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

Abstract

Background: Severe gonadal steroid deficiency induces bone loss in adult men; however, the specific roles of androgen and estrogen deficiency in hypogonadal bone loss are unclear. Additionally, the threshold levels of testosterone and estradiol that initiate bone loss are uncertain.

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.

Figures

Figure 1. Trial profile.

T, testosterone gel. G, group. G1, 0 g (placebo) testosterone gel daily; G2, 1.25 g of testosterone daily; G3, 2.5 g of testosterone daily; G4, 5 g of testosterone gel daily; G5, 10 g of testosterone gel daily.

Figure 2. Serum testosterone and estradiol levels on treatment according to testosterone dose in individual subjects.

(A and B) Subjects in cohort 1 (blue dots, n = 184) received goserelin acetate plus 0 (placebo), 1.25, 2.5, 5, or 10 g of testosterone gel daily without anastrozole. Subjects in cohort 2 (red dots, n = 174) received the same treatments plus anastrozole 1 mg per day. Cohort 3 (controls, black dots, n = 35) received placebos for both goserelin acetate and for the testosterone gel. The horizontal black line represents the mean, and the error bars represent ± 1 SD.

Figure 3. Percent change from baseline in bone turnover markers according to testosterone dose and mean serum testosterone levels on treatment in individual subjects.

(A–D) Results are shown for CTX (A and B) and P1NP (C and D). Subjects in cohort 1 (blue dots, n = 184) received testosterone gel daily without anastrozole. Subjects in cohort 2 (red dots, n = 174) received the same treatments plus anastrozole 1 mg per day. Subjects in cohort 3 (controls, black dots, n = 35) received placebos for both goserelin acetate and for the testosterone gel. The horizontal black line represents the mean, and the error bars represent ± 1 SD. T, testosterone. *P < 0.05 using Duncan’s multiple range test.

Figure 4. Percent change from baseline in BMD according to testosterone dose and mean serum testosterone levels on treatment in individual subjects.

(A–F) Results are shown for BMD by DXA at the lumbar spine (A and B), total hip (C and D), and total body (E and F). (G and H) Spine trabecular BMD by QCT is also shown. Subjects in cohort 1 (blue dots, n = 174 for A–F and n = 169 for G and H) received goserelin acetate plus 0 (placebo), 1.25, 2.5, 5, or 10 g of testosterone gel daily without anastrozole. Subjects in cohort 2 (red dots, n = 171 for A–F and n = 168 for G and H) received the same treatments plus 1 mg anastrozole per day. Subjects in cohort 3 (black dots, n = 34) received placebos for both goserelin acetate and for the testosterone gel. The horizontal black line represents the mean, and the error bars represent ± 1 SD. T, testosterone. *P < 0.05 using Duncan’s multiple range test.

Figure 5. Percent change from baseline in bone turnover markers and BMD according to mean serum estradiol levels on treatment in individual subjects in cohort 1.

(A–F) Results are shown for CTX (n = 184, A), P1NP (n = 184, B), lumbar spine BMD by DXA (n = 174, C) and QCT (n = 171, D), total hip BMD by DXA (n = 174, E), and total body BMD by DXA (n = 174, F). Subjects in cohort 1 (blue dots, n = 198) received goserelin acetate plus 0 (placebo), 1.25, 2.5, 5, or 10 g of testosterone gel daily without anastrozole. Subjects in cohort 2 had uniformly low estradiol levels due to anastrozole and are therefore not depicted on this graph. Subjects in cohort 3 (controls, black dots, n = 35 for A and B, n = 34 for C–F) received placebos for both goserelin acetate and for the testosterone gel. The horizontal black line represents the mean, and the error bars represent ± 1 SD. *P < 0.05 using Duncan’s multiple range test.