Gonadal steroid–dependent effects on bone turnover and bone mineral density in men

Abstract

METHODS.One hundred ninety-eight healthy men, ages 20-50, received goserelin acetate, which suppresses endogenous gonadal steroid production, and were randomized to treatment with 0, 1.25, 2.5, 5, or 10 grams of testosterone gel daily for 16 weeks. An additional cohort of 202 men was randomized to receive these treatments plus anastrozole, which suppresses conversion of androgens to estrogens. Thirty-seven men served as controls and received placebos for goserelin and testosterone. Changes in bone turnover markers, bone mineral density (BMD) by dual-energy x-ray absorptiometry (DXA), and BMD by quantitative computed tomography (QCT) were assessed in all men. Bone microarchitecture was assessed in 100 men. RESULTS.As testosterone dosage decreased, the percent change in C-telopeptide increased. These increases were considerably greater when aromatization of testosterone to estradiol was also suppressed, suggesting effects of both testosterone and estradiol deficiency. Decreases in DXA BMD were observed when aromatization was suppressed but were modest in most groups. QCT spine BMD fell substantially in all testosterone-dose groups in which aromatization was also suppressed, and this decline was independent of testosterone dose. Estradiol deficiency disrupted cortical microarchitecture at peripheral sites. Estradiol levels above 10 pg/ml and testosterone levels above 200 ng/dl were generally sufficient to prevent increases in bone resorption and decreases in BMD in men. CONCLUSIONS.Estrogens primarily regulate bone homeostasis in adult men, and testosterone and estradiol levels must decline substantially to impact the skeleton. TRIAL REGISTRATION. ClinicalTrials.gov, NCT00114114.FUNDING. AbbVie Inc., AstraZeneca Pharmaceuticals LP, NIH.

Battle of the sex steroids in the male skeleton: and the winner is…

“…More importantly, there appears to be a fairly consistent threshold estrogen level (~16 pg/ml), below which the risk of fracture appears to increase in an exponential manner. This level is somewhat higher than the 10 pg/ml level reported by Finkelstein et al to confer increased skeletal catabolism in younger men (17). These discrepancies may potentially be reconciled by differences in estrogen assay type and sensitivity, as well as by differences in patient populations (young vs. old).…”

“…In this issue, Finkelstein and colleagues attempted to further dissect the relative contributions of estrogen and testosterone to skeletal homeostasis (17). Specifically, young men were rendered either testosterone deficient (cohort 1) or both testosterone and estrogen deficient (cohort 2) via a gonadotropin-releasing hormone (GnRH) agonist without or with aromatase inhibitor letrozole, respectively.…”

“…gesting that sex steroid regulation of bone may well be compartment specific (17,18,28). This model postulates that androgens and estrogens in men primarily modulate cancellous and cortical bone, respectively, though observed anabolic effects on cortical bone by both sex steroids may well be ligand independent (29).…”

“…Although improved, immunoassays for determining levels of sex steroids have continued challenges related to sensitivity, accuracy, and interference by other factors (33). As such, the use of LCMS, as was used by Finkelstein et al (17), should be considered, given that this technique has become more widely and commercially available. Increased utilization of LCMS may ultimately reduce the above, there is prospectively acquired data that does associate higher fracture risk in older men with lower estrogen levels (11,12).…”

“…Although the data presented by Finkelstein and colleagues strongly suggest that estrogen, irrespective of sex, is the dominant sex steroid in male bone metabolism, there is evidence that other sex steroids and factors contribute to male skeletal health (17). For example, testosterone appears to be critical for periosteal bone expansion that occurs both during growth and with aging in older men, likely conferring a biomechanical advantage for men over women for many types of appendicular fracture (22,23).…”