Skip to main content

Advertisement

Log in

Glucocorticoid-induced osteonecrosis

  • Review
  • Published:
Endocrine Aims and scope Submit manuscript

Abstract

Awareness of the need for prevention of glucocorticoid-induced fractures is growing, but glucocorticoid administration is often overlooked as the most common cause of nontraumatic osteonecrosis. Glucocorticoid-induced osteonecrosis develops in 9–40% of patients receiving long-term therapy although it may also occur with short-term exposure to high doses, after intra-articular injection, and without glucocorticoid-induced osteoporosis. The name, osteonecrosis, is misleading because the primary histopathological lesion is osteocyte apoptosis. Apoptotic osteocytes persist because they are anatomically unavailable for phagocytosis and, with glucocorticoid excess, decreased bone remodeling retards their replacement. Glucocorticoid-induced osteocyte apoptosis, a cumulative and unrepairable defect, uniquely disrupts the mechanosensory function of the osteocyte–lacunar–canalicular system and thus starts the inexorable sequence of events leading to collapse of the femoral head. Current evidence indicates that bisphosphonates may rapidly reduce pain, increase ambulation, and delay joint collapse in patients with osteonecrosis.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

References

  1. E.W. Boland, N.E. Headley, Management of rheumatoid arthritis with smaller (maintenance) doses of cortisone acetate. JAMA 144, 365–372 (1950)

    Article  CAS  Google Scholar 

  2. R.H. Freyberg, C.H. Traeger, M. Patterson, W. Squires, C.H. Adams, C. Stevenson, Problems of prolonged cortisone treatment for rheumatoid arthritis. JAMA 147, 1538–1543 (1951)

    Article  CAS  Google Scholar 

  3. A.J. Bollet, R. Black, J.J. Bumin, Major undesirable side-effects resulting from prednisolone and prednisone. JAMA 157, 459–463 (1955)

    Article  Google Scholar 

  4. W.G. Heiman, R.H. Freiberger, Avascular necrosis of the femoral and humeral heads after high-dosage corticosteroid therapy. N. Engl. J. Med. 263, 672–675 (1960)

    Article  Google Scholar 

  5. V. Pietrogrande, R. Mastromarino, Osteopathia da prolungato trattmento cortisonico. Ortop. Tramatol. 25, 791–810 (1957)

    Google Scholar 

  6. S.M.S. Nasser, P.W. Ewan, Depot corticosteroid treatment for hay fever causing avascular necrosis of both hips. Br. Med. J. 322, 1589–1591 (2010)

    Article  Google Scholar 

  7. C.J. McClean, R.F.J. Lobo, D.J. Brazier, Cataracts, glaucoma, and femoral avascular necrosis caused by topical corticosteroid ointment. Lancet 345, 330 (1995)

    Article  Google Scholar 

  8. T. Kubo, A. Kojima, S. Yamazoe, K. Ueshima, T. Yamamoto, Y. Hirasawa, Osteonecrosis of the femoral head that developed after long-term topical steroid application. J. Orthop. Sci. 6, 92–94 (2001)

    Article  PubMed  CAS  Google Scholar 

  9. R.S. Weinstein, Clinical practice: glucocorticoid-induced bone disease. N. Engl. J. Med. 365, 62–70 (2011)

    Article  PubMed  CAS  Google Scholar 

  10. D.E. Fisher, W.H. Bickel, Corticosteroid-induced avascular necrosis. J. Bone Jt. Surg. Am. 53, 859–873 (1971)

    CAS  Google Scholar 

  11. H.F. Mankin, Nontraumatic necrosis of bone (osteonecrosis). N. Engl. J. Med. 326, 1473–1479 (1992)

    Article  PubMed  CAS  Google Scholar 

  12. J.D. Kawedia, S.C. Kaste, D. Pei, J.C. Panetta, X. Cai, C. Cheng, G. Neale, S.C. Howard, W.E. Evans, C.-H. Pui, M.V. Rellinh, Pharmacokinetic, pharmacodynamic, and pharmacogenetic determinants of osteonecrosis in children with acute lymphoblastic leukemia. Blood 117, 2340–2347 (2011)

    Article  PubMed  CAS  Google Scholar 

  13. J.J. Nash, A.G. Nash, M.E. Leach, D.M. Poetker, Medical malpractice and corticosteroid use. Otolaryngol. Head Neck Surg. 144, 10–15 (2011)

    Article  PubMed  Google Scholar 

  14. W. Drescher, G. Schlieper, J. Floege, F. Eitner, Steroid-related osteonecrosis—an update. Nephrol. Dial. Transplant. 26, 1728–2731 (2010)

    Google Scholar 

  15. R.A. Adler, J.R. Curtis, K. Saag, R.S. Weinstein, Glucocorticoid-induced osteoporosis, in Osteoporosis, 3rd edn., ed. by R. Marcus, D. Feldman, D.A. Nelsen, C.J. Rosen (Elsevier-Academic Press, San Diego, 2008), pp. 1135–1166

    Chapter  Google Scholar 

  16. C.C. Cooper, M. Steinbuch, R. Stevenson, R. Miday, N.B. Watts, The epidemiology of osteonecrosis: findings from the GPRD and THIN databases in the UK. Osteoporos. Int. 21, 569–577 (2010)

    Article  PubMed  CAS  Google Scholar 

  17. D.T. Felson, J.J. Anderson, Across-study evaluation of association between steroid dose and bolus steroids and avascular necrosis of bone. Lancet i, 902–905 (1987)

    Article  Google Scholar 

  18. S. McAvoy, K.S. Baker, D. Mulrooney, A. Blaes, M. Arora, L.J. Burns, N.S. Majhail, Corticosteroid dose as a risk factor for avascular necrosis of the bone after hematopoietic cell transplantation. Biol. Blood Marrow Transplant. 16, 1231–1236 (2010)

    Article  PubMed  CAS  Google Scholar 

  19. C.N. Chandler, V. Wright, Deleterious effect of intra-articular hydrocortisone. Lancet ii, 661–663 (1958)

    Article  Google Scholar 

  20. G.S. Habib, W. Saliba, M. Nashashibi, Local effects of intra-articular corticosteroids. Clin. Rheumatol. 29, 347–356 (2010)

    Article  PubMed  Google Scholar 

  21. T. Yamamoto, R. Schneider, Y. Iwamoto, P.G. Bullough, Rapid destruction of the femoral head after a single intraarticular injection of corticosteroid into the hip joint. J. Rheumatol. 33, 1701–1704 (2006)

    PubMed  Google Scholar 

  22. Y.J. Lee, J.S. Lee, E.H. Kang, Y.-K. Lee, S.-Y. Kim, Y.W. Song, K.-H. Koo, Vascular endothelial growth factor polymorphisms in patients with steroid-induced femoral head osteonecrosis. J. Orthop. Res. (2011). doi:10.1002/jor.21492

  23. H. Russcher, P. Smit, E.L.T. van den Akker, E.F.C. van Rossum, A.O. Brinkman, F.H. de Jong, S.W.J. Lamberts, J.W. Koper, Two polymorphisms in the glucocorticoid receptor gene directly affect glucocorticoid-regulated gene expression. J. Clin. Endocrinol. Metab. 90, 5804–5810 (2005)

    Article  PubMed  CAS  Google Scholar 

  24. M.S. Cooper, E.H. Rabbitt, P.E. Goddard, W.A. Bartlett, M. Hewison, P.M. Stewart, Osteoblastic 11β-hydroxysteroid dehydrogenase type 1 activity increases with age and glucocorticoid exposure. J. Bone Miner. Res. 17, 979–986 (2002)

    Article  PubMed  CAS  Google Scholar 

  25. D.J. Prockop, Type II collagen and avascular necrosis of the femoral head. N. Engl. J. Med. 352, 2268–2270 (2005)

    Article  PubMed  CAS  Google Scholar 

  26. N. Han, Z. Yan, C.-a. Guo, F. Shen, J. Liu, Y. Ski, Z. Zhang, Effects of P-glycoprotein on steroid-induced osteonecrosis of the femoral head. Calcif. Tissue Int. 87, 246–253 (2010)

    Article  PubMed  CAS  Google Scholar 

  27. M. Elmantaser, G. Stewart, D. Young, R. Duncan, B. Gibson, S.F. Ahmed, Skeletal morbidity in children receiving chemotherapy for acute lymphoblastic leukemia. Arch. Dis. Child. 95, 805–809 (2010)

    Article  PubMed  CAS  Google Scholar 

  28. A.H. Hautmann, S. Elad, A. Lawitschka, H. Greinix, H. Bertz, J. Halter, M. Faraci, L.C. Hofbauer, S. Lee, D. Wolff, E. Holler, Metabolic bone diseases in patients after allogeneic hematopoietic stem cell transplantation: report from the consensus conference on clinical practice in chronic graft-versus-host disease. Transpl. Int. (2011). doi:10.1111/j.1432-2277.2011.01264.x

  29. P. Mehta, M. Nelson, A. Brand, F. Boag, Avascular necrosis in HIV. Rheumatol. Int. (2011). doi:10.1007/s00296-011-2114-5

  30. H.M. Frost, A.R. Villananueva, Human osteoblast activity: III. Effect of cortisone on lamellar osteoblast activity. Henry Ford Hosp. Med. Bull. 9, 97–99 (1961)

    PubMed  CAS  Google Scholar 

  31. M. Güven, K. Ünay, C. Bes, O. Poyanli, B. Akman, Hip osteonecrosis in Cushing’s disease treated with bone-preserving procedures. J. Orthop. Sci. (2009). doi:10.1007/s00776-009-1360-1369

  32. M. Zaidi, L. Sun, J. Robinson, I.L. Tourkova, L. Liu, Y. Wang, L.-.L. Zhu, X. Liu, J. Li, Y. Peng, G. Yang, X. Shi, A. Levine, J. Iqbal, B.B. Yaroslavskly, C. Isales, H.C. Blair, ACTH protects against glucocorticoid-induced osteonecrosis of bone. Proc. Natl. Acad. Sci. 107, 8782–8787 (2010)

    Article  PubMed  CAS  Google Scholar 

  33. R.S. Weinstein, R.L. Jilka, A.M. Parfitt, S.C. Manolagas, Inhibition of osteoblastogenesis and promotion of apoptosis of osteoblasts and osteocytes by glucocorticoids: potential mechanisms of the deleterious effects on bone. J. Clin. Invest. 102, 274–282 (1998)

    Article  PubMed  CAS  Google Scholar 

  34. C.A. O’Brien, D. Jia, L.I. Plotkin, T. Bellido, C.C. Powers, S.A. Stewart, S.C. Manolagas, R.S. Weinstein, Glucocorticoids act directly on osteoblasts and osteocytes to induce their apoptosis and reduce bone formation and strength. Endocrinology 145, 1835–1841 (2004)

    Article  PubMed  Google Scholar 

  35. R.S. Weinstein, J.R. Chen, C.C. Powers, S.A. Stewart, R.D. Landes, T. Bellido, R.L. Jilka, A.M. Parfitt, S.C. Manolagas, Promotion of osteoclast survival and antagonism of bisphosphonate-induced osteoclast apoptosis by glucocorticoids. J. Clin. Invest. 109, 1041–1048 (2002)

    PubMed  CAS  Google Scholar 

  36. D. Jia, C.A. O’Brien, S.A. Stewart, S.C. Manolagas, R.S. Weinstein, Glucocorticoids act directly on osteoclasts to increase their lifespan and reduce bone density. Endocrinology 147, 5592–5599 (2006)

    Article  PubMed  CAS  Google Scholar 

  37. R.S. Weinstein, C. Wan, Q. Liu, Y. Wang, M. Almeida, C.A. O’Brien, J. Thostenson, P.K. Roberson, A.L. Boskey, T.L. Clemens, S.C. Manolagas, Endogenous glucocorticoids decrease angiogenesis, vascularity, hydration, and strength in aged mice. Aging Cell 9, 147–161 (2010)

    Article  PubMed  CAS  Google Scholar 

  38. P.A. Lotke, M.L. Ecker, Osteonecrosis of the knee. J. Bone Jt. Surg. Am. 70, 470–473 (1988)

    CAS  Google Scholar 

  39. N.V. Bardakos, R.N. Villar, The ligamentum teres of the adult hip. J. Bone Joint Surg. Br. 91, 8–15 (2009)

    PubMed  CAS  Google Scholar 

  40. R.S. Weinstein, R.W. Nicholas, S.C. Manolagas, Apoptosis of osteocytes in glucocorticoid-induced osteonecrosis of the hip. Endocrinology 85, 2907–2912 (2000)

    CAS  Google Scholar 

  41. T. Kabata, T. Kubo, T. Matsumoto, M. Nishino, K. Tomita, S. Katsuda, T. Horii, N. Uto, I. Kitajima, Apoptotic cell death in steroid induced osteonecrosis: an experimental study in rabbits. J. Rheumatol. 27, 2166–2177 (2000)

    PubMed  CAS  Google Scholar 

  42. A.W. Eberhardt, A. Yeager-Jones, H.C. Blair, Regional trabecular bone matrix degeneration and osteocyte death in femora of glucocorticoid-treated rabbits. Endocrinology 142, 1333–1340 (2001)

    Article  PubMed  CAS  Google Scholar 

  43. J.D.F. Calder, L. Buttery, P.A. Revell, M. Pearse, J.M. Polak, Apoptosis—a significant cause of bone cell death in osteonecrosis of the femoral head. J. Bone Joint Surg. Br. 86, 1209–1213 (2004)

    Article  PubMed  CAS  Google Scholar 

  44. J.-Y. Ko, F.-S. Wang, C.-J. Wang, T. Wong, W.-Y. Chou, S.-L. Tseng, Increased Dickkopf-1 expression accelerates bone cell apoptosis in femoral head osteonecrosis. Bone 46, 584–591 (2010)

    Article  PubMed  CAS  Google Scholar 

  45. Y.-S. Youm, S.-Y. Lee, S.-H. Lee, Apoptosis in the osteonecrosis of the femoral head. Clin. Orthop. Surg. 2, 250–255 (2010)

    Article  PubMed  Google Scholar 

  46. M.A. Mont, M.G. Zywiel, D.R. Marker, M.S. McGrath, R.E. Delanois, The natural history of asymptomatic osteonecrosis of the femoral head. J. Bone Jt. Surg. Am. 92, 2165–2170 (2010)

    Article  Google Scholar 

  47. K.-A. Lai, W.-J. Shen, C.-Y. Yang, C.-J. Shao, J.-T. Hsu, R.-M. Lin, The use of alendronate to prevent early collapse of the femoral head in patients with nontraumatic osteonecrosis. J. Bone Jt. Surg. Am. 87, 2155–2159 (2005)

    Article  Google Scholar 

  48. S. Agarwala, S.B. Shah, Ten-year follow-up of avascular necrosis of femoral head treated with alendronate for 3 years. J. Arthroplast. (2011). doi:10.1016/j.arth.2010.11.010

  49. L.I. Plotkin, R.S. Weinstein, A.M. Parfitt, S.C. Manolagas, T. Bellido, Prevention of osteocyte and osteoblast apoptosis by bisphosphonates and calcitonin. J. Clin. Invest. 104, 1363–1374 (1999)

    Article  PubMed  CAS  Google Scholar 

  50. R.S. Weinstein, C.A. O’Brien, H. Zhao, P.K. Roberson, S.C. Manolagas, Osteoprotegerin prevents glucocorticoid-induced osteocyte apoptosis in mice. Endocrinology 152, 3323–3331 (2011)

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

I am grateful to Drs. Stavros C. Manolagas, Robert L. Jilka, Maria Almeida, and Charles A. O’Brien for their advice and helpful discussions about the adverse skeletal effects of glucocorticoids and for review of the manuscript. This study was supported by VA Merit Review Grants from the Office of Research and Development, Department of Veterans Affairs and the National Institutes of Health (P01-AG13918).

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Robert S. Weinstein.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Weinstein, R.S. Glucocorticoid-induced osteonecrosis. Endocrine 41, 183–190 (2012). https://doi.org/10.1007/s12020-011-9580-0

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12020-011-9580-0

Keywords

Navigation