Advertisement

Clinical Reviews in Allergy & Immunology

, Volume 41, Issue 1, pp 102–113 | Cite as

Current Concepts on the Pathogenesis and Natural History of Steroid-Induced Osteonecrosis

  • Christian Powell
  • Christopher Chang
  • M. Eric Gershwin
Article

Abstract

The pathophysiology of non-traumatic osteonecrosis is more complex than that of traumatic osteonecrosis, and corticosteroid-induced osteonecrosis presents the greatest challenge because of the multiple effects of corticosteroids on multi-system pathways; these pathways include the effects of corticosteroids on osteoblast differentiation, osteoblast and osteoclast apoptosis, lipid metabolism, coagulation pathways, and calcium metabolism. These pathways are frequently interrelated with each other, which makes the pathogenesis even more difficult to understand. Host factors and underlying disease have been shown to play a significant role in the risk of developing osteonecrosis, and our understanding of the pathogenesis must be able to explain why some patients are at greater risk than others. Identification of genetic variants that convey additional risk will also help to personalize the way we deliver care, both in the prevention and treatment of osteonecrosis. Further understanding of the intricate immunologic and genetic pathways contributing to osteonecrosis is at the forefront of research and may soon lead to viable and less invasive non-surgical therapeutic strategies.

Keywords

Corticosteroids Avascular necrosis Dose response 

References

  1. 1.
    Powell C, Chang C, Naguwa SM, Cheema G, Gershwin ME (2010) Steroid induced osteonecrosis: an analysis of steroid dosing risk. Autoimmun Rev 9:721–743PubMedCrossRefGoogle Scholar
  2. 2.
    Chang C, Greenspan A, Gershwin ME. Osteonecrosis. In Firestein GS, Budd RC, Harris ED, McInnes IB, Ruddy S, Sergent JS (2009) Textbook of Rheumatology, 8th Edition, Saunders, Philadelphia, pp 1611–1628Google Scholar
  3. 3.
    Assouline-Dayan Y, Chang C, Greenspan A, Shoenfeld Y, Gershwin ME (2002) Pathogenesis and natural history of osteonecrosis. Semin Arthritis Rheum 32:94–124PubMedGoogle Scholar
  4. 4.
    Spencer JD, Brookes M (1988) Avascular necrosis and the blood supply of the femoral head. Clin Orthop Relat Res 235:127–140PubMedGoogle Scholar
  5. 5.
    Jacobs B (1978) Epidemiology of traumatic and nontraumatic osteonecrosis. Clin Orthop Relat Res 130:51–67PubMedGoogle Scholar
  6. 6.
    Atsumi T, Kuroki Y (1992) Role of impairment of blood supply of the femoral head in the pathogenesis of idiopathic osteonecrosis. Clin Orthop Relat Res 277:22–30PubMedGoogle Scholar
  7. 7.
    Jones LC, Mont MA, Le TB, Petri M, Hungerford DS, Wang P, Glueck CJ (2003) Procoagulants and osteonecrosis. J Rheumatol 30:783–791PubMedGoogle Scholar
  8. 8.
    Jones JP Jr (1999) Coagulopathies and osteonecrosis. Acta Orthop Belg 65(Suppl 1):5–8PubMedGoogle Scholar
  9. 9.
    Chandler FA (1948) Coronary disease of the hip. J Int Coll Surg 11:34–36PubMedGoogle Scholar
  10. 10.
    Chandler FA (1949) Coronary disease of the hip. Clin Orthop Relat Res 2001:7–10Google Scholar
  11. 11.
    Silvestrini G, Mocetti P, Ballanti P, Di Grezia R, Bonucci E (1999) Cytochemical demonstration of the glucocorticoid receptor in skeletal cells of the rat. Endocr Res 25:117–128PubMedGoogle Scholar
  12. 12.
    Dempster DW, Moonga BS, Stein LS, Horbert WR, Antakly T (1997) Glucocorticoids inhibit bone resorption by isolated rat osteoclasts by enhancing apoptosis. J Endocrinol 154:397–406PubMedCrossRefGoogle Scholar
  13. 13.
    Liesegang P, Romalo G, Sudmann M, Wolf L, Schweikert HU (1994) Human osteoblast-like cells contain specific, saturable, high-affinity glucocorticoid, androgen, estrogen, and 1 alpha, 25-dihydroxycholecalciferol receptors. J Androl 15:194–199PubMedGoogle Scholar
  14. 14.
    Yoshioka T, Sato B, Matsumoto K, Ono K (1980) Steroid receptors in osteoblasts. Clin Orthop Relat Res 148:297–303PubMedGoogle Scholar
  15. 15.
    Kerachian MA, Seguin C, Harvey EJ (2009) Glucocorticoids in osteonecrosis of the femoral head: a new understanding of the mechanisms of action. J Steroid Biochem Mol Biol 114:121–128PubMedCrossRefGoogle Scholar
  16. 16.
    Calder JD, Buttery L, Revell PA, Pearse M, Polak JM (2004) Apoptosis—a significant cause of bone cell death in osteonecrosis of the femoral head. J Bone Joint Surg Br 86:1209–1213PubMedCrossRefGoogle Scholar
  17. 17.
    Weinstein RS, Nicholas RW, Manolagas SC (2000) Apoptosis of osteocytes in glucocorticoid-induced osteonecrosis of the hip. J Clin Endocrinol Metab 85:2907–2912PubMedCrossRefGoogle Scholar
  18. 18.
    Kogianni G, Mann V, Ebetino F, Nuttall M, Nijweide P, Simpson H, Noble B (2004) Fas/CD95 is associated with glucocorticoid-induced osteocyte apoptosis. Life Sci 75:2879–2895PubMedCrossRefGoogle Scholar
  19. 19.
    Weinstein RS, Chen JR, Powers CC, Stewart SA, Landes RD, Bellido T, Jilka RL et al (2002) Promotion of osteoclast survival and antagonism of bisphosphonate-induced osteoclast apoptosis by glucocorticoids. J Clin Invest 109:1041–1048PubMedGoogle Scholar
  20. 20.
    Kawai K, Tamaki A, Hirohata K (1985) Steroid-induced accumulation of lipid in the osteocytes of the rabbit femoral head. A histochemical and electron microscopic study. J Bone Joint Surg Am 67:755–763PubMedGoogle Scholar
  21. 21.
    Boskey AL, Raggio CL, Bullough PG, Kinnett JG (1983) Changes in the bone tissue lipids in persons with steroid- and alcohol-induced osteonecrosis. Clin Orthop Relat Res 172:289–295PubMedGoogle Scholar
  22. 22.
    Weinstein RS, Jilka RL, Parfitt AM, Manolagas SC (1998) Inhibition of osteoblastogenesis and promotion of apoptosis of osteoblasts and osteocytes by glucocorticoids. Potential mechanisms of their deleterious effects on bone. J Clin Invest 102:274–282PubMedCrossRefGoogle Scholar
  23. 23.
    Wang GJ, Cui Q, Balian G (2000) The Nicolas Andry award. The pathogenesis and prevention of steroid-induced osteonecrosis Clin Orthop Relat Res 370:295–310Google Scholar
  24. 24.
    Aspenberg P (2006) Osteonecrosis of the jaw: what do bisphosphonates do? Expert Opin Drug Saf 5:743–745PubMedCrossRefGoogle Scholar
  25. 25.
    Assael LA (2009) Oral bisphosphonates as a cause of bisphosphonate-related osteonecrosis of the jaws: clinical findings, assessment of risks, and preventive strategies. J Oral Maxillofac Surg 67:35–43PubMedCrossRefGoogle Scholar
  26. 26.
    Bilezikian JP (2006) Osteonecrosis of the jaw—do bisphosphonates pose a risk? N Engl J Med 355:2278–2281PubMedCrossRefGoogle Scholar
  27. 27.
    Pendrys DG, Silverman SL (2008) Osteonecrosis of the jaws and bisphosphonates. Curr Osteoporos Rep 6:31–38PubMedCrossRefGoogle Scholar
  28. 28.
    Walter C, Pabst A, Ziebart T, Klein M, Al-Nawas B. Bisphosphonates affect migration ability and cell viability of HUVEC, fibroblasts and osteoblasts in vitro. Oral Dis 2010 (In press)Google Scholar
  29. 29.
    Harper RN, Moore MA, Marr MC, Watts LE, Hutchins PM (1978) Arteriolar rarefaction in the conjunctiva of human essential hypertensives. Microvasc Res 16:369–372PubMedCrossRefGoogle Scholar
  30. 30.
    Kerachian MA, Harvey EJ, Cournoyer D, Chow TY, Seguin C (2006) Avascular necrosis of the femoral head: vascular hypotheses. Endothelium 13:237–244PubMedCrossRefGoogle Scholar
  31. 31.
    Feng Y, Yang SH, Xiao BJ, et al (2010) Decreased in the number and function of circulation endothelial progenitor cells in patients with avascular necrosis of the femoral head. Bone 46:32–40Google Scholar
  32. 32.
    Li YM, Wang SX, Gao HS, Wang JG, Wei CS, Chen LM, Hui WL et al (2004) Factors of avascular necrosis of femoral head and osteoporosis in SARS patients' convalescence. Zhonghua Yi Xue Za Zhi 84:1348–1353PubMedGoogle Scholar
  33. 33.
    Jones JP Jr, Ramirez S, Doty SB (1993) The pathophysiologic role of fat in dysbaric osteonecrosis. Clin Orthop Relat Res 296:256–264PubMedGoogle Scholar
  34. 34.
    Gray E, Thomas S, Mistry Y, Poole S (1996) Inhibition of tissue factor and cytokine release. Haemostasis 26(Suppl 1):92–95PubMedGoogle Scholar
  35. 35.
    van Giezen JJ, Jansen JW (1992) Correlation of in vitro and in vivo decreased fibrinolytic activity caused by dexamethasone. Ann NY Acad Sci 667:199–201PubMedCrossRefGoogle Scholar
  36. 36.
    Minneci PC, Deans KJ, Banks SM, Eichacker PQ, Natanson C (2004) Meta-analysis: the effect of steroids on survival and shock during sepsis depends on the dose. Ann Intern Med 141:47–56PubMedGoogle Scholar
  37. 37.
    Boss JH, Misselevich I (2003) Osteonecrosis of the femoral head of laboratory animals: the lessons learned from a comparative study of osteonecrosis in man and experimental animals. Vet Pathol 40:345–354PubMedCrossRefGoogle Scholar
  38. 38.
    Hirata T, Fujioka M, Takahashi KA, Asano T, Ishida M, Akioka K, Okamoto M et al (2007) Low molecular weight phenotype of Apo(a) is a risk factor of corticosteroid-induced osteonecrosis of the femoral head after renal transplant. J Rheumatol 34:516–522PubMedGoogle Scholar
  39. 39.
    Ferrari P, Schroeder V, Anderson S, Kocovic L, Vogt B, Schiesser D, Marti HP et al (2002) Association of plasminogen activator inhibitor-1 genotype with avascular osteonecrosis in steroid-treated renal allograft recipients. Transplantation 74:1147–1152PubMedCrossRefGoogle Scholar
  40. 40.
    Kang P, Shen B, Yang J, Pei F (2008) Circulating platelet-derived microparticles and endothelium-derived microparticles may be a potential cause of microthrombosis in patients with osteonecrosis of the femoral head. Thromb Res 123:367–373PubMedCrossRefGoogle Scholar
  41. 41.
    Chotanaphuti T, Heebthamai D, Chuwong M, Kanchanaroek K (2009) The prevalence of thrombophilia in idiopathic osteonecrosis of the hip. J Med Assoc Thai 92(Suppl 6):S141–S146PubMedGoogle Scholar
  42. 42.
    Glueck CJ, Freiberg RA, Boppana S, Wang P (2008) Thrombophilia, hypofibrinolysis, the eNOS T-786 C polymorphism, and multifocal osteonecrosis. J Bone Joint Surg Am 90:2220–2229PubMedCrossRefGoogle Scholar
  43. 43.
    Glueck CJ, Freiberg RA, Wang P (2008) Heritable thrombophilia–hypofibrinolysis and osteonecrosis of the femoral head. Clin Orthop Relat Res 466:1034–1040PubMedCrossRefGoogle Scholar
  44. 44.
    Seguin C, Kassis J, Busque L, Bestawros A, Theodoropoulos J, Alonso ML, Harvey EJ (2008) Non-traumatic necrosis of bone (osteonecrosis) is associated with endothelial cell activation but not thrombophilia. Rheumatology (Oxford) 47:1151–1155CrossRefGoogle Scholar
  45. 45.
    Arlet J, Ficat P, Lartigue G, Tran MA (1972) Clinical research on intraosseous pressure in the upper femoral metaphysis and epiphysis in humans. Application to the diagnosis of ischemia and necrosis. Rev Rhum Mal Osteo-artic 39:717–723Google Scholar
  46. 46.
    Wang KZ, Mao LZ, Hu CG (1994) Experimental study on mechanism of steroid-induced avascular necrosis of femoral head. Zhonghua Wai Ke Za Zhi 32:515–517PubMedGoogle Scholar
  47. 47.
    Wang KZ, Wang CS, Wu YG, Chen H (2006) Changes of vessel in steroid-induced osteonecrosis of femoral head: experimental study of rabbits. Zhonghua Yi Xue Za Zhi 86:2024–2027PubMedGoogle Scholar
  48. 48.
    Wang ZX, Yang ZX (1985) Experimental observations on the biological features and pathogenicity of Thelazia callipaeda parasitized in rabbits. Ji Sheng Chong Xue Yu Ji Sheng Chong Bing Za Zhi 3:128–130PubMedGoogle Scholar
  49. 49.
    Welch RD, Johnston CE 2nd, Waldron MJ, Poteet B (1993) Bone changes associated with intraosseous hypertension in the caprine tibia. J Bone Joint Surg Am 75:53–60PubMedGoogle Scholar
  50. 50.
    Saito S, Ohzono K, Ono K (1992) Early arteriopathy and postulated pathogenesis of osteonecrosis of the femoral head. The intracapital arterioles Clin Orthop Relat Res 277:98–110Google Scholar
  51. 51.
    Yang C, Yang S, Du J, Li J, Xu W, Xiong Y (2003) Experimental study of vascular endothelial growth factor gene therapy for avascular necrosis of the femoral head. J Huazhong Univ Sci Technolog Med Sci 23(297–299):316Google Scholar
  52. 52.
    Li X, Jin L, Cui Q, Wang GJ, Balian G (2005) Steroid effects on osteogenesis through mesenchymal cell gene expression. Osteoporos Int 16:101–108PubMedCrossRefGoogle Scholar
  53. 53.
    Harada I (1992) The effects of glucocorticoids on angiogenesis in vitro. Nippon Seikeigeka Gakkai Zasshi 66:763–770PubMedGoogle Scholar
  54. 54.
    Wolff JE, Guerin C, Laterra J, Bressler J, Indurti RR, Brem H, Goldstein GW (1993) Dexamethasone reduces vascular density and plasminogen activator activity in 9 L rat brain tumors. Brain Res 604:79–85PubMedCrossRefGoogle Scholar
  55. 55.
    Boss JH (2004) Experimental models of osteonecrosis of the femoral head. J Orthop Sci 9:533–534PubMedCrossRefGoogle Scholar
  56. 56.
    Ichiseki T, Matsumoto T, Nishino M, Kaneuji A, Katsuda S (2004) Oxidative stress and vascular permeability in steroid-induced osteonecrosis model. J Orthop Sci 9:509–515PubMedCrossRefGoogle Scholar
  57. 57.
    Ichiseki T, Kaneuji A, Katsuda S, Ueda Y, Sugimori T, Matsumoto T (2005) DNA oxidation injury in bone early after steroid administration is involved in the pathogenesis of steroid-induced osteonecrosis. Rheumatology (Oxford) 44:456–460CrossRefGoogle Scholar
  58. 58.
    Ichiseki T, Matsumoto T (2006) Oxidative stress may underlie the sex differences seen in steroid-induced osteonecrosis models. Med Hypotheses 66:1256PubMedCrossRefGoogle Scholar
  59. 59.
    Jaffe WL, Epstein M, Heyman N, Mankin HJ (1972) The effect of cortisone on femoral and humeral heads in rabbits. An experimental study. Clin Orthop Relat Res 82:221–228PubMedCrossRefGoogle Scholar
  60. 60.
    Zhou Q, Li Q, Yang L, Liu F (2000) Changes of blood vessels in glucocorticoid-induced avascular necrosis of femoral head in rabbits. Zhonghua Wai Ke Za Zhi 38(212–215):213Google Scholar
  61. 61.
    Chen XC, Weng J, Chen XQ, Du JZ, Zhu MP, Pan YQ, Liu M (2008) Relationships among magnetic resonance imaging, histological findings, and IGF-I in steroid-induced osteonecrosis of the femoral head in rabbits. J Zhejiang Univ Sci B 9:739–746PubMedCrossRefGoogle Scholar
  62. 62.
    Cui Q, Wang GJ, Su CC, Balian G (1997) The Otto Aufranc Award. Lovastatin prevents steroid induced adipogenesis and osteonecrosis Clin Orthop Relat Res 344:8–19Google Scholar
  63. 63.
    Wang GJ, Moga DB, Richemer WG, Sweet DE, Reger SI, Thompson RC (1978) Cortisone induced bone changes and its response to lipid clearing agents. Clin Orthop Relat Res 130:81–85PubMedGoogle Scholar
  64. 64.
    Jones JP Jr (1985) Fat embolism and osteonecrosis. Orthop Clin North Am 16:595–633PubMedGoogle Scholar
  65. 65.
    Motomura G, Yamamoto T, Irisa T, Miyanishi K, Nishida K, Iwamoto Y (2008) Dose effects of corticosteroids on the development of osteonecrosis in rabbits. J Rheumatol 35:2395–2399PubMedCrossRefGoogle Scholar
  66. 66.
    Motomura G, Yamamoto T, Miyanishi K, Jingushi S, Iwamoto Y (2004) Combined effects of an anticoagulant and a lipid-lowering agent on the prevention of steroid-induced osteonecrosis in rabbits. Arthritis Rheum 50:3387–3391PubMedCrossRefGoogle Scholar
  67. 67.
    Yamamoto T, Irisa T, Sugioka Y, Sueishi K (1997) Effects of pulse methylprednisolone on bone and marrow tissues: corticosteroid-induced osteonecrosis in rabbits. Arthritis Rheum 40:2055–2064PubMedCrossRefGoogle Scholar
  68. 68.
    Motomura G, Yamamoto T, Miyanishi K, Kondo K, Hirota Y, Iwamoto Y (2008) Risk factors for developing osteonecrosis after prophylaxis in steroid-treated rabbits. J Rheumatol 35:2391–2394PubMedCrossRefGoogle Scholar
  69. 69.
    Tokuhara Y, Wakitani S, Oda Y, Kaneshiro Y, Masada T, Kim M, Kadoya Y et al (2009) Low levels of steroid-metabolizing hepatic enzyme (cytochrome P450 3A) activity may elevate responsiveness to steroids and may increase risk of steroid-induced osteonecrosis even with low glucocorticoid dose. J Orthop Sci 14:794–800PubMedCrossRefGoogle Scholar
  70. 70.
    Masada T, Iwakiri K, Oda Y, Kaneshiro Y, Iwaki H, Ohashi H, Takaoka K (2008) Increased hepatic cytochrome P4503A activity decreases the risk of developing steroid-induced osteonecrosis in a rabbit model. J Orthop Res 26:91–95PubMedCrossRefGoogle Scholar
  71. 71.
    Kaneshiro Y, Oda Y, Iwakiri K, Masada T, Iwaki H, Hirota Y, Kondo K et al (2006) Low hepatic cytochrome P450 3A activity is a risk for corticosteroid-induced osteonecrosis. Clin Pharmacol Ther 80:396–402PubMedCrossRefGoogle Scholar
  72. 72.
    Asano T, Takahashi KA, Fujioka M, Inoue S, Satomi Y, Nishino H, Tanaka T et al (2003) Genetic analysis of steroid-induced osteonecrosis of the femoral head. J Orthop Sci 8:329–333PubMedCrossRefGoogle Scholar
  73. 73.
    Wang XY, Niu XH, Chen WH, Lin N, Song JN, Chen B, Jin H (2008) Effects of apolipoprotein A1 and B gene polymorphism on avascular necrosis of the femoral head in Chinese population. Zhongguo Gu Shang 21:99–102PubMedGoogle Scholar
  74. 74.
    Asano T, Takahashi KA, Fujioka M, Inoue S, Ueshima K, Hirata T, Okamoto M et al (2004) Relationship between postrenal transplant osteonecrosis of the femoral head and gene polymorphisms related to the coagulation and fibrinolytic systems in Japanese subjects. Transplantation 77:220–225PubMedCrossRefGoogle Scholar
  75. 75.
    Kim TH, Hong JM, Shin ES, Kim HJ, Cho YS, Lee JY, Lee SH et al (2009) Polymorphisms in the annexin gene family and the risk of osteonecrosis of the femoral head in the Korean population. Bone 45:125–131PubMedCrossRefGoogle Scholar
  76. 76.
    Kim TH, Hong JM, Oh B, Cho YS, Lee JY, Kim HL, Lee JE et al (2008) Association of polymorphisms in the Interleukin 23 receptor gene with osteonecrosis of femoral head in Korean population. Exp Mol Med 40:418–426PubMedCrossRefGoogle Scholar
  77. 77.
    Kenzora JE (1983) Ischemic necrosis of femoral head. Part I. Accumulative cell stress: a hypothesis for the etiology of idiopathic osteonecrosis. Instr Course Lect 32:242–252PubMedGoogle Scholar
  78. 78.
    Kenzora JE (1985) Treatment of idiopathic osteonecrosis: the current philosophy and rationale. Orthop Clin North Am 16:717–725PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2010

Authors and Affiliations

  • Christian Powell
    • 1
  • Christopher Chang
    • 1
  • M. Eric Gershwin
    • 1
  1. 1.Division of Rheumatology, Allergy and Clinical ImmunologyUniversity of California at Davis School of MedicineDavisUSA

Personalised recommendations