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Estrogen, androgen, and the pathogenesis of bone fragility in women and men

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Abstract

During growth, estrogen deficiency in females may produce increased bone size as a result of removal of inhibition of periosteal apposition, while failed endosteal apposition produces thin cortices and trabeculae in the smaller bone. In males, androgen deficiency produces reduced periosteal and endosteal apposition, reduced bone size, and cortical and trabecular thickness. At completion of longitudinal growth, advancing age is associated with emergence of a negative bone balance in each basic multicellular unit (BMU) because of reduced bone formation. Bone loss occurs, but slowly because the remodeling rate is slow. In midlife, in females, estrogen deficiency increases remodeling rate, increases the volume of bone resorbed, and decreases the volume of bone formed in each of the numerous BMUs remodeling bone on its endosteal (endocortical, trabecular, intracortical) surfaces so bone loss accelerates. In males, remodeling rate remains slow and is driven largely by reduced bone formation in the BMU. Hypogonadism in 20% to 30% of elderly men contributes to bone loss. In both sexes, calcium malabsorption and secondary hyperparathyroidism may partly be sex-hormone dependent and contributes to cortical bone loss. Concurrent periosteal apposition partly offsets endosteal bone loss, but less so in women than in men. More women than men fracture because their smaller skeleton incurs greater architectural damage and adapts less by periosteal apposition. Sex hormone deficiency during growth and aging is pivotal in the pathogenesis of bone fragility.

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References and Recommended Reading

  1. Parfitt AM: Skeletal heterogeneity and the purposes of bone remodelling; implications for the understanding of osteoporosis. In Osteoporosis. Edited by Marcus R, Feldman D, Kelsey J. San Diego: Academic Press; 2001:433–444.

    Google Scholar 

  2. Seeman E: From density to structure: growing up and growing old on the surfaces of bone. J Bone Miner Res 1997, 12:1–13.

    Article  Google Scholar 

  3. Seeman E: Growth in bone mass and size are racial and gender differences in bone mineral density are more apparent than real? J Clin Endocrinol Metab 1998, 83:1414–1419.

    Article  PubMed  CAS  Google Scholar 

  4. Lu PW, Cowell CT, Lloyd-Jones SA, et al.: Volumetric bone mineral density in normal subjects aged 5–27 years. J Clin Endocrinol Metab 1996, 81:1586–1590.

    Article  PubMed  CAS  Google Scholar 

  5. Duan Y, Turner CH, Kim BT, Seeman E: Sexual dimorphism in vertebral fragility is more the result of gender differences in age-related bone gain than bone loss. J Bone Miner Res 2001, 16:2267–2275. This paper emphasizes the important role of periosteal apposition in offsetting the loss of bone strength and loss of vertebral volumetric density produced by endosteal bone loss during aging.

    Article  PubMed  CAS  Google Scholar 

  6. Duan Y, Parfitt M, Seeman E: Vertebral bone mass, size and volumetric bone mineral density in premenopausal women, and postmenopausal women with and without spine fractures. J Bone Miner Res 1999, 14:1796–1802.

    Article  PubMed  CAS  Google Scholar 

  7. Tabensky A, Duan Y, Edmonds J, Seeman E: The contribution of reduced peak accrual of bone and age-related bone loss to osteoporosis at the spine and hip: insights from the daughters of women with vertebral or hip fractures. J Bone Miner Res 2001, 16:1101–1107.

    Article  PubMed  CAS  Google Scholar 

  8. Riggs BL, Wahner HW, Dunn WL, et al.: Differential changes in bone mineral density of the appendicular and axial skeleton with aging: relationship to spinal osteoporosis. J Clin Invest 1981, 67:328–335.

    PubMed  CAS  Google Scholar 

  9. Eastell R, Wahner HW, O’Fallon WM, et al.: Unequal decrease in bone density of lumbar spine and ultradistal radius in Colles’ and vertebral fracture syndromes. J Clin Invest 1989, 83:168–174.

    PubMed  CAS  Google Scholar 

  10. Riggs BL, Melton LJ III: Evidence for two distinct syndromes of involutional osteoporosis. Am J Med 1983, 75:899–901.

    Article  PubMed  CAS  Google Scholar 

  11. Gilsanz V, Loro ML, Roe TF, et al.: Vertebral size in elderly women with osteoporosis. J Clin Invest 1995, 95:2332–2337.

    PubMed  CAS  Google Scholar 

  12. Seeman E, Duan Y, Fong C, Edmonds J: Fracture site-specific deficits in bone size and volumetric density in men with spine or hip fractures. J Bone Miner Res 2001, 16:120–127.

    Article  PubMed  CAS  Google Scholar 

  13. Vega E, Ghiringhelli G, Mautalen C, et al.: Bone mineral density and bone size in men with primary osteoporosis and vertebral fractures. Calcif Tissue Int 1988, 62:465–469.

    Article  Google Scholar 

  14. Meunier PJ, Sellami S, Briancon D, Edouard C: Histological heterogeneity of apparently idiopathic osteoporosis. In Osteoporosis: Recent Advances in Pathogenesis and Treatment. Edited by Deluca HF, Frost HM, Jee WSS, Johnston CC, Parfitt AM. Baltimore: University Park Press; 1990:293–301.

    Google Scholar 

  15. Oleksik A, Ott SM, Vedi S, et al.: Bone structure in patients with low bone mineral density with or without vertebral fracture. J Bone Miner Res 2000, 15:1368–1375.

    Article  PubMed  CAS  Google Scholar 

  16. Eriksen EF, Hodgson SF, Eastell R, et al.: Cancellous bone remodeling in type I (postmenopausal) osteoporosis: quantitative assessment of rates of formation, resorption, and bone loss at tissue and cellular levels. J Bone Miner Res 1990, 5:311–319.

    PubMed  CAS  Google Scholar 

  17. Hordon LD, Raisi M, Aaron JE, et al.: Trabecular architecture in women and men of similar bone mass with and without vertebral fracture: I: two-dimensional histology. Bone 2001, 27:271–276.

    Article  Google Scholar 

  18. Kimmel DB, Recker RR, Gallagher JC, et al.: A comparison of iliac bone histomorphometric data in post-menopausal osteoporotic and normal subjects. Bone Miner 1990, 11:217–235.

    Article  PubMed  CAS  Google Scholar 

  19. Foldes J, Parfitt AM, Shih M-S, et al.: Structural and geometric changes in iliac bone: relationship to normal aging and osteoporosis. J Bone Miner Res 1991, 6:759–766.

    PubMed  CAS  Google Scholar 

  20. Legrand E, Chappard D, Pascaretti C, et al.: Trabecular bone microarchitecture, bone mineral density and vertebral fractures in male osteoporosis. J Bone Miner Res 2000, 15:13–19.

    Article  PubMed  CAS  Google Scholar 

  21. Beck TJ, Ruff CB, Scott WW Jr, et al.: Sex differences in geometry of the femoral neck with aging: a structural analysis of bone mineral data. Calcif Tissue Int 1992, 50:24–29.

    Article  PubMed  CAS  Google Scholar 

  22. Boonen S, Koutri R, Dequeker J, et al.: Measurement of femoral geometry in type I and type II osteoporosis: differences in hip axis length consistent with heterogeneity in the pathogenesis of osteoporotic fractures. J Bone Miner Res 1995, 10:1908–1912.

    PubMed  CAS  Google Scholar 

  23. Cheng XG, Lowet G, Boonen S, et al.: Assessment of the strength of proximal femur in vitro: relationship to femoral bone mineral density and femoral geometry. Bone 1997, 20:213–218.

    Article  PubMed  CAS  Google Scholar 

  24. Karlsson KM, Sernbo I, Obrant KJ, et al.: Femoral neck geometry and radiographic signs of osteoporosis as predictors of hip fracture. Bone 1996, 18:327–330.

    Article  PubMed  CAS  Google Scholar 

  25. Jordan GR, Loveridge N, Bell KL, et al.: Spatial clustering of remodeling osteons in the femoral neck cortex: a cause of weakness in hip fracture? Bone 2000, 26:305–313.

    Article  PubMed  CAS  Google Scholar 

  26. Seeman E, Hopper JL, Bach L, et al.: Reduced bone mass in the daughters of women with osteoporosis. N Engl J Med 1989, 320:554–558.

    Article  PubMed  CAS  Google Scholar 

  27. Cohen-Solal ME, Baudoin C, Omouri M, et al.: Bone mass in middle-aged osteoporotic men and their relatives: familial effect. J Bone Miner Res 1998, 13:1909–1914.

    Article  PubMed  CAS  Google Scholar 

  28. Duan Y, Seeman E: Proximal femoral dimensions in women and men with hip fractures. Unpublished data.

  29. Beck TJ, Oreskovic TL, Stone KL, et al.: Structural adaptation to changing skeletal load in the progression toward hip fragility: the study of osteoporotic fractures. J Bone Miner Res 2000, 16:1106–1119.

    Google Scholar 

  30. Tupman GS: A study of bone growth in normal children and its relationship to skeletal maturation. J Bone Joint Surg 1962, 44:42–67.

    Google Scholar 

  31. Duval-Beaupere G, Combes J: Segments superieur et inferieur au cours de la croissance physiologue des filles. Arch Franc Ped 1971, 28:1057–1071.

    CAS  Google Scholar 

  32. Bass S, Delmas PD, Pearce G, et al.: The differing tempo of growth in bone size, mass and density in girls is regionspecific. J Clin Invest 1999, 104:795–804.

    PubMed  CAS  Google Scholar 

  33. Smith EP, Boyd J, Frank GR, et al.: Estrogen resistance caused by a mutation in the estrogen receptor gene in a man. N Engl J Med 1994, 331:1056–1061.

    Article  PubMed  CAS  Google Scholar 

  34. Carani C, Qin K, Simoni M, et al.: Effect of testosterone and estradiol in a man with aromatase deficiency. N Engl J Med 1997, 337:91–95.

    Article  PubMed  CAS  Google Scholar 

  35. Bilezikian JP, Morishiman A, Bell J, Grumbach MM: Increased bone mass as a result of estrogen therapy in a man with aromatase deficiency. N Engl J Med 1998, 339:599–603.

    Article  PubMed  CAS  Google Scholar 

  36. Seeman E, Karlsson MK, Duan Y: On exposure to anorexia nervosa, the temporal variation in axial and appendicular skeletal development predisposes to site-specific deficits in bone size and density: a cross-sectional study. J Bone Miner Res 2000, 5:2259–2265.

    Article  Google Scholar 

  37. Garn S: The earlier gain and later loss of cortical bone. In Nutritional Perspectives. Springfield: Charles C. Thomas; 1970:3–120.

  38. Schoenau E, Neu CM, Mokov E, et al.: Influence of puberty on muscle area and cortical bone area of the forearm in boys and girls. J Clin Endocrinol Metab 2000, 85:1095–1098.

    Article  PubMed  CAS  Google Scholar 

  39. Bradney M, Karlsson MK, Duan Y, et al.: Heterogeneity in the growth of the axial and appendicular skeleton in boys: implications for the pathogenesis of bone fragility in men. J Bone Miner Res 2000, 15:1871–1878.

    Article  PubMed  CAS  Google Scholar 

  40. Finkelstein JS, Neer RM, Biller BMK, et al.: Osteopenia in men with a history of delayed puberty. N Engl J Med 1992, 326:600–604.

    Article  PubMed  CAS  Google Scholar 

  41. Finkelstein JS, Klibanski A, Neer RM: A longitudinal evaluation of bone mineral density in adult men with histories of delayed puberty. J Clin Endocrinol Metab 1996, 81:1152–1155.

    Article  PubMed  CAS  Google Scholar 

  42. Bertelloni S, Baroncelli GI, Fereghini M, et al.: Normal volumetric bone density and bone turnover in young men with histories of constitutional delay of puberty. J Clin Endocrinol Metab 1998, 83:4280–4283.

    Article  PubMed  CAS  Google Scholar 

  43. Moore B, Briody J, Cowell CT, Mobbs E: Does maturational delay affect bone mineral density? [abstract]. Horm Res 1997, 48(Suppl 2):91.

    Google Scholar 

  44. Zhang XZ, Kalu DN, Erbas B, et al.: The effect of gonadectomy on bone size, mass and volumetric density in growing rats may be gender-, site-, and growth hormone-dependent. J Bone Miner Res 1999, 14:802–809.

    Article  PubMed  CAS  Google Scholar 

  45. Zamberlan N, Radetti G, Paganini C, et al.: Evaluation of cortical thickness and bone density by roentgen microdensitometry in growing males and females. Eur J Pediatr 1996, 155:377–382.

    Article  PubMed  CAS  Google Scholar 

  46. Gilsanz V, Gibbens DT, Roe TF, et al.: Vertebral bone density in children: effect of puberty. Radiology 1988, 166:847–850.

    PubMed  CAS  Google Scholar 

  47. Parfitt AM, Travers R, Rauch F, Glorieux FH: Structural and cellular changes during bone growth in healthy children. Bone 2000, 27:487–494. This is a magnificent paper that contains a huge amount of information regarding the structural basis of bone growth.

    Article  PubMed  CAS  Google Scholar 

  48. Gilsanz V, Roe TF, Stefano M, et al.: Changes in vertebral bone density in black girls and white girls during childhood and puberty. New Engl J Med 1991, 325:1597–1600.

    Article  PubMed  CAS  Google Scholar 

  49. Loro ML, Sayre J, Roe T, et al.: Early identification of children predisposed to low peak bone mass and osteoporosis later in life. J Clin Endocrinol Metab 2000, 85:3908–3918.

    Article  PubMed  CAS  Google Scholar 

  50. Kalender WA, Felsenberg D, Louis O, et al.: Reference values for trabecular and cortical vertebral bone density in single and dual-energy quantitative computed tomography. Eur J Radiol 1989, 9:75–80.

    PubMed  CAS  Google Scholar 

  51. Riggs BL, Wahner HW, Melton LJ III, et al.: Rate of bone loss in the axial and appendicular skeleton of women: evidence of substantial vertebral bone loss prior to menopause. J Clin Invest 1986, 77:1847–1891.

    Google Scholar 

  52. Gilsanz V, Gibbens DT, Carlson M, et al.: Peak trabecular bone density: a comparison of adolescent and adult. Calcif Tissue Int 1987, 43:260–262.

    Article  Google Scholar 

  53. Matkovic V, Jelic T, Wardlaw GM, et al.: Timing of peak bone mass in Caucasian females and its implication for the prevention of osteoporosis. J Clin Invest 1994, 93:799–808.

    PubMed  CAS  Google Scholar 

  54. Lips P, Courpron P, Meunier PJ, Mean wall thickness of trabecular bone packets in the human iliac crest: changes with age. Calcif Tissue Res 1978, 10:13–17.

    Article  Google Scholar 

  55. Riggs BL, Kholsa S, Melton LJ III: A unitary model for involutional osteoporosis: estrogen deficiency causes both type 1 and type 2 osteoporosis in postmenopausal women and contributes to bone loss in aging men. J Bone Miner Res 1998, 13:763–773.

    Article  PubMed  CAS  Google Scholar 

  56. Falahati-Nini A, Riggs BL, Atkinson EJ, et al.: Relative contributions of testosterone and estrogen in regulating bone resorption and formation in normal elderly men. J Clin Invest 2000, 106:1553–1560. This is a beautifully designed study providing insight into the differing roles of estrogen and testosterone on bone remodeling.

    Article  PubMed  CAS  Google Scholar 

  57. Szulc P, Munoz F, Claustrat B, et al.: Bioavailable estradiol may be an important determinant of osteoporosis in men: the MINOS Study. J Clin Endocrinol Metab 2001, 86:192–199.

    Article  PubMed  CAS  Google Scholar 

  58. Khosla S, Melton LJ III, Atkinson EJ, O’Fallon WM: Relationship of serum sex steroid levels to longitudinal changes in bone density in young versus elderly men. J Clin Endocrinol Metab 2001, 86:3555–3561.

    Article  PubMed  CAS  Google Scholar 

  59. Parfitt AM: Morphological basis of bone mineral measurements: transient and steady state effects of treatment in osteoporosis. Miner Electrolyte Metab 1980, 4:273–287.

    Google Scholar 

  60. Heaney RP: The bone-remodeling transient: implications for the interpretation of clinical studies of bone mass change. J Bone Miner Res 1994, 9:1515–1523.

    Article  PubMed  CAS  Google Scholar 

  61. Manolagas SC: Birth and death of bone cells: basic regulatory mechanisms and implications for the pathogenesis and treatment of osteoporosis. Endocr Rev 2000, 21:115–137. This paper is a classic in the study of the cells participating in bone remodeling.

    Article  PubMed  CAS  Google Scholar 

  62. Hughes DE, Dai A, Tiffee JC, et al.: Estrogen promotes apoptosis of murine osteoclasts mediated by TGF-beta. Nat Med 1996, 2:1132–1136.

    Article  PubMed  CAS  Google Scholar 

  63. Martin TJ, Ng KW: Mechanisms by which cells of the osteoblast lineage control osteoclast formation and activity. J Cell Biochem 1994, 56:357–366.

    Article  PubMed  CAS  Google Scholar 

  64. Suda T, Takahashi N, Martin TJ: Modulation of osteoclast differentiation. Endocr Rev 1992, 13:66–80.

    Article  PubMed  CAS  Google Scholar 

  65. Suda T, Takahashi N, Martin TJ: Modulation of osteoclast differentiation: update. Endocr Rev 1995, 4:266–270.

    CAS  Google Scholar 

  66. Simonet WS, Lacey DL, Dunstan CR, et al.: Amgen EST Program Boyle WJ. Osteoprotegerin: a novel secreted protein involved in the regulation of bone density. Cell 1997, 89:309–319.

    Article  PubMed  CAS  Google Scholar 

  67. Yasuda H, Shima N, Nakagawa N, et al.: Osteoclast differentation factor is a ligand for osteoprotegerin/osteoclastogenesisinhibitory factor and is identical to TRANCE/RANKL. Proc Natl Acad Sci USA 1998, 95:3597–3602.

    Article  PubMed  CAS  Google Scholar 

  68. Suda T, Takahashi N, Udagawa N, et al.: Modulation of osteoclast differentiation and function by the new members of the tumor necrosis factor receptor and ligand families. Endocr Rev 1999, 20:345–357.

    Article  PubMed  CAS  Google Scholar 

  69. Bucay N, Sarosi I, Dunstan CR, et al.: Osteoprotegerin-deficient mice develop early onset osteoporosis and arterial calcification. Genes Dev 1998, 12:1260–1268.

    PubMed  CAS  Google Scholar 

  70. Kong Y-Y, Yoshida H, Sarosi I, et al.: OPGL is a key regulator of osteoclastogenesis, lymphocyte development and lymphnode organogenesis. Nature 1999, 397:315–323.

    Article  PubMed  CAS  Google Scholar 

  71. Li J, Sarosi I, Yan XQ, et al.: RANK is the intrinsic hematopoietic cell surface receptor that controls osteoclastogenesis and regulation of bone mass and calcium metabolism. Proc Nat Acad Sci USA 2000, 97:1566–1571.

    Article  PubMed  CAS  Google Scholar 

  72. Sone T, Miyake M, Takeda N, Fukunaga M: Urinary excretion of type I collagen crosslinked N-telopeptides in healthy Japanese adults: age- and sex-related changes and reference limits. Bone 1995, 17:335–339.

    Article  PubMed  CAS  Google Scholar 

  73. Aaron JE, Makins NB, Sagreiy K: The microanatomy of trabecular bone loss in normal aging men and women. Clin Orth RR 1987, 215:260–271.

    Google Scholar 

  74. Moverare S, Venken K, Eriksson A-L, et al.: Differential effects on bone of estrogen receptor and androgen receptor activation in orchidectomized adult male mice. Proc Natl Acad Sci U S A 2003, 100:13573–13578.

    Article  PubMed  CAS  Google Scholar 

  75. Bousson V, Meunier A, Bergot C, et al.: Distribution of intracortical porosity in human midfemoral cortex by age and gender. J Bone Miner Res 2001, 16:1308–1317.

    Article  PubMed  CAS  Google Scholar 

  76. Riggs BL, Kholsa S, Melton LJ III: Sex steroids and the construction and conservation of the adult skeleton. Endocr Rev 2002, 23:279–302. A masterpiece in breath and depth.

    Article  PubMed  CAS  Google Scholar 

  77. Currey JD: The mechanical consequences of variation in the mineral content of bone. J Biomechanics 1969, 2:1–11.

    Article  CAS  Google Scholar 

  78. Mashiba T, Hirano T, Turner CH, et al.: Suppressed bone turnover by bisphosphonates increases microdamage accumulation and reduces some biomechanical properties in dog rib. J Bone Miner Res 2000, 15:613–620.

    Article  PubMed  CAS  Google Scholar 

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  1. Department of Endocrinology, Austin Hospital, Heidelberg 3084, Melbourne, Australia

    Ego Seeman BSc, MBBS, FRACP, MD

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  1. Ego Seeman BSc, MBBS, FRACP, MD
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Seeman, E. Estrogen, androgen, and the pathogenesis of bone fragility in women and men. Curr Osteoporos Rep 2, 90–96 (2004). https://doi.org/10.1007/s11914-004-0016-0

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