The effects of tibolone in older postmenopausal women.

BACKGROUND: Tibolone has estrogenic, progestogenic, and androgenic effects. Although tibolone prevents bone loss, its effects on fractures, breast cancer, and cardiovascular disease are uncertain. METHODS: In this randomized study, we assigned 4538 women, who were between the ages of 60 and 85 years and had a bone mineral density T score of -2.5 or less at the hip or spine or a T score of -2.0 or less and radiologic evidence of a vertebral fracture, to receive once-daily tibolone (at a dose of 1.25 mg) or placebo. Annual spine radiographs were used to assess for vertebral fracture. Rates of cardiovascular events and breast cancer were adjudicated by expert panels. RESULTS: During a median of 34 months of treatment, the tibolone group, as compared with the placebo group, had a decreased risk of vertebral fracture, with 70 cases versus 126 cases per 1000 person-years (relative hazard, 0.55; 95% confidence interval [CI], 0.41 to 0.74; P<0.001), and a decreased risk of nonvertebral fracture, with 122 cases versus 166 cases per 1000 person-years (relative hazard, 0.74; 95% CI, 0.58 to 0.93; P=0.01). The tibolone group also had a decreased risk of invasive breast cancer (relative hazard, 0.32; 95% CI, 0.13 to 0.80; P=0.02) and colon cancer (relative hazard, 0.31; 95% CI, 0.10 to 0.96; P=0.04). However, the tibolone group had an increased risk of stroke (relative hazard, 2.19; 95% CI, 1.14 to 4.23; P=0.02), for which the study was stopped in February 2006 at the recommendation of the data and safety monitoring board. There were no significant differences in the risk of either coronary heart disease or venous thromboembolism between the two groups. CONCLUSIONS: Tibolone reduced the risk of fracture and breast cancer and possibly colon cancer but increased the risk of stroke in older women with osteoporosis. (ClinicalTrials.gov number, NCT00519857.)

Endometrial effects of tibolone.

BACKGROUND AND OBJECTIVES: The Tibolone Histology of the Endometrium and Breast Endpoints Study is a multicenter, randomized, double-blind study designed to address the conflicting reports in the literature about the endometrial safety of tibolone (1.25 or 2.5 mg/d). Tibolone was compared with continuous combined conjugated equine estrogen (CEE) plus medroxyprogesterone acetate (MPA) (0.625 + 2.5 mg/d). METHODS: Subjects were randomized in a 1:1:2 ratio to tibolone 1.25 mg/d, 2.5 mg/d, and CEE/MPA, respectively. The one-sided 95% confidence interval (CI) has been evaluated for the incidence of abnormal endometrial histology (hyperplasia or carcinoma) and hyperplasia and carcinoma separately for each of the two treatment groups and the treatment groups combined after 1 and 2 yr of treatment with tibolone, compared with CEE/MPA. RESULTS: A total of 3240 women were randomized, with 3224 receiving at least one dose of study medication. The incidence and upper one-sided 95% CI for the incidence of abnormal endometrium (hyperplasia or carcinoma), and hyperplasia and carcinoma separately, were calculated at end point, yr 1, and yr 2. The incidence (upper one-sided 95% CI) of abnormal endometrium at end point was 0.0 (0.5), 0.0 (0.4), and 0.2 (0.5) in the tibolone 1.25 mg, 2.5 mg, and CEE/MPA groups, respectively. During the entire treatment period, amenorrhea was reported more frequently with tibolone 1.25 mg (78.7%) and 2.5 mg (71.4%) than CEE/MPA (44.9%). CONCLUSION: The Tibolone Histology of the Endometrium and Breast Endpoints Study results confirm previous findings that tibolone does not induce endometrial hyperplasia or carcinoma in postmenopausal women, and it is associated with a better vaginal bleeding profile than CEE/MPA.

Tibolone for the treatment of moderate to severe vasomotor symptoms and genital atrophy in postmenopausal women: a multicenter, randomized, double-blind, placebo-controlled study.

OBJECTIVE: To demonstrate the safety and efficacy of tibolone (1.25 and 2.5 mg) in the treatment of moderate to severe vasomotor symptoms and symptoms associated with vaginal atrophy. DESIGN: A placebo-controlled, double-blind, randomized, multicenter study was conducted on 396 healthy postmenopausal women experiencing a minimum of 7 moderate to severe hot flashes per day (60 per week). Participants were randomized to receive tibolone 1.25 or 2.5 mg or placebo once daily for 12 weeks. Assessments were done at weeks 4, 8, and 12. The severity and frequency of hot flashes were recorded in patient diaries on a daily basis. RESULTS: Tibolone 2.5 mg significantly (P < 0.001) reduced the average number of hot flashes compared with placebo at week 4 (-7.82 vs -5.27), week 8 (-9.71 vs -5.86), and week 12 (-10.14 vs -5.85). The difference between tibolone 1.25 mg and placebo was significant (P < 0.001) at week 8 (-7.96) and week 12 (-8.32). Findings for the average daily severity of hot flashes were similar, with significantly greater reductions at week 4 (P < 0.05) and weeks 8 and 12 (P < 0.001) for tibolone 2.5 mg versus placebo and at weeks 8 and 12 for tibolone 1.25 mg versus placebo (P < 0.001). A menopausal atrophic symptom questionnaire revealed that tibolone 2.5 mg significantly (P < 0.05) reduced nocturia compared with placebo at weeks 4, 8, and 12 and urinary urgency at week 4. Compared with placebo, both doses of tibolone also significantly (P < 0.001) increased the vaginal maturation value from baseline. The overall incidence of adverse events was similar in all treatment groups. CONCLUSIONS: Tibolone is effective and well tolerated for the treatment of moderate to severe vasomotor symptoms and the effects of vaginal atrophy associated with menopause.

Tibolone histology of the endometrium and breast endpoints study: design of the trial and endometrial histology at baseline in postmenopausal women.

OBJECTIVE: To address the endometrial safety of tibolone. DESIGN: The Tibolone Histology of the Endometrium and Breast Endpoints Study (THEBES) is a randomized, double-blind, parallel-group trial of tibolone compared with continuous combined conjugated equine estrogen (CEE) and medroxyprogesterone acetate (MPA). SETTING: Multi-country, multi-center ambulatory care setting. PATIENT(S): A total of 5,185 subjects were screened, and biopsies were obtained from 4,446 women. INTERVENTION(S): Participants were randomized in a 1:1:2 ratio, to tibolone (1.25 or 2.5 mg/d) or CEE-MPA. MAIN OUTCOME MEASURE(S): The one-sided 95% confidence intervals for the incidence of hyperplasia or cancer were evaluated for tibolone compared with CEE-MPA. RESULT(S): Endometrial biopsy results at baseline: atrophic (87.29%), inactive (0.25%), proliferative (6.12%), secretory (2.86%), menstrual type (0.40%), and hyperplasia (0.18%). Only subjects with atrophic or inactive endometrium were eligible for this study, and 3% of the women at screening either had no tissue (0.18%) or had an amount of tissue that was insufficient for diagnosis (2.72%). Three thousand two hundred forty postmenopausal women with a mean (+/-SD) age of 54.4 +/- 4.4 years and a mean time since menopause of 4.5 +/- 3.6 years were randomized. CONCLUSION(S): The Tibolone Histology of the Endometrium and Breast Endpoints Study is a prospective, randomized clinical trial, designed to provide evidence of the endometrial safety of tibolone compared with estrogen and progestogen. Screening endometrial histology shows a low prevalence of endometrial hyperplasia (0.18%) and no carcinoma.