Increases in Bone Mineral Density in Response to Oral Dehydroepiandrosterone Replacement in Older Adults Appear to Be Mediated by Serum Estrogens

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


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.


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

Main Outcome Measures:

BMD and serum DHEAS, testosterone, estradiol (E2), estrone (E1), SHBG, IGF-I, and IGF binding protein 3 were measured before and after intervention. Free testosterone and estrogen (FEI) indices were calculated.


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, E1, E2, FEI, and IGF-I (all P < 0.001) and decreased SHBG (P = 0.02) in women and, in men, increased DHEAS, E1, FEI (all P < 0.001), and E2 (P = 0.02) and decreased SHBG (P = 0.037). The changes in total and regional hip BMD were associated with 12-month E2 (all P ≤ 0.001) and FEI (all P ≤ 0.013). The effects of DHEA treatment were eliminated by adjustment for 12-month E2.


The significant increases in hip BMD in older adults undergoing DHEA replacement were mediated primarily by increases in serum E2 rather than direct effects of DHEAS.

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