Raloxifene is an antiestrogen labeled for the prevention of osteoporosis in postmenopausal women. Because data on raloxifene are rapidly accumulating, Khovidhunkit and Shoback reviewed the literature published in the past 18 years on raloxifene.

Raloxifene has both estrogen-agonistic and estrogen-antagonistic properties: it acts as an estrogen antagonist on the uterus and breast, and as an estrogen agonist on bone and lipids. The term “selective estrogen receptor modulator” (SERM) has been coined to describe agents that interact with the estrogen receptor but have tissue-specific activities. SERMs compete with endogenous estrogens for binding to the receptor and may either activate or block estrogen activity.

Studies suggest that raloxifene inhibits bone loss by reducing bone resorption through the same mechanism as estrogen. It does not have an anabolic action on the skeleton. One study of postmenopausal women showed that raloxifene in a dosage of 60 mg per day for two years increased bone mineral density by 1.2 percent at the femoral neck and by 1.6 percent at the spine and total hip. Total-body bone mass had increased by 1.4 percent.

Raloxifene has been shown to have beneficial effects on lipid levels. A study of post-menopausal women demonstrated that 60 mg per day decreased the total cholesterol concentration by 6.4 percent and the LDL concentration by 10 to 12 percent. HDL cholesterol and triglycerides were unaffected.

No reports indicate that raloxifene exerts some of the other favorable cardiovascular effects of estrogen. For example, the agent has not been reported to reduce arterial vasoconstriction produced by regulation of the generation of nitric oxide and other vasoactive peptides, to improve insulin and glucose metabolism, or to improve hepatic cholesterol metabolism. No data support the idea that raloxifene can reduce cardiovascular events in humans.

Raloxifene was initially developed as a treatment for breast cancer but was found to be less effective than tamoxifen. Other SERMs seem to be more efficacious than raloxifene in controlling breast cancer cell growth. Two large trials are under way to evaluate whether raloxifene reduces the risk of breast cancer after two years of therapy in postmenopausal women.

Unlike estrogen and tamoxifen, raloxifene has no stimulatory effect on the uterus, suggesting that it may be associated with a lower risk for endometrial cancer. Long-term data to substantiate this effect are not available. This estrogen-antagonistic effect on the uterus is blunted in environments of high circulating estrogen, implying that raloxifene is unlikely to be useful in the treatment of estrogen-responsive diseases such as endometriosis and uterine leiomyoma.

Higher dosages of raloxifene have been found to result in a higher frequency of side effects, including fatigue, leg cramps and nausea. The most serious side effect is a threefold increase in the risk for venous thromboembolism, similar to that occurring with estrogen therapy.

The authors conclude that estrogen seems to be a better choice for prevention of osteoporosis in most postmenopausal women, especially in the early postmenopausal years, when the incidence of hot flushes is high, and bone loss is rapid.