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.
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References
E.W. Boland, N.E. Headley, Management of rheumatoid arthritis with smaller (maintenance) doses of cortisone acetate. JAMA 144, 365–372 (1950)
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)
A.J. Bollet, R. Black, J.J. Bumin, Major undesirable side-effects resulting from prednisolone and prednisone. JAMA 157, 459–463 (1955)
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)
V. Pietrogrande, R. Mastromarino, Osteopathia da prolungato trattmento cortisonico. Ortop. Tramatol. 25, 791–810 (1957)
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)
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)
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)
R.S. Weinstein, Clinical practice: glucocorticoid-induced bone disease. N. Engl. J. Med. 365, 62–70 (2011)
D.E. Fisher, W.H. Bickel, Corticosteroid-induced avascular necrosis. J. Bone Jt. Surg. Am. 53, 859–873 (1971)
H.F. Mankin, Nontraumatic necrosis of bone (osteonecrosis). N. Engl. J. Med. 326, 1473–1479 (1992)
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)
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)
W. Drescher, G. Schlieper, J. Floege, F. Eitner, Steroid-related osteonecrosis—an update. Nephrol. Dial. Transplant. 26, 1728–2731 (2010)
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
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)
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)
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)
C.N. Chandler, V. Wright, Deleterious effect of intra-articular hydrocortisone. Lancet ii, 661–663 (1958)
G.S. Habib, W. Saliba, M. Nashashibi, Local effects of intra-articular corticosteroids. Clin. Rheumatol. 29, 347–356 (2010)
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)
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
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)
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)
D.J. Prockop, Type II collagen and avascular necrosis of the femoral head. N. Engl. J. Med. 352, 2268–2270 (2005)
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)
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)
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
P. Mehta, M. Nelson, A. Brand, F. Boag, Avascular necrosis in HIV. Rheumatol. Int. (2011). doi:10.1007/s00296-011-2114-5
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)
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
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)
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)
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)
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)
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)
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)
P.A. Lotke, M.L. Ecker, Osteonecrosis of the knee. J. Bone Jt. Surg. Am. 70, 470–473 (1988)
N.V. Bardakos, R.N. Villar, The ligamentum teres of the adult hip. J. Bone Joint Surg. Br. 91, 8–15 (2009)
R.S. Weinstein, R.W. Nicholas, S.C. Manolagas, Apoptosis of osteocytes in glucocorticoid-induced osteonecrosis of the hip. Endocrinology 85, 2907–2912 (2000)
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)
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)
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)
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)
Y.-S. Youm, S.-Y. Lee, S.-H. Lee, Apoptosis in the osteonecrosis of the femoral head. Clin. Orthop. Surg. 2, 250–255 (2010)
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)
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)
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
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)
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)
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).
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Weinstein, R.S. Glucocorticoid-induced osteonecrosis. Endocrine 41, 183–190 (2012). https://doi.org/10.1007/s12020-011-9580-0
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DOI: https://doi.org/10.1007/s12020-011-9580-0