Androgens and bone growth: it's location, location, location
Introduction
Although it is well-established that androgens play a key role in skeletal growth and turnover, the mechanisms remain controversial given that the major androgen metabolite, testosterone, is also a substrate for the production of estradiol through aromatase activity. Additional complications arise with the complex nature of bone itself. There is, however, little controversy regarding anabolic effects of androgens on one skeletal compartment: the periosteal or outside surface of bone. Androgen action at the onset of puberty is responsible for the development of a sexually dimorphic skeleton (i.e. male bones are wider than female) and is a significant determinant of bone strength. Androgens are also important for the production of peak bone mass in males. Cell types known to express androgen receptors (ARs) include osteoblasts, osteoclasts and mesenchymal stromal cells that differentiate toward the osteoblast lineage. Proof-of-concept for AR action is demonstrated in androgen-insensitivity models, with production of a nonfunctional AR associated with a dramatic reduction in total bone mass in humans even with excellent estrogen compliance. AR null mice have high turnover osteopenia with increased formation but even stronger enhancement of resorption. Targeted AR overexpression in the skeleton further supports these findings, as it results in enhanced periosteal formation, reduced endosteal formation, increased trabecular bone formation and a reduction of osteoclast activity, all without changes in circulating steroid levels.
Although both estrogen and androgen circulate in men and women, the influence of each on the remodeling skeleton is distinct as shown by divergent responses to gonadectomy in either gender and during modeling, particularly with respect to bone size (periosteal apposition). Non-parallel pathways of action are also indicated with the observation that combination therapy combining estrogen and androgen is more beneficial than either steroid alone in post-menopausal women [1, 2, 3]; this has been confirmed in animal models [4•, 5]. Estrogens are thought to maintain adult bone mass predominantly through inhibition of bone resorption by osteoclasts (i.e. they act as anti-resorptive agents), which protect the skeleton from further loss of bone. Non-aromatizable androgens such as 5α-dihydrotestosterone (DHT), conversely, are anabolic agents that increase bone mass by stimulation of bone formation, and thus represent an important therapeutic class that has the potential to re-build lost bone.
The purpose of this review is to discuss recently published data regarding the anabolic effects of androgen on bone growth, with a focus on the mechanisms by which androgen regulates skeletal modeling and remodeling through transactivation of the AR.
Section snippets
The complexity of bone: distinct compartments and cell types
The cell biology that underlies bone development is complex. Two processes are evident in the development of bone: endochondral formation from a cartilage anlage as seen in long bones, and intramembraneous formation seen in calvaria (skull cap). Long bones are organized in compartments of cortical lamellar bone and trabecular spiny or cancellous bone. Cortical bone is formed at mid-shaft (diaphysis/cortical), whereas trabecular bone is formed at the growing end (metaphysis/trabecular). The
Androgen, the AR and bone cells
Ultimately, bone mass is determined by two processes: formation and resorption. Distinct cell types mediate these processes. The bone-forming cell, the osteoblast, synthesizes bone matrix and regulates mineralization, and is responsive to most calciotropic hormones. The osteoclast is responsible for bone resorption. Although bone is clearly a target tissue with respect to androgen action, the mechanisms of action and cell types by which androgens exert their effects on bone biology are
The effects of sex steroids in the development of a sexually dimorphic skeleton
During childhood and adolescence, skeletal development is characterized by marked expansion of cortical proportions and increasing trabecular density. During this process, the skeleton develops distinctly in males and females, particularly at the periosteal surface. Sex differences in skeletal morphology and physiology occur at or around puberty, with little effect of gonadal steroids prior to puberty [27]. For that reason, it is hypothesized that gender differences, particularly with respect
The importance of androgens in bone formation: human studies
It is also clear that androgens play an important role in maintaining the adult skeleton. Hypogonadism in both sexes is associated with bone loss. Replacement therapy with estrogen, aromatizable testosterone or non-aromatizable androgen (e.g. DHT) are all generally effective at ameliorating this loss. Clinical data demonstrate that estrogen replacement therapy tends to suppress bone resorption with only modest effects on bone formation. By contrast, androgen replacement data have demonstrated
Animal studies: androgen administration and AR null and transgenic mice
Results from animal studies also support an effect of androgen on bone formation. Experimental strategies, such as surgical or pharmacological intervention, and examination of genetic models have all been employed to characterize androgen signaling. Distinct effects of androgen are seen with gonadectomy when comparing the effects of orchidectomy (ORX) in male versus ovariectomy (OVX) in female rats. OVX and the associated loss of sex steroids in the female generally results in decreased
Potential therapeutic options for bone
Testosterone treatment has been shown to be effective in stimulating bone turnover in boys with growth or pubertal delay [31•, 47], and at ameliorating bone loss during aging in men with low testosterone levels [48•, 49]. Nevertheless, androgen replacement in hypogonadal men remains a controversial issue [50] even though low testosterone is associated with increased mortality risk in geriatric patients [51]. It appears that androgens in a form that cannot be 5α-reduced might be preferable to
Conclusions
Androgens are important in the maintenance of a healthy skeleton, and have been shown to stimulate bone formation (Table 1). Androgens influence skeletal modeling and remolding by multiple mechanisms through effects on osteoblasts and osteoclasts and an influence on the differentiation of pluripotent stem cells toward the osteoblast lineage. The specific effects of androgen on bone cells are mediated directly through an AR signaling pathway, but there are also indirect contributions to overall
Update
As noted, androgens increase muscle mass and have thus been postulated to influence bone density through skeletal loading. Although it has been shown that appendicular skeletal muscle mass is positively correlated with bone mineral content and areal BMD in men [61•], controversy remains regarding the influence of fat mass versus muscle mass on bone formation in both sexes during aging and at specific sites [62•].
Interestingly, recent data demonstrate both direct inhibition of osteoclast
References and recommended reading
Papers of particular interest, published within the annual period of review, have been highlighted as:
• of special interest
•• of outstanding interest
Acknowledgements
I would like to thank Karl Jepsen, Shun-Ichi Harada, Michael Gentile and Xiao-Wei Zhang for their contributions to this work. This work is funded by Veterans Affairs Medical Research Service Merit Review program and the Department of Defense, United States Army Research Acquisition Activity Award No. W81XWH-05-1-0086.
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