Tissue-Selective Agents: Selective Estrogen Receptor Modulators and the Tissue-Selective Estrogen Complex

Abstract

Menopause has been associated with vasomotor symptoms, vulvar-vaginal atrophy and osteoporosis. One of the goals in exploring the potential of selective estrogen receptor modulators (SERMs) was to determine if they could prevent fractures, reduce menopausal symptoms and treat vaginal atrophy, while being neutral or protective on the uterus, breast and cardiovascular system. However, no SERM to date has achieved this goal. More recently, the idea of pairing a SERM with estrogen(s), known as a tissue-selective estrogen complex (TSEC), has been studied in postmenopausal women. A TSEC combines the complementary tissue-selective activities of a SERM and estrogen(s), in an attempt to gain the benefits of each with better overall tolerability. The Selective estrogen Menopause And Response to Therapy (SMART) trials were multicentre, randomized, double-blind, placebo- and active-controlled phase 3 studies evaluating the safety and efficacy of the SERM, bazedoxifene (BZA) paired with conjugated estrogens (CEs) in healthy postmenopausal women. In the first SMART trial, BZA/CE protected the endometrium from estrogenic stimulation, relieved hot flushes and maintained bone mass, with rates of amenorrhea, breast pain and overall adverse events similar to those with placebo in more than 3400 women over two years. BZA 20 mg was the lowest effective dose of BZA in BZA/CE to protect the endometrium and maintain bone mass when paired with CE 0.625 mg and CE 0.45 mg. In SMART-2, these BZA/CE doses significantly reduced the frequency and severity of hot flushes over 12 weeks. Collectively, these data support the TSEC containing BZA/CE as a new paradigm for treating menopausal symptoms and preventing osteoporosis while protecting the endometrium from unopposed estrogenic stimulation.

Keywords

Estrogen menopause selective estrogen receptor modulator tissue-selective estrogen complex

Key points

•

Selective estrogen receptor modulators (SERMs) have been approved for a variety of indications, including those related to breast cancer, postmenopausal osteoporosis and fertility; no SERM to date addresses menopausal symptoms.

•

The activity of a tissue-selective estrogen complex (TSEC), or the pairing of a SERM with estrogen(s), is the result of the blended activities of each of its components.

•

A TSEC is a potential strategy to treat postmenopausal osteoporosis and menopausal symptoms, while having neutral or beneficial effects on the endometrium and breast.

•

The TSEC containing bazedoxifene and conjugated estrogens has been shown to relieve hot flushes and increase bone mass in postmenopausal women, with amenorrhea rates and breast pain incidence similar to those with placebo.

Introduction

The number of women approaching menopause will continue to increase in the upcoming years. Worldwide, the number of women aged 45–54 years was estimated to rise from 9.8% of the female population in 2000 to 11.2% in 2010 and 12.1% in 2020.¹ In the UK, women aged 45 and over were estimated as being 43% of the female population, and by 2051, this could increase to 49% of women.² Similarly, in the USA, women aged ≥45 years were estimated to represent 43% of women in 2010, which may reach 50% of women in 2050.³ In addition, because the life-expectancy of women has been increasing, women will be postmenopausal longer. According to estimates from 2008, the life-expectancy of women in the UK was 81.9 years.²

The cessation of ovarian function at menopause may be associated with vasomotor symptoms, loss of bone mass and vulvar-vaginal atrophy. Hot flushes have been shown to occur in approximately 88% of perimenopausal women,⁴ and 75% of women 3–12 months away from their last menstrual period, decreasing thereafter, but still being reported by as many as 66% of women up to nine years after their last menstrual period.⁵ Importantly, up to 40% of women have reported that hot flushes interfere with daily activities.⁶ Women also start to have vasomotor symptoms at different times and experience them for different durations. One study of 438 women (aged 29–82 years) found that 50% of the women started experiencing hot flushes before menopause, when the menstrual cycle was still regular or becoming irregular, while most of the others began having hot flushes within one year of menopause.⁷ A recent study showed that the mean duration women experienced hot flushes was 5.2 years after 13 years of follow-up.⁸ Hot flush duration has been shown to range from a few months to 44 years, with most (60%) of the women experiencing hot flushes for <7 years; however, 15% were shown to have them for >15 years.⁷ Hot flushes have also been observed in women with a mean age of 67 years who were an average of 18 years since menopause.⁹

Estrogens alone and estrogens plus progestin therapy have well-known efficacy for treating the consequences of menopause, including vasomotor symptoms and osteoporosis. Because the use of unopposed estrogens in women with a uterus increases the risk for endometrial hyperplasia^10,11 and endometrial cancer,¹² a progestin is generally added to protect the endometrium.^10,11 However, progestins are not always well tolerated by women, creating a need for a progestin-free menopausal therapy.¹³

Selective estrogen receptor modulator (SERMs) have been in development for many years and have been studied for a variety of different uses, including breast cancer prevention and treatment, postmenopausal osteoporosis, contraception and vulvovaginal atrophy, as well as in men for osteoporosis, prostate cancer, and secondary hypogonadism and its associated diseases.¹⁴ While SERMs are currently used in postmenopausal women for osteoporosis, the goal of developing an optimal SERM has been to create a molecule that treats postmenopausal osteoporosis and menopausal symptoms, while having neutral or beneficial effects on the endometrium, breast and cardiovascular system.¹⁴ No SERM to date has reached this therapeutic goal.

This article is based in part on a lecture given at the British Menopause Society in December of 2009. Additionally, it describes some history of SERMs leading up to the concept of a tissue-selective estrogen complex (TSEC), or the pairing of a SERM with estrogen(s), and reviews published preclinical and clinical evidence for using the TSEC containing the SERM, bazedoxifene (BZA), paired with conjugated estrogens (CEs) to treat menopausal symptoms and osteoporosis.

Estrogens and SERMs

Both estrogens and SERMs are ligands that bind to estrogen receptors (ERs), but display different tissue-selective activities. While estrogens function as ER agonists and differ primarily based on potency,⁶ SERMs possess agonist and antagonist activity depending on target genes and tissues.^6,15–17

One of the first SERMs approved for clinical use was tamoxifen, which is used for the treatment of metastatic breast cancer and the prevention of breast cancer recurrence.¹⁸ Based on early breast cancer studies, tamoxifen was thought to be an anti-estrogen.¹⁹ Later however, tamoxifen was found to have beneficial (agonist) effects on the lumbar spine, significantly increasing bone mineral density (BMD) by 0.61% per year compared with a decrease of 1.0% per year with placebo.²⁰ The tissueselective effects of tamoxifen, and other SERMs, may be explained in part by an understanding of their molecular mechanism of action. Once bound to the ER, each ligand creates a unique conformation, allowing or disallowing transcriptional coregulator recruitment and subsequent gene transcription. Once tamoxifen binds to the ER, it repositions helix 12 in the ER ligand-binding domain, which hampers coactivator interaction with the AF-2 region, thus blocking the transcription of genes dependent on the function of the AF-2 region.^21,22

In addition to tamoxifen, a variety of SERMs are approved in different countries, including raloxifene (RAL), BZA, lasofoxifene (LAS), toremifene, clomifene and ormeloxifene. RAL is indicated for the treatment and prevention of osteoporosis in postmenopausal women,^23,24 and for reduction in risk of invasive breast cancer in postmenopausal women with osteoporosis and those at high risk for invasive breast cancer.²³ BZA and LAS are approved in Europe for the treatment of postmenopausal osteoporosis in women at high risk for fracture.^25,26 Other SERMs approved for various indications include toremifene for treating postmenopausal women for metastatic breast cancer that is estrogen-receptor positive or unknown,²⁷ clomiphene for fertility treatment and ormeloxifene for contraception.¹⁴ SERMs have also been explored for their use in men, for osteoporosis, prostate cancer, and secondary hypogonadism and its associated diseases.¹⁴ During their development, not all SERMs were continued on the clinical track, including arzoxifene and droloxifene because of efficacy inferior to current breast cancer therapies, and idoxifene and levormeloxifene for adverse effects on the endometrium or urogenital tract.¹⁴

Although some SERMs (RAL, LAS and BZA) are approved in certain countries to treat postmenopausal osteoporosis in high-risk women, none of these SERMs address symptoms related to menopause.

The tissue-selective estrogen complex

An ideal therapy for menopause would treat vasomotor symptoms, prevent fractures, and treat vulvar-vaginal atrophy and its symptoms without stimulating the endometrium or breast, and provide a similar incidence of amenorrhea as that of untreated women. A new paradigm in the treatment of postmenopausal women is the TSEC, which combines a SERM with estrogen(s) to provide the efficacy of both components with fewer adverse effects and better tolerability than either component alone. The rationale is that the tissue-selective activity or clinical profile of the TSEC would be the result of the blended activities of the SERM and estrogen(s). Evidence indicates that combining estrogens and SERMs does not simply result in additive effects, as demonstrated by preclinical studies.^{15,17,28–32}

Molecular studies show that estrogens and SERMs alone and in combination each have unique gene expression profiles in a breast cancer cell line.^15,28 Microarray gene analysis studies showed both qualitative and quantitative changes in gene expression with the SERMs, BZA, RAL and LAS alone and combined with CE.^15,28

Further, preclinical studies show that not all SERMs have the same antagonist effects when combined with estrogens. In rat models, BZA alone was associated with a consistently lower uterine wet weight than with other SERMs, did not affect hot flushes in a rat hot flash model and maintained bone mass.^29,30 A later preclinical study found that BZA inhibited an estradiol-induced increase in uterine wet weight of ovariectomized mice, and was the most potent antagonist in the uterus compared with RAL and LAS.³¹ Additionally, BZA was the most effective inhibitor of CE-induced increases in uterine wet weight in rodent models compared with RAL and LAS.^17,32 In the breast, BZA was also shown to block the effects of estrogens. In the mouse mammary gland, investigators found that BZA reversed terminal end bud formation seen in response to 17β-estradiol.³¹ In addition, BZA was also the only SERM that inhibited an increase in the number of branch points and the degree of ductal tree invasion into the fat pad seen in response to CE in the mouse.³² In human breast cancer cells (MCF-7), BZA alone did not stimulate proliferation and potently antagonized 17β-estradiol-stimulated proliferation.³⁰

Clinical studies with BZA/CE

Study design and methods

The Selective estrogen Menopause And Response to Therapy (SMART) trials were randomized, double-blind, placebo- and active-controlled phase 3 studies designed to evaluate the safety and efficacy of BZA/CE in postmenopausal women. Detailed methodology and findings for the SMART-1 and -2 studies have been published and are summarized here.^33–37 The SMART-1 study was conducted at 94 centres in the USA, Europe and Brazil in healthy postmenopausal women aged 40–75 years with an intact uterus, body mass index ≤32.2 kg/m² and no evidence of endometrial hyperplasia at baseline.³³ Postmenopausal status was confirmed by cessation of menses for at least 12 months with follicle-stimulating hormone ≥30 mIU/mL and 17β-estradiol ≤50 pg mL.³³ Women were randomly assigned to take BZA 10, 20 or 40 mg combined with CE 0.625 mg or 0.45 mg; RAL 60 mg; or placebo for two years. A total of 3397 women were randomized and received at least one dose of study drug.³³

Incidence of endometrial hyperplasia at one year was a primary endpoint of the SMART-1 study that was analysed in the efficacy evaluable population (n = 2546; subjects who took at least one dose of study medication and had an endometrial biopsy at screening and during treatment). Endometrial biopsies were performed at screening and at 6, 12 and 24 months. An incidence of endometrial hyperplasia deemed acceptable was defined as ≤2%.³³

Mean percent change from baseline in lumbar spine BMD (assessed by dual-energy X-ray absorptiometry at baseline, 6, 12, 18 and 24 months) for BZA/CE versus placebo at 12 months was also a primary endpoint in SMART-1.^33,35 BMD effects were studied in two subpopulations: substudy I included women who were >5 years postmenopausal at 40 international sites and substudy II included women who were 1–5 years postmenopausal, enrolled at 25 international sites. Women in substudy I had to have a BMD T-score in the lumbar spine or total hip of –1 to –2.5 at screening and at least one other risk factor for osteoporosis; substudy II patients had to have at least one risk factor for osteoporosis.³⁵ BMD was analysed in the modified intent-to-treat (MITT) population, which included all women who took at least one dose of study medication, had a BMD measure at baseline and had at least one BMD measurement during therapy, using a last observation carried forward approach.³⁵

Secondary endpoints in the SMART-1 study on bone included changes in lumbar spine and total hip BMD for up to two years. Other secondary endpoints included the number and severity of hot flushes at four and 12 weeks (in a subpopulation of women who had at least 7 moderate-to-severe hot flushes per day or 50 per week [n = 261]), vaginal maturation and the incidences of amenorrhea and breast pain, which were assessed from data in daily diaries and vaginal smears.³⁴

Based on the endometrial safety results from SMART-1, BZA 20 mg/CE 0.625 and BZA 20 mg/CE 0.45 mg were chosen for subsequent studies. The effects of these doses on hot flush frequency and severity were studied in SMART-2, a randomized, double-blind, placebocontrolled study performed at 43 sites in the USA. Participants (n = 332) were healthy postmenopausal women aged 40–65 years with an intact uterus, who had at least seven moderate-to-severe hot flushes per day or 50 per week, and sought treatment for hot flushes.³⁷ All data on hot flushes were self-recorded in daily diaries. The primary endpoints were change from baseline in number and severity of hot flushes at four and 12 weeks. Secondarily, responder analyses were calculated.

Overall safety was monitored in both SMART-1 and -2 studies. As uterine bleeding and breast pain are two of the more common reasons women discontinue hormone therapy,^38,39 the effects of BZA/CE on uterine bleeding were evaluated in SMART-1 and the incidence of breast pain in SMART-1 and -2.^36,37 In the SMART-1 trial, women recorded bleeding and spotting in daily diaries. Amenorrhea (absence of bleeding/spotting) was also analysed in cumulative four-week intervals for two years in the MITT population, which included women who took at least one dose of the study drug and had at least one day of bleeding data during therapy.³⁶

Results of clinical studies with BZA/CE

Endometrial safety

In the SMART-1 study, the incidence of endometrial hyperplasia was ≤1% in placebo, RAL and all BZA/CE groups, except for BZA 10/CE 0.625 mg (Table 1). By 24 months, BZA/CE with 20 mg or 40 mg of BZA still protected against endometrial hyperplasia (incidence <1% each) similar to placebo and RAL. However, endometrial hyperplasia incidence increased with BZA 10 mg/CE 0.625 mg (7.14%) and BZA 10 mg/CE 0.45 mg (2.53%), both of which were significantly higher compared with incidence for placebo and RAL.³³ Thus, BZA 20 mg was the lowest effective dose that effectively prevented endometrial hyperplasia when added to CE 0.625 and CE 0.45 mg for up to two years.³³

Table 1

Incidence of endometrial hyperplasia after 12 months of therapy with BZA/conjugated estrogens

	Conjugated estrogens 0.625 mg			Conjugated estrogens 0.45 mg
	BZA 10 mg n = 341	BZA 20 mg n = 314	BZA 40 mg n = 311	BZA 10 mg n = 320	BZA 20 mg n = 336	BZA 40 mg n = 309
Total cases (%)	13 (3.81)*	1 (0.32)	0 (0.00)	3 (0.94)	0 (0.00)	0 (0.00)
95% CI (%)^†	2.27–5.99*	0.02–1.50	0.00–0.96	0.26–2.41	0.00–1.09^‡	0.00–1.19^‡

BZA, bazedoxifene; CI, confidence interval

Hyperplasia rate is not acceptable per study criteria

†

One-sided 95% CI

‡

One-sided 97.5% CI per stepwise procedure to adjust for simultaneous comparisons (BZA 20 and 40 mg combined with CE 0.45 mg) Adapted from Pickar et al.³³

Bone mineral density

Women who were more than five years from menopause (n = 1454) had a mean age of 58.5 years, were 11.1 mean years from menopause and had a T-score of –1.47.³⁵ Women 1–5 years from menopause (n = 861) had a mean age of 52.3 years, were 3.0 mean years from menopause and had a T-score of –0.83.³⁵

Adjusted mean percent changes in lumbar spine BMD significantly increased in all BZA/CE groups at most time points compared with baseline (P < 0.01) and at all time points compared with placebo (P < 0.001) in both substudies (Figure 1a and b). Additionally, most BZA/CE doses were significantly different from RAL at most time points (P < 0.05). In both substudies, mean annual percent changes from baseline were significantly greater with all BZA/CE doses than with placebo. In women >5 years from menopause, the range of changes was 0.51–1.59% for BZA/CE regimens versus –1.08% for placebo and 0.79% for RAL. Similarly, in women 1–5 years from menopause, these changes were 0.55–1.60% with BZA/CE and –1.41% for placebo and –0.07% for RAL. In addition, the rates of responders (women with no change or an increase in lumbar spine BMD at month 12 or 24) were significantly higher in all BZA/CE groups than for placebo at 12 and 24 months (P < 0.001) in both substudies.³⁵

Figure 1

Adjusted mean percent change in lumbar spine BMD from baseline to months 6, 12, 18 and 24 from the MITT population (LOCF) for osteoporosis prevention substudies I (a) and II (b). (a) P < 0.01 versus baseline for all BZA/CE groups at all time points; P < 0.001 versus placebo for all BZA/CE groups at all time points; P < 0.05 for BZA/CE versus raloxifene for all doses and at all time points, except for BZA 40/CE 0.625 or 0.45 at all time points and BZA 20/CE 0.45 at months 6 and 12. (b) P < 0.01 versus baseline for all BZA/CE groups at all time points, except for BZA/CE 40/CE 0.625 or 0.45 at months 6 and 12; P < 0.001 versus placebo for all BZA/CE groups at all time points; P < 0.05 BZA/CE versus raloxifene for all doses and at all time points, except for BZA 40/CE 0.625 or 0.45 at months 6 and 12 or months 6 and 18, respectively. Reprinted with permission from publisher.³⁵ BZA, bazedoxifene; CE, conjugated estrogen; BMD, bone mineral density; MITT, modified intent-to-treat; LOCF, last observation carried forward

For total hip BMD, all BZA/CE doses in both substudies had significantly greater adjusted mean percent changes at most time points versus baseline and at all time points compared with placebo (P < 0.05), and with some BZA/CE doses compared with RAL.³⁵ Therefore, all BZA/CE doses increased or maintained BMD at the lumbar spine and hip over two years in postmenopausal women at risk for osteoporosis.³⁵ It was noted, however, that the effects of BZA/CE on postmenopausal bone mass at the lumbar spine and hip were generally not as great with 40 mg of BZA combined with either dose of CE, compared with lower doses of BZA combined with CE.³⁵

Hot flushes

In the SMART-1 study, the mean change in daily number of moderate to severe hot flushes was significantly lower with all BZA/CE doses compared with placebo at most time points. All BZA/CE doses were significantly better (P < 0.05) than placebo for each week between weeks 5 and 12.³⁴ Mean reductions in hot flush severity from baseline were also significantly greater for BZA/CE groups with BZA 10 mg at both weeks 4 and 12, and with BZA 20 mg at week 12 compared with placebo (P < 0.001).³⁴ The higher, 40 mg dose of BZA tended to attenuate the effects of CE on hot flushes, similar to that seen on bone.³⁴

In the SMART-2 trial, both BZA/CE doses significantly improved the mean daily number and the daily severity of hot flushes from baseline (P < 0.001), and improvements were significantly greater than those with placebo at both 4 and 12 weeks (P < 0.001; Figure 2a and b).³⁷ Significant reductions in hot flush number compared with placebo were observed as early as week 3 with BZA 20 mg/CE 0.45 mg and week 2 for BZA 20 mg/CE 0.625 mg.³⁷ Table 2 shows the higher percent change in hot flush frequency for BZA/CE compared with placebo in both the SMART-1 and -2 trials. In SMART-2 at week 12, the percentages of women achieving a ≥50% and ≥75% decreases in the number of hot flushes were significantly greater in BZA/CE groups compared with those in the placebo group, respectively (P < 0.001; Table 2).³⁷

Figure 2

Mean daily number (a) and severity (b) of hot flushes with up to 12 weeks of treatment with BZA/CE or placebo. At week 2, the mean daily number of hot flushes with BZA 20 mg/CE 0.625 mg was statistically significant (P < 0.01) from placebo. Statistical significance (P < 0.01) was achieved for both doses of BZA/CE during weeks 3–12 compared with placebo. The mean daily severity score of hot flushes was statistically significant (P < 0.001) for both BZA/CE doses during weeks 3–12 compared with placebo. Reprinted with permission from publisher.³⁷ BZA, bazedoxifene; CE, conjugated estrogens

Table 2

Percent change in hot flushes/week and response analysis

	Percent change in mean daily number of hot flushes at 12 week	Percentage of subjects with 75% reduction in hot flush number	Percentage of subjects with 50% reduction in hot flush number
SMART-1 ³⁴
All BZA/CE doses, range	–52% to –86%	NA	NA
Placebo	–17%	NA	NA
SMART-2 ³⁷
All BZA/CE doses, range	–74% to –80%	61 %–73%	83%–86%
Placebo	–51%	27%	52%

BZA, bazedoxifene; CE, conjugated estrogen; SMART, Selective estrogen Menopause And Response to Therapy

Tolerability

The percentages of women with cumulative amenorrhea were similar for all BZA/CE doses containing 20 and 40 mg of BZA and were not significantly different than those with placebo over one year (Figure 3). Women taking these doses achieved cumulative amenorrhea rates of >83% for cycles 1–13 and > 93% for cycles 10–13.³⁶ In addition, BZA/CE doses with BZA 10 mg were associated with slightly lower rates of cumulative amenorrhea when compared with placebo during year 1 and year 2, and were significantly lower for BZA 10 mg/CE 0.625 mg versus placebo (P < 0.01).³⁶ These rates of amenorrhea were maintained through year 2.³⁶ Overall amenorrhea rates observed with BZA/CE³⁶ were greater than those with CE/medroxyprogesterone reported in the Women's HOPE Study (Figure 3).⁴⁰

Figure 3

Percentage of women with cumulative amenorrhea over one year in the SMART-1 study. Cumulative amenorrhea rates were similar to placebo for BZA/CE doses with 20 or 40 mg, and significantly lower than placebo for BZA 10 mg/CE 0.625 mg.³⁶ Data on CE/MPA are from the Women's HOPE study and are provided for relative comparisons.⁴⁰ BZA, bazedoxifene; CE, conjugated estrogens; MPA, medroxyprogesterone

Overall, the incidence of breast pain was not affected by BZA/CE in the SMART-1 and -2 studies. In SMART-1, the frequency of breast pain up to week 12 was similar among groups, and the incidence in any 28-day interval was not significantly different among the BZA/CE, RAL and placebo groups.³⁴ Similarly in SMART-2, the proportion of subjects reporting at least one day of breast pain was not significantly different between BZA/CE and placebo.³⁷ Additionally, the incidence of breast pain as collected by adverse events (AEs) was similar between BZA/CE and placebo in both studies.^34,37

Overall safety

In general, the overall safety of BZA/CE was supported by no significant differences between BZA/CE and placebo in AEs or discontinuations due to AEs (Table 3). The incidence of all treatment-emergent AEs (TEAEs) in SMART-1 did not differ significantly among the groups (P = 0.696).³⁴ Most TEAEs were mild to moderate and were considered by the investigators to be unrelated to the study drug.³⁴ The only most frequent TEAE that was significantly different among the treatment groups overall was muscle spasm.³⁴ There were also no significant differences among the treatment groups for the incidence of serious AEs, which ranged from 6% to 8% across groups.³⁴ The rate of AEs of endometrial hyperplasia was significantly higher for BZA/CE dose combinations containing BZA 10 mg versus placebo, which was consistent with the reported endometrial hyperplasia incidence with the BZA/CE doses containing BZA 10 mg.³³ Similar incidences of venous thromboembolism, myocardial infarction, and coronary artery disease and coronary artery insufficiency were reported between BZA/CE groups and placebo.³⁴ In SMART-2, no significant differences (P = 0.215) were noted among groups for any TEAE.³⁷

Table 3

Rates of overall adverse events and discontinuations

	Incidence of all AEs	Discontinuation rates due to AEs
SMART-1 ³⁴
All BZA/CE doses, range	90%–94%	10%–15%
Placebo	92%	14%
SMART-2 ³⁷
All BZA/CE doses, range	61%–67%	2%–4%
Placebo	73%	9%

BZA, bazedoxifene; CE, conjugated estrogen; SMART, Selective estrogen Menopause And Response to Therapy; AE, adverse event

One of the most common reasons for discontinuation was AEs in both the SMART-1 and 2 studies. The percentages of those who discontinued due to AEs were not significantly different between groups in the two-year SMART-1 study and in the 12-week SMART-2 study (Table 3).

Summary and conclusions

SERMs have been in development for many years and approved for a variety of indications, including postmenopausal osteoporosis, reduction of breast cancer risk and fertility treatments. Not all have successfully completed clinical development, and no SERM to date has met the goal of treating menopausal symptoms and osteoporosis in postmenopausal women. Recently, the TSEC, which pairs a SERM with estrogen(s), has been developed as a new paradigm for the treatment of menopausal symptoms and prevention of osteoporosis, with endometrial protection from unopposed estrogens. The clinical profile of a TSEC represents the blended activity of each of its components, resulting in an effective but more tolerable therapy than either of it components alone.

The reports reviewed here are the first phase 3 trials of a TSEC containing BZA/CE, which alleviated menopausal symptoms and maintained bone mass without stimulating the endometrium. Not all SERM–estrogen combinations will successfully treat menopausal symptoms in this manner. For example, while hot flushes were relieved when RAL was combined with oral⁴¹ or transdermal⁴² 17β-estradiol, or esterified CEs,⁴³ endometrial stimulation was also observed.

The SMART trials found that 20 mg of BZA was the lowest effective dose of BZA that prevented the endometrial hyperplasia observed with CE 0.625 and 0.45 mg. In the SMART studies, BZA 20 mg/CE 0.625 mg and BZA 20 mg/CE 0.45 mg significantly reduced hot flush frequency and severity, and increased or maintained bone mass, while at the same time not stimulating the endometrium, and had a good overall safety and tolerability profile compared with placebo. Those BZA/CE doses also had rates of amenorrhea and incidences of breast pain similar to those with placebo, unlike current hormonal therapies. In conclusion, SERMs, in addition to their use as single agents may also, in selected appropriate cases, be combined with estrogens (TSECs) for treating menopausal symptoms and postmenopausal loss of bone mass, without stimulating the endometrium.

Footnotes

Competing interests: James H Pickar, MD was formerly an employee of Wyeth, and has consulted for Wyeth and Depomed. Sebastián Mirkin, MD is an employee of Pfizer Inc. Medical writing support was provided by Kathleen Ohleth, PhD and Laura Ninger, ELS at Precise Publications, LLC, and was funded by Pfizer Inc.

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