The effect of low-dose continuous estrogen and progesterone therapy with calcium and vitamin D on bone in elderly women. A randomized, controlled trial

Ann Intern Med. 1999 Jun 1;130(11):897-904. doi: 10.7326/0003-4819-130-11-199906010-00005.


Background: Hormone replacement therapy (HRT), the mainstay of osteoporosis prevention, is limited because of dose-related risks, side effects, and patient acceptance. The bone-sparing efficacy and tolerability of the lowest available doses of HRT have not been adequately studied in elderly women.

Objective: To determine the bone-sparing effect of continuous low-dose HRT in elderly women.

Design: Randomized, double-blind, placebo-controlled trial.

Setting: University osteoporosis research and clinical center.

Patients: 128 healthy white women (age > 65 years) with low bone mass recruited by word of mouth and by local advertisement. The principal eligibility criterion was spinal bone mineral density of 0.90 g/cm2 or less.

Intervention: Continuous therapy with conjugated equine estrogen, 0.3 mg/d, and medroxyprogesterone, 2.5 mg/d, or matching placebo. Sufficient calcium supplementation was given to bring all calcium intakes above 1000 mg/d in both groups; supplemental oral 25-hydroxyvitamin D was given to maintain serum 25-hydroxyvitamin D levels of at least 75 nmol/L in both groups.

Measurements: Bone mineral density of the spine, hip, total body, and forearm; serum total alkaline phosphatase and serum osteocalcin levels at 6-month intervals; and 24-hour urine creatinine and hydroxyproline excretion at baseline, 12 months, and 42 months.

Results: During 3.5 years of observation, spinal bone mineral density increased by 3.5% (P < 0.001) in an intention-to-treat analysis and by 5.2% among patients with greater than 90% adherence to therapy. Significant increases were seen in total-body and forearm bone density (P < 0.01). Symptoms related to HRT (breast tenderness, spotting, pelvic discomfort, and mood changes) were mild and short-lived.

Conclusions: Continuous low-dose HRT with conjugated equine estrogen and oral medroxyprogesterone combined with adequate calcium and vitamin D provides a bone-sparing effect that is similar or superior to that provided by other, higher-dose HRT regimens in elderly women. This combination is well tolerated by most patients.

Publication types

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

MeSH terms

  • Aged
  • Alkaline Phosphatase / blood
  • Analysis of Variance
  • Biomarkers / blood
  • Biomarkers / urine
  • Bone Density
  • Calcium / administration & dosage*
  • Creatinine / urine
  • Dietary Supplements*
  • Estrogen Replacement Therapy / adverse effects
  • Estrogen Replacement Therapy / methods*
  • Estrogens, Conjugated (USP) / administration & dosage*
  • Estrogens, Conjugated (USP) / adverse effects
  • Female
  • Humans
  • Hydroxyproline / urine
  • Medroxyprogesterone / administration & dosage*
  • Medroxyprogesterone / adverse effects
  • Osteocalcin / blood
  • Osteoporosis, Postmenopausal / prevention & control*
  • Vitamin D / administration & dosage
  • Vitamin D / analogs & derivatives*


  • Biomarkers
  • Estrogens, Conjugated (USP)
  • Osteocalcin
  • Vitamin D
  • 25-hydroxyvitamin D
  • Creatinine
  • Alkaline Phosphatase
  • Medroxyprogesterone
  • Hydroxyproline
  • Calcium