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

Abstract

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 (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. 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, 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. Conclusions: 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.