Results of this clinical trial suggest a small beneficial effect of DHEA treatment on bone metabolism and bone mineral density, but only for women. Treatment with a 50 mg daily dose of DHEA for 12 months had a small but significant positive effect on BMD of the lumbar spine in women, as well as a beneficial effect on CTx, a marker of bone resorption. These results were independent of known confounders or baseline levels of DHEA. Similar positive bone effects were not observed in men and no beneficial (or adverse) effect of DHEA treatment on body composition was found in either sex. The administration of 50 mg of DHEA was safe and no major adverse effects were observed.
Unlike many published studies, men and women were recruited for the present study without selecting for lower levels of DHEA, enabling an examination of the effects of DHEA in the general population. DHEA is available over-the-counter in the United States as well as other countries, and is largely used as a preventive agent for age related diseases without a thorough understanding or careful examination of adverse effects versus possible benefits. The present study addresses the effect of DHEA in an older sample of relatively healthy community-dwelling men and women.
Evidence from previous studies indicates that DHEA supplementation may increase levels of BMD and have a beneficial effect on bone turnover markers in older adults with low levels of endogenous DHEA [5
], in men and women with adrenal insufficiency [5
], and in women with anorexia nervosa [6
]. A recent clinical trial with 87 men and 57 women aged 60 and older selected for low DHEAS levels, found that 75 mg of DHEA daily for men and 50 mg of DHEA daily for women administered for 2 years was associated with a small but significant increase in femoral neck BMD in men and a small but significant increase in BMD at the ultradistal radius in women when compared to participants receiving placebo [14
The case for a beneficial effect in older individuals unselected for low levels of DHEA is less clear, with small studies using varying dosages and reporting contradictory results. For example, Labrie and colleagues [8
] conducted a cross-over clinical trial with 14 women aged 60-70, and reported that use of a 10% DHEA cream for 16 months led to a significant decrease in markers of bone resorption (hydroxyproline/creatinine ratio) and bone formation (BSAP), and an increase in hip BMD, but had no effect on lumbar spine. In a clinical trial of 86 men with osteoporosis [15
], daily use of 100 mg of DHEA for 6 months increased BMD at both the lumbar spine and femoral neck. In contrast, a small study of ten women and nine men aged 50 to 65 years using a 100 mg dose of DHEA and a cross-over design, reported no effect on BMD at the hip, lumbar spine or total body, and no change in urinary pyridinoline, a marker of bone resorption [9
The only other relatively large clinical trial conducted in a sample non-selected for low DHEA was done by Baulieu and colleagues [11
], who recruited 280 older French men and women attending a geriatric clinic for a variety of minor age-related symptoms, such as asthenia, memory complaints and anxiety. After 12 months of supplementation with 50 mg of DHEA versus placebo, a significant increase was found in BMD at the femoral neck and Ward’s triangle (trabecular bone) in women less than 70yrs old, and at the total radius in women 70 years and older. As in our study, no effect of DHEA was found among the men. The results from Baulieu and colleagues along with those observed in the present study suggest a sex-specific effect of DHEA on bone metabolism in healthy older adults.
Body mass index is recognized as one of the strongest predictors for BMD in both men and women [16
], and recent studies suggest that body composition has a stronger contribution as a determinant of BMD than body size [18
]. However, in accord with most previous studies [5
], DHEA supplementation in this trial did not alter measures of body size and body composition in either men or women, suggesting that the small effect of DHEA on bone was not mediated by an effect on body composition.
The sex-specific biotransformation of exogenously administered DHEA might help explain the sex differences observed in this study. Both testosterone and estradiol levels were increased in women receiving DHEA treatment as seen in other studies [11
], while no changes were observed among the men. The apparent absence of any discernible bioconversion of DHEA to active sex hormones among men, despite a two- to fourfold increase in circulating DHEA levels was unexpected. While most studies using 50 to 100 mg of DHEA also reported no change in testosterone levels in men [4
], most have described a change in estradiol. An increase in estradiol levels was reported by Kahn and colleagues after 6 months of daily DHEA supplementation (90 mg) in 43 healthy men aged 56 to 80 years old [4
], and by Baulieu and colleagues after administering 50 mg of DHEA daily for 12 months to 140 healthy men 60 to 79 years old [11
]. Recently, Nair and colleagues reported an increase in estradiol levels after 24 months using 75 mg/daily in 87 men aged 60 years and older [14
]. However, no effect was reported by Morales and colleagues in two different studies using doses of 50 and 100 mg DHEA daily for 6 months [9
], or by Villareal and colleagues using a daily dose of 50 mg for 6 months [29
]. It is possible that a longer duration or higher dose than that used in the present study is necessary for DHEA supplementation to augment estrogen levels in men.
In accord with previous studies [26
], we found that DHEA increased the concentration of circulating IGF-1 in women, but unlike the same studies, we did not find any effect in men. Insulin-like growth factors are growth-promoting polypeptides that have an important role in regulating osteoblastic and osteoclastic functions, and maintaining bone mass [31
]. Previous animal and human studies provide indirect support for the hypothesis that circulating IGF-1 plays an important role in the acquisition of bone mass [32
]. Cross-sectional studies show positive correlations between serum IGF-1 and BMD in areas with a high proportion of trabecular bone and high bone turnover such as the spine [34
]. Langlois et al. [35
] reported a relatively strong correlation between serum IGF-1 levels and BMD at several sites in women from the Framingham cohort, and low serum levels of IGF-1 were also associated with greater risk of hip fractures among a large cohort of older postmenopausal women in France [36
]. Systemic and local effects of IGF-1 are modulated by a group of proteins, the insulin-like growth factor binding proteins (IGFBPs), which have high affinity and specificity for the IGFs. Approximately 75% of the IGF-1 in the circulation is carried in a complex with IGFBP-3 [37
], and IGFBP-3 is believed to play a significant role in regulation of the bone remodeling process in humans by enhancing the anabolic effects of IGF-1 on bone [31
]. IGFBP-3 levels were not changed in this trial, but the 20% increase in IGF-1 in women resulted in a significant elevation of the IGF-1/IGFBP-3 ratio. The selective increase in both IGF-1 and lumbar spine BMD, a site with abundant trabecular bone among the women randomized to DHEA suggests a causal link.
The observed beneficial changes in BMD and bone markers in women may reflect the combined effects of peripheral conversion of DHEA to sex steroids and a DHEA-induced increase in circulating IGF-1. Similar results were not observed in men, and the clinical significance of DHEA in preventing or treating osteoporosis in women is questionable. Longer trials may be necessary to allow for a positive and clinically significant effect of DHEA on bone mineral density. Although there were no serious adverse events related to DHEA treatment during this study, other more effective and as well tolerated treatments for osteoporosis are available.