Official reprint from UpToDate®
www.uptodate.com ©2016 UpToDate®

Pathogenesis of osteoporosis

Stavros C Manolagas, MD, PhD
Section Editor
Clifford J Rosen, MD
Deputy Editor
Jean E Mulder, MD


Osteoporosis is a skeletal disorder characterized by compromised bone strength predisposing to an increased risk of fractures. Throughout life, older bone is periodically resorbed by osteoclasts at discrete sites and replaced with new bone made by osteoblasts. This process is known as remodeling. Remodeling is orchestrated and targeted to a particular site that is in need for repair by osteocytes [1]. An oversupply of osteoclasts relative to the need for remodeling or an undersupply of osteoblasts relative to the need for cavity repair are the seminal pathophysiological changes in osteoporosis [2,3].

The amount of bone mass accrued by an individual reaches a peak by the third decade of life. Low peak bone mass probably contributes to the development of osteoporosis later in life. However, old age, sex steroid deficiency, lipid oxidation, decreased physical activity, use of glucocorticoids, and a propensity to fall are the most critical determinants of increased fracture risk.

This topic will address each of these pathogenetic factors and, when it is known, how they interact with each other. Bone remodelling and osteoporotic fracture risk assessment are reviewed separately. (See "Normal skeletal development and regulation of bone formation and resorption" and "Osteoporotic fracture risk assessment".)


Osteoporosis is a skeletal disorder characterized by compromised bone strength predisposing to an increased risk of fractures. Although osteoporosis (a term used to define decreased bone mass per unit volume of anatomical bone) has become synonymous with decreased bone mineral density (BMD), this feature is not always present. Small bone size, unfavorable macro-architecture (eg, increased length of the femoral neck), disrupted micro-architecture (image 1 and figure 1), cortical porosity, compromised quality of the material, and decreased viability of osteocytes (former osteoblasts buried within mineralized bone that sense and respond to changes in mechanical forces) are some other factors contributing to decreased strength.

The diagnosis of osteoporosis or estimates of the risk for developing it in the future rely almost exclusively on measures of bone mass by imaging studies such as dual energy x-ray absorptiometry (DXA) (table 1) and quantitative computed tomography (CT). These measures are fairly good clinical surrogates, but it is important to remember that the disease is bone fragility, and decreased BMD on DXA is just one of many risk factors. (See "Clinical manifestations, diagnosis, and evaluation of osteoporosis in postmenopausal women" and "Clinical manifestations, diagnosis, and evaluation of osteoporosis in men".)


Subscribers log in here

To continue reading this article, you must log in with your personal, hospital, or group practice subscription. For more information or to purchase a personal subscription, click below on the option that best describes you:
Literature review current through: Sep 2016. | This topic last updated: May 9, 2016.
The content on the UpToDate website is not intended nor recommended as a substitute for medical advice, diagnosis, or treatment. Always seek the advice of your own physician or other qualified health care professional regarding any medical questions or conditions. The use of this website is governed by the UpToDate Terms of Use ©2016 UpToDate, Inc.
  1. Xiong J, Onal M, Jilka RL, et al. Matrix-embedded cells control osteoclast formation. Nat Med 2011; 17:1235.
  2. 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.
  3. Manolagas SC, Kousteni S, Jilka RL. Sex steroids and bone. Recent Prog Horm Res 2002; 57:385.
  4. Duncan EL, Danoy P, Kemp JP, et al. Genome-wide association study using extreme truncate selection identifies novel genes affecting bone mineral density and fracture risk. PLoS Genet 2011; 7:e1001372.
  5. Estrada K, Styrkarsdottir U, Evangelou E, et al. Genome-wide meta-analysis identifies 56 bone mineral density loci and reveals 14 loci associated with risk of fracture. Nat Genet 2012; 44:491.
  6. Looker AC, Melton LJ 3rd, Borrud LG, Shepherd JA. Lumbar spine bone mineral density in US adults: demographic patterns and relationship with femur neck skeletal status. Osteoporos Int 2012; 23:1351.
  7. Crabtree NJ, Kibirige MS, Fordham JN, et al. The relationship between lean body mass and bone mineral content in paediatric health and disease. Bone 2004; 35:965.
  8. Wetzsteon RJ, Kalkwarf HJ, Shults J, et al. Volumetric bone mineral density and bone structure in childhood chronic kidney disease. J Bone Miner Res 2011; 26:2235.
  9. Liu W, Qi M, Konermann A, et al. The p53/miR-17/Smurf1 pathway mediates skeletal deformities in an age-related model via inhibiting the function of mesenchymal stem cells. Aging (Albany NY) 2015; 7:205.
  10. Vu MQ, Weintraub N, Rubenstein LZ. Falls in the nursing home: are they preventable? J Am Med Dir Assoc 2006; 7:S53.
  11. Zebaze RM, Ghasem-Zadeh A, Bohte A, et al. Intracortical remodelling and porosity in the distal radius and post-mortem femurs of women: a cross-sectional study. Lancet 2010; 375:1729.
  12. Hui SL, Slemenda CW, Johnston CC Jr. Age and bone mass as predictors of fracture in a prospective study. J Clin Invest 1988; 81:1804.
  13. Balaban RS, Nemoto S, Finkel T. Mitochondria, oxidants, and aging. Cell 2005; 120:483.
  14. Manolagas SC. From estrogen-centric to aging and oxidative stress: a revised perspective of the pathogenesis of osteoporosis. Endocr Rev 2010; 31:266.
  15. Bartell SM, Kim HN, Ambrogini E, et al. FoxO proteins restrain osteoclastogenesis and bone resorption by attenuating H2O2 accumulation. Nat Commun 2014; 5:3773.
  16. Khosla S, Melton LJ 3rd, Riggs BL. The unitary model for estrogen deficiency and the pathogenesis of osteoporosis: is a revision needed? J Bone Miner Res 2011; 26:441.
  17. Recker R, Lappe J, Davies K, Heaney R. Characterization of perimenopausal bone loss: a prospective study. J Bone Miner Res 2000; 15:1965.
  18. Parfitt AM, Villanueva AR, Foldes J, Rao DS. Relations between histologic indices of bone formation: implications for the pathogenesis of spinal osteoporosis. J Bone Miner Res 1995; 10:466.
  19. Han ZH, Palnitkar S, Rao DS, et al. Effects of ethnicity and age or menopause on the remodeling and turnover of iliac bone: implications for mechanisms of bone loss. J Bone Miner Res 1997; 12:498.
  20. Parfitt AM. Skeletal heterogeneity and the purposes of bone remodeling: implications for the understanding of osteoporosis. In: Osteoporosis, 3rd Ed, Marcus R, Feldman D, Nelson D, Rosen C. (Eds), Elsevier, San Diego 2007. p.71.
  21. 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.
  22. Jones ME, Boon WC, McInnes K, et al. Recognizing rare disorders: aromatase deficiency. Nat Clin Pract Endocrinol Metab 2007; 3:414.
  23. Santen RJ, Brodie H, Simpson ER, et al. History of aromatase: saga of an important biological mediator and therapeutic target. Endocr Rev 2009; 30:343.
  24. Manolagas SC, O'Brien CA, Almeida M. The role of estrogen and androgen receptors in bone health and disease. Nat Rev Endocrinol 2013; 9:699.
  25. Almeida M, Iyer S, Martin-Millan M, et al. Estrogen receptor-α signaling in osteoblast progenitors stimulates cortical bone accrual. J Clin Invest 2013; 123:394.
  26. Ucer S, Iyer S, Bartell SM, et al. The Effects of Androgens on Murine Cortical Bone Do Not Require AR or ERα Signaling in Osteoblasts and Osteoclasts. J Bone Miner Res 2015; 30:1138.
  27. Nakamura T, Imai Y, Matsumoto T, et al. Estrogen prevents bone loss via estrogen receptor alpha and induction of Fas ligand in osteoclasts. Cell 2007; 130:811.
  28. Martin-Millan M, Almeida M, Ambrogini E, et al. The estrogen receptor-alpha in osteoclasts mediates the protective effects of estrogens on cancellous but not cortical bone. Mol Endocrinol 2010; 24:323.
  29. Windahl SH, Börjesson AE, Farman HH, et al. Estrogen receptor-α in osteocytes is important for trabecular bone formation in male mice. Proc Natl Acad Sci U S A 2013; 110:2294.
  30. Määttä JA, Büki KG, Gu G, et al. Inactivation of estrogen receptor α in bone-forming cells induces bone loss in female mice. FASEB J 2013; 27:478.
  31. Melville KM, Kelly NH, Khan SA, et al. Female mice lacking estrogen receptor-alpha in osteoblasts have compromised bone mass and strength. J Bone Miner Res 2014; 29:370.
  32. Kondoh S, Inoue K, Igarashi K, et al. Estrogen receptor α in osteocytes regulates trabecular bone formation in female mice. Bone 2014; 60:68.
  33. Parfitt AM. The two-stage concept of bone loss revisited. Triangle 1992; 31:99.
  34. Ebeling PR. Clinical practice. Osteoporosis in men. N Engl J Med 2008; 358:1474.
  35. Chiang C, Chiu M, Moore AJ, et al. Mineralization and bone resorption are regulated by the androgen receptor in male mice. J Bone Miner Res 2009; 24:621.
  36. Notini AJ, McManus JF, Moore A, et al. Osteoblast deletion of exon 3 of the androgen receptor gene results in trabecular bone loss in adult male mice. J Bone Miner Res 2007; 22:347.
  37. Sinnesael M, Claessens F, Laurent M, et al. Androgen receptor (AR) in osteocytes is important for the maintenance of male skeletal integrity: evidence from targeted AR disruption in mouse osteocytes. J Bone Miner Res 2012; 27:2535.
  38. Määttä JA, Büki KG, Ivaska KK, et al. Inactivation of the androgen receptor in bone-forming cells leads to trabecular bone loss in adult female mice. Bonekey Rep 2013; 2:440.
  39. Smith EP, Specker B, Bachrach BE, et al. Impact on bone of an estrogen receptor-alpha gene loss of function mutation. J Clin Endocrinol Metab 2008; 93:3088.
  40. Khosla S. New Insights Into Androgen and Estrogen Receptor Regulation of the Male Skeleton. J Bone Miner Res 2015; 30:1134.
  41. Almeida M, Han L, Martin-Millan M, et al. Skeletal involution by age-associated oxidative stress and its acceleration by loss of sex steroids. J Biol Chem 2007; 282:27285.
  42. Almeida M, Han L, Ambrogini E, et al. Oxidative stress stimulates apoptosis and activates NF-kappaB in osteoblastic cells via a PKCbeta/p66shc signaling cascade: counter regulation by estrogens or androgens. Mol Endocrinol 2010; 24:2030.
  43. Weitzmann MN, Pacifici R. Estrogen deficiency and bone loss: an inflammatory tale. J Clin Invest 2006; 116:1186.
  44. Lee SK, Kadono Y, Okada F, et al. T lymphocyte-deficient mice lose trabecular bone mass with ovariectomy. J Bone Miner Res 2006; 21:1704.
  45. Manolagas SC, Parfitt AM. What old means to bone. Trends Endocrinol Metab 2010; 21:369.
  46. Winkler DG, Sutherland MK, Geoghegan JC, et al. Osteocyte control of bone formation via sclerostin, a novel BMP antagonist. EMBO J 2003; 22:6267.
  47. Bonewald LF. Osteocytes as dynamic multifunctional cells. Ann N Y Acad Sci 2007; 1116:281.
  48. Manolagas SC. Choreography from the tomb: An emerging role of dying osteocytes in the purposeful, and perhaps not so purposeful, targeting of bone remodeling. BoneKey Osteovision 2006; 3:5. http://www.nature.com/bonekey/knowledgeenvironment/2006/0601/bonekey20060193/full/bonekey20060193.html (Accessed on September 19, 2012).
  49. FROST HM. In vivo osteocyte death. J Bone Joint Surg Am 1960; 42-A:138.
  50. FROST HM. Micropetrosis. J Bone Joint Surg Am 1960; 42-A:144.
  51. Qiu S, Rao DS, Palnitkar S, Parfitt AM. Age and distance from the surface but not menopause reduce osteocyte density in human cancellous bone. Bone 2002; 31:313.
  52. Qiu S, Rao DS, Fyhrie DP, et al. The morphological association between microcracks and osteocyte lacunae in human cortical bone. Bone 2005; 37:10.
  53. Qiu S, Rao DS, Palnitkar S, Parfitt AM. Reduced iliac cancellous osteocyte density in patients with osteoporotic vertebral fracture. J Bone Miner Res 2003; 18:1657.
  54. Qiu S, Rao DS, Palnitkar S, Parfitt AM. Relationships between osteocyte density and bone formation rate in human cancellous bone. Bone 2002; 31:709.
  55. Heaney RP. Is the paradigm shifting? Bone 2003; 33:457.
  56. Cardoso L, Herman BC, Verborgt O, et al. Osteocyte apoptosis controls activation of intracortical resorption in response to bone fatigue. J Bone Miner Res 2009; 24:597.
  57. Weinstein RS, Wan C, Liu Q, et al. Endogenous glucocorticoids decrease skeletal angiogenesis, vascularity, hydration, and strength in aged mice. Aging Cell 2010; 9:147.
  58. Zhao H, Xiong,J, Onal,M, Cazer,P, Weinstein R., Manolagas S., O'Brien C. Osteocyte autophagy declines with age in mice and suppression of autophagy decreases bone mass. J Bone Min Res 2011
  59. Plotkin LI, Mathov I, Aguirre JI, et al. Mechanical stimulation prevents osteocyte apoptosis: requirement of integrins, Src kinases, and ERKs. Am J Physiol Cell Physiol 2005; 289:C633.
  60. Aguirre JI, Plotkin LI, Stewart SA, et al. Osteocyte apoptosis is induced by weightlessness in mice and precedes osteoclast recruitment and bone loss. J Bone Miner Res 2006; 21:605.
  61. Marcus R. Mechanisms of exercise effects on bone. In: Principles of bone biology, 2nd, Bilezikian JP, Raisz LG, Rodan GA (Eds), Academic Press, San Diego 2002. Vol 1, p.1477.
  62. Kousteni S, Bellido T, Plotkin LI, et al. Nongenotropic, sex-nonspecific signaling through the estrogen or androgen receptors: dissociation from transcriptional activity. Cell 2001; 104:719.
  63. Kousteni S, Chen JR, Bellido T, et al. Reversal of bone loss in mice by nongenotropic signaling of sex steroids. Science 2002; 298:843.
  64. Tomkinson A, Reeve J, Shaw RW, Noble BS. The death of osteocytes via apoptosis accompanies estrogen withdrawal in human bone. J Clin Endocrinol Metab 1997; 82:3128.
  65. Tomkinson A, Gevers EF, Wit JM, et al. The role of estrogen in the control of rat osteocyte apoptosis. J Bone Miner Res 1998; 13:1243.
  66. Frost HM. The mechanostat: a proposed pathogenic mechanism of osteoporoses and the bone mass effects of mechanical and nonmechanical agents. Bone Miner 1987; 2:73.
  67. Schiessl H, Frost HM, Jee WS. Estrogen and bone-muscle strength and mass relationships. Bone 1998; 22:1.
  68. Lee K, Jessop H, Suswillo R, et al. Endocrinology: bone adaptation requires oestrogen receptor-alpha. Nature 2003; 424:389.
  69. Lee KC, Jessop H, Suswillo R, et al. The adaptive response of bone to mechanical loading in female transgenic mice is deficient in the absence of oestrogen receptor-alpha and -beta. J Endocrinol 2004; 182:193.
  70. O'Brien CA, Jia D, Plotkin LI, et al. Glucocorticoids act directly on osteoblasts and osteocytes to induce their apoptosis and reduce bone formation and strength. Endocrinology 2004; 145:1835.
  71. Van Staa TP, Laan RF, Barton IP, et al. Bone density threshold and other predictors of vertebral fracture in patients receiving oral glucocorticoid therapy. Arthritis Rheum 2003; 48:3224.
  72. Weinstein RS, Jilka RL, Parfitt AM, Manolagas SC. Inhibition of osteoblastogenesis and promotion of apoptosis of osteoblasts and osteocytes by glucocorticoids. Potential mechanisms of their deleterious effects on bone. J Clin Invest 1998; 102:274.
  73. Weinstein RS, Nicholas RW, Manolagas SC. Apoptosis of osteocytes in glucocorticoid-induced osteonecrosis of the hip. J Clin Endocrinol Metab 2000; 85:2907.
  74. Weinstein RS, Chen JR, Powers CC, et al. Promotion of osteoclast survival and antagonism of bisphosphonate-induced osteoclast apoptosis by glucocorticoids. J Clin Invest 2002; 109:1041.
  75. Jia D, O'Brien CA, Stewart SA, et al. Glucocorticoids act directly on osteoclasts to increase their life span and reduce bone density. Endocrinology 2006; 147:5592.
  76. Weinstein RS. Clinical practice. Glucocorticoid-induced bone disease. N Engl J Med 2011; 365:62.
  77. Manolagas SC. Corticosteroids and fractures: a close encounter of the third cell kind. J Bone Miner Res 2000; 15:1001.
  78. Mani A, Radhakrishnan J, Wang H, et al. LRP6 mutation in a family with early coronary disease and metabolic risk factors. Science 2007; 315:1278.
  79. Parhami F, Tintut Y, Beamer WG, et al. Atherogenic high-fat diet reduces bone mineralization in mice. J Bone Miner Res 2001; 16:182.
  80. Schulz E, Arfai K, Liu X, et al. Aortic calcification and the risk of osteoporosis and fractures. J Clin Endocrinol Metab 2004; 89:4246.
  81. Navab M, Ananthramaiah GM, Reddy ST, et al. The oxidation hypothesis of atherogenesis: the role of oxidized phospholipids and HDL. J Lipid Res 2004; 45:993.
  82. Manolagas SC, Almeida M. Gone with the Wnts: beta-catenin, T-cell factor, forkhead box O, and oxidative stress in age-dependent diseases of bone, lipid, and glucose metabolism. Mol Endocrinol 2007; 21:2605.
  83. Almeida M, Ambrogini E, Han L, et al. Increased lipid oxidation causes oxidative stress, increased peroxisome proliferator-activated receptor-gamma expression, and diminished pro-osteogenic Wnt signaling in the skeleton. J Biol Chem 2009; 284:27438.