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 ********** 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. 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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: Hamdy@etsu.edu 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.
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