Menopause Live - IMS Updates

Date of release: 17 January, 2011

Interaction of FRAX probabilities with raloxifene efficacy

There is a great interest in examining the evidence for an interaction of FRAX® probabilities with drug efficacy. A recent article from Kanis and colleagues [1] has evaluated the distribution of fracture risk assessed at baseline using the FRAX tool in the MORE study and has determined the efficacy of raloxifene as a function of baseline fracture risk. 


They concluded that raloxifene (both 60 and 120 mg doses) significantly decreased the risk of all clinical fractures (18%; hazard ratio (HR )  0.82; 95% confidence interval (CI) 0.71–0.95; p = 0.0063) and morphometric vertebral fractures (42%; HR 0.58; 95% CI 0.48–0.69; p = 0.001). Efficacy was shown over the whole range of fracture probability and the interaction between fracture probability and treatment was not significant.


FRAX is a computer-based algorithm [2] that provides models for the assessment of fracture probability in men and women [3, 4]. FRAX uses easily obtained clinical risk factors to estimate fracture risk. The estimate can be used alone or with bone mineral density. In addition to fracture risk, FRAX uses Poisson regression to derive hazard functions of death. These hazard functions are continuous as a function of time which permits the calculation of the 10-year probability of hip fracture and the 10-year probability of a major osteoporotic fracture (hip, clinical spine, humerus or wrist).
Two phase III studies have provided evidence for an interaction of FRAX probabilities with efficacy in the cases of bazedoxifene [5] and oral clodronate [6]. 
The hypotheses tested in this study [1] and after analysis of the MORE study [7] were, first, that the efficacy of raloxifene on vertebral fracture risk was greater the higher the pretreatment fracture probability and, second, that there was a similar effect of raloxifene on clinical fracture outcomes such that significant effects would be observed in women with the higher baseline fracture probabilities.
The principal findings of this study are that raloxifene had a modest but significant effect on clinical fracture outcome and a more marked effect on the incidence of new morphometric vertebral fractures. The present analysis showed no evidence of a significant interaction of fracture probability with efficacy. A second finding is that FRAX results were a predictor of fracture outcomes. This may not seem surprising given that FRAX has been validated, but the validation has been largely confined to population-based cohorts rather than to high-risk populations.
The findings from the present study [1] contrast with assessments of the two other phase III studies mentioned [5, 6]. Both studies reported that the efficacy of intervention (clodronate and bazedoxifene) was greater at higher fracture probabilities, with or without the use of bone mineral density. Efficacy was evident at fracture probabilities that exceeded 20%. The present results with raloxifene are in marked contrast. This indicates that interactions between fracture efficacy and fracture probability differ with different agents, since both raloxifene and bazedoxifene are considered to be selective estrogen receptor modulators. The authors discuss these findings and speculate that perhaps FRAX components provide some explanation for the efficacy on fracture risk, which was greater at younger ages and in women with the less marked deficits in bone mineral densities. 
Irrespective of its speculative explanation, the present study is not consistent with the initial hypothesis that effectiveness (relative risk reduction) is higher in women at high fracture risk, and it is suggested that raloxifene can probably be targeted effectively to younger women at relatively low risk of fracture.


Santiago Palacios
Director of the Palacios Institute of Womens Health, Madrid, Spain


  1. Kanis JA, Johansson H, Oden A, et al. A meta-analysis of the efficacy of raloxifene on all clinical and vertebral fractures and its dependency on FRAX. Bone 2010;47:729-35.

  2. Kanis JA, on behalf of the World Health Organization Scientific Group. Assessment of osteoporosis at the primary health-care level. WHO Collaborating Centre for Metabolic Bone Diseases, University of Sheffield, UK, 2007.

  3. Kanis JA, Johnell O, Oden A, et al. FRAX and the assessment of fracture probability in men and women from the UK. Osteoporos Int 2008;19:385-97.

  4. Kanis JA, Johansson H, Oden A, McCloskey EV. Bazedoxifene reduces vertebral and clinical fractures in postmenopausal women at high risk assessed with FRAX. Bone 2009;44:1049-54.

  5. McCloskey EV, Johansson H, Oden A, et al. Ten-year fracture probability identifies women who will benefit from clodronate therapy additional results from a double-lind, placebo-controlled randomised study. Osteoporos Int 2009;20:811-17.

  6. Ettinger B, Black DM, Mitlak BH, et al. Reduction of vertebral fracture risk in postmenopausal women with osteoporosis treated with raloxifene: results from a 3-year randomized clinical trial. Multiple Outcomes of Raloxifene Evaluation (MORE) Investigators. JAMA 1999;282:637-45.