Medication-Related Osteonecrosis of the Jaw: Risk Factors, Management and Prevention in Dental Practices

Abstract

Medication-related osteonecrosis of the jaw (MRONJ) is a major clinical problem that particularly affects patients receiving antiresorptive therapy for primary or metastatic bone malignancies and osteoporosis. The incidence of MRONJ varies by drug type and route of administration, with a higher incidence observed in patients receiving intravenous bisphosphonate therapy. This review examines the risk factors, management strategies and preventive measures for MRONJ, emphasizing the impact tooth extraction, implant treatment, oral surgery, periodontitis and poorly fitting removable dentures. Dental implants have been shown to have different risks for MRONJ, and some studies show that they do not significantly increase the risk of MRONJ and may even decrease it compared to other dental procedures. On the other hand, tooth extraction remains an important local risk factor for MRONJ and requires careful planning and execution to minimize trauma and subsequent complications. Effective prevention and treatment of MRONJ requires a multifaceted approach, including a thorough pretreatment dental evaluation, careful oral hygiene, and less traumatic dental procedures. Collaboration between dentists, physicians and patients is critical to optimize outcomes and minimize the risk of MRONJ. In addition, increasing knowledge and awareness of MRONJ among healthcare providers and patients is important for early detection and prevention. Future research should aim to further elucidate the pathophysiology of MRONJ and develop targeted treatment and complex prevention strategies. By advancing the understanding and treatment of MRONJ, dentists can provide safer and more effective treatment for patients undergoing antiresorptive therapy, ultimately improving their quality of life.

Keywords

• Medication-Related Osteonecrosis of the Jaw (MRONJ)
• Antiresorptive therapy
• Dental implants
• Tooth extraction
• Bisphosphonates (BPs)

References

1. 1. Aghaloo T, Hazboun R, Tetradis S. Pathophysiology of Osteonecrosis of the Jaws. Oral Maxillofac Surg Clin North Am. 2015;27(4):489-96.
2. 2. Aminoshariae A, Donaldson M, Horan M, Mackey SA, Kulild JC, Baur D. Emerging antiresorptive medications and their potential implications for dental surgeries. J Am Dent Assoc. 2022;153(7):649-58.
3. 3. 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):920-943.
4. 4. Ruggiero SL, Dodson TB, Fantasia J, et al. American Association of Oral and Maxillofacial Surgeons. 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.
5. 5. Jiang A, Zhang Z, Qiu X, Guo Q. Medication-related osteonecrosis of the jaw (MRONJ): a review of pathogenesis hypothesis and therapy strategies. Arch Toxicol. 2024;98(3):689-708.
6. 6. Kuroshima S, Al-Omari FA, Sasaki M, Sawase T. Medication-related osteonecrosis of the jaw: A literature review and update. Genesis. 2022;60(8-9):e23500.
7. 7. Beth-Tasdogan NH, Mayer B, Hussein H, Zolk O, Peter J-U. Interventions for managing medication-related osteonecrosis of the jaw. Cochrane Database of Systematic Reviews 2022; 7(7):CD012432.
8. 8. Di Fede O, Panzarella V, Mauceri R, 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; 16;2018:2684924.

9. 9. Yarom N, Shapiro CL, Peterson DE, et al. Alston-Johnson D, Mendes RA, Beadle BM, Jensen SB, Saunders DP. Medication-Related Osteonecrosis of the Jaw: MASCC/ISOO/ASCO Clinical Practice Guideline. J Clin Oncol. 2019;37(25):2270-90.
10. 10. Hadad H, Matheus HR, Pai SI, Souza FA, Guastaldi FPS. Rodents as an animal model for studying tooth extraction-related medication-related osteonecrosis of the jaw: assessment of outcomes. Arch Oral Biol. 2024;159:105875.
11. 11. Hongyuan H, Qiao Q, Zhao N, Zhou Y, Zou YW, Li Q, Li S, Zhou B, Zhang Y, Guo C, Guo Y. Efficacy of submental island flap closing advanced mandibular MRONJ lesion in malignancy patients. Head Neck. 2024;46(9):2315-26.
12. 12. Kimathi D, Butt F, Guthua S, Waweru W. Medication-related osteonecrosis of the jaw: Case series and literature review. Clin Case Rep. 2024;12(4):e8788.
13. 13. Sher J, Kirkham-Ali K, Luo JD, Miller C, Sharma D. Dental Implant Placement in Patients With a History of Medications Related to Osteonecrosis of the Jaws: A Systematic Review. J Oral Implantol. 2021;47(3):249-68.
14. 14. Veszelyné Kotán E, Bartha-Lieb T, Parisek Z, et al. Database analysis of the risk factors of bisphosphonate-related osteonecrosis of the jaw in Hungarian patients. BMJ Open. 2019;9:e025600.
15. 15. Yao S, Ding X, Rong G, Zhou J, Zhang B. Association Between Malignant Diseases and Medication-Related Osteonecrosis of the Jaw (MRONJ): A Systematic Review and Meta-Analysis. J Craniofac Surg. 2023;34(2):669-73.
16. 16. Saad F, Brown JE, Van Poznak C, et al. 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. 2012;23(5):1341-47.
17. 17. Srivastava A, Nogueras Gonzalez GM, Geng Y, Won AM, Myers J, Li Y, Chambers MS. Medication-Related Osteonecrosis of the Jaw in Patients Treated Concurrently with Antiresorptive and Antiangiogenic Agents: Systematic Review and Meta-Analysis. J Immunother Precis Oncol. 2021;4(4):196-207.
18. 18. Srivastava A, Nogueras Gonzalez GM, Geng Y, et al. Prevalence of medication related osteonecrosis of the jaw in patients treated with sequential antiresorptive drugs: systematic review and meta-analysis. Support Care Cancer. 2021;29(5):2305-17.
19. 19. Zhang C, Shen G, Li H, et al. Incidence rate of osteonecrosis of jaw after cancer treated with bisphosphonates and denosumab: A systematic review and meta-analysis. Spec Care Dentist. 2024;44(2):530-541.
20. 20. de-Freitas NR, Lima LB, de-Moura MB, Veloso-Guedes CCF, Simamoto-Júnior PC, de-Magalhães D. Bisphosphonate treatment and dental implants: A systematic review. Med Oral Patol Oral Cir Bucal. 2016;21 (5):e644-51.
21. 21. Stavropoulos A, Bertl K, Pietschmann P, Pandis N, Schiødt M, Klinge B. The effect of antiresorptive drugs on implant therapy: Systematic review and meta-analysis. Clin Oral Implants Res. 2018;29 Suppl 18:54-92.
22. 22. Hasegawa T, Hayashida S, Kondo E, et al. Japanese Study Group of Co-operative Dentistry with Medicine (JCDM). Medication-related osteonecrosis of the jaw after tooth extraction in cancer patients: a multicenter retrospective study. Osteoporos Int. 2019;30(1):231-39.
23. 23. Ristow O, Rückschloß T, Moratin J, et al. Wound closure and alveoplasty after preventive tooth extractions in patients with antiresorptive intake-A randomized pilot trial. Oral Dis. 2021;27(3):532-46.
24. 24. Aguirre JI, Castillo EJ, Kimmel DB. Preclinical models of medication-related osteonecrosis of the jaw (MRONJ). Bone. 2021;153:116184.
25. 25. Boffano P, Agnone AM, Neirotti F, et al. Epidemiology, etiopathogenesis, and management of MRONJ: A European multicenter study. J Stomatol Oral Maxillofac Surg. 2024;125(5):101931.
26. 26. France K, Yogarajah S, Gueiros LA, et al. World Workshop on Oral Medicine VII: Oral adverse effects to biologic agents in patients with inflammatory disorders. A scoping review. J Oral Pathol Med. 2023;52(1):1-8.
27. 27. McGowan K, McGowan T, Ivanovski S. Risk factors for medication-related osteonecrosis of the jaws: A systematic review. Oral Dis. 2018;24(4):527-36.
28. 28. Woolley J, Akintola O, Yates J, et al. The risk of osteonecrosis of the jaw and adverse outcomes in patients using antiresorptive drugs undergoing orthodontic treatment: A systematic review. Heliyon. 2021;7(1):e05914.
29. 29. Aljohani S, Fliefel R, Ihbe J, Kühnisch J, Ehrenfeld M, Otto S. What is the effect of anti-resorptive drugs (ARDs) on the development of medication-related osteonecrosis of the jaw (MRONJ) in osteoporosis patients: A systematic review. J Craniomaxillofac Surg. 2017;45(9):1493-502.
30. 30. Palla B, Burian E, Deek A, Scott C, Anderson J, Callahan N, Carlson ER. Comparing the Surgical Response of Bisphosphonate-Related Versus Denosumab-Related Osteonecrosis of the Jaws. J Oral Maxillofac Surg. 2021;79(5):1045-52
31. 31. AlRowis R, Aldawood A, AlOtaibi M, et al. Medication-Related Osteonecrosis of the Jaw (MRONJ): A Review of Pathophysiology, Risk Factors, Preventive Measures and Treatment Strategies. Saudi Dent J. 2022;34(3):202-210.
32. 32. Komatsu Y, Kawai T, Hirano T, et al. Risk factors of medication-related osteonecrosis of the jaw: A clinical investigation. J Stomatol Oral Maxillofac Surg. 2024;125(6):101791.
33. 33. Landi L, Oteri G, Barbato L, et al. Anti-resorptive therapy and MRONJ. A survey of the Italian Society of Periodontology and Implantology. Oral Dis. 2024; 30, 4528–4537.
34. 34. Cabras M, Gambino A, Broccoletti R, Sciascia S, Arduino PG. Lack of evidence in reducing risk of MRONJ after teeth extractions with systemic antibiotics. J Oral Sci. 2021;63(3):217-26.
35. 35. Chalem M, Medina A, Sarmiento AK, et al. Therapeutic approach and management algorithms in medication-related osteonecrosis of the jaw (MONJ): recommendations of a multidisciplinary group of experts. Arch Osteoporos. 2020;15(1):101.
36. 36. Boffano P, Agnone AM, Neirotti F, et al. Epidemiology, etiopathogenesis, and management of MRONJ: A European multicenter study. J Stomatol Oral Maxillofac Surg. 2024: 125.5:101931.
37. 37. Moreno-Rabié C, Gaêta-Araujo H, Ferreira-Leite A, et al. Local radiographic risk factors for MRONJ in osteoporotic patients undergoing tooth extraction. Oral Dis. 2024;30(3):1632-42.
38. 38. Duarte NT, Rech Bruna de O, Martins IG, Franco JB, Ortega KL. Can children be affected by bisphosphonaterelated osteonecrosis of the jaw? A systematic review. Int J Oral Maxillofac Surg. 2020;49:183-191.
39. 39. Rosales HD, Guevara GH. Requejo S, Jensen MD. Acero J, Olate S. Medication-Related Osteonecrosis of the Jaws (MRONJ) in Children and Young Patients-A Systematic Review. J Clin Med. 2023;12(4):1416.
40. 40. Mitsuhata C, Kozai K. Management of bisphosphonate preparation-treated children in the field of pediatric dentistry. Jpn Dent Sci Rev. 2022;58:155-61.
41. 41. Innes-Taylor D, Adams V. Medication-related osteonecrosis of the jaw in a paediatric patient taking denosumab: a case report. Br Dent J. 2024;236(6):453-56.
42. 42. Contaldo M, Luzzi V, Ierardo G, Raimondo E, Boccellino M, Ferati K, Bexheti-Ferati A, Inchingolo F, Di Domenico M, Serpico R, Polimeni A, Bossù M. Bisphosphonate-related osteonecrosis of the jaws and dental surgery procedures in children and young people with osteogenesis imperfecta: A systematic review. J Stomatol Oral Maxillofac Surg. 2020;121(5):556-62.
43. 43. Li JTW, Leung YY. Effect of Antiresorptive Drugs on Osseointegrated Dental Implants: A Systematic Review. J Clin Med. 2024 3;13(7):2091.
44. 44. Park JH, Lee JR, Lee H. et al. No increased risk of osteonecrosis of the jaw in osteoporotic patients with dental implants: a nationwide cohort study. Clin Oral Invest. 2024;28(1):83.
45. 45. Ryu JI, Kim HY, Kwon YD. Is implant surgery a risk factor for osteonecrosis of the jaw in older adult patients with osteoporosis? A national cohort propensity score-matched study. Clin Oral Implants Res. 2021;32(4):437-47.
46. 46. Anitua E, Alkhraisat M, Eguia A. Clinical Performance of Implant-Supported Prostheses in the Rehabilitation of Patients Previously Treated for Medication-Related Osteonecrosis of the Jaws (MRONJ): A Systematic Review. Cureus. 2024;16(6):e61658.
47. 47. Pichardo SEC, van der Hee JG, Fiocco M, Appelman-Dijkstra NM, van Merkesteyn JPR. Dental implants as risk factors for patients with medication-related osteonecrosis of the jaws (MRONJ). Br J Oral Maxillofac Surg. 2020;58(7):771-76.
48. 48. Gelazius R, Poskevicius L, Sakavicius D, Grimuta V, Juodzbalys G. Dental Implant Placement in Patients on Bisphosphonate Therapy: a Systematic Review. J Oral Maxillofac Res. 2018;9(3):e2
49. 49. Sulaiman, N.; Fadhul, F.; Chrcanovic, B.R. Bisphosphonates and Dental Implants: A Systematic Review and Meta-Analysis. Materials 2023;16(18):6078.
50. 50. Papadakis I, Spanou A, Kalyvas D. Success Rate and Safety of Dental Implantology in Patients Treated with Antiresorptive Medication: A Systematic Review. J Oral Implantol. 2021;47(2):169-80.
51. 51. Granate-Marques A, Polis-Yanes C, Seminario-Amez M, Jané-Salas E, López-López J. Medication-related osteonecrosis of the jaw associated with implant and regenerative treatments: Systematic review. Med Oral Patol Oral Cir Bucal. 2019;24 (2): e195-203.
52. 52. Altalhi AM, Alsubaihi AA, Aldosary MM, et al. Enhancing the Oral Rehabilitation and Quality of Life of Bisphosphonate-Treated Patients: The Role of Dental Implants. Cureus. 2023;15(10):e46654.
53. 53. J. Abtahi, G. Henefalk P. Aspenberg: Randomised trial of bisphosphonate-coated dental implants: Radiographic follow-up after five years of loading. Int J Oral Maxillofac Surg. 2016; 45: 1564-69.
54. 54. Holzinger D, Seemann R, Matoni N, Ewers R, Millesi W, Wutzl A. Effect of dental implants on bisphosphonate-related osteonecrosis of the jaws. J Oral Maxillofac Surg. 2014;72(10):1937.e1-8.
55. 55. Javed F, Almas K. Osseointegration of dental implants in patients undergoing bisphosphonate treatment: a literature review. J Periodontol. 2010;81(4):479-84.
56. 56. Nisi M, La Ferla F, Karapetsa D, et al. Risk factors influencing BRONJ staging in patients receiving intravenous bisphosphonates: a multivariate analysis. Int J Oral Maxillofac Surg. 2015;44:586-91.
57. 57. Yajima N, Munakata M, Fuchigami K, Sanda M, Kasugai S. Influence of Bisphosphonates on Implant Failure Rates and Characteristics of Postmenopausal Woman Mandibular Jawbone. J Oral Implantol. 2017 Oct;43(5):345-49.
58. 58. Bedogni A, Mauceri R, Fusco V, et al. Italian position paper (SIPMO-SICMF) on medication-related osteonecrosis of the jaw (MRONJ). Oral Dis. 2024; 30:3679-709
59. 59. Yılmaz Altıntaş N, Balaban E, Uğur M, Altıntaş SH. Oral bifosfonat tedavisi görmüş olan bir hastanın dental implant destekli protez ile rehabilitasyonu: Olgu sunumu. Selcuk Dent J. 2016;3(2):69-74.
60. 60. Bodem JP, Kargus S, Eckstein S, Saure D, Engel M, Hoffmann J, Freudlsperger C. Incidence of bisphosphonate-related osteonecrosis of the jaw in high-risk patients undergoing surgical tooth extraction. J Craniomaxillofac Surg. 2015;43(4):510-14.
61. 61. Gaudin E, Seidel L, Bacevic M, Rompen E, Lambert F. Occurrence and risk indicators of medication-related osteonecrosis of the jaw after dental extraction: a systematic review and meta-analysis. J Clin Periodontol. 2015; 42: 922–32.
62. 62. Jeong HG, Hwang JJ, Lee JH, Kim YH, Na JY, Han SS. Risk factors of osteonecrosis of the jaw after tooth extraction in osteoporotic patients on oral bisphosphonates. Imaging Sci Dent. 2017;47(1):45-50.
63. 63. Hasegawa T, Kawakita A, Ueda N, et al. Japanese Study Group of Cooperative Dentistry with Medicine (JCDM). A multicenter retrospective study of the risk factors associated with medication-related osteonecrosis of the jaw after tooth extraction in patients receiving oral bisphosphonate therapy: can primary wound closure and a drug holiday really prevent MRONJ? Osteoporos Int. 2017;28(8):2465-73.
64. 64. Mozzati M, Arata V, Gallesio G. Tooth extraction in osteoporotic patients taking oral bisphosphonates. Osteoporos Int. 2013;24(5):1707-12.
65. 65. Schwech N, Nilsson J, Gabre P. Incidence and risk factors for medication-related osteonecrosis after tooth extraction in cancer patients-A systematic review. Clin Exp Dent Res. 2023;9(1):55-65.
66. 66. Carvalho EM, Segalla Y, Corrêa K, Luiz C, Fabiano H. Clinical and Surgical Management for Placement of Osseointegrated Implants in a Patient taking Bisphosphonate Medication: Case Report / Manejo Clínico e Cirúrgico para Colocação de Implantes Osseointegrados em Paciente Em Uso de Bifosfonatos: Relato de Caso. Braz J Develop. 2021;7(12):115304-115317.
67. 67. Kim JW, Kwak MK, Han JJ, et al. Medication Related Osteonecrosis of the Jaw: 2021 Position Statement of the Korean Society for Bone and Mineral Research and the Korean Association of Oral and Maxillofacial Surgeons. J Bone Metab. 2021;28(4):279-96.
68. 68. Aboalela AA, Farook FF, Alqahtani AS, Almousa MA, Alanazi RT, Almohammadi DS. The Effect of Antiresorptive Drug Holidays on Medication-Related Osteonecrosis of the Jaw: A Systematic Review and Meta-Analysis. Cureus. 2022;14(10):e30485.
69. 69. Ottesen C, Schiodt M, Gotfredsen K. Efficacy of a high-dose antiresorptive drug holiday to reduce the risk of medication-related osteonecrosis of the jaw (MRONJ): A systematic review. Heliyon. 2020;6(4):e03795.
70. 70. 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. 2020;35(11):2179-92.