Selective Estrogens, Menopause, And Response To Therapy Research Articles

Time to transient and stable reductions in hot flush frequency in postmenopausal women using conjugated estrogens/bazedoxifene.

This post hoc analysis estimates time to transient and stable reductions in hot flush frequency in postmenopausal women using conjugated estrogens/bazedoxifene. In the 12-week Selective estrogens, Menopause, And Response to Therapy (SMART)-2 trial of conjugated estrogens/bazedoxifene 0.45 mg/20 mg and 0.625 mg/20 mg, women with at least seven moderate/severe hot flushes per day or 50 per week at screening recorded frequency of moderate/severe hot flushes in diaries. Nonparametric models and SAS Proc Lifetest were used to estimate median times to various degrees of transient reductions (first day with improvement) and stable reductions (first day with improvement maintained through study's end) in hot flush frequency. Treatment produced transient hot flush reductions of 40% to 100% and stable reductions of 30% to 100% significantly faster than placebo. Median time to a transient 50% reduction was 8 days for conjugated estrogens/bazedoxifene 0.45 mg/20 mg, 9.5 for 0.625 mg/20 mg, and 10 for placebo; median time to a stable 50% reduction was 9, 10, and 38 days. Median time to a transient 90% reduction was 32 and 22.5 days for 0.45 mg/20 mg and 0.625 mg/20 mg, and median time to a stable 90% reduction was 83 and 29 days, respectively; median times to transient/stable 90% reductions were not reached during the 12-week study in the placebo group. Although not all women using conjugated estrogens/bazedoxifene achieve permanent elimination of hot flushes, the frequency is likely to be substantially reduced during the first week to month. Women can expect approximately 50% reduction in hot flush frequency after about 8 to 10 days, and sustained improvement with continued treatment.

An Overview of the Clinical Efficacy and Safety of Tissue Selective Estrogen Complex: From the Selective Estrogens, Menopause, and Response to Therapy (SMART) Trials

Hormone therapy (HT) is the most effective treatment for menopausal symptoms, and reduces both spinal and non-spinal postmenopausal osteoporotic fractures. However, a Women's Health Initiative (WHI) trial revealed that progestin-containing HT is associated with higher incidences of breast cancer and coronary heart disease than those associated with placebo. Tissue selective estrogen complex (TSEC) is a novel progestin-free HT option composed of conjugated estrogens (CE) and a selective estrogen receptor modulator. CE at a dose of 0.45 mg combined with 20 mg of bazedoxifene was the first TSEC medication approved in the United States and Korea for women with moderate to severe menopause-related vasomotor symptoms (VMS) and for preventing postmenopausal osteoporosis. This review summarizes the clinical efficacy, safety, and tolerability of TSEC as obtained from the five SMART clinical trials.

Pooled Analysis of the Effects of Conjugated Estrogens/Bazedoxifene on Vasomotor Symptoms in the Selective Estrogens, Menopause, and Response to Therapy Trials

Conjugated estrogens/bazedoxifene (CE/BZA) reduced menopause-related hot flashes (HFs) in the Selective estrogens, Menopause, And Response to Therapy (SMART) trials. This post hoc pooled analysis of SMART-1 and -2 further characterized effects of CE/BZA on HFs in the overall population and patient subgroups. Data from two randomized, double-blind, placebo- and active-controlled, phase 3 studies were pooled for nonhysterectomized postmenopausal women with moderate/severe HFs given CE 0.45 mg/BZA 20 mg, CE 0.625 mg/BZA 20 mg, or placebo for 12 weeks. HF frequency and severity were assessed by daily diary. The pooled analysis included 403 participants. At 12 weeks, CE 0.45 mg/BZA 20 mg and CE 0.625 mg/BZA 20 mg significantly (all p < 0.001) decreased moderate/severe HF frequency versus placebo (-7.9, -8.2, -4.1), reduced adjusted average daily HF severity score versus placebo (-1.0, -1.3, -0.3), increased the percentage of women who had a ≥50% (81.2%,87.1%, 50.6%) and ≥75% (62.4%, 74.8%, 26.4%) reduction from baseline in daily frequency of moderate/severe HFs, increased the percentage with ≥50% (38.3%, 58.1%, 11.0%) and ≥75% (24.2%, 38.1%, 5.5%) reductions in average daily HF severity score, and improved MENQOL vasomotor function versus placebo (adjusted mean change-3.08, -3.69, -1.37). CE/BZA was significantly more effective than placebo irrespective of time since menopause, with some evidence of a lower placebo response in women in later menopause (>5 years) versus early menopause (≤5 years). CE/BZA effectively reduces moderate/severe HFs in postmenopausal women. NCT#'s: NCT00675688; NCT00234819.

Bazedoxifene and Conjugated Equine Estrogen: A Combination Product for the Management of Vasomotor Symptoms and Osteoporosis Prevention Associated with Menopause.

Bazedoxifene (BZA), a third-generation selective estrogen receptor modulator (SERM), has been combined with conjugated equine estrogen (CE) to create a tissue selective estrogen complex (TSEC) for the management of vasomotor symptoms (VMS) and the prevention of osteoporosis (OP) associated with menopause. Both of these outcomes of menopause contribute to significant negative effects on quality of life and increases in utilization of health care resources and dollars. Current treatment modalities for VMS and OP include estrogen therapy that requires the use of progestin in women who have a uterus to reduce the risk of endometrial hyperplasia and resultant cancer. However, progestin use results in nuisance bleeding as well as a further increased risk of breast cancer when combined with estrogen. And while SERMs can be used to prevent OP, their use alone has been shown to increase hot flashes. The combination of BZA and CE does not require progestin treatment with CE as the BZA component acts as an antagonist on endometrial tissue. The U.S. Food and Drug Administration approval of BZA/CE in 2013 was based on a series of five phase 3 studies known as the Selective estrogens, Menopause And Response to Therapy (SMART) trials. These trials, in their entirety, evaluated the impact of BZA/CE on VMS frequency and severity, bone mineral density, bone turnover markers, vaginal symptoms, lipid profiles, sleep, quality of life, breast density, and endometrial safety. The approved dose of BZA/CE is 20 mg BZA and 0.45 mg CE. Although this TSEC manages VMS while opposing breast and endometrial proliferation, preventing bone resorption, and improving lipid profiles, long-term experience with BZA/CE is currently lacking.

The effect of conjugated estrogens/bazedoxifene therapy on body weight of postmenopausal women

This post hoc analysis compared body weight, body mass index (BMI), and BMI category changes in postmenopausal women treated with conjugated estrogens/bazedoxifene (CE/BZA) versus placebo in the Selective Estrogens, Menopause, and Response to Therapy (SMART) trials. Data were pooled from five randomized, double-blind, placebo- and active-controlled studies in postmenopausal women aged 40 to 75 years with a uterus given CE 0.45 mg/BZA 20 mg (n = 1,607), CE 0.625 mg/BZA 20 mg (n = 1,598), or placebo (n = 1,256) for at least 12 weeks and up to 2 years. Changes from baseline in body weight, BMI (kg/m(2)), and World Health Organization BMI category (underweight <18.5; normal 18.5 to <25; overweight 25 to <30; obese ≥30) during treatment were evaluated. Mean body weight increased less than 0.9 kg and mean BMI increased less than 0.4 kg/m(2) in all treatment groups at all time points. There were no statistically significant between-group differences, except for significantly greater increases in weight (P = 0.015) and BMI (P = 0.014) with placebo versus CE 0.625 mg/BZA 20 mg at month 12. Approximately, 10% of women in the CE/BZA groups and 11% in the placebo group had increases in body weight greater than 7% of baseline. The majority of BMI changes were within ±7%, and there were no statistically significant between-group differences in BMI category distributions during treatment. Significant increases in body weight or BMI were not observed in postmenopausal women receiving CE 0.45 mg/BZA 20 mg or CE 0.625 mg/BZA 20 mg for up to 2 years in the Selective Estrogens, Menopause, and Response to Therapy trials.

A Pooled Analysis of the Effects of Conjugated Estrogens/Bazedoxifene on Lipid Parameters in Postmenopausal Women From the Selective Estrogens, Menopause, and Response to Therapy (SMART) Trials.

Menopausal lipid profile changes may increase cardiovascular risk. The effects of conjugated estrogens (CE)/bazedoxifene (BZA), an approved menopausal therapy, on lipids have not been fully characterized. The purpose of this study was to determine the effects of CE/BZA on lipids in the Selective estrogens, Menopause, And Response to Therapy (SMART) trials for ≥ 1 year. This was a pooled analysis of 3 randomized, double-blind, placebo (PBO)-controlled phase 3 trials (SMART-1, -4, and -5). The study was conducted in North America, Europe, Asia-Pacific Region, and Latin America. Participants were nonhysterectomized postmenopausal women aged 40 to 75 years, not taking lipid-lowering medications (N = 2796). Treatments were CE 0.45 mg/BZA 20 mg, CE 0.625 mg/BZA 20 mg, and PBO. The adjusted mean percentage changes from baseline in total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), triglycerides, and the LDL-C/HDL-C ratio at 12 and 24 months were measured. At 12 months, CE 0.45 mg/BZA 20 mg and CE 0.625 mg/BZA 20 mg produced significant (P < .001) improvements vs PBO in TC (-4.20% and -4.37% vs -0.88%), LDL-C (-9.33% and -10.78% vs -1.08%), HDL-C (4.59% and 6.21% vs 1.30%), and the LDL-C/HDL-C ratio (-11.59% and -14.00% vs -0.84%). Triglycerides were significantly (P < .001) increased from baseline with both doses vs PBO (15.13% and 15.74% vs 4.43%). Similar trends (all P < .001) were seen at 24 months when SMART-1 and SMART-4 were pooled (TC: -3.25% and -3.13% vs 0.95%; LDL-C: -7.47% and -8.08% vs 2.95%; HDL-C: 5.91% and 7.19% vs 1.72%; triglycerides: 18.87% and 18.82% vs 6.49%; and the LDL-C/HDL-C ratio: -10.05% and -12.82% vs 2.56%). CE/BZA was associated with mostly favorable changes in lipid parameters for up to 2 years in nonhysterectomized postmenopausal women.

Evaluation of the direct and indirect effects of bazedoxifene/conjugated estrogens on sleep disturbance using mediation modeling

Mediation modeling was used to evaluate the direct effects of bazedoxifene (BZA)/conjugated estrogens (CE) on sleep, compared with its indirect effects via improvements in hot flushes, in postmenopausal women enrolled in the SMART (Selective estrogens, Menopause, And Response to Therapy)-2 and SMART-5 trials. Statistical mediation modeling estimated the direct effects of BZA/CE on sleep disturbance (Medical Outcomes Study sleep scale) and its indirect effects via hot flush improvement (item 1 of the Menopause-Specific Quality of Life questionnaire). In SMART-2, a total of 318 women with moderate to severe vasomotor symptoms (VMS) received BZA 20 mg/CE 0.45 mg, BZA 20 mg/CE 0.625 mg, or placebo; in SMART-5, a total of 1,843 women seeking menopausal symptom treatment received BZA 20 mg/CE 0.45 mg, BZA 20 mg/CE 0.625 mg, CE 0.45 mg/medroxyprogesterone acetate 1.5 mg, BZA 20 mg, or placebo. The SMART-5 sleep substudy enrolled 459 women with bothersome VMS and sleep disturbances. In SMART-2, BZA 20 mg/CE 0.45 mg and BZA 20 mg/CE 0.625 mg had a primarily direct effect on sleep in symptomatic women (64% and 66%, respectively; P < 0.001). Conversely, in the overall SMART-5 population, effects were primarily indirect (82% and 75% for BZA 20 mg/CE 0.45 mg and BZA 20 mg/CE 0.625 mg, respectively; P < 0.01), suggesting that sleep improvement was largely mediated via hot flush improvements. In a subpopulation of SMART-5 (participants with bothersome VMS), BZA 20 mg/CE 0.45 mg and BZA 20 mg/CE 0.625 mg affected sleep disturbance directly (82% and 76%, respectively; P < 0.0001). BZA/CE improves sleep in postmenopausal women with moderate to severe and milder VMS. This study suggests that improvements occur directly in women with moderate to severe VMS and indirectly in less symptomatic women.

Effects of Bazedoxifene/Conjugated Estrogens on the Endometrium and Bone: A Randomized Trial

This phase 3 study evaluated the endometrial safety of bazedoxifene (BZA)/conjugated estrogens (CE) and bone mineral density (BMD) effects vs BZA alone, hormone therapy, and placebo (PBO). The Selective estrogens, Menopause, And Response to Therapy (SMART)-5 trial was a multicenter, randomized, double-blind, PBO- and active-controlled study in postmenopausal women with an intact uterus (N = 1843; aged 40-65 years) seeking treatment for menopausal symptoms. Subjects received daily oral BZA 20 mg/CE 0.45 or 0.625 mg, BZA 20 mg, CE 0.45 mg/medroxyprogesterone acetate (MPA) 1.5 mg, or PBO. Primary endpoints were incidence of endometrial hyperplasia and percent change in lumbar spine BMD at 12 months. Secondary endpoints included additional osteoporosis parameters and assessments of tolerability and safety. At 12 months, endometrial hyperplasia incidence was low (<1%) and similar among groups. The BZA/CE group showed significantly greater increases in lumbar spine and total hip BMD vs decreases with PBO (P < .001); the CE/MPA group had increased lumbar spine BMD compared with that in the BZA/CE group. The BZA 20 mg/CE 0.45 and 0.625 mg groups had cumulative amenorrhea rates similar to those with PBO and BZA and significantly higher than those with CE 0.45 mg/MPA 1.5 mg (P < .001). The incidence of breast tenderness with BZA/CE was similar to that with PBO and BZA and significantly lower than with that with CE/MPA (P < .01). Although adverse event (AE) rates were similar among the groups, the incidence of serious AEs overall and AE-related discontinuation rates were higher with CE/MPA than with BZA/CE, BZA, or PBO. BZA/CE showed low rates of endometrial hyperplasia and improved lumbar spine and total hip BMD and was generally safe and well tolerated.

Evaluation of the Efficacy and Safety of Bazedoxifene/Conjugated Estrogens for Secondary Outcomes Including Vasomotor Symptoms in Postmenopausal Women by Years Since Menopause in the Selective Estrogens, Menopause and Response to Therapy (SMART) Trials

Bazedoxifene/conjugated estrogens (BZA/CE), a novel tissue-selective estrogen complex (TSEC), has been evaluated in the Selective estrogens, Menopause And Response to Therapy (SMART) trials. Secondary outcomes from these trials were evaluated to determine whether the effects of BZA/CE are influenced by years since menopause (YSM). SMART-1 and SMART-2 were randomized, double-blind, placebo (PBO)-controlled phase 3 trials in nonhysterectomized postmenopausal women. Outcomes were evaluated for women <5 or ≥5 YSM in SMART-1 (BZA 20 mg/CE 0.45 mg, n=433; BZA 20 mg/CE 0.625 mg, n=414; PBO, n=427) and SMART-2 (BZA 20 mg/CE 0.45 mg, n=127; BZA 20 mg/CE 0.625 mg, n=128; PBO, n=63). Hot-flush frequency and severity, health-related quality of life (HRQoL), sleep, treatment satisfaction, cumulative amenorrhea, and breast pain were assessed for each study individually, using defined statistical analysis protocols. For <5 and ≥5 YSM subgroups, BZA 20 mg/CE 0.45 and 0.625 mg showed significant decreases in hot-flush frequency and severity at 3 months compared with PBO (p<0.05 for both). Both BZA/CE doses showed significant improvements compared with PBO in HRQoL scores, sleep parameters, and satisfaction with treatment at 3 months irrespective of YSM (p≤0.05 vs. PBO for all). Similar to PBO, BZA/CE showed high proportions of cumulative amenorrhea (SMART-1) and low incidences of breast pain (SMART-1 and SMART-2) for women <5 and ≥5 YSM. The positive effects of BZA/CE on secondary outcomes were consistent among women <5 or ≥5 YSM.

Management of osteoporosis and menopausal symptoms: focus on bazedoxifene/conjugated estrogen combination

Loss of estrogen production in women during menopause results in a state of estrogen deficiency which has been associated with multiple problems, including vasomotor symptoms, symptoms of vulvovaginal atrophy, bone loss, and difficulties with sleep, mood, memory, and sexual activity. The only treatment option currently available to address multiple postmenopausal symptoms in women with an intact uterus is estrogen/progestin-containing hormone therapy (HT). Concerns surrounding side effects and published data regarding the association of HT with the increased risk for breast cancer have induced a decrease in the number of women seeking, initiating, and continuing this type of therapy. A combination containing bazedoxifene and conjugated estrogens (BZA/CE) maintains the established benefits of estrogen therapy for treatment of postmenopausal vasomotor symptoms, vulvovaginal atrophy, and osteoporosis, while certain estrogenic effects, such as stimulation of the uterus and breast, are antagonized without the side effects associated with HT. BZA/CE has been evaluated in a series of multicenter, randomized, double-blind, placebo-controlled, and active-controlled Phase III trials known as the Selective estrogens, Menopause, And Response to Therapy (SMART) trials. BZA/CE demonstrated clinically meaningful improvements in vasomotor symptoms, vulvovaginal atrophy, and a protective effect on the skeleton. These clinical benefits were associated with an acceptable safety profile and an improved tolerability compared with HT. BZA/CE showed a favorable safety profile on the breast, endometrium, and ovaries. The incidence of venous thromboembolism was low and the risk does not appear to be any greater than for CE alone or BZA alone or greater than HT. The incidence of coronary heart disease and cerebrovascular accidents were similar to placebo. The overall incidence of cancer (including breast cancer) was low and similar to placebo. The SMART trials demonstrate that BZA/CE is an alternative option for treating non-hysterectomized, symptomatic, postmenopausal women.

Effects of bazedoxifene/conjugated estrogens on endometrial safety and bone in postmenopausal women

ABSTRACTObjectives Bazedoxifene/conjugated estrogens (BZA/CE) has demonstrated efficacy in improving vasomotor and vulvar/vaginal atrophy symptoms in postmenopausal women. This study evaluated the endometrial safety of BZA/CE and effects on bone mineral density (BMD) compared with CE/medroxyprogesterone acetate (MPA) and placebo.Methods The Selective estrogens, Menopause, And Response to Therapy (SMART)-4 trial was a 1-year, multicenter, double-blind, randomized, placebo– and active-controlled, phase-3 study in non-hysterectomized, postmenopausal women (n = 1061; aged 40 −< 65 years). Subjects received BZA 20 mg/CE 0.45 or 0.625 mg, CE 0.45 mg/MPA 1.5 mg, or placebo daily. Primary endpoints were the incidence of endometrial hyperplasia and the change in lumbar spine BMD at 1 year. Secondary endpoints included the change in total hip BMD and rates of amenorrhea and breast pain.Results At 1 year, no cases of endometrial hyperplasia were identified in the BZA 20-mg/CE 0.45-mg group, while three cases (1.1%) were confirmed for the BZA 20-mg/CE 0.625-mg group (95% one-sided confidence interval upper limit < 4%). Both BZA/CE doses significantly increased lumbar spine and total hip BMD versus placebo (p ≤ 0.001) and showed low incidences of bleeding and breast tenderness, similar to placebo and significantly lower than for CE 0.45 mg/MPA 1.5 mg (p < 0.05). BZA/CE treatment was generally safe and well tolerated.Conclusions BZA 20 mg/CE 0.45 and 0.625 mg significantly improved BMD while maintaining endometrial safety and showed a favorable safety/tolerability profile over 1 year. BZA/CE may be a promising therapy for treating menopausal symptoms and preventing osteoporosis in non-hysterectomized, postmenopausal women.

The Tissue Selective Estrogen Complex: A Novel Approach to the Treatment of Menopausal Symptoms

Menopause-related health issues, including vasomotor symptoms, vulvar/vaginal atrophy, and osteoporosis, can decrease women's quality of life. Hormone therapy is the primary treatment option targeting both menopausal symptoms and bone loss but has been associated with some safety concerns. The tissue selective estrogen complex (TSEC) is a novel therapy, partnering a selective estrogen receptor modulator (SERM) with one or more estrogens. The pairing of bazedoxifene (BZA) with conjugated estrogens (CE) has been evaluated in the Selective estrogens, Menopause, And Response to Therapy (SMART) phase 3 trials. This article reviews key findings for BZA/CE and discusses its potential as a treatment option for postmenopausal women. A review of BZA/CE findings from the SMART trials was conducted based on relevant publications and presentations. BZA 20 mg/CE 0.45 and 0.625 mg have been shown to reduce hot flush frequency (by 74% and 80%, respectively, versus 51% for placebo [SMART-2 trial]) and severity, improve measures of vulvar/vaginal atrophy (SMART-3 trial), and prevent bone loss (mean percent change in lumbar spine bone mineral density [BMD] of 0.24 and 0.60, respectively, versus-1.28 for placebo [SMART-5 trial]) in postmenopausal women. These BZA/CE doses are associated with a favorable safety and tolerability profile, with high rates of cumulative amenorrhea and low incidences of breast pain. Overall, BZA/CE has been shown to be effective in relieving menopausal symptoms and preventing osteoporosis while maintaining endometrial and breast safety. BZA/CE is a unique TSEC and a promising option for postmenopausal women seeking a safe and comprehensive therapy.

Incorporating bazedoxifene/conjugated estrogens into the current paradigm of menopausal therapy

Many women experience bothersome vasomotor and vaginal symptoms during the menopausal transition. Decreasing levels of estrogens during menopause are also associated with reduced bone density and an increased risk of osteoporosis. Combined estrogen/progestin therapy (hormone therapy) effectively treats menopausal symptoms and prevents bone loss, but has been associated with some safety and tolerability concerns. A novel menopausal therapy is the tissue selective estrogen complex, which pairs a selective estrogen receptor modulator with one or more estrogens. In preclinical studies, the tissue selective estrogen complex partnering bazedoxifene (BZA) with conjugated estrogens (CE) antagonized stimulation of breast and endometrial tissue, reduced vasomotor instability, and preserved bone mass in rat and mouse models. The specific attributes seen with BZA/CE were different from those observed with other selective estrogen receptor modulator/estrogen pairings. BZA/CE has undergone clinical evaluation in the Phase III Selective estrogens, Menopause, And Response to Therapy (SMART) trials in postmenopausal women with an intact uterus. Of the various doses of BZA/CE evaluated, BZA 20 mg/CE 0.45 mg and 0.625 mg were associated with a low incidence of endometrial hyperplasia (<1%) similar to placebo, and showed significant improvements in hot flushes and vulvar/vaginal symptoms and increases in bone mineral density. BZA 20 mg/CE 0.45 mg and 0.625 mg were associated with a low incidence of breast-related adverse events and demonstrated no difference from placebo in age-related changes in mammographic breast density. Both BZA/ CE doses showed a favorable tolerability profile, with no increases in uterine bleeding or breast tenderness, and had positive effects on metabolic parameters and quality of life. BZA/CE may be a promising alternative to hormone therapy for the treatment of menopausal symptoms and prevention of osteoporosis in nonhysterectomized postmenopausal women.

The Tissue-Selective Estrogen Complex (TSEC): A Promising New Therapy for Menopausal Symptoms and Postmenopausal Osteoporosis

The menopausal transition may be associated with bothersome symptoms and increased risk of osteoporosis that can decrease quality of life for women. The primary treatment option is hormone therapy, which has been associated with some safety and tolerability concerns. The tissue-selective estrogen complex (TSEC) is a novel therapy that pairs a selective estrogen receptor modulator with one or more estrogens. The first TSEC in clinical development partners bazedoxifene (BZA) with conjugated estrogens (CE) and has been evaluated in the phase 3 Selective estrogens, Menopause, And Response to Therapy (SMART) trials. BZA 20 mg/CE 0.45 and 0.625 mg have been shown to be effective in reducing the frequency and severity of hot flushes and improving measures of vulvar/vaginal atrophy. These BZA/CE doses have also been shown to increase bone mineral density and reduce bone turnover without stimulating the endometrium and breast. BZA/CE represents a promising new therapy for postmenopausal women.

Smart trials: endometrial effects of the tissue selective estrogen complex (TSEC) comprised of bazedoxifene (BZA)/conjugated estrogens (CEs)

A TSEC partners a selective estrogen receptor modulator with estrogens to achieve clinical results based on their blended tissue-selective activity profile. The first TSEC pairs BZA with CE; we report results from the Selective estrogens Menopause And Response to Therapy (SMART) trials that evaluated its effect on the endometrium.

Smart trials: effects of a tissue selective estrogen complex (TSEC) comprised of bazedoxifene (BZA) and conjugated estrogens (CEs) on bone mineral density (BMD) in postmenopausal women

The first member of the TSEC class of menopausal therapy (pairing of a selective estrogen receptor modulator with estrogens) in clinical development pairs CE with BZA, a new selective estrogen receptor modulator with a unique endometrial profile. The effect of this combination on BMD was evaluated in 2 of the Selective estrogens Menopause And Response to Therapy (SMART) trials. Osteoporosis substudies of 2 randomized double-blind, placebo-controlled, multicenter, phase III trials—SMART-1 and SMART-4. SMART-1 trial randomized postmenopausal women (40–75 years) to 2 years of daily therapy with 6 doses of a TSEC comprised of BZA 10, 20, or 40 mg paired with CE 0.45 or 0.625 mg; raloxifene 60 mg (RLX); or placebo. Endpoints included the rate of endometrial hyperplasia and lumbar spine and hip BMD assessed by dual energy x-ray absorptiometry. SMART-4 trial, the first to compare BZA/CE with hormone therapy, randomized postmenopausal women (aged 40–64 years) to 2 years of daily therapy with 2 doses of a TSEC (BZA 20 mg/CE 0.45 or BZA 20 mg/CE 0.625 mg); hormone therapy (CE 0.45/medroxyprogesterone acetate 1.5 mg); or placebo. The primary endpoints were the rate of endometrial hyperplasia and prevention of osteoporosis at 1 year. SMART-1 osteoporosis substudy enrolled 2315 women (861 women ≤5 years postmenopause and 1454 women >5 years postmenopause). Among women ≤5 years postmenopause, the mean increase from baseline in lumber spine BMD at 2 years was significantly greater with all TSECs (range, 1.15%-2.61%) compared to RLX (0.15%; P<0.05) or placebo (−1.92%; P<0.001). Among women >5 years postmenopause, the increase from baseline in lumbar spine BMD at 2 years was significantly greater with TSECs containing BZA 10 and 20mg (range, 1.57%–2.42%) than with RLX (0.73%; P<0.05); all TSECs were significantly greater than placebo (−1.51%; P<0.001). Similar results were observed for hip BMD. Results will be also presented for the SMART-4 trial osteoporosis substudy, which enrolled >500 postmenopausal women (<5 years postmenopausal). BZA/CE, the first TSEC, significantly improves lumbar spine and hip BMD in postmenopausal women. Together with its favorable endometrial safety profile and efficacy for vasomotor symptoms (reported elsewhere), the clinical profile of BZA/CE may change the way women and physicians approach menopausal symptoms.