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Menopause Health

Current and Future SERMs: An Update

Valerie Flores, MD; Hugh S. Taylor, MD

While most readers are familiar with currently available SERMs, presented here is an update on the variety of new SERMs in development, including a potential combination therapy.

Selective estrogen receptor modulators (SERMs)—although they do not treat hot flushes—are an alternative approach for the prevention and treatment of postmenopausal symptoms, most notably postmenopausal bone loss. The potential advantage of SERMs over estrogen treatment is that estrogens exert primarily agonist effects on estrogen receptors. In SERMs, the differing estrogen-like actions on various tissues can potentially be better controlled—exerting agonist effects on some target tissues, while exerting antagonistic effects on tissues known to undergo potentially harmful changes with estrogen receptors stimulation.

A single SERM that demonstrates all of the favorable effects of estrogens while lacking all negative effects has yet to be developed and probably is not achievable.1 Hence, the current aim is to develop a SERM that provides at least some of the benefits of estrogen or hormone therapy without the associated risk of breast or endometrial cancer, and without an increased incidence of thrombosis or cardiac disease.2

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FDA-Approved SERMs

The approved SERMs include tamoxifen, toremifene, raloxifene, and clomiphene. For each, the risk-benefit ratio must be evaluated so as to better tailor a particular SERM for a given individual.

Tamoxifen acts as an estrogen receptor antagonist in breast tissue and is indicated in the treatment and prevention of breast cancer. It has also been found to provide skeletal benefits. However, because of the increased risk of thromboembolism, vasomotor symptoms, stroke, and estrogen-like effects in the uterus that increase the risk of endometrial cancer, it is indicated only in postmenopausal women with breast cancer.2

Raloxifene is a second generation SERM that increases bone mineral density (BMD) and decreases markers of bone turnover by acting as an estrogen agonist in bone. Administration of 60 mg/d to postmenopausal women who had low to normal BMD increased lumbar spine BMD by 2.4% compared with placebo.3 Administration of 60 to 120 mg/d for 3 years reduced vertebral fracture risk by 30% to 50% (depending on dosage) in postmenopausal women with osteoporosis, although it did not significantly decrease the risk of nonvertebral fractures.4,5

Raloxifene is just as effective as tamoxifen in reducing the risk of breast cancer, with the added benefit of not increasing the risk of endometrial carcinoma (however, there is a statistically significant increase in endometrial thickening). Raloxifene has recently been shown to increase the risk of stroke.6 Also, like tamoxifen, it may worsen or cause vasomotor symptoms and increases the risk (by about 1%) of thromboembolism.6 Raloxifene is mainly used in the prevention and treatment of osteoporosis, with the added benefit of breast cancer prevention in postmenopausal women.7

Toremifene is approved for treatment of advanced (metastatic) breast cancer that is either estrogen receptor–positive or of unknown etiology.8 Like all SERMs, it acts by blocking estrogen binding in cancer cells, although it does not actually cause cancer cell death.

Clomiphene is a SERM that is indicated in women with ovulatory dysfunction who desire pregnancy.9 Clomiphene is widely used to improve ovulation and increase pregnancy rates in women with ovulatory dysfunction.

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Future SERMs

Bazedoxifene was recently approved in Europe for the treatment of osteoporosis. It is in the late stages of clinical development in the United States for the prevention and treatment of postmenopausal osteoporosis. Phase III trials have shown prevention of bone loss in postmenopausal women with normal to low BMD.10 These results are seen with 10, 20, or 40 mg/d of bazedoxifene. Doses of 20 and 40 mg/d were found to decrease the risk of new vertebral fractures. In addition, the advantage of bazedoxifene over currently available SERMs was shown in the finding that 20 mg/d of bazedoxifene reduced the risk of all nonvertebral fractures in a subgroup at high risk of fracture.

Bazedoxifene also beneficially alters the levels of HDL, LDL, and total cholesterol.11 While women using bazedoxifene do have an incidence of hot flushes and thromboembolic events similar to raloxifene, overall it appears to be well tolerated and does not increase the risk of endometrial or breast cancer.7,12 This is the first of the third-generation SERMs expected to be available for clinical use in the United States.

Lasofoxifene is currently under investigation for the treatment of osteoporosis and vulvar vaginal atrophy. After 2 years, its ability to increase BMD, decrease levels of bone turnover markers, and decrease LDL cholesterol levels (at a 0.25 to 1 mg/d dose) was found to be comparable to that of raloxifene at 60 mg/d.13 Furthermore, at a dose range of 0.25 to 0.5 mg/d, lasofoxifene was found to improve the signs and symptoms of vaginal atrophy. In fact, more than half of the patients receiving treatment reported a decrease in dyspareunia.14

The FDA is awaiting further efficacy data and has not yet approved lasofoxifene. Recent and still unpublished reports suggest that this third-generation SERM is safe, reducing the incidence of breast cancer and stroke. A lingering concern is that lasofoxifene increased the thickness of the endometrium and the incidence of polyps and vaginal bleeding, yet it has not been shown to increase the risk of hyperplasia or cancer of the endometrium.13

Ospemifene is undergoing a phase III study for the treatment of vulvar vaginal atrophy. Clinically, ospemifene exerts an estrogenic effect on the vaginal epithelium—stimulating the maturation of vaginal epithelial cells.1 In phase II studies, ospemifene, like raloxifene, decreased markers of bone resorption and increased BMD.15,16 In addition, ospemifene does not precipitate vasomotor events, although the incidence of such events is still comparable to that of raloxifene. Lastly, ospemifene does not significantly stimulate the endometrium.11

Arzoxifene is a chemically modified form of raloxifene, which serves to enhance its effects as an estrogen receptor antagonist.17 Although it was developed for the prevention and treatment of breast cancer, studies were prematurely terminated after the discovery that tamoxifen was a superior therapeutic agent.18 Arzoxifene was also in phase III studies for analysis of its ability to prevent and treat osteoporosis; however, these studies were discontinued because data did not demonstrate a significant reduction in nonvertebral or clinical fractures, nor did arzoxifene reduce cardiovascular episodes when compared to placebo.19

The tissue selective estrogen complex (TSEC) is a novel concept aimed at pairing a SERM with an estrogen for a new form of menopausal therapy.20 This pairing is thought to mediate a blending of the effects of a SERM and estrogen in a more favorable way than simply treating with one form of therapy alone. Preclinical findings have looked at the pairing of SERMs with conjugated estrogens; of the available SERMs, bazedoxifene was the SERM of choice for pairing because of its ability to serve as a strong estrogen antagonist in the endometrium.21 The use of bazedoxifene with conjugated estrogens has undergone extensive testing in humans, and it is has been shown that this TSEC treats hot flushes and vulvar vaginal atrophy and prevents osteoporosis, while avoiding the need to administer progestogen in postmenopausal women with a uterus.10,22,23

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Conclusion

Women need to be assessed on an individual basis to determine which menopausal treatment option will give them the most relief, while also minimizing associated risks. SERMs are best suited for the prevention/treatment of osteoporosis and breast cancer in menopausal women who do not experience severe hot flushes. Estrogen therapy can be used to treat hot flushes or vaginal atrophy in women who also need bone protection. A number of new SERMs are in development, and TSECs, although still under investigation in late-stage clinical trials, will hopefully provide prevention/treatment of osteoporosis, vaginal atrophy, and hot flushes, while also having neutral effects on breast and endometrial tissue.

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Valerie Flores, MD, is a Research Associate, and Hugh S. Taylor, MD, is Professor and Director, Division of Reproductive Endocrinology and Infertility, both at Yale University School of Medicine, New Haven, CT.

References

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