Alendronate and Alendronate/Cholecalciferol (Fosamax Plus D)
The safety and fracture efficacy of alendronate in the treatment of PMO were established with the Alendronate Phase 3 Group trials and the Fracture Intervention Trial (FIT). Data from the three-year trials were combined to determine a reduced fracture risk. A total of 994 postmenopausal women were randomly assigned to receive placebo, 10 mg, or 20 mg/day. The risk of vertebral fractures in women treated with alendronate, compared with placebo, was reduced by 48% (P < 0.05). A 12% reduction in nonvertebral fracture was observed but was not significant.
Three trial extensions provided a total study period of 10 years. The 5-mg and 10-mg treatment groups continued with the same dose after the third year; the 20-mg group received 5 mg/day for the fourth and fifth years and then placebo for years six to 10. Fracture data from years six to 10 were evaluated for 228 women. These patients were observed for the full 10 years. During this five-year extension period, the proportion of women with vertebral fractures did not differ between those who discontinued therapy (6.6%), the 5-mg treatment group (13.9%), or the 10-mg treatment group (5%).
FIT was a randomized, controlled, double-blinded clinical trial of postmenopausal women with low BMD. The study authors compared placebo and alendronate 5 mg/day for 24 months, followed by 10 mg/day for the third year. In a three-year analysis of the 2,027 postmenopausal women with a history of fractures, alendronate was associated with a 47% lower risk of new vertebral fractures, compared with placebo (P < 0.001). Women treated with alendronate also had a lower risk of any fracture, compared with the placebo group, but the difference did not reach statistical significance.
In a four-year analysis of 4,432 postmenopausal women participating in FIT who did not have a previous fracture, the risk of vertebral fracture was reduced by 44% (P = 0.002); the trend toward lower risk of any nonvertebral fracture did not reach significance. The reduction in fracture risk was observed in women with baseline hip BMD T-scores below or equal to -2.5 (e.g., -3.0). In this low BMD group, treatment was associated with a 50% lower risk of vertebral fractures and a 36% lower risk of any fracture, compared with placebo (P < 0.001). Fracture risk reduction was not statistically significant for women with base line hip BMD T-scores above -2.5.
The Fracture Intervention Trial Long-Term Extension (FLEX) study evaluated the effects of discontinuing alendronate after five years of treatment compared with 10 years of treatment. In this study, 1,099 alendronate participants from the FIT trial were randomly assigned to receive alendronate 5 mg, alendronate 10 mg, or placebo. After five years, the authors found no significant difference between treated and placebo groups in the risk of nonvertebral fractures (risk ratio [RR] = 1.0; 95% confidence interval [CI], 0.76-1.32) or in the risk of morpho-metric vertebral fractures (RR = 0.86; 95% CI, 0.60-1.22). However, there was a significant reduction in clinical vertebral fractures with alendronate compared with placebo (RR = 0.45; 95% CI, 0.24-0.85).
Risedronate (Actonel with Calcium) Randomized, placebo-controlled, double-blind studies evaluated the efficacy of risedronate in reducing the incidence of fractures in postmenopausal women in the U.S. In the Vertebral Efficacy with Risedronate study (VERT), 2,458 postmenopausal women with BMD T-scores of less than -2.0 and a history of at least one vertebral fracture were randomly assigned to receive risedronate 2.5 mg, risedronate 5 mg daily, or placebo. The risk of new vertebral fractures with day was 41% lower than with placebo at three years (P = 0.003), and the risk of new nonvertebral fractures was 40% lower than with placebo (P = 0.02). A significant reduction in vertebral fracture risk at the end of the first year was observed with 5 mg.
Risedronate also demonstrated efficacy in preventing hip fractures in the randomized Hip Intervention Program (HIP) trial. HIP included these groups:
Participants received risedronate 2.5 mg or 5 mg/day or placebo. Treatment was associated with a 40% decrease in risk of hip fracture (P = 0.009) but did not have a significant impact on hip fracture rates in the 70- to 79-year-old patients. However, only 16% of this older cohort had been recruited on the basis of low BMD; the rest of the subjects had been recruited on the basis of other risk factors, such as a recent fall-related injury.
The efficacy of ibandronate was shown in the Oral Iban-dronate Osteoporosis Vertebral Fracture Trial in North America and Europe (BONE), a randomized, placebo-controlled, double-blind study. Participants were 2,946 postmenopausal women with lumbar spine BMD T-scores of less than -2.0 and at least one but no more than four prior vertebral fractures.
Patients were randomly assigned to receive daily (the “daily” group), ibandronate 20 mg every other day for 12 doses every three months (the “intermittent” group), or placebo. At three years, the risk of new vertebral fracture with ibandronate, relative to placebo, was reduced by 62% in the daily group (P = 0.0001) and by 50% in the intermittent group (P = 0.006). The risk reduction for new vertebral fractures was significant after two years.
Etidronate (Generic Didronel)
Etidronate disodium is available in the U.S. in an oral formulation for the treatment of Paget’s disease. In a large, placebo-controlled, double-blind study, 423 generally healthy postmenopausal women were randomly assigned to receive placebo only, phosphate plus placebo, phosphate plus, or etidronate plus placebo for three years.61,62 Phosphate was administered at 1 g twice daily, and etidronate was given at 400 mg daily for 14 consecutive days of a 91-day cycle.
At the end of three years, reductions in fracture risk did not differ between the etidronate and non-etidronate groups. Although the study was not specifically powered to detect a difference in the risk of fracture, there was a 44% reduction in ver-tebral fractures with etidronate (P < 0.05), compared with the non-etidronate groups, for patients with BMD below the 50th percentile (-2.67 or less). ADEs reported in clinical trials with canadian etidronate included leg cramps, headache, gastritis, and arthralgia.
Zoledronic Acid (Reclast, Zometa)
An injectable bisphosphonate, zoledronic acid is approved in the U.S. for use in Paget’s disease, hypercalcemia of malignancy, and bone metastases of solid tumors. Its efficacy in PMO was studied in the Health Outcomes and Reduced Incidence with Zoledronic Acid Once Yearly (HORIZON) Pivotal Fracture Trial. This was a large double-blind, placebo-controlled study of 3,889 postmenopausal women 65 to 89 years of age.
Subjects were eligible for enrollment if they had T-scores of -2.5 or less, with or without evidence of an existing vertebral fracture, or T-scores of -1.5 or less, with evidence of two mild vertebral fractures or one moderate vertebral fracture. They were randomly assigned to receive IV zoledronic acid 5 mg or placebo over 15 minutes one time a year for three doses.
Over three years of follow-up and compared with placebo, zoledronic acid therapy reduced vertebral fracture risk by 70% (P < 0.001), hip fracture risk by 41% (P = 0.002), and non-vertebral fracture risk by 25% (P < 0.001). Notable ADEs occurred with zoledronic acid more frequently than with placebo, including an increased incidence of serious atrial fibrillation and elevated serum creatinine levels (above 0.5 mg/dL), but mean creatine clearance did not differ with placebo.
Selective Estrogen Receptor Modulators Raloxifene
Raloxifene (Evista, Eli Lilly) decreases bone resorption through activation and modulation of the estrogenic pathways, thus mitigating bone loss associated with reduction of estrogen levels after menopause. Raloxifene canadian is available in an oral formulation for daily administration.
The efficacy and safety of raloxifene were established in the three-year Multiple Outcomes of Raloxifene Evaluation (MORE) study. MORE was a randomized, blinded, placebo-controlled trial that included 7,705 postmenopausal women with T-scores of less than -2.5 or a low T-score plus a history of fracture. Participants received raloxifene 60 mg/day, 120 mg/day, or placebo.
At three years, raloxifene 60 mg, the approved dose in the U.S., was associated with a 30% reduced risk of vertebral fractures in women with a pre-existing fracture (P< 0.05). The risk reduction in women without a previous vertebral fracture was 50% (P < 0.05) and was significant at 12 months. There was no difference in the risk of nonvertebral fractures between ralox-ifene and placebo. ADEs include leg cramps and hot flashes.
Continuing Outcomes Relevant to Evista (CORE) was a four-year follow-up study of 3,200 patients from the MORE study. In CORE, patients originally assigned to receive raloxifene 60 mg/day or 120 mg/day continued with day; those receiving placebo continued with placebo for four years. The study measured the rate of new nonvertebral fractures. No difference between nonvertebral fracture rates was observed with raloxifene (22.8%) or placebo (22.9%) during the four-year follow-up period. Differences in fracture rates were not significant according to fracture location or in terms of other bone-active agents during the follow-up study. However, women with a prevalent vertebral fracture at the start of MORE had a 22% lower fracture rate with raloxifene compared with placebo (P < 0.05). Fracture rates were also 37% lower in women with a severe vertebral fracture at the start of MORE (P < 0.05).