of menopause when there may be predominant effects of estrogen deficiency and other hormonal changes (7). A meta-analysis of randomized clinical studies in postmenopausal women of the effects of calcium on bone showed that calcium decreased bone loss about 2% after two years or more (8). The Institute of Medicine's recommendations for daily calcium intake are shown in Table 1 (9). Unless a patient has an underlying disorder of calcium homeostasis, these amounts are generally safe. The risk of hypercalciuria and renal stones increases with a daily calcium intake of greater than 2500 mg; thus this is the upper safety limit.

While dairy products contain the largest amount of endogenous calcium, many foods including juices, cereals, cereal bars, and other products may contain added calcium. An 8-ounce glass of calcium-supplemented orange juice or milk contains ~300 mg of elemental calcium. Calcium carbonate contains 40% of elemental calcium and is a commonly used calcium supplement (e.g., Tums^TM, Oscal^TM, Caltrate^TM, and generic preparations). Calcium carbonate should be taken with food because patients with achlorhydria cannot absorb this calcium salt well on an empty stomach (10). Adverse effects of calcium carbonate may include bloating and constipation. Calcium phosphate (e.g., Posture^TM) may be associated with less constipation and fewer gastrointestinal side effects than calcium carbonate. Calcium citrate (e.g., CitracalTM), which contains 24% elemental calcium, is more bioavailable than calcium carbonate and can be taken while fasting.

VITAMIN D

Mild vitamin D deficiency is common. Low dietary intake, malabsorption, inadequate sunlight exposure, and diminished ability of the skin to synthesize vitamin D can each lead to vitamin D deficiency and secondary hyperparathyroidism. Mild vitamin D deficiency may not cause symptoms, but can contribute to low bone mass. Severe vitamin D deficiency causes osteomalacia. Currently, deficient levels of vitamin D are generally defined as a 25-(OH) vitamin D <15 ng/ml (11) and sufficient levels of vitamin D to prevent the rise in parathyroid hormone levels as a 25-hydroxy (OH)-vitamin D concentration of >32 ng/ml {12}. A study of women admitted with hip fractures showed that 57% had vitamin D deficiency with 25-hydroxy (OH)-vitamin D levels <15 ng/ml (13}. An observational study evaluating the relationship between postmenopausal hip fracture risk and calcium, vitamin D and milk consumption by Feskanich et al. reported that women consuming = 500 IU total vitamin D/day had a 37% lower risk of hip fracture than did women consuming < 140 IU/day (14). In a longitudinal, placebo-controlled study in nursing home subjects with low vitamin D levels, calcium (1200 mg) plus vitamin D (800 IU) reduced hip fractures by 43% at 18 months (15). In another study, calcium (500 mg) and vitamin D (700 IU) decreased bone loss and led to a 50% reduction in the incidence of non-spine fractures (16). A randomized controlled trial of British women and men between ages of 65 and 85 years reported reduction of fractures and restoration of Vitamin D levels to approximately 30ng/ml by intervention with 100,000 U of Vitamin D every 4 months. In addition, a meta-analysis of the effects of vitamin D on bone indicated that vitamin D reduced spinal fractures and may reduce non-spinal fractures (17). The effects of vitamin D on fractures may, in part, be mediated by its beneficial effects on lower extremity muscle function and fall reduction (18). Data from the Women’s Health Initiative, a large prospective, randomized, placebo-controlled study of the effects of calcium and vitamin D on fractures, bone density, and colorectal and breast cancers will be available after this study ends in 2005.

To prevent vitamin D deficiency, most treatment regimens should ensure adequate vitamin D intake (400-800 IU daily), although some newer data indicate that 1000 IU/d or more is required (19, 20}. Multivitamins typically contain 400 IU of vitamin D, and many calcium preparations are available with additional vitamin D. In the presence of vitamin D deficiency, vitamin D levels should be normalized to a 25-(OH) vitamin D concentration of >32 ng/ml to prevent the compensatory rise in parathyroid hormone (PTH) level (21, 22). High doses of vitamin D are needed (e.g., 50,000 IU weekly for 8 weeks or according to the 25-hydroxyvitamin D level), but patients on a high-dose regimen should be monitored closely for the development of hypercalciuria and hypercalcemia. Data show that supplemental cholecalciferol (vitamin D₃ ) leads to a 1.7-fold or greater rise in 25-OH vitamin D levels than supplementation with the plant sterol ergocalciferol (vitamin D₂ ) (23). Multivitamins vary greatly in whether they contain the more potent cholecaliferol or ergocalciferol; moreover, in the United States, 50,000 units of vitamin D is only available as ergocalciferol.

Other nutritional factors may contribute to the development of osteoporosis. Two research studies reported with tremendous concordance a link between the biochemical protein homocysteine and the occurrence of fractures in women and men (24, 25). Moreover, in elderly Japanese adults with stroke-related hemiplegia and a high hip fracture risk , compared with a placebo-treated group, those treated with 5 mg of folate and 1500 mcg of vitamin B₁₂ had lower homocysteine levels and a 5 times lower risk of hip fracture (26). If validated in larger populations and if the mechanisms are elucidated, then testing for homocysteine levels and repletion with folate and vitamin B₁₂ in some individuals may potentially play a role in the prevention and treatment of osteoporosis.

HORMONE REPLACEMENT THERAPY

In postmenopausal women, hormone replacement therapy (HRT) prevents bone loss and increases bone density through interaction with estrogen receptors on bone cells, activation of tissue-specific genes and proteins, and/or a reduction in cytokines that stimulate osteoclast function (27-30). As reviewed by Dr. Michelle Warren and Ms. Jennifer Dominquez in chapter 11 of the Female Reproductive Endocrinology section of Endotext, HRT has previously been the standard of care for postmenopausal women with low bone mass largely because observational studies showed that HRT reduced heart disease by about 50% (31-33). However, HRT is approved by the Food and Drug Administration (FDA) for the prevention, but not treatment, of osteoporosis. HRT has been shown to increase bone mineral density (BMD), but until recently fracture data from randomized controlled trials was limited and did not consistently show fracture reduction. Table 2 is a summary of several cohort studies and meta-analyses of the effects of HRT on bone density and fractures (34). This table does not include data from the Women's Health Initiative (WHI).

As indicated in Table 2, clinical trials have shown that HRT increases BMD. The Postmenopausal Estrogen/Progestin Interventions (PEPI) trial, a prospective, placebo-controlled clinical trial, studied the effects of 4 hormone replacement regimens on bone density in postmenopausal women (35). While estrogen and progestin replacement for 3 years led to an increase in bone density (3.5-5% at the spine and 1.7% at the hip), a subsequent 4-year extension in a subset of these women did not show any additional increments in bone mass (36). These data indicate that the greatest gains in bone density occur within the first 3 years of treatment.

While there are abundant data supporting a bone density benefit, the WHI is the first randomized clinical trial to show that HRT decreases hip fractures (37). The WHI is a large multicenter study of 161,809 postmenopausal women between 50 and 79 years investigating the effects of hormones (estrogen plus progestin or estrogen alone), calcium and vitamin D, and low-fat diets on cardiovascular disease, fractures, and breast and colorectal malignancies. In July 2002 the estrogen plus progestin arm of this study was stopped after 5.2 instead of the expected 8.5 years because health risks exceeded benefits. (The estrogen-only arm of the WHI in 10,739 hysterectomized women is scheduled for completion in 2005, as there has been no evidence of increased risk in this group of women. Of note, the Breast Cancer Detection Demonstration Project showed an increased risk of ovarian cancer among long-term estrogen-only users (38).

In the estrogen plus progestin arm of the WHI, 16,608 postmenopausal women were randomized to conjugated estrogen (0.625 mg/d) and medroxyprogesterone (2.5 mg/d) or placebo. Among these women, there were 106 cases of hip fracture (44 in the HRT group and 62 in the placebo group) and 101 cases of clinical vertebral fractures (41 in the HRT group and 60 in the placebo group). Both hip and clinical vertebral fractures were decreased by 34%. In addition there was a 23% decrease in other osteoporotic fractures (with a total of 1280 cases). For every 10,000 person-years, the HRT group experienced 5 fewer hip fractures and 6 fewer colorectal cancers (37).

While the WHI showed that HRT reduces fractures, the harm (increases in breast cancer, coronary heart disease (CHD), pulmonary embolism (PE), and stroke) outweighed the benefits. In this cohort, there were 290 cases of invasive breast cancer (166 and 124 in the HRT and placebo groups, respectively), 229 nonfatal myocardial infarctions (133 and 96 in the HRT and placebo groups, respectively), 59 CHD deaths (33 and 26 in the HRT and placebo groups, respectively), 212 strokes (127 and 85 in the HRT and placebo groups, respectively), and 101 cases of pulmonary embolism (70 and 31 in the HRT and placebo groups, respectively). These figures represent increases in the risk of breast cancer by 26%, CHD by 29%, stroke by 41% and pulmonary emboli by 113%. According to absolute risk analyses, for 10,000 person-years of estrogen plus progestin, there were 8 more cases of invasive breast cancer, 7 more CHD events, 8 more strokes, and 8 more pulmonary emboli (37). Of note, the increased risk of stroke and thromboembolic disease was evident in the first 1-2 years of use. The risk of breast cancer increased after 4 years of HRT and was greater in the older groups (34). In addition, in a smaller analysis of a subset of women older than 65 years many of whom started taking hormones later in life, there was a 2-fold increased risk of dementia among estrogen and progesterone treated women compared with placebo (39). The estrogen only arm of the WHI was stopped after 6.8 years because the data did not show prevention of cardiovascular disease and the risk of stroke increased (40). Compared with placebo, women randomized to estrogen showed a 39% reduction in hip fractures, and a 39% increase in the risk of stroke. There was no increased risk of breast cancer or an excess risk according to the global index; with a nonsignificant absolute risk of 2 events per 10,000 person years Among the women in the estrogen only arm who had a hysterectomy, about 40% of the women also had an oophorectomy. Topical estrogen can be used to treat urogenital symptoms (vaginal estrogen rings, pills, or creams). Estrogen and HRT are effective for the relief of moderate to severe menopausal symptoms.

The Heart and Estrogen/Progestin Replacement Study (HERS), a large randomized study of 2763 postmenopausal women with established CHD, also showed that HRT use increased the early risk of cardiac events, without long-term benefit when women were followed for up to 7 years (HERS II) (41, 42). The HERS study showed no reduction in the risk of fractures. The lack of fracture efficacy may be a result of more use of osteoporosis treatments in the placebo arm and possibly the low percentage of women with osteoporosis (15%) enrolled in the trial.

These data have important implications for the many women on HRT. On the basis of the available results from the HERS study and the WHI, there is no cardiac indication for long-term use of HRT. With data to support that HRT increases the risk of breast cancer and CHD, many postmenopausal women are stopping this therapy. For women on HRT, discontinuation of therapy is often best achieved by tapering off this treatment over several weeks to prevent or attenuate the development of menopausal symptoms. While earlier studies indicated that rapid bone loss occurred with discontinuation of HRT, recent data show that cessation of HRT leads to bone loss comparable to women not on HRT (36). On the basis of the data from the WHI, for control of vasomotor symptoms, estrogen or HRT (in women with an intact uterus) should be use at the lowest dose for the shortest duration of time and women should be informed about the potential risks. In women with severe symptoms associated with menopause, after a careful review of risks and benefits, short-term use of HRT (up to 5 years) at the lowest dose to control menopausal symptoms might be considered. Low doses of estrogen in HRT regimens (e.g., 0.3 mg conjugated estrogen or 0.3 mg esterified estrogen) increase bone mass in placebo-controlled trials, although the long-term safety has not been established (43, 44). Transdermal estrogens prevent bone loss and are available in low doses. Unlike oral estrogens, transdermal estrogens do not adversely affect clotting factors. Before estrogen is prescribed, the benefits versus the risks of cardiovascular disease, stroke, and breast cancer should be reviewed. Clonidine or venlafaxine (EffexorTM) may help reduce hot flashes (45). Alternative approaches (e.g., increased soy intake and black cohash) have been used, but studies are not available to support long-term efficacy and safety. Cardiovascular and osteoporosis risk can be prevented with lifestyle modifications that include smoking cessation, exercise, and limited alcohol. In addition, cardiac events can be prevented with lipid-lowering medications, aspirin, and control of hypertension. Osteoporosis can be treated with calcium, vitamin D, and the other effective interventions reviewed herein. According to the Surgeon General’s report on Bone Health and Osteoporosis 2004, effective prevention strategies and therapeutic interventions are available to optimize bone health and reduce the fractures that rise exponentially with age (46).Table 3 summarizes the current FDA approved therapies for the prevention and treatment of osteoporosis.

*Postmenopausal osteoporosis       †Glucocorticoid-induced osteoporosis

SELECTIVE ESTROGEN RECEPTOR MODULATORS

Selective Estrogen Receptor Modulators (SERMs) are a class of drugs that bind to estrogen receptors and selectively function as agonists or antagonists in different tissues. Raloxifene (Evista^TM) is a SERM that is FDA approved for the prevention and treatment of osteoporosis. The Multiple Outcomes of Raloxifene Evaluation (MORE) study is a randomized clinical trial of the effects of raloxifene versus placebo on bone density and fractures in 7705 postmenopausal women (mean age of 67 years) with osteoporosis (mean T-score of the spine and femoral neck of -2.6 and -3.2, respectively). Compared with placebo, raloxifene treatment for 3 years increased bone density of the spine by 2.6% and of the femoral neck by 2.1%. Over 3 years, raloxifene reduced spine fractures by 55% in women without prevalent vertebral fractures and by 30% in women with >1 prevalent vertebral fracture (47). Raloxifene therapy did not lead to a reduction in hip or wrist fractures, but there was not sufficient power to detect a 20% reduction in risk for these fractures. A 1-year extension of the MORE study showed vertebral fracture reduction at year 4 similar to that at year 3 (48). Data from the MORE study indicate that women with osteoporosis treated with raloxifene had a 76% reduction in the risk of breast cancer compared with the placebo group (49). In addition, raloxifene decreased LDL-cholesterol by 12%. Recent data, moreover, indicate that raloxifene did not produce an early increase in the risk of cardiovascular disease (CVD) and lowered cardiac events by 40% in women with a high cardiovascular risk (50). Large longitudinal studies to determine the effects of raloxifene on breast cancer and cardiovascular risk in women at risk for these diseases are in progress. The side effects of raloxifene include an increase in deep venous thrombosis similar to use of estrogen, along with hot flashes and leg cramps.

Tamoxifen, a SERM used for the prevention and treatment of estrogen receptor-positive breast cancer, has estrogen-like effects in bone. However, it also stimulates the endometrium and can result in uterine hyperplasia or malignancy (51). Investigations of the effects of several other SERMS on bone and other organ systems are underway.

CALCITONIN

Calcitonin is a 32-amino acid peptide produced by the parafollicular cells of the thyroid that inhibits bone resorption through direct effects on the osteoclasts. Calcitonin receptors, present on osteoclasts, have also been identified in numerous other cells including those in the gonads, the immune system, kidney, placenta, and central nervous system. Calcitonin is a highly conserved protein, with human and salmon calcitonin differing by only one amino acid.

Because of its antiresorptive properties, calcitonin has been used in the treatment of osteoporosis. In osteoporotic subjects, several studies have revealed that parenteral calcitonin (100 IU daily or every other day) prevented bone loss or produced a small increase in the bone density in the forearm, vertebrae, femoral diathesis, or total body. Following the administration of injectable calcitonin, Gennari et al. showed a dose-dependent increment in bone density (52). Civitelli and co-workers reported that parenteral calcitonin (only 50 IU on alternate days) was more effective in increasing vertebral bone density in women with a high turnover than in those with a normal bone turnover (53). A plateau effect at 19-26 months of treatment (tachyphylaxis) has been documented by Gruber et al., possibly as a consequence of a refilling of the remodeling spaces and/or down-regulation of the calcitonin receptors (54). Injectable salmon calcitonin was approved by the FDA in 1984 for the treatment of osteoporosis, although current use is limited because of the availability of calcitonin nasal spray and oral medications for the treatment of osteoporosis.

Calcitonin nasal spray is a newer form of calcitonin (55) and is approved by the FDA for the treatment of osteoporosis in women more than 5 years past menopause. The prospective, 5-year, placebo-controlled, Prevent Recurrence of Osteoporotic Fractures (PROOF) study examined the effects of calcitonin nasal spray (100, 200, or 400 IU/d) (MiacalcinTM) with calcium 1000 mg and vitamin D 400 IU per day on bone density and fractures. The PROOF study included 1255 postmenopausal osteoporotic women (average age 69 years) with low bone density (lumbar spine T-score of -2.0 or less) (56). Calcitonin nasal spray (200 IU daily) reduced the risk of new vertebral fractures by 33% compared with placebo. In women with one to five prevalent vertebral fractures calcitonin reduced the risk of new vertebral fracture by 36%. According to the PROOF study, there was no effect of calcitonin nasal spray on hip or other nonspine fractures. Although calcitonin nasal spray decreased spine fractures, there were minimal or no changes in bone density and small decrements in markers of bone turnover. Calcitonin may have alternative effects on microarchitecture and/or bone strength. Limitations of this study were the large drop-out rate and the lack of a dose-response curve for bone density and fracture efficacy for the 3 doses of calcitonin studied.

Calcitonin, particularly the calcitonin nasal spray preparation, has been shown to have an analgesic effect associated with an elevation in B-endorphin levels, although the pain relief persists in the presence of naloxone. Side effects of calcitonin are minimal and include flushing and pain at the injection site (with injections) and rhinorrhea (with calcitonin nasal spray).

BISPHOSPHONATES

Bisphosphonates, analogues of pyrophosphate, were first synthesized in the 19th century and were used for many years to prevent build-up of calcium crystals in industrial tanks. The biological properties of these compounds, however, were not recognized until the 1960s (57). Pyrophosphate, an endogenous substance, was shown to inhibit both formation and dissolution of calcium crystals in vitro and, when administered subcutaneously, to prevent ectopic calcification in vivo (58, 59). These observations led to the idea that pyrophosphate might serve as a regulator of bone turnover. Oral pyrophosphate, however, could not be used as a pharmacological agent because its P-O-P structure is rapidly degraded in vivo. Thus investigators turned to the bisphosphonates which are resistant to hydrolysis owing to their P-C-P structure. Subsequent studies showed that the bisphosphonates modulate bone and mineral metabolism in vivo (60). Potency and side effects of the bisphosphonates vary according to the side chains (see Table 4) (61, 62).

Mechanism of Action

Bisphosphonates inhibit bone resorption through complex cellular mechanisms. They have a strong affinity for calcium crystals and bind avidly to the surface of bone. Bisphosphonates interrupt osteoclast activity directly by inhibiting acid production, lysosomal enzymes, and the mevalonate pathway (63-65) and indirectly by acting through osteoblasts and macrophages. They also inhibit osteoclast recruitment (66) and induce osteoclast apoptosis (67). Thus, through various mechanisms, bisphosphonates reduce the depth of resorption pits (thereby producing positive bone balance at individual bone remodeling units) and decrease the formation of new bone remodeling units (68).

Pharmacodynamics

Oral bisphosphonates are poorly absorbed. Less than 3% is absorbed in the fasting state, and absorption is significantly reduced if the drug is taken with food or beverages other than water. The skeleton rapidly takes up approximately half of the absorbed bisphosphonate. The remainder is excreted unchanged by the kidney within hours. The drug remains at the bone surface for several weeks before becoming embedded in bone, where it is biologically inert. The embedded drug remains in bone for many years and is slowly released.

Effective Therapy for Osteoporosis

Alendronate (Fosamax^TM), risedronate (Actonel^TM), and ibandronate (Boniva^TM) are FDA-approved for osteoporosis; however, only alendronate and risedronate are commercially available in the United States (See Table 3).

Alendronate

Several longitudinal studies have shown that oral alendronate increases BMD and decreases the risk of osteoporotic fractures. In a study by Liberman et al., 994 postmenopausal women with osteoporosis (baseline T score of -2.5 or below at the lumbar spine) were randomized to daily oral alendronate or placebo for 3 years. Alendronate increased BMD (lumbar spine by 8.8%, femoral neck by 5.9%, trochanter by 7.8% and total body by 2.5%) and reduced the incidence of radiographic vertebral fractures by approximately 50% (69). This study, however, lacked sufficient power to demonstrate a significant effect on nonvertebral fractures.

The Fracture Intervention Trial (FIT), which had two study arms, investigated the effect of daily alendronate on vertebral and nonvertebral fractures in postmenopausal women with low bone mass. In the vertebral fracture study arm, 2027 women with at least one vertebral fracture at baseline and a femoral neck T score of -2.1 or less were randomized to receive alendronate or placebo for 3 years. Alendronate treatment increased femoral neck and spine BMD by 4.1% and 6.2%, respectively, and reduced the risk of vertebral, hip, and wrist fractures by approximately 50% (70). In the clinical fracture study arm, 4432 women without a vertebral fracture at baseline but with a femoral neck T score of -1.6 or less were randomized to alendronate or placebo for 4 years. Alendronate treatment increased BMD and reduced the risk of radiographic vertebral fractures by 44% but did not significantly decrease the risk of hip, wrist, or all clinical fractures. However, in a subgroup of the subjects in the clinical fracture study arm who had osteoporosis (baseline femoral neck T score of -2.5 or less), alendronate reduced the risk of hip and all clinical fractures by 56% and 36%, respectively (71). In summary, this trial demonstrated that alendronate therapy protects postmenopausal women with osteoporosis against vertebral and nonvertebral fractures and protects postmenopausal women with osteopenia against radiographic vertebral fractures but not clinical vertebral or nonvertebral fractures.

Hosking et al. demonstrated that alendronate is effective for the prevention of osteoporosis. They randomized 1174 postmenopausal women under 60 years of age to estrogen-progestin (either conjugated estrogens/medroxyprogesterone or cyclic micronized estradiol/norethindrone), alendronate, or placebo and measured BMD annually for 2 years. The placebo group lost BMD, whereas the alendronate (5 mg daily) and estrogen-progestin groups gained BMD. The alendronate group gained 3.5% in the lumbar spine, 1.9% in the hip, and 0.7% in the total body. The estrogen-progestin group gained 1% to 2% more than the alendronate group (72).
The prevalence of osteoporosis is lower in men than in women. Few longitudinal studies have evaluated the efficacy of treatment interventions on bone in osteoporotic men. Orwoll et al. enrolled 241 men with a femoral neck T score of -2 or less and a lumbar spine T score of -1 or less or a femoral neck T score of -1 or less and a history of osteoporotic fracture. Compared with placebo, alendronate significantly increased BMD at each site and decreased markers of bone turnover over 2 years. From baseline, alendronate increased BMD by 3.1% in the total hip and by 7.1% in the lumbar spine and decreased urinary N-telopeptides by 59% and bone-specific alkaline phosphatase by 38%. The incidence of vertebral fractures was 7.1% in the placebo group vs. 0.8% in the alendronate group. There was no significant difference in the incidence of nonvertebral fractures; however, the study was not powered to look at this endpoint (73).

Alendronate is effective in the treatment of glucocorticoid-induced osteoporosis. Alendronate increases BMD (74, 75) and decreases the incidence of radiographic vertebral fractures at 2 years (6.8% vs. 0.7%) in glucocorticoid-treated men and women (75).

Data show that weekly alendronate (70 mg) is effective and well tolerated, and this dosage has become the standard of care for use of this oral bisphosphonate. Alendronate is suitable for weekly dosing because of its long skeletal retention. In a one-year study of 1258 postmenopausal women with osteoporosis, there were no differences between alendronate 10 mg daily and 70 mg weekly on BMD or markers of bone turnover (76). Although clinical use of alendronate is associated with some GI symptoms and rare esophagitis, Lanza et al. carried out a placebo-controlled endoscopic study in 277 subjects and found that the incidence of upper GI symptoms and endoscopic lesions was similar in the placebo and weekly alendronate groups (77).

Long-term treatment with alendronate has beneficial effects on BMD. Bone et al. showed that spine BMD continued to rise in small increments during 7 years of treatment. Femoral neck and trochanter BMD increased during the first 3 years and then remained stable (78, 79).

Risedronate

Risedronate increases BMD and decreases fracture risk among postmenopausal women with osteoporosis. Harris et al. randomized 2458 postmenopausal women with established osteoporosis (subjects had either two or more vertebral fractures or one vertebral fracture and lumbar spine T score of -2 or less) to risedronate or placebo. Over 3 years, risedronate (5 mg daily) increased lumbar spine BMD by 5.4% and femoral neck BMD by 1.6%. Over 6 months, risedronate (5 mg daily) decreased the deoxypyridinoline-creatinine ratio by 38% and bone-specific alkaline phosphatase by 35%. Risedronate (5 mg daily) decreased the risk of new vertebral fractures by 41% and decreased the risk of nonvertebral fractures by 39% at 3 years (80). Reginster et al. provided further evidence that risedronate protects against fracture among postmenopausal women with established osteoporosis (subjects had two or more vertebral fractures at baseline). Within 6 months risedronate increased spine and hip BMD and during the first year decreased the risk of new vertebral fracture by 61%. This study demonstrated radiologically that risedronate can have an important impact on fractures within the first year of therapy. Over 3 years the risk of vertebral and nonvertebral fractures was reduced by 49% and 33%, respectively (81).

In a large study of 9331 postmenopausal women, McClung et al. demonstrated that risedronate reduces the risk of hip fracture among postmenopausal women with osteoporosis but not among elderly women selected on the basis of clinical risk factors for hip fracture. Among 5445 postmenopausal women with osteoporosis, risedronate decreased the risk of hip fracture by 40% over 3 years. However, among the 3886 elderly women with clinical risk factors (i.e., difficulty standing from a seated position, poor gait, recent fall-related injury, poor hand-eye coordination, recent smoking, maternal history of hip fracture), risedronate had no effect on the incidence of hip fractures (82).

These results highlight the importance of BMD measurement and the presence of prevalent fractures instead of clinical risk factors in identifying patients likely to benefit from bisphosphonate therapy.

Risedronate is effective in the prevention and treatment of glucocorticoid-induced osteoporosis in men and women. Risedronate (5 mg daily) prevents glucocorticoid-induced bone loss (83) and reduces the risk of radiographic vertebral fractures by 70% after 1 year of treatment (84).

Weekly risedronate (35 mg) is effective and well tolerated (85-87). Brown et al. randomized 1468 women to daily or weekly risedronate. The increase in lumbar spine BMD at 1 year was similar between groups. Weekly risedronate was well tolerated, and the occurrence of adverse events was similar in daily and weekly treatment groups (85).Long-term treatment with risedronate has beneficial effects on bone. Mellstrom et al. showed that lumbar spine BMD continued to increase during 7 years of treatment and fracture data demonstrate no loss of anti-fracture efficacy during the 6-7 year time period (88).

Recently the first head-to-head BMD comparison trial between alendronate and risedronate was published. Alendronate produced greater increases in BMD at 12 months at all sites and produced greater decreases in markers of bone turnover at 3 months compared with risedronate (89). However, this 12 month trial was not powered to look at fractures and it is unclear whether greater increases in BMD correlate with improved anti-fracture efficacy.

Other Bisphosphonates

Etidronate is not FDA-approved for the prevention or treatment of osteoporosis; however, it is used in other countries for this indication. Continuous treatment with high-dose etidronate can inhibit mineralization and potentially lead to osteomalacia. This adverse effect is decreased by use of cyclic administration (5-10 mg/kg daily for 2 weeks repeated every 3 months). A recent meta-analysis revealed that etidronate increased BMD (by 4.06% in the spine and 2.35% in the femoral neck) after 1 to 3 years of treatment in postmenopausal women and reduced the risk of vertebral fracture by 37% (90). Concerns about the efficacy and safety of etidronate have limited its use.

Ibandronate is FDA-approved for the prevention and treatment of postmenopausal osteoporosis at a dose of 2.5 mg daily. However, it is not currently available in the United States. While ibandronate is approved as a daily agent, it has also been shown to increase bone density and decrease vertebral fractures when administered intermittently (91).
Pamidronate does not have FDA approval for use in osteoporosis; however, it is occasionally used "off-label" for patients with a variety of conditions, including esophageal abnormalities (i.e., stricture or achalasia) and organ transplants. Usually 30 to 60 mg is infused over 2 to 4 hours every 3 months. Data regarding the efficacy of pamidronate on increasing BMD and reducing fractures are limited.

Zoledronic acid, an intravenous bisphosphonate, is FDA-approved for the treatment of hypercalcemia of malignancy, multiple myeloma, and bone metastases from solid tumors. It is considerably more potent than other available bisphosphonates. Thus small doses and longer dosing intervals may be used (92). Reid et al. showed that zoledronic acid increases BMD and decreases markers of bone turnover in postmenopausal women. A single infusion of 4 mg of zoledronic acid increased BMD at the lumbar spine by about 4.5% and suppressed markers of bone turnover (serum C-telopeptide and the ratio of urinary N-telopeptide to creatinine) by approximately 50% to 65% at 12 months (93). The observed effects on bone were similar to those achieved with daily oral bisphosphonates. Phase III trials are currently under way to assess the efficacy of zoledronic acid for the prevention of osteoporotic fractures.

Combination Therapy

Combined use of a bisphosphonate plus estrogen/progesterone, estrogen, or raloxifene appears to be well tolerated and has been shown to produce slightly greater increments in bone mass than monotherapy (94-97). However, there are no fracture data on combination therapy. The role of combination therapy is unclear, but perhaps patients with severe osteoporosis or those who lose bone with monotherapy without a known secondary cause for continued bone loss might benefit from this approach. Combined use of a bisphosphonate plus PTH is not recommended and is discussed in the PTH section of this chapter.

Adverse Effects

In general, the bisphosphonates, and rare cases of severe chemical esophagitis have been reported with alendronate and oral pamidronate. Because of the risk of esophagitis, alendronate is contraindicated for patients with esophageal abnormalities such as stricture or achalasia and both alendonate and risedronate are contraindicated for patients who are unable to stand or sit upright for at least 30 minutes after drug administration. In controlled trials, the incidence of GI adverse effects did not differ in the alendronate and placebo groups, but in clinical practice, some patients discontinue bisphosphonates because of adverse GI experiences. Weekly alendronate appears to be better tolerated than daily alendronate (77), and weekly risedronate is well tolerated among patients who discontinued alendronate because of adverse upper GI experiences (87). In a 2-week head-to-head endoscopic trial, risedronate was associated with fewer gastric ulcers than was alendronate. No significant between-group difference was noted in esophageal or duodenal endoscopic scores; however, the study was not powered to detect a difference in these endpoints (98). In a 12 month head-to-head comparison trial between alendronate and risedronate there was no difference in the incidence of upper GI side effects between the alendronate and risedronate groups (99).

Acute-phase reactions (i.e., fever, malaise, myalgia) may occur and are seen in up to 10% to 20% of subjects following intravenous administration of pamidronate or zoledronic acid (93). Patients often are premedicated with acetominophen, and symptoms are usually mild and transient. Hypocalcemia may occur, but this is usually mild and asymptomatic; to avert marked hypocalcemia it is important to ensure that the patient is vitamin D sufficient. Bisphosphonates are excreted by the kidneys and because of lack of experience should not be used for patients with severe renal insufficiency (creatinine clearance < 35 ml/min). Further studies using lower doses of bisphosphonates for patients with renal insufficiency are warranted.

Drug Administration

Oral bisphosphonates should be taken in the morning with water on an empty stomach. Because oral bisphosphonates are poorly absorbed, patients should wait at least 30 minutes before ingesting other beverages, food, or medications. To help patients avoid esophageal irritation, they are instructed to swallow oral bisphosphonates with 6 to 8 ounces of water and to remain upright for at least 30 minutes and until they have had their first meal of the day (100).

Intravenous preparations must be infused slowly (3-4 hours for pamidronate or 15 minutes for zoledronic acid) to avoid renal toxicity.

PARATHYROID HORMONE

Anabolic Action on Bone

In November 2002, the FDA approved teriparatide (ForteoTM), injectable recombinant human PTH (1-34), for the treatment of men and postmenopausal women with osteoporosis who are at high risk for fracture. Antiresorptive agents, such as estrogen, raloxifene, and the bisphosphonates, increase BMD by up to 8%. However, many patients with osteoporosis have lost as much as 30% of their peak bone mass. Thus, agents that trigger more dramatic recovery of BMD are desirable (101). PTH directly stimulates bone formation and can have robust effects on BMD.

It may seem paradoxical that PTH increases BMD, given that primary hyperparathyroidism is associated with low bone mass. Severe longstanding primary hyperparathyroidism can cause bone destruction, fractures, and bone cysts. However, mild primary hyperparathyroidism is often asymptomatic and has variable effects on bone. While cortical BMD (e.g., in the distal 1/3 of the radius) tends to be decreased in mild primary hyperparathyroidism, trabecular BMD (e.g., in the vertebral bodies) is often well preserved even in postmenopausal women (102, 103). Clearly, the effects of PTH on bone metabolism are complex.

Animal studies show that PTH is capable of both anabolic and catabolic actions on bone. PTH stimulates both bone formation and bone resorption; the net effect on BMD depends on the balance between these two processes (104). A continuous infusion of PTH increases both formation and resorption and leads to bone breakdown (104,105). However, intermittent exposure preferentially increases formation thereby producing an anabolic effect on bone (104,106,107). Thus, PTH can increase or decrease BMD depending on the pattern of exposure.

Cellular Mechanisms

PTH acts directly on osteoblasts and cells of the osteoblast lineage. PTH promotes differentiation of preosteoblasts to osteoblasts (105) and inhibits osteoblast apoptosis, thereby increasing the number of active osteoblasts (108). Furthermore, PTH triggers the production of several growth factors in bone cells, including insulin-like growth factor I (IGF-I) (105, 109).

Clinical Studies

In 1976, Reeve et al. published the first clinical trial of PTH for osteoporosis in humans. The investigators treated four postmenopausal osteoporotic women with 100 mg PTH (1-34) daily for 6 months and noted marked increases in bone turnover (as measured by isotopic tracer and histological methods) with greater increases in formation than resorption (110). In a subsequent study of osteoporotic men and women, PTH (1-34) increased iliac trabecular bone mass by approximately 70% (111). Slovik et al. treated 8 osteoporotic men with PTH (1-34) plus 1,25 dihydroxyvitamin D. After one year of treatment, BMD of the lumbar spine BMD (measured by quantitative computed tomography) increased almost twofold and BMD of the radius (measured by single photon absorptiometry) remained stable (112).

Subsequent trials using dual-energy X-ray absorptiometry (DXA) as a measure of BMD have confirmed these earlier studies. A beneficial effect of PTH (1-34) on BMD has been documented in a variety of patient populations including men with idiopathic osteoporosis (113, 114), young women with estrogen deficiency caused by gonadotropin-releasing hormone (GnRH) agonists (115,116), patients with glucocorticoid-induced osteoporosis (117,118), and postmenopausal women with osteoporosis (119-121). In men, daily doses of 400 IU PTH (1-34) increased lumbar spine BMD by 13.5% and femoral neck BMD by 2.9% over 18 months. BMD in the distal 1/3 of the radius did not change (113). Finkelstein et al. studied the effects of PTH in young women with acute estrogen deficiency caused by GnRH analogues. At 12 months, PTH maintained BMD in the hip and total body and increased BMD in the anterior-posterior lumbar spine by 2.1% (the control group lost 2.8% from the lumbar spine) (116). PTH has been shown to increase markers of bone turnover by as much as 200% (113;117), with earlier effects on markers of bone formation than on markers of bone resorption (117). Paired iliac crest biopsies reveal that, in addition to increasing bone mass, PTH also improves trabecular bone microarchitecture (122).

Fracture data

In addition to increasing BMD, PTH has also been shown to decrease fracture risk. In a 3-year trial, investigators randomized 52 postmenopausal women on HRT (T score -2.5 or less or baseline vertebral fracture) to PTH (1-34) (25 µg daily) or control. The PTH + HRT group (average age 57.7) showed progressive increases in BMD over 3 years, whereas the HRT alone group (average age 62.9) had no significant change in BMD. The PTH + HRT group showed an increase of 13.4% in the spine, 4.4% in the total hip, and 3.7% in the total body at 3 years. PTH + HRT therapy was associated with a 75-100% decrease in the rate of radiographic vertebral fractures compared with HRT alone. (This study did not have sufficient power to assess the effect of PTH on nonvertebral fractures.) Of note, subjects were followed for one year after discontinuing PTH (HRT was continued in all subjects), and their BMD remained stable (119,120), suggesting that PTH may have sustained benefit on bone.

In a multicenter randomized placebo-controlled trial, 1637 postmenopausal women with baseline vertebral fractures were randomized to 20 µg PTH daily, 40 µg PTH daily, or placebo. At a mean of 18 months follow-up, 20 µg PTH daily increased lumbar spine BMD by 9.7%, femoral neck BMD by 2.8%, and total hip BMD by 2.6%. There was a decrease of 0.1% at the distal radius, but this was not significantly different from the change seen in the placebo group. PTH (20 µg daily) reduced the risk of vertebral fractures by 65% and nonvertebral fragility fractures by 53%. The two PTH doses reduced fractures to a similar degree, but headache and nausea were more common in the group receiving the higher dose of 40 µg daily (121).

Combination Therapy

The effects of concurrent or sequential therapy with PTH and antiresorptive agents have been studied. Black et al. compared the effects of PTH (1-84), alendronate, or both in combination in postmenopausal women (123}. At one year, spine DXA had increased in all 3 groups. There was no difference in spine DXA between the PTH group and the combination group. However, the PTH group had a significantly greater increase in volumetric BMD of the spine on quantitative CT than the alendronate and combination groups. Finkelstein et al. also carried out a study in men (124). PTH (1-34) was started at month 6 and all three groups were followed for 30 months. Spine BMD as measured by both DXA and quantitative CT increased to a greater degree in the PTH group than in the alendronate and combination groups. Combination therapy produced greater increases in spine BMD than alendronate, but PTH alone appears more effective than combination therapy. These studies show no evidence of synergy between PTH and alendronate. Furthermore, alendronate may impair the anabolic activity of PTH. It is hypothesized that PTH is less effective when bone turnover is suppressed. Ettinger et al. found that prior treatment with alendronate prevented PTH-induced increases in BMD while the group previously treated with raloxifene experienced the expected increase in BMD with PTH treatment. Baseline markers of bone turnover were lower in the alendronate group (125). This is an important area for further research as many patients being considered for PTH therapy have been previously treated with antiresorptive agents.

While concurrent treatment with PTH and alendronate does not appear to be additive, bisphosphonate therapy initiated immediately upon completion of PTH course is beneficial. Rittmaster et al. demonstrated that PTH followed by alendronate produces progressive increases in BMD. In this study, 66 postmenopausal women were randomized to either 50 µg recombinant human PTH (1-84) daily or placebo for the first year, and then all subjects were treated with alendronate on an open label extension for the second year. During the first year, the PTH group gained 4.3% BMD at the lumbar spine while the placebo group gained 1.3%. During the second year, the PTH group gained 6.3% BMD at the lumbar spine while the placebo group gained 5.7%. Thus, subjects previously treated with PTH continued to gain BMD with subsequent alendronate therapy (126). Kurland et al. reported similar findings in men {127). Twenty-one men were followed for up to 2 years after discontinuing PTH (1-34). Those who decided to go on bisphosphonate therapy immediately upon completion of the PTH course gained an additional 8.9% BMD at the lumbar spine at 2 years while the men who did not go on bisphosphonate therapy lost 3.7% BMD at the lumbar spine at 1 year. These studies support the immediate use of bisphosphonates upon completion of the recommended 18- to 24-month course of PTH therapy

Adverse Effects

In general, teriparatide, recombinant human PTH (1-34), injections are well tolerated. PTH is cleared from the circulation within 4 hours of subcutaneous administration (87). A daily injection is necessary and transient redness at the injection site has been noted. Headache and nausea occur in fewer than 10% of subjects receiving a daily dose of 20 µg. Mild transient hypercalcemia can occur, but severe hypercalcemia is rare. Increases in urinary calcium (by 30 µg per day) and serum uric acid concentrations (by 13%) are seen but do not appear to have clinical consequences.

Fisher 344 rats treated with nearly life-long daily teriparatide have an increased risk of osteosarcoma. There are no reported cases of osteosarcoma in humans treated with teriparatide, and no association has been found between primary hyperparathyroidism and osteosarcoma. On the basis of the above data, teriparatide should not be used for patients at increased risk for bone tumors. The manufacturer warns against using teriparatide in the following settings: Paget's disease or unexplained elevations of alkaline phosphatase, children or young adults with open epiphyses, bone metastases, prior radiation therapy involving the skeleton, metabolic bone disease other than osteoporosis, and hypercalcemia.

Drug Administration

Teriparatide is supplied in a disposable pen device for subcutaneous injection into the thigh or abdominal wall. The recommended dosage is 20 µg once a day for no more than 2 years. The safety and efficacy of the teriparatide preparation have not been evaluated beyond 2 years of treatment.

OTHER THERAPEUTIC CONSIDERATIONS

Strontium ranelate is another therapeutic agent that increases bone turnover with a net rise in bone formation that is greater than bone resorption. Although not FDA-approved for therapy in the United States, in a multi-centered study in 1442 postmenopausal women compared with the placebo group, strontium ranelate increased bone density and reduced spine fractures by 41% in 3 years (128). Emerging data shows that the receptor activator of nuclear factor-kappa B ligand (RANKL) produced by the osteoblast plays an important role in osteoclast activation, recruitment, and differentiation. New data from animal studies and postmenopausal women show that a monoclonal antibody to the RANKL can inhibit bone turnover with sustained effects over several months (129). In addition, use of other inhibitors of RANKL may also suppress bone resorption. Additional studies are necessary in humans to show safety and efficacy of these inhibitors of bone turnover for the treatment of osteoporosis.

SUMMARY

At present, a number of safe effective therapies for osteoporosis are available. Antiresorptive agents, such as the bisphosphonates, estrogen, and raloxifene, produce modest improvements in bone mass and substantially reduce fractures, in some instances within 1 year of use. Teriparatide, recombinant human PTH (1-34), is the only anabolic agent currently available and it may prove most useful when the recommended 18- to 24-month course is followed with bisphosphonate therapy. For osteoporosis, a disease with a strong genetic component, the impact of genetic discovery and pharmacogenomics hold promise for the future.