Risedronate

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The efficacy of risedronate in increasing lumbar spine BMD was studied in 648 postmenopausal women for 18 months by McClung et al. (150). The average age of the women was 62 years and all were at least 1 year postmenopausal with an average duration of menopause of16 years. At entry into the study, the lumbar spine T-score was -2 or less. BMD was measured by DXA at the PA lumbar spine, proximal femur, and at the distal and midradius. The women received either 2.5 mg or 5 mg of risedronate daily or placebo. All of the women received 1 g of calcium daily. Risedronate increased BMD at the lumbar spine, femoral neck, and trochanter and at the distal radius in a dose-dependent fashion.

7 This data was not directly reported in the referenced publication. The changes in lumbar spine bone density from baseline noted above for the treatment groups are based on a visual inspection of the published graph showing the percent changes in bone density from baseline over time in the study.

8 The 60 mg dose of raloxifene is the amount that is approved by the Food and Drug Administration for the prevention and treatment of postmenopausal osteoporosis.

9 This data was not directly reported in the publication and is extrapolated from a visual inspection of the published graph showing the percent change from baseline during the study at the femoral neck for the three treatment groups.

At the lumbar spine, both risedronate groups had significant changes in BMD from baseline, whereas the placebo group did not change significantly. The 5 mg risedronate group had a significantly greater increase than the 2.5 mg group. The gains in lumbar spine BMD at the end of 18 months for the 2.5 mg and 5 mg risedronate groups were 2 to 3% and 4 to 5%, respectively. In the femoral neck and trochanter, both risedronate groups again demonstrated significant increases from baseline and significant increases in comparison to the placebo group. The 5 mg risedronate group again demonstrated a significantly greater increase in BMD at both sites than the 2.5 mg group. The average gain in BMD at the femoral neck in the 5 mg group was approximately 3% and at the trochanter, approximately 5%. At the distal radius, only the 5 mg risedronate group had a significant increase in BMD from baseline at 18 months of slightly more than 1%. At the midradius, no group demonstrated a significant change in BMD from baseline values. This data was presented in abstract form at the 19th annual meeting of the American Society for Bone and Mineral Research.

Two major trials of risedronate therapy in postmenopausal osteoporosis were published in 1999 and 2000 (151,152). The trials were almost identical in design and are known as the North American and European Vertebral Efficacy with Risedronate Therapy (VERT) trials. In both trials, the primary endpoint of interest was the reduction in vertebral fracture risk.

In the North American VERT trial (151), 2458 postmenopausal women participated. The women were eligible if they were at least 5 years postmenopausal and not more than 85 years of age. They were required to have at least two spine fractures at study entry or one spine fracture and a PA lumbar spine BMD T-score of -2 or less. All the women received 1000 mg of elemental calcium daily. If a serum 25-hydroxyvitamin D level was low at study start, the women also received up to 500 IU of cholecalciferol supplementation daily. The women then received either a placebo, 2.5 mg of risedronate or 5 mg of risedronate daily. DXA was used to measure bone density at the PA lumbar spine and proximal femur at 6-month intervals during the 3-year trial. Approximately 1 year after the trial was started, the 2.5 mg risedronate arm was discontinued. At the end of 3 years, treatment with 5 mg of risedronate daily significantly reduced the cumulative incidence of morphometric vertebral fractures by 41% compared with placebo. At the end of only 1 year, a statistically significant 65% reduction in spine fracture risk was seen in the 5 mg risedronate group. At the end of 3 years at the PA lumbar spine, women receiving 5 mg of risedronate daily increased their bone density by 5.4% from baseline compared to the 1.1% increase in the placebo group. In the proximal femur, the 5 mg risedronate group had increases from baseline of 1.6% at the femoral neck and 3.3% at the trochanter compared to losses of 1.2% and 0.7% in the placebo group. The increases in bone density in the risedronate-treated women were both statistically significant from baseline and significantly different from the changes seen in the placebo group. Bone density was maintained in the risedronate treated women at the midradius at the end of 3 years while the placebo group lost midradial bone density.

In the European VERT trial (152) the women had to have at least two spine fractures to be eligible. The trial was otherwise identical in design and involved 1226 postmeno-pausal women with average lumbar spine T-scores in the WHO osteoporotic category. Because the European VERT trial started before the North American VERT trial, the 2.5 mg risedronate group was discontinued after 2 years of this 3-year trial. Morphometric spine fracture risk was significantly reduced in the 5 mg risedronate group by 47%

compared to the placebo group at the end of the trial. At the end of 1 year, the reduction in morphometric spine fracture risk in the 5 mg risedronate group was 61%. Much as was seen in the North American VERT trial, bone density increased significantly from baseline in the 5 mg risedronate treated women at the PA lumbar spine, femoral neck, and trochanter and was maintained at the midradius at the end of 3 years. These changes in bone density in the 5 mg risedronate-treated women were also significantly different from the placebo group.

The effect of risedronate therapy on hip fracture as the primary endpoint of interest was studied in 9331 postmenopausal women age 70 and older by McClung et al. (153). In this study, only women age 70 to 79 were enrolled entirely on the basis of a very low femoral neck bone density T-score of -4 or -3 and at least one clinical risk factor for hip fracture. Women age 80 and older could be enrolled on the basis of clinical risk factors for hip fracture alone. As in the VERT trials, all the women received 1000 mg of elemental calcium a day and up to 500 IU of vitamin D a day if the serum 25-hydroxyvitamin D level was low at baseline. The women were then divided into three groups, receiving a placebo, 2.5 mg risedronate, or 5 mg risedronate per day. The duration of the trial was 3 years. The primary endpoint in this study was the reduction in hip fracture risk. Changes in bone density in the proximal femur were considered a secondary endpoint. In the women age 70 to 79 years, bone density at the femoral neck was 2.1% and 3.4% higher than placebo in the 2.5 mg and 5 mg risedronate groups, respectively. At the trochanter, bone density was 3.8% and 4.8% higher than placebo in the 2.5 mg and 5 mg risedronate groups. The actual changes from baseline are not cited in the New England Journal of Medicine publication. Hip fracture risk was statistically significantly reduced by 40% in the 70- to 79-year-old women for the two risedronate groups combined compared to the placebo group.

The original formulation of risedronate for the prevention or treatment of osteoporosis called for a dose of 5 mg daily. The effect of 35 mg and 50 mg of risedronate given only once a week compared to the 5 mg daily dose on lumbar spine bone density was reported in Calcified Tissue International by Brown et al. (154). The participants in this trial were ambulatory women age 50 and older who were at least 5 years postmenopausal. They were required to have PA lumbar spine T-scores of -2.5 or poorer in the absence of a spine fracture or -2 or poorer with a spine fracture. Bone density was measured by DXA at the PA lumbar spine and proximal femur at 6 and 12 months. In addition to 1000 mg of elemental calcium a day, each woman received 5 mg risedronate daily, 35 mg risedronate once weekly, or 50 mg risedronate once weekly. At the end of 1 year, the average increase from baseline in lumbar spine bone density was 4.00%, 3.94%, and 4.25% for the 5 mg daily, 35 mg once weekly, and 50 mg once weekly risedronate groups, respectively. At the total hip, the increases from baseline were 2.51%, 2.35%, and 2.88% for the same three groups at the end of 12 months. At the femoral neck, there were increases of 2.05%, 1.92%, and 2.12% from baseline and at the trochanter there were increases of 3.34%, 3%, and 3.68% for the three dosage groups. The changes in bone density from baseline at all sites for all three groups were statistically significant.

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