Differential Effects of Androgens and Estrogens on Bone Turnover in Normal Men

Abstract

The physiologic role of androgens and estrogens in the maintenance of normal bone turnover in men is a fundamental issue in bone biology. To address this question, we randomized 70 men between the ages of 20 and 44 yr to receive one of three treatment regimens. Group 1 (n = 25) received a GnRH analog (goserelin acetate 3.6 mg by sc injection every 4 wk) alone for 12 wk to suppress endogenous gonadal steroids to prepubertal levels. Group 2 (n = 22) received goserelin plus transdermal testosterone (Androderm 5 mg topically daily) to normalize circulating testosterone and estradiol levels. Group 3 (n = 23) received goserelin plus testosterone plus an aromatase inhibitor (anastrozole 1 mg orally daily) to induce selective estrogen deficiency. The selective effects of androgens and estrogens on skeletal homeostasis were then assessed by measuring changes in biochemical markers of bone turnover and analyzing the between-group differences. Bone resorption markers increased in both the hypogonadal group (group 1) and in the group with selective estrogen deficiency (group 3). Urinary deoxypyridinoline excretion increased more in group 1 than in group 3 (P = 0.023), suggesting a significant effect of androgens on bone resorption, whereas serum N-telopeptide levels increased more in group 3 than in group 2 (P = 0.037), suggesting a significant effect of estrogen on bone resorption. Bone formation markers initially declined in all groups and then increased in groups 1 and 3. The between-group comparisons were consistent for all formation markers. Bone formation markers increased more in group 1 than in group 2 (P = 0.001, 0.037, 0.005 for osteocalcin, carboxy-terminal propeptide of type I procollagen, and amino-terminal propeptide of type I procollagen, respectively). Bone formation markers also increased more in group 1 than in group 3 but these differences were not statistically significant (P = 0.065 0.073, 0.099 for osteocalcin, carboxy-terminal propeptide of type I procollagen, and amino-terminal propeptide of type I procollagen, respectively). Taken together, these data suggest that both androgens and estrogens play independent and fundamental roles in regulating bone resorption in men. These data also suggest that androgens may play an important role in the regulation of bone formation in men.

Targeting of androgen receptor in bone reveals a lack of androgen anabolic action and inhibition of osteogenesis

“…Since osteoporosis is often coupled with a hypogonadal state in both men and women, sex steroids are implicated in the maintenance of skeletal health. Although both estrogen and androgen circulate in men and women, albeit at different levels, the influence of each on the remodeling skeleton is distinct [34,55]. Consistent with this, combination therapy with both estrogen and androgen provides an improved response in post-menopausal women compared to estrogen alone [2,47].…”

Neuropeptide Y and sex hormone interactions in humoral and neuronal regulation of bone and fat

“…Estrogen inhibits osteoclastogenesis by suppressing the production of the receptor activator of NF-kB ligand (RANKL), thereby increasing the production of the soluble decoy receptor osteoprotegerin (OPG) [22,23], as well as via regulation of various bone-acting cytokines such as interleukins IL-1 and IL-6 and tumor necrosis factor (TNF) [24,25]. Moreover, estrogen (as well as testosterone) inhibits bone resorption [26,27] by inducing osteoclast apoptosis [28] and suppressing activity of mature osteoclasts through direct receptor interactions [29]. In brief, estrogen has numerous effects on bone -some via direct tissue actions -to stimulate bone formation and decrease bone resorption.…”

Male osteoporosis: A review

“…Up to 70% of bone turnover and resorption appear to be modulated by estrogens and 30% by testosterone [31] . Moreover both hormones are substantial in bone formation mechanisms [26] .…”