Review of treatment modalities for postmenopausal osteoporosis.

Abstract: This review summarizes and updates data presented at recent annual Southern Medical Association conferences on postmenopausal osteoporosis. As part of any osteoporosis treatment program, it is important to maintain adequate calcium and 25-hydroxyvitamin D levels either through diet or supplementation. Among the available pharmacologic therapies, the bisphosphonates alendronate and risedronate have demonstrated the most robust fracture risk reductions--approximately 40 to 50% reduction in vertebral fracture risk, 30 to 40% in nonvertebral fracture risk, and 40 to 60% in hip fracture risk. Ibandronate, a new bisphosphonate, has demonstrated efficacy in reducing vertebral fracture risk. Salmon calcitonin nasal spray and raloxifene demonstrated significant reductions in vertebral fracture risk in pivotal studies. Teriparatide significantly reduced vertebral and nonvertebral fracture risk. Drugs on the horizon include strontium ranelate, which has been shown to reduce vertebral and nonvertebral fracture risk, and zoledronic acid, an injectable bisphosphonate that increased bone density with once-yearly administration.

Key Words: postmenopausal osteoporosis, drug therapy, fractures, efficacy, tolerability 

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Osteoporosis is a disease of compromised bone strength that results from decreased bone mass and bone quality as people age, especially in women as they enter their postmenopausal years. In the United States, the number of women aged 50 or older with osteoporosis is estimated at 8 million, and those with low bone mass, at 22 million. (1) By 2010, these numbers are predicted to increase to 9 million and 26 million, respectively.

The most devastating consequence of osteoporosis is fractures, especially those of the hip. More than 1.5 million osteoporotic fractures occur annually in the United States, of which 700,000 are vertebral fractures and 300,000 are hip fractures. (2) A 50-year-old white woman has a 50% risk of experiencing an osteoporotic fracture in her lifetime. (1) Compared with women without fractures, peri- and postmenopausal women with fractures have a higher risk of subsequent fracture. (3,4) Osteoporotic fractures are associated with significant increases in morbidity and mortality, and a compromised quality of life. (5-9) Direct medical expenditures for managing osteoporotic fractures are estimated to be S17 billion annually. (2)

Despite attempts to increase awareness of osteoporosis among clinicians and the general public, osteoporosis remains underdiagnosed and, consequently, undertreated. (10-16) An osteoporosis diagnosis or workup is often not performed, even in patients who have experienced a fragility fracture. (12) The challenge for primary care physicians is to diagnose and treat those at risk for osteoporosis before fractures occur, as well as to treat patients who have already experienced an osteoporosis-related fracture to prevent further fractures.

There are currently a number of pharmacologic options available for patients with osteoporosis in addition to lifestyle modifications. This review summarizes and expands on the antifracture efficacy and tolerability data presented at recent Southern Medical Association annual conferences on currently available therapeutic modalities for postmenopausal osteoporosis, as well as new therapies in development.

Calcium and Vitamin D 

The skeleton contains more than 98% of the body's calcium stores; calcium is mobilized from the skeleton to maintain constant serum levels if exogenous supplies of calcium are low. (17) Calcium absorption increases in children during periods of rapid growth and in women during pregnancy and lactation. Aging decreases the adaptation that absorbs calcium from a low-calcium diet. (17) On average, 100 to 200 mg of calcium are lost in gastrointestinal (GI) secretions daily, 50 to 300 mg/d are lost through urinary excretion, and about 100 mg are lost in sweat on a warm day. (17)

Adequate daily intake of calcium is 1,000 mg/d for adults up to the age of 50, and 1,200 mg/d for adults older than 50 years of age. (18) The National Osteoporosis Foundation recommends a daily calcium intake of 1,200 mg for postmenopausal women. (19) Major dietary sources of calcium include dairy products (Table 1). (20)

There are also many formulations of calcium supplementation available. In order for the calcium supplements to be absorbed, they must dissolve in the stomach. (21) Most commercial preparations meet the dissolution standards of the US Pharmacopeia. (21) In order for patients to determine whether their calcium supplement is bioavailable, they can dissolve their supplement in white vinegar, which mimics the pH of the stomach. If the supplement does not dissolve in 20 minutes, then it will not dissolve in their stomach. Calcium supplements that are chewed are automatically bioavailable. Patients should also take calcium supplements with food, which increases absorption because the grinding action of the stomach breaks up the calcium tablet. Calcium carbonate is absorbed in achlorhydric patients as long as it is taken with a meal. (22)

Vitamin D is essential for increasing the efficiency of intestinal calcium absorption. Indeed, in individuals who are vitamin D deficient, no more than 15% of dietary calcium is absorbed, whereas in individuals who are not vitamin D deficient, 30 to 80% of the dietary calcium is absorbed. (23) The body has a large capacity to make vitamin D. A person wearing a bathing suit and being exposed to an amount of sunlight that causes a slight pinkness to the skin (1 minimal erythemal dose [MED]) receives the equivalent of between 10,000 to 20,000 IU of vitamin [D.sub.2] orally. Thus, exposure of 25% of the body to approximately 0.25 MEDs (approximately 5-10 min of sun exposure 2-3 times a week from 10 AM to 3 pm) will satisfy the body's vitamin D requirement in the spring, summer, and fall. Vitamin [D.sub.3] can not be produced during the winter at latitudes above Atlanta, Georgia (37[degrees]). Vitamin D absorption and formation in the skin decreases with aging.

Some fish liver oils like cod, tuna, shark, and oily fish are a good natural source of vitamin D. Typically, a teaspoon of cod liver oil contains 400 IU of vitamin D, and a 3.5 ounce serving of salmon provides 400 to 500 IU of vitamin D. Egg yolk will sometimes contain vitamin D (approximately 50 IU), but this is not a good source because there are relatively tiny amounts present, and it is highly variable. Other dietary sources include fortified foods such as cereals and beverages such as milk, orange juice, soy or rice beverages, some yogurts, and margarines. (24)

Although vitamin D deficiency is highly prevalent in adults older than 50 years of age, (25-29) it is now being appreciated that vitamin D deficiency is also very common in young and middle-aged adult patients, (30) as well as teenagers and young adults. (31-33) The recommended adequate intake of vitamin D is 200, 400 or 600 IU/d for all children and adults up to the age of 50, 51 to 70 years, and 71 years and above, respectively. (34) However, this amount is inadequate if the child or adult has little exposure to sunlight. Without exposure to sunlight, 1,000 IU of vitamin [D.sub.3]/d is now recommended. (35) Individuals with vitamin D deficiency (ie, 25-hydroxyvitamin D [25(OH)D] <20 ng/mL or 50 nmol/L) should receive 50,000 IU of vitamin [D.sub.2] once a week for 8 weeks. (26) To maintain vitamin D sufficiency, keeping a patient on 50,000 IU vitamin [D.sub.2] once or twice a month is effective in maintaining a 25(OH)D in what is considered to be a healthy range of 30 to 40 ng/mL. (24)

Clinical efficacy

Vertebral fractures. Calcium supplementation significantly reduced morphometric vertebral fracture incidence in patients with prevalent vertebral fractures at baseline (36,37) but not in patients without prevalent vertebral fracture (37) (Table 2). In a study that compared calcitriol, a synthetic vitamin D analog, 0.25 [micro]g twice daily against calcium 1,000 mg/d in postmenopausal women with prevalent vertebral fracture, vertebral fracture risk was significantly reduced after 2 years and after 3 years in calcitriol recipients versus calcium recipients (Table 2). (38)

Hip/nonvertebral fractures. Neither hip nor nonvertebral fracture risk was significantly reduced after 3.5 years of vitamin D treatment in a study of 2,578 older women and men (about 25% of the study population) living either independently (about 40%) or in an elderly housing setting (Table 2). (39) The results were similar when the female patients were considered separately. (40) Patients in this study did not receive a calcium supplement and may have been in overall better health than patients in the other studies discussed in Table 2.

Vitamin D plus calcium 1,200 mg/d significantly reduced hip fracture incidence by 43% (P = 0.043) after 18 months' treatment with 800 IU/d in older women living in a nursing home or elderly housing setting (Table 2). (41) Nonvertebral fracture incidence was reduced by 32% (P = 0.015) in this study. (41) Similarly, 3-year nonvertebral fracture risk was significantly reduced by vitamin D (700 IU vitamin [D.sub.3]/d) treatment in a population of 389 patients living at home (50% reduction; P = 0.02). (42) About 45% of the study population were men; however, the results were not different when women were considered separately (55% reduction; P < 0.05). (40) Calcitriol 0.25 [micro]g twice daily versus calcium 1,000 mg/d significantly reduced 3-year nonvertebral fracture risk in 622 postmenopausal women with prevalent vertebral fracture (Table 2). (38)

In the Randomized Evaluation of Calcium or vitamin D (RECORD) trial, vitamin [D.sub.3] alone, calcium alone, or a combination of the 2 agents did not produce a significant reduction in further fractures in mobile elderly patients (85% women) who had already experienced a low-trauma fracture. (43) Patients in the RECORD trial were younger, healthier, and more mobile than patients in the Chapuy et al study (41) and, therefore, were less likely to have vitamin D deficiency.

Results from another recent large study in older postmenopausal women living in the community with at least 1 risk factor for hip fracture reported no significant reduction in clinical fractures over 2 years. (44) Poor compliance in this study (63% adherence after 1 yr) and the RECORD trial (60% of patients took 80% of their doses over 2 years) may have been a factor in the lack of response to treatment. Nonetheless, these studies suggest that vitamin D/calcium supplementation alone is probably insufficient therapy for prevention of nonvertebral fractures.

Tolerability

Calcium and vitamin D supplementation are generally well tolerated. Adverse events in the calcium studies were minor and mild in severity, and were mostly GI in nature, including abdominal cramping, constipation, bloating, or diarrhea. (36,37) In the vitamin D studies, the most commonly reported adverse events were GI in nature, with both studies reporting slightly more withdrawals due to GI adverse events in the calcium group than in the control group (40/1,634 versus 28/1,636). (36,37,41)

Bisphosphonates

Bisphosphonates have a strong affinity for hydroxyapatite crystals in bone and are potent inhibitors of bone resorption. (45) These agents are nitrogen-containing bisphosphonates that inhibit enzymes of the mevalonate pathway, disrupting the function of key regulatory proteins and ultimately induce apoptosis and a reduction in osteoclast activity. (46,47) The 3 bisphosphonates currently approved for the prevention and treatment of postmenopausal osteoporosis, in order of their approval by the Food and Drug Administration (FDA), are alendronate, (48) risedronate, (49) and ibandronate. (50) Alendronate is available as a once-daily or once-weekly dose (5 mg/d or 35 mg once weekly for prevention and 10 mg/d or 70 mg once weekly for treatment). (48) Recently, a once-weekly preparation containing alendronate 70 mg and cholecalciferol 70 [micro]g (equivalent to vitamin D 2,800 IU) was approved for treatment of postmenopausal osteoporosis. (51) Risedronate is also available as once-daily or once-weekly doses for the prevention and treatment of postmenopausal osteoporosis (5 mg daily or 35 mg once weekly for both indications). (52) In addition, ibandronate 2.5 mg/d or 150 mg/mo can be prescribed for both indications. (50) This section reviews data from large pivotal studies of the available bisphosphonates. It should be emphasized that in all trials, controls received various amounts of calcium and vitamin D. It also should be noted that in many studies enrollment was based on the densitometer manufacturers' reference population and only later were National Health and Nutrition Examination Survey equivalents applied.

Alendronate

Clinical efficacy. Vertebral fracture. Table 3 summarizes clinical data from large prospective clinical trials of alendronate. Morphometric vertebral fracture risk was consistently reduced by alendronate in 3 of these studies (range 44-48% risk reduction after 3 or 4 years of treatment). (53-55) These data are consistent with those obtained in a meta-analysis, which reported a 48% reduction in morphometric vertebral fracture risk for pooled alendronate studies of at least 2 years' duration and using a dose of at least 5 mg/d. (56)

In a post hoc analysis of combined Fracture Intervention Trial (FIT) data, alendronate significantly reduced the 1-year risk of clinical vertebral fractures by 59% (P < 0.001) in a subgroup of FIT patients with at least 1 vertebral fracture or femoral neck bone mineral density (BMD) T-score of -2.5 or less. (57) In another post hoc analysis of this same osteoporotic group, alendronate significantly reduced the risk of multiple new clinical vertebral fractures by 84% (P < 0.001) over 4.3 years. (58) Clinical vertebral fractures were those that came to the medical attention of the investigators as a result of back pain.

Clinical vertebral fracture data have also been reported from a study comparing once-daily and once-weekly alendronate. All of the treatment regimens (70 mg once weekly, 35 mg twice weekly, or 10 mg daily) produced similar improvements in lumbar spine and hip BMD, and similar reductions of bone turnover marker levels. (59,60) The incidence of clinical fractures captured as adverse events was similar among the 3 groups after 1 (59) and 2 (60) years.

Although long-term fracture data are not available, alendronate has been studied for 10 years in 247 women. (61) In this continuation study, 10-year increases in BMD in the alendronate 10 mg/d group were 13.7% at the lumbar spine, 10.3% at the trochanter, and 5.4% at the femoral neck relative to baseline. Smaller gains in BMD were realized in the alendronate 5-mg/d group, and a gradual loss of effect was observed in patients who discontinued alendronate after 5 years. Vertebral fracture risk could not be calculated. (61)

Hip fracture/nonvertebral fractures. Hip fracture results were reported as a secondary endpoint in FIT1 and FIT2 (Table 3). In FIT1, alendronate significantly reduced hip fracture risk by 51% (P = 0.047) in women with low femoral neck BMD and prevalent vertebral fracture (Table 3). (54) Hip fracture risk was not significantly reduced in women without prevalent vertebral fracture in FIT2 (21% risk reduction; P = 0.44). (55) A post hoc analysis of combined FIT patients reported a 59% (P = 0.003) reduction in 3-year hip fracture risk in 3,658 patients with confirmed osteoporosis (prevalent vertebral fracture or femoral neck T-score -2.5 or below). (57)

The risk of nonvertebral fractures was not significantly reduced in the individual FIT studies (20% reduction in FIT1 [P = 0.063] (54) and 12% reduction in FIT2 [P = 0.13]). (55) In a post hoc analysis of combined FIT data, alendronate significantly reduced 3-year nonvertebral fracture risk by 26% (P = 0.002) in women with confirmed osteoporosis. (57) In the 1-year Fosamax Intervention Trial, clinical nonvertebral fracture risk was significantly reduced by 47% (P = 0.021) (Table 3). (62) A meta-analysis of alendronate studies reported a 49% (P < 0.01) risk reduction compared with placebo in patients given alendronate 10 mg/d, which was a greater effect than that seen with the 5-mg/d dose (13% reduction, P = 0.09). (56)

Tolerability. In prospective clinical trials, the incidence of adverse events was similar for alendronate and placebo recipients. (53-55,62) Adverse upper GI events are commonly reported with bisphosphonates. The incidence of any upper GI event for alendronate and placebo recipients was 41.3% and 40.0%, respectively, in FIT1 (54) and 47.5% and 47.2%, respectively, in FIT2. (55) There was no significant difference between the 2 groups in the incidence of any subcategory of upper GI adverse event (eg, dyspepsia, abdominal pain, nausea, esophagitis). (54,55) Similar proportions of women discontinued treatment due to adverse drug events in the FIT studies (about 10% of patients who received alendronate and placebo). (54,55) About 3% of women in each group discontinued treatment because of an upper GI adverse event. (63) The FIT studies excluded patients with peptic ulcer disease or dyspepsia requiring daily treatment. (54,55)

Tolerability profiles were similar after once-weekly and once-daily administration. The incidence of upper GI adverse events with alendronate 10 mg daily and 70 mg once weekly, respectively, was 23.5% and 22.4% at 1 year (59) and 30.0% and 29.3% at 2 years. (60)

Risedronate

Clinical efficacy. Vertebral fracture. After 1 year of treatment, risedronate 5 mg/d reduced the risk of new morphometric vertebral fractures by 65% (P < 0.001) and 61% (P = 0.001) in the 3-year Vertebral Efficacy With Risedronate Therapy North American (VERT-NA; n = 2,458) (64) and Multinational (VERT-MN; n = 1,226) (65) studies, respectively (Table 4). (64,65) Morphometric vertebral fracture risk reductions with risedronate 5 mg/d were maintained after 3 years by 41% and 49%, respectively (Table 4). (64,65) In a pooled analysis of combined VERT study data, the incidence of new clinical vertebral fractures was significantly reduced after 6 months of treatment (0.1% versus 1.0% for placebo; P < 0.05). (66) In another post hoc analysis of osteoporotic patients from 4 placebo-controlled trials, risedronate reduced the risk of the first morphometric vertebral fracture by 75% (P = 0.002) over a median 2-year follow up. (67)

The clinical efficacy of once-weekly risedronate has been evaluated in a multicenter, randomized, double-blind study. (68) One-year data indicated that the once-weekly (35 mg/wk and 50 mg/wk) and once-daily (5 mg/d) doses were similar at increasing BMD and decreasing markers of bone turnover. (68) A post hoc analysis of this study was performed using matched historical risedronate 5 mg/d and placebo control groups to compare vertebral fracture incidence with that in the 35-mg once-weekly group. (69) There was no statistically significant difference in fracture incidence observed between the 5-mg/d groups from the phase III (1.7%) and once-weekly (1.5%) studies; however, the reduction in the relative risk of new vertebral fractures in the 35-mg/wk group relative to the historical placebo control group (77%) (69) was similar to the reductions reported in the VERT studies with the daily dose (65% and 61%). (64,65)

The vertebral fracture reduction benefit of risedronate is maintained with long-term therapy. In an analysis of 689 patients over 5 years, a 50% (P < 0.001) reduction in the risk of new morphometric vertebral fractures with risedronate 5 mg/d relative to placebo was observed. (70) An open-label extension of this study was conducted in 83 and 81 patients from the risedronate and placebo groups, respectively. (71) The annualized incidence of new morphometric fractures was similar in the risedronate 5-mg/d groups over the 7 years of follow-up (about 4-5%), suggesting a sustained antifracture effect. (71) In addition, the incidence of new vertebral fractures declined rapidly during years 6 and 7 in the risedronate 5-mg/d group that had received placebo for the initial 5 years of the study.

Hip/nonvertebral fracture. The Hip Intervention Program (HIP) study enrolled 2 groups of patients: Group 1 consisted of 5,445 patients aged 70 to 79 years with a low femoral neck BMD (T-score -4 or below) or low femoral neck BMD (T-score -3 or below) plus at least 1 nonskeletal risk factor for hip fracture, and Group 2 had 3,886 patients aged 80 years and older who had at least 1 or more clinical risk factors for hip fracture besides age. (72) Treatment with risedronate significantly reduced the 3-year risk of hip fracture by 40% (P = 0.009) in women with confirmed osteoporosis (Group 1), and by 60% (P = 0.003) in a posthoc analysis of women in Group 1 with a prevalent vertebral fracture at baseline (Table 4). Three-year hip fracture risk was significantly reduced by 30% (P = 0.02) in the combined Groups 1 and 2 (Table 4). There was a nonsignificant decrease in hip fracture risk of 20% (P = 0.35) in Group 2 patients, or women who were enrolled primarily on the basis of clinical risk factors. These results underscore the importance of BMD testing in evaluating patients with risk factors for osteoporosis.

Three-year nonvertebral fracture risk was reduced by 39% (P = 0.02) in the VERT-NA (64) trial and by 33% (P = 0.063) in the VERT-MN (65) trial (Table 4). Nonvertebral fracture risk reduction was maintained for 5 years in the 2-year extension of the VERT-MN study (37% reduction; P = 0.022). (70) Short-term fracture efficacy was also observed. A post hoc analysis of 1,172 patients from risedronate clinical trials with lumbar spine BMD below -2.5 with or without prevalent vertebral fractures reported a 74% reduction in nonvertebral fracture risk at 1 year (1.2% for risedronate 5 mg/d versus 4.5% for controls; P = 0.001), and a significant reduction was observed as early as 6 months (by 66%; P = 0.048). (73)

Tolerability. In clinical trials in postmenopausal women with osteoporosis, the incidence of adverse events with risedronate was similar to placebo. (64,65,72) The incidence of any upper GI adverse event with risedronate 5 mg/d and placebo was 30% and 27%, respectively, in VERT-NA, (64) and 27% and 26%, respectively, in VERT-MN. (65) Similarly, in the HIP study, which had an older population than that in the VERT studies (approximate mean ages 80 yr versus 70 yr), the incidence of upper GI adverse events was similar in risedronate 5-mg/d and placebo recipients (21.2% versus 21.8%). (72) The percentages of patients withdrawing from these studies because of adverse events ranged from 15 to 20%, and were similar in risedronate 5-mg/d and placebo groups. Pooled data from 10,068 risedronate clinical trial patients (>98% postmenopausal women) showed a similar incidence of upper GI adverse events in risedronate and placebo recipients (29.8% versus 29.6%). (74) The risedronate clinical trials did not exclude patients with dyspepsia and concurrent medications such as [H.sub.2]-blockers or proton pump inhibitors.

Once-weekly risedronate has a tolerability profile similar to that of once-daily risedronate. In the study comparing risedronate 5 mg daily and 35 mg or 50 mg once weekly, the percentage of women who reported adverse events, and specifically upper GI adverse events (17.5%, 18.4%, and 18.7%, respectively), was similar among all 3 treatment groups over 1 year. (68)

Ibandronate

Clinical efficacy. Vertebral fractures. In the Oral Ibandronate Osteoporosis Vertebral Fracture Trial in North America and Europe (BONE) study, (75,76) the 3-year risk of new morphometric vertebral fractures was significantly reduced by 62% (P = 0.0001) in the daily ibandronate group (2.5 mg/d) and by 50% (P = 0.0006) in the intermittent ibandronate group (2.5 mg every other day for 12 doses every 3 mo) (Table 5). (76) The 2-year risk of new morphometric vertebral fractures was also significantly reduced in the daily and intermittent ibandronate groups relative to placebo (61% [P = 0.0006] and 56% [P = 0.0017], respectively). One-year vertebral fracture risk was also reduced in the daily ibandronate group relative to placebo, the difference nearly reaching statistical significance (58%, P = 0.0561).

Although fracture data are not available, in a 1-year non-inferiority study (Monthly Oral iBandronate In LadiEs, MOBILE) in 1,609 women with postmenopausal osteoporosis, ibandronate 100 mg or 150 mg once monthly was at least as effective as ibandronate 2.5 mg once daily at increasing hip and spine BMD, as well as reducing bone turnover markers. (77) Hip/nonvertebral fractures.

The incidence of clinical nonvertebral fractures was similar for the ibandronate daily and intermittent groups and the placebo group (9.1%, 8.9%, and 8.2%, respectively) (Table 5). (76) The authors suggested that the study population had a relatively low risk of nonvertebral fractures (mean total hip and femoral neck T-scores of -1.7 and -2.0, respectively). (76) When the data were reanalyzed, a significant reduction in the 3-year risk of nonvertebral fractures was observed only in a subgroup of patients receiving the daily dose who had a baseline femoral neck T-score of -3.0 or lower (69%; P = 0.013).

Tolerability. In the BONE and MOBILE studies, ibandronate was generally well tolerated. (76,77) Patients with a history of gastrointestinal problems and those using nonsteroidal anti-inflammatory drugs were not excluded in these trials. In the BONE study, the most commonly reported upper gastrointestinal adverse events in the ibandronate daily, ibandronate intermittent, and placebo groups were dyspepsia (11.4%, 9.0%, and 9.1%, respectively), gastroenteritis (5.5%, 6.3%, and 5.5%), and nausea (4.2%, 6.4%, and 6.3%). (76) The percentages of patients withdrawing from the BONE study owing to an adverse event were similar (7.5% for ibandronate daily, 7.2% for ibandronate intermittent, and 8.1% for placebo). The once-monthly 150 mg preparation of ibandronate was generally well tolerated in the MOBILE study. (77) The incidence of upper GI adverse events was similar for ibandronate 150 mg/d and 2.5 mg/d recipients (16.9% versus 18.0%). (77)

Raloxifene

Raloxifene is a selective estrogen receptor modulator that binds to estrogen receptors and inhibits bone resorption in postmenopausal women without stimulating the uterine endometrium. (78) It is approved for the prevention and treatment of postmenopausal osteoporosis. (79) Data for the antifracture effect of raloxifene come from 1 large clinical trial, the Multiple Outcomes of Raloxifene Evaluation (MORE) study. (80)

Clinical efficacy

Vertebral fractures. Raloxifene 60 mg/d (the FDA-approved dose) significantly reduced 3-year morphometric vertebral fracture risk by 50% in women without prevalent vertebral fracture and by 30% in women with prevalent vertebral fracture (both P < 0.05) (Table 6). A post hoc analysis of MORE data reported that raloxifene 60 mg/d significantly reduced the risk of new clinical vertebral fractures by 68% after 1 year of therapy in the overall study population, and by 66% in women with prevalent vertebral fracture at baseline (both P < 0.05). (81) In a 1-year blinded extension of the MORE study (n = 6,828), raloxifene 60 mg/d significantly (all P < 0.05) reduced 4-year morphometric vertebral fracture risk by 36% in the pooled study population, by 34% in women with at least 1 prevalent vertebral fracture at baseline, and by 49% in women without a prevalent vertebral fracture at baseline. (82)

Hip/nonvertebral fractures. Raloxifene did not significantly reduce the 3-year risk of hip or overall nonvertebral fractures in the MORE study (Table 6). These nonvertebral fracture data represent results for the pooled raloxifene 60-mg/d and 120-mg/d groups.

Tolerability

Most adverse events reported in the MORE trial were mild or moderate. Venous thromboembolism was the most common serious adverse event related to raloxifene treatment. (80) Venous thromboembolic events were reported by 0.3%, 1.0%, and 1.0% of placebo, raloxifene 60-mg/d, and raloxifene 120-mg/d recipients, respectively (relative risk 3.1 for raloxifene groups versus placebo). (80) Hot flashes were reported more frequently in the raloxifene 60-mg/d and 120-mg/d groups than in the placebo group (9.7% and 11.6% versus 6.4%; P < 0.001 for raloxifene groups versus placebo). (80) Leg cramps and peripheral edema were also reported more frequently in raloxifene than placebo recipients--these symptoms have also been reported in women receiving estrogen therapy. (83) Recent data from a 1-year extension of the MORE study indicated that 4 years' treatment with raloxifene did not significantly affect the risk of cardiovascular events in the overall cohort. (84) The risk of these events was significantly reduced in a posthoc analysis of a subset of women at higher risk for these events (ie, those with multiple cardiovascular risk factors or prior coronary events or revascularization procedures). (84)

Salmon Calcitonin Nasal Spray

Salmon calcitonin nasal spray 200 IU/d is approved for the treatment of postmenopausal osteoporosis. (85) Fracture data are available from 1 major clinical trial, the 5-year Prevent Recurrence of Osteoporotic Fractures (PROOF) study. (86)

Clinical efficacy

Vertebral fractures. Salmon calcitonin nasal spray 200 IU/d significantly reduced morphometric vertebral fracture risk by 33% (P = 0.03), whereas vertebral fracture risk was reduced by 15% and 16% in the 100- and 400-IU/d groups, respectively (both not significant) (Table 6). (86) In patients with at least 1 vertebral fracture at baseline, calcitonin significantly reduced vertebral fracture by 36% (P = 0.03) in the 200-IU/d group, and by 6% and 22% in the 100- and 400-IU/d groups, respectively (both not significant). Overall, the vertebral fracture risk reduction data were based on relatively small numbers of patients (about 275 per group had a follow-up spine x-ray). The lack of a dose-response effect in this study has raised some concerns about the reliability of the data. (86)

Hip/nonvertebral fractures. The 5-year risk of hip fracture was not significantly reduced in the 200 IU/d group (Table 6) but was significantly reduced relative to placebo in the 100 IU/d group. Similarly, nonvertebral fracture risk was significantly reduced by 36% (P < 0.05) in the 100-IU/d group but not in the 200-IU/d (12%; not significant) or 400-IU/d (19%; not significant) groups. (86) Because of the low numbers of nonvertebral fracture events, the study was not sufficiently powered to show meaningful differences in hip and nonvertebral fracture risk.

Tolerability

Salmon calcitonin was generally well tolerated in the PROOF study. Rhinitis (defined as nasal congestion, nasal discharge, or sneezing) was the most commonly reported adverse event, occurring in 22% of active drug recipients and in 15% of placebo recipients (P < 0.01). (86) Ninety-seven percent of the rhinitis adverse events were rated as mild or moderate in severity. The possibility of an allergic reaction should also be considered, and patients suspected of having an allergy to salmon calcitonin should undergo skin testing before treatment. (85)

Teriparatide

Teriparatide is a recombinant form of human parathyroid hormone (1-34) approved by the FDA for treatment of osteoporosis in postmenopausal women who are at high risk for fracture. (87) Teriparatide is an anabolic agent that acts by stimulating bone formation. Fracture data for teriparatide are available from 1 major clinical trial. The study was terminated early to investigate reports of osteosarcoma in rats during a long-term toxicologic study. (88)

Clinical efficacy

Vertebral fractures. Once-daily teriparatide 20 [micro]g, the FDA-approved dose, significantly reduced the risk of new morphometric vertebral fractures by 65% (Table 6) after a median follow-up of 21 months (P [less than or equal to] 0.001). (89) The corresponding reduction for the 40-[micro]g/d dosage was 69% (P [less than or equal to] 0.001). The risk of multiple morphometric vertebral fractures was significantly reduced by 77% (P [less than or equal to] 0.001) in the teriparatide 20-[micro]g/d group.

Hip/nonvertebral fractures. The number of hip fractures were too small to provide a meaningful analysis. (89) Teriparatide 20 [micro]g/d significantly reduced the risk of nonvertebral fragility fractures by 53% (P = 0.02) (Table 6). A similar reduction (54%) was observed in the 40-[micro]g/d group.

Tolerability

The incidence of adverse events reported in the teriparatide 20-[micro]g/d group was generally similar to that in the placebo group. (89) The incidences of dizziness (9% versus 6%; P = 0.05) or leg cramps (3% versus 1%; P = 0.02) were slightly higher in the teriparatide 20-[micro]g/d group than in the placebo group but similar for the 40-[micro]g/d and placebo groups. The incidences of nausea (18% versus 8%; P < 0.001) or headache (13% versus 8%; P = 0.01) were significantly higher in the teriparatide 40-[micro]g/d group than in the placebo group. Overall, 6% of patients in the teriparatide 20-[micro]g/d and placebo groups withdrew because of adverse events compared with 11% in the 40-[micro]g/d group.

The product label for teriparatide includes a black box warning for patients at risk for osteosarcoma, and use of teriparatide for more than 2 years is not recommended. (87) The clinical relevance of the rat data that led to the early termination of the above study is uncertain given the long duration of therapy (80-90% of the normal life span of the rats being tested) and the suprapharmacologic dosages used (rats were treated for about 25-30 bone turnover cycles compared with 1-3 bone turnover cycles for postmenopausal women). (88)

Combination therapy

The issue of combination therapy with parathyroid hormone plus antiresorptive drugs is of particular interest to clinicians. Many patients who are candidates to receive parathyroid hormone therapies like teriparatide are currently receiving antiresorptive drugs. To date, there is no fracture data for combination therapy. (88a) In a 30-month study of 83 men with low BMD, the increase in lumbar spine and femoral neck BMD was significantly greater in patients who received teriparatide monotherapy than in those who received either alendronate monotherapy or teriparatide plus alendronate combination therapy (patients received alendronate for 6 mo, then concurrent alendronate and teriparatide for 24 mo). (90) Similarly, the anabolic effects of parathyroid hormone (1-84) were reduced by concomitant administration of alendronate in a study of 238 previously untreated women with postmenopausal osteoporosis. (91) Increases in spine BMD measured by dual-energy x-ray absorptiometry and quantitative computed tomography were greater in the parathyroid hormone (1-84) group than in the combination group, (91) although the difference between these groups was not statistically significant. (91) There are data to suggest that raloxifene is associated with less blunting of the anabolic effect of teriparatide than alendronate, which may be due to the lower antiresorptive potency of the former. (92)

The effects of starting antiresorptive therapy after parathyroid hormone treatment have also been evaluated. In a follow-up study, 119 women receiving parathyroid hormone (1-84) monotherapy had their treatment stopped and then received either alendronate or placebo for 1 year. (93) Gains in spine and hip BMD were quickly lost during the year on placebo, and there were significant gains in the alendronate group. These data suggest that treatment with an antiresorptive agent is needed after discontinuation of parathyroid hormone therapy to maintain the drug-induced improvements in BMD.

Comparative Studies

In a number of head-to-head studies, alendronate has demonstrated greater improvements in BMD and greater reductions in markers of bone turnover than estrogen, (94) raloxifene, (95,96) salmon calcitonin nasal spray, (97-99) and risedronate. (100) A small study (n = 146) comparing the effects of teriparatide versus alendronate in postmenopausal women with osteoporosis reported BMD and fracture risk. Teriparatide 40 [micro]g/d produced significantly greater increases in lumber spine, femoral neck, and total hip BMD than alendronate 10 mg/d (median follow-up 14 mo). (101) The incidence of nonvertebral fractures was significantly lower in the teriparatide than in the alendronate group (4.1% versus 13.7%; P = 0.042). (101) This small study was not specifically designed to compare fracture rates, and therefore, it is difficult to draw any firm conclusions regarding the relative efficacy at reducing fracture risk for these agents. Similarly, comparative trials of antiresorptive agents, such as the Fosamax Actonel Comparison Trial, have usually assessed BMD or biochemical markers of efficacy, and they were not specifically designed to assess relative fracture efficacy. Moreover, there are data to suggest that changes in BMD with antiresorptive agents account for only a small proportion of the observed vertebral fracture risk reductions. (102-104) Therefore, head-to-head fracture trials would be needed to definitively determine relative antifracture efficacy between agents.

Treatments on the Horizon

Strontium ranelate is an orally active drug that appears to both stimulate bone formation and inhibit bone resorption, suggesting a dissociation of the bone remodeling process. (105) The Spinal Osteoporosis Therapeutic Intervention (SOTI) trial in 1,649 postmenopausal women with osteoporosis reported a 49% (P < 0.001) reduction in new morphometric vertebral fractures with strontium ranelate 2 g/d relative to placebo after 1 year, and a 41% (P < 0.001) reduction over 3 years. (106) Similar reductions in vertebral fracture risk were observed in the Treatment Of Peripheral Osteoporosis (TROPOS) study. (107) In addition, the TROPOS study showed that treatment with strontium 2 g/d significantly reduced the risk of all nonvertebral fractures by 16% (P = 0.04) and of major nonvertebral fragility fractures (hip, wrist, pelvis and sacrum, ribs and sternum, clavicle and humerus) by 19% (P = 0.031) in 4,932 postmenopausal women with osteoporosis. (107)

The most commonly reported adverse event for strontium in the SOTI study was diarrhea (6.1% versus 3.6% for placebo; P = 0.02). (106) In the TROPOS study, nausea (7.2% versus 4.4% for placebo), diarrhea (6.7% versus 5.0%), headache (3.4% versus 2.4%), dermatitis, and eczema (5.5% versus 4.1%) were reported more frequently (not significant) in strontium than placebo recipients. (107) In both studies, the differences in diarrhea and nausea between strontium and placebo disappeared after 3 months.

The bisphosphonate zoledronic acid is approved for hypercalcemia of malignancy. (108) The use of zoledronic acid for the treatment of postmenopausal osteoporosis is appealing because of its extended dosing interval. Phase III trials are in progress. No fracture data is available. In a 1-year dose-ranging BMD study in 351 women with postmenopausal osteoporosis, patients who received any of 5 dosing regimens of IV zoledronic acid (0.25 mg every 3 mo, 0.5 mg every 3 mo, 1 mg every 3 mo, 2 mg every 6 mo, or 4 mg X 1 dose) had significantly (all P < 0.001) greater increases in lumbar spine (range 4.3%-5.1% higher) and femoral neck (range 3.1%-3.5% higher) BMD than patients who received placebo. (109) Musculoskeletal pain (10-20% of patients), fever (9-20%), and arthralgia (8-25%) were commonly reported in zoledronic acid recipients. (109)

Summary and Conclusions

The data from these multiple trials indicate that clinicians have many options for treating postmenopausal osteoporosis. This review focused on the endpoint of antifracture efficacy of available drugs for osteoporosis instead of other measures of efficacy such as BMD, because fracture reduction is the most clinically relevant endpoint of osteoporosis treatment.

On the basis of available evidence, it is important to ensure calcium and vitamin D sufficiency in all patients. Although calcium and vitamin D supplementation alone does not reduce the risk of vertebral fractures in women with symptomatic osteoporosis, they complement the antifracture efficacy of the other agents discussed. It is optimal to meet calcium and vitamin D requirements through a well-balanced diet and sufficient exposure to sunlight; however, if this is not possible, one can select from many over-the-counter supplements.

Of the available pharmacologic agents, the bisphosphonates alendronate and risedronate have been shown to produce the most robust fracture risk reductions: approximately 40 to 50% reduction in vertebral fracture risk, 30 to 40% in nonvertebral fracture risk, and 40 to 60% in hip fracture risk. Daily and intermittent ibandronate have also demonstrated similar reductions in vertebral fracture, but not nonvertebral fracture risk. Similarly, raloxifene and salmon calcitonin nasal spray reduced only vertebral fracture risk in pivotal studies. Teriparatide significantly reduced both vertebral and nonvertebral fracture risk; however, the long-term adverse effects of daily teriparatide are unknown and the FDA has recommended use of this agent for a maximum of 2 years. (87)

There are new therapies in development that hold promise for the management of postmenopausal osteoporosis. Strontium was shown to significantly reduce vertebral and nonvertebral fractures in pivotal studies. In addition, the potential for once-yearly administration of zoledronic acid is of interest, but it is currently approved only for hypercalcemia of malignancy. These agents will contribute to the existing armamentarium of agents available to reduce fracture risk in postmenopausal women.

Acknowledgments

The authors wish to thank Rick Davis, MS, RPh, for his research and editorial assistance in the preparation of this manuscript.

References

1. National Osteoporosis Foundation. America's Bone Health: The State of Osteoporosis and LowBone Mass in Our Nation. Washington, DC: National Osteoporosis Foundation; 2002.

2. National Osteoporosis Foundation: Disease statistics. Available at: http://www.nof.org/osteoporosis/stats.htm. Accessed December 1, 2003.

3. Klotzbuecher CM, Ross PD, Landsman PB, et al. Patients with prior fractures have an increased risk of future fractures: a summary of the literature and statistical synthesis. J Bone Miner Res 2000;15:721-739.

4. Lindsay R, Silverman SL, Cooper C, et al. Risk of new vertebral fracture in the year following a fracture. JAMA 2001;285:320-323.

5. Adachi JD, Loannidis G, Berger C, et al. The influence of osteoporotic fractures on health-related quality of life in community-dwelling men and women across Canada. Osteoporos Int 2001;12:903-908.

6. Cooper C. The crippling consequences of fractures and their impact on quality of life. Am J Med 1997;103(2A):12S-17S

7. Ensrud KE, Thompson DE, Cauley JA, et al. Prevalent vertebral deformities predict mortality and hospitalization in older women with low bone mass. Fracture Intervention Trial Research Group. J Am Geriatr Soc 2000;48:241-249.

8. Oleksik A, Lips P, Dawson A, et al. Health-related quality of life in postmenopausal women with low BMD with or without prevalent vertebral fractures. J Bone Miner Res 2000;15:1384-1392.

9. Cauley JA, Thompson DE, Ensrud KC, et al. Risk of mortality following clinical fractures. Osteoporos Int 2000;11:556-561.

10. Black JN, Follin SL, McDermott MT. Osteoporosis diagnosis and management following hip fracture [abstract no. F295]. J Bone Miner Res 2001;16(suppl 1):S214.

11. Cuddihy MT, Gabriel SE, Crowson CS, et al. Osteoporosis intervention following distal forearm fractures: a missed opportunity? Arch Intern Med 2002;162:421-426.

12. Gehlbach SH, Bigelow C, Heimisdottir M, et al. Recognition of vertebral fracture in a clinical setting. Osteoporos Int 2000;11:577-582.

13. Kamel HK, Duthie EH. The underuse of therapy in the secondary prevention of hip fractures. Drugs Aging 2002;19:1-10.

14. Torgerson DJ, Dolan P. Prescribing by general practitioners after an osteoporotic fracture. Ann Rheum Dis 1998;57:378-379.

15. Solomon DH, Finkelstein JS, Katz JN, et al. Underuse of osteoporosis medications in elderly patients with fractures. Am J Med 2003;115:398-400.

16. Andrade SE, Majumdar SR, Chan KA, et al. Low frequency of treatment of osteoporosis among postmenopausal women following a fracture. Arch Intern Med 2003;163:2052-2057.

17. Holick MF, Krane SM, Potts JT Jr. Calcium, phosphorus, and bone metabolism: calcium-regulating hormones. In: Fauci, AS, Braunwald E, Isselbacher KJ, et al, eds. Harrison's Principles of Internal Medicine. New York: McGraw-Hill; 1998:2214-2227.

18. Standing Committee on the Scientific Evaluation of Dietary Reference Intakes. Dietary Reference Intakes for Calcium, Phophorus, Magnesium, Vitamin D, and Fluoride. Washington, DC: National Academy Press; 1997.

19. National Osteoporosis Foundation. Physician's Guide to Prevention and Treatment of Osteoporosis. Washington, DC: National Osteoporosis Foundation; 2003.

20. United States Department of Agriculture: USDA National Nutrient Database for Standard Reference, Release 17. Available at: http://www.nal.usda.gov/fnic/foodcomp/. Accessed April 2, 2005.

21. Calcium supplements. The Medical Letter 2000;42:29-31.

22. Recker RR. Calcium absorption and achlorhydria. N Engl J Med 1985;313:70-73.

23. Holick MF. Vitamin D: the underappreciated D-lightful hormone that is important for skeletal and cellular health. Curr Opin Endocr Diab 2002;9:87-98.

24. Holick MF, Vitamin D: importance in the prevention of cancers, type 1 diabetes, heart disease, and osteoporosis. Am J Clin Nutr 2004;79:362-371.

25. Chapuy MC, Preziosi P, Maamer M, et al. Prevalence of vitamin D insufficiency in an adult normal population. Osteoporos Int 1997;7:439-443.

26. Malabanan A, Veronikis IE, Holick MF. Redefining vitamin D insufficiency. Lancet 1998;351:805-806.

27. Harris SS, Soteriades E, Coolidge JA, et al. Vitamin D insufficiency and hyperparathyroidism in a low income, multiracial, elderly population. J Clin Endocrinol Metab 2000;85:4125-4130.

28. Gloth FM, 3rd, Gundberg, CM, Hollis BW, et al. Vitamin D deficiency in homebound elderly persons. Jama 1995;274:1683-1686.

29. Lips P, Duong T, Oleksik A, et al. A global study of vitamin D status and parathyroid function in postmenopausal women with osteoporosis: baseline data from the multiple outcomes of raloxifene evaluation clinical trial. J Clin Endocrinol Metab 2001;86:1212-1221.

30. Thomas MK, Lloyd-Jones DM, Thadhani RI, et al. Hypovitaminosis D in medical inpatients. N Engl J Med 1998;338:777-783.

31. Gordon CM, DePeter KC, Feldman HA, et al. Prevalence of vitamin D deficiency among healthy adolescents. Arch Pediatr Adolesc Med 2004;158:531-537.

32. Tangpricha V, Pearce EN, Chen TC, et al. Vitamin D insufficiency among free-living healthy young adults. Am J Med 2002;112:659-662.

33. Sullivan SS, Rosen CJ, Halteman WA, et al. Adolescent girls in Maine are at risk for vitamin D insufficiency. J Am Diet Assoc 2005;105:971-974.

34. Standing Committee on the Scientific Evaluation of Dietary Reference Intakes. Dietary Reference Intakes for Calcium, Phosphorus, Magnesium, Vitamin D, and Fluoride. Washington, D.C.: National Academy Press; 1997.

35. Tangpricha V, Koutkia P, Ricke SM, et al. Fortification of orange juice with vitamin D: a novel approach for enhancing vitamin D nutritional health, Am J Clin Nutr 2003;77:1478-1483.

36. Riggs BL, O'Fallon, WM, Muhs J, et al. Long-term effects of calcium supplementation on serum parathyroid hormone level, bone turnover, and bone loss in elderly women. J Bone Miner Res 1998;13:168-174.

37. Recker RR, Hinders S, Davies KM, et al. Correcting calcium nutritional deficiency prevents spine fractures in elderly women. J Bone Miner Res 1996;11:1961-1966.

38. Tilyard MW, Spears GF, Thomson J, et al. Treatment of postmenopausal osteoporosis with calcitriol or calcium. N Engl J Med 1992;326:357-362.

39. Lips P, Graafmans WC, Ooms ME, et al. Vitamin D supplementation and fracture incidence in elderly persons. A randomized, placebo-controlled clinical trial. Ann Intern Med 1996;124:400-406.

40. Papadimitropoulos E, Wells G, Shea B, et al. Meta-analyses of therapies for postmenopausal osteoporosis. VIII: Meta-analysis of the efficacy of vitamin D treatment in preventing osteoporosis in postmenopausal women. Endocr Rev 2002;23:560-569.

41. Chapuy MC, Arlot ME, Duboeuf F, et al. Vitamin [D.sub.3] and calcium to prevent hip fractures in elderly women. N Engl J Med 1992;327:1637-1642.

42. Dawson-Hughes B, Harris SS, Krall EA, et al. Effect of calcium and vitamin D supplementation on bone density in men and women 65 years of age or older. N Engl J Med 1997;10:670-676.

43. Grant AM, Avenell A, Campbell MK, et al. Oral vitamin D3 and calcium for secondary prevention of low-trauma fractures in elderly people (Randomised Evaluation of Calcium Or vitamin D, RECORD): a randomised placebo-controlled trial. Lancet 2005;365:1621-1628.

44. Porthouse J, Cockayne S, King C, et al. Randomised controlled trial of calcium and supplementation with cholecalciferol (vitamin D3) for prevention of fractures in primary care. Bmj 2005;330:1003.-

45. Rodan GA, Fleisch HA. Bisphosphonates: mechanisms of action. J Clin Invest 1996;97:2692-2696.

46. Russell RG, Croucher PI, Rogers MJ. Bisphosphonates: pharmacology, mechanisms of action and clinical uses. Osteoporos Int. 9(suppl 2):S66-80, 1999.

47. Fleisch H. Bisphosphonates: mechanisms of action. Endocr Rev 1998;19:80-100.

48. Fosamax[R] (alendronate sodium, Merck & Co Inc. Whitehouse Station, NJ). Full prescribing information, 2004.

49. Actonel[R] (risedronate sodium, Procter & Gamble Pharmaceuticals, Cincinnati, OH). Full prescribing information, 2003.

50. Boniva[R] (ibandronate sodium, Roche Pharmaceuticals, Nutley, New Jersey). Full prescribing information, 2005.

51. Fosamax Plus D[R] (alendronate sodium/cholecalciferol, Merck & Co Inc, Whitehouse Station, NJ). Full prescribing information, 2005.

52. Actonel[R] (risedronate sodium, Procter & Gamble Pharmaceuticals, Cincinnati, OH). Full prescribing information, 2003.

53. Liberman UA, Weiss SR, Broll J, et al. Effect of oral alendronate on bone mineral density and the incidence of fractures in postmenopausal osteoporosis. The Alendronate Phase III Osteoporosis Treatment Study Group. N Engl J Med 1995;333:1437-1443.

54. Black DM, Cummings SR, Karpf DB, et al. Randomised trial of effect of alendronate on risk of fracture in women with existing vertebral fractures. Fracture Intervention Trial Research Group. Lancet 1996;348:1535-1541.

55. Cummings SR, Black DM, Thompson DE, et al. Effect of alendronate on risk of fracture in women with low bone density but without vertebral fractures: results from the Fracture Intervention Trial. JAMA 1998;280:2077-2082.

56. Cranney A, Wells G, Willan A, et al. Meta-analyses of therapies for postmenopausal osteoporosis, II. Meta-analysis of alendronate for the treatment of postmenopausal women. Endocr Rev 2002;23:508-516.

57. Black DM, Thompson DE, Bauer DC, et al. Fracture risk reduction with alendronate in women with osteoporosis: the Fracture Intervention Trial. FIT Research Group. J Clin Endocrinol Metab 2000;85:4118-4124.

58. Levis S, Quandt SA, Thompson D, et al. Alendronate reduces the risk of multiple symptomatic fractures: results from the fracture intervention trial. J Am Geriatr Soc 2002;50:409-415.

59. Schnitzer T, Bone H, Crepaldi G, et al. Therapeutic equivalence of alendronate 70 mg once-weekly and alendronate 10 mg daily in the treatment of osteoporosis. Alendronate Once-Weekly Study Group. Aging (Milano) 2000;12:1-12.

60. Rizzoli R, Greenspan SL, Bone G, et al. Two-year results of once-weekly administration of alendronate 70 mg for the treatment of postmenopausal osteoporosis. J Bone Miner Res 2002;17:1988-1996.

61. Bone HG, Hosking D, Devogelaer JP, et al. Ten years' experience with alendronate for osteoporosis in postmenopausal women. N Engl J Med 2004;350:1189-1199.

62. Pols HA, Felsenberg D, Hanley DA, et al. Multinational, placebo-controlled, randomized trial of the effects of alendronate on bone density and fracture risk in postmenopausal women with low bone mass: results of the FOSIT study. Fosamax International Trial Study Group. Osteoporos Int 1999;9:461-468.

63. Bauer DC, Black D, Ensrud K, et al. Upper gastrointestinal tract safety profile of alendronate: the Fracture Intervention Trial. Arch Intern Med 2000;160:517-525.

64. Harris ST, Watts NB, Genant HK, et al. Effects of risedronate treatment on vertebral and nonvertebral fractures in women with postmenopausal osteoporosis: a randomized controlled trial. Vertebral Efficacy with Risedronate Therapy (VERT) Study Group. JAMA 1999;282:1344-1352.

65. Reginster J, Minne HW, Sorensen OH, et al. Randomized trial of the effects of risedronate on vertebral fractures in women with established postmenopausal osteoporosis. Vertebral Efficacy with Risedronate Therapy (VERT) Study Group. Osteoporos Int 2000;11:83-91.

66. Roux C, Seeman E, Eastell R, et al. Efficacy of risedronate on clinical vertebral fractures within 6 months. Curr Med Res Opin 2004;20:433-439.

67. Heaney RP, Zizic TM, Fogelman I, et al. Risedronate reduces the risk of first vertebral fracture in osteoporotic women. Osteoporos Int 2002;13:501-505.

68. Brown JP, Kendler DL, McClung MR, et al. The efficacy and tolerability of risedronate once a week for the treatment of postmenopausal osteoporosis. Calcif Tissue Int 2002;71:103-111.

69. Watts NB, Lindsay R, Li Z, et al. Use of matched historical controls to evaluate the anti-fracture efficacy of once-a-week risedronate. Osteoporos Int 2003;14:437-441.

70. Sorensen OH, Crawford GM, Mulder H, et al. Long-term efficacy of risedronate: a 5-year placebo-controlled clinical experience. Bone 2003;32:120-126.

71. Mellstrom DD, Sorensen OH, Goemaere S, et al. Seven years of treatment with risedronate in women with postmenopausal osteoporosis. Calcif Tissue Int 2004;75:462-468.

72. McClung MR, Geusens P, Miller PD, et al. Effect of risedronate on the risk of hip fracture in elderly women. N Engl J Med 2001;344:333-340.

73. Harrington JT, Ste-Marie LG, Brandi ML, et al. Risedronate rapidly reduces the risk for nonvertebral fractures in women with postmenopausal osteoporosis. Calcif Tissue Int 2004;74:129-135.

74. Taggart H, Bolognese MA, Lindsay R, et al. Upper gastrointestinal tract safety of risedronate: a pooled analysis of 9 clinical trials. Mayo Clin Proc 2002;77:262-270.

75. Delmas PD, Recker RR, Chesnut 3rd, CH, et al. Daily and intermittent oral ibandronate normalize bone turnover and provide significant reduction in vertebral fracture risk: results from the BONE study. Osteoporos Int 2004;15(10):792-798.

76. Chesnut IC, Skag A, Christiansen C, et al. Effects of oral ibandronate administered daily or intermittently on fracture risk in postmenopausal osteoporosis. J Bone Miner Res 2004;19:1241-1249.

77. Miller P, McClung M, Macovei L, et al. Monthly oral ibandronate therapy in postmenopausal osteoporosis: 1-year results from the MOBILE study. J Bone Min Res Published online April 18, 2005.

78. Delmas PD, Bjarnason NH, Mitlak BH, et al. Effects of raloxifene on bone mineral density, serum cholesterol concentrations, and uterine endometrium in postmenopausal women. N Engl J Med 1997;337:1641-1647.

79. Evista[R] (raloxifene HCl, Eli Lilly and Company, Indianapolis, IN). Full prescribing information, 2003.

80. Ettinger B, Black DM, Mitlak BH, et al. Reduction of vertebral fracture risk in postmenopausal women with osteoporosis treated with raloxifene: results from a 3-year randomized clinical trial. Multiple Outcomes of Raloxifene Evaluation (MORE) Investigators. JAMA 1999;282:637-645.

81. Maricic M, Adachi JD, Sarkar S, et al. Early effects of raloxifene on clinical vertebral fractures at 12 months in postmenopausal women with osteoporosis. Arch Intern Med 2002;162:1140-1143.

82. Delmas PD, Ensrud KE, Adachi JD, et al. Efficacy of raloxifene on vertebral fracture risk reduction in postmenopausal women with osteoporosis: four-year results from a randomized clinical trial. J Clin Endocrinol Metab 2002;87:3609-3617.

83. Premarin[R] (conjugated estrogens, Wyeth Pharmaceuticals, Philadelphia, PA). Full prescribing information, 2004.

84. Barrett-Connor E, Grady D, Sashegyi A, et al. Raloxifene and cardiovascular events in osteoporotic postmenopausal women: four-year results from the MORE (Multiple Outcomes of Raloxifene Evaluation) randomized trial. JAMA 2002;287:847-857.

85. Miacalcin[R] (calcitonin salmon, Novartis Pharmaceuticals Corporation, East Hanover, NJ). Full preseribing information, 2003.

86. Chesnut C, III, Silverman, S, Andriano K, et al. A randomized trial of nasal spray salmon calcitonin in postmenopausal women with established osteoporosis: The Prevent Recurrence of Osteoporotic Fractures Study. PROOF Study Group. Am J Med 2000;109:267-276.

87. Forteo[R] (teriparatide, Eli Lilly and Company, Indianapolis, IN). Full prescribing information, 2002.

88. Vahle JL, Sato M, Long GG, et al. Skeletal changes in rats given daily subcutaneous injections of recombinant human parathyroid hormone (1-34) for 2 years and relevance to human safety. Toxicol Pathol 2002;30:312-321.

88a. Heaney, RP, Recher RR. Combination and sequential therapy for osteoporosis. N Engl J Med 2005;353:624-625.

89. Neer RM, Arnaud CD, Zanchetta JR, et al. Effect of parathyroid hormone (1-34) on fractures and bone mineral density in postmenopausal women with osteoporosis. N Engl J Med 2001;344:1434-1441.

90. Finkelstein JS, Hayes A, Hunzelman JL, et al. The effects of parathyroid hormone, alendronate, or both in men with osteoporosis. N Engl J Med 2003;349:1216-1226.

91. Black DM, Greenspan SL, Ensrud KE, et al. The effects of parathyroid hormone and alendronate alone or in combination in postmenopausal osteoporosis. N Engl J Med 2003;349:1207-1215.

92. Ettinger B, Crans GG, et al. Response of markers of bone turnover and bone density to teriparatide in postmenopausal women previously treated with an antiresorptive drug. J Bone Miner Res 2003;18(Suppl 2):S15.

93. Black D, Rosen C, Palermo L, et al. The effect of 1 year of alendronate following 1 year of PTH 1-84: second year results from the PTH and Alendronate (PATH) trial [abstract]. Presented at: 26th Annual Meeting of the American Society for Bone and Mineral Research; 2004; Seattle, WA

94. Bone HG, Greenspan SL, McKeever C, et al. Alendronate and estrogen effects in postmenopausal women with low bone mineral density Alendronate/Estrogen Study Group. J Clin Endocrinol Metab 2000;85:720-726.

95. Sambrook PN, Geusens P, Ribot C, et al. Alendronate produces greater effects than raloxifene on bone density and bone turnover in postmenopausal women with low bone density: results of EFFECT (Efficacy of FOSAMAX versus EVISTA Comparison Trial) International. J Intern Med 2004;255:503-511.

96. Luckey M, Kagan R, Greenspan S, et al. Once-weekly alendronate 70 mg and raloxifene 60 mg daily in the treatment of postmenopausal osteoporosis. Menopause 2004;11:405-415.

97. Downs RW, Bell NH, Ettinger MP, et al. Comparison of alendronate and intranasal calcitonin for treatment of osteoporosis in postmenopausal women. J Clin Endocrinol Metab 2000;85:1783-1788.

98. Adami S, Passeri M, Ortolani S, et al. Effects of oral alendronate and intranasal salmon calcitonin on bone mass and biochemical markers of bone turnover in postmenopausal women with osteoporosis. Bone 1995;17:383-390.

99. Dursun N, Dursun E, Yalcin S. Comparison of alendronate, calcitonin and calcium treatments in postmenopausal osteoporosis. Int J Clin Pract 2001;55:505-509.

100. Rosen CJ, Hochberg MC, Bonnick SL, et al. Treatment with once-weekly alendronate 70 mg compared with once-weekly risedronate 35 mg in women with postmenopausal osteoporosis: a randomized double-blind study. J Bone Miner Res 2005;20:141-151.

101. Body JJ, Gaich GA, Scheele WH, et al. A randomized double-blind trial to compare the efficacy of teriparatide [recombinant human parathyroid hormone (1-34)] with alendronate in postmenopausal women with osteoporosis. J Clin Endocrinol Metab 2002;87:4528-4535.

102. Cummings SR, Karpf DB, Harris F, et al. Improvement in spine bone density and reduction in risk of vertebral fractures during treatment with antiresorptive drugs. Am J Med 2002;112:281-289.

103. Watts NB, Cooper C, Lindsay R, et al. Relationship between changes in bone mineral density and vertebral fracture risk associated with risedronate: greater increases in bone mineral density do not relate to greater decreases in fracture risk. J Clin Densitom 2004;7:255-261.

104. Sarkar S, Mitlak BH, Wong M, et al. Relationships between bone mineral density and incident vertebral fracture risk with raloxifene therapy. J Bone Miner Res 2002;17:1-10.

105. Marie PJ, Ammann P, Boivin G, et al. Mechanisms of action and therapeutic potential of strontium in bone. Calcif Tissue Int 2001;69:121-129.

106. Meunier PJ, Roux C, Seeman E, et al. The effects of strontium ranelate on the risk of vertebral fracture in women with postmenopausal osteoporosis. N Engl J Med 2004;350:459-468.

107. Reginster JY, Seeman E, De VernejoulMC, et al. Strontium Ranelate Reduces the Risk of Nonvertebral Fractures in Post-Menopausal Women with Osteoporosis: Tropos Study. J Clin Endocrinol Metab 2005;902816-2822.

108. Zometa[R] (zoledronic acid, Novartis, Stein, Switzerland). Full prescribing information, 2004.

109. Reid IR, Brown JP, Burckhardt P, et al. Intravenous zoledronic acid in postmenopausal women with low bone mineral density. N Engl J Med 2002;346:653-661.

Ronald C. Hamdy, MD, Charles H. Chesnut III, MD, Margery L. Gass, MD, Michael F. Holick, PHD, MD, Edward S. Leib, MD, Michael E. Lewiecki, MD, Michael Maricic, MD, and Nelson B. Watts, MD

From the East Tennessee State University, Johnson City, TN; University of Washington Medical Center, Seattle, WA; University of Cincinnati College of Medicine, Cincinnati, OH; Boston University Medical Center, Boston, MA; University of Vermont College of Medicine, Burlington, VT; New Mexico Clinical Research & Osteoporosis Center, Albuquerque, NM; Southern Arizona VA Health Care System, Tucson, AZ; and University of Cincinnati Bone Health and Osteoporosis Center, Cincinnati, OH.

Reprint requests to Ronald C. Hamdy, MD, FRCP, FACP, Professor of Medicine, Director, Osteoporosis Center, East Tennessee State University, P.O. Box 70439, Johnson City, TN 37614. Email: [e-mail]

Dr. Hamdy receives research grants from Merck and Procter & Gamble and is a consultant for Merck, Procter & Gamble, Eli Lilly, and GlaxoSmithKline. He is also a member of the Merck Speaker's Bureau.

Dr. Chesnut receives grants from Novartis, is a consultant with Novartis, and is on the Speaker's Bureau for Novartis, Roche, and GlaxoSmithKline.

Dr. Gass receives grants and contracts from Pfizer, Inc., Organon, Procter & Gamble, Roche, and Wyeth-Ayerst. He receives honoraria and consultation fees from Aventis, GlaxoSmithKline, Organon, Merck, Procter & Gamble, and Wyeth-Ayerst. And he is an Advisory Board member with Eli Lilly, Merck, and Procter & Gamble.

Dr. Holick is a consultant for Nichols Institute and is on the Speaker's Bureau for Merck, Eli Lilly, and Procter & Gamble.

Dr. Leib receives research grants from Allelix and Eli Lilly. He is a consultant for Alliance for Bone Health and is on the Speaker's Bureau for Procter & Gamble, Aventis, Roche, and GlaxoSmithKline.

Dr. Lewiecki receives research grants for Merck, Eli Lilly, Novartis, Aventis, Amgen, Pfizer, Wyeth-Ayerst, Roche, GlaxoSmithKline, and Procter & Gamble. He is a consultant and is on the Advisory Board and Speaker's Bureau for Merck, Eli Lilly, Novartis, Procter & Gamble, Aventis, Roche, GlaxoSmithKline, Wyeth-Ayerst, and Servier. He is also a direct stock shareholder in General Electric.

Dr. Maricic receives research grants from Merck, Eli Lilly, Procter & Gamble, Roche, and Novartis. He is also on the Speaker's Bureau for Merck, Eli Lilly, Procter & Gamble, and Novartis.

Dr. Watts receives lecture honoraria from Aventis, Merck, and Procter & Gamble. He receives consulting fees from Aventis, Eli Lilly, GlaxoSmithKline, Merck, Novartis, NPS, Proctor & Gamble, Roche, Servier, and Wyeth and research support from Amgen, Aventis, Eli Lilly, Merck, Novartis, and Proctor & Gamble.

Accepted August 24, 2005.

RELATED ARTICLE: Key Points

* An adequate intake of calcium and vitamin D is important because it complements the antifracture efficacy of drugs used to treat postmenopausal osteoporosis.

* The bisphosphonates alendronate and risedronate produce the most robust fracture risk reductions: approximately 40 to 50% reduction in vertebral fracture risk; 30 to 40% in nonvertebral fracture risk; and 40 to 60% in hip fracture risk. Ibandronate has been shown to reduce the risk of vertebral fractures.

* Raloxifene and salmon calcitonin nasal spray demonstrated protection against vertebral fractures in their pivotal studies. Teriparatide stimulates bone formation and significantly reduced vertebral and nonvertebral fracture risk in a pivotal study. The increases in BMD with combining teriparatide and a bisphosphonate are smaller than those induced by teriparatide alone, although still exceeding those induced by bisphosphonate therapy. This blunting of response was less pronounced when raloxifene was combined with teriparatide.

* Treatments on the horizon include strontium ranelate, which has demonstrated significant reductions in vertebral and nonvertebral fracture risk, and zoledronic acid, an injectable bisphosphonate that increased bone density with once-yearly administration.

* There are no head-to-head comparison trials that have prospectively assessed fractures as an endpoint. Available studies have compared the increase in BMD and reduction in bone markers. The changes induced by alendronate are more pronounced than those produced by risedronate, raloxifene, and calcitonin. In the absence of fracture data, the significance of these observed differences is debatable.

Table 1. Calcium content of commonly consumed foods (a)

Food and portion size                               Calcium content (mg)

Ricotta cheese, 1 cup                                       669
Plain, skim milk, yogurt, 8-ounce container                 452
Skim milk, 1 cup                                            306
Frozen spinach, 1 cup                                       291
Plain, whole milk, yogurt, 8-ounce container                275
Swiss cheese, 1 ounce                                       224
Mozzarella cheese, part skim milk, 1 ounce                  207
Soybeans, 1 cup                                             175
American cheese, 1 ounce                                    156
Low-fat cottage cheese, 1 cup                               156
Cheeseburger, single patty, 1 sandwich                      141
Navy beans, 1 cup                                           126
Chocolate pudding, ready-to-eat, 4 ounces                   102
Instant oatmeal, plain, prepared with water, 1               99
  packet
Frozen peas, 1 cup                                           94
Vanilla ice cream, 1/2 cup                                   84
Raisins, seedless, 1 cup                                     73
Almonds, 1 ounce (24 nuts)                                   70
Haddock, 1 filet                                             63
Dried figs, 2                                                62
Orange, 1                                                    52
Broccoli, 1 cup                                              41
Tuna salad, 1 cup                                            35
Fried egg, 1 large                                           27

(a) Adapted from United States Department of Agriculture. National
Nutrient Database for Standard Reference, Release 17. Available at:
http://www.nal.usda.gov/fnic/foodcomp/. Accessed April 2, 2005. (20)

Table 2. Summary of antifracture efficacy of calcium supplementation and
vitamin D supplementation from prospective studies in postmenopausal
women (a)

                          Osteoporosis                  Fracture End
Reference                 Inclusion                     Point
(intervention)            Criteria                      (duration)

Calcium vs placebo
Riggs 1998 (36)           Postmenopausal for            Vertebral (4 y)
  (calcium 1600 mg/d)       [greater than or equal to]    Nonvertebral
                            10 y                          (4 y)
Reeker 1996 (37)          Postmenopausal and age        Vertebral (4 y)
  (calcium 1200 mg/d)       > 60 y with calcium
                            intake < 1 g/d
Vitamin D vs calcium
Tilyard 1992 (38)         [greater than or equal to] 1  Vertebral (3 y)
  (calcitriol 0.25          prevalent vertebral
  [micro]g twice daily      fracture
  vs calcium 1000 mg/d)
                                                        Nonvertebral
                                                          (3 y)
Vitamin D vs placebo
Lips 1996 (39)            Men and women with age        Hip (3.5 y)
  (vitamin D 400 IU/d)      [greater than or equal to]
                            70 y
                                                        Other
                                                          nonvertebral
                                                          (3.5 y)
Vitamin D plus calcium
  vs placebo
Chapuy 1992 (41)          Women living in               Hip (1.5 y)
  (vitamin [D.sub.3] 800    nursing home                  Nonvertebral
  IU/d plus calcium 1200                                  (1.5 y)
  mg/d)
Dawson-Hughes 1997 (42)   Men and women with age        Nonvertebral
  vitamin [D.sub.3] 700     [greater than or equal to]    (3 y)
  IU/d plus calcium 500       65 y
  mg/d)
RECORD Trial Group        Men and women with age        New fractures
  2005 (43)                 [greater than or equal to]    (2 y)
  (vitamin [D.sub.3] 800    70 y with low-trauma
  IU/d vs calcium 1000      fracture
  mg/d vs combination
  vitamin [D.sub.3] plus
  calcium)
Porthouse 2005 (44)       Age                           Clinical
  (vitamin [D.sub.3] 800    [greater than or equal to]    fractures (2
  IU/d plus calcium 1000    70 y with                     y) Hip
  mg/d)                     [greater than or equal to]    fractures
                            1 risk factor for hip         (2 y)
                            fracture

                                                    Fracture With
                          Fracture With             Placebo or
Reference                 Treatment, n/N            Control, n/N
(intervention)            (%)                       (%)

Calcium vs placebo
Riggs 1998 (36)           8/88 (9.1)                9/89 (10.1)
  (calcium 1600 mg/d)     11/88 (12.5)              12/89 (13.5)
Reeker 1996 (37)          Prevalent VF: 15/53       Prevalent VF: 21/41
  (calcium 1200 mg/d)     (28.3)                    (51.2)
                          No prevalent VF: 12/42    No prevalent VF:
                          (28.6)                    13/61 (21.3)
Vitamin D vs calcium
Tilyard 1992 (38)         9.9/100 patient-y         31.5/100 patient-y
  (calcitriol 0.25
  [micro]g twice daily
  vs calcium 1000 mg/d)
                          Calcitriol 11 fractures   Calcium 24 fractures
                                                      in 22 women
Vitamin D vs placebo
Lips 1996 (39)            58/1291 (4.5)             48/1287 (3.7)
  (vitamin D 400 IU/d)
                          77/1291 (6.0)             74/1287 (5.7)
Vitamin D plus calcium
  vs placebo
Chapuy 1992 (41)          80/1387 (5.8)             110/1403 (7.8)
  (vitamin [D.sub.3] 800  160/1387 (11.5)           215/1403 (15.3)
  IU/d plus calcium 1200
  mg/d)
Dawson-Hughes 1997 (42)   11/187 (5.9)              26/202 (12.9)
  vitamin [D.sub.3] 700
  IU/d plus calcium 500
  mg/d)
RECORD Trial Group        Vitamin D: 188/1343       179/1332 (13.4)
  2005 (43)               (14.0)
  (vitamin [D.sub.3] 800  Calcium: 166/1311 (12.7)
  IU/d vs calcium 1000    Vitamin D + calcium:
  mg/d vs combination     165/1306 (12.6)
  vitamin [D.sub.3] plus
  calcium)
Porthouse 2005 (44)       58/1321 (4.4)             91/1993 (4.6)
  (vitamin [D.sub.3] 800  8/1321 (1.2)              17/1993 (1.4)
  IU/d plus calcium 1000
  mg/d)

                          RR of
Reference                 Fracture
(intervention)            (95% CI)            P Value

Calcium vs placebo
Riggs 1998 (36)           NA                  NS
  (calcium 1600 mg/d)     NA                  NS
Reeker 1996 (37)          NA                    0.023
  (calcium 1200 mg/d)                         NS
                          NA
Vitamin D vs calcium
Tilyard 1992 (38)         NA                  < 0.001 vs calcium
  (calcitriol 0.25
  [micro]g twice daily
  vs calcium 1000 mg/d)
                          NA                  < 0.05 vs calcium
Vitamin D vs placebo
Lips 1996 (39)            1.18 (0.81-1.71)    NS
  (vitamin D 400 IU/d)
                          NA                  NS
Vitamin D plus calcium
  vs placebo
Chapuy 1992 (41)          NA                    0.004
  (vitamin [D.sub.3] 800  NA                  < 0.001
  IU/d plus calcium 1200
  mg/d)
Dawson-Hughes 1997 (42)   0.5 (0.2-0.9)         0.02
  vitamin [D.sub.3] 700
  IU/d plus calcium 500
  mg/d)
RECORD Trial Group        With calcium vs     All NS vs placebo
  2005 (43)                 without
  (vitamin [D.sub.3] 800    calcium: 0.99
  IU/d vs calcium 1000      (0.86-1.15)
  mg/d vs combination     With vitamin
  vitamin [D.sub.3] plus    D vs without
  calcium)                  vitamin D:
                            1.01 (0.88-1.17)
Porthouse 2005 (44)       1.01 (0.71-1.43)    NS
  (vitamin [D.sub.3] 800  0.75 (0.31-1.78)
  IU/d plus calcium 1000
  mg/d)

(a) CI, confidence interval; NA, not available; NS, not significant;
RECORD, Randomised Evaluation of Calcium Or Vitamin D; RR, relative
risk; VF, vertebral fracture.

Table 3. Summary of antifracture efficacy of alendronate from
prospective studies of postmenopausal osteoporosis (a)

                                                             Fracture
                    Osteoporosis               Fracture      With
                    Inclusion                  End Point     Treatment,
Reference           Criteria                   (duration)    n/N (%)

Liberman 1995 (53)  Lumbar spine T-score -2.5  Vertebral      17/526
                      or lower, with or          (3 y)         (3.2)
                      without prevalent
                      vertebral fracture
                                               Nonvertebral   45/597
                                                 (3 y)         (7.5)
Black 1996 (54)     Femoral neck T-score -2.1  Vertebral      78/981
  (FIT1)              or lower and prevalent     (3 y)         (8.0)
                      vertebral fracture
                                               Hip (3 y)      11/1022
                                                               (1.1)
                                               Nonvertebral  122/1022
                                                 (3 y)         (11.9)
Cummings 1998 (55)  Femoral neck T-score -2.1  Vertebral      43/2057
  (FIT2)              or lower and no            (4 y)         (2.1)
                      prevalent vertebral
                      fracture
                                               Hip (4 y)      19/2214
                                                               (0.9)
                                               Nonvertebral  261/2214
                                                 (4 y)         (11.8)
Pols 1999 (62)      Lumbar spine T-score -2.0  Nonvertebral   19/950
  (FOSIT)             or lower                   (1 y)         (2.4) (b)

                    Fracture           RR of
                    With Placebo,      Fracture
Reference           n/N (%)            (95% CI)           P Value

Liberman 1995 (53)   22/355 (6.2)      0.52 (0.28-0.95)    0.03
                     38/397 (9.6)      0.79 (0.52-1.22)    NS
Black 1996 (54)     145/965 (15.0)     0.53 (0.44-0.66)   <0.001
  (FIT1)
                     22/1005 (2.2)     0.49 (0.23-0.99)    0.047
                    148/1005 (14.7)    0.80 (0.53-1.01)    NS
Cummings 1998 (55)   78/2077 (3.8)     0.56 (0.39-0.80)    0.002
  (FIT2)
                     24/2218 (1.1)     0.79 (0.43-1.44)    NS
                    294/2218 (13.3)    0.88 (0.74-1.04)    NS
Pols 1999 (62)       37/958 (4.4) (b)  0.53 (0.30-0.90)    0.021
  (FOSIT)

(a) CI, confidence interval; FIT, Fracture Intervention Trial; FOSIT,
Fosamax International Trial; NS, not significant; RR, relative risk.
(b) Cumulative incidence of nonvertebral fracture incidence captured as
adverse events from Kaplan-Meier survival estimates.

Table 4. Summary of antifracture efficacy of risedronate from
prospective studies of postmenopausal osteoporosis (a)

                     Osteoporosis                     Fracture End
                     Inclusion                        Point
Reference            Criteria                         (duration)

Harris 1999 (64)     [greater than or equal to] 2     Vertebral (1 y)
  (VERT-NA)            prevalent vertebral fractures
                       or 1 prevalent vertebral
                       fracture and lumbar spine T-
                       score -2.0 or lower
                                                      Vertebral (3 y)
                                                      Nonvertebral (3 y)
Reginster 2000 (65)  [greater than or equal to] 2     Vertebral (1 y)
  (VERT-MN)            prevalent vertebral fractures
                                                      Vertebral (3 y)
                                                      Nonvertebral (3 y)
McClung 2001 (72)    Group 1 (aged 70-79 y with       Hip (3 y)
  (HIP)                osteoporosis)
                     Group 1 with                     Hip (3 y)
                       [greater than or equal to] 1
                       prevalent vertebral fracture
                     Group 2 (aged                    Hip (3 y)
                       [greater than or equal to] 80
                       y with
                       [greater than or equal to]1
                       risk factors for hip
                       fracture)
                     Groups 1 and 2 combined          Hip (3 y)

                                     Fracture
                     Fracture With   With           RR of
                     Treatment,      Placebo, n/N   Fracture
Reference            n/N (%) (b)     (%) (b)        (95% CI)

Harris 1999 (64)      16/669 (2.4)   42/660 (6.4)   0.35 (0.19-0.62)
  (VERT-NA)
                      61/696 (11.3)  93/678 (16.3)  0.59 (0.43-0.82)
                      33/812 (5.2)   52/815 (8.4)   0.61 (0.39-0.94)
Reginster 2000 (65)   19/333 (5.6)   45/334 (13.0)  0.39 (0.22-0.68)
  (VERT-MN)
                      53/344 (18.1)  89/346 (29.0)  0.51 (0.36-0.73)
                      36/406 (10.9)  51/406 (16.0)  0.67 (0.44-1.04)
McClung 2001 (72)     55/3624 (1.9)  46/1821 (3.2)  0.6 (0.4-0.9)
  (HIP)
                      22/1128 (2.3)  25/575 (5.7)   0.4 (0.2-0.8)
                      82/2573 (4.2)  49/1313 (5.1)  0.8 (0.6-1.2)
                     137/6197 (2.8)  95/3134 (3.9)  0.7 (0.6-0.9)

Reference             P Value

Harris 1999 (64)      <0.001
  (VERT-NA)
                       0.003
                       0.02
Reginster 2000 (65)    0.001
  (VERT-MN)
                      <0.001
                       NS
McClung 2001 (72)      0.009
  (HIP)
                       0.003
                       NS
                       0.02

(a) CI, confidence interval; HIP, Hip Intervention Program; NS, not
significant; RR, relative risk; VERT-MN, Vertebral Efficacy With
Risedronate Therapy-Multinational; VERT-NA, Vertebral Efficacy With
Risedronate Therapy-North American
(b) Cumulative incidence of fracture incidence from Kaplan-Meier
survival estimates.

Table 5. Summary of antifracture efficacy of ibandronate from
prospective studies of postmenopausal osteoporosis (a)

                   Osteoporosis     Fracture End        Fracture With
                   Inclusion        Point               Treatment,
Reference          Criteria         (duration)          n (%)

Chesnut 2004 (76)  Lumbar spine T-  Vertebral (3 y)     Daily 37
                     score -2.0 or                        (4.7) (b)
                     lower, with
                     prevalent
                     vertebral
                     fracture
                                                        Intermittent 39
                                                          (4.9) (b)
                                    Nonvertebral (3 y)  Daily (9.1) (c)
                                                          Intermittent
                                                          (8.9) (c)

                   Fracture With  RR Reduction of
                   Placebo,       Fracture
Reference          n (%)          (95% CI)         P Value

Chesnut 2004 (76)  73 (9.6) (b)   62% (41%-75%)    0.0001
                                  50% (26%-66%)    0.0006
                      (8.2) (c)   Not reported     NS

(a) CI, confidence interval; NS, not significant; RR, relative risk.
(b) Cumulative incidence of vertebral fracture incidence from life-
table analysis estimates.
(c) Cumulative incidence of nonvertebral fracture incidence from Kaplan-
Meier survival estimates.

Table 6. Summary of antifracture efficacy of raloxifene, salmon
calcitonin nasal spray, and teriparatide from prospective studies (a)

                      Osteoporosis                  Fracture End
                      Inclusion                     Point
Reference             Criteria                      (duration)

Raloxifene 60 mg/d
  Ettinger 1999 (80)  Group 1 (femoral)             Vertebral (3 y)
    (MORE)              neck or lumbar
                        spine T-score
                        below -2.5)
                      Group 2 (low BMD              Vertebral (3 y)
                        and prevalent
                        vertebral fracture)
                      Groups 1 and 2                Vertebral (3 y)
                        combined
                                                    Hip (3 y) (b)
                                                    Nonvertebral
                                                      (3 y) (b)
Salmon Calcitonin
  Nasal Spray 200
  IU/d
  Chesnut 2000 (86)   1-5 prevalent                 Vertebral (5 y)
    (PROOF)             vertebral
                        fracture(s) and
                        lumbar spine T-
                        score -2 or below
                                                    Hip (5 y)
                                                    Nonvertebral (5 y)
Teriparatide 20
  [micro]g/d
  Neer 2001 (89)      [greater than or equal to] 2  Vertebral (21 mo)
                        prevalent vertebral
                        fractures or, if
                        [less than or equal to] 2
                        vertebral fractures, hip
                        or lumbar spine T-score -1
                        or below
                                                    Hip (21 mo)
                                                    Nonvertebral (21
                                                      mo) (c)

                      Fracture        Fracture
                      With            With             RR of
                      Treatment,      Placebo,         Fracture
Reference             n/N (%) (b)     n/N (%) (b)      (95% CI)

Raloxifene 60 mg/d
  Ettinger 1999 (80)   35/1490 (2.3)   68/1522 (4.5)   0.5 (0.4-0.8)
    (MORE)
                      113/769 (14.7)  163/770 (21.2)   0.7 (0.6-0.9)
                      148/2259 (6.6)  231/2292 (10.1)  0.7 (0.5-0.8)
                       40/5129 (0.8)   18/2576 (0.7)   1.1 (0.6-0.9)
                      437/5129 (8.5)  240/2576 (9.3)   0.9 (0.8-1.1)
Salmon Calcitonin
  Nasal Spray 200
  IU/d
  Chesnut 2000 (86)    51/287 (18)     70/270 (26)     0.67 (0.47-0.97)
    (PROOF)
                        5/315 (2)       9/305 (3)      0.5 (0.2-1.6)
                       46/315 (15)     48/305 (16)     0.88 (0.59-1.32)
Teriparatide 20
  [micro]g/d
  Neer 2001 (89)       22/444 (5.0)    64/448 (14.3)   0.35 (0.22-0.55)
                        2/541 (0.4)     4/544 (0.7)    NA
                       14/541 (2.6)    30/544 (5.5)    0.47 (0.25-0.88)

Reference             P Value

Raloxifene 60 mg/d    <0.05
  Ettinger 1999 (80)
    (MORE)
                      <0.05
                      <0.05
                       NS
                       NS
Salmon Calcitonin
  Nasal Spray 200
  IU/d
  Chesnut 2000 (86)    0.03
    (PROOF)
                       NS
                       NS
Teriparatide 20
  [micro]g/d
  Neer 2001 (89)      <0.001
                       NA
                       0.02

(a) BMD, bone mineral density; CI, confidence interval; MORE, Multiple
Outcomes of Raloxifene Evaluation; NA, not available; NS, not
significant; PROOF, Prevent Recurrence of Osteoporotic Fractures; RR,
relative risk.
(b) Combined raloxifene 60 mg/d and 120 mg/d treatment groups.
(c) Fragility fractures, defined as those that would not have resulted
in a fracture of normal bone.