0163-769X/04/$20.00/0 Endocrine Reviews 25(3):389–425 Printed in U.S.A. Copyright © 2004 by The Endocrine Society doi: 10.1210/er.2003-0003 Androgens and Bone DIRK VANDERSCHUEREN, LIESBETH VANDENPUT, STEVEN BOONEN, MARIE K. LINDBERG, ROGER BOUILLON, AND CLAES OHLSSON Laboratory for Experimental Medicine and Endocrinology (D.V., L.V., S.B., R.B.), and Leuven University Centre for Metabolic Bone Diseases and Division of Geriatric Medicine (S.B.), Katholieke Universiteit Leuven, B-3000 Leuven, Belgium; and Division of Endocrinology, Department of Internal Medicine (M.K.L., C.O.), Sahlgrenska University Hospital, SE-41345 Go¨teborg, Sweden Loss of estrogens or androgens increases the rate of bone chondral bone formation, whereas they induce epiphyseal clo- remodeling by removing restraining effects on osteoblasto- sure at the end of puberty. Androgen action on the growth genesis and osteoclastogenesis, and also causes a focal imbal- plate is, however, clearly mediated via aromatization in es- ance between resorption and formation by prolonging the trogens and interaction with ER␣. Androgens increase radial lifespan of osteoclasts and shortening the lifespan of osteo- growth, whereas estrogens decrease periosteal bone forma- blasts. Conversely, androgens, as well as estrogens, maintain tion. This effect of androgens may be important because bone cancellous bone mass and integrity, regardless of age or sex. strength in males seems to be determined by relatively higher Although androgens, via the androgen receptor (AR), and es- periosteal bone formation and, therefore, greater bone dimen- trogens, via the estrogen receptors (ERs), can exert these ef- sions, relative to muscle mass at older age. Experiments in fects, their relative contribution remains uncertain. Recent mice again suggest that both the AR and ER␣ pathways are studies suggest that androgen action on cancellous bone de- involved in androgen action on radial bone growth. ER␤ may pends on (local) aromatization of androgens into estrogens. mediate growth-limiting effects of estrogens in the female but However, at least in rodents, androgen action on cancellous does not seem to be involved in the regulation of bone size in bone can be directly mediated via AR activation, even in the males. absence of ERs. In conclusion, androgens may protect men against osteo- Androgens also increase cortical bone size via stimulation porosis via maintenance of cancellous bone mass and expan- of both longitudinal and radial growth. First, androgens, like sion of cortical bone. Such androgen action on bone is medi- estrogens, have a biphasic effect on endochondral bone for- ated by the AR and ER␣.(Endocrine Reviews 25: 389–425, 2004) mation: at the start of puberty, sex steroids stimulate endo- I. Introduction A. The rodent as a model for the study of skeletal andro- II. General Aspects of Androgen Action gen action A. Androgen metabolism B. Skeletal consequences of gonadectomy in rodents B. Mechanism of action of androgens C. Skeletal effects of androgen replacement in rodents C. Nongenomic effects of sex steroids D. Skeletal effects of selective modulation of estrogen and D. Expression of androgen and estrogen receptors in the androgen action in rodents skeleton E. Skeletal effects of selective manipulation of androgen III. Effects of Androgens in Vitro on Skeletal Cells and estrogen action in transgenic mice A. Growth plate chondrocytes F. Skeletal effects of androgen resistance in rodents B. Osteoblasts/osteocytes G. Animal data in support of a dual mode of androgen C. Osteoclasts action on the skeleton IV. Effects of Androgens on the Rodent Skeleton V. Indirect Mechanisms of Action of Androgens with Skeletal Implications A. Androgens, body growth, and body composition Abbreviations: AF, Activation function; ANDRKO, AR knockout; AR, androgen receptor; ArKO, aromatase knockout; BERKO, ER␤ knockout; B. Androgens and the GH-IGF-I axis BMD, bone mineral density; cAIS, complete androgen insensitivity syn- VI. Effects of Androgens on the Human Skeleton drome; DERKO, double ER knockout; DHEA, dehydroepiandrosterone; A. Skeletal consequences of castration, male hypogonad- DHEA-S, DHEA sulfate; DHT, 5␣-dihydrotestosterone; DPA, dual pho- ism, and androgen resistance in men ton absorptiometry; DXA, dual energy x-ray absorptiometry; E2, estra- B. Skeletal effects of androgens in women ␣ ␤ ␤ diol; ER, estrogen receptor; ERKO, ER knockout; 17 -HSD, 17 -hy- C. Skeletal effects of androgen replacement droxysteroid dehydrogenase; IGFBP, IGF binding protein; IHH, isolated hypogonadotropic hypogonadism; KS, Klinefelter’s syndrome; LBD, D. Skeletal effects of selective modulation of androgen and ligand-binding domain; OPG, osteoprotegerin; orch, orchidectomized or estrogen action in men orchidectomy; ovx, ovariectomized or ovariectomy; PCOS, polycystic VII. General Conclusions ovary syndrome; pQCT, peripheral QCT; QCT, quantitative computed tomography; RANK, receptor activator of nuclear factor ␬B; RANKL, RANK ligand; SERM, selective ER modulator; SPA, single photon absorp- I. Introduction tiometry; T, testosterone; Tfm, testicular feminized male. Endocrine Reviews is published bimonthly by The Endocrine Society NDROGENS INDUCE MALE sexual differentiation (http://www.endo-society.org), the foremost professional society serving A before birth and sexual maturation during puberty; in the endocrine community. adult men, they maintain the function of the male genital 389 Downloaded from edrv.endojournals.org on September 19, 2005 390 Endocrine Reviews, June 2004, 25(3):389–425 Vanderschueren et al. • Androgens and Bone system, including spermatogenesis. However, the role of but this is due to a greater bone volume and not to a greater androgens in other target organs—including muscle tissue; volumetric density. The greater areal bone mineral density the cardiovascular, central nervous, and immune systems; (BMD) in males is thus only an artifact of the dual energy and bone—is less well-established (1). x-ray absorptiometry (DXA) software by expression of bone In the early 1940s, Albright and Reifenstein were among mass as projected areal (grams per square centimeter) instead the first to refer to the antiosteoporotic and anabolic prop- of true or volumetric density (grams per cubic centimeter). erties of androgens (2). From a public health perspective, In the current review, we will focus on the potential mech- osteoporosis is a greater problem in women than in men (3). anisms through which androgens may prevent bone loss, This explains why most research efforts to explore skeletal increase bone mass (size), and improve bone strength. effects of sex steroids have been devoted to estrogens. More- In this manuscript, in vitro, experimental animal data and over, androgens may be converted into estrogens via the clinical human data with respect to skeletal androgen action P450 aromatase enzyme complex and may therefore act as will be reviewed in an attempt to define the possible impact prohormones for estrogens. In this respect, there is increasing of androgen action [through the estrogen receptor (ER) and evidence that at least part of the effects of androgens in men AR pathways] on different aspects of skeletal homeostasis can be explained by their aromatization into estrogens (4, 5). during growth and aging. Recent clinical and experimental Epiphyseal closure at the end of puberty, for example, is now data have indeed provided evidence that at least some of the generally accepted to be estrogen-dependent in both genders skeletal androgen actions are not solely ER-dependent. Fur- (6). In recent years, a specific role of androgens in skeletal thermore, we will discuss potential indirect nonbone cell- homeostasis has even been questioned, although androgen mediated effects of androgens on the skeleton. receptors (ARs) in bone cells and AR-mediated actions on Finally, the potential clinical benefits of androgen replace- bone have been documented for more than a decade (7, 8). ment in the context of male hypogonadism as well as in The aim of this review is to address the question whether different patient groups will be discussed. Recent studies and how (through which receptors and/or pathways) an- have explored different modes of action of androgens via the drogens may affect bone strength and provide protection AR and ER pathways and may ultimately contribute to the against osteoporosis. The clinical relevance of this question potential use of selective AR or ER modulators in selected results from the recognition that, even in men, fractures due male target populations. to skeletal fragility represent a huge public health problem. Elderly men maintain cancellous bone integrity in com- parison with postmenopausal women, although their bone II. General Aspects of Androgen Action trabeculae become thinner. From a biomechanical perspec- A. Androgen metabolism tive, compromised bone strength in men is the result of gender-related differences in the loss of bone mass during Androgens are C-19 steroids secreted primarily from the aging and, even more importantly, in the accumulation of testes and the adrenals. The synthesis and metabolism of sex bone mass during childhood and adolescence (9) (Table 1). steroids have been extensively reviewed in several recent During puberty, men develop a bigger bone size than publications (4, 12). Therefore, we will just briefly mention women, due to increased periosteal apposition. In females, the major pathways to facilitate the interpretation of exper- on the other hand, estrogens