Effects of hormone therapy on bone mineral density: results from the postmenopausal estrogen/progestin interventions (PEPI) trial. The Writing Group for the PEPI

JAMA. 1996 Nov 6;276(17):1389-96.


Objective: To assess the effects of hormone therapy on bone mineral density (BMD) in the spine and hip of postmenopausal women.

Design: A 3-year, multicenter, randomized, double-blinded, placebo-controlled clinical trial.

Participants: A total of 875 healthy women aged 45 to 64 years recruited at 7 clinical centers.

Interventions: Treatments were (1) placebo; (2) conjugated equine estrogens (CEE), 0.625 mg/d; (3) CEE, 0.625 mg/d plus medroxyprogesterone acetate (MPA), 10 mg/d for 12 d/mo; (4) CEE, 0.625 mg/d plus MPA, 2.5 mg/d daily; or (5) CEE, 0.625 mg/d plus micronized progesterone (MP), 200 mg/d for 12 d/mo.

Main outcome measures: Bone mineral density at baseline, 12 months, and 36 months.

Results: Participants assigned to the placebo group lost an average of 1.8% of spine BMD and 1.7% of hip BMD by the 36-month visit, while those assigned to active regimens gained BMD at both sites, ranging from 3.5% to 5.0% mean total increases in spinal BMD and a mean total increase of 1.7% of BMD in the hip. Changes in BMD for women assigned to active regimens were significantly greater than those assigned to placebo. Women assigned to CEE plus continuous MPA had significantly greater increases in spinal BMD (increase of 5%) than those assigned to the other 3 active regimens (average increase, 3.8%). Findings were similar among those adhering to assigned therapy, although, among adherent participants, there were no significant differences in BMD changes among the 4 active treatment groups. Older women, women with low initial BMD, and those with no previous hormone use gained significantly more bone than younger women, women with higher initial BMD, and those who had used hormones previously.

Conclusions: Postmenopausal women assigned to placebo demonstrated decreased BMD at the spine and hip, whereas women assigned to estrogen therapy increased BMD during a 36-month period. These findings demonstrate that estrogen replacement therapy increases BMD at clinically important sites.

Publication types

  • Clinical Trial
  • Multicenter Study
  • Randomized Controlled Trial
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Absorptiometry, Photon
  • Bone Density / drug effects*
  • Double-Blind Method
  • Estrogen Replacement Therapy*
  • Estrogens, Conjugated (USP) / administration & dosage
  • Estrogens, Conjugated (USP) / therapeutic use*
  • Female
  • Fractures, Bone
  • Hip
  • Humans
  • Medroxyprogesterone Acetate / administration & dosage
  • Medroxyprogesterone Acetate / therapeutic use*
  • Middle Aged
  • Postmenopause
  • Progesterone / administration & dosage
  • Progesterone / therapeutic use*
  • Progesterone Congeners / administration & dosage
  • Progesterone Congeners / therapeutic use*
  • Spine
  • Statistics as Topic


  • Estrogens, Conjugated (USP)
  • Progesterone Congeners
  • Progesterone
  • Medroxyprogesterone Acetate