Skeletal Effects of Raloxifene After 8 Years: Results from the Continuing Outcomes Relevant to Evista (CORE) Study

Abstract

In the CORE breast cancer trial of 4011 women continuing from MORE, the incidence of nonvertebral fractures at 8 years was similar between placebo and raloxifene 60 mg/day. CORE had limitations for assessing fracture risk. In a subset of 386 women, 7 years of raloxifene treatment significantly increased lumbar spine and femoral neck BMD compared from the baseline of MORE. Introduction:The multicenter, double-blind Continuing Outcomes Relevant to Evista (CORE) trial assessed the effects of raloxifene on breast cancer for 4 additional years beyond the 4-year Multiple Outcomes of Raloxifene Evaluation (MORE) osteoporosis treatment trial. Materials and Methods:In CORE, placebo-treated women from MORE continued with placebo (n ‫ס‬ 1286), whereas those previously given raloxifene (60 or 120 mg/day) received raloxifene 60 mg/day (n ‫ס‬ 2725). As a secondary endpoint, new nonvertebral fractures were analyzed as time-to-first event in 4011 postmenopausal women at 8 years. A substudy assessed lumbar spine and femoral neck BMD at 7 years, with the primary analysis based on 386 women (127 placebo, 259 raloxifene) who did not take other bone-active agents from the fourth year of MORE and who were Ն80% compliant with study medication in CORE. Results: The risk of at least one new nonvertebral fracture was similar in the placebo (22.9%) and raloxifene (22.8%) groups (hazard ratio [HR], 1.00; Bonferroni-adjusted CI, 0.82, 1.21). The incidence of at least one new nonvertebral fracture at six major sites (clavicle, humerus, wrist, pelvis, hip, lower leg) was 17.5% in both groups. Posthoc Poisson analyses, which account for multiple events, showed no overall effect on nonvertebral fracture risk, and a decreased risk at six major nonvertebral sites in women with prevalent vertebral fractures (HR, 0.78; 95% CI, 0.63, 0.96). At 7 years after MORE randomization, the differences in mean lumbar spine and femoral neck BMD with raloxifene were 1.7% (p ‫ס‬ 0.30) and 2.4% (p ‫ס‬ 0.045), respectively, from placebo. Compared with MORE baseline, after 7 years, raloxifene treatment significantly increased lumbar spine (4.3% from baseline, 2.2% from placebo) and femoral neck BMD (1.9% from baseline, 3.0% from placebo). BMDs were significantly increased from MORE baseline at all time-points at both sites with raloxifene. Conclusion: Raloxifene therapy had no effect on nonvertebral fracture risk after 8 years, although CORE had limitations for fracture risk assessment. BMD increases were maintained after 7 years of raloxifene.

Clinical Significance of 1-year Treatment with Raloxifene on Bone and Lipid Metabolism in Japanese Postmenopausal Women with Osteoporosis

“…Therefore, we do not think that our findings of no increase of BMD at the non-vertebral sites rule out the potential effects of RLX to reduce the risk of non-vertebral fractures. Actually, its effects on prevention of hip fractures in those patients, mostly Caucasian, with high risk of fractures, have already been demonstrated in MORE study [20], although not in all of the patients. A large-scale double-blinded prospective randomized study to evaluate its effects on prevention of fractures, vertebral or non-vertebral, is warranted for Japanese postmenopausal women.…”

Postmenopausal osteoporosis treatment with antiresorptives: Effects of discontinuation or long-term continuation on bone turnover and fracture risk—a perspective

“…(36) Only raloxifene and bazedoxifene have long-term data, and treatment discontinuation has only been studied in raloxifene. (37)(38)(39) The magnitude of the effect of raloxifene on BMD and BTMs is generally lower than that of standard-dose HT, (40) and fracture protection appears confined to the spine. (41) The Continuing Outcomes Relevant to Evista (CORE) study indicated that 7 years of raloxifene therapy maintained the initial increments seen in spine and hip BMD over 3 years, but showed no further gains (Table 1).…”

“…(41) The Continuing Outcomes Relevant to Evista (CORE) study indicated that 7 years of raloxifene therapy maintained the initial increments seen in spine and hip BMD over 3 years, but showed no further gains (Table 1). (38) Long-term BTM data (!5 years) were not available. No effect on nonvertebral fracture incidence was seen in the MORE, (42) CORE, (38) or the Raloxifene Use for the Heart (RUTH) trial of over 10,000 women with documented or at high risk for coronary heart disease.…”

“…(38) Long-term BTM data (!5 years) were not available. No effect on nonvertebral fracture incidence was seen in the MORE, (42) CORE, (38) or the Raloxifene Use for the Heart (RUTH) trial of over 10,000 women with documented or at high risk for coronary heart disease. (43) Cessation of raloxifene results in a rapid decline of BMD values 1 year after treatment discontinuation ( Table 2).…”

Influence of hepatic and intestinal efflux transporters and their genetic variants on the pharmacokinetics and pharmacodynamics of raloxifene in osteoporosis treatment

“…Raloxifene therapy suppresses the bone turnover to normal premenopausal range, thereby increasing bone mineral density (BMD) in the spine, hip and total body [3,4], reducing the risk for vertebral fractures [5] but not changing non-vertebral fracture risk [6]. After peroral application, raloxifene undergoes a rapid absorption, an extensive first-pass metabolism and an entero-hepatic cycling.…”