Alendronate and Risedronate for the Treatment of Postmenopausal Osteoporosis: Clinical Profiles of the Once-Weekly and Once-Daily Dosing Formulations

Ronald Emkey, MD

Disclosures

Medscape General Medicine. 2004;6(3):6 

In This Article

Clinical Efficacy of the Bisphosphonates: Once-Daily Regimens

The antifracture efficacy and safety of daily administered alendronate for the treatment of postmenopausal osteoporosis have been reported in 3 randomized, placebo-controlled trials.[25,26,27] Patients received 5 mg, 10 mg, or 20 mg alendronate daily, or placebo. In addition to the study drug, patients also received a calcium supplement of 500 mg per day. The Fracture Intervention Trial (FIT) was conducted in 2 separate arms -- a 3-year arm that enrolled 2027 subjects with existing vertebral fractures at baseline[25] (FIT I) and a 4-year arm that included 4432 subjects without vertebral fractures at baseline[26] (FIT II), one third of whom had osteoporosis based on femoral neck bone mineral density (BMD) -- and investigated the effect of alendronate on fracture incidence in postmenopausal women with low femoral neck BMD (≤ 0.68 g/cm2, about -1.6 standard deviations [SDs] below peak bone mass). Excluded from the studies were women with recent peptic ulcer disease or ulcers requiring hospitalization, and dyspepsia requiring daily treatment. Women with past or current histories of upper gastrointestinal tract disease requiring less frequent treatment were eligible. Patients treated with nonsteroidal anti-inflammatory drugs were not excluded for the same reason.[28] Lateral spine radiographs were obtained to detect morphometric vertebral fractures at 2 and 3 years (FIT I) and at 4 years (FIT II).

After 3 and 4 years of treatment in the FIT I and II studies, alendronate reduced vertebral fracture risk by 47% (P < .001)[25] and 44% (P = .002),[26] respectively ( Table 1 ). A 59% reduction in clinical vertebral fractures was observed after 1 year of treatment with alendronate (P < .001).[29] Nonvertebral fracture risk reduction was not statistically significant in either study (20%; P = .06 and 12%; P = .13, respectively). In patients in the FIT II trial, while there was no reduction in the risk of hip fractures in the two thirds of subjects with higher hip BMD (T-score > -2.5), hip fracture was reduced by 56% (P < .05) in one third of subjects with lower hip BMD (T-score ≤ -2.5). Patients from FIT I (those with prevalent vertebral fractures) experienced a 51% reduction in the risk of hip fracture (P = .047); clinical vertebral fractures were reduced by 55% (P ≤ .001). In a 1-year multicenter, placebo-controlled trial, risk of nonvertebral fracture was significantly reduced vs placebo (47%; P = .021).[30]

The efficacy of alendronate was also evaluated in 2 nearly identical 3-year dose-ranging studies of postmenopausal women with osteoporosis (lumbar spine T-score ≤ -2.5).[27] Women with active peptic ulcer disease were excluded from these studies. Subjects were randomized to receive alendronate 5 mg or 10 mg daily for 3 years, alendronate 20 mg daily for 2 years, followed by 5 mg daily in the third year, or placebo for 3 years.

Alendronate 10 mg/day and alendronate 20 mg/day for 2 years followed by 5 mg/day for the third year were found to be more effective than the 5-mg/day dose at building BMD.[27] A significant reduction in new vertebral fractures vs placebo was observed when all patients receiving alendronate were pooled (48%; P = .03).

The long-term efficacy and tolerability of alendronate were evaluated in two 2-year extensions,[31] followed by a 3-year extension of the dose-ranging studies.[32] During the first 2-year extension, patients receiving placebo in the original studies were switched to alendronate 10 mg/day for years 4 and 5.[31] During the second 2-year extension, patients who received the 20-mg/day followed by the 5-mg/day regimen were switched to placebo and remained on placebo during the following 3-year extension.[31] Patients receiving placebo during the original study were not eligible for enrollment into the second and third extensions.[31,32]

In patients receiving continuous treatment (alendronate 5 mg/day or 10 mg/day), bone density continued to increase over the 10-year evaluation period. Patients receiving alendronate 20 mg/day for 2 years, followed by alendronate 5 mg/day for 1 year of the original study and 2 years of the first extension, and then placebo for years 6 to 10, showed no significant change in BMD at both the lumbar spine and total body during the 5 years in which they received placebo. Because the first extension was not placebo-controlled, fracture risk reduction for years 4 to 10 could not be calculated.

The antifracture efficacy and safety of the 5-mg daily regimen of risedronate in postmenopausal women with osteoporosis have been demonstrated in 3 large, multicenter, double-blind clinical trials.[33,34,35] Patients were randomly assigned to treatment with either oral risedronate (2.5 mg/day or 5.0 mg/day) or placebo. In the vertebral fracture trials discussed here, osteoporosis was defined as the presence of at least 2 vertebral fractures or a lumbar spine BMD T-score of < -2 with at least 1 prevalent vertebral fracture ( Table 2 ).[33,34] In the hip fracture study, those enrolled on the basis of low BMD had a T-score < -3.[35] All patients received supplemental calcium of 1000 mg/day. Patients with a below-normal baseline serum 25-hydroxy vitamin D concentration received supplemental vitamin D (up to 500 IU/day).[33,34,35] Although bisphosphonates are associated with irritation of the upper gastrointestinal mucosa,[13,14] risedronate trials did not exclude patients with a history of or active gastrointestinal disease, and patients taking medications for active gastrointestinal disorders (eg, histamine H2-receptor antagonists, proton pump inhibitors, or antacids).

In two 3-year, placebo-controlled trials, the Vertebral Efficacy With Risedronate Therapy-Multinational (VERT-MN) and -North America (VERT-NA) trials, the risk of new vertebral fractures in postmenopausal women with osteoporosis was significantly reduced by 61% to 65%, respectively, (P≤ .001; Table 1 ) after 1 year of risedronate 5-mg/day therapy vs placebo.[33,34] Furthermore, in pooled analyses, risedronate 5 mg/day significantly reduced clinical vertebral and nonvertebral fracture risk after 6 months of treatment (P < .05).[36,37] After 3 years of risedronate 5 mg/day, the risk of new vertebral fractures remained significantly reduced ( Table 1 ).

A post hoc analysis combining the 3-year data from the VERT-MN study and a 2-year extension of the same study found that antifracture efficacy was sustained during 5 years of treatment, with a 50% reduction in vertebral fracture risk vs placebo (P < .001).[38] Daily treatment with risedronate 5 mg resulted in a 33% (P = .06) decrease in the risk of nonvertebral fractures in postmenopausal women with osteoporosis after 3 years[33] ( Table 1 ) and a 37% reduction in nonvertebral fracture risk after 5 years (P = .022) vs placebo.[38] No hip fractures were observed in either treatment group during the extension study.

The placebo-controlled 2-year extension described earlier was followed by an open-label 2-year extension.[39] During years 6 and 7, BMD continued to increase, similar to the findings over 7 years in a study of alendronate.[31] Reduction of fracture risk could not be calculated for the second 2-year risedronate extension trial because it was not placebo-controlled.[39]

The Hip Intervention Program study specifically examined the effect of risedronate therapy on the risk of hip fracture over 3 years.[35] In women aged 70 to 79 years with confirmed osteoporosis (femoral neck BMD more than 3 SDs below young adult women), once-daily risedronate (2.5- and 5-mg groups combined) significantly reduced the risk of hip fracture by 40% (P = .009) vs placebo. In women with confirmed osteoporosis and 1 or more vertebral fractures at baseline, risedronate reduced the risk of hip fracture by 60% (P = .003).[35] Risedronate therapy had no significant effect (P = .35) on hip fracture risk in the group of women aged ≥ 80 years that were selected primarily on the basis of nonskeletal risk factors.

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