Osteoporosis International

, Volume 19, Issue 11, pp 1517–1525 | Cite as

Sex hormones, their receptors and bone health

  • K. Venken
  • F. Callewaert
  • S. Boonen
  • D. Vanderschueren
Review

Abstract

Sex steroids regulate skeletal maturation and preservation in both men and women, as already recognized in the 1940s by Albright and Reifenstein. The impact of gonadal insufficiency on skeletal integrity has been widely recognized in adult men and women ever since. In the context of their skeletal actions, androgens and estrogens are no longer considered as just male and female hormones, respectively. Androgens can be converted into estrogens within the gonads and peripheral tissues and both are present in men and women, albeit in different concentrations. In the late 1980s, sex steroid receptors were discovered in bone cells. However, the understanding of sex steroid receptor activation and translation into biological skeletal actions is still incomplete. Due to the complex metabolism, sex steroids may have not only endocrine but also paracrine and/or autocrine actions. Also, circulating sex steroid concentrations do not necessarily reflect their biological activity due to strong binding to sex hormone binding globulin (SHBG). Finally, sex steroid signaling may include genomic and non-genomic effects in bone and non-bone cells. This review will focus on our current understanding of gonadal steroid metabolism, receptor activation, and their most relevant cellular and biological actions on bone.

Keywords

Bone growth Bone maintenance Osteoporosis Sex steroids Sex steroid receptors Sex steroid receptor signaling 

References

  1. 1.
    Melton LJ 3rd, Kan SH, Wahner HW, Riggs BL (1988) Lifetime fracture risk: an approach to hip fracture risk assessment based on bone mineral density and age. J Clin Epidemiol 41:985–994CrossRefPubMedGoogle Scholar
  2. 2.
    Wilson JD (2001) The role of 5alpha-reduction in steroid hormone physiology. Reprod Fertil Dev 13:673–678CrossRefPubMedGoogle Scholar
  3. 3.
    Simpson ER, Clyne C, Rubin G, Boon WC, Robertson K, Britt K, Speed C, Jones M (2002) Aromatase–a brief overview. Annu Rev Physiol 64:93–127CrossRefPubMedGoogle Scholar
  4. 4.
    Kaufman JM, Vermeulen A (2005) The decline of androgen levels in elderly men and its clinical and therapeutic implications. Endocr Rev 26:833–876CrossRefPubMedGoogle Scholar
  5. 5.
    Vermeulen A, Verdonk L (1968) Studies on the binding of testosterone to human plasma. Steroids 11:609–635CrossRefPubMedGoogle Scholar
  6. 6.
    Giorgi EP, Stein WD (1981) The transport of steroids into animal cells in culture. Endocrinology 108:688–697CrossRefPubMedGoogle Scholar
  7. 7.
    Khosla S, Melton LJ, Atkinson EJ, O-Fallon WM, Klee GG, Riggs BL (1998) Relationship of serum sex steroid levels and bone turnover markers with bone mineral density in men: a key role for bio-available estrogen. J Clin Endocrinol Metab 83:2266–2275PubMedGoogle Scholar
  8. 8.
    Vanderschueren D, Vandenput L, Boonen S, Lindberg MK, Bouillon R, Ohlsson C (2004) Androgens and bone. Endocr Rev 25:389–425CrossRefPubMedGoogle Scholar
  9. 9.
    Tsai MJ, O’Malley BW (1994) Molecular mechanisms of action of steroid/thyroid receptor superfamily members. Annu Rev Biochem 63:451–486CrossRefPubMedGoogle Scholar
  10. 10.
    McKenna NJ, Lanz RB, O’Malley BW (1999) Nuclear receptor coregulators: cellular and molecular biology. Endocr Rev 20:321–344PubMedGoogle Scholar
  11. 11.
    Shang Y, Myers M, Brown M (2002) Formation of the androgen receptor transcription complex. Mol Cell 9:601–610CrossRefPubMedGoogle Scholar
  12. 12.
    Weigel NL, Zhang Y (1998) Ligand-independent activation of steroid hormone receptors. J Mol Med 76:469–479CrossRefPubMedGoogle Scholar
  13. 13.
    Kushner PJ, Agard DA, Greene GL, Scanlan TS, Shiau AK, Uht RM, Webb P (2000) Estrogen receptor pathways to AP-1. J Steroid Biochem Mol Biol 74:311–317CrossRefPubMedGoogle Scholar
  14. 14.
    Whitmarsh AJ, Davis RJ (1996) Transcription factor AP-1 regulation by mitogen-activated protein kinase signal transduction pathways. J Mol Med 74:589–607CrossRefPubMedGoogle Scholar
  15. 15.
    Wiren KM, Toombs AR, Zhang XW (2004) Androgen inhibition of MAP kinase pathway and Elk-1 activation in proliferating osteoblasts. J Mol Endocrinol 32:209–226CrossRefPubMedGoogle Scholar
  16. 16.
    Safe S (2001) Transcriptional activation of genes by 17 beta-estradiol through estrogen receptor-Sp1 interactions. Vitam Horm 62:231–252CrossRefPubMedGoogle Scholar
  17. 17.
    Falkenstein E, Tillmann HC, Christ M, Feuring M, Wehling M (2000) Multiple actions of steroid hormones–a focus on rapid, nongenomic effects. Pharmacol Rev 52:513–556PubMedGoogle Scholar
  18. 18.
    Losel RM, Falkenstein E, Feuring M, Schultz A, Tillmann HC, Rossol-Haseroth K, Wehling M (2003) Nongenomic steroid action: controversies, questions, and answers. Physiol Rev 83:965–1016CrossRefPubMedGoogle Scholar
  19. 19.
    Pietras RJ, Szego CM (1977) Specific binding sites for oestrogen at the outer surfaces of isolated endometrial cells. Nature 265:69–72CrossRefPubMedGoogle Scholar
  20. 20.
    Konoplya EF, Popoff EH (1992) Identification of the classical androgen receptor in male rat liver and prostate cell plasma membranes. Int J Biochem 24:1979–1983CrossRefPubMedGoogle Scholar
  21. 21.
    Song RX, McPherson RA, Adam L, Bao Y, Shupnik M, Kumar R, Santen RJ (2002) Linkage of rapid estrogen action to MAPK activation by ERalpha-Shc association and Shc pathway activation. Mol Endocrinol 16:116–127PubMedGoogle Scholar
  22. 22.
    Migliaccio A, Castoria G, Di Domenico M, de Falco A, Bilancio A, Lombardi M, Barone MV, Ametrano D, Zannini MS, Abbondanza C, Auricchio F (2000) Steroid-induced androgen receptor-oestradiol receptor beta-Src complex triggers prostate cancer cell proliferation. Embo J 19:5406–5417CrossRefPubMedPubMedCentralGoogle Scholar
  23. 23.
    Kousteni S, Bellido T, Plotkin LI, O’Brien CA, Bodenner DL, Han L, Han K, DiGregorio GB, Katzenellenbogen JA, Katzenellenbogen BS, Roberson PK, Weinstein RS, Jilka RL, Manolagas SC (2001) Nongenotropic, sex-nonspecific signaling through the estrogen or androgen receptors: dissociation from transcriptional activity. Cell 104:719–730PubMedGoogle Scholar
  24. 24.
    Kousteni S, Han L, Chen JR, Almeida M, Plotkin LI, Bellido T, Manolagas SC (2003) Kinase-mediated regulation of common transcription factors accounts for the bone-protective effects of sex steroids. J Clin Invest 111:1651–1664CrossRefPubMedPubMedCentralGoogle Scholar
  25. 25.
    Kousteni S, Chen JR, Bellido T, Han L, Ali AA, O’Brien CA, Plotkin L, Fu Q, Mancino AT, Wen Y, Vertino AM, Powers CC, Stewart SA, Ebert R, Parfitt AM, Weinstein RS, Jilka RL, Manolagas SC (2002) Reversal of bone loss in mice by nongenotropic signaling of sex steroids. Science 298:843–846CrossRefPubMedGoogle Scholar
  26. 26.
    Moverare S, Dahllund J, Andersson N, Islander U, Carlsten H, Gustafsson JA, Nilsson S, Ohlsson C (2003) Estren is a selective estrogen receptor modulator with transcriptional activity. Mol Pharmacol 64:1428–1433CrossRefPubMedGoogle Scholar
  27. 27.
    Windahl SH, Galien R, Chiusaroli R, Clement-Lacroix P, Morvan F, Lepescheux L, Nique F, Horne WC, Resche-Rigon M, Baron R (2006) Bone protection by estrens occurs through non-tissue-selective activation of the androgen receptor. J Clin Invest 116:2500–2509CrossRefPubMedPubMedCentralGoogle Scholar
  28. 28.
    Centrella M, McCarthy TL, Chang WZ, Labaree DC, Hochberg RB (2004) Estren (4-estren-3alpha,17beta-diol) is a prohormone that regulates both androgenic and estrogenic transcriptional effects through the androgen receptor. Mol Endocrinol 18:1120–1130CrossRefPubMedGoogle Scholar
  29. 29.
    Krishnan V, Bullock HA, Yaden BC, Liu M, Barr RJ, Montrose-Rafizadeh C, Chen K, Dodge JA, Bryant HU (2005) The nongenotropic synthetic ligand 4-estren-3alpha17beta-diol is a high-affinity genotropic androgen receptor agonist. Mol Pharmacol 67:744–748CrossRefPubMedGoogle Scholar
  30. 30.
    Moverare S, Venken K, Eriksson AL, Andersson N, Skrtic S, Wergedal J, Mohan S, Salmon P, Bouillon R, Gustafsson JA, Vanderschueren D, Ohlsson C (2003) Differential effects on bone of estrogen receptor alpha and androgen receptor activation in orchidectomized adult male mice. Proc Natl Acad Sci USA 100:13573–13578CrossRefPubMedPubMedCentralGoogle Scholar
  31. 31.
    Seeman E (1997) From density to structure: growing up and growing old on the surfaces of bone. J Bone Miner Res 12:509–521CrossRefPubMedGoogle Scholar
  32. 32.
    Juul A (2001) The effects of oestrogens on linear bone growth. Hum Reprod Update 7:303–313CrossRefPubMedGoogle Scholar
  33. 33.
    Vanderschueren D, Van Herck E, Geusens P, Suiker A, Visser W, Chung K, Bouillon R (1994) Androgen resistance and deficiency have different effects on the growing skeleton of the rat. Calcif Tissue Int 55:198–203CrossRefPubMedGoogle Scholar
  34. 34.
    Kawano H, Sato T, Yamada T, Matsumoto T, Sekine K, Watanabe T, Nakamura T, Fukuda T, Yoshimura K, Yoshizawa T, Aihara K, Yamamoto Y, Nakamichi Y, Metzger D, Chambon P, Nakamura K, Kawaguchi H, Kato S (2003) Suppressive function of androgen receptor in bone resorption. Proc Natl Acad Sci USA 100:9416–9421CrossRefPubMedPubMedCentralGoogle Scholar
  35. 35.
    Vandenput L, Swinnen JV, Boonen S, Van Herck E, Erben RG, Bouillon R, Vanderschueren D (2004) Role of the androgen receptor in skeletal homeostasis: the androgen-resistant testicular feminized male mouse model. J Bone Miner Res 19:1462–1470CrossRefPubMedGoogle Scholar
  36. 36.
    Venken K, De Gendt K, Boonen S, Ophoff J, Bouillon R, Swinnen JV, Verhoeven G, Vanderschueren D (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 knock-out mouse model: A Study in the Androgen Receptor Knock-out Mouse Model. J Bone Miner Res 21:576–585CrossRefPubMedGoogle Scholar
  37. 37.
    Gennari L, Nuti R, Bilezikian JP (2004) Aromatase activity and bone homeostasis in men. J Clin Endocrinol Metab 89:5898–5907CrossRefPubMedGoogle Scholar
  38. 38.
    Smith EP, Boyd J, Frank GR, Takahashi H, Cohen RM, Specker B, Williams TC, Lubahn DB, Korach KS (1994) Estrogen resistance caused by a mutation in the estrogen-receptor gene in a man. N Engl J Med 331:1056–1061CrossRefPubMedGoogle Scholar
  39. 39.
    Seeman E (2001) Clinical review 137: Sexual dimorphism in skeletal size, density, and strength. J Clin Endocrinol Metab 86:4576–4584CrossRefPubMedGoogle Scholar
  40. 40.
    Turner RT, Wakley GK, Hannon KS (1990) Differential effects of androgens on cortical bone histomorphometry in gonadectomized male and female rats. J Orthop Res 8:612–617CrossRefPubMedGoogle Scholar
  41. 41.
    Lea C, Kendall N, Flanagan AM (1996) Casodex (a nonsteroidal antiandrogen) reduces cancellous, endosteal, and periosteal bone formation in estrogen-replete female rats. Calcif Tissue Int 58:268–272CrossRefPubMedGoogle Scholar
  42. 42.
    Dagogo-Jack S, al-Ali N, Qurttom M (1997) Augmentation of bone mineral density in hirsute women. J Clin Endocrinol Metab 82:2821–2825PubMedGoogle Scholar
  43. 43.
    Windahl SH, Vidal O, Andersson G, Gustafsson JA, Ohlsson C (1999) Increased cortical bone mineral content but unchanged trabecular bone mineral density in female ERbeta(-/-) mice. J Clin Invest 104:895–901CrossRefPubMedPubMedCentralGoogle Scholar
  44. 44.
    Bouillon R, Bex M, Vanderschueren D, Boonen S (2004) Estrogens are essential for male pubertal periosteal bone expansion. J Clin Endocrinol Metab 89:6025–6029CrossRefPubMedGoogle Scholar
  45. 45.
    Rochira V, Zirilli L, Madeo B, Aranda C, Caffagni G, Fabre B, Montangero VE, Roldan EJ, Maffei L, Carani C (2007) Skeletal effects of long-term estrogen and testosterone replacement treatment in a man with congenital aromatase deficiency: evidences of a priming effect of estrogen for sex steroids action on bone. Bone 40:1662–1668CrossRefPubMedGoogle Scholar
  46. 46.
    Vidal O, Lindberg MK, Hollberg K, Baylink DJ, Andersson G, Lubahn DB, Mohan S, Gustafsson JA, Ohlsson C (2000) Estrogen receptor specificity in the regulation of skeletal growth and maturation in male mice. Proc Natl Acad Sci USA 97:5474–5479CrossRefPubMedPubMedCentralGoogle Scholar
  47. 47.
    Vanderschueren D, van Herck E, Nijs J, Ederveen AG, De Coster R, Bouillon R (1997) Aromatase inhibition impairs skeletal modeling and decreases bone mineral density in growing male rats. Endocrinology 138:2301–2307PubMedGoogle Scholar
  48. 48.
    Vanderschueren D, Venken K, Bouillon R (2004) Animal models for gender-based skeletal differences. In: Legato M (ed) Principles of gender-specific medicine. Elsevier Academic Press, pp 1043–1051Google Scholar
  49. 49.
    Bass S, Delmas PD, Pearce G, Hendrich E, Tabensky A, Seeman E (1999) The differing tempo of growth in bone size, mass, and density in girls is region-specific. J Clin Invest 104:795–804CrossRefPubMedPubMedCentralGoogle Scholar
  50. 50.
    Jarvinen TL, Kannus P, Sievanen H (2003) Estrogen and bone–a reproductive and locomotive perspective. J Bone Miner Res 18:1921–1931CrossRefPubMedGoogle Scholar
  51. 51.
    Behre HM, Kliesch S, Leifke E, Link TM, Nieschlag E (1997) Long-term effect of testosterone therapy on bone mineral density in hypogonadal men. J Clin Endocrinol Metab 82:2386–2390CrossRefPubMedGoogle Scholar
  52. 52.
    Manolagas SC (2000) Birth and death of bone cells: basic regulatory mechanisms and implications for the pathogenesis and treatment of osteoporosis. Endocr Rev 21:115–137PubMedGoogle Scholar
  53. 53.
    Riggs BL (2000) The mechanisms of estrogen regulation of bone resorption. J Clin Invest 106:1203–1204CrossRefPubMedPubMedCentralGoogle Scholar
  54. 54.
    Hughes DE, Dai A, Tiffee JC, Li HH, Mundy GR, Boyce BF (1996) Estrogen promotes apoptosis of murine osteoclasts mediated by TGF-b. Nat Med 2:1132–1136CrossRefPubMedGoogle Scholar
  55. 55.
    Michael H, Harkonen PL, Vaananen HK, Hentunen TA (2005) Estrogen and testosterone use different cellular pathways to inhibit osteoclastogenesis and bone resorption. J Bone Miner Res 20:2224–2232CrossRefPubMedGoogle Scholar
  56. 56.
    Nakamura T, Imai Y, Matsumoto T, Sato S, Takeuchi K, Igarashi K, Harada Y, Azuma Y, Krust A, Yamamoto Y, Nishina H, Takeda S, Takayanagi H, Metzger D, Kanno J, Takaoka K, Martin TJ, Chambon P, Kato S (2007) Estrogen Prevents Bone Loss via Estrogen Receptor alpha and Induction of Fas Ligand in Osteoclasts. Cell 130:811–823CrossRefPubMedGoogle Scholar
  57. 57.
    Chen Q, Kaji H, Kanatani M, Sugimoto T, Chihara K (2004) Testosterone increases osteoprotegerin mRNA expression in mouse osteoblast cells. Horm Metab Res 36:674–678CrossRefPubMedGoogle Scholar
  58. 58.
    Bellido T, Jilka RL, Boyce BF, Girasole G, Broxmeyer H, Dalrymple SA, Murray R, Manolagas SC (1995) Regulation of interleukin-6, osteoclastogenesis, and bone mass by androgens. The role of the androgen receptor. J Clin Invest 95:2886–2895CrossRefPubMedPubMedCentralGoogle Scholar
  59. 59.
    Huber DM, Bendixen AC, Pathrose P, Srivastava S, Dienger KM, Shevde NK, Pike JW (2001) Androgens suppress osteoclast formation induced by RANKL and macrophage-colony stimulating factor. Endocrinology 142:3800–3808CrossRefPubMedGoogle Scholar
  60. 60.
    Riggs BL, Khosla S, Melton LJ 3rd (2002) Sex steroids and the construction and conservation of the adult skeleton. Endocr Rev 23:279–302CrossRefPubMedGoogle Scholar
  61. 61.
    Seeman E (2002) Pathogenesis of bone fragility in women and men. Lancet 359:1841–1850CrossRefPubMedGoogle Scholar
  62. 62.
    Seeman E (2003) Periosteal bone formation–a neglected determinant of bone strength. N Engl J Med 349:320–323CrossRefPubMedGoogle Scholar
  63. 63.
    Vandenput L, Boonen S, Van Herck E, Swinnen JV, Bouillon R, Vanderschueren D (2002) Evidence from the aged orchidectomized male rat model that 17beta-estradiol is a more effective bone-sparing and anabolic agent than 5alpha-dihydrotestosterone. J Bone Miner Res 17:2080–2086CrossRefPubMedGoogle Scholar
  64. 64.
    Venken K, Boonen S, Van Herck E, Vandenput L, Kumar N, Sitruk-Ware R, Sundaram K, Bouillon R, Vanderschueren D (2005) Bone and muscle protective potential of the prostate-sparing synthetic androgen 7alpha-methyl-19-nortestosterone: Evidence from the aged orchidectomized male rat model. Bone 36:663–670CrossRefPubMedGoogle Scholar
  65. 65.
    Riggs BL, Parfitt AM (2005) Drugs used to treat osteoporosis: the critical need for a uniform nomenclature based on their action on bone remodeling. J Bone Miner Res 20:177–184CrossRefPubMedGoogle Scholar
  66. 66.
    Barrett-Connor E, Mueller JE, van Mühlen DG, Laughlin GA, Schneider DL, Sartoris DJ (2000) Low levels of estradiol are associated with vertebral fractures in older men but not in women. The Rancho Bernardo Study. J Clin Endocrinol Metab 85:219–223PubMedGoogle Scholar
  67. 67.
    Van Pottelbergh I, Goemaere S, Kaufman JM (2003) Bioavailable estradiol and an aromatase gene polymorphism are determinants of bone mineral density changes in men over 70 years of age. J Clin Endocrinol Metab 88:3075–3081CrossRefPubMedGoogle Scholar
  68. 68.
    Riggs BL, Khosla S, Melton LJ 3rd (1998) A unitary model for involutional osteoporosis: estrogen deficiency causes both type I and type II osteoporosis in postmenopausal women and contributes to bone loss in aging men. J Bone Miner Res 13:763–773CrossRefPubMedGoogle Scholar
  69. 69.
    Eastell R (2007) Aromatase inhibitors and bone. J Steroid Biochem Mol Biol 106:157–161CrossRefPubMedGoogle Scholar
  70. 70.
    Snyder PJ, Peachey H, Hannoush P, Berlin JA, Loh L, Holmes JH, Dlewati A, Staley J, Santanna J, Kapoor SC, Attie MF, Haddad Jr JG, Strom BL (1999) Effect of testosterone treatment on bone mineral density in men over 65 years of age. J Clin Endocrinol Metab 84:1966–1972PubMedGoogle Scholar
  71. 71.
    Kenny AM, Prestwood KM, Marcello KM, Raisz LG (2000) Determinants of bone density in healthy older men with low testosterone levels. J Gerontol A Biol Sci Med Sci 55A:M492–M497CrossRefGoogle Scholar
  72. 72.
    Emmelot-Vonk MH, Verhaar HJ, Nakhai Pour HR, Aleman A, Lock TM, Bosch JL, Grobbee DE, van der Schouw YT (2008) Effect of testosterone supplementation on functional mobility, cognition, and other parameters in older men: a randomized controlled trial. Jama 299:39–52PubMedGoogle Scholar
  73. 73.
    Rossouw JE, Anderson GL, Prentice RL, LaCroix AZ, Kooperberg C, Stefanick ML, Jackson RD, Beresford SA, Howard BV, Johnson KC, Kotchen JM, Ockene J (2002) Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results From the Women’s Health Initiative randomized controlled trial. Jama 288:321–333CrossRefPubMedGoogle Scholar
  74. 74.
    Anderson GL, Limacher M, Assaf AR, Bassford T, Beresford SA, Black H, Bonds D, Brunner R, Brzyski R, Caan B, Chlebowski R, Curb D, Gass M, Hays J, Heiss G, Hendrix S, Howard BV, Hsia J, Hubbell A, Jackson R, Johnson KC, Judd H, Kotchen JM, Kuller L, LaCroix AZ, Lane D, Langer RD, Lasser N, Lewis CE, Manson J, Margolis K, Ockene J, O’Sullivan MJ, Phillips L, Prentice RL, Ritenbaugh C, Robbins J, Rossouw JE, Sarto G, Stefanick ML, Van Horn L, Wactawski-Wende J, Wallace R, Wassertheil-Smoller S (2004) Effects of conjugated equine estrogen in postmenopausal women with hysterectomy: the Women’s Health Initiative randomized controlled trial. Jama 291:1701–1712CrossRefPubMedGoogle Scholar
  75. 75.
    Johnell O, Kanis JA, Black DM, Balogh A, Poor G, Sarkar S, Zhou C, Pavo I (2004) Associations between baseline risk factors and vertebral fracture risk in the Multiple Outcomes of Raloxifene Evaluation (MORE) Study. J Bone Miner Res 19:764–772CrossRefPubMedGoogle Scholar
  76. 76.
    Seeman E, Crans GG, Diez-Perez A, Pinette KV, Delmas PD (2006) Anti-vertebral fracture efficacy of raloxifene: a meta-analysis. Osteoporos Int 17:313–316CrossRefPubMedGoogle Scholar
  77. 77.
    McDonnell DP, Clemm DL, Hermann T, Goldman ME, Pike JW (1995) Analysis of estrogen receptor function in vitro reveals three distinct classes of antiestrogens. Mol Endocrinol 9:659–669PubMedGoogle Scholar
  78. 78.
    Chen J, Kim J, Dalton JT (2005) Discovery and therapeutic promise of selective androgen receptor modulators. Mol Interv 5:173–188CrossRefPubMedPubMedCentralGoogle Scholar
  79. 79.
    Bhasin S, Calof OM, Storer TW, Lee ML, Mazer NA, Jasuja R, Montori VM, Gao W, Dalton JT (2006) Drug insight: Testosterone and selective androgen receptor modulators as anabolic therapies for chronic illness and aging. Nat Clin Pract Endocrinol Metab 2:146–159CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© International Osteoporosis Foundation and National Osteoporosis Foundation 2008

Authors and Affiliations

  • K. Venken
    • 1
  • F. Callewaert
    • 1
  • S. Boonen
    • 1
  • D. Vanderschueren
    • 1
  1. 1.Bone Research Unit, Laboratory for Experimental Medicine and Endocrinology, Department of Experimental MedicineKatholieke Universiteit LeuvenLeuvenBelgium

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