SERMs

Selective Estrogen Receptor Modulators

raloxifene (Evista)

SERMS are "designer" drugs that activate the estrogen receptors, but have different effects on different tissues. There are two kinds of estrogen receptors, and after binding to receptors, the drug-receptor complex can have various conformations. Some of these will act like estrogen, others will inhibit the actions of estrogen. Scientists are searching for those which act like estrogen in the desireable ways (stablize bone mass, improve lipid profile, reduce hot flashes) but do not act like estrogen in undesireable ways (cause breast cancer, stimulate the endometrium). Tamoxifen is a SERM that is used to treat breast cancer. It has some beneficial effects on the bones, but it does stimulate the endometrium. Raloxifene is a newer SERM that has been approved for prevention and treatment of postmenopausal osteoporosis. Other SERMS are being studied but are not available.

Dose

The dose of raloxifene is 60mg/day. It can be taken at any time with or without food. It has been studied in placebo-controlled trials with durations up to 8 years.

Indications

Treatment and prevention of postmenopausal osteoporosis.

Contra-indications

Effects of Raloxifene

This set of graphs shows results from the three large raloxifene clinical trials in comparison to other studies. The MORE study enrolled 7705 postmenopausal women who had osteoporosis defined by a bone density T-score of -2.5 or lower or a vertebral compression fracture and included two doses of raloxifeme. After 4 years subjects remained blinded to treatment and most were followed another 4 years (CORE). The STAR study enrolled 19,747 women at high risk for breast cancer who were randomly assigned to raloxifene 60mg/day or tamoxifen 20mg/day for 5 years. The RUTH study enrolled over 10,101 women with heart disease who were given placebo or raloxifene for up to 7 years. Comparison studies were the FIT study of alendronate, the WHI study of estrogen + progestin and the WHI study of estrogen only, and the expected incidence of fractures from Rochester, Minn.

Summary of major effects

Beneficial	Harmful	Neutral
Reduced breast cancer Reduced vertebral fractures Improved cholesterol	More venous thrombosis More fatal strokes More hot flashes More gallbladder disease	Heart disease Total strokes Non-vertebral fractures Endometrial disease Ovarian cancer

Other comments

A case has been reported of raloxifene inhibiting the absorption of thyroxine, so the drug should not be given at the same time as thyroxine (Siraj ES).

One study showed that raloxifene improved the lipid profile and bone density in women with renal failure on dialysis (Hernandez E).

Raloxifene has beneficial effects on the bone in patients with primary hyperparathyroidism ( Zanchetta JR).

In women who are closer to menopause, the incidence of hot flashes is higher than in the MORE study. Over 1/4 of women will experience worsening of hot flashes, so this medication is often difficult to use when women are in their 50s. It should NOT be used in premenopausal women. Not only will it cause more troublesome hot flashes, but it will not help the bone - possibly because it could antagonize estrogen in women who are premenopausal.

Several studies have compared raloxifene to alendronate. These have been of short duration. Alendronate increases the bone density more than raloxifene does, in several clinical situations. One study (presented by Recker at the 2005 ASBMR meetings) attempted to evaluate the difference in fracture risk. This randomized study was designed to look at 3,000 women for 5 years, but it was stopped early, after only an average of one year, and about 1,400 women. The stated reason was that it was too difficult to recruit women into the study. During the study, the fracture rates were not different using raloxifene or alendronate (numerically they were similar and there was no statistical differences), but due to the sample size this study did not have power to prove that the drugs had equal effects on fractures.

Many women who have had breast cancer in the past wonder if they should take raloxifene. Currently this medication is NOT approved for treatment of the breast cancer itself. It also has not been studied in women who have had breast cancer in the past. Some rat studies have suggested that breast cancer cells which have been exposed to tamoxifene for many years may become resistant to other SERMS as well, so raloxifene should be used cautiously in women who have had 5 years of tamoxifen. Otherwise, I have used it in women with a past history of breast cancer who do not currently have any evidence of recurrance, based on extrapolation of data instead of direct evidence. This is one area that really needs more research (Habel LA).

Raloxifene is synergistic with teriparatide; this is different from other anti-resorptive agents which diminish the benefits of teriparatide (Deal C). This is discussed in the section about intermittent PTH.

Raloxifene has been used in men with prostate cancer who were treated with GnRH agonists to make them hypogonadal. The bone density improved with raloxifene whereas it decreased without it (Smith MR).

Effects on bone physiology

Decreased bone formation and resorption Fracture risk reduction related to decreased biochemical markers of turnover but not to changes in bone density No significant change in bone volume Slight increase in mineralization density No evidence of osteomalacia or bone toxicity

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