No increase in incidence or risk of recurrence of breast cancer in ospemifene-treated patients with vulvovaginal atrophy (VVA).

OBJECTIVE: To estimate the incidence and recurrence of breast cancer (BC) in patients with vulvovaginal atrophy (VVA) treated with ospemifene and matched untreated VVA patients using real-world data. STUDY DESIGN: Retrospective matched cohort study. MAIN OUTCOME MEASURES: VVA patients were identified from the 2011-2018 US MarketScan® insurance claims database. For incidence, ospemifene-treated VVA patients without evidence of BC prior to index treatment were matched to two untreated VVA controls similarly without history of BC on age, index VVA year, geographic region, Charlson Comorbidity categories, and follow-up time. BC after the index treatment was identified by BC diagnosis codes, mastectomy, chemotherapy, or radiation procedure. Incidence rate, rate ratio (RR) and their 95 % confidence intervals (CI) were calculated. The process was repeated to estimate BC recurrence in patients with a history of BC in 1:1, 1:2 and 1:3 matches. RESULTS: 1728 ospemifene users and 3456 untreated patients met the inclusion and matching criteria for assessing incidence. The average number of days for which ospemifene was supplied was 314 (standard deviation [SD] = 340). Average follow-up time from index treatment was 937 days (SD = 392) for treated patients and 915 days (SD = 396) for controls. BC incidence rates per 1000 person-years was 2.03 (95 % CI: 1.06-3.91) for treated patients and 3.53 (95 % CI: 2.49-4.99) for controls (RR = 0.58, 95 % CI: 0.28-1.21). No difference in recurrence was observed between ospemifene-treated and matched untreated patients. Ten (32.3 %) treated vs. 25 (40.3 %) controls in the 1:2 matched analysis had a recurrence. CONCLUSION: No differences were observed in the BC incidence and recurrence rates in ospemifene users compared with matched controls.

Effects of ospemifene on genitourinary health assessed by prospective vulvar-vestibular photography and vaginal/vulvar health indices.

OBJECTIVE: To prospectively evaluate the effects of ospemifene on the vulva and vagina in postmenopausal women using vulvar-vestibular photography and direct visual assessments. METHODS: Postmenopausal women (aged 40-80 years) with moderate to severe vaginal dryness as their most bothersome symptom (MBS) were randomized to daily ospemifene 60 mg or placebo in this 12-week, multicenter, double-blind, phase 3 study. Vulvar-vestibular photographic images were captured at baseline and week 12 and were independently assessed with the Vulvar Imaging Assessment Scale (VIAS). Changes from baseline in Vaginal and Vulvar Health Indices (VHI and VuHI) with ospemifene versus placebo were analyzed at weeks 4, 8, and 12. Correlations between VIAS, VHI, and VuHI, with vaginal dryness severity and the Female Sexual Function Index (FSFI) scores were also assessed. RESULTS: In all, 631 eligible participants were randomized (ospemifene 316, placebo 315) and included in the intention-to-treat population. Compared with placebo, ospemifene significantly improved total scores for VIAS (P = 0.0154), VHI (P < 0.0001), and VuHI (P < 0.0001) from baseline to week 12; significant VHI (P < 0.0001) and VuHI (P = 0.002) improvements were observed at week 4. Most VHI and VuHI individual items were significantly better with ospemifene versus placebo at week 12 (P < 0.05). Most correlations between the vulvovaginal assessment total scores versus vaginal dryness severity and FSFI scores were significant (P < 0.05). CONCLUSION: Improvements observed in vulvovaginal health with ospemifene assessed by prospective vulvar-vestibular photography and other direct visual assessments support its efficacy in addition to the treatment of moderate to severe vaginal dryness due to menopause and the use of photographic and direct visual evaluations in future clinical trials. VIDEO SUMMARY: Supplemental Digital Content 1, http://links.lww.com/MENO/A415.

Efficacy and safety of ospemifene in postmenopausal women with moderate-to-severe vaginal dryness: a phase 3, randomized, double-blind, placebo-controlled, multicenter trial.

OBJECTIVE: To evaluate the safety and efficacy of ospemifene for the treatment of moderate to severe vaginal dryness in postmenopausal women with vulvovaginal atrophy (VVA). METHODS: This 12-week, multicenter, double-blind phase 3 study randomized postmenopausal women (aged 40-80 years) with VVA and moderate to severe vaginal dryness as their most bothersome symptom to daily oral ospemifene 60 mg or placebo. Coprimary efficacy endpoints included changes from baseline to week 12 in percentages of vaginal parabasal and superficial cells, vaginal pH, and vaginal dryness severity with ospemifene versus placebo; other secondary endpoints were evaluated (weeks 4, 8, and 12). Safety was assessed by treatment-emergent adverse events (TEAEs) and endometrial biopsies. RESULTS: Women (n = 631; ospemifene [n = 316], placebo [n = 315]) had a mean age of 59.8 years, a mean body mass index of 27.2 kg/m, and most were white. Ospemifene significantly improved (P < 0.0001) the percentages of parabasal and superficial cells, vaginal pH, and severity of vaginal dryness severity compared with placebo at week 12; significant between-group differences were noted by week 4. Secondary endpoints of dyspareunia (P < 0.001), maturation value (P < 0.0001), and the Female Sexual Function Index (P < 0.05) also significantly improved with ospemifene versus placebo at week 12. Significantly more women responded (31.5% vs 6.0%; P < 0.0001) or were satisfied (49.2% vs 33.8%; P = 0.0007) with ospemifene versus placebo at week 12. No unexpected TEAEs, treatment-related serious TEAEs, thrombotic events, or endometrial hyperplasia or carcinoma were observed. CONCLUSIONS: Ospemifene was effective and well tolerated for the treatment of moderate-to-severe vaginal dryness in postmenopausal women with VVA.

Overall Safety of Ospemifene in Postmenopausal Women from Placebo-Controlled Phase 2 and 3 Trials.

OBJECTIVE: To evaluate the safety of daily oral ospemifene 60 mg, estrogen agonist/antagonist, used to treat moderate-to-severe dyspareunia due to postmenopausal vulvovaginal atrophy, which is part of genitourinary syndrome of menopause. METHODS: Post hoc analysis of safety data (treatment-emergent adverse events [TEAEs]) pooled from six phase 2 and 3 randomized, double-blind, multicenter placebo-controlled studies, evaluating the effects of ospemifene 60 mg on the breast, cardiovascular system, and bone in postmenopausal women. RESULTS: At least one TEAE was reported by 67.6% (840/1242) and 54.1% (518/958) of women taking ospemifene 60 mg and placebo, respectively. Most TEAEs were mild or moderate and occurred within 4 to 12 weeks. The most commonly reported TEAEs with ospemifene were hot flush (8.5% vs. 3.3% for placebo) and urinary tract infection (6.5% vs. 4.8%). Discontinuation due to TEAEs was 7.6% with ospemifene and 3.8% with placebo. Most women discontinued treatment due to adverse events (AEs): hot flushes, muscle spasms, headache, and vaginal discharge. Serious AEs occurred infrequently (ospemifene, 2.6%; placebo, 1.8%); most were not considered related to treatment. Breast cancer and other breast-related TEAE incidences were comparable between ospemifene (2.5%) and placebo (2.2%), and cardiovascular TEAE incidence, including deep vein thrombosis, was low with ospemifene (0.3%) and placebo (0.1%). CONCLUSION: No unexpected safety signals were reported, and discontinuation due to TEAEs was low, with use of ospemifene 60 mg versus placebo in six phase 2 and 3 trials, suggesting a lack of detrimental effects on the breast, bone, and cardiovascular health of postmenopausal women when ospemifene is used to effectively treat moderate-to-severe postmenopausal dyspareunia.

Ospemifene's effects on lipids and coagulation factors: a post hoc analysis of phase 2 and 3 clinical trial data.

OBJECTIVE: To evaluate the effect of ospemifene 60 mg on the lipid and coagulation parameters of postmenopausal women using data from five phase 2 and 3 clinical trials. METHODS: Data for lipids and coagulation factors for 2,166 postmenopausal women were pooled from five randomized, placebo-controlled studies. Lipid and coagulation parameters included in this analysis were total cholesterol, high-density lipoproteins (HDL), low-density lipoproteins (LDL), triglycerides, activated partial thromboplastin time (aPTT), fibrinogen, antithrombin antigen, protein C Ag, and protein S Ag free. RESULTS: Mean percent changes in HDL and LDL were significantly greater with ospemifene versus placebo at month 3 (HDL: 4.4% vs 0.2%; LDL: -5.2% vs 2.4%), month 6 (HDL: 5.1% vs 1.5%; LDL: -6.7% vs 2.4%), and month 12 (HDL: 2.3% vs -1.9%; LDL: -7.0% vs -2.1%; P < 0.05, for all comparisons). Ospemifene significantly reduced total cholesterol at 6 months (-1.8% vs 1.6%; P = 0.0345 versus placebo), and changes in triglycerides with ospemifene were similar to placebo at all three time points. In subgroup analyses based on age, body mass index, and baseline triglyceride level, ospemifene increased HDL and decreased LDL, but had no significant effect on total cholesterol and triglycerides relative to placebo. Ospemifene significantly improved fibrinogen and protein C antigen levels relative to placebo at months 3 (-8.7% vs -0.8% and -2.7% vs 0.5%, respectively), 6 (-6.0% vs 6.7% and -3.6 vs 8.0%), and 12 (-8.7% vs 7.3% and -4.5% vs 6.6%; P < 0.01, for all). The levels of all coagulation factors remained within the normal range throughout the studies. CONCLUSION: Ospemifene 60 mg does not have a detrimental effect on lipid and coagulation parameters of postmenopausal women with up to 12 months of use.

Knowledge of clinical trials regarding hormone therapy and likelihood of prescribing hormone therapy.

OBJECTIVE: The aim of the study was to examine whether physicians who are better informed about large, published hormone therapy (HT) trials (eg, the Women's Health Initiative) are more likely to prescribe HT for menopausal symptoms. METHODS: US obstetricians/gynecologists and primary care physicians completed a 15- to 20-minute Internet-based survey. Knowledge was assessed via nine true-false statements about HT trials (range: 0-9). Prescribing practices were assessed via six case studies with a seven-point response scale of "extremely unlikely" to "extremely likely" in relation to treatment options (range: 6-42). The primary analysis examined the correlation between HT trial knowledge and likelihood of prescribing HT. Secondary analyses gauged knowledge and prescribing practices based on practice type, sex, and years in practice. RESULTS: Among 501 physicians who completed the survey (representing 10.7% of those invited; median age: 51.0 y; female: 26.9%; obstetricians/gynecologists: 49.9%; median 19.0 y in practice), HT knowledge (mean [SD] 3.8 [2.3]), and prescribing (mean [SD] 24.5 [5.6]) exhibited a statistically significant, moderate positive correlation (0.30; 95% CI, 0.21-0.37; P < 0.0001). Obstetricians/gynecologists were significantly (P < 0.0001) more knowledgeable and more likely to prescribe HT than primary care physicians. Male physicians were more likely (P < 0.05) to prescribe HT but not more knowledgeable about it than female physicians. Knowledge (but not likelihood of prescribing) significantly increased as a function of years in practice. CONCLUSIONS: Physicians who are more knowledgeable about large, published HT trials are more likely to prescribe HT for menopausal symptoms.

Ospemifene's effect on vasomotor symptoms: a post hoc analysis of phase 2 and 3 clinical data.

OBJECTIVE: To examine the effect of ospemifene 60 mg/d on vasomotor symptoms in postmenopausal women using clinical safety and efficacy data from five phase 2 and 3 studies. METHODS: The incidence of hot flush treatment-emergent adverse events (TEAEs) was compiled from five randomized, placebo-controlled clinical studies; baseline parameters associated with hot flush incidence were also identified. Ospemifene's effects on the frequency and severity of hot flushes were evaluated in a previously unpublished, 6-week, placebo-controlled study. RESULTS: Analysis of pooled hot flush TEAE data for 2,166 women showed an incidence of hot flush of 8.5% for ospemifene and 3.2% for placebo (P < 0.0001). Hot flushes were most frequent during the first 4 weeks of ospemifene treatment and decreased in frequency thereafter. Logistic regression analysis revealed that hormone therapy within 6 months before study start (P = 0.0234), longer study treatment duration (P = 0.0234), and more hot flush days per month at baseline (P = 0.0313) were associated with more hot flushes. Ospemifene 60 mg/d did not worsen the frequency and severity of existing hot flushes in a 6-week, placebo-controlled trial of 198 postmenopausal women who were experiencing moderate to very severe hot flushes. CONCLUSIONS: In randomized trials, hot flush TEAEs were more frequent with ospemifene 60 mg/d than with placebo, particularly among women with prior history of hormone therapy use. The majority of hot flushes, however, waned after 4 weeks of ospemifene treatment. Ospemifene did not worsen existing hot flushes in women experiencing moderate to very severe hot flushes.

The impact of multimorbidity on quality of life among midlife women: findings from a U.S. nationally representative survey.

BACKGROUND: Little is known about the prevalence and cumulative burden of coexisting health conditions including chronic joint and muscular pain, urinary incontinence (UI), depression, osteoporosis risk, moderate/severe vasomotor symptoms, and vulvar/vaginal atrophy (VVA). We surveyed a nationally representative U.S. sample of midlife (age 40-64 years) women to ascertain the prevalence, general health-related quality of life (HRQoL), and health-seeking behaviors associated with these six conditions. METHODS: This cross-sectional, telephone survey collected data from a sample of English- and Spanish-speaking U.S. women. The survey contained demographic and menopausal status questions, and also five condition-specific symptom/disease risk-screening instruments. The EuroQol 5 dimensions (EQ-5D) questionnaire was used to measure HRQoL. Health-seeking behavior was measured based on clinician discussion of and recent treatment for each condition. RESULTS: Three thousand fifty eight women (mean age 53.4 years) completed the survey. The majority were white (75.6%), married (60.5%), employed full- or part-time (59.0%), and postmenopausal (69.8%; based on self-report). The prevalence [95% confidence interval] of 0, 1, 2, and ≥3 conditions was 35.2% [33.5-36.9], 34.2% [32.5-35.9], 17.9% [16.6-19.3], and 12.7% [11.5-13.9], respectively. Osteoporosis risk (30.6%) was most prevalent, followed by VVA (27.8%) and UI (26.6%). UI and VVA coexisted most frequently (11.3%), followed by osteoporosis risk and VVA (9.8%). EQ-5D scores decreased with increasing number of illnesses (0, 1, 2, and ≥3 conditions, means: 0.92, 0.87, 0.77, 0.61, respectively; p<0.01). Health-seeking behavior varied by condition. CONCLUSION: Over 25% of women surveyed had multiple coexisting conditions. Lower HRQoL was associated with multiple conditions and with each added condition.

Current and evolving approaches to individualizing estrogen receptor-based therapy for menopausal women.

CONTEXT: Adding progestogens to estrogens changes the risk profile of hormonal therapy for menopausal women, and recent data support the need for progestogen-free options. Several current and evolving approaches to managing estrogen deficiency allow for progestogen omission. We review the mechanisms of estrogen activity and provide an overview of emerging and available estrogen receptor (ER)-based therapies. EVIDENCE ACQUISITION: PubMed was searched for relevant English-language articles using keywords pertaining to estrogen deficiency, menopause, hormone therapy, and estrogen-only therapy. Pivotal or recent randomized controlled trials, large observational studies, comprehensive meta-analyses, and established therapeutic guidelines were compiled. EVIDENCE SYNTHESIS: Advances in our understanding of ER pharmacology have led to therapies designed to optimize ER activity, including selective ER modulators (SERMs) and tissue-selective estrogen complexes (TSECs). Each estrogen, SERM, and TSEC exhibits a unique profile of tissue-specific activity, spanning the spectrum from ER agonism to antagonism. Systemic estrogens unopposed by progestogens effectively manage menopausal symptoms in hysterectomized postmenopausal women but require progestogen use in postmenopausal women with a uterus. SERMs are effective for managing certain aspects of estrogen deficiency in postmenopausal women, but data suggest that pairing a SERM with estrogens to form a TSEC provides a more optimal therapeutic profile for women with a uterus. CONCLUSIONS: Treating signs and symptoms of estrogen deficiency requires an individualized approach based on a woman's goals and the purported risks of different therapies. New and emerging agents have demonstrated efficacy in postmenopausal women with a uterus, while allowing these women to avoid progestogens and their possible adverse effects.

Efficacy and safety of low-dose regimens of conjugated estrogens cream administered vaginally.

OBJECTIVE: The aim of this study was to evaluate the efficacy and safety of low-dose conjugated estrogens (CE) cream for treatment of atrophic vaginitis. METHODS: Postmenopausal women (N = 423) with moderate-to-severe vaginal atrophy were randomized to CE cream 0.3 mg or placebo once daily (21 days on/7 days off) or twice weekly for 12 weeks, followed by open-label treatment with CE cream for 40 weeks consistent with their prior regimen. Primary endpoints were changes in vaginal maturation index (VMI; percentage of superficial cells), vaginal pH, and severity of participant-reported most bothersome symptom (vaginal dryness, itching, burning, or dyspareunia) at week 12. Endometrial safety was assessed by transvaginal ultrasound and endometrial biopsy for 52 weeks. RESULTS: At week 12, improvements in VMI with daily and twice-weekly use of low-dose CE cream (27.9% and 25.8%, respectively) were significantly greater compared with placebo (3.0% and 1.0%, respectively; P < 0.001). Improvements in vaginal pH with daily and twice-weekly CE cream (-1.6 for both) were also significantly greater relative to placebo (-0.4 and -0.3, respectively; P < 0.001). VMI and vaginal pH responses were sustained through 52 weeks. Both CE cream regimens significantly reduced most bothersome symptom scores compared with placebo (P < or = 0.001), including those for dyspareunia (P < or = 0.01). There was no report of endometrial hyperplasia or carcinoma. Adverse events occurred with similar frequency among the active and placebo groups during the double-blind phase. CONCLUSIONS: Daily and twice-weekly use of low-dose CE cream was equally effective in relieving symptoms of vulvovaginal atrophy. Both regimens showed endometrial safety and sustained efficacy during 1 year of therapy.