Increases in bone mineral density in response to oral dehydroepiandrosterone replacement in older adults appear to be mediated by serum estrogens

J Clin Endocrinol Metab. 2008 Dec;93(12):4767-73. doi: 10.1210/jc.2007-2614. Epub 2008 Sep 23.


Context: The mechanisms by which dehydroepiandrosterone (DHEA) replacement increases bone mineral density (BMD) in older adults are not known.

Objective: The aims were to determine the effects of DHEA therapy on changes in sex hormones and IGF-I and their associations with changes in BMD.

Design, setting, and participants: A randomized, double-blinded, placebo-controlled trial was conducted at an academic research institution. Participants were 58 women and 61 men, aged 60-88 yr, with low serum DHEA sulfate (DHEAS) levels.

Intervention: The intervention was oral DHEA 50 mg/d or placebo for 12 months.

Main outcome measures: BMD and serum DHEAS, testosterone, estradiol (E(2)), estrone (E(1)), SHBG, IGF-I, and IGF binding protein 3 were measured before and after intervention. Free testosterone and estrogen (FEI) indices were calculated.

Results: The average changes in hip and spine BMD (DHEA vs. placebo) ranged from 1.1 to 1.6%. Compared with placebo, DHEA replacement increased serum DHEAS, testosterone, free testosterone index, E(1), E(2), FEI, and IGF-I (all P < 0.001) and decreased SHBG (P = 0.02) in women and, in men, increased DHEAS, E(1), FEI (all P < 0.001), and E(2) (P = 0.02) and decreased SHBG (P = 0.037). The changes in total and regional hip BMD were associated with 12-month E(2) (all P <or= 0.001) and FEI (all P <or= 0.013). The effects of DHEA treatment were eliminated by adjustment for 12-month E(2).

Conclusions: The significant increases in hip BMD in older adults undergoing DHEA replacement were mediated primarily by increases in serum E(2) rather than direct effects of DHEAS.

Publication types

  • Randomized Controlled Trial
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Absorptiometry, Photon
  • Aged
  • Aged, 80 and over
  • Biomarkers
  • Bone Density / drug effects*
  • Dehydroepiandrosterone Sulfate / administration & dosage
  • Dehydroepiandrosterone Sulfate / blood
  • Dehydroepiandrosterone Sulfate / therapeutic use*
  • Double-Blind Method
  • Estrogens / blood*
  • Estrogens / physiology*
  • Female
  • Hormone Replacement Therapy*
  • Humans
  • Insulin-Like Growth Factor I / metabolism
  • Male
  • Middle Aged
  • Sex Hormone-Binding Globulin / metabolism
  • Testosterone / blood


  • Biomarkers
  • Estrogens
  • Sex Hormone-Binding Globulin
  • Testosterone
  • Dehydroepiandrosterone Sulfate
  • Insulin-Like Growth Factor I