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Selective Estrogen Receptor Modulators (SERMs)

Estrogen is currently the most common therapy for preventing or limiting the bone loss that occurs in women following menopause. It has a desirable effect on bone and cardiovascular tissue, but it has an undesirable effect in the breast and uterus, where it can possibly promote breast or endometrial cancer (cancer of the uterine lining). New “designer drugs” are being developed in an effort to find a treatment that will stimulate bone and cardiovascular tissue the way estrogen does (agonistic effect) while not stimulating breast and uterine tissue (antagonistic effect). The following is a brief explanation of how these therapies work and what these names mean!

Following menopause, women are at risk for at least two chronic disorders: osteoporosis and cardiovascular disease. At menopause, estrogen replacement therapy (ERT), or hormone replacement therapy (HRT) in women with a uterus, is typically used to alleviate hot flashes, vaginal dryness, bone loss, and cardiovascular disease.

Specifically, estrogen works by stimulating tissue at sites in the body that are known as estrogen receptors. These sites include tissue in the bone, the breast, the uterus, and the cardiovascular system. As stated above, estrogen has been shown to have an adverse effect on breast and uterine tissue and, when used alone, may result in endometrial cancer, a condition that can be prevented by including a progestin with the estrogen. The risk of breast cancer may increase with long-term estrogen therapy, but studies documenting this are inconclusive. Partly because of the known and suspected liabilities, compliance with HRT is poor.

If the estrogens at one end of the spectrum have an agonistic (stimulating) effect on all of the estrogen receptor sites, then anti-estrogens at the other end of the spectrum have an antagonistic (nonstimulating) effects on the same sites. Anti-estrogens were designed to block estrogen at the cell level in the breast and the uterus; however, they provide very little benefit for bone, and their effect on the cardiovascular system is unknown at present.

In between estrogens and anti-estrogens are the selective estrogen receptor modulators (SERMs), which are referred to as “designer drugs” because they are designed to act in specific ways at each of the receptor sites. These compounds, which are in development have a positive effect on bone and cardiovascular tissue and have no effect on the breast and the uterus.

One of first SERMs to be developed was tamoxifen, which has been used to treat breast cancer because it appears to block the effect of estrogen in breast tissue (antagonist). It slightly increases activity in bone tissue, which results in reduction of bone loss. It is a partial agonist in uterine tissue (i.e., it does stimulate uterine tissue but not as much as estrogen), and it produces an estrogen agonist-like effect on the cardiovascular system that may or may not involve estrogen receptors.

One of the newer SERMs is raloxifene which, like tamoxifen, was originally looked at for the treatment of breast cancer. However, in early studies, raloxifene has been shown to inhibit bone resorption. It also appears to have a beneficial effect on the cardiovascular system and does not appear to stimulate tissue activity in the breast or the uterus. Other SERMs that are being studied for treatment of osteoporosis in postmenopausal women include droloxifene and idoxifene. All of these SERMs are in Phase 1 or 2 trials and at least two to four years away from possible FDA approval.

In summary, an ideal therapy for postmenopausal women with osteoporosis would be one that prevents bone loss, has a positive effect on the cardiovascular system, and provides no risk of breast or uterine cancer. Selective estrogen receptor modulators appear to fit this profile, but more studies are needed before SERMs are considered as therapy for women with postmenopausal osteoporosis.

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