Abstract
Antiresorptive agent-related osteonecrosis of the jaw (ARONJ) is an intractable, though rare, complication in cancer patients with bone metastases and patients with osteoporosis who are treated with antiresorptive agents, including bisphosphonates and denosumab. Despite the more than 10 years that have passed since the first cases of bisphosphonate-related osteonecrosis of the jaw (BRONJ) were reported, our understanding of the epidemiology and pathophysiology of ARONJ remains limited, and data supported by evidence-based medicine are still sparse. However, the diagnosis and staging of ARONJ, identification of risk factors, and development of preventive and therapeutic approaches have advanced significantly over the past decade. The Position Paper 2017 is an updated version of the Position Paper 2010 of the Japanese Allied Committee on Osteonecrosis of the Jaw, which now comprises six Japanese academic societies. The Position Paper 2017 describes a new diagnostic definition for ARONJ, as proposed by the American Association of Oral and Maxillofacial Surgeons (AAOMS), summarizes our current understanding of the pathophysiology of ARONJ based on a literature search, and suggests methods for physicians and dentists/oral surgeons to manage the disease. In addition, the appropriateness of discontinuing antiresorptive medications (drug holiday) before, during, and after invasive dental treatments is discussed extensively. More importantly, the manuscript also proposes, for the first time, the importance of interactive communication and cooperation between physicians and dentists/oral surgeons for the successful treatment of ARONJ. The Position Paper 2017 is intended to serve as a guide for improving the management of ARONJ patients in Japan.
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References
Marx RE (2003) Pamidronate (Aredia) and zoledronate (Zometa) induced avascular necrosis of the jaws: a growing epidemic. J Oral Maxillofac Surg 61:1115–1117
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 (2015) Diagnosis and management of osteonecrosis of the jaw: a systematic review and international consensus. J Bone Miner Res 30:3–23
Otto S, Tröltzsch M, Jambrovic V, Panya S, Probst F, Ristow O, Ehrenfeld M, Pautke C (2015) Tooth extraction in patients receiving oral or intravenous bisphosphonate administration: a trigger for BRONJ development? J Craniomaxillofac Surg 43:847–854
Campisi G, Fedele S, Fusco V, Pizzo G, Di Fede O, Bedogni A (2014) Epidemiology, clinical manifestations, risk reduction and treatment strategies of jaw osteonecrosis in cancer patients exposed to antiresorptive agents. Future Oncol 10:257–275
Baron R, Ferrari S, Russell RG (2011) Denosumab and bisphosphonates: different mechanisms of action and effects. Bone 48:677–692
Saad F, Brown JE, Van Poznak C, Ibrahim T, Stemmer SM, Stopeck AT, Diel IJ, Takahashi S, Shore N, Henry DH, Barrios CH, Facon T, Senecal F, Fizazi K, Zhou L, Daniels A, Carrière P, Dansey R (2012) Incidence, risk factors, and outcomes of osteonecrosis of the jaw: integrated analysis from three blinded active-controlled phase III trials in cancer patients with bone metastases. Ann Oncol 23:1341–1347
Hellstein JW, Adler RA, Edwards B, Jacobsen PL, Kalmar JR, Koka S, Migliorati CA, Ristic H; American Dental Association Council on Scientific Affairs Expert Panel on Antiresorptive Agents (2011) Managing the care of patients receiving antiresorptive therapy for prevention and treatment of osteoporosis: executive summary of recommendations from the American Dental Association Council on Scientific Affairs. J Am Dent Assoc 142:1243–1251
Ruggiero SL, Dodson TB, Fantasia J, Goodday R, Aghaloo T, Mehrotra B, O’Ryan F (2014) American association of oral and maxillofacial surgeons position paper on medication-related osteonecrosis of the jaw-2014 update. J Oral Maxillofac Surg 72:1938–1956
Yoneda T, Hagino H, Sugimoto T, Ota H, Takahashi S, Soen S, Taguchi A, Toyosawa S, Nagata T, Urade M (2010) Bisphosphonate-related osteonecrosis of the jaw: position paper from the allied task force committee of Japanese Society for Bone and Mineral Research, Osteoporosis Society Japan, Japanese Society of Periodontology, Japanese Society for Oral and Maxillofacial Radiology and Japanese Society of Oral and Maxillofacial Surgeons. J Bone Miner Metab 28:365–383
Hinson AM, Smith CW, Siegel ER, Stack BC Jr (2014) Is bisphosphonate-related osteonecrosis of the jaw an infection? A histological and microbiological ten-year summary. Int J Dent 2014:452737
Lipton A, Fizazi K, Stopeck AT, Henry DH, Brown JE, Yardley DA, Richardson GE, Siena S, Maroto P, Clemens M, Bilynskyy B, Charu V, Beuzeboc P, Rader M, Viniegra M, Saad F, Ke C, Braun A, Jun S (2012) Superiority of denosumab to zoledronic acid for prevention of skeletal-related events: a combined analysis of 3 pivotal, randomised, phase 3 trials. Eur J Cancer 48:3082–3092
Urade M, Tanaka N, Furusawa K, Shimada J, Shibata T, Kirita T, Yamamoto T, Ikebe T, Kitagawa Y, Fukuta J (2011) Nationwide survey for bisphosphonate-related osteonecrosis of the jaws in Japan. J Oral Maxillofac Surg 69:e364–e371
Japanese Society of Oral and Maxillofacial Surgeons (2015) Nationwide survey for BRONJ management (in Japanese)
Fedele S, Porter SR, D’Aiuto F, Aljohani S, Vescovi P, Manfredi M, Arduino PG, Broccoletti R, Musciotto A, Di Fede O, Lazarovici TS, Campisi G, Yarom N (2010) Nonexposed variant of bisphosphonate-associated osteonecrosis of the jaw: a case series. Am J Med 123:1060–1064
Khan A, Morrison A, Cheung A, Hashem W, Compston J (2016) Osteonecrosis of the Jaw (ONJ) diagnosis and management in 2015. Osteoporos Int 27:853–859
Boquete-Castro A, Gómez-Moreno G, Calvo-Guirado JL, Aguilar-Salvatierra A, Delgado-Ruiz RA (2016) Denosumab and osteonecrosis of the jaw. A systematic analysis of events reported in clinical trials. Clin Oral Implants Res 27:367–375
Marx RE, Cillo JE Jr, Ulloa JJ (2007) Oral bisphosphonate-induced osteonecrosis: risk factors, prediction of risk using serum CTX testing, prevention, and treatment. J Oral Maxillofac Surg 65:2397–2410
Taguchi A, Akiyama H, Koseki T, Shimizutani K (2013) Recognition of bisphosphonate-related osteonecrosis of the jaw among oral and maxillofacial radiologists: results from a questionnaire-based survey in Japan. Oral Radiol 29:98–104
Miyashita H, Shiba H, Kawana H, Nakahara T (2015) Clinical utility of three-dimensional SPECT/CT imaging as a guide for the resection of medication-related osteonecrosis of the jaw. Int J Oral Maxillofac Surg 44:1106–1109
Assaf AT, Zrnc TA, Remus CC, Adam G, Zustin J, Heiland M, Friedrich RE, Derlin T (2015) Intraindividual comparison of preoperative (99 m)Tc-MDP SPECT/CT and intraoperative and histopathological findings in patients with bisphosphonate- or denosumab-related osteonecrosis of the jaw. J Craniomaxillofac Surg 43:1461–1469
Weinstein RS, Roberson PK, Manolagas SC (2009) Giant osteoclast formation and long-term oral bisphosphonate therapy. N Engl J Med 360:53–62
Favia G, Pilolli GP, Maiorano E (2009) Histologic and histomorphometric features of bisphosphonate-related osteonecrosis of the jaws: an analysis of 31 cases with confocal laser scanning microscopy. Bone 45:406–413
De Ceulaer J, Tacconelli E, Vandecasteele SJ (2014) Actinomyces osteomyelitis in bisphosphonate-related osteonecrosis of the jaw (BRONJ): the missing link? Eur J Clin Microbiol Infect Dis 33:1873–1880
Matsushita Y, Hayashida S, Morishita K, Sakamoto H, Naruse T, Sakamoto Y, Yamada SI, Yanamoto S, Fujita S, Ikeda T, Umeda M (2016) Denosumab-associated osteonecrosis of the jaw affects osteoclast formation and differentiation: pathological features of two cases. Mol Clin Oncol 4:191–194
Holzinger D, Seemann R, Matoni N, Ewers R, Millesi W, Wutzl A (2014) Effect of dental implants on bisphosphonate-related osteonecrosis of the jaws. J Oral Maxillofac Surg 72(1937):e1–e8
Matsuo A, Hamada H, Takahashi H, Okamoto A, Kaise H, Chikazu D (2016) Evaluation of dental implants as a risk factor for the development of bisphosphonate-related osteonecrosis of the jaw in breast cancer patients. Odontology 104:363–371
Nakamura T, Ito M, Hashimoto J, Shinomiya K, Asao Y, Katsumata K, Hagino H, Inoue T, Nakano T, Mizunuma H, MOVEST Study Group (2015) Clinical efficacy and safety of monthly oral ibandronate 100 mg versus monthly intravenous ibandronate 1 mg in Japanese patients with primary osteoporosis. Osteoporos Int 26:2685–2693
Ramírez L, López-Pintor RM, Casañas E, Arriba L, Hernández G (2015) New non-bisphosphonate drugs that produce osteonecrosis of the jaws. Oral Health Prev Dent 13:385–393
Allen MR (2015) Medication-related osteonecrosis of the jaw: basic and translational science updates. Oral Maxillofac Surg Clin North Am 27:497–508
Aghaloo TL, Cheong S, Bezouglaia O, Kostenuik P, Atti E, Dry SM, Pirih FQ, Tetradis S (2014) RANKL inhibitors induce osteonecrosis of the jaw in mice with periapical disease. J Bone Miner Res 29:843–854
de Molon RS, Shimamoto H, Bezouglaia O, Pirih FQ, Dry SM, Kostenuik P, Boyce RW, Dwyer D, Aghaloo TL, Tetradis S (2015) OPG-Fc but not zoledronic acid discontinuation reverses osteonecrosis of the jaws (ONJ) in mice. J Bone Miner Res 30:1627–1640
Taguchi A, Shiraki M, Tsukiyama M, Miyazaki T, Soen S, Ohta H, Nakamura T, Orimo H (2015) Impact of osteonecrosis of the jaw on osteoporosis treatment in Japan: results of a questionnaire-based survey by the adequate treatment of osteoporosis (A-TOP) research group. Calcif Tissue Int 97:542–550
Taguchi A, Shiraki M, Sugimoto M, Ohta H, Soen S (2016) Lack of cooperation between physicians and dentists during osteoporosis treatment may increase fractures and osteonecrosis of the jaw. Curr Med Res Opin 32:1261–1268
Curtis JR, Westfall AO, Cheng H, Deizell E, Saag KG (2008) Risk of hip fracture after bisphosphonate discontinuation: implications for a drug holiday. Osteoporos Int 19:1613–1620
Black DM, Rosen CJ (2016) Postmenopausal osteoporosis. N Engl J Med 374:254–262
Chiu WY, Chien JY, Yang WS, Juang JM, Lee JJ, Tsai KS (2014) The risk of osteonecrosis of the jaws in Taiwanese osteoporotic patients treated with oral alendronate or raloxifene. J Clin Endocrinol Metab 99:2729–2735
Barasch A, Cunha-Cruz J, Curro FA, Hujoel P, Sung AH, Vena D, Voinea-Griffin AE; CONDOR Collaborative Group, Beadnell S, Craig RG, DeRouen T, Desaranayake A, Gilbert A, Gilbert GH, Goldberg K, Hauley R, Hashimoto M, Holmes J, Latzke B, Leroux B, Lindblad A, Richman J, Safford M, Ship J, Thompson VP, Williams OD, Yin W (2011) Risk factors for osteonecrosis of the jaws: a case-control study from the CONDOR dental PBRN. J Dent Res 90:439–444
Kim KM, Rhee Y, Kwon YD, Kwon TG, Lee JK, Kim DY (2015) Medication related osteonecrosis of the jaw: 2015 Position statement of the Korean Society for Bone and Mineral Research and the Korean Association of Oral and Maxillofacial Surgeons. J Bone Metab 22:151–165
Sugimoto T, Matsumoto T, Hosoi T, Miki T, Gorai I, Yoshikawa H, Tanaka Y, Tanaka S, Fukunaga M, Sone T, Nakano T, Ito M, Matsui S, Yoneda T, Takami H, Watanabe K, Osakabe T, Shiraki M, Nakamura T (2015) Three years of denosumab treatment in Japanese postmenopausal women and men with osteoporosis: results from a 1-year open-label extension of the denosumab fracture intervention randomized placebo controlled trial (DIRECT). Osteoporosis Int 26:765–774
Matsumoto A, Sasaki M, Schmelzeisen R, Oyama Y, Mori Y, Voss PJ (2016) Primary wound closure after tooth extraction for prevention of medication-related osteonecrosis of the jaw in patients under denosumab. Clin Oral Invest. doi:10.1007/s00784-016-1762-y
Ohga N, Yamazaki Y, Tsuboi K, Kitagawa Y (2015) Healing of osteonecrosis of the jaw (ONJ) after discontinuation of denosumab in a patient with bone metastases of colorectal cancer: a case report and hypothesis. Quintessence Int 46:621–626
Guidelines on the prevention and treatment of osteoporosis 2015. The committee for development of the guidelines on the prevention and treatment of osteoporosis. Japan Osteoporosis Society (in Japanese)
Chahine C, Cheung MS, Head TW, Schwartz S, Glorieux FH, Rauch F (2008) Tooth extraction socket healing in pediatric patients treated with intravenous pamidronate. J Pediatr 153:719–720
Maines E, Monti E, Doro F, Morandi G, Cavarzere P, Antoniazzi F (2012) Children and adolescents treated with neridronate for osteogenesis imperfecta show no evidence of any osteonecrosis of the jaw. J Bone Miner Metab 30:434–438
Hoyer-Kuhn H, Semler O, Schoenau E (2014) Effect of denosumab on the growing skeleton in osteogenesis imperfecta. J Clin Endocrinol Metab 99:3954–3955
Carlson ER (2014) Management of antiresorptive osteonecrosis of the jaws with primary surgical resection. J Oral Maxillofac Surg 72:655–657
Bodem JP, Kargus S, Engel M, Hoffmann J, Freudlsperger C (2015) Value of nonsurgical therapeutic management of stage I bisphosphonate-related osteonecrosis of the jaw. J Craniomaxillofac Surg 43:1139–1143
Bodem JP, Schaal C, Kargus S, Saure D, Mertens C, Engel M, Hoffmann J, Freudlsperger C (2016) Surgical management of bisphosphonate-related osteonecrosis of the jaw stages II and III. Oral Surg Oral Med Oral Pathol Oral Radiol 121:367–372
Ikeda T, Kuraguchi J, Kogashiwa Y, Yokoi H, Satomi T, Kohno N (2015) Successful treatment of bisphosphonate-related osteonecrosis of the jaw (BRONJ) patients with sitafloxacin: new strategies for the treatment of BRONJ. Bone 73:217–222
Chan HL, McCauley LK (2013) Parathyroid hormone applications in the craniofacial skeleton. J Dent Res 92:18–25
Ohbayashi Y, Miyake M, Sawai F, Minami Y, Iwasaki A, Matsui Y (2013) Adjunct teriparatide therapy with monitoring of bone turnover markers and bone scintigraphy for bisphosphonate-related osteonecrosis of the jaw. Oral Surg Oral Med Oral Pathol Oral Radiol 115:e31–e37
Kakehashi H, Ando T, Minamizato T, Nakatani Y, Kawasaki T, Ikeda H, Kuroshima S, Kawakami A, Asahina I (2015) Administration of teriparatide improves the symptoms of advanced bisphosphonate-related osteonecrosis of the jaw: preliminary findings. Int J Oral Maxillofac Surg 44:1558–1564
Hinson AM, Siegel ER, Stack BC Jr (2015) Temporal correlation between bisphosphonate termination and symptom resolution in osteonecrosis of the jaw: a pooled case report analysis. J Oral Maxillofac Surg 73:53–62
Thorsteinsson AL, Vestergaard P, Eiken P (2014) External auditory canal and middle ear cholesteatoma and osteonecrosis in bisphosphonate-treated osteoporosis patients: a Danish national register-based cohort study and literature review. Osteoporos Int 25:1937–1944
Akintoye SO, Hersh EV (2016) Impact of communication between physicians and dentists on the incidence of jaw osteonecrosis caused by bone anti-resorptives. Curr Med Res Opin 18:1–2
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Toshiyuki Yoneda: consultant fee (Daiichi-Sankyo). Hiroaki Ohta: lecture fee (Pfizer), manuscript fee (Medical Review Co., Ltd.). Toshitsugu Sugimoto: lecture fee, consultant fee (Asahi Kasei Pharma, Pfizer), research grant (Astellas Pharma, Eisai, Ono Pharmaceutical, Daiichi-Sankyo, Chugai Pharmaceutical, Eli Lilly Japan). Satoshi Soen: lecture fee (Asahi Kasei Pharma, Astellas Pharma, Eisai, MSD, Ono Pharmaceutical, Daiichi-Sankyo, Takeda Pharmaceutical, Chugai Pharmaceutical, Teijin Pharma), research grant (Eisai, Daiichi-Sankyo, Takeda Pharmaceutical). Shunji Takahashi: lecture fee (Eisai, Daiichi-Sankyo), research grant (AstraZeneca, Daiichi-Sankyo, Chugai Pharmaceutical, Novartis Pharma, Bayer, Parexel International). Akira Taguchi: lecture fee (Asahi Kasei Pharma, MSD, Ono Pharmaceutical, Daiichi-Sankyo, Takeda Pharmaceutical, Chugai Pharmaceutical, Teijin Pharma), consultant fee (Asahi Kasei Pharma). Hiroshi Hagino: lecture fee (Asahi Kasei Pharma, EA Pharma, MSD, Daiichi-Sankyo, Taisho Toyama Pharmaceutical, Takeda Pharmaceutical, Chugai Pharmaceutical, Pfizer), research grant (Chugai Pharmaceutical). Masahiro Urade: none. Takahiko Shibahara: none. Satoru Toyosawa: none. Toshihiko Nagata: none.
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An erratum to this article is available at http://dx.doi.org/10.1007/s00774-017-0816-9.
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Japanese Allied Committee on Osteonecrosis of the Jaw., Yoneda, T., Hagino, H. et al. Antiresorptive agent-related osteonecrosis of the jaw: Position Paper 2017 of the Japanese Allied Committee on Osteonecrosis of the Jaw. J Bone Miner Metab 35, 6–19 (2017). https://doi.org/10.1007/s00774-016-0810-7
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DOI: https://doi.org/10.1007/s00774-016-0810-7