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By Jeffrey T. Jensen, MD, MPH
SYNOPSIS: Selective estrogen receptor modulators (SERMs) like tamoxifene and raloxifene are now well-established therapeutics, and new agents such as bazedoxifene and ospemifene have recently been introduced. These new agents have unique tissue-specific profiles that allow for a customization of therapeutic effect. In this review, the profiles of bazedoxifene and ospemifene will be compared and discussed relevant to their place in clinical practice.
The primary impact of publications resulting from the Women’ Health Initiative (WHI) has been a movement away from traditional estrogen/progestin hormone replacement therapy (HRT). In my opinion, this has been a disservice to menopausal women. More recently, there has been some positive movement to counter the negativism associated with hormonal treatment. The 2014 revision of the American Congress of Obstetricians and Gynecologists Practice Bulletin for management of menopausal symptoms provides a balanced discussion of benefits and risks of HRT that places the WHI findings in perspective with other literature.1 Still, the public and many primary care providers remain confused and frightened.
Despite the well-established benefits of treatment of hot flushing, maintenance of bone density, and prevention or treatment of vulvovaginal atrophy (VVA) and dyspareunia, many primary care providers and some gynecologists are reluctant to recommend HRT. The biggest concern among most women is breast cancer, even though the primary risk of estrogen is an increased risk of thrombosis.2 Thrombosis is an estrogen effect related to hepatic production of prothrombotic globulins. Bypassing the liver with transdermal or vaginal administration of estrogen can avoid this first pass metabolism. Transdermal estradiol is rapidly isomerized to estrone and estriol, and circulates at physiologic levels. However, if a potent synthetic estrogen like ethinyl estradiol is administered transdermally, the metabolites are highly potent, and the liver continues to interpret the overall estrogen milieu as elevated (i.e., pregnant) shifting the balance toward coagulation. An important multicenter case-control study in France (ESTHER study) documented that oral estradiol increases the risk of VTE, but that transdermal estradiol does not.3
The results of the combined oral estrogen/progestin and estrogen-only WHI studies also suggest that the inclusion of a progestin (or at least medroxyprogesterone acetate, MPA) may change the risk/benefit ratio. There was no overall impact on coronary heart disease with estrogen only treatment and a decreased risk of invasive breast cancer.4 The evidence suggesting that MPA may attenuate the favorable effects of oral estrogens on lipids first emerged in the 1995 PEPI study.5 Although we have no large randomized studies documenting the safety of alternative progestin regimens, it would make sense to reduce systemic exposure. I am a big fan of off-label use of locally administered levonorgestrel in the intrauterine system along with transdermal estradiol. Unfortunately, few women use this approach as insurance will not cover the off-label use.
One of the reasons that we don’t have better options for endometrial protection is that the pharmaceutical industry has adopted a cautious approach to HRT. Since WHI, the emphasis has moved to alternatives to traditional estrogen therapy.
Selective estrogen receptor modulators (SERMs) provide tissue-specific effects through agonist and antagonist action on the two estrogen receptors (ERα and ERβ). The tissue expression of the two estrogen receptors, as well as downstream promoters of estrogen action, differ such that selective activation and blocking yield a variety of tissue-specific actions with various ligands. For example, tamoxifene, a SERM that has been in widespread use for many years for breast cancer treatment, antagonizes estrogen action in the breast and in the vagina, but acts as an agonist in the endometrium and in bone. Raloxifene is similar to tamoxifene. Neither is effective in the management of hot flushing. Both increase clotting risk similar to orally administered estradiol.
Recently, two new SERMS, ospemifene and bazedoxifene, have received FDA approval. A third, lasofoxifene, was associated with an increased risk of genital prolapse in a pre-marketing study and has not received FDA approval.
Ospemifene received FDA approval in 2013 for the treatment of moderate-to-severe dyspareunia due to menopause. The drug is provided as a 60 mg tablet to be taken once daily and is marketed on the company’s website as the "only FDA-approved, NON-ESTROGEN, ORAL pill that actually improves certain vaginal tissue and significantly relieves moderate to severe painful intercourse due to menopause." Like raloxifene and tamoxifene, it does not treat hot flushes. The data for management of vaginal symptoms are good; in a Phase 3 clinical trial, postmenopausal women with VVA and self-reported vaginal dryness were randomized to once-daily ospemifene 60 mg/day (n = 303) or placebo (n = 302) for 12 weeks. The co-primary efficacy endpoints were the change from baseline to week 12 for the maturation index (MI) of vaginal epithelial cells and in the severity of the most bothersome dyspareunia symptom (MBS; vaginal dryness or pain). Significant improvements in the MI and vaginal pH were observed. The reduction in MBS severity score was significantly better with ospemifene (-1.5) compared to placebo (-1.2, P = 0.0001). The paper reports that, compared to placebo, the percentage of participants reporting no (38% vs 28%) or mild (25% vs 19%) vaginal pain with sexual activity at week 12 was greater in the ospemifene group, and that the severity of vaginal pain improved by two to three levels in 53% of the ospemifene group compared with 39% of the placebo group. However, the statistical significance of these findings is not reported.6 Another Phase 3, double-blind, RCT evaluated 30 mg and 60 mg doses vs placebo with the MI as a primary outcome and included dyspareunia as a subjective complaint.7 Both doses of ospemifene improved the MI and reduced complaints of vaginal dryness, but only the 60 mg dose resulted in a statistically significant reduction in complaints of moderate-to-severe dyspareunia (mean decrease 60 mg 1.19, 30 mg 1.02, placebo 0.89). In a third RCT, postmenopausal women with VVA and self-reported vaginal dryness were randomized to once-daily ospemifene 60 mg/day (n = 160) or placebo (n = 154) for 12 weeks with the same outcomes as the earlier studies. Significant improvements in the MI and vaginal pH were observed. While there was improvement from baseline in the severity score of vaginal dryness in women receiving ospemifene, this was not significantly different from placebo.8
Clinical trials also have evaluated the endometrial safety of ospemifene.9 In a combined series of 1242 women who received ospemifene 60 mg/day and 924 women who received placebo for up to 52 weeks in Phase 2 and 3 trials, no endometrial cancer or endometrial hyperplasia occurred with treatment. One participant who received ospemifene was reported to have simple endometrial hyperplasia without atypia on a biopsy done 3 months after the last dose of active drug.
Although the numbers of subjects in Phase 3 studies are typically insufficient to evaluate uncommon serious adverse events like thrombosis, the data with ospemifene are reassuring. In the overall clinical trial program, the incidence rate for deep vein thrombosis (DVT) was 1.45/1000 in women using ospemifene vs 1.04/1000 in placebo.10 Despite this low event rate (1.5/1000 was the rate of DVT in the placebo arm of WHI), the FDA has placed the risk of DVT in the "Black Box" warnings related to this drug. The risk of endometrial cancer is also in this "Black Box."
Bazedoxifene (BZA) is a SERM that is marketed as a combination therapy with conjugated estrogens (CE). The idea is that the combination results in a "tissue selective estrogen complex" (TSEC) that allows for beneficial effects of estrogen action in some tissues (bone, brain [hot flushing], vagina [dyspareunia]) while blocking estrogen action in the endometrium and breast.11 The FDA-approved product is an oral tablet containing 20 mg of BZA and 0.45 mg of CE. The approved indications are treatment of moderate-to-severe vasomotor symptoms associated with menopause and prevention of postmenopausal osteoporosis. The treatment of vulvovaginal atrophy and dyspareunia are not in the approved label.
The Selective estrogens, Menopause, And Response to Therapy (SMART)-5 trial was a multicenter, randomized, double-blind, placebo- and active-controlled study in postmenopausal women with an intact uterus evaluating endometrial safety and bone effects of BZA/EE.12 Subjects (n = 1843) received oral BZA 20 mg/CE 0.45 or 0.625 mg, BZA 20 mg alone, CE 0.45 mg/ MPA 1.5 mg, or placebo. At 12 months, the incidence of endometrial hyperplasia in all active treatment groups was similar (< 1%) and no different from placebo. Bleeding patterns were significantly better with CE/BZA than with CE/MPA. At 12 months, all active treatment groups had increases from baseline in lumbar spine BMD, whereas the placebo group lost BMD; the results for CE/MPA were significantly better than CE/BZA. Results at the hip were similar with all active treatments. The incidences of breast tenderness with both doses of BZA/CE were similar to that with placebo and BZA and significantly lower than with that with CE/MPA. There was one VTE in a subject receiving CE/MPA. Cardiac disorders were seen among subjects receiving CE/BZA (coronary artery disease, myocardial infarction, angina pectoris; n = 1 each), but the overall incidence was no different than in the placebo group (arteriosclerosis, myocardial infarction; n = 1 each). None were observed in the CE/MPA group. Although a favorable breast-related safety profile (no increase in mammographic breast density or breast tenderness) was seen in the SMART-5 study with both doses of CE/BZA, there are no long-term clinical data on breast cancer prophylaxis or treatment with the combination.13 The SMART-2 study demonstrated a significant reduction in hot flushes with both doses of CE/BZA compared to placebo.12
The CE/BZA label contains a "Black Box" that warns women: not to take additional estrogens; of an increased risk of endometrial cancer when using unopposed estrogens; that estrogen therapy should not be used for the prevention of cardiovascular disease or dementia; that women in the estrogen arm of WHI reported increased risks of stroke and DVT; and that women in the WHI Memory Study (WHIMS) estrogen only arm reported an increased risk of probable dementia. Since none of these refer to bazedoxifene, the warnings appear to reflect the conjugated estrogen component.
So does either of these new SERMs offer a groundbreaking advance in the treatment of menopause? In my opinion, the answer is no. I see little advantage over transdermal or vaginal estrogen with appropriate endometrial protection (e.g., lowest possible systemic dose, no MPA). While ospemifene does improve vaginal health and is technically not an estrogen, it offers no advantage over low-dose local estradiol available in vaginal tablets or the low-dose vaginal rings that also do not stimulate the endometrium. CE/BZA will offer bone protection similar to raloxifene with a reduction in hot flushing, but still uses oral CE. I think avoiding first pass effects with transdermal estradiol makes better sense for most women.
To summarize, you may have started reading this feeling uncomfortable about your knowledge of these new agents, wondering how they should fit into modern practice. Given the evidence, you may feel better about and more comfortable with your old friend estrogen.