Introduction: Medication-related osteonecrosis of the jaw (MRONJ) is a rare but serious condition, caused by several classes of pharmaceutical agents, the most common of which are antiresorptive and antiangiogenic drugs. It is characterized by exposed necrotic bone, most commonly associated with antiangiogenic or antiresorptive therapy, and without a history of radiation exposure to the head and neck.
Aim: This review aims to compare, and summarize the current knowledge on the etiology, pathophysiology, clinical and radiological characteristics, and staging of MRONJ, to identify the research gaps in the scientific literature, and to give recommendations for further research.
Materials and Methods: An advanced electronic search was performed in PubMed, Scopus, and Web of Science, using selected keywords. Results were extracted to an MS Excel spreadsheet and assessed for eligibility after duplicate removal. After analysis of the obtained data, 35 articles were included in this study.
Results and Discussion: The most common medications that cause MRONJ are antiresorptive and antiangiogenic drugs. Other possible agents are immunomodulators, monoclonal antibodies, corticoids, cytostatic drugs, etc. Numerous hypotheses for the pathophysiology of MRONJ have been suggested, including bone remodeling inhibition, impaired angiogenesis, specific infections, etc. Further research is necessary to confirm the role of different drugs in the pathogenesis of MRONJ.
Conclusion: Despite the strong association between MRONJ and antiresorptive and antiangiogenic drugs, the exact pathophysiology of the disease is not fully understood. Future studies should investigate their mechanisms of action and correlation to MRONJ. Understanding its etiopathogenesis is essential for all medical practitioners in order to reduce MRONJ incidence and avoid its misdiagnosis.
Otto S, Pautke C, Van den Wyngaert T, Niepel D, Schiødt M. Medication-related osteonecrosis of the jaw: Prevention, diagnosis and management in patients with cancer and bone metastases. Cancer Treat Rev. 2018;69:177-87. doi: 10.1016/j.ctrv.2018.06.007.
Marx RE. Pamidronate (Aredia) and zoledronate (Zometa) induced avascular necrosis of the jaws: a growing epidemic. J Oral Maxillofac Surg. 2003;61(9):1115-7. doi: 10.1016/S0278-2391(03)00720-1.
Aghaloo TL, Felsenfeld AL, Tetradis S. Osteonecrosis of the jaw in a patient on Denosumab. J Oral Maxillofac Surg. 2010;68(5):959-63. doi: 10.1016/j.joms.2009.10.010.
Otto S, Aljohani S, Fliefel R, Ecke S, Ristow O, Burian E, et al. Infection as an important factor in medication-related osteonecrosis of the jaw (MRONJ). Medicina(Kaunas). 2021;57(5):463. doi: 10.3390/medicina57050463.
Eguia A, Bagan L, Cardona F. Review and update on drugs related to the development of osteonecrosis of the jaw. Med Oral Patol Oral Cir Bucal. 2020;25(1):e71. doi: 10.4317/medoral.23191.
Di Fede O, Panzarella V, Mauceri R, Fusco V, Bedogni A, Lo Muzio L, et al. The dental management of patients at risk of medication‐related osteonecrosis of the jaw: new paradigm of primary prevention. BioMed Res Int. 2018;2018(1):2684924. doi: 10.1155/2018/2684924.
Akashi M, Kusumoto J, Takeda D, Shigeta T, Hasegawa T, Komori T. A literature review of perioperative antibiotic administration in surgery for medication-related osteonecrosis of the jaw. Oral Maxillofac Surg. 2018;22:369-78. doi: 10.1007/s10006-018-0732-8.
Kuehn S, Scariot R, Elsalanty M. Medication-Related Osteonecrosis: Why the Jawbone? Dent J. 2023 Apr 23;11(5):109. doi: 10.3390/dj11050109.
Campisi G, Mauceri R, Bertoldo F, Bettini G, Biasotto M, Colella G, et al. Medication-related osteonecrosis of jaws (MRONJ) prevention and diagnosis: Italian consensus update 2020. Int J Environ Res Public Health. 020 Aug 18;17(16):5998. doi: 10.3390/ijerph17165998.
Anastasilakis AD, Pepe J, Napoli N, Palermo A, Magopoulos C, Khan AA, et al. Osteonecrosis of the jaw and antiresorptive agents in benign and malignant diseases: a critical review organized by the ECTS. J Clin Endocrinol Metab. 2022;107(5):1441-60. doi: 10.1210/clinem/dgab888.
Tai TW, Su FC, Chen CY, Jou IM, Lin CF. Activation of p38 MAPK-regulated Bcl-xL signaling increases survival against zoledronic acid-induced apoptosis in osteoclast precursors. Bone. 2014;67:166-74. doi: 10.1016/j.bone.2014.07.003.
Lončar Brzak B, Horvat Aleksijević L, Vindiš E, Kordić I, Granić M, Vidović Juras D, et al. Osteonecrosis of the Jaw. Dent J. 2023;11(1):23. doi: 10.3390/dj11010023.
Yamashita J, McCauley LK. Antiresorptives and osteonecrosis of the jaw. J Evid Based Dent Pract. 2012;12(3):233-47. doi: 10.1016/S1532-3382(12)70046-5.
Pabst AM, Krüger M, Blatt S, Ziebart T, Rahimi-Nedjat R, Goetze E, Walter C. Angiogenesis in the development of medication-related osteonecrosis of the jaws: an overview. Dent J. 2016;5(1):2. doi: 10.3390/dj5010002.
Ruggiero SL, Dodson TB, Aghaloo T, Carlson ER, Ward BB, Kademani D. American Association of Oral and Maxillofacial Surgeons’ position paper on medication-related osteonecrosis of the jaws—2022 update. J Oral Maxillofac Surg. 2022;80(5):920-43. doi: 10.1016/j.joms.2022.02.008.
Shibahara T. Antiresorptive agent-related osteonecrosis of the jaw (ARONJ): a twist of fate in the bone. Tohoku J Exp Med. 2019;247(2):75-86. doi: 10.1620/tjem.247.75.
Ruggiero SL, Dodson TB, Fantasia J, Goodday R, Aghaloo T, Mehrotra B, et al. American Association of Oral and Maxillofacial Surgeons position paper on medication-related osteonecrosis of the jaw—2014 update. J Oral Maxillofac Surg. 2014;72(10):1938-56. doi: 10.1016/j.joms.2014.04.031.
AlDhalaan NA, BaQais A, Al-Omar A. Medication-related osteonecrosis of the jaw: a review. Cureus. 2020;12(2). doi: 10.7759/cureus.6944.
Lo JC, O'Ryan FS, Gordon NP, Yang J, Hui RL, Martin D, et al. Prevalence of osteonecrosis of the jaw in patients with oral bisphosphonate exposure. J Oral Maxillofac Surg. 2010;68(2):243-53. doi: 10.1016/j.joms.2009.03.050.
Qi WX, Tang LN, He AN, Yao Y, Shen Z. Risk of osteonecrosis of the jaw in cancer patients receiving denosumab: a meta-analysis of seven randomized controlled trials. Int J Clin Oncol. 2014;19:403-10. doi: 10.1007/s10147-013-0561-6.
Mauri D, Valachis A, Polyzos IP, Polyzos NP, Kamposioras K, Pesce LL. Osteonecrosis of the jaw and use of bisphosphonates in adjuvant breast cancer treatment: a metanalysis. Breast Cancer Res Treat. 2009;116:433-9. doi: 10.1007/s10549-009-0432-z.
Nicolatou-Galitis O, Schiødt M, Mendes RA, Ripamonti C, Hope S, Drudge-Coates L, et al. Medication-related osteonecrosis of the jaw: definition and best practice for prevention, diagnosis, and treatment. Oral Surg Oral Med Oral Pathol Oral Radiol. 2019;127(2):117-35. doi: 10.1016/j.oooo.2018.09.008.
Mander KA, Finnie JW. Tumour angiogenesis, anti‐angiogenic therapy and chemotherapeutic resistance. Aust Vet J. 2018;96(10):371-8. doi: 10.1111/avj.12747.
Pimolbutr K, Porter S, Fedele S. Osteonecrosis of the jaw associated with antiangiogenics in antiresorptive‐naïve patient: A comprehensive review of the literature. BioMed Res Int. 2018;2018(1):8071579. doi: 10.1155/2018/8071579.
Chang J, Hakam AE, McCauley LK. Current Understanding of the Pathophysiology of Osteonecrosis of the Jaw. Curr Osteoporos Rep. 2018;16:584-95. doi: 10.1007/s11914-018-0474-4.
Weinstein RS. Glucocorticoid-induced osteonecrosis. Endocrine. 2012;41:183-90. doi: 10.1007/s12020-011-9580-0.
Powell C, Chang C, Gershwin ME. Current concepts on the pathogenesis and natural history of steroid-induced osteonecrosis. Clin Rev Allergy Immunol. 2011;41:102-13. doi: 10.1007/s12016-010-8217-z.
Henien M, Carey B, Hullah E, Sproat C, Patel V. Methotrexate-associated osteonecrosis of the jaw: A report of two cases. Oral Surg Oral Med Oral Pathol Oral Radiol. 2017;124(6):e283-7. doi: 10.1016/j.oooo.2017.09.005.
Kün-Darbois JD, Fauvel F. Medication-related osteonecrosis and osteoradionecrosis of the jaws: Update and current management. Morphologie. 2021; 105(349):170-87. doi: 10.1016/j.morpho.2020.11.008.
Soundia A, Hadaya D, Esfandi N, de Molon RS, Bezouglaia O, Dry SM, et al. Osteonecrosis of the jaws (ONJ) in mice after extraction of teeth with periradicular disease. Bone. 2016;90:133-41. doi: 10.1016/j.bone.2016.06.011.
Wehrhan F, Gross C, Creutzburg K, Amann K, Ries J, Kesting M, et al. Osteoclastic expression of higher-level regulators NFATc1 and BCL6 in medication-related osteonecrosis of the jaw secondary to bisphosphonate therapy: a comparison with osteoradionecrosis and osteomyelitis. J Transl Med. 2019;17(1):69. doi: 10.1186/s12967-019-1819-1.
de Molon RS, Shimamoto H, Bezouglaia O, Pirih FQ, Dry SM, Kostenuik P, et al. OPG-Fc but Not Zoledronic Acid Discontinuation Reverses Osteonecrosis of the Jaws (ONJ) in Mice. J Bone Miner Res. 2015;30(9):1627-40. doi: 10.1002/jbmr.2490.
Hadaya D, Soundia A, Gkouveris I, Bezouglaia O, Dry SM, Pirih FQ, et al. Antiresorptive-Type and Discontinuation-Timing Affect ONJ Burden. J Dent Res. 2021;100(7):746-53. doi: 10.1177/0022034520986804.
Sedghizadeh PP, Kumar SK, Gorur A, Schaudinn C, Shuler CF, Costerton JW. Identification of microbial biofilms in osteonecrosis of the jaws secondary to bisphosphonate therapy. J Oral Maxillofac Surg. 2008;66(4):767-75. doi: 10.1016/j.joms.2007.11.035.
Boff RC, Salum FG, Figueiredo MA, Cherubini K. Important aspects regarding the role of microorganisms in bisphosphonate-related osteonecrosis of the jaws. Arch Oral Biol. 2014;59(8):790-9. doi: 10.1016/j.archoralbio.2014.05.002.
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