Raloxifene and the Heart
Source: Clarkson TB, et al. J Clin Endocrinol Metab 1998;83:721-726.
Clarkson and colleagues, in their monkey model of atherosclerosis at Bowman Gray School of Medicine, performed a two-year randomized trial comparing raloxifene to conjugated equine estrogens.
The dose of conjugated equine estrogens was equivalent to 0.625 mg of Premarin per day administered to women. Raloxifene was given in two doses: a low dose equivalent to the recommended therapeutic dose of 60 mg per day for women and a high-dose level approximately five-fold higher. The animals were fed a moderately atherogenic diet, and, after two years, autopsy studies were performed to measure the prevalence, extent, and severity of coronary artery atherosclerosis. Conjugated equine estrogens and low-dose raloxifene lowered total cholesterol concentrations and LDL cholesterol concentrations. Whereas conjugated equine estrogens increased HDL cholesterol, raloxifene had no effect on HDL cholesterol. Animals treated with conjugated equine estrogens had, after two years, less coronary artery atherosclerosis. The prevalence and extent of atherosclerosis in the raloxifene-treated monkeys was the same as that in the placebo-treated group. Indeed, the group of animals treated with low-dose raloxifene had twice as much atherosclerosis as the group treated with conjugated equine estrogens. Clarkson et al conclude that raloxifene does not protect against coronary artery atherosclerosis.
Comment by Leon Speroff, MD
Raloxifene exerts selective estrogen agonistic or antagonistic actions depending upon the target tissue. In two-year clinical trial data, women treated with raloxifene have about a 2% gain in bone density. Raloxifene has no effect on the endometrium, and, based upon pre-clinical studies, we have good reason to believe that raloxifene will exert a protective effect against breast cancer. The actual effects on endometrium and breast must await the outcome of the clinical trials currently underway-more than two years' exposure will be necessary to provide accurate data.
The raloxifene effect on circulating lipids is relatively comparable as measured in women and in the monkey study reported by Clarkson et al. However, despite the favorable effect on cholesterol and LDL cholesterol, there was no protection observed against coronary atherosclerosis in the monkey model. This emphasizes the growing appreciation for the many actions of estrogen, and especially the important direct effects on the arterial vessels. These direct effects of estrogen are significantly reduced in a mouse knockout model for the estrogen alpha-receptor. This implies that the direct effects of estrogen on vessel walls are mediated by the estrogen receptor beta. An agent that minimally activates estrogen receptor beta, therefore, would have a minimal effect on coronary arteries. It is possible that raloxifene does not activate the estrogen receptor beta.
Another problem with raloxifene treatment is the lack of effect on hot flushing. Indeed, in the clinical trials, the raloxifene-treated women reported hot flushing at a greater rate than the placebo group. This, too, may reflect the prevalence of estrogen receptor beta in the central nervous system. This also raises the possibility that raloxifene will have no effect on cognition and, ultimately, Alzheimer's disease.
The evidence indicates that raloxifene should not be viewed as an equal substitute for estrogen therapy of postmenopausal women. I view it as an option for women who wish to protect their bones and possibly reduce the risk of breast cancer but are unwilling to or cannot take estrogen therapy. Raloxifene does not provide the broad spectrum of benefits associated with estrogen therapy, and we should be careful to appropriately educate our patients regarding the advantages and disadvantages of raloxifene.
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