Raloxifene on Serum Lipids and Coagulation in Healthy Postmenopausal Women
ABSTRACT & COMMENTARY
Synopsis: The effects of two doses of raloxifene, continuous combined conjugated equine estrogens and hormone replacement therapy (HRT), and placebo upon multiple markers were compared in 390 postmenopausal women after three and six months of use. HDL-cholesterol and triglycerides rose most with HRT. Lipoprotein (a) decreased most with HRT. Fibrinogen was unaffected by placebo and HRT but declined with raloxifene use.
Source: Walsh BW, et al. JAMA 1998;279:1445-1451.
Raloxifene is categorized as a selective estrogen receptor modulator because it has estrogenic actions on bone but not on breast and uterus. It is marketed for use in preventing osteoporosis in postmenopausal women, but its effects on other tissues and organ systems are not well defined. The present study was undertaken to determine its actions upon surrogate markers of cardiovascular disease and coagulation, including LDL-cholesterol, HDL-cholesterol and its subfractions, triglycerides, fibrinogen, lipoprotein (a), and plasminogen activator inhibitor-1. Postmenopausal women with "intolerable postmenopausal symptoms" were excluded. Subjects were studied at baseline and after three and six months of hormone or placebo use. The two uses of raloxifene were 60 mg and 120 mg. HRT consisted of continuous combined use of 0.625 mg conjugated equine estrogens and 2.5 mg of medroxyprogesterone acetate. Twenty-two percent of women who received the 120 mg dose of raloxifene reported hot flashes.
COMMENT BY SARAH L. BERGA, MD
The need for "designer estrogens," such as raloxifene, is predicated upon the assumption that long-term estrogen use increases the risks of breast cancer. In most other regards, estrogen use appears to confer the following beneficial effects: improved cognition and mood, relief from hot flashes, better sleep, neuroprotection from dementia, smoother skin and thicker hair, better urogenital and sexual function, cardiovascular protection, reduced risk of osteoporosis, better dentition, and so forth. Granted, there is the troublesome issue of protecting the endometrium, but it is highly unlikely that there will be a selective estrogen receptor modulator that has nil effect on endometrium while conferring better urogenital and sexual function. What if estrogen use does not promote breast cancer? Remember that tamoxifen use has not been compared to estrogen use in women at high risk for breast cancer or in women who have had breast cancer. Further, as Rifkind and Rossouw point out in an accompanying editorial, even tamoxifen has stimulatory effects upon endometrium (Rifkind BM, Rossouw JE. JAMA 1998;279:1483-1484), so tamoxifen and raloxifene cannot be lumped together. In assessing the risk benefit profile of a new designer estrogen, one needs to consider its composite effect for a given individual. What are the tradeoffs? The shortcoming of the present study is that it is difficult to interpret and we are no closer to an answer. Markers are not clinical events, so even the present study does not help us to understand if raloxifene use for 10 or more years will be cardioprotective. Further, although raloxifene use decreased fibrinogen levels in the present study, its use is associated with an increase in clinical thromboembolic events. If raloxifene causes hot flashes in symptomatic postmenopausal women, does that mean that it is not neuroprotective? We know that raloxifene is about half as effective as estrogens in preserving bone mass. If a woman has osteoporosis and won't take an estrogen, wouldn't she be better off using a bisphosphanate such as alendronate? Women fear breast cancer, and fear is a powerful motivator. Does fear alone justify the use of a designer estrogen whose overall risk benefit ratio is unknown, but is unlikely to be favorable? Physicians need to help women manage their fears by placing them in proper perspective. While I acknowledge that this is not an easy undertaking, it can be done in most instances. The physician who prescribes raloxifene must be motivated by a clear appreciation of the risks and benefits and should avoid being motivated by the patient's fear.
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