Androgens and Bone

Abstract

Loss of estrogens or androgens increases the rate of bone remodeling by removing restraining effects on osteoblastogenesis and osteoclastogenesis, and also causes a focal imbalance between resorption and formation by prolonging the lifespan of osteoclasts and shortening the lifespan of osteoblasts. Conversely, androgens, as well as estrogens, maintain cancellous bone mass and integrity, regardless of age or sex. Although androgens, via the androgen receptor (AR), and estrogens, via the estrogen receptors (ERs), can exert these effects, their relative contribution remains uncertain. Recent studies suggest that androgen action on cancellous bone depends on (local) aromatization of androgens into estrogens. However, at least in rodents, androgen action on cancellous bone can be directly mediated via AR activation, even in the absence of ERs. Androgens also increase cortical bone size via stimulation of both longitudinal and radial growth. First, androgens, like estrogens, have a biphasic effect on endochondral bone formation: at the start of puberty, sex steroids stimulate endochondral bone formation, whereas they induce epiphyseal closure at the end of puberty. Androgen action on the growth plate is, however, clearly mediated via aromatization in estrogens and interaction with ERalpha. Androgens increase radial growth, whereas estrogens decrease periosteal bone formation. This effect of androgens may be important because bone strength in males seems to be determined by relatively higher periosteal bone formation and, therefore, greater bone dimensions, relative to muscle mass at older age. Experiments in mice again suggest that both the AR and ERalpha pathways are involved in androgen action on radial bone growth. ERbeta may mediate growth-limiting effects of estrogens in the female but does not seem to be involved in the regulation of bone size in males. In conclusion, androgens may protect men against osteoporosis via maintenance of cancellous bone mass and expansion of cortical bone. Such androgen action on bone is mediated by the AR and ERalpha.

Adequacy of androgen replacement influences bone density response to testosterone in androgen-deficient men

“…Each of these factors may contribute to the increased fracture risk associated with male hypogonadism (1,30). Recent findings also highlight that a significant proportion of testosterone effects on bone depends upon aromatization to estradiol (31).…”

Osteoporosis and male age-related hypogonadism: role of sex steroids on bone (patho)physiology

“…Thus DHT seems not to be necessary for the beneficial effects of testosterone on BMD in men and this evidence indirectly focuses on the positive effects on bone induced by the aromatization of androgens (74). A possible role of DHT on BMD was previously suggested on the basis of animal studies and in vitro research (29), but DHT was able to prevent bone loss in castrated rodents only when used at supraphysiological doses in vivo (75). Even though androgens seem to exert a direct action on bone cells (osteoblast, osteoclast, osteocytes), all these effects linked to the activation of androgen receptor (such as apoptosis, modulation and proliferation of osteoblasts and osteoclasts) have been proved only in vitro or in animal studies (29).…”

“…Nowadays it is known that bone tissue is able to produce sex steroids (i.e. estrogens and androgen metabolites) locally (28) and bone represents a target tissue for both locally produced and circulating sex steroids, since both androgen and estrogen receptors (a and b) as well as aromatase enzyme, are expressed in bone cells (29). Thus sex steroids may act on bone in an endocrine, paracrine and autocrine fashion.…”

“…Our understanding of the role of estrogen on human male bone physiology has certainly revisited and, in part, reduced the role of androgens on male bone physiology (29), but a direct action of androgens on bone cannot be ruled out even if its mechanism is now too complex to be characterized in vivo. Paradoxically, we know more about estrogens and less about androgens (Tables 2 and 4).…”

Inactivation of the androgen receptor in bone-forming cells leads to trabecular bone loss in adult female mice

“…1,2 Reduction of serum androgen levels in aging men or in patients treated with anti-androgen therapy has been shown to be associated with the reduced bone mineral density (BMD) of the skeleton. 3 In mice, the androgen receptor (AR) is expressed in osteoblasts, osteocytes [4][5][6] and osteoclasts.…”