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.

The safety and tolerability profile of therapies for the prevention and treatment of osteoporosis in postmenopausal women.

At a time when the prevalence of osteoporosis and related fractures is increasing, initiation and continuation of pharmacologic therapies for prevention and treatment of postmenopausal osteoporosis have declined. This decline has been at least in part attributable to concerns about safety of these agents, such as atypical fractures with bisphosphonates and breast cancer with estrogen/progestin therapy, particularly when they are used long term by older women. However, in many cases, absolute risk of serious adverse effects is small and should be balanced against the larger potential for fracture reduction. Here, we review the safety and tolerability of available therapies for postmenopausal osteoporosis. Taking into consideration their relative efficacy, we also provide strategies for optimization of the risk:benefit ratio.

Development of conjugated estrogens/bazedoxifene, the first tissue selective estrogen complex (TSEC) for management of menopausal hot flashes and postmenopausal bone loss.

Conjugated estrogens (CE) combined with the selective estrogen receptor modulator (SERM) bazedoxifene (BZA) is a new option for alleviating menopausal symptoms and preventing postmenopausal bone loss. The rationale for developing the tissue selective estrogen complex (TSEC) CE/BZA was to combine CE's benefits with the SERM's tissue-specific properties to offset estrogenic stimulation of endometrial and breast tissue. TSECs provide a progestin-free alternative to traditional estrogen-progestin therapy (EPT) in women with a uterus. Preclinical studies supported bazedoxifene as the SERM of choice and demonstrated that CE/BZA provided an optimal balance of estrogen receptor agonist/antagonist activity compared with other potential TSEC pairings. Initial clinical development of CE/BZA focused on determining the appropriate dose ratio that would demonstrate efficacy with minimal to no stimulation of the breast or endometrium. Clinical studies confirmed the efficacy of the selected doses for maintaining bone mass; relieving vasomotor symptoms, vulvar-vaginal atrophy, and dyspareunia; and improving sexual function in postmenopausal women. Reduction of hot flashes also translated into improved menopause-specific quality of life and sleep. Unlike EPT, the FDA-approved dose of CE 0.45 mg/BZA 20mg does not cause a change in breast density or the endometrium, or increase breast pain compared with placebo. In clinical trials up to 2 years, CE 0.45 mg/BZA 20 mg has a favorable tolerability profile and rates of coronary heart disease, venous thromboembolism, and amenorrhea similar to placebo. Therefore, CE 0.45 mg/BZA 20 mg is an effective, well-tolerated alternative to EPT for menopausal symptom relief and osteoporosis prevention for postmenopausal women with a uterus.