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

J Womens Health (Larchmt). 2016 May;25(5):431-42. doi: 10.1089/jwh.2015.5351. Epub 2016 Apr 8.

Abstract

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.

Publication types

  • Randomized Controlled Trial

MeSH terms

  • Bone Density / drug effects*
  • Bone Density Conservation Agents / administration & dosage
  • Bone Density Conservation Agents / adverse effects
  • Breast / drug effects
  • Drug Therapy, Combination
  • Endometrial Hyperplasia / chemically induced
  • Endometrial Hyperplasia / epidemiology
  • Estrogens / administration & dosage
  • Estrogens / adverse effects*
  • Estrogens, Conjugated (USP) / administration & dosage
  • Estrogens, Conjugated (USP) / adverse effects*
  • Female
  • Humans
  • Incidence
  • Indoles / administration & dosage
  • Indoles / adverse effects*
  • Menopause / drug effects*
  • Middle Aged
  • Osteoporosis, Postmenopausal / prevention & control*
  • Placebos
  • Selective Estrogen Receptor Modulators / adverse effects
  • Uterine Hemorrhage / chemically induced
  • Uterine Hemorrhage / epidemiology

Substances

  • Bone Density Conservation Agents
  • Estrogens
  • Estrogens, Conjugated (USP)
  • Indoles
  • Placebos
  • Selective Estrogen Receptor Modulators
  • bazedoxifene