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Discussion
The overall findings for 7 years of BZA treatment are consistent with those at 3 and 5 years. We observed significant reductions in the relative risks of new vertebral fractures through 7 years (BZA, 36.5%; BZA20, 30.4%), comparable to findings reported for RLX60 and raloxifene 120 mg (36% and 43%, respectively) after 4 years. During extension II, the BZA group had a 32.6% relative risk reduction in the rate of new vertebral fractures.
BZA had no effect on the incidence of nonvertebral fractures at 3, 5, or 7 years. In a higher-risk subpopulation, there were reductions in the risk of nonvertebral fracture at 7 years (BZA, 28%; BZA20, 32%) versus PBO, but they were not statistically significant. These trends are consistent with findings at 3 years showing a significant reduction in the risk of nonvertebral fractures among higher-risk women treated with BZA20. They are also consistent with results from an independent reanalysis of data from the core study, in which BZA had a greater treatment effect on women with increasing fracture probability, as assessed using the Fracture Risk Assessment Tool.
Significant improvements from baseline in lumbar spine BMD were seen with BZA and PBO at 7 years. The increase was greater, but not statistically significantly, in the BZA group than in the PBO group; however, statistical power was limited by the increase in lumbar spine BMD observed in the PBO group starting on year 5. Calcium and vitamin D supplementation may have contributed to this increase. Although the core study showed a significant increase in total hip BMD with BZA at 3 years, decreases in total hip BMD were seen at 5 years and 7 years in all groups. Reductions in hip BMD at 5 and 7 years were significantly smaller in the BZA groups than in the PBO group. The difference in the change in total hip BMD between BZA and PBO was approximately 1% at 3, 5, and 7 years.
The significant difference in vertebral fracture incidence, but not changes in BMD, observed with BZA (compared with PBO) at 7 years suggests that factors independent of BMD may contribute to fracture risk reduction. Reductions in bone turnover and/or improvements in bone properties/microarchitecture have been linked to enhanced bone strength with other osteoporosis treatments (eg, risedronate and alendronate). Significant reductions in bone turnover markers were seen in the core study and were still apparent in the BZA groups after 5 years.
BZA treatment was safe and well tolerated, with no increase in the risk of ischemic cardiac disorders or stroke across 7 years, consistent with findings at 3 and 5 years. BZA was associated with higher incidences of hot flushes and leg cramps across 7 years. Increases in hot flushes and leg cramps have also been reported for 8 years of treatment with raloxifene. The BZA group also showed higher incidences of VTEs, primarily DVT, compared with PBO. Most DVTs occurred during the core study (HR of 8.7 for years 0-3 vs HR of 3.4 for years 0-5 and years 0-7). No new cases were reported during years 6 to 7, and the overall risk of VTEs was stable across 3, 5, and 7 years. Safety data from years 6 to 7 should be interpreted with caution, as women with a history of VTEs, stroke, or transient ischemic attack were excluded from extension II. Like all SERMs, BZA is contraindicated in women with a history of blood clots. An increased risk of VTEs has been observed for estrogens, tamoxifen, raloxifene, and lasofoxifene.
BZA treatment showed no evidence of breast or endometrial stimulation. The incidence of endometrial carcinoma was significantly lower in the BZA group compared with the PBO group at 7 years, as at 5 years. The incidence of breast carcinoma was low and similar for BZA and PBO at 7 years.
An important strength of this study is the inclusion of a continuous PBO group, along with two active arms, across the 7-year study period. Results are also strengthened by the relatively large number of women on BZA entering the extensions. This study is one of the longest PBO-controlled SERM studies and is the only study to have examined long-term treatment effects on new vertebral fractures. The Continuing Outcomes Relevant to Evista (CORE) trial, a 4-year extension of the 4-year Multiple Outcomes of Raloxifene Evaluation osteoporosis treatment trial, evaluated the long-term effects of raloxifene on breast cancer; new nonvertebral fractures and BMD were also assessed. After 8 years, raloxifene had no effect on nonvertebral fracture risk, but increases in BMD with raloxifene relative to PBO were maintained for 7 years. The CORE study differed from the current study in that it included women who did not continue to take study medication, and fracture data were not adjudicated. Because the CORE study was designed as a breast cancer prevention trial, the strength and validity of the skeletal data are limited.
On post hoc analyses, the incidence of new vertebral fractures during years 6 to 7 was similar to those for the BZA20 (3.4%) and PBO (3.4%) groups in the safety population. Nonetheless, the observed decline in vertebral fractures in the MITT population was statistically significant across 7 years, suggesting that the efficacy of BZA is maintained through this period. The primary comparison of study arms by stratified log-rank test compares survival experience stratified by baseline fracture status and should not be construed as a direct comparison of (unstratified) Kaplan-Meier estimates.
A potential limitation of this study is that only 23% of women randomized in the core BZA study completed extension II. Furthermore, women were enrolled in extensions I and II on a self-selected basis and, as suggested in other long-term osteoporosis studies, the baseline characteristics of the extension population may differ from those of the core BZA study. This may limit the ability to make comparisons between treatment groups and the ability to relate findings from extension II to findings from the randomized core BZA study population. However, the baseline and demographic characteristics of extension II women did not differ significantly between treatment groups and were generally similar to those of the overall study population. Another potential limitation is that women enrolled in extension II, unlike those enrolled in the core BZA study, were allowed to remain in the study and to take other bone-active medications such as bisphosphonates or calcitonin when they developed new vertebral fractures or low BMD. However, similar results were obtained when only data up to the first use of bone-active nonstudy medications were analyzed.
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