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F O R P H Y S I C I A N S – resources
Selective Estrogen Receptor Modulators
Raloxifene
Raloxifene, a benzothiophene, was initially investigated as a treatment for breast cancer based on preliminary studies showing that it binds to both ERa and ERb with high affinity and has antagonist activity within the breast (22,23). In clinical trials, raloxifene has been shown to have beneficial effects on bone and serum lipids and lipoproteins without stimulating the endometrial lining of the uterus. A dose of 60 mg per day has similar antiresorptive effects as compared to 0.625 mg of conjugated estrogen (24). There was a decrease bone turnover markers of 23% in serum levels of bone-specific alkaline phosphatase and a decrease of 15% in osteocalcin. In a more recent study, raloxifene was found to increase bone density at the hip and spine by 2% (25). Results from the Multiple Outcomes of Raloxifene Evaluation (MORE) revealed that therapy with 60 or 120 mg/day for 2 years was associated with approximately 50% reduction in the risk of asymptomatic and symptomatic vertebral fractures compared with calcium and vitamin D therapy plus placebo alone (26). Findings also revealed a 2 to 3% increase in BMD above baseline at the spine and hip and a reduction in the markers of bone metabolism. No significant effect was found in the risk for nonvertebral fractures.
The beneficial effects of raloxifene on serum lipids have shown a significant reduction from baseline in LDL-C and total-C. HDL-C and triglycerides levels were not significantly affected. In a 6-month randomized, placebo and HRT-control trial raloxifene at doses of 60 and 120mg/day decreased LDL-C by 11%, similar to that of conjugated HRT (26). However, raloxifene lowered lipoprotein(a) less than HRT and increased HDL-C2 (high density lipoprotein cholesterol 2 subfraction) only 15 to 17% as compared to 33% with HRT. Evidence suggests that increases in HDL-C2 may correlate with a cardiovascular protective effect (27). Furthermore, raloxifene did not change levels of plasminogen activator inhibitor-a (PAI-1) as compared to HRT. Based on these studies, raloxifene exerts a favorable effect on serum lipids however physicians should not assume that SERMs have cardioprotective effects solely based on their estrogen-like effects on lipids. In fact, results of a study of raloxifene in menopausal monkeys showed no cardioprotective effect (28).
One particular advantage of raloxifene is the lack of proliferative effect on endometrial tissue. Data has shown that raloxifene has minimal effects on the uterus and causes no significant changes in the histologic appearance of the endometrium. Two six-month studies involving a total of 969 postmenopausal women showed no difference in endometrial thickness than women receiving placebo (29). Another short-term study found no evidence of endometrial proliferation as measured by endometrial biopsies after eight weeks of treatment with doses of 200 to 600mg/day (30). Short-term trials appear to support that raloxifene does not stimulate the endometrial lining, however it is unclear whether raloxifene provides long-term protection against endometrial cancer.
Adverse effects reported by women treated with raloxifene have included hot flushes (24.6 percent versus 18.3 percent for placebo) and leg cramps (5.9 percent versus 1.9 percent for placebo) (26). There was no significant uterine bleeding or breast tenderness as compared to continuous or cyclic HRT. The risk of thromboembolic events has also been reported with raloxifene and is more likely to occur during the first four months of treatment (31). Due to the risk of thromboembolism it has proposed that raloxifene be discontinued 72 hours before surgery and until the patient is fully ambulatory.
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