Not all SERMs are created equal: chapter 2.

Abstract

I n 2006, I wrote an article titled BNot all SERMs are created equal.[ There are certainly marked differences in the uterus and vagina. Ospemifene and lasofoxifene are estrogenic in the vagina and effective in treating vulvovaginal atrophy (more recently known as GSM or genitourinary syndrome of menopause), whereas other selective estrogen receptor modulators (SERMs) are not. Tamoxifen increases endometrial neoplasia, whereas Evista does not. Ospemifene does not, despite Food and Drug Administration labeling. Bazedoxifene (BZA) was the first SERM to actually decrease endometrial thickness for 1 year, but there are more true Bclass effects[ such as estrogen antagonism in the breast and antiresorption in bone. How different are these results, and how long do they persist? The article by Palacios et al in this issue of Menopause examined long-term results with BZA and its antiresorptive capabilityVand thus its ability to reduce osteoporotic fracturesVand reporting on adverse events, mainly invasive breast cancer. Originally, 7,492 postmenopausal women with osteoporosis were randomized to either of two doses of BZA or placebo. BZA 20 mg significantly reduced new vertebral fractures by 42%. A 2-year extension was undertaken, transitioning all treated women to BZA 20 mg. The current article reports a second 2-year extension for 1,530 of these women, thus yielding 7-year data. The cumulative incidence of new vertebral fractures was significantly lower in women treated with BZA than in women treated with placebo, although there was no difference in nonvertebral fractures. There was a loss of bone density at the total hip, although it was significantly less than that in the placebo group. Although BZA is clearly antiresorptive in bone and despite the fact that this BZA extension study and the CORE (Continuation of Raloxifene Evaluation) trial with raloxifene were not head-to-head trials, there seems to be fewer effects in this study than in the CORE trial with raloxifene. The CORE trial reported a statistically significant increase in hip bone mineral density; in the current study, not only was a statistically significant increase in hip bone mineral density not seen but there was a decrease in total hip bone mineral density, although this decrease was significantly smaller than that in the placebo group. From a safety perspective, there were no differences in cardiovascular events between the BZA-treated group and the placebo group. As expected, cumulatively, there was a statistically significant 3.38-fold increase in deep vein thrombosis, the incidence of which was highest on the first year. There were no cases in year 6 or year 7. The overall incidence of endometrial carcinoma was 0.1% with BZA versus 0.4% with placebo (P = 0.02). The CORE trial with raloxifene had no decrease in uterine cancer. The current study found no difference in breast cancer incidence, although it was low (0.6%) overall in both BZA and placebo cohorts. In the current study, breast cancer was only recorded as an adverse event. In the 4-year CORE extension trial of MORE (Multiple Outcomes of Raloxifene Evaluation), there was a 59% statistically significant reduction in estrogen receptorYpositive invasive breast cancer; for the entire 8 years of MORE/CORE combination, there was a 66% statistically significant reduction. Obviously, it is very tempting to compare these results with the CORE trial. However, these are not head-to-head trials; in CORE, breast cancer was a primary endpoint. The incidence of breast cancer in the placebo group of CORE was 1.6%, whereas it was 0.6% in the current study. In the current study, the mean age was 66 years, with a mean body mass index of 26 kg/m. In the CORE trial, the mean age was also 66 years, and the mean body mass index was 25 kg/m. Thus, how does one explain the difference? At first look, one might suppose that raloxifene is a more potent antiestrogen in the breast; however, recall that the Third National Health and Nutrition Examination Survey correction rendered a significant number of women in MORE as osteopenic, not osteoporotic. Women with osteoporosis tend to be at lower risk for breast cancer than women without osteoporosis. Furthermore, in MORE/CORE, there was no statistically significant reduction in endometrial cancer, whereas in the current report, the reduction in endometrial cancer was statistically significant. This certainly is also not surprising because BZA is the only SERM to ever result in a decrease in endometrial thickness on transvaginal ultrasound and also because it possesses uteroprotective propertiesVthe reason for its pairing with conjugated estrogens for treatment of vasomotor symptoms and prevention of osteoporosis among women with intact uterus who do not use progestogen for endometrial protection. BZA is not available as a stand-alone drug in the United States, although it is available in many parts of the world. What can one hypothesize from this? Would Osphena show similar results? Can clinicians (off-label) switch women from raloxifene (in my clinical practice, most women on raloxifene use concomitant intravaginal estrogen) to Osphena and expect bone, breast, and vaginal benefits? This is an interesting idea. However, the effects of ospemifene (as SERM) on the bone and breast are not in doubt, but the magnitude of those effects are unstudied and thus untested. One would be foolhardy to make that leapVjust like it would be foolhardy to believe that the combination of 17A-estradiol and any SERM (such as raloxifene) would be similar to the BZA/conjugated estrogens combination recently approved by the Food and Drug Administration. In fact,

DOI: 10.1097/GME.0000000000000504

Cite this paper

@article{Goldstein2015NotAS, title={Not all SERMs are created equal: chapter 2.}, author={S. R. Goldstein}, journal={Menopause}, year={2015}, volume={22 8}, pages={802-3} }