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Are Oral SERMs Safe for Dyspareunia?

Thus as you can see above, the efficacy of ospemifene is quite robust and, in my opinion, should be of little concern to our patients. I believe that safety will be their primary issue since this is a systemic drug to treat a local problem (moderate to severe dyspareunia due to VVA of menopause) and a problem while although quite disturbing to many, many patients, is not life threatening. In addition, in spite of usual "FDA speak" ("shortest duration consistent with treatment goals for the individual woman") presumably this will be used long term since the underlying cause (hypoestrogenemia of menopause) will remain if therapy is stopped and eventually symptoms will recur.

So what are the main safety issues? I believe they are breast safety, endometrial safety, and cardiovascular issues (especially VTE).

Breast Safety

The label of Osphena states it "has not been adequately studied with breast cancer, therefore it should not be used in women with known or suspected breast cancer or with a history of breast cancer". While it is true that Osphena has not been studied in such women, the class effect of all SERMs in addition to the basic science data speak for themselves.

When tested in normal human mammary tissue explant cultures, ospemifene was also found to have antiestrogenic, growth inhibitory effects, similar to raloxifene and tamoxifen. (1) Studies utilizing the ovariectomized nude mouse model examined the effects of ospemifene on MCF-7 human breast cancer xenografts. These studies demonstrated that not only does ospemifene lack estrogenic activity in breast tumors, but it also acts as an antiestrogen in an ERa-dependent fashion, consistent with the results seen in vitro. (2) While there were reports of breast tenderness, breast mass and breast pain, the frequency was low, and similar to that which occurred in the placebo group. There were two cases of breast cancer reported in 300 patient years of placebo treatment, which is a frequency that is to be expected in this population. Interestingly, in the 805 patient years of treatment with ospemifene, no cases of breast cancer were reported. (3)

Every SERM adequately studied thus far has reduced breast cancer risk, and none of the others has suggested any harm to the breasts. As a clinician, there is a large unmet need for an agent that treats dyspareunia due to VVA in women who cannot, should not, or will not use estrogen products, and these are often women with a history of breast cancer or at high risk for breast cancer. On the contrary, this is the ideal group for such a new agent as ospemifene. Any claim about breast cancer prevention with such an agent would be premature; however, based on class labeling, a statement about not using it in such women is, in my opinion, not appropriate.

Endometrial Safety

The boxed warning for Osphena states, "in the endometrium Osphena has estrogenic agonistic effects. There is an increased risk of endometrial cancer in a woman with a uterus who uses unopposed estrogen." In fact, this statement caused the Medical Letter to initially suggest the addition of a progestational agent to patients receiving Osphena. The statement in this boxed warning is, in my opinion, not remotely supported by the data. While the label goes on to state, "the incidence of any type of proliferative (weakly plus active plus disordered) endometrium was 86.1 per thousand in Osphena vs. 13.3 per thousand for placebo," this needs clarification. Proliferation is characterized by abundant mitotic activity and glandular progression. (FIGURE 1)

"Weakly proliferative" is much closer to an inactive endometrium and should be thought of as a variant of that, not true proliferation. Histologically, "weakly proliferative" appears as an inactive endometrium with rare mitoses. (FIGURE 2)

In addition, data from the uterine safety study of raloxifene (4) is crucial to understanding an estrogen agonistic effect. That study included 415 participants. At 1 year, the incidence of proliferation with raloxifene 60 mg was 3%, and the incidence of hyperplasia was 0%. With unopposed estrogen at endpoint, the incidence of proliferation was 39%, and the incidence of hyperplasia was 23%. With ospemifene, the safety data at 52 weeks revealed a 1.0% incidence of proliferation and one case of hyperplasia (0.3%). (5) Thus I believe ospemifene's effect on the endometrium is much more akin to the SERM raloxifene than it is to estrogen. I will grant that the ospemifene data does not have the weight of a study like the Multiple Outcomes of Raloxifene Evaluation trial (6), which showed a 20% nonsignificant reduction in endometrial cancer in 3,958 women treated with raloxifene for 3 years. However, I believe Ospemifene's effect on the endometrium is much more akin to the SERM raloxifene than it is to estrogen.

Cardiovascular safety, including VTE

A total of 1892 patients were exposed during the Phase II and Phase III studies, with an average duration of exposure of 182 days. This represents approximately 1000 patient years of exposure under monitored conditions, the majority of which was at the 60-mg dose. Over 400 patients had in excess of one year of treatment with ospemifene. All patients were postmenopausal with an average age of 59 years, and 86% were on concomitant medications.

Of particular interest with SERMs is the frequency of cardiovascular events. Six ospemifene-treated patients (0.3%) and one placebo-treated patient (0.1%) discontinued because of a cardiovascular event. These included two DVTs, three cerebrovascular accidents (CVA), and one myocardial infarction. No cases of thromboembolism were reported. One cardiovascular event occurred in the placebo group. The rate of occurrence of any cardiovascular event was approximately 6 per 1000 patient years of treatment. The incidence of DVT was 0.1%, which is lower than that reported for recently approved SERMs. (3) However, in my opinion, I believe this lower rate of VTE is likely due to the small number of events. In clinical practice I would expect the rates, and therefore the risks of VTE, to be similar to all other SERMs or systemic estrogen containing preparations.

One Caveat

Most women in my practice who are on raloxifene for prevention or treatment of osteoporosis, or breast cancer risk reduction, are also on a concomitant vaginal estrogen since raloxifene does not improve the vulvovaginal atrophy of menopause. I fear that some clinicians will abandon raloxifene in favor of ospemifene believing that they can get benefit in bone, breast, and vagina. This would be foolhardy, for while I am certain that the direction of effect in bone and breast with ospemifene will be favorable, the magnitude of that effect with this drug at this dose is unknown.

In Summary

In spite of language in the labeling for ospemifene, the preclinical and clinical data seems to support the fact that it is 1) no more estrogenic in the endometrium than the well studied raloxifene 2) an estrogen antagonist in the breast; and 3) estrogenic in the venous system (in spite of low rates of VTE in the clinical trials to date). This combined with excellent efficacy in treating moderate to severe dyspareunia due to VVA of menopause makes it a promising option for women who prefer an oral medication to a topical vaginal insert or women who do not want any estrogenic product, even the low dose vaginal estrogens in spite of their proven safety. (7)


(1.) Kangas, L, Unkila M. Tissue selectivity of ospemifene: pharmacologic profile and clinical implications. Steroids 2013 Dec 11 ;78(12-13):1273-1280.

(2.) Taras TL, Wurz GT, DeGregorio MW. In vitro and in vivo biologic effects of Ospemifne (FC1271a) in breast cancer. J Steroid Biochem Mol Biol 2001 Jun;77(4-5):271-279.

(3.) DeGregorio MW, Zerbe RL, Wurz GT. Ospemifene: A first-in-class, non-hormonal selective estrogen receptor modulator approved for the treatment of dyspareunia associated with vulvar and vaginal atrophy. Steroids 2014 Nov; 90:82-93.

(4.) Goldstein SR, Scheele WH, Rajagopalan SK, Wilkie JL, Walsh BW, Parsons AK. A 12-month comparative study of raloxifene, estrogen, and placebo on the postmenopausal endometrium. Obstet Gynecol 2000 Jan;95(1):95-103.

(5.) Goldstein S, Bachmann G, Un V, Simon J, Portman D, Phelps M. Endometrial safety profile of ospemifene 60 mg when used for long-term treatment of vulvar and vaginal atrophy for up to 1 year. Climacteric 2011 June;14:77.

(6.) Cummings SR, Eckert S, Krueger KA, et al. The effect of raloxifene on risk of breast cancer in postmenopausal women: results from the MORE randomized trial. Multiple Outcomes of Raloxifene Evaluation JAMA 1999 Jun 16;281 (23):2189-2197.

(7.) Manson JE, Goldstein SR, Kagan R, Kaunitz AM, Liu JH, Pinkerton JV, et al. Why the product labeling for low-dose vaginal estrogen should be changed. Menopause 2014 Sep;21 (9): 911-916.

Steven R. Goldstein, MD, FACOG, CCD, NCMP, FRCOG(H)
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Title Annotation:Non-Estrogen Oral Therapy for Dyspareunia Secondary to Vulvovaginal Atrophy
Author:Goldstein, Steven R.
Publication:OBG Management
Date:Mar 1, 2015
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