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01-01-2015 | Editorial

Estrogens, the be-all and end-all of male hypogonadal bone loss?

Authors: M. R. Laurent, E. Gielen, D. Vanderschueren

Published in: Osteoporosis International | Issue 1/2015

Excerpt

Gender is one of the strongest predictors of osteoporotic fracture risk, second only to ageing. A recent systematic review of worldwide epidemiology revealed that hip fracture incidence is about twofold lower in men compared to women, despite greater than tenfold variation between geographic regions [1]. This lower fracture incidence occurs despite persisting underdiagnosis and undertreatment of osteoporosis in men, which probably explains why hip fracture incidence may be decreasing in women but not men [2‐5]. It is well known that men generally have a more robust body composition; even after correction for an average 10 % greater height and bone length, men at the age of peak bone mass have 25 % greater bone mineral content [6], almost 50 % greater muscle mass and power and half the fat mass of women [7]. Conversely, late-onset male hypogonadism increases the risk of bone loss, muscle atrophy and fat accumulation [3, 8]. Understanding the underlying mechanisms involved in this gender dimorphism in body composition may thus identify additional therapeutic targets not only for osteoporosis, but also for sarcopenia and obesity. …

Kanis JA, Oden A, McCloskey EV, Johansson H, Wahl DA, Cooper C (2012) A systematic review of hip fracture incidence and probability of fracture worldwide. Osteoporos Int 23(9):2239–2256PubMedCentralPubMedCrossRef

Hiligsmann M, Bruyère O, Roberfroid D, Dubois C, Parmentier Y, Carton J et al (2012) Trends in hip fracture incidence and in the prescription of antiosteoporosis medications during the same time period in Belgium (2000–2007). Arthritis Care Res (Hoboken) 64(5):744–750CrossRef

Laurent M, Gielen E, Claessens F, Boonen S, Vanderschueren D (2013) Osteoporosis in older men: recent advances in pathophysiology and treatment. Best Pract Res Clin Endocrinol Metab 27(4):527–539PubMedCrossRef

Amin S, Achenbach SJ, Atkinson EJ, Khosla S, Melton LJ 3rd (2014) Trends in fracture incidence: a population-based study over 20 years. J Bone Miner Res 29(3):581–589PubMedCrossRef

Siggeirsdottir K, Aspelund T, Jonsson BY, Mogensen B, Gudmundsson EF, Gudnason V et al (2014) Epidemiology of fractures in Iceland and secular trends in major osteoporotic fractures 1989–2008. Osteoporos Int 25(1):211–219PubMedCrossRef

Riggs BL, Khosla S, Melton LJ 3rd (2002) Sex steroids and the construction and conservation of the adult skeleton. Endocr Rev 23(3):279–302PubMedCrossRef

Lindle RS, Metter EJ, Lynch NA, Fleg JL, Fozard JL, Tobin J et al (1997) Age and gender comparisons of muscle strength in 654 women and men aged 20–93 yr. J Appl Physiol (1985) 83(5):1581–1587

Tajar A, Huhtaniemi IT, O’Neill TW, Finn JD, Pye SR, Lee DM et al (2012) Characteristics of androgen deficiency in late-onset hypogonadism: results from the European Male Aging Study (EMAS). J Clin Endocrinol Metab 97(5):1508–1516PubMedCrossRef

Van Caenegem E, Wierckx K, Taes Y, Schreiner T, Vandewalle S, Toye K, et al. (2014) Preservation of volumetric bone density and geometry in trans women during cross-sex hormonal therapy: a prospective observational study. Osteoporos Int. doi:10.1007/s00198-014-2805-3

10.

Van Caenegem E, Wierckx K, Taes Y, Dedecker D, Van de Peer F, Toye K et al (2012) Bone mass, bone geometry, and body composition in female-to-male transsexual persons after long-term cross-sex hormonal therapy. J Clin Endocrinol Metab 97(7):2503–2511PubMedCrossRef

11.

Laurent M, Antonio L, Sinnesael M, Dubois V, Gielen E, Claessens F et al (2014) Androgens and estrogens in skeletal sexual dimorphism. Asian J Androl 16(2):213–222PubMedCentralPubMedCrossRef

12.

Callewaert F, Venken K, Ophoff J, De Gendt K, Torcasio A, van Lenthe GH et al (2009) Differential regulation of bone and body composition in male mice with combined inactivation of androgen and estrogen receptor-alpha. FASEB J 23(1):232–240PubMedCrossRef

13.

Wiren KM, Zhang XW, Toombs AR, Kasparcova V, Gentile MA, Harada S et al (2004) Targeted overexpression of androgen receptor in osteoblasts: unexpected complex bone phenotype in growing animals. Endocrinology 145(7):3507–3522PubMedCrossRef

14.

Dubois V, Laurent MR, Sinnesael M, Cielen N, Helsen C, Clinckemalie L et al (2014) A satellite cell-specific knockout of the androgen receptor reveals myostatin as a direct androgen target in skeletal muscle. FASEB J 28(7):2979–2994PubMedCrossRef

15.

Ophoff J, Van Proeyen K, Callewaert F, De Gendt K, De Bock K, Vanden Bosch A et al (2009) Androgen signaling in myocytes contributes to the maintenance of muscle mass and fiber type regulation but not to muscle strength or fatigue. Endocrinology 150(8):3558–3566PubMedCrossRef

16.

McInnes KJ, Smith LB, Hunger NI, Saunders PT, Andrew R, Walker BR (2012) Deletion of the androgen receptor in adipose tissue in male mice elevates retinol binding protein 4 and reveals independent effects on visceral fat mass and on glucose homeostasis. Diabetes 61(5):1072–1081PubMedCentralPubMedCrossRef

17.

Venken K, De Gendt K, Boonen S, Ophoff J, Bouillon R, Swinnen JV et al (2006) Relative impact of androgen and estrogen receptor activation in the effects of androgens on trabecular and cortical bone in growing male mice: a study in the androgen receptor knockout mouse model. J Bone Miner Res 21(4):576–585PubMedCrossRef

18.

Argoud T, Boutroy S, Claustrat B, Chapurlat R, Szulc P (2014) Association between sex steroid levels and bone microarchitecture in men: the STRAMBO study. J Clin Endocrinol Metab 99(4):1400–1410PubMedCrossRef

19.

Ward KA, Pye SR, Adams JE, Boonen S, Vanderschueren D, Borghs H et al (2011) Influence of age and sex steroids on bone density and geometry in middle-aged and elderly European men. Osteoporos Int 22(5):1513–1523PubMedCentralPubMedCrossRef

20.

van den Beld AW, de Jong FH, Grobbee DE, Pols HA, Lamberts SW (2000) Measures of bioavailable serum testosterone and estradiol and their relationships with muscle strength, bone density, and body composition in elderly men. J Clin Endocrinol Metab 85(9):3276–3282PubMed

21.

Renoud A, Ecochard R, Marchand F, Chapurlat R, Szulc P (2014) Predictive parameters of accelerated muscle loss in men-MINOS study. Am J Med 127(6):554–561PubMedCrossRef

22.

Amin S, Zhang Y, Felson DT, Sawin CT, Hannan MT, Wilson PW et al (2006) Estradiol, testosterone, and the risk for hip fractures in elderly men from the Framingham Study. Am J Med 119(5):426–433PubMedCrossRef

23.

Meier C, Nguyen TV, Handelsman DJ, Schindler C, Kushnir MM, Rockwood AL et al (2008) Endogenous sex hormones and incident fracture risk in older men: the Dubbo Osteoporosis Epidemiology Study. Arch Intern Med 168(1):47–54PubMedCrossRef

24.

LeBlanc ES, Nielson CM, Marshall LM, Lapidus JA, Barrett-Connor E, Ensrud KE et al (2009) The effects of serum testosterone, estradiol, and sex hormone binding globulin levels on fracture risk in older men. J Clin Endocrinol Metab 94(9):3337–3346PubMedCentralPubMedCrossRef

25.

Woo J, Kwok T, Leung JC, Ohlsson C, Vandenput L, Leung PC (2012) Sex steroids and bone health in older Chinese men. Osteoporos Int 23(5):1553–1562PubMedCrossRef

26.

Khosla S (2010) Update in male osteoporosis. J Clin Endocrinol Metab 95(1):3–10PubMedCentralPubMedCrossRef

27.

Laurent MR, Vanderschueren D (2014) Reproductive endocrinology: functional effects of sex hormone-binding globulin variants. Nat Rev Endocrinol. doi:10.1038/nrendo.2014.120 PubMed

28.

Smith MR, Fallon MA, Lee H, Finkelstein JS (2004) Raloxifene to prevent gonadotropin-releasing hormone agonist-induced bone loss in men with prostate cancer: a randomized controlled trial. J Clin Endocrinol Metab 89(8):3841–3846PubMedCrossRef

29.

Smith MR, Morton RA, Barnette KG, Sieber PR, Malkowicz SB, Rodriguez D et al (2010) Toremifene to reduce fracture risk in men receiving androgen deprivation therapy for prostate cancer. J Urol 184(4):1316–1321PubMedCentralPubMedCrossRef

30.

Burnett-Bowie SA, McKay EA, Lee H, Leder BZ (2009) Effects of aromatase inhibition on bone mineral density and bone turnover in older men with low testosterone levels. J Clin Endocrinol Metab 94(12):4785–4792PubMedCentralPubMedCrossRef

31.

Idan A, Griffiths KA, Harwood DT, Seibel MJ, Turner L, Conway AJ et al (2010) Long-term effects of dihydrotestosterone treatment on prostate growth in healthy, middle-aged men without prostate disease: a randomized, placebo-controlled trial. Ann Intern Med 153(10):621–632PubMedCrossRef

32.

Falahati-Nini A, Riggs BL, Atkinson EJ, O’Fallon WM, Eastell R, Khosla S (2000) Relative contributions of testosterone and estrogen in regulating bone resorption and formation in normal elderly men. J Clin Invest 106(12):1553–1560PubMedCentralPubMedCrossRef

33.

Leder BZ, LeBlanc KM, Schoenfeld DA, Eastell R, Finkelstein JS (2003) Differential effects of androgens and estrogens on bone turnover in normal men. J Clin Endocrinol Metab 88(1):204–210PubMedCrossRef

34.

Meier C, Liu PY, Ly LP, de Winter-Modzelewski J, Jimenez M, Handelsman DJ et al (2004) 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 89(6):3033–3041PubMedCrossRef

35.

Finkelstein JS, Lee H, Burnett-Bowie SA, Pallais JC, Yu EW, Borges LF et al (2013) Gonadal steroids and body composition, strength, and sexual function in men. N Engl J Med 369(11):1011–1022PubMedCentralPubMedCrossRef

36.

Yu E, Wulcyzn K, Webb W, Perros N, Bouxsein M, Finkelstein J (2012) Hypogonadism with Estrogen Removal (HER): differential effects of androgens and estrogens on bone microarchitecture in adult men. J Bone Miner Res 27(Suppl 1)

37.

Tracz MJ, Sideras K, Bolona ER, Haddad RM, Kennedy CC, Uraga MV et al (2006) Testosterone use in men and its effects on bone health. A systematic review and meta-analysis of randomized placebo-controlled trials. J Clin Endocrinol Metab 91(6):2011–2016PubMedCrossRef

38.

Basaria S, Coviello AD, Travison TG, Storer TW, Farwell WR, Jette AM et al (2010) Adverse events associated with testosterone administration. N Engl J Med 363(2):109–122PubMedCentralPubMedCrossRef

39.

Ferlin A, Selice R, Carraro U, Foresta C (2013) Testicular function and bone metabolism—beyond testosterone. Nat Rev Endocrinol 9(9):548–554PubMedCrossRef

40.

Allan CM, Kalak R, Dunstan CR, McTavish KJ, Zhou H, Handelsman DJ et al (2010) Follicle-stimulating hormone increases bone mass in female mice. Proc Natl Acad Sci U S A 107(52):22629–22634PubMedCentralPubMedCrossRef

41.

Uihlein AV, Finkelstein JS, Lee H, Leder BZ (2014) FSH suppression does not affect bone turnover in eugonadal men. J Clin Endocrinol Metab 99(7):2510–2515PubMedCrossRef

42.

Perrien DS, Akel NS, Edwards PK, Carver AA, Bendre MS, Swain FL et al (2007) Inhibin A is an endocrine stimulator of bone mass and strength. Endocrinology 148(4):1654–1665PubMedCrossRef

43.

Perrien DS, Achenbach SJ, Bledsoe SE, Walser B, Suva LJ, Khosla S et al (2006) Bone turnover across the menopause transition: correlations with inhibins and follicle-stimulating hormone. J Clin Endocrinol Metab 91(5):1848–1854PubMedCrossRef

44.

Foresta C, Strapazzon G, De Toni L, Perilli L, Di Mambro A, Muciaccia B et al (2011) Bone mineral density and testicular failure: evidence for a role of vitamin D 25-hydroxylase in human testis. J Clin Endocrinol Metab 96(4):E646–E652PubMedCrossRef

45.

Estrada K, Styrkarsdottir U, Evangelou E, Hsu YH, Duncan EL, Ntzani EE et al (2012) Genome-wide meta-analysis identifies 56 bone mineral density loci and reveals 14 loci associated with risk of fracture. Nat Genet 44(5):491–501PubMedCentralPubMedCrossRef

46.

Oury F, Ferron M, Huizhen W, Confavreux C, Xu L, Lacombe J et al (2013) Osteocalcin regulates murine and human fertility through a pancreas-bone-testis axis. J Clin Invest 123(6):2421–2433PubMedCentralPubMedCrossRef

47.

Schwartz AV, Schafer AL, Grey A, Vittinghoff E, Palermo L, Lui LY et al (2013) Effects of antiresorptive therapies on glucose metabolism: results from the FIT, HORIZON-PFT, and FREEDOM trials. J Bone Miner Res 28(6):1348–1354PubMedCrossRef

48.

Andrews NA (2013) Skeletal regulation of glucose metabolism: challenges in translation from mouse to man. IBMS BoneKEy 10(353) doi:10.1038/bonekey.2013.87

Title: Estrogens, the be-all and end-all of male hypogonadal bone loss?
Authors: M. R. Laurent
E. Gielen
D. Vanderschueren
Publication date: 01-01-2015
Publisher: Springer London
Published in: Osteoporosis International / Issue 1/2015
Print ISSN: 0937-941X
Electronic ISSN: 1433-2965
DOI: https://doi.org/10.1007/s00198-014-2865-4

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