Letter by Choi et al Regarding Article, “Effects of the Selective Estrogen Receptor Modulator Raloxifene on Coronary Outcomes in the Raloxifene Use for the Heart Trial: Results of Subgroup Analyses by Age and Other Factors”
To the Editor:
We read with great interest the subgroup analyses of the Raloxifene use for the Heart (RUTH) trial.1 Although this post hoc analysis did not show benefit of raloxifene for any prespecified group, we believe that one particular subgroup, not defined in this study, may benefit from raloxifene in the reduction of coronary outcomes.
Although RUTH did not show an overall benefit in postmenopausal women with established coronary disease or risk factors, osteoporotic women enrolled in the Multiple Outcomes of Raloxifene Evaluation (MORE) trial who were at high risk for coronary disease had 40% fewer cardiovascular events than those receiving placebo.2 Why might there have been discrepant results between the hypothesis-generating MORE and the conclusive RUTH? MORE enrolled only postmenopausal women with osteoporosis, whereas RUTH did not use osteoporosis as an enrollment criterion. Might raloxifene be cardioprotective only in osteoporotic women?
In both experimental and epidemiological studies, menopause results in the curious phenomenon of skeletal orthotopic bone loss and vascular heterotopic bone formation.3,4 The cytokine-signaling pathways that regulate orthotopic bone remodeling also influence vascular calcification. It came as no surprise when we demonstrated that raloxifene, a bone-active drug, remodels vascular calcification. Via an increase in bone-morphogenetic protein-2, raloxifene influences vascular calcification morphology into a more laminar structure that may enhance plaque stability.5 However, in postmenopausal women without osteoporosis who may not have concomitant calcified vessels, as in RUTH, raloxifene would have benefit neither for osteoporosis nor for plaque stability. The MORE women, who were all osteoporotic, may be more likely to have calcified vessels, and it was in these women that cardiovascular benefit was demonstrated. If the RUTH trial had included prespecified osteoporotic women as a subgroup, a benefit from the remodeling effects of raloxifene on plaque morphology might have been seen.
We would encourage a study of raloxifene for the prevention of cardiovascular events in osteoporotic postmenopausal women or, at the very least, an analysis of existing MORE or RUTH data to see whether there is a correlation between the severity of osteoporosis and the degree of cardiovascular benefit.
Collins P, Mosca L, Geiger MJ, Grady D, Kornitzer M, Amewou-Atisso MG, Effron MB, Dowsett SA, Barrett-Connor E, Wenger NK. Effects of the selective estrogen receptor modulator raloxifene on coronary outcomes in the Raloxifene Use for the Heart Trial: results of subgroup analyses by age and other factors. Circulation. 2009; 119: 922–930.
Barrett-Connor E, Grady D, Sashegyi A, Anderson PW, Cox DA, Hoszowski K, Rautaharju P, Harper KD. Raloxifene and cardiovascular events in osteoporotic postmenopausal women: four-year results from the MORE (Multiple Outcomes of Raloxifene Evaluation) randomized trial. JAMA. 2002; 287: 847–857.