Ospemifene and Urogenital Atrophy

Estrogen and androgen deficiency from menopause causes vulvo-vaginal and urogenital changes and a plethora of symptoms, most prominently dyspareunia. The nomenclature recently has been expanded to genitourinary syndrome of menopause (GSM).

Reproductive hormone deficiency leads to vulvar and vaginal thinning, loss of rugal folds, diminished elasticity, diminished vaginal glycogen, and decreased acidity (increased pH) of the vaginal secretions, thereby reducing the vagina’s natural defences [1].

Few women with GSM report their symptoms to their health care professionals [2], and conversely most health care professionals do not sufficiently query patients or inform them of their therapeutic options. Furthermore, class labelling of most available treatments has emphasized unsubstantiated risks [3] (i.e. increased endometrial cancer, stroke, myocardial infarction [MI], deep vein thrombosis [DVT], pulmonary embolism [PE], probable dementia, and invasive breast cancer), thus resulting in only 7 per cent of symptomatic women using any pharmacologic agent [4].

Clinical Development of Ospemifene

Until recently, all available vulvo-vaginal atrophy (VVA)/GSM treatments were systemic or local steroid hormones (estradiol, conjugated estrogens, dehydroepiandrosterone [DHEA]). Fear of estrogens from the ‘class labelling’ and the nuisance of vaginal administration undermines utilization for some women.

Ospemifene, a third-generation SERM originally developed for osteoporosis, has estrogenic effects on bone, lipids and vaginal tissue while remaining antiestrogenic or neutral in the breast and endometrium, respectively [5]. Multiple phase 3, placebo-controlled, clinical trials were conducted [6, 7]. Compared to placebo, ospemifene improved superficial cells and reduced parabasal cells as seen on a maturation index; lowered vaginal pH, and improved most bothersome symptoms (original studies for dyspareunia). This resulted in US Food and Drug Administration (FDA) approval for moderate to severe dyspareunia from vulvo-vaginal atrophy of menopause. Subsequent studies allowed for the indication to be broadened to include moderate to severe dryness due to menopause [8]. The American College of Obstetricians and Gynecologists (ACOG) endorsed ospemifene (Level A evidence) as first-line therapy for dyspareunia noting absent endometrial stimulation [9]. The most common adverse reactions in these ospemifene trials versus placebo were hot flashes and sweating (9.1 per cent vs 3.2 per cent), and muscle spasms (3.2 per cent vs 0.9 per cent), mostly leg cramps [6, 7]. Only 1 per cent of participants discontinued due to hot flashes, and there were no differences in rates of bleeding or breast tenderness.

Endometrial Safety

There is a boxed warning in the ospemifene label that says, ‘in the uterus, ospemifene has estrogenic agonistic effects’ [10]. Despite the fact that ospemifene is not an estrogen (it’s a SERM), it goes on to state, ‘there is an increased risk of endometrial cancer in a woman with a uterus who uses unopposed estrogen’. This statement actually caused The Medical Letter to initially suggest that patients receiving ospemifene also should receive a progestational agent (something they later retracted) [11, 12]. In trying to understand why the labelling might possibly be worded in such a way, one has to review the actual data and understand the error the FDA made in response to the poorly named entity, ‘weakly proliferative endometrium’. If one combines any proliferative endometrium (weakly + actively + disordered) in the clinical trial, 86.1 per 1000 in the ospemifene-treated patients (versus 13.3 per 1000 for those taking placebo) had any one of the proliferative types. The problem is that actively proliferating endometrial glands will have mitotic activity in virtually every nucleus of the gland as well as abundant glandular progression, whereas ‘weakly proliferative’ is actually closer to inactive or atrophic endometrium with just an occasional mitotic figure in just a few of the nuclei of each gland.

Furthermore, at 1 year, the incidence of active proliferation with ospemifene was 1 per cent [13]. Compare this finding with the Uterine Safety Study for raloxifene – both doses of that agent had an incidence of active proliferation at 1 year of 3 per cent [11]. Furthermore, that study had an estrogen-only arm in which, at endpoint, the incidence of proliferative endometrium was 39 per cent and hyperplasia, 23 per cent [14]! Thus, it is evident that, in the endometrium, ospemifene is much more like the SERM raloxifene than it is like estrogen.

Other Effects of Ospemifene

Ospemifene was originally approved for use in the US in 2013. Since that time a great deal of clinical and preclinical work has been brought to the attention of clinicians. As a SERM, based on class effects, one would expect it to be an estrogen antagonist in breast and estrogenic in bone. Additionally, improvement in overactive bladder (OAB) symptoms as well as prevention of recurrent lower urinary tract infections have been reported.

Previous data have demonstrated that ospemifene inhibits breast cancer cell growth in in vitro cultures as well as experimental animals [15] and inhibits proliferation of human breast tissue epithelial cells [16], with such breast effects similar to tamoxifen and raloxifene. Thus, although one would not choose ospemifene as a primary treatment, or risk-reducing agent, for breast cancer, the direction of its activity in breast tissue is indisputable and is likely the reason that in the European Union, unlike in the US, it is approved to treat dyspareunia from VVA of menopause in women with a prior history of breast cancer.

Furthermore, with increased aging, the morbidity and mortality associated with osteoporotic fractures becomes increasingly important. Ospemifene effectively reduced bone loss in ovariectomized rats, with activity comparable to estradiol and raloxifene [17]. Clinical data from three phase 1 or 2 clinical trials found ospemifene 60 mg/day to have a positive effect on biochemical markers for bone turnover in healthy postmenopausal women with significant improvements relative to placebo and effects comparable to raloxifene [18]. Actual fracture or bone mineral density (BMD) data in postmenopausal women are lacking but it is known that there is a good correlation between biochemical markers for bone turnover and occurrence of fracture [19]. Once again, women needing treatment for osteoporosis should not be treated with ospemifene but women using ospemifene for dyspareunia can expect positive activity on bone metabolism.

Shiavi and colleagues [20] reported on 46 postmenopausal women with VVA and OAB syndrome who were evaluated at baseline and after 12 weeks of treatment with 60 mg/day of ospemifene. There was a statistically significant decrease in detrusor overactivity, mean number of voids, nocturia and urinary incontinence episodes.

That same research group [21] studied 39 women (mean age, 59) with a history of recurrent urinary tract infections (UTIs). Twenty-one of the 39 reported being sexually active. After treatment for 6 months with ospemifene 60 mg/day, only two of these women had a UTI confirmed by culture. Thus, the ospemifene behaved like estrogen, which has been shown to reduce recurrent UTIs [22].

Summary

Ospemifene is an oral SERM approved for treatment of moderate to severe dyspareunia as well as dryness from VVA due to menopause. The label currently states that, ‘because ospemifene has not been tested in women with breast cancer, it should not be used in women with a history of breast cancer’, although preclinical in vitro, experimental animal in vivo and human in vitro testing all point to antagonistic activity in the breast, similar to other SERMs. The preclinical animal data and human markers of bone turnover all support the antiresorptive action of ospemifene on bones. Thus, it appears, one can safely surmise that the direction of activity of ospemifene in bone and breast is virtually indisputable. The magnitude of that activity is, however, unstudied. Therefore, in trying to choose an agent to treat women with dyspareunia or vaginal dryness from VVA of menopause, determination of any potential add-on benefit for that particular patient in either bone and/or breast is appropriate. There is also promising preliminary data that suggest a positive effect of ospemifene in patients with OAB or recurrent UTIs. Clearly, further study for both of these is necessary.

Bazedoxifene and Combined Bazedoxifene/Conjugated Estrogen

Osteoporosis is widespread in postmenopausal women because the decrease in estrogen production can accelerate bone loss [23]. High morbidity and mortality of osteoporosis-related fractures impose a heavy economic burden for patients and society [24]. Bazedoxifene is a SERM that has been shown to prevent bone loss and reduce the risk of new vertebral fractures in postmenopausal women with an increased risk of fracture and has a favourable safety/tolerability profile with no adverse effects on the reproductive system [25–27]. A meta-analysis of four randomized, placebo-controlled trials [28] showed that bazedoxifene can significantly decrease the incidence of vertebral fracture at follow-up of 5–7 years as well as confirming the long-term favourable safety/tolerability of bazedoxifene with no increase in adverse events, serious adverse events, myocardial infarction, stroke, venous thromboembolic event and breast carcinoma using bazedoxifene. However, bazedoxifene may result in an increased incidence of hot flushes and leg cramps across 7 years.

In summary, bazedoxifene shows an important ability to reduce the risk of vertebral fracture, and increase spine BMD at 3 and 7 years in postmenopausal women as well as showing long-term favourable safety/tolerability.

TSEC (Tissue-Specific Estrogen Complex)

The rationale for developing a tissue-specific estrogen complex is the partnering of a SERM with one or more estrogens to achieve pharmacologic results based on their blended tissue-selective activity profile [29]. The desire to pursue this grows mainly out of data derived from the two arms of the Women’s Health Initiative. In the arm that combined conjugated estrogen with medroxyprogesterone acetate through 11.3 years, there was a 25 per cent increase in the incidence of invasive breast cancer, which was statistically significant [30]. Contrast that with the arm in hysterectomized women who received only conjugated estrogen (often inaccurately referred to as the ‘estrogen-only’ arm of the WHI). In that study, the relative risk of invasive breast cancer was reduced 23 per cent and was also statistically significant. Thus, it appears that the culprit in the breast cancer incidence difference in these two arms was the addition of the progestogen medroxyprogesterone acetate. It is well known that a progestogen is only added to confer endometrial protection to those patients with a uterus who are receiving any estrogenic therapy. Thus, the question arises, can one protect the endometrium with a non-progestogen substance (i.e. a SERM) and, thus, avoid the negative consequences especially in the breast (as well as bleeding) seen with the combination of estrogen plus a progestogen in the WHI? As further evidence of the above, Manson and colleagues [31] looked at mortality outcomes in the Women’s Health Initiative trials with 18-year cumulative follow-up. Although, all-cause mortality, cancer mortality, cardiovascular mortality were not significantly different in either arm, when one drills down on breast cancer mortality alone, there is a difference between conjugated estrogen plus medroxyprogesterone versus placebo in conjugated estrogen alone versus placebo. In the CEE plus MPA arm, there was a 44 per cent increase, which, although trending towards statistical significance (p = 0.07), was not quite statistically significant. On the other hand, the CE-only arm had a 45 per cent reduction in breast cancer mortality, with p = 0.02 and was thus statistically significant. Various SERMs were looked at in preclinical trials and bazedoxifene was chosen because of its potent uterine protective qualities. In fact, bazedoxifene is the only SERM that has actually been shown to decrease endometrial thickness compared to placebo in a clinical trial [32]. Preclinical trials showed that a combination of BZA/CE in various doses of estrogen resulted in uterine wet weight in an ovariectomized rat model that was no different than placebo [33]. In terms of effects on breast, preclinical models showed that conjugated estrogen resulted in less mammary duct elongation and end bud proliferation than estradiol by itself [34] and that the combination of CE/BZA resulted in mammary duct elongation and end bud proliferation that was similar to the ovariectomized animal and considerably less than a combination of estradiol with bazedoxifene [34].

Five phase 3 studies known as the SMART (Selective estrogens, Menopause, And Response Therapy) trials were then conducted. Collectively they looked at frequency and severity of vasomotor symptoms, bone mineral density, bone turnover markers, lipid profiles, sleep, quality of life, breast density and endometrial safety [35]. On the basis of these trials in over 7500 women, the US Food and Drug Administration approved this conjugated estrogen 0.45 mg/bazedoxifene 20 mg compound in 2013 and it was branded as Duavee in the US and Duavive outside the US.

In terms of frequency of vasomotor symptoms (VMS) there was a 74 per cent reduction from baseline at 12 weeks, which, compared to placebo, had a p-value of < 0.001 as well as a 37 per cent reduction in VMS severity score (p < 0.001) [36]. There were statistically significant improvements in lumbar spine and hip BMD (p < 0.01) for women 1–5 years since menopause as well as those greater than 5 years since menopause [37].

The incidence of endometrial hyperplasia at 12 months was consistently less than 1 per cent, which is the FDA guidance for approval of hormone therapies. The incidence of bleeding or spotting in each 4-week interval over 12 months mirror-imaged placebo and ranged from 3.9 per cent in the first 4-week interval to 1.7 per cent in the last 4 weeks, compared to CE 0.45 mg/MPA 1.5 mg, which had a 20.8 per cent incidence of bleed or spotting in the first 4-week interval and was still 8.8 per cent in the last 4 weeks [38]. This is extremely relevant in clinical practice. There was no difference from placebo in breast cancer incidence, breast pain or tenderness, abnormal mammograms, or breast density at month 12 [39–41].

Realize that all of these data were for this particular estrogen (conjugated estrogen) with this particular SERM (bazedoxifene). Others have tried to combine raloxifene and 17 beta-estradiol to obtain similar results [42]. That study was meant to be a 52-week treatment study with either raloxifene 60 mg alone or in combination with 17 beta-estradiol 1 mg/day on vasomotor symptoms and endometrial safety. The study was stopped early because signs of endometrial stimulation were observed in the raloxifene plus estradiol group. Thus, one cannot combine any estrogen with any SERM and expect similar results.

In summary, this particular combination of conjugated estrogen/bazedoxifene is approved for treatment of vasomotor symptoms of menopause as well as prevention of osteoporosis. Although not approved for treatment of moderate to severe vulvo-vaginal atrophy, it should allow the prevention of younger women who initiate treatment from developing moderate to severe symptoms of VVA. Finally, this drug should be protective of breast. As discussed above conjugated estrogen has clearly shown a reduction in breast cancer incidence and mortality and bazedoxifene is a SERM. All SERMs have been shown, as a class effect, to be antiestrogens in breast tissue as well as abundant preclinical data that point in that direction. Thus, this combination of conjugated estrogen/bazedoxifene may well provide a new paradigm of hormone therapy that is progestogen free, in whom the benefit/risk ratio is severely tilted towards its benefits.