ONJ has been increasingly suspected to be a potential complication of bisphosphonate therapy in recent years. Thus, the ASBMR leadership appointed a multidisciplinary task force to address key questions related to case definition, epidemiology, risk factors, diagnostic imaging, clinical management, and future areas for research related to the disorder. This report summarizes the findings and recommendations of the task force.
Introduction: The increasing recognition that use of bisphosphonates may be associated with osteonecrosis of the jaw (ONJ) led the leadership of the American Society for Bone and Mineral Research (ASBMR) to appoint a task force to address a number of key questions related to this disorder.
Materials and Methods: A multidisciplinary expert group reviewed all pertinent published data on bisphosphonate-associated ONJ. Food and Drug Administration drug adverse event reports were also reviewed.
Results and Conclusions: A case definition was developed so that subsequent studies could report on the same condition. The task force defined ONJ as the presence of exposed bone in the maxillofacial region that did not heal within 8 wk after identification by a health care provider. Based on review of both published and unpublished data, the risk of ONJ associated with oral bisphosphonate therapy for osteoporosis seems to be low, estimated between 1 in 10,000 and <1 in 100,000 patient-treatment years. However, the task force recognized that information on incidence of ONJ is rapidly evolving and that the true incidence may be higher. The risk of ONJ in patients with cancer treated with high doses of intravenous bisphosphonates is clearly higher, in the range of 1–10 per 100 patients (depending on duration of therapy). In the future, improved diagnostic imaging modalities, such as optical coherence tomography or MRI combined with contrast agents and the manipulation of image planes, may identify patients at preclinical or early stages of the disease. Management is largely supportive. A research agenda aimed at filling the considerable gaps in knowledge regarding this disorder was also outlined.
|2020||Messer JG, Castillo EJ, Abraham AM, Jiron JM, Israel R, Yarrow JF, Thomas S, Reynolds MC, Wnek RD, Jorgensen M, Wanionok N, Van Poznak C, Bhattacharyya I, Kimmel DB, Aguirre JI. Anti-vascular endothelial growth factor antibody monotherapy causes destructive advanced periodontitis in rice rats (Oryzomys palustris). Bone. January 2020;130:115141.|
|2020||Ferrari S, Lewiecki EM, Butler PW, Kendler DL, Napoli N, Huang S, Crittenden DB, Pannacciulli N, Siris E, Binkley N. Favorable skeletal benefit/risk of long-term denosumab therapy: a virtual-twin analysis of fractures prevented relative to skeletal safety events observed. Bone. May 2020;134:115287.|
|2020||Cremers S, Ebetino F, Phipps R. On the pharmacological evaluation of bisphosphonates in humans. Bone. October 2020;139:115501.|
|2021||Suva LJ, Cooper A, Watts AE, Ebetino FH, Price J, Gaddy D. Bisphosphonates in veterinary medicine: the new horizon for use. Bone. January 2021;142:115711.|
|2021||Boraschi-Diaz I, Chen G, Polak-Nachumow J, Young RN, Rauch F. Effects of treatment with a bone-targeted prostaglandin E2 receptor 4 agonist C3 (Mes-1007) in a mouse model of severe osteogenesis imperfecta. Bone. April 2021;145:115867.|
|2010||Papaioannou A, Morin S, Cheung AM, Atkinson S, Brown JP, Feldman S, Hanley DA, Hodsman A, Jamal SA, Kaiser SM, Kvern B, Siminoski K, Leslie WD; Scientific Advisory Council of Osteoporosis Canada. 2010 clinical practice guidelines for the diagnosis and management of osteoporosis in Canada: summary. Can Med Assoc J. November 23, 2010;182(17):1864-1873.|
|2016||Camacho PM, Petak SM, Binkley N, Clarke BL, Harris ST, Hurley DL, Kleerekoper M, Lewiecki EM, Miller PD, Narula HS, Pessah-Pollack R, Tangpricha V, Wimalawansa SJ, Watts NB. American Association of Clinical Endocrinologists and American College of Endocrinology clinical practice guidelines for the diagnosis and treatment of postmenopausal osteoporosis — 2016. Endocr Pract. September 1, 2016;22(suppl 4):1-42.|
|2010||Shane E, Burr D, Ebeling PR, Abrahamsen B, Adler RA, Brown TD, Cheung AM, Cosman F, Curtis JR, Dell R, Dempster D, Einhorn TA, Genant HK, Geusens P, Klaushofer K, Koval K, Lane JM, McKiernan F, McKinney R, Ng A, Nieves J, O'Keefe R, Papapoulos S, Sen HT, van der Meulen MCH, Weinstein RS, Whyte M. Atypical subtrochanteric and diaphyseal femoral fractures: report of a task force of the American Society for Bone and Mineral Research. J Bone Miner Res. November 2010;25(11):2267-2294.|
|2012||Black DM, Reid IR, Boonen S, Bucci-Rechtweg C, Cauley JA, Cosman F, Cummings SR, Hue TF, Lippuner K, Lakatos P, Leung PC, Man Z, Martinez RLM, Tan M, Ruzycky ME, Su G, Eastell R. The effect of 3 versus 6 years of Zoledronic acid treatment of osteoporosis: a randomized extension to the HORIZON-Pivotal Fracture Trial (PFT). J Bone Miner Res. February 2012;27(2):243-254.|
|2012||Bala Y, Depalle B, Farlay D, Douillard T, Meille S, Follet H, Chapurlat R, Chevalier J, Boivin G. Bone micromechanical properties are compromised during long-term alendronate therapy independently of mineralization. J Bone Miner Res. April 2012;27(4):825-834.|
|2014||Shane E, Burr D, Abrahamsen B, Adler RA, Brown TD, Cheung AM, Cosman F, Curtis JR, Dell R, Dempster DW, Ebeling PR, Einhorn TA, Genant HK, Geusens P, Klaushofer K, Lane JM, McKiernan F, McKinney R, Ng A, Nieves J, O’Keefe R, Papapoulos S, Howe TS, van der Meulen MCH, Weinstein RS, Whyte MP. Atypical subtrochanteric and diaphyseal femoral fractures: second report of a task force of the American Society for Bone and Mineral Research. J Bone Miner Res. January 2014;29(1):1-23.|
|2015||Khan AA, Morrison A, Hanley DA, Felsenberg D, McCauley LK, O'Ryan F, Reid IR, Ruggiero SL, Taguchi A, Tetradis S, Watts NB, Brandi ML, Peters E, Guise T, Eastell R, Cheung AM, Morin SN, Masri B, Cooper C, Morgan SL, Obermayer-Pietsch B, Langdahl BL, Al Dabagh R, Davison KS, Kendler DL, Sándor GK, Josse RG, Bhandari M, El Rabbany M, Pierroz DD, Sulimani R, Saunders DP, Brown JP, Compston J; International Task Force on Osteonecrosis of the Jaw. Diagnosis and management of osteonecrosis of the jaw: a systematic review and international consensus. J Bone Miner Res. January 2015;30(1):3-23.|
|2016||Adler RA, Fuleihan GE-H, Bauer DC, Camacho PM, Clarke BL, Clines GA, Compston JE, Drake MT, Edwards BJ, Favus MJ, Greenspan SL, McKinney R Jr, Pignolo RJ, Sellmeyer DE. Managing osteoporosis in patients on long-term bisphosphonate treatment: report of a task force of the American Society for Bone and Mineral Research. J Bone Miner Res. 2016;31(1):16-35.|
|2020||Nordström P, Bergman J, Ballin M, Björk S, Nordström A. Bone‐specific drugs and osteonecrosis of sites other than the jaw: a nationwide cohort study. J Bone Miner Res. September 2020;35(9):1703-1710.|
|2020||Otto S, Pautke C, Arens D, Poxleitner P, Eberli U, Nehrbass D, Zeiter S, Stoddart MJ. A drug holiday reduces the frequency and severity of medication‐related osteonecrosis of the jaw in a minipig model. J Bone Miner Res. November 2020;35(11):2179-2192.|
|2022||Everts-Graber J, Lehmann D, Burkard J-P, Schaller B, Gahl B, Häuselmann H, Studer U, Ziswiler H-R, Reichenbach S, Lehmann T. Risk of osteonecrosis of the jaw under denosumab compared to bisphosphonates in patients with osteoporosis. J Bone Miner Res. February 2022;37(2):340-348.|
|2011||Rachner TD, Khosla S, Hofbauer LC. Osteoporosis: now and the future. Lancet. April 9, 2011;377(9773):1276-1287.|
|2017||Khosla S, Hofbauer LC. Osteoporosis treatment: recent developments and ongoing challenges. Lancet Diabetes Endocrinol. November 2017;5(11):898-907.|
|2008||Drake MT, Clarke BL, Khosla S. Bisphosphonates: mechanism of action and role in clinical practice. Mayo Clin Proc. September 2008;83(9):1032-1045.|
|2009||Cummings SR, San Martin J, McClung MR, Siris ES, Eastell R, Reid IR, Delmas P, Zoog HB, Austin M, Wang A, Kutilek S, Adami S, Zanchetta J, Libanati C, Siddhanti S, Christiansen C; FREEDOM Trial. Denosumab for prevention of fractures in postmenopausal women with osteoporosis. NEJM. August 20, 2009;361(8):756-765.|
|2014||Cosman F, de Beur SJ, LeBoff MS, Lewiecki EM, Tanner B, Randall S, Lindsay R. Clinician’s guide to prevention and treatment of osteoporosis. Osteoporos Int. October 2014;25(10):2359-2381.|
|2015||Brock GR Jr. Changes in Bone Tissue Properties With Osteoporosis Treatment [PhD thesis]. Ithaca, NY: Cornell University; January 2015.|
|2018||Chen JTH. Alterations in Bone Tissue Properties With Parathyroid Hormone Treatment [PhD thesis]. Ithaca, NY: Cornell University; May 2018.|
|2019||Piet J. Restoring Mechano-Adaptation in Aged Murine Bone [PhD thesis]. Northeastern University; March 2019.|
|2009||Temiyasathit S. Investigating the Role of Primary Cilia in Mechanotransduction in Bone [PhD thesis]. Stanford University; September 2009.|
|2021||Frank M. Mechanical Characterization of Individual Trabeculae [PhD thesis]. Vienna University of Technology; February 2021.|
|2014||Kaipatur NR. Impact of Bisphosphonate Bone Burden on Orthodontic Tooth Movement [PhD thesis]. Edmonton, AB: University of Alberta; 2014.|
|2019||David MA. Local, Intra-Articular Delivery of Zoledronic Acid as a Disease-Modifying Therapeutic for Post-Traumatic Osteoarthritis [PhD thesis]. University of Delaware; 2019.|