Oral lasofoxifene's effects on moderate to severe vaginal atrophy in postmenopausal women: two phase 3, randomized, controlled trials.

OBJECTIVE: The aim of this study was to demonstrate whether lasofoxifene improves vaginal signs/symptoms of genitourinary syndrome of menopause. METHODS: Two identical, phase 3 trials randomized postmenopausal women with moderate to severe vaginal symptoms to oral lasofoxifene 0.25 or 0.5 mg/d, or placebo, for 12 week. Changes from baseline to week 12 in most bothersome symptom, vaginal pH, and percentages of vaginal parabasal and superficial cells were evaluated. These coprimary endpoints were analyzed using analysis of covariance, except superficial cells, which were analyzed by the nonparametric, rank-based Kruskal-Wallis test. RESULTS: The two studies enrolled 444 and 445 women (mean age, ~60 y), respectively. Coprimary endpoints at week 12 improved with lasofoxifene 0.25 and 0.5 mg/d greater than with placebo ( P < 0.0125 for all). Study 1: most bothersome symptom (least square mean difference from placebo: -0.4 and -0.5 for 0.25 and 0.5 mg/d, respectively), vaginal pH (-0.65, -0.58), and vaginal superficial (5.2%, 5.4%), and parabasal (-39.9%, -34.9%) cells; study 2: most bothersome symptom (-0.4, -0.5), vaginal pH (-0.57, -0.67), and vaginal superficial (3.5%, 2.2%) and parabasal (-34.1%, -33.5%) cells. Some improvements occurred as early as week 2. Most treatment-emergent adverse events were mild or moderate and hot flushes were most frequently reported (lasofoxifene vs placebo: 13%-23% vs 9%-11%). Serious adverse events were infrequent and no deaths occurred. CONCLUSIONS: In two phase 3 trials, oral lasofoxifene 0.25 and 0.5 mg/d provided significant and clinically meaningful improvements in vaginal signs/symptoms with a favorable safety profile, suggesting beneficial effects of lasofoxifene on genitourinary syndrome of menopause.

Epigenetic and transcriptome responsiveness to ER modulation by tissue selective estrogen complexes in breast epithelial and breast cancer cells.

Selective estrogen receptor modulators (SERMs), including the SERM/SERD bazedoxifene (BZA), are used to treat postmenopausal osteoporosis and may reduce breast cancer (BCa) risk. One of the most persistent unresolved questions regarding menopausal hormone therapy is compromised control of proliferation and phenotype because of short- or long-term administration of mixed-function estrogen receptor (ER) ligands. To gain insight into epigenetic effectors of the transcriptomes of hormone and BZA-treated BCa cells, we evaluated a panel of histone modifications. The impact of short-term hormone treatment and BZA on gene expression and genome-wide epigenetic profiles was examined in ERαneg mammary epithelial cells (MCF10A) and ERα+ luminal breast cancer cells (MCF7). We tested individual components and combinations of 17ß-estradiol (E2), estrogen compounds (EC10) and BZA. RNA-seq for gene expression and ChIP-seq for active (H3K4me3, H3K4ac, H3K27ac) and repressive (H3K27me3) histone modifications were performed. Our results show that the combination of BZA with E2 or EC10 reduces estrogen-mediated patterns of histone modifications and gene expression in MCF-7ERα+ cells. In contrast, BZA has minimal effects on these parameters in MCF10A mammary epithelial cells. BZA-induced changes in histone modifications in MCF7 cells are characterized by altered H3K4ac patterns, with changes at distal enhancers of ERα-target genes and at promoters of non-ERα bound proliferation-related genes. Notably, the ERα target gene GREB1 is the most sensitive to BZA treatment. Our findings provide direct mechanistic-based evidence that BZA induces epigenetic changes in E2 and EC10 mediated control of ERα regulatory programs to target distinctive proliferation gene pathways that restrain the potential for breast cancer development.

Evaluation of endometrial progesterone receptor expression after 12 weeks of exposure to a low-dose vaginal estradiol insert.

OBJECTIVE: To evaluate endometrial progesterone receptor (PGR) expression in menopausal women who used vaginal 4-µg and 10-µg estradiol (E2) inserts or placebo. METHODS: REJOICE was a randomized, placebo-controlled trial investigating vaginal E2 inserts in women with moderate to severe dyspareunia due to menopause. In this post hoc analysis, 25 eligible women with endometrial biopsies were randomly selected from each treatment group (4-µg and 10-µg E2 vaginal inserts and placebo). Endometrial biopsy sections were immunostained using an anti-PR (A and B) monoclonal antibody. Cell staining was quantified using an artificial intelligence feature-recognition algorithm. Mean PGR expression levels were analyzed between baseline and week 12. RESULTS: PGR expression results were available for 22 women in the 4-µg E2 group, and 25 women each for the 10-µg E2 and placebo groups. Similar PGR expression levels were observed at baseline (0.301-0.470 pmol/mg) and after 12 weeks of treatment (0.312-0.432 pmol/mg) for all treatment groups, with no significant differences between baseline and week 12. CONCLUSIONS: No meaningful differences in endometrial PGR expression were observed with the vaginal E2 (4- and 10-µg) inserts at week 12 from baseline, supporting the hypothesis that local exposure to E2 from a low-dose, vaginal insert placed near the vaginal introitus will not be sufficient to upregulate endometrial PGR expression. Coupled with the lack of histologic changes and systemic absorption, our data suggest that these softgel vaginal E2 inserts would not be expected to stimulate endometrial hyperplasia leading to a potential endometrial safety issue in postmenopausal women with moderate to severe dyspareunia, a symptom of vulvar and vaginal atrophy. Further study on the endometrial safety of softgel vaginal E2 inserts is under way.

Lasofoxifene as a potential treatment for therapy-resistant ER-positive metastatic breast cancer.

BACKGROUND: Endocrine therapy remains the mainstay of treatment for estrogen receptor-positive (ER+) breast cancer. Constitutively active mutations in the ligand binding domain of ERα render tumors resistant to endocrine agents. Breast cancers with the two most common ERα mutations, Y537S and D538G, have low sensitivity to fulvestrant inhibition, a typical second-line endocrine therapy. Lasofoxifene is a selective estrogen receptor modulator with benefits on bone health and breast cancer prevention potential. This study investigated the anti-tumor activity of lasofoxifene in breast cancer xenografts expressing Y537S and D538G ERα mutants. The combination of lasofoxifene with palbociclib, a CDK4/6 inhibitor, was also evaluated. METHODS: Luciferase-GFP tagged MCF7 cells bearing wild-type, Y537S, or D538G ERα were injected into the mammary ducts of NSG mice (MIND model), which were subsequently treated with lasofoxifene or fulvestrant as single agents or in combination with palbociclib. Tumor growth and metastasis were monitored with in vivo and ex vivo luminescence imaging, terminal tumor weight measurements, and histological analysis. RESULTS: As a monotherapy, lasofoxifene was more effective than fulvestrant at inhibiting primary tumor growth and reducing metastases. Adding palbociclib improved the effectiveness of both lasofoxifene and fulvestrant for tumor suppression and metastasis prevention at four distal sites (lung, liver, bone, and brain), with the combination of lasofoxifene/palbociclib being generally more potent than that of fulvestrant/palbociclib. X-ray crystallography of the ERα ligand binding domain (LBD) shows that lasofoxifene stabilizes an antagonist conformation of both wild-type and Y537S LBD. The ability of lasofoxifene to promote an antagonist conformation of Y537S, combined with its long half-life and bioavailability, likely contributes to the observed potent inhibition of primary tumor growth and metastasis of MCF7 Y537S cells. CONCLUSIONS: We report for the first time the anti-tumor activity of lasofoxifene in mouse models of endocrine therapy-resistant breast cancer. The results demonstrate the potential of using lasofoxifene as an effective therapy for women with advanced or metastatic ER+ breast cancers expressing the most common constitutively active ERα mutations.

Initial investigation into the optimal dose ratio of conjugated estrogens and bazedoxifene: a double-blind, randomized, placebo-controlled phase 2 dose-finding study.

OBJECTIVE: The aim of the study was to explore dose-related endometrial effects of conjugated estrogens/bazedoxifene (CE/BZA). METHODS: In this randomized, double-blind, phase 2 study, 408 nonhysterectomized, symptomatic (with hot flushes [HFs]) postmenopausal women received ≥1 dose of CE 0.3 or 0.625 mg alone or with BZA 5, 10, or 20 mg/d; placebo; BZA 5 mg/d alone; or CE 0.625 mg with medroxyprogesterone acetate 2.5 mg/d for 84 days. The primary outcome was endometrial thickness on transvaginal ultrasound. HF frequency and severity based on diaries were key secondary outcomes. RESULTS: CE 0.625 mg alone increased endometrial thickness compared with placebo (mean 5.5 vs 2.95 mm, P < 0.001); BZA countered this in a dose-related manner such that average thickness with the addition of BZA 5, 10, and 20 mg was 5.99, 4.33, and 3.54 mm, respectively. On average, endometrium was significantly less thick with CE 0.625 mg/BZA 20 mg than CE 0.625 mg (P < 0.001) and CE 0.3 mg/BZA 20 mg versus CE 0.3 mg (2.94 vs 3.92 mm, P < 0.05); endometrial thickness was similar to placebo with CE 0.625 mg/BZA 20 mg. Lower BZA doses failed to reduce endometrial thickness relative to the same dose of CE alone. Regimens containing CE 0.625 mg reduced HF frequency and severity versus placebo; CE 0.3 mg with BZA 10 or 20 mg was ineffective. CONCLUSIONS: BZA ≥20 mg is needed to counter endometrial growth resulting from treatment with CE 0.3 or 0.625 mg. CE 0.3 mg inadequately controls HFs if given with BZA 20 mg.

Efficacy and safety of bazedoxifene in postmenopausal Latino women with osteoporosis.

OBJECTIVE: Bazedoxifene (BZA) reduces fractures and bone turnover in postmenopausal women with osteoporosis. This report evaluates safety and efficacy of BZA in Latin American women in the global trial. METHODS: In the 3-year, phase 3, randomized, double-blind trial, postmenopausal women with osteoporosis (N = 7,492) received BZA 20 or 40 mg/d, raloxifene 60 mg/d, or placebo. Outcomes included vertebral fractures, bone mineral density, bone turnover markers, and safety. This post hoc analysis included 3,036 Latin American women. RESULTS: Incidence of vertebral fractures at month 36 with BZA 20 mg, BZA 40 mg, raloxifene, and placebo was 1.87%, 1.90%, 1.43%, and 2.83%, respectively (differences not significant). Adjusted mean percentage increases in bone mineral density were 2.49%, 2.79%, 3.18%, and 1.26% for lumbar spine, and 0.40%, 0.95%, 1.11%, and -0.41% for total hip (P < 0.001 for BZA 20/40 mg vs placebo). Adjusted median percentage reductions in osteocalcin at month 12 were -43.0%, -44.1%, -46.9%, and -27.0%, and C-telopeptide were -50.7%, -53.4%, -57.6%, and -32.1% (P < 0.001 for BZA 20/40 mg vs placebo). Common adverse events included pain and flu syndrome. CONCLUSIONS: BZA significantly improved bone mineral density and reduced bone turnover, and numerically reduced fractures, compared with placebo in postmenopausal Latin American women with osteoporosis. Results were similar to the global trial.

Time to first occurrence of breast pain and vaginal bleeding in phase 3 trials of CE/BZA.

OBJECTIVE: In studies of the menopausal therapy, conjugated estrogens/bazedoxifene, breast pain and vaginal bleeding rates were comparable to placebo and lower than conjugated estrogens/medroxyprogesterone acetate (MPA). This post hoc analysis determined median time to occurrence of these events. METHODS: Participants in phase 3 conjugated estrogens/bazedoxifene trials recorded breast pain and vaginal bleeding in daily diaries. Median time to first incident was determined in women taking conjugated estrogens 0.45 mg/bazedoxifene 20 mg, conjugated estrogens 0.625 mg/bazedoxifene 20 mg, placebo, and conjugated estrogens 0.45 mg/MPA 1.5 mg (active control in Selective estrogens, Menopause, And Response to Therapy [SMART]-5 trial). We included on-treatment data (12 weeks-2 years) in healthy postmenopausal women (SMART-1), those seeking treatment for menopausal symptoms (SMART-5), and those with moderate/severe vasomotor symptoms (SMART-2). Analyses were performed using SAS Proc Lifetest. RESULTS: With conjugated estrogens/MPA as comparator, median time to breast pain was 299 days for conjugated estrogens/MPA, 353 for placebo, and more than 365 (median not reached) for conjugated estrogens 0.45 mg/bazedoxifene 20 mg and conjugated estrogens 0.625 mg/bazedoxifene 20 mg. Median time to vaginal bleeding was 314, 341, 357, and 362 days, respectively. Breast pain and vaginal bleeding survival curves were not significantly different for conjugated estrogens/bazedoxifene and placebo in any study, but were (P < 0.0001) when conjugated estrogens/MPA was added to the sample in SMART-5. CONCLUSIONS: The time course of breast pain and vaginal bleeding with conjugated estrogens/bazedoxifene was similar to that of placebo during treatment for up to 2 years. Events occurred significantly earlier with conjugated estrogens/MPA versus conjugated estrogens/bazedoxifene or placebo.

Hot flush frequency and severity at baseline as predictors of time to transient and stable treatment success: pooled analysis of two CE/BZA studies.

OBJECTIVE: To evaluate the impact of baseline hot flush frequency and severity on time to symptom improvement during treatment with conjugated estrogens/bazedoxifene (CE/BZA). METHODS: Data were pooled through week 12 from two randomized placebo-controlled trials (SMART-1 and SMART-2) of nonhysterectomized postmenopausal women with hot flushes treated with CE 0.45 mg/BZA 20 mg or CE 0.625 mg/BZA 20 mg. Time to transient and stable improvement (≥ 50% reduction in hot flush frequency/severity) was estimated using nonparametric models. RESULTS: Transient improvement in hot flush frequency occurred earlier in women treated with CE 0.45 mg/BZA 20 mg with less frequent versus more frequent baseline hot flushes per day: median time to transient improvement was 2, 7, and 11 days for women with < 3, 3 to < 8, and ≥ 8 hot flushes per day at baseline, respectively (P = 0.0009). Transient improvement in severity occurred earlier for women with less severe versus more severe baseline hot flushes: median time to transient improvement was 2, 6, and 16 days for women with mild, moderate, and severe hot flushes at baseline, respectively (P < 0.0001). Stable improvement typically occurred 2 to 3 days after the transient event and was less influenced by baseline status. A similar pattern was observed with CE 0.625 mg/BZA 20 mg treatment, though improvement occurred a few days earlier than with CE 0.45 mg/BZA 20 mg. CONCLUSION: Women with more frequent/severe hot flushes take longer to achieve transient improvements with CE/BZA and should be encouraged to continue treatment, as it may take longer than a few weeks to achieve significant improvement.

Relationship between changes in vulvar-vaginal atrophy and changes in sexual functioning.

OBJECTIVE: Conjugated estrogens/bazedoxifene (CE/BZA) has demonstrated benefit in vulvar-vaginal atrophy (VVA, part of genitourinary syndrome of menopause) and the sexual function domain of the Menopause-specific Quality of Life (MENQOL) questionnaire. The study's objective was to determine the relationship of VVA symptoms and clinical parameters with MENQOL sexual functioning in postmenopausal women receiving VVA treatment. STUDY DESIGN: Post hoc analysis data were derived from the 12-week SMART-3 trial, which evaluated CE/BZA's effect on VVA in nonhysterectomized postmenopausal women (aged 40-65 years) experiencing one or more moderate to severe VVA symptoms (dryness, itching/irritation, pain with intercourse) and vaginal pH>5.0 (N=664). MAIN OUTCOME MEASURES: Repeated measures models were used to determine relationships of VVA symptoms and clinical parameters (vaginal pH, parabasal/superficial cells) with sexual functioning; sensitivity analyses were performed to check assumptions of linearity. RESULTS: VVA symptoms showed an approximately linear relationship with sexual functioning. A 1-point improvement in pain on intercourse (which has a large effect size [ES]=0.85) corresponded to medium improvement (ES=0.57) in MENQOL sexual functioning. Equivalent improvements (in terms of ES) in dryness and itching/irritation corresponded to small to medium (ES=0.35) and small (ES=0.27) improvements in sexual functioning, respectively. The same ES improvement in clinical parameters corresponded to small-trivial improvements in sexual functioning. CONCLUSIONS: VVA symptoms have an approximately linear relationship with sexual functioning. Sexual functioning was most improved when pain on intercourse was reduced. Similar magnitudes of improvements in other VVA symptoms were linked with smaller, though potentially beneficial, improvements in sexual functioning. Changes in clinical parameters had only small or trivial associations with sexual functioning. Trial registration number NCT00238732.

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

OBJECTIVE: This post hoc analysis estimates time to transient and stable reductions in hot flush frequency in postmenopausal women using conjugated estrogens/bazedoxifene. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

Direct and indirect effects of conjugated estrogens/bazedoxifene treatment on quality of life in postmenopausal women.

OBJECTIVE: Determine the direct and indirect effects of conjugated estrogens/bazedoxifene (CE/BZA) treatment on menopause-specific quality of life in a post-hoc analysis of 2 phase 3 Selective estrogens, Menopause, And Response to Therapy (SMART-1, SMART-2) trials. STUDY DESIGN: Data from participants in SMART-1 and SMART-2 who received CE 0.45mg/BZA 20mg, CE 0.625mg/BZA 20mg, or placebo were analyzed, including week 12 data from 1274 healthy postmenopausal women in SMART-1 and pooled week 1-4 and 9-12 data from 332 women with moderate to severe vasomotor symptoms (≥7 HFs/d or ≥50/wk) in SMART-2. MAIN OUTCOME MEASURES: A statistical mediation model included treatment as a binary predictor variable (pooled active treatment vs placebo), Menopause-Specific Quality of Life (MENQOL) questionnaire domains (vasomotor, sexual, psychosocial, and physical function) as the outcomes variables, and frequency/severity of hot flushes (HFs) as treatment effect mediators on MENQOL. RESULTS: Vasomotor function was affected directly (SMART-1: 35.8%, P<0.05; SMART-2: 48.7%, P<0.05)] by CE/BZA and indirectly through improvements in HF severity (57.0%, P<0.05; 42.1%, P<0.05), and to a lesser extent, through reduction in HF frequency (7.2%, P<0.05; 9.2%, P<0.05). The effects of CE/BZA on the sexual, psychosocial, and physical function domains were fully mediated via improvements in HF severity. Final models for both studies were similar, indicating that direct and indirect effects of CE/BZA on menopause-specific quality of life are consistent and stable in different samples of women. CONCLUSIONS: CE/BZA affected the MENQOL vasomotor domain both directly and indirectly, whereas effects on other domains were fully mediated via HF severity reductions.

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

OBJECTIVES: 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. METHODS: 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. RESULTS: 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). CONCLUSIONS: CE/BZA effectively reduces moderate/severe HFs in postmenopausal women. NCT#'s: NCT00675688; NCT00234819.

CE/BZA effects on bone and quality of life in European postmenopausal women: a pooled analysis.

OBJECTIVES: To evaluate the efficacy of conjugated estrogens/bazedoxifene (CE/BZA) on bone mineral density (BMD), bone turnover markers (BTM), and menopause-specific quality of life (MENQOL) in European women. METHODS: Data through 12 months were pooled from two double-blind, randomized, controlled trials in non-hysterectomized postmenopausal women who received CE/BZA or placebo. Women from European study sites with evaluable BMD (n = 60), BTM (n = 56), and MENQOL questionnaire (n = 236) data were included and compared with 1523 women from US study sites (n = 730 with evaluable data for bone outcomes). RESULTS: At month 12, CE 0.45 mg/BZA 20 mg and CE 0.625 mg/BZA 20 mg, respectively, significantly improved BMD (adjusted difference vs. placebo) in lumbar spine (2.5%, 2.9%; both p ≤ 0.011) and total hip (1.7%, 2.2%, both p ≤ 0.002), significantly improved serum BTMs (osteocalcin: -31.1%, -33.1%; C-telopeptide: -48.5%, -36.8%) vs. placebo (osteocalcin: 6.7%, C-telopeptide: 4.2%; all p < 0.001), and significantly improved MENQOL vasomotor function scores (-2.1, -2.2) vs. placebo (-0.7; both p < 0.001). No significant treatment × subpopulation interactions were observed for any of the outcomes. CONCLUSIONS: Twelve-month CE/BZA treatment prevented bone loss and improved vasomotor function in European postmenopausal women. Findings were similar to those in the subpopulation of women enrolled at US study sites.

Most bothersome symptom in women with genitourinary syndrome of menopause as a moderator of treatment effects.

OBJECTIVE: Conjugated estrogens/bazedoxifene (CE/BZA) is indicated to treat moderate/severe menopausal vasomotor symptoms and prevent postmenopausal osteoporosis. This analysis examines the impact of the most bothersome vaginal symptom at baseline on effects of CE/BZA. METHODS: This post hoc analysis used data from a 12-week clinical trial of nonhysterectomized postmenopausal women (n = 664) randomly assigned to double-blind treatment with CE/BZA (0.45/20 mg and 0.625/20 mg), BZA 20 mg, or placebo. At baseline, women indicated which moderate/severe vaginal symptom (dryness, itching/irritation, or pain with intercourse) bothered them most. Repeated measures models were used to explore treatment effects in relationship to the most bothersome symptom. We calculated effect sizes for treatment differences versus placebo (effect sizes: trivial, 0.1; small, 0.2; medium, 0.5; large, 0.8). RESULTS: At baseline, 52% of women selected pain with intercourse, 35% selected vaginal dryness, and 13% selected vaginal itching/irritation as most bothersome. For these three symptom groups respectively, CE/BZA was associated with statistically significant improvements in Menopause-Specific Quality of Life sexual functioning (effect size: 0.45/20 mg, -0.36, -0.30, -0.67; 0.625/20 mg, -0.37, -0.40, -0.26) and/or overall score (effect size: 0.45/20 mg, -0.29, -0.41, -0.78; 0.625/20 mg, -0.41, -0.48, -0.68). Both those doses significantly improved the ease of lubrication item on the Arizona Sexual Experiences Scale in those with pain with intercourse (effect size: 0.45/20 mg, -0.43; 0.625/20 mg, -0.50) and produced some statistically significant improvements in vaginal cell counts in women with dryness or pain with intercourse as the most bothersome symptom. The higher dose was associated with greater treatment satisfaction on the Menopause Symptoms Treatment Satisfaction Questionnaire versus placebo in women who selected pain with intercourse (effect size: 0.40) or dryness (effect size: 0.43) as most bothersome. CONCLUSIONS: The approved dose of CE/BZA had clear benefits, particularly in women with pain with intercourse (the most common bothersome symptom), in whom it improved lubrication, superficial cell counts, and sexual functioning.

Relationship between changes in vasomotor symptoms and changes in menopause-specific quality of life and sleep parameters.

OBJECTIVE: This study characterizes and quantifies the relationship of vasomotor symptoms (VMS) of menopause with menopause-specific quality of life (MSQOL) and sleep parameters to help predict treatment outcomes and inform treatment decision-making. METHODS: Data were derived from a 12-week randomized, double-blind, placebo-controlled phase 3 trial that evaluated effects of two doses of conjugated estrogens/bazedoxifene on VMS in nonhysterectomized postmenopausal women (N = 318, mean age = 53.39) experiencing at least seven moderate to severe hot flushes (HFs) per day or at least 50 per week. Repeated measures models were used to determine relationships between HF frequency and severity and outcomes on the Menopause-Specific Quality of Life questionnaire and the Medical Outcomes Study sleep scale. Sensitivity analyses were performed to check assumptions of linearity between VMS and outcomes. RESULTS: Frequency and severity of HFs showed approximately linear relationships with MSQOL and sleep parameters. Sensitivity analyses supported assumptions of linearity. The largest changes associated with a reduction of five HFs and a 0.5-point decrease in severity occurred in the Menopause-Specific Quality of Life vasomotor functioning domain (0.78 for number of HFs and 0.98 for severity) and the Medical Outcomes Study sleep disturbance (7.38 and 4.86) and sleep adequacy (-5.60 and -4.66) domains and the two overall sleep problems indices (SPI: 5.17 and 3.63; SPII: 5.82 and 3.83). CONCLUSIONS: Frequency and severity of HFs have an approximately linear relationship with MSQOL and sleep parameters-that is, improvements in HFs are associated with improvements in MSQOL and sleep. Such relationships may enable clinicians to predict changes in sleep and MSQOL expected from various VMS treatments.

Effect of conjugated estrogens/bazedoxifene on postmenopausal bone loss: pooled analysis of two randomized trials.

OBJECTIVE: Conjugated estrogens/bazedoxifene reduces vasomotor symptoms and prevents postmenopausal bone loss without stimulating the breast and endometrium. We analyzed changes in bone mineral density (BMD) and bone markers using pooled data from two phase-3 trials. METHODS: Selective Estrogens, Menopause, and Response to Therapy (SMART)-1 and SMART-5 were randomized, double-blind, placebo- and active-controlled studies conducted in postmenopausal nonhysterectomized women. BMD and turnover marker data were pooled for women given conjugated estrogens (0.45 or 0.625 mg) plus bazedoxifene 20 mg or placebo over 12 months. Sensitivity analyses were conducted using baseline Fracture Risk Assessment Tool score, age, years since menopause, body mass index, race, and geographic region. RESULTS: There were 1,172 women, mean age 54.9 years, mean 6.21 years since menopause, mean lumbar spine, and total hip T scores -1.05 and -0.58; 58.8% had a Fracture Risk Assessment Tool score less than 5% indicating low fracture risk. At 12 months, adjusted differences (vs placebo) in BMD change in the groups taking conjugated estrogens 0.45 or 0.625 mg plus bazedoxifene 20 mg were 2.3% and 2.4% for lumbar spine, 1.4% and 1.5% for total hip, and 1.1% and 1.5% for femoral neck (all P < 0.001 vs placebo). These increases were unrelated to baseline Fracture Risk Assessment Tool score, age, years since menopause, body mass index, or geographic region. Both doses reduced bone turnover markers (P < 0.001). CONCLUSIONS: Conjugated estrogens/bazedoxifene significantly improved BMD and turnover in a large population of younger postmenopausal women at low fracture risk and is a promising therapy for preventing postmenopausal bone loss.

Timing and persistence of effect of conjugated estrogens/bazedoxifene in postmenopausal women.

OBJECTIVE: The aim of the study was to determine the time course of effect with conjugated estrogens/bazedoxifene (CE/BZA) in nonhysterectomized postmenopausal women in five phase 3 trials. METHODS: This post hoc analysis identified when CE 0.45 mg/BZA 20 mg and CE 0.625 mg/BZA 20 mg first achieved a statistically significant difference (P < 0.05) versus placebo in individual trials and the duration the difference persisted for prespecified efficacy endpoints. RESULTS: CE/BZA significantly reduced hot flush frequency beginning at weeks 2 to 4 and severity at weeks 3 to 6; benefits were maintained through month 24. Significant improvements in lumbar spine, total hip, femoral neck, and femoral trochanter bone mineral density were evident at month 6 or 12 and changes in bone turnover markers at month 3 or 6; benefits were maintained throughout the studies (12 or 24 mo). In symptomatic women with less than 5% vaginal superficial cells at baseline, vaginal maturation index was significantly improved by week 4. Reductions in parabasal cells were maintained throughout the studies (through months 3 and 24), but superficial cell count changes persisted only with the higher CE/BZA dose. Menopause-Specific Quality of Life total and vasomotor domain scores were improved at all assessments, from months 3 through 24. Some measures of sleep, especially quality and time to fall asleep, improved during weeks 4 to 8 and were maintained in a majority of weeks thereafter. CONCLUSIONS: In the context of studies designed primarily to evaluate efficacy at final study endpoints, both doses of CE/BZA achieved significance versus placebo at early assessments for most outcomes, and benefits were well maintained.

Conjugated estrogens and bazedoxifene in minority populations: pooled analysis of four phase 3 trials.

OBJECTIVE: The aim of the study was to compare efficacy of conjugated estrogens (CE)/bazedoxifene (BZA) for treatment of menopausal symptoms and prevention of postmenopausal osteoporosis in minorities (black/Hispanic) versus whites. METHODS: In a post hoc analysis, data were pooled from 3,424 white or minority nonhysterectomized postmenopausal women randomized to CE 0.45 or 0.625 mg/BZA 20 mg or placebo in four double-blind, phase 3 Selective Estrogens, Menopause, and Response to Therapy (SMART) trials. Outcomes included hot flush frequency/severity (daily diary) in women with at least seven moderate-to-severe hot flushes per day (SMART-1, -2), vaginal cytology in women with at most 5% superficial cells (SMART-1, -3), lumbar spine and total hip bone mineral density (BMD) (SMART-1, -5), and the Menopause-Specific Quality of Life (MENQOL) questionnaire (SMART-1, -2, -3, -5). RESULTS: The analysis included 2,907 white (84.9%), 315 black (9.2%), and 202 Hispanic (5.9%) women. The reduction in hot flush frequency/severity versus placebo (P < 0.05; week 12) was similar in white and minority women. In both populations, both doses significantly (P < 0.05 vs placebo) improved MENQOL vasomotor function, sexual function, and total scores at 3 months; decreased the percentage of parabasal cells at 2 years; and increased the percentage of BMD responders at 12 and 24 months. Significant differential treatment effects by race/ethnicity were observed only for effects on vaginal superficial cells at month 24 and vaginal pH at month 3. CONCLUSIONS: Notwithstanding a limited sample size, CE/BZA had a similar and beneficial impact on hot flushes, MENQOL, and BMD in minorities and whites.

Gynecologic Safety of Conjugated Estrogens Plus Bazedoxifene: Pooled Analysis of Five Phase 3 Trials.

OBJECTIVE: To evaluate gynecologic safety of conjugated estrogens/bazedoxifene treatment for menopausal symptoms and osteoporosis prevention in nonhysterectomized women. MATERIALS AND METHODS: We pooled data from five randomized, placebo-controlled trials of conjugated estrogens 0.625 mg/bazedoxifene 20 mg (n = 1583), conjugated estrogens 0.45 mg/bazedoxifene 20 mg (n = 1585), and placebo (n = 1241). Gynecologic safety was evaluated by pelvic examination, Papanicolaou smear, endometrial biopsy, transvaginal ultrasound, mammogram, adverse events, and diary records of vaginal bleeding and breast pain/tenderness. Incidence rates and relative risks (RR) versus placebo were calculated with inverse variance weighting. Data for conjugated estrogens 0.45 mg/medroxyprogesterone acetate 1.5 mg, an active comparator in two trials (n = 399), are included for comparison. RESULTS: Endometrial hyperplasia occurred in <1% (n = 4 [0.3%], 2 [0.2%], 1 [0.5%], and 2 [0.2%] for conjugated estrogens 0.625 mg/bazedoxifene 20 mg, conjugated estrogens 0.45 mg/bazedoxifene 20 mg, conjugated estrogens/medroxyprogesterone acetate, and placebo). There was one endometrial cancer, which occurred with conjugated estrogens 0.45 mg/bazedoxifene 20 mg (0.44/1000 woman-years [95% confidence interval (CI), 0.00-2.37]; RR versus placebo 0.91 [95% CI, 0.17-4.82]). There were seven cases of breast cancer: four with conjugated estrogens 0.45 mg/bazedoxifene 20 mg (1.00/1000 woman-years [95% CI, 0.00-3.21] RR 1.11 [95% CI, 0.33-3.78]), two with placebo, and one with conjugated estrogens/medroxyprogesterone acetate. Unlike conjugated estrogens/medroxyprogesterone acetate, conjugated estrogens/bazedoxifene did not increase breast density, breast pain/tenderness, or vaginal bleeding versus placebo. No active treatment increased ovarian cysts. CONCLUSION: Conjugated estrogens/bazedoxifene provides endometrial protection without increasing breast pain/density, vaginal bleeding, or ovarian cysts in nonhysterectomized postmenopausal women studied up to 2 years.

Efficacy and tolerability of bazedoxifene in Mexican women with osteoporosis: a subgroup analysis of a randomized phase 3 trial.

OBJECTIVE: Bazedoxifene (BZA) is a selective estrogen receptor modulator that reduces fracture risk and bone turnover in postmenopausal women with osteoporosis. This analysis evaluated BZA's effects on bone mineral density (BMD) and bone turnover in Mexican women with osteoporosis from the global pivotal trial (Study Evaluating Bazedoxifene Acetate in Osteoporosis in Postmenopausal Women). METHODS: In this 3-year, phase 3, randomized, double-blind trial, healthy postmenopausal women with osteoporosis (N = 7,492) received BZA 20 or 40 mg/d, raloxifene 60 mg/d, or placebo. The subanalyses of Mexican women assessed serum concentrations of osteocalcin and collagen type 1 C-telopeptide, BMD, and tolerability with BZA 20 mg/d versus placebo. RESULTS: In the Mexican subgroup (BZA, n = 39; placebo, n = 37) at month 12, BZA 20 mg/d produced significant (P < 0.001) percentage decreases from baseline in osteocalcin (-40.5 vs -18.5) and C-telopeptide (-45.7 vs -29.4). For BZA versus placebo, percentage change in BMD from baseline to month 36 was 3.3 versus 0.64 for lumbar spine, -0.18 versus -1.8 for total hip, 0.21 versus -2.6 for femoral neck, and -0.55 versus -1.4 for femoral trochanter; differences were not statistically significant. Results were comparable to the overall study population in which differences were statistically significant. Common adverse events (≥20%) included arthralgia, back pain, gastritis, headache, influenza, and pain; none led to study withdrawal. CONCLUSIONS: In Mexican women with osteoporosis, BZA was well tolerated and seems to produce BMD changes comparable to the global phase 3 population, although differences versus placebo were not statistically significant in this smaller subgroup.