Elsevier

Bone

Volume 44, Issue 6, June 2009, Pages 1049-1054
Bone

Bazedoxifene reduces vertebral and clinical fractures in postmenopausal women at high risk assessed with FRAX®

https://doi.org/10.1016/j.bone.2009.02.014Get rights and content

Abstract

Introduction

Bazedoxifene has been shown to significantly decrease the risk of vertebral fractures in postmenopausal women. No significant effect was noted on the risk of clinical fractures, but fracture risk reduction was reported in a post hoc subgroup analysis in a high risk group categorised on the basis of BMD and prior fracture.

Aims

The aim of this study was to re-evaluate the efficacy of bazedoxifene on fracture outcomes avoiding subgroup analysis by examining the efficacy of intervention as a function of fracture risk.

Methods

The phase III study was a double-blind, randomised, placebo- and raloxifene-controlled randomised 3-year multinational study that enrolled 7492 osteoporotic women aged 55 years or more (mean age = 66 years). For the present analysis, women taking raloxifene were excluded (n = 1849), and we compared the effects of two doses of bazedoxifene (20 and 40 mg daily combined) with placebo on the risk of all clinical fractures as well as the risk of morphometric vertebral fracture. The risk of a major osteoporotic fracture was assessed using region specific FRAX® algorithms, and the relationship between pre hoc 10-year fracture probabilities and efficacy examined by Poisson regression.

Results

Overall, bazedoxifene was associated with a significant 39% decrease in incident morphometric vertebral fractures (hazard ratio HR = 0.61; 95% CI = 0.43–0.86; p = 0.005) and a non-statistically significant 16% decrease in all clinical fractures (hazard ratio HR = 0.84; 95% CI = 0.67–1.06; p = 0.14) compared to placebo. Hazard ratios for the effect of bazedoxifene on all clinical fractures decreased with increasing fracture probability. In patients with 10-year fracture probabilities at or above 16%, bazedoxifene was associated with a significant decrease in the risk of all clinical fractures. The 16% probability threshold corresponded to the 80th percentile of the study population. Hazard ratios for the effect of bazedoxifene on morphometric vertebral fractures also decreased with increasing fracture probability. In patients with 10-year fracture probabilities above 6.9% (corresponding to the 41st percentile), bazedoxifene was associated with a significant decrease in the risk of morphometric vertebral fractures. At equivalent fracture probability percentiles, the treatment effect of bazedoxifene was greater on vertebral fracture risk than on the risk of all clinical fractures. For example, at the 90th percentile of FRAX® probability, bazedoxifene was associated with a relative risk reduction of 33% (95% CI = 7–51%) for all clinical fractures and 51% reduction (95% CI = 21–69%) for morphometric vertebral fractures. The findings were robust to several sensitivity analyses.

Conclusion

Bazedoxifene (20 and 40 mg doses combined) significantly decreased the risk of all clinical fractures and morphometric vertebral fractures in women at or above a FRAX® based fracture probability threshold. These results, consistent with the previous subgroup analysis, suggest that bazedoxifene should be targeted preferentially to women at high fracture risk.

Introduction

Bazedoxifene acetate is a new chemical entity, and on the basis of biochemical, in vitro cellular, and in vivo data, can be considered a mixed-function estrogen that demonstrates tissue selectivity. Preclinical and clinical studies suggest that it exerts estrogenic activity on bone without adverse effects on breast and uterine tissue [1], [2], [3], [4]. This profile prompted the development of bazedoxifene for the prevention of fractures in postmenopausal women. The principal phase III study was designed to elucidate the effect of this agent on vertebral fracture risk in postmenopausal women with osteoporosis as a primary outcome [5]. A secondary endpoint was the effects of bazedoxifene on the risk of non-vertebral fractures.

The trial showed a significant effect of bazedoxifene on vertebral fracture risk for each of the two doses tested. Bazedoxifene 20 mg daily decreased the risk of morphometric vertebral fractures by 42% (hazard ratio, HR = 0.58 (95% confidence interval, CI = 0.38–0.89) and a similar effect was noted with a 40 mg daily dose (HR = 0.63; 95% CI = 0.42–0.96). There was no significant effect on non-vertebral fractures, even when data from the two doses were combined (HR = 0.89; 95% CI = 0.70–1.14) [6]. A post hoc analysis in a subgroup of patients at high risk (femoral neck T-score   3 SD and or ≥ 1 moderate or severe, or multiple mild vertebral fractures) reported that bazedoxifene 20 mg daily reduced the incidence of non-vertebral fractures by 50% compared to placebo (HR = 0.50; 95% CI = 0.28–0.90; p = 0.020). The effect of the higher dose was not significant (HR = 0.70; 95% CI = 0.41–1.20). A significant effect was seen with the two doses combined (HR = 0.60; 95% CI = 0.37–0.95), but the subgroup analysis lost power to detect a significant effect on vertebral fracture of the 20 mg dose (HR = 0.50; 95% CI = 0.24–1.03), though a significant effect was seen with the two doses combined (HR = 0.54; 95% CI = 0.30–0.98) [6].

There are obvious difficulties with post hoc analyses. These are particularly acute when undertaken on subgroups, and in subgroups that may be difficult to justify on clinical grounds. The post hoc nature, the change in the significance of the primary outcome, and the way of categorising the high risk group based on femoral neck T-score and prevalent vertebral fracture status weaken the validity of the analysis and the conclusion that bazedoxifene is effective in decreasing the risk of non-vertebral fractures.

Against this background the present study, although it cannot avoid post hoc status, aimed to avoid subgroup analysis and the associated loss of statistical power. The specific aim was to apply multivariate models to the entire study population to assess the efficacy of bazedoxifene on both all clinical fracture outcomes and on morphometric vertebral fracture risk. This analysis incorporated a clinically relevant metric of high risk as a continuous variable (the FRAX® tool for fracture probability) as requested for new phase III studies by the Committee for Medicinal Products for Human Use (CHMP) [7]. The hypothesis tested was that bazedoxifene reduced the risk of fracture in women with the higher fracture probabilities assessed at study entry.

Section snippets

The osteoporosis study

Details of this study are published elsewhere [5]. In brief, the multinational study included women from the Asia/Pacific countries, Canada, Europe, Latin America, South Africa, and the United States. The study was double-blind, randomised, placebo- and raloxifene-controlled study including 7492 osteoporotic women aged 55 years or more (mean age = 66 years). The primary analysis was over a three year exposure. The study was extended twice; each extension was for 2 years. The first 2-year

Results

The study comprised 5643 patients, of whom 5632 had a base line estimate of fracture probability without BMD and 5213 a baseline estimate with BMD.

Discussion

The primary aims of this analysis were to explore the effects of bazedoxifene on clinical fractures and on morphometric vertebral fractures. With regard to all clinical fractures, a specific aim was to seek possible treatment effects in high risk patients. The principal findings are that, although bazedoxifene had no overall significant effect on clinical fracture outcome, a significant effect was seen in patients with the higher probability of a major osteoporotic fracture. Significant effects

Acknowledgments

This work was an independent study funded by a grant from Wyeth Research. We thank Dr Arkadi Chines and Monika Ciesielska for their help with the preparation and transfer of the data.

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