Current Osteoporosis Reports

, Volume 8, Issue 4, pp 235–240 | Cite as

The Pathophysiology of the Aging Skeleton

  • Farhan A. SyedEmail author
  • Alvin C. NgEmail author


In recent decades the population of both elderly men and women has grown substantially worldwide. Aging is associated with a number of pathologies involving various organs including the skeleton. Age-related bone loss and resultant osteoporosis put the elderly population at an increased risk for fractures and morbidity. Fortunately, in parallel our understanding of this malady has also grown substantially in recent years. A number of clinical as well as translational studies have been pivotal in providing us with an understanding of the pathophysiology of this condition. This article discusses the current concepts of age-related modulation of the skeleton involving intrinsic factors such as genetics, hormonal changes, levels of oxidative stress, and changes in telomere length, as well as extrinsic factors such as nutritional and lifestyle choices. It also briefly outlines recent studies on the relationship between bone and fat in the marrow as well as the periphery.


Bone loss Aging Osteoporosis Hormones 



Dr. Farhan A. Syed is an employee of Abbott Laboratories. He has also received honoraria from the University of Massachusetts for delivering a lecture at the Bone and Joint Seminar Series. Dr. Alvin C. Ng has no disclosures.


Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. 1.
    Riggs BL, Wahner HW, Seeman E, et al.: Changes in bone mineral density of the proximal femur and spine with aging. Differences between the postmenopausal and senile osteoporosis syndromes. J Clin Invest 1982, 70:716–723.CrossRefPubMedGoogle Scholar
  2. 2.
    Riggs BL, Khosla S, Melton LJ III: The type I/type II model for involutional osteoporosis: update and modifications based on new observations. In Osteoporosis, 2nd edition. Edited by Marcus R, Feldman D, Kelsey J. Salt Lake City: Academic Press; 2001:49–58.Google Scholar
  3. 3.
    Riggs BL, Khosla S, Melton LJ III: Sex steroids and the construction and conservation of the adult skeleton. Endocr Rev 2002, 23:279–302.CrossRefPubMedGoogle Scholar
  4. 4.
    Lee CA, Einhorn TA: The Bone Organ System: Form and Function. In Osteoporosis, 2nd edition. Edited by Marcus R, Feldman D, Kelsey J. Salt Lake City: Academic Press; 2001:2–20.Google Scholar
  5. 5.
    Center JR, Eisman JA: Genetics of osteoporosis. In Primer on the Metabolic Bone Diseases and Disorders of Mineral Metabolism. Edited by Rosen CJ. Washington DC: American Society for Bone and Mineral Research; 2008:213–219.CrossRefGoogle Scholar
  6. 6.
    Newton-John HF, Morgan DB. The loss of bone with age, osteoporosis, and fractures. Clin Orthop Relat Res 1970, 71:229–252.CrossRefPubMedGoogle Scholar
  7. 7.
    Matkovic V, Kostial K, Simonovic I, et al.: Bone status and fracture rates in two regions of Yugoslavia. Am J Clin Nutr 1979, 32:540–549.PubMedGoogle Scholar
  8. 8.
    Ferrari S, Rizzoli R, Slosman D, Bonjour JP: Familial resemblance for bone mineral mass is expressed before puberty. J Clin Endocrinol Metab 1998, 83:358–361.CrossRefPubMedGoogle Scholar
  9. 9.
    Dertina LM, Sayre J, Kaufman F, Gilsanz V: Childhood bone measurements predict values at young adulthood. Bone 1998, 23:S288.Google Scholar
  10. 10.
    Halloran BP, Ferguson VL, Simske SJ, et al.: Changes in bone structure and mass with advancing age in the male C57BL/6J mouse. J Bone Miner Res 2002, 17:1044–1050.CrossRefPubMedGoogle Scholar
  11. 11.
    Bollerslev J, Wilson SG, Dick IM, et al.: LRP5 gene polymorphisms predict bone mass and incident fractures in elderly Australian women. Bone 2005, 36:599–606.CrossRefPubMedGoogle Scholar
  12. 12.
    Khosla S, Atkinson EJ, Melton LJ III, Riggs BL: Effects of age and estrogen status on serum parathyroid hormone levels and biochemical markers of bone turnover in women: a population-based study. J Clin Endocrinol Metab 1997, 82:1522–1527.CrossRefPubMedGoogle Scholar
  13. 13.
    Rahmani P, Morin S: Prevention of osteoporosis related fractures among postmenopausal women and older men. CMAJ 2009, 181:815–820.PubMedGoogle Scholar
  14. 14.
    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.CrossRefPubMedGoogle Scholar
  15. 15.
    Khosla S, Melton LJ III, Atkinson EJ, et al.: 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.CrossRefPubMedGoogle Scholar
  16. 16.
    Sun L, Peng Y, Sharrow AC, et al.: FSH directly regulates bone mass. Cell 2006, 125:247–260.CrossRefPubMedGoogle Scholar
  17. 17.
    Sowers MR, Greendale GA, Bondarenko J, et al.: Endogenous hormones and bone turnover markers in pre- and perimenopausal women: SWAN. Osteoporos Int 2003, 14:191–197.CrossRefPubMedGoogle Scholar
  18. 18.
    • Wu XY, Wu XP, Xie H, et al.: Age-related changes in biochemical markers of bone turnover and gonadotropins levels and their relationship among Chinese adult women. Osteoporos Int 2010, 21:275–285. This paper provides clinical evidence for a correlation between high serum FSH and bone resorption in aging Chinese women.CrossRefPubMedGoogle Scholar
  19. 19.
    Sowers MR, Jannausch M, McConnell D, et al.: Hormone predictors of bone mineral density changes during the menopausal transition. J Clin Endocrinol Metabol 2006, 91:1261–1267.CrossRefGoogle Scholar
  20. 20.
    Devleta B, Adem B, Senada S: Hypergonadotropic amenorrhea and bone density: new approach to an old problem. J Bone Min Res 2004, 22:360–364.Google Scholar
  21. 21.
    • Drake MT, McCready LK, Hoey KA, et al.: Effects of suppression of follicle stimulating hormone secretion on bone resorption markers in postmenopausal women. J Clin Endocrinol Metab 2010 Jul 7 [Epub ahead of print]. This is a clinical study in postmenopausal women on GnRH agonist that does not show a correlation between suppression of FSH and decreases in serum bone resorption markers.Google Scholar
  22. 22.
    Rosen CJ, Donahue LR, Hunter SJ: Insulin-like growth factors and bone: the osteoporosis connection. Proc Soc Exp Biol Med 1994, 206:83–102.PubMedGoogle Scholar
  23. 23.
    Boonen S, Mohan S, Dequeker J, et al.: Down-regulation of the serum stimulatory components of the insulin-like growth factor (IGF) system (IGF-I, IGF-II, IGF binding protein [BP]-3, and IGFBP-5) in age-related (type II) femoral neck osteoporosis. J Bone Miner Res 1999,14:2150–2158.CrossRefPubMedGoogle Scholar
  24. 24.
    Bauer DC, Rosen CJ, Cauley J, Cummings SR: Low serum IGF-1 but not IGFBP-3 predicts hip and spine fractures. Bone 1997, 20(Suppl):561.Google Scholar
  25. 25.
    Amin S, Riggs BL, Melton LJ III, et al.: High serum IGFBP-2 is predictive of increased bone turnover in aging men and women. J Bone Miner Res 2007, 22:799–807.CrossRefPubMedGoogle Scholar
  26. 26.
    Thomas T, Gori F, Khosla S, et al.: Leptin acts on human marrow stromal cells to enhance differentiation to osteoblasts and to inhibit differentiation to adipocytes. Endocrinology 1999, 140:1630–1638.CrossRefPubMedGoogle Scholar
  27. 27.
    Ducy P, Amling M, Takeda S, et al.: Leptin inhibits bone formation through a hypothalamic relay: a central control of bone mass. Cell 2000,100:197–207.CrossRefPubMedGoogle Scholar
  28. 28.
    Takeda S, Elefteriou F, Levasseur R, et al.: Leptin regulates bone formation via the sympathetic nervous system. Cell 2002, 111:305–317.CrossRefPubMedGoogle Scholar
  29. 29.
    Elefteriou F, Ahn JD, Takeda S, et al.: Leptin regulation of bone resorption by the sympathetic nervous system and CART. Nature 2005, 434 :514–520.CrossRefPubMedGoogle Scholar
  30. 30.
    Sato S, Hanada R, Kimura A, et al.: Central control of bone remodeling by neuromedin U. Nat Med 2007, 13:1234–1240.CrossRefPubMedGoogle Scholar
  31. 31.
    Pasco JA, Henry MJ, Sanders KM, et al.: Beta-adrenergic blockers reduce the risk of fracture partly by increasing bone mineral density: Geelong Osteoporosis Study. J Bone Miner Res 2004, 19:19–24.CrossRefPubMedGoogle Scholar
  32. 32.
    •• Yadav VK, Oury F, Suda N, et al.: A serotonin-dependent mechanism explains the leptin regulation of bone mass, appetite, and energy expenditure. Cell 2009, 138:976–989. This study shows that brainstem-derived serotonin favors bone mass accrual following its binding to Htr2C receptors on ventromedial hypothalamic neurons and modulates appetite via Htr1a and 2b receptors on arcuate neurons. Leptin inhibits these functions by reducing serotonin synthesis and firing of serotonergic neurons.CrossRefPubMedGoogle Scholar
  33. 33.
    • Modder UI, Achenbach SJ, Amin S, et al.: Relation of serum serotonin levels to bone density and structural parameters in women. J Bone Miner Res 2010, 25:415–422. This is the first demonstration of the relationship between serum serotonin levels and postmenopausal bone loss; it shows a potential for use of serotonin as a marker.PubMedGoogle Scholar
  34. 34.
    Duque G, Troen BR: Understanding the mechanisms of senile osteoporosis: new facts for a major geriatric syndrome. J Am Geriatr Soc 2008, 56:935–941.CrossRefPubMedGoogle Scholar
  35. 35.
    Rosen CJ, Ackert-Bicknell C, Rodriguez JP, et al.: Marrow fat and the bone microenvironment: developmental, functional, and pathological implications. Crit Rev Eukaryot Gene Expr 2009,19:109–124.PubMedGoogle Scholar
  36. 36.
    Syed FA, Oursler MJ, Hefferan TE, et al.: Effects of estrogen therapy on bone marrow adipocytes in postmenopausal osteoporotic women. Osteopor Int 2008, 19:1323–1330.CrossRefGoogle Scholar
  37. 37.
    Griffith JF, Yeung DK, Antonio GE, et al.: Vertebral bone mineral density, marrow perfusion, and fat content in healthy men and men with osteoporosis: dynamic contrast-enhanced MR imaging and MR spectroscopy. Radiology 2005, 236:945–951.CrossRefPubMedGoogle Scholar
  38. 38.
    Hsu YH, Venners SA, Terwedow HA, et al.: Relation of body composition, fat mass, and serum lipids to osteoporotic fractures and bone mineral density in Chinese men and women. Am J Clin Nutr 2006, 83:146–154.PubMedGoogle Scholar
  39. 39.
    • Zhao LJ, Liu YJ, Liu PY, et al.: Relationship of obesity with osteoporosis. J Clin Endocrinol Metab 2007, 92:1640–1646. This study shows the inverse relationship between bone mass and fat mass, after taking into account the mechanical loading effects due to total body weight.CrossRefPubMedGoogle Scholar
  40. 40.
    Cooper C, Westlake S, Harvey N, et al.: Review: developmental origins of osteoporotic fracture. Osteoporos Int 2006, 17:337–347.CrossRefPubMedGoogle Scholar
  41. 41.
    Lips P: Vitamin D deficiency and secondary hyperparathyroidism in the elderly: consequences for bone loss and fractures and therapeutic implications. Endocr Rev 2001, 22:477–501.CrossRefPubMedGoogle Scholar
  42. 42.
    Eastell R, Yergey AL, Vieira NE, et al.: Interrelationship among vitamin D metabolism, true calcium absorption, parathyroid function, and age in women: evidence of an age-related intestinal resistance to 1,25-dihydroxyvitamin D action. J Bone Miner Res 1991, 6:125–132.CrossRefPubMedGoogle Scholar
  43. 43.
    Melton LJ 3rd, Riggs BL, Achenbach SJ, et al.: Does reduced skeletal loading account for age-related bone loss? J Bone Miner Res 2006, 21:1847–1855.CrossRefPubMedGoogle Scholar
  44. 44.
    Leichter I, Simkin A, Margulies JY, et al.: Gain in mass density of bone following strenuous physical activity. J Orthop Res 1989, 7:86–90.CrossRefPubMedGoogle Scholar
  45. 45.
    Tinetti ME, Gordon C, Sogolow E, et al.: Fall-risk evaluation and management: challenges in adopting geriatric care practices. Gerontologist 2006, 46:717–725.PubMedGoogle Scholar
  46. 46.
    Crepaldi G, Maggi S: Epidemiologic link between osteoporosis and cardiovascular disease. J Endocrinol Invest 2009, 32(4 Suppl):2–5.PubMedGoogle Scholar
  47. 47.
    Ozgocmen S, Kaya H, Fadillioglu, et al.: Effects of calcitonin, risedronate and raloxifene on erythrocyte antioxidant enzyme activity, lipid peroxidation and nitric oxide in postmenopausal osteoporosis. Arch Med Res 2007, 38:196–205.CrossRefPubMedGoogle Scholar
  48. 48.
    Sanders JL, Cauley JA, Boudreau RM, et al.: Leukocyte telomere length is not associated with BMD, osteoporosis, or fracture in older adults: results from the Health, Aging and Body Composition Study. J Bone Miner Res 2009, 24:1531–1536.CrossRefPubMedGoogle Scholar
  49. 49.
    Tang NL, Woo J, Suen EW, et al.: The effect of telomere length, a marker of biological aging, on bone mineral density in the elderly population. Osteoporos Int 2010, 21:89–97.CrossRefPubMedGoogle Scholar
  50. 50.
    Valdes AM, Richards JB, Gardner JP, et al.: Telomere length in leukocytes correlates with bone mineral density and is shorter in women with osteoporosis. Osteoporos Int 2007, 18:1203–1210.CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2010

Authors and Affiliations

  1. 1.Abbott Bioresearch CenterWorcesterUSA
  2. 2.Department of EndocrinologySingapore General HospitalSingaporeSingapore

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