Effects of bazedoxifene/conjugated estrogens on the endometrium and bone: a randomized trial

J Clin Endocrinol Metab. 2014 Feb;99(2):E189-98. doi: 10.1210/jc.2013-1707. Epub 2014 Jan 17.


Objective: This phase 3 study evaluated the endometrial safety of bazedoxifene (BZA)/conjugated estrogens (CE) and bone mineral density (BMD) effects vs BZA alone, hormone therapy, and placebo (PBO).

Methods: The Selective estrogens, Menopause, And Response to Therapy (SMART)-5 trial was a multicenter, randomized, double-blind, PBO- and active-controlled study in postmenopausal women with an intact uterus (N = 1843; aged 40-65 years) seeking treatment for menopausal symptoms. Subjects received daily oral BZA 20 mg/CE 0.45 or 0.625 mg, BZA 20 mg, CE 0.45 mg/medroxyprogesterone acetate (MPA) 1.5 mg, or PBO. Primary endpoints were incidence of endometrial hyperplasia and percent change in lumbar spine BMD at 12 months. Secondary endpoints included additional osteoporosis parameters and assessments of tolerability and safety.

Results: At 12 months, endometrial hyperplasia incidence was low (<1%) and similar among groups. The BZA/CE group showed significantly greater increases in lumbar spine and total hip BMD vs decreases with PBO (P < .001); the CE/MPA group had increased lumbar spine BMD compared with that in the BZA/CE group. The BZA 20 mg/CE 0.45 and 0.625 mg groups had cumulative amenorrhea rates similar to those with PBO and BZA and significantly higher than those with CE 0.45 mg/MPA 1.5 mg (P < .001). The incidence of breast tenderness with BZA/CE was similar to that with PBO and BZA and significantly lower than with that with CE/MPA (P < .01). Although adverse event (AE) rates were similar among the groups, the incidence of serious AEs overall and AE-related discontinuation rates were higher with CE/MPA than with BZA/CE, BZA, or PBO.

Conclusions: BZA/CE showed low rates of endometrial hyperplasia and improved lumbar spine and total hip BMD and was generally safe and well tolerated.

Trial registration: ClinicalTrials.gov NCT00808132.

Publication types

  • Clinical Trial, Phase III
  • Multicenter Study
  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Bone Density / drug effects*
  • Bone Density Conservation Agents / adverse effects
  • Bone Density Conservation Agents / pharmacology*
  • Bone Density Conservation Agents / therapeutic use
  • Double-Blind Method
  • Drug Therapy, Combination
  • Endometrial Hyperplasia / chemically induced*
  • Endometrium / drug effects*
  • Estrogens, Conjugated (USP) / adverse effects
  • Estrogens, Conjugated (USP) / pharmacology*
  • Estrogens, Conjugated (USP) / therapeutic use
  • Female
  • Humans
  • Indoles / adverse effects
  • Indoles / pharmacology*
  • Indoles / therapeutic use
  • Lumbar Vertebrae / drug effects*
  • Medroxyprogesterone Acetate / adverse effects
  • Medroxyprogesterone Acetate / pharmacology
  • Medroxyprogesterone Acetate / therapeutic use
  • Middle Aged
  • Selective Estrogen Receptor Modulators / adverse effects
  • Selective Estrogen Receptor Modulators / pharmacology
  • Selective Estrogen Receptor Modulators / therapeutic use
  • Treatment Outcome


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

Associated data

  • ClinicalTrials.gov/NCT00808132