Bazedoxifene reduces vertebral and clinical fractures in postmenopausal women at high risk assessed with FRAX®
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.
References (30)
- et al.
Cost-effectiveness of alendronate
Bone
(2008) - et al.
Recommendations for bone mineral density reporting in Canada: a shift to absolute fracture risk assessment
J. Clin. Densitom.
(2007) - et al.
Developing a SERM: stringent preclinical selection criteria leading to an acceptable candidate (WAY-140424) for clinical evaluation
Ann. N. Y. Acad. Sci.
(2001) - et al.
Bazedoxifene acetate: a selective estrogen receptor modulator with improved selectivity
Endocrinology
(2005) - et al.
Effects of bazedoxifene on bone mineral density and turnover in postmenopausal women: 2-year results of a randomized, double-blind, placebo- and active-controlled study
J. Bone Miner. Res.
(2008) - et al.
Endometrial effects of bazedoxifene acetate, a novel selective estrogen receptor modulator, in postmenopausal women
Obstet. Gynecol.
(2005) - et al.
Efficacy of bazedoxifene in reducing new vertebral fracture risk in postmenopausal women with osteoporosis: results from a 3-year, randomized, placebo- and active-controlled clinical trial
J Bone Miner Res
(2008) - Wyeth Research (2008) Data on...
- Committee for Medicinal Products for Human Use (CHMP). Guideline on the evaluation of medicinal products in the...
- Kanis JA on behalf of the World Health Organization Scientific Group. Assessment of osteoporosis at the primary...
FRAX™ and the assessment of fracture probability in men and women from the UK
Osteoporos. Int.
The use of clinical risk factors enhances the performance of BMD in the prediction of hip and osteoporotic fractures in men and women
Osteoporos. Int.
The assessment of vertebral deformity
Comparison of methods for the visual identification of prevalent vertebral fracture in osteoporosis
Osteoporos. Int.
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