Osteoporosis in men has only recently begun to receive more attention despite it being estimated that about one third of all osteoporotic fractures occur in men and that the residual lifetime fracture risk in a man aged 60 years may be as high as 30%. Accrual of bone mass and age-related bone loss in aging healthy men are multifactorial processes involving hormonal, environmental, and genetic factors. This review will summarise the effects of gonadal steroids on bone turnover and bone mass in men.
Get full access to this article
View all access options for this article.
References
1.
CooperC., CampionG., MeltonL.J.3rd. Hip fractures in the elderly: a world-wide projection. Osteoporos Int, 1992; 2(6):285–289.
2.
GullbergB., JohnellO., KanisJ.A.World-wide projections for hip fracture. Osteoporos Int, 1997; 7(5):407–413.
3.
JonesG., NguyenT., SambrookP.N., KellyP.J., GilbertC., EismanJ.A.Symptomatic fracture incidence in elderly men and women: the Dubbo Osteoporosis Epidemiology Study (DOES). Osteoporos Int, 1994; 4(5):277–282.
4.
CenterJ.R., NguyenT.V., SchneiderD., SambrookP.N., EismanJ.A.Mortality after all major types of osteoporotic fracture in men and women: an observational study. Lancet, 1999; 353(9156):878–882.
5.
BilezikianJ.P.Osteoporosis in men. J Clin Endocrinol Metab, 1999; 84(10):3431–3434.
6.
HandelsmanD.J. In: Androgen action and pharmacologic uses. DeGrootL. editor. Endocrinology. 4th edn. Philadelphia: W.B. Saunders; 2001. p. 2232–2242.
7.
de RondeW., PolsH.A., van LeeuwenJ.P., de JongF.H.The importance of oestrogens in males. Clin Endocrinol (Oxf), 2003; 58(5):529–542.
SaitoH., YanaiharaT.Steroid formation in osteoblast-like cells. J Int Med Res, 1998; 26(1):1–12.
10.
JanssenJ.M., BlandR., HewisonM., CoughtrieM.W., SharpS., ArtsJ., et al.Estradiol formation by human osteoblasts via multiple pathways: relation with osteoblast function. J Cell Biochem, 1999; 75(3):528–537.
11.
SasanoH., UzukiM., SawaiT., NaguraH., MatsunagaG., KashimotoO., et al.Aromatase in human bone tissue. J Bone Miner Res, 1997; 12(9):1416–1423.
12.
ShozuM., SimpsonE.R.Aromatase expression of human osteoblast-like cells. Mol Cell Endocrinol, 1998; 139(1–2):117–129.
13.
OzO.K., MillsapsR., WelchR., BirchJ., ZerwekhJ.E.Expression of aromatase in the human growth plate. J Mol Endocrinol, 2001; 27(2):249–253.
14.
GennariL., NutiR., BilezikianJ.P.Aromatase activity and bone homeostasis in men. J Clin Endocrinol Metab, 2004; 89(12):5898–5907.
15.
Van Der EerdenB.C., Van De VenJ., LowikC.W., WitJ.M., KarperienM.Sex steroid metabolism in the tibial growth plate of the rat. Endocrinology, 2002; 143(10):4048–4055.
16.
ShimodairaK., FujikawaH., OkuraF., ShimizuY., SaitoH., YanaiharaT.Osteoblast cells (MG-63 and HOS) have aromatase and 5 alpha-reductase activities. Biochem Mol Biol Int, 1996; 39(1):109–116.
17.
SchweikertH.U., RulfW., NiederleN., SchaferH.E., KeckE., KruckF.Testosterone metabolism in human bone. Acta Endocrinol (Copenh), 1980; 95(2):258–264.
FeixM., WolfL., SchweikertH.U.Distribution of 17beta-hydroxysteroid dehydrogenases in human osteoblast-like cells. Mol Cell Endocrinol, 2001; 171(1–2):163–164.
20.
KuwanoY., FujikawaH., WatanabeA., ShimodairaK., SekizawaA., SaitoH., et al.3Beta-hydroxysteroid dehydrogenase activity in human osteoblast-like cells. Endocr J, 1997; 44(6):847–853.
21.
ColvardD.S., EriksenE.F., KeetingP.E., WilsonE.M., LubahnD.B., FrenchF.S., et al.Identification of androgen receptors in normal human osteoblast-like cells. Proc Natl Acad Sci USA, 1989; 86(3):854–857.
22.
AbuE.O., HornerA., KusecV., TriffittJ.T., CompstonJ.E.The localization of androgen receptors in human bone. J Clin Endocrinol Metab, 1997; 82(10):3493–3497.
23.
MizunoY., HosoiT., InoueS., IkegamiA., KanekiM., AkedoY., et al.Immunocytochemical identification of androgen receptor in mouse osteoclast-like multinucleated cells. Calcif Tissue Int, 1994; 54(4):325–326.
24.
PedersonL., KremerM., JuddJ., PascoeD., SpelsbergT.C., RiggsB.L., et al.Androgens regulate bone resorption activity of isolated osteoclasts in vitro. Proc Natl Acad Sci USA, 1999; 96(2):505–510.
25.
EriksenE.F., ColvardD.S., BergN.J., GrahamM.L., MannK.G., SpelsbergT.C., et al.Evidence of estrogen receptors in normal human osteoblast-like cells. Science, 1988; 241(4861):84–86.
26.
BordS., HornerA., BeavanS., CompstonJ.Estrogen receptors alpha and beta are differentially expressed in developing human bone. J Clin Endocrinol Metab, 2001; 86(5):2309–2314.
27.
GreenS., WalterP., GreeneG., KrustA., GoffinC., JensenE., et al.Cloning of the human oestrogen receptor cDNA. J Steroid Biochem, 1986; 24(1):77–83.
28.
KuiperG.G., EnmarkE., Pelto-HuikkoM., NilssonS., GustafssonJ.A.Cloning of a novel receptor expressed in rat prostate and ovary. Proc Natl Acad Sci USA, 1996; 93(12):5925–5930.
29.
GrayA., BerlinJ.A., McKinlayJ.B., LongcopeC.An examination of research design effects on the association of testosterone and male aging: results of a meta-analysis. J Clin Epidemiol, 1991; 44(7):671–684.
30.
LiuP.Y., SwerdloffR.S., VeldhuisJ.The rationale, efficacy and safety of androgen therapy in older men: future research and current practice recommendations. J Clin Endocrinol Metab, 2004; 89(10):4789–4796.
31.
LyL.P., HandelsmanD.J.Empirical estimation of free testosterone from testosterone and sex hormone-binding globulin immunoassays. Eur J Endocrinol, 2005; 152(3):471–478.
32.
KaufmanJ.M., VermeulenA.Declining gonadal function in elderly men. Baillière's Clin Endocrinol Metab, 1997; 11(2):289–309.
33.
HarmanS.M., MetterE.J., TobinJ.D., PearsonJ., BlackmanM.R.Longitudinal effects of aging on serum total and free testosterone levels in healthy men. Baltimore Longitudinal Study of Aging. J Clin Endocrinol Metab, 2001; 86(2):724–731.
34.
FeldmanH.A., LongcopeC., DerbyC.A., JohannesC.B., AraujoA.B., CovielloA.D., et al.Age trends in the level of serum testosterone and other hormones in middle-aged men: longitudinal results from the Massachusetts male aging study. J Clin Endocrinol Metab, 2002; 87(2):589–598.
35.
LiuP.Y., DeathA.K., HandelsmanD.J.Androgens and cardiovascular disease. Endocr Rev, 2003; 24(3):313–340.
36.
VermeulenA., KaufmanJ.M., GoemaereS., van PottelbergI.Estradiol in elderly men. Aging Male, 2002; 5(2):98–102.
37.
KhoslaS., MeltonL.J.3rd, AtkinsonE.J., O’FallonW.M., KleeG.G., RiggsB.L.Relationship of serum sex steroid levels and bone turnover markers with bone mineral density in men and women: a key role for bioavailable estrogen. J Clin Endocrinol Metab, 1998; 83(7):2266–2274.
38.
SeemanE.Invited Review: Pathogenesis of osteoporosis. J Appl Physiol, 2003; 95(5):2142–2151.
39.
SeemanE.Pathogenesis of bone fragility in women and men. Lancet, 2002; 359(9320):1841–1850.
40.
KhoslaS., MeltonL.J.3rd, RiggsB.L.Clinical review 144: estrogen and the male skeleton. J Clin Endocrinol Metab, 2002; 87(4):1443–1450.
41.
RiggsB.L., KhoslaS., MeltonL.J.3rd. Sex steroids and the construction and conservation of the adult skeleton. Endocr Rev, 2002; 23(3):279–302.
42.
LederB.Z., FinkelsteinJ.S.Gonadal steroids and the skeleton in men. In: OrwollE.S., BliziotesM. editors. Contemporary Endocrinolgy: Osteoporosis. Pathophysiology and Clinical Management. Totowa, NJ: Humana Press; 2003. p. 393–411.
43.
StepanJ.J., LachmanM., ZverinaJ., PacovskyV., BaylinkD.J.Castrated men exhibit bone loss: effect of calcitonin treatment on biochemical indices of bone remodeling. J Clin Endocrinol Metab, 1989; 69(3):523–527.
44.
GoldrayD., WeismanY., JaccardN., MerdlerC., ChenJ., MatzkinH.Decreased bone density in elderly men treated with the gonadotropin-releasing hormone agonist decapeptyl (D-Trp6-GnRH). J Clin Endocrinol Metab, 1993; 76(2):288–290.
45.
SmithM.R., McGovernF.J., ZietmanA.L., FallonM.A., HaydenD.L., SchoenfeldD.A., et al.Pamidronate to prevent bone loss during androgen-deprivation therapy for prostate cancer. N Engl J Med, 2001; 345(13):948–955.
46.
StochS.A., ParkerR.A., ChenL., BubleyG., KoY.J., VinceletteA., et al.Bone loss in men with prostate cancer treated with gonadotropin-releasing hormone agonists. J Clin Endocrinol Metab, 2001; 86(6):2787–2791.
47.
DiamondT., CampbellJ., BryantC., LynchW.The effect of combined androgen blockade on bone turnover and bone mineral densities in men treated for prostate carcinoma: longitudinal evaluation and response to intermittent cyclic etidronate therapy. Cancer, 1998; 83(8):1561–1566.
48.
BasariaS., LiebJ.2nd, TangA.M., DeWeeseT., CarducciM., EisenbergerM., et al.Long-term effects of androgen deprivation therapy in prostate cancer patients. Clin Endocrinol (Oxf), 2002; 56(6):779–786.
49.
MittanD., LeeS., MillerE., PerezR.C., BaslerJ.W., BruderJ.M.Bone loss following hypogonadism in men with prostate cancer treated with GnRH analogs. J Clin Endocrinol Metab, 2002; 87(8):3656–3661.
50.
WeiJ.T., GrossM., JaffeC.A., GravlinK., LahaieM., FaerberG.J., et al.Androgen deprivation therapy for prostate cancer results in significant loss of bone density. Urology, 1999; 54(4):607–611.
51.
DaniellH.W.Osteoporosis after orchiectomy for prostate cancer. J Urol, 1997; 157(2):439–444.
52.
TownsendM.F., SandersW.H., NorthwayR.O., GrahamS.D.Jr.. Bone fractures associated with luteinizing hormone-releasing hormone agonists used in the treatment of prostate carcinoma. Cancer, 1997; 79(3):545–550.
53.
HatanoT., OishiY., FurutaA., IwamuroS., TashiroK.Incidence of bone fracture in patients receiving luteinizing hormone-releasing hormone agonists for prostate cancer. BJU Int, 2000; 86(4):449–452.
54.
OefeleinM.G., RicchuitiV., ConradW., SeftelA., BodnerD., GoldmanH., et al.Skeletal fracture associated with androgen suppression induced osteoporosis: the clinical incidence and risk factors for patients with prostate cancer. J Urol, 2001; 166(5):1724–1728.
SmithM.R., FallonM.A., LeeH., FinkelsteinJ.S.Raloxifene to prevent gonadotropin-releasing hormone agonist-induced bone loss in men with prostate cancer: a randomized controlled trial. J Clin Endocrinol Metab, 2004; 89(8):3841–3846.
57.
LopezA.M., PenaM.A., HernandezR., ValF., MartinB., RianchoJ.A.Fracture risk in patients with prostate cancer on androgen deprivation therapy. Osteoporos Int, 2005; 16(6):707–711.
58.
FrancisR.M.The effects of testosterone on osteoporosis in men. Clin Endocrinol (Oxf), 1999; 50(4):411–414.
59.
SmithD.A., WalkerM.S.Changes in plasma steroids and bone density in Klinefelter's syndrome. Calcif Tissue Res, 1977; 22(Suppl):225–228.
60.
ForestaC., RuzzaG., MioniR., MeneghelloA., BaccichettiC.Testosterone and bone loss in Klinefelter syndrome. Horm Metab Res, 1983; 15(1):56–57.
GreenspanS.L., NeerR.M., RidgwayE.C., KlibanskiA.Osteoporosis in men with hyperprolactinemic hypogonadism. Ann Intern Med, 1986; 104(6):777–782.
63.
LuisettoG., MastrogiacomoI., BonanniG., PozzanG., BotteonS., TizianL., et al.Bone mass and mineral metabolism in Klinefelter's syndrome. Osteoporos Int, 1995; 5(6):455–461.
64.
BojesenA., JuulS., GravholtC.H.Prenatal and postnatal prevalence of Klinefelter syndrome: a national registry study. J Clin Endocrinol Metab, 2003; 88(2):622–626.
65.
JacksonJ.A., KleerekoperM., ParfittA.M., RaoD.S., VillanuevaA.R., FrameB.Bone histomorphometry in hypogonadal and eugonadal men with spinal osteoporosis. J Clin Endocrinol Metab, 1987; 65(1):53–58.
66.
GuoC.Y., JonesT.H., EastellR.Treatment of isolated hypogonadotropic hypogonadism effect on bone mineral density and bone turnover. J Clin Endocrinol Metab, 1997; 82(2):658–665.
67.
BaranD.T., BergfeldM.A., TeitelbaumS.L., AvioliL.V.Effect of testosterone therapy on bone formation in an osteoporotic hypogonadal male. Calcif Tissue Res, 1978; 26(2):103–106.
68.
FrancisR.M., PeacockM., AaronJ.E., SelbyP.L., TaylorG.A., ThompsonJ., et al.Osteoporosis in hypogonadal men: role of decreased plasma 1,25-dihydroxyvitamin D, calcium malabsorption, and low bone formation. Bone, 1986; 7(4):261–268.
GreenspanS.L., OppenheimD.S., KlibanskiA.Importance of gonadal steroids to bone mass in men with hyperprolactinemic hypogonadism. Ann Intern Med, 1989; 110(7):526–531.
71.
KatznelsonL., FinkelsteinJ.S., SchoenfeldD.A., RosenthalD.I., AndersonE.J., KlibanskiA.Increase in bone density and lean body mass during testosterone administration in men with acquired hypogonadism. J Clin Endocrinol Metab, 1996; 81(12):4358–4365.
72.
BehreH.M., KlieschS., LeifkeE., LinkT.M., NieschlagE.Long-term effect of testosterone therapy on bone mineral density in hypogonadal men. J Clin Endocrinol Metab, 1997; 82(8):2386–2390.
73.
SnyderP.J., PeacheyH., BerlinJ.A., HannoushP., HaddadG., DlewatiA., et al.Effects of testosterone replacement in hypogonadal men. J Clin Endocrinol Metab, 2000; 85(8):2670–2677.
74.
WangC., SwerdloffR.S., IranmaneshA., DobsA., SnyderP.J., CunninghamG., et al.Effects of transdermal testosterone gel on bone turnover markers and bone mineral density in hypogonadal men. Clin Endocrinol (Oxf), 2001; 54(6):739–750.
75.
LeifkeE., KornerH.C., LinkT.M., BehreH.M., PetersP.E., NieschlagE.Effects of testosterone replacement therapy on cortical and trabecular bone mineral density, vertebral body area and paraspinal muscle area in hypogonadal men. Eur J Endocrinol, 1998; 138(1):51–58.
76.
DevogelaerJ.P., De CoomanS., Nagant de DeuxchaisnesC.Low bone mass in hypogonadal males. Effect of testosterone substitution therapy, a densitometric study. Maturitas, 1992; 15(1):17–23.
77.
IsaiaG., MussettaM., PecchioF., SciollaA., di StefanoM., MolinattiG.M.Effect of testosterone on bone in hypogonadal males. Maturitas, 1992; 15(1):47–51.
78.
AminorroayaA., KelleherS., ConwayA.J., LyL.P., HandelsmanD.J.Adequacy of androgen replacement influences bone density response to testosterone in androgen-deficient men. Eur J Endocrinol, 2005; 152(6):881–886.
79.
WangC., SwedloffR.S., IranmaneshA., DobsA., SnyderP.J., CunninghamG., et al.Transdermal testosterone gel improves sexual function, mood, muscle strength, and body composition parameters in hypogonadal men. Testosterone Gel Study Group. J Clin Endocrinol Metab, 2000; 85(8):2839–2853.
80.
WangC., CunninghamG., DobsA., IranmaneshA., MatsumotoA.M., SnyderP.J., et al.Long-term testosterone gel (AndroGel) treatment maintains beneficial effects on sexual function and mood, lean and fat mass, and bone mineral density in hypogonadal men. J Clin Endocrinol Metab, 2004; 89(5):2085–2098.
81.
WangC., SwerdloffR., KipnesM., MatsumotoA.M., DobsA.S., CunninghamG., et al.New testosterone buccal system (Striant) delivers physiological testosterone levels: pharmacokinetics study in hypogonadal men. J Clin Endocrinol Metab, 2004; 89(8):3821–3829.
82.
WangC., EyreD.R., ClarkR., KleinbergD., NewmanC., IranmaneshA., et al.Sublingual testosterone replacement improves muscle mass and strength, decreases bone resorption, and increases bone formation markers in hypogonadal men–a clinical research center study. J Clin Endocrinol Metab, 1996; 81(10):3654–3662.
83.
MorleyJ.E., PerryH.M.3rd, KaiserF.E., KraenzleD., JensenJ., HoustonK., et al.Effects of testosterone replacement therapy in old hypogonadal males: a preliminary study. J Am Geriatr Soc, 1993; 41(2):149–152.
84.
SzulcP., MunozF., ClaustratB., GarneroP., MarchandF., DuboeufF., et al.Bioavailable estradiol may be an important determinant of osteoporosis in men: the MINOS study. J Clin Endocrinol Metab, 2001; 86(1):192–199.
85.
SlemendaC.W., LongcopeC., ZhouL., HuiS.L., PeacockM., JohnstonC.C.Sex steroids and bone mass in older men. Positive associations with serum estrogens and negative associations with androgens. J Clin Invest, 1997; 100(7):1755–1759.
86.
KhoslaS., MeltonL.J.3rd, AtkinsonE.J., O’FallonW.M.Relationship of serum sex steroid levels to longitudinal changes in bone density in young versus elderly men. J Clin Endocrinol Metab, 2001; 86(8):3555–3561.
87.
GennariL., MerlottiD., MartiniG., GonnelliS., FranciB., CampagnaS., et al.Longitudinal association between sex hormone levels, bone loss, and bone turnover in elderly men. J Clin Endocrinol Metab, 2003; 88(11):5327–5333.
88.
GreendaleG.A., EdelsteinS., Barrett-ConnorE.Endogenous sex steroids and bone mineral density in older women and men: the Rancho Bernardo Study. J Bone Miner Res, 1997; 12(11):1833–1843.
89.
KennyA.M., PrestwoodK.M., MarcelloK.M., RaiszL.G.Determinants of bone density in healthy older men with low testosterone levels. J Gerontol A Biol Sci Med Sci, 2000; 55(9):M492–M497.
90.
MellstromD., JohnellO., LjunggrenO., ErikssonA.L., LorentzonM., MallminH., et al.Free testosterone is an independent predictor of BMD and prevalent fractures in elderly men: MrOS Sweden. J Bone Miner Res, 2006; 21(4):529–535.
91.
Goderie-PlompH.W., van der KliftM., de RondeW., HofmanA., de JongF.H., PolsH.A.Endogenous sex hormones, sex hormone-binding globulin, and the risk of incident vertebral fractures in elderly men and women: the Rotterdam Study. J Clin Endocrinol Metab, 2004; 89(7):3261–3269.
92.
TenoverJ.S.Effects of testosterone supplementation in the aging male. J Clin Endocrinol Metab, 1992; 75(4):1092–1098.
93.
SnyderP.J., PeacheyH., HannoushP., BerlinJ.A., LohL., HolmesJ.H., et al.Effect of testosterone treatment on bone mineral density in men over 65 years of age. J Clin Endocrinol Metab, 1999; 84(6):1966–1972.
94.
AmoryJ.K., WattsN.B., EasleyK.A., SuttonP.R., AnawaltB.D., MatsumotoA.M., et al.Exogenous testosterone or testosterone with finasteride increases bone mineral density in older men with low serum testosterone. J Clin Endocrinol Metab, 2004; 89(2):503–510.
95.
KennyA.M., PrestwoodK.M., GrumanC.A., MarcelloK.M., RaiszL.G.Effects of transdermal testosterone on bone and muscle in older men with low bioavailable testosterone levels. J Gerontol A Biol Sci Med Sci, 2001; 56(5):M266–M272.
96.
Falahati-NiniA., RiggsB.L., AtkinsonE.J., O’FallonW.M., EastellR., KhoslaS.Relative contributions of testosterone and estrogen in regulating bone resorption and formation in normal elderly men. J Clin Invest, 2000; 106(12):1553–1560.
97.
DoranP.M., RiggsB.L., AtkinsonE.J., KhoslaS.Effects of raloxifene, a selective estrogen receptor modulator, on bone turnover markers and serum sex steroid and lipid levels in elderly men. J Bone Miner Res, 2001; 16(11):2118–2125.
98.
MeierC., LiuP.Y., LyL.P., de Winter-ModzelewskiJ., JimenezM., HandelsmanD.J., et al.Recombinant human chorionic gonadotropin but not dihydrotestosterone alone stimulates osteoblastic collagen synthesis in older men with partial age-related androgen deficiency. J Clin Endocrinol Metab, 2004; 89(6):3033–3041.
99.
LederB.Z., LeBlancK.M., SchoenfeldD.A., EastellR., FinkelsteinJ.S.Differential effects of androgens and estrogens on bone turnover in normal men. J Clin Endocrinol Metab, 2003; 88(1):204–210.
100.
MeierC., LiuP.Y., HandelsmanD.J., SeibelM.J.Endocrine regulation of bone turnover in men. Clin Endocrinol (Oxf), 2005; 63(6):603–616.