Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • General
  • Published:

Emerging therapies with potential risks of medicine-related osteonecrosis of the jaw: a review of the literature

British Dental Journal volume 228, pages 886–892 (2020)Cite this article

Abstract

In the past, osteonecrosis of the jaw (ONJ) was generally reported with bisphosphonate drugs; hence, the term BRONJ (bisphosphonate-related osteonecrosis of the jaw) was initially proposed. This was followed by the term ARONJ (antiresorptive osteonecrosis of the jaw). More recently, other novel medications such as vascular endothelial growth factor (VEGF) inhibitors, tyrosine kinase inhibitors and humanised antibodies that affect osteoclastic action have been reported to initiate ONJ in several cases. For this reason, in 2014, the American Association of Oral and Maxillofacial Surgeons (AAOMS) changed the term to MRONJ - medication-related osteonecrosis of the jaw. The review primarily focuses on ONJ associated with emerging therapies for the management of bone disorders. This article sheds some light on the risk factors that predispose dental patients to the development of osteonecrosis, the mechanisms of drug therapies associated with MRONJ, and potential treatment and management regimes for MRONJ patients. The current review noted that the incidence and associated risk of MRONJ is significant with the new therapeutic agents discussed. Therefore, for optimised patient care, pharmacovigilance with the new medications is essential for dental professionals.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Fig. 1

Similar content being viewed by others

References

  1. Marx R E. Pamidronate (Aredia) and zoledronate (Zometa) induced avascular necrosis of the jaws: a growing epidemic. J Oral Maxillofac Surg 2003; 61: 1115-1117.

  2. Ruggiero S L, Fantasia J, Carlson E. Bisphosphonate-related osteonecrosis of the jaw: Background and guidelines for diagnosis, staging and management. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2006; 102: 433-441.

  3. Ruggiero S L, Dodson T B, Fantasia J 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: 1938-1956.

  4. Almazrooa S A, Woo S B. Bisphosphonate and Nonbisphosphonate-Associated Osteonecrosis of the Jaw. J Am Dent Assoc 2009; 140: 864-875.

  5. Russmueller G, Seemann R, Weiss K, Stadler V, Speiss M, Perisanidis C. The association of medication-related osteonecrosis of the jaw with Actinomyces spp. infection. Sci Rep 2016; 6: 31604.

  6. Beth-Tasdogan N H, Mayer B, Hussein H, Zolk O. Interventions for managing medication-related osteonecrosis of the jaw. Cochrane Database Syst Rev 2017; DOI: 10.1002/14651858.CD012432.pub2.

  7. Chahine C J, Cheung M S, Head T W, Schwartz S, Glorieux F H, Rauch F. Tooth extraction socket healing in paediatric patients treated with intravenous pamidronate. J Pediatr 2008; 153: 719-720.

  8. Cohen N, Cohen-Lévy J. Healing processes following tooth extraction in orthodontic cases. J Dentofacial Anom Orthod 2014; 17: 304.

  9. Rucci N. Molecular biology of bone remodelling. Clin Cases Mineral Bone Metab 2008; 5: 49-56.

  10. Farina R, Trombelli L. Wound healing of extraction sockets. Endod Topics 2011; 25: 16-43.

  11. Allen M R. The effects of bisphosphonates on jaw bone remodeling, tissue properties, and extraction healing. Odontology 2011; 99: 8-17.

  12. Lizuka T, Miller S C, Marks Jr S C. Alveolar bone remodeling after tooth extraction in normal and osteopetrotic (ia) rats. J Oral Pathol Med 1992; 21: 150-155.

  13. Siddiqi A, Payne A G, Zafar S. Bisphosphonate-induced osteonecrosis of the jaw: a medical enigma? Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2009; DOI: 10.1016/j.tripleo.2009.04.027.

  14. Otto S, Schreyer C, Hafner S et al. Bisphosphonate-related osteonecrosis of the jaws - characteristics, risk factors, clinical features, localization and impact on oncological treatment. J Craniomaxillofac Surg 2012; 40: 303-309.

  15. Otto S, Tröltzsch M, Jambrovic V, Panya S, Probst F, Ristow O. Tooth extraction in patients receiving oral or intravenous bisphosphonate administration: A trigger for BRONJ development? J Craniomaxillofac Surg 2015; 43: 847-854.

  16. Mavrokokki T, Cheng A, Stein B, Goss A. Nature and frequency of bisphosphonate-associated osteonecrosis of the jaws in Australia. J Oral Maxillofac Surg 2007; 65: 415-423.

  17. Hellstein J. Osteochemonecrosis: An Overview. Head Neck Pathol 2014; 8: 482-490.

  18. Aghaloo T L, Felsenfeld A L, Tetradis S. Osteonecrosis of the Jaw in a Patient on Denosumab. J Oral Maxillofac Surg 2010; 68: 959-963.

  19. Vahtsevanos K, Kyrgidis A, Verrou E et al. Longitudinal cohort study of risk factors in cancer patients of bisphosphonate-related osteonecrosis of the jaw. J Clin Oncol. 2009; 27: 356-362.

  20. Sharma D, Ivanovski S, Slevin M, Hamlet S, Pop T S, Brinzaniuc K. Bisphosphonate-related osteonecrosis of jaw (BRONJ): diagnostic criteria and possible pathogenic mechanisms of an unexpected anti-angiogenic side effect. Vasc Cell 2013; 5: 1.

  21. Tohashi K, Nakabayashi M, Kodani I, Kidani K, Ryoke K. Associations between Systemic Markers of Bone Turnover or Bone Mineral Density and Anti-Resorptive Agent-Related Osteonecrosis of the Jaw in Patients Treated with Anti-Resorptive Agents. Yonago Acta Medica 2016; 59: 45-53.

  22. Rosella D, Papi P, Giardino R, Cicalini E, Piccoli L, Pompa G. Medication-related osteonecrosis of the jaw: Clinical and practical guidelines. J Int Soc Prevent Communit Dent 2016; 6: 97-104.

  23. Nisi M, La Ferla F, Karapetsa D, Gennai S, Miccoli M, Baggiani A. Risk factors influencing BRONJ staging in patients receiving intravenous bisphosphonates: a multivariate analysis. Int J Oral Maxillofac Surg 2015; 44: 586-591.

  24. Ristow O, Otto S, Troeltzsch M, Hohlweg-Majert B, Pautke C. Treatment perspectives for medication-related osteonecrosis of the jaw (MRONJ). J Craniomaxillofac Surg 2015; 43: 290-293.

  25. Devlin H, Greenwall-Cohen J, Benton J, Goodwin T L, Littlewood A, Horner K. Detecting the earliest radiological signs of bisphosphonate-related osteonecrosis. Br Dent J 2018; 224: 26-31.

  26. Ruggiero S L, Dodson T B, Assael L A, Landesberg R, Marx R E, Mehrotra B. American Association of Oral and Maxillofacial Surgeons position paper on bisphosphonate-related osteonecrosis of the jaws - 2009 update. J Oral Maxillofac Surg 2009; 67(5 Suppl): 2-12.

  27. Estilo C L, Van Poznak C H, Wiliams T et al. Osteonecrosis of the maxilla and mandible in patients with advanced cancer treated with bisphosphonate therapy. Oncologist 2008; 13: 911-920.

  28. McGowan K, McGowan T, Ivanovski S. Risk factors for medication-related osteonecrosis of the jaws: A systematic review. Oral Dis 2018; 24: 527-536.

  29. Lazarovici T S, Yahalom R, Taicher S et al. Bisphosphonate-related osteonecrosis of the jaw associated with dental implants. J Oral Maxillofac Surg 2010; 68: 790-796.

  30. Diniz-Freitas M, Fernández-Feijoo J, Diz-Dios P, Pousa X, Limeres J. Denosumab-related osteonecrosis of the jaw following non-surgical periodontal therapy: A case report. J Clin Periodontol 2018; 45: 570-577.

  31. Fleisher K E, Welch G, Kottal S, Craig R G, Saxena D, Glickman R S. Predicting risk for bisphosphonate-related osteonecrosis of the jaws: CTX versus radiographic markers. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2010; 110: 509-516.

  32. Marx R E, Cillo Jr J E, Ulloa J J. Oral bisphosphonate-induced osteonecrosis: risk factors, prediction of risk using serum CTX testing, prevention, and treatment. J Oral Maxillofac Surg 2007; 65: 2397-2410.

  33. Moore A, Renton T, Taylor T, Popat S, Popat R, Sivardeen Z. Oral surgery: ARONJ masterclass. Br Dent J 2014; 216: 488-489.

  34. Fliefel R, Tröltzsch M, Kühnisch J, Ehrenfeld M, Otto S. Treatment strategies and outcomes of bisphosphonate-related osteonecrosis of the jaw (BRONJ) with characterization of patients: a systematic review. Int J Oral Maxillofac Surg 2015; 44: 568-585.

  35. Neer R M, Arnaud C D, Zanchetta J R et al. Effect of parathyroid hormone (1-34) on fractures and bone mineral density in postmenopausal women with osteoporosis. N Engl J Med 2001; 344: 1434-1441.

  36. Bakr M M, Kelly W L, Brunt A R et al. Single injection of PTH improves osteoclastic parameters of remodeling at a stress fracture site in rats. J Orthop Res 2019; 37: 1172-1182.

  37. Spanou A, Lyritis G P, Chronopoulos E, Tournis S. Management of bisphosphonate-related osteonecrosis of the jaw: a literature review. Oral Diseases 2015; 21: 927-936.

  38. Bagan J, Peydró A, Calvo J, Leopoldo M, Jiménez Y, Bagan L. Medication-related osteonecrosis of the jaw associated with bisphosphonates and denosumab in osteoporosis. Oral Diseases 2016; 22: 324-329.

  39. Vescovi P. Bisphosphonates and osteonecrosis: an open matter. Clin Cases Miner Bone Metab 2012; 9: 142-144.

  40. Rollason V, Laverrière A, MacDonald L C I, Walsh T, Tramèr M R, Vogt-Ferrier N B. Interventions for treating bisphosphonate-related osteonecrosis of the jaw (BRONJ). Cochrane Database Syst Rev 2016; DOI: 10.1002/14651858.CD008455.pub2.

  41. Lopez-Jornet P, Sanchez Perez A, Amaral Mendes R, Tobias A. Medication-related osteonecrosis of the jaw: Is autologous platelet concentrate application effective for prevention and treatment? A systematic review. J Craniomaxillofac Surg 2016; 44: 1067-1072.

  42. Melville J C, Tursun R, Shum J W, Young S, Hanna I A, Marx R E. A technique for the treatment of oral-antral fistulas resulting from medication-related osteonecrosis of the maxilla: the combined buccal fat pad flap and radical sinusotomy. Oral Surg Oral Med Oral Pathol Oral Radiol 2016; 122: 287-291.

  43. João B, Blessmann W, Camilotti R S, Ponte M E. Efficacy of laser therapy in the management of bisphosphonate-related osteonecrosis of the jaw (BRONJ): a systematic review. Lasers Med Sci 2016; 31: 1261-1272.

  44. Mester E, Spiry T, Szende B, Tota J G. Effect of laser rays on wound healing. Am J Surg 1971; 122: 532-535.

  45. Halon A, Donizy P, Dziegala M, Dobrakowski R, Simon K. Tissue laser biostimulation promotes post-extraction neoangiogenesis in HIV-infected patients. Lasers Med Sci 2015; 30: 701-706.

  46. Lyttle C V, Paterson H. Denosumab: a case of MRONJ with resolution. Br Dent J 2016; 220: 623-625.

  47. American Association of Oral and Maxillofacial Surgeons. American Association of Oral and Maxillofacial Surgeons position paper on bisphosphonate-related osteonecrosis of the jaws. J Oral Maxillofac Surg 2007; 65: 369-376.

  48. Bedogni A. Position papers in the medical literature: lights and shadows for ONJ treatment. Annali di Stomatologia 2015; 6: 64-66.

  49. Aghaloo T L, Kang B, Sung E C et al. Periodontal Disease and Bisphosphonates Induce Osteonecrosis of the Jaws in the Rat. J Bone Miner Res 2011; 26: 1871-1882.

  50. Brown J P, Prince R L, Deal C et al. Comparison of the effect of denosumab and alendronate on BMD and biochemical markers of bone turnover in postmenopausal women with low bone mass: a randomized, blinded, phase 3 trial. J Bone Miner Res 2009: 24: 153-161.

  51. Badr M, Kyriakidou E, Atkins A, Harrison S. Aggressive denosumab-related jawnecrosis - a case series. Br Dent J 2017; 223: 13-16.

  52. Cassoni A, Romeo U, Terenzi V et al. Adalimumab: Another Medication Related to Osteonecrosis of the Jaws? Case Rep Dent 2016; DOI: 10.1155/2016/2856926.

  53. Preidl R H M, Ebker T, Raithel M, Wehrhan F, Neukam F W, Stockmann P. Osteonecrosis of the jaw in a Crohn's disease patient following a course of Bisphosphonate and Adalimumab therapy: a case report. BMC Gastroenterol 2014; 14: 1-6.

  54. Scheinfeld N. Adalimumab: a review of side effects. Expert Opin Drug Saf 2005; 4: 637-641.

  55. Lawrance I C, Radford-Smith G L, Bampton P A et al. Serious infections in patients with inflammatory bowel disease receiving antitumournecrosisfactoralpha therapy: An Australian and New Zealand experience. J Gastroenterol Hepatolo 2010; 25: 1732-1738.

  56. Ebker T, Rech J, von Wilmowsky C, Neukam F W, Stockmann P. Fulminant course of osteonecrosis of the jaw in a rheumatoid arthritis patient following oral bisphosphonate intake and biologic therapy. Rheumatology (Oxford) 2013; 52: 218-220.

  57. Hoefert S, Eufinger H. Sunitinib may raise the risk of bisphosphonate-related osteonecrosis of the jaw: presentation of three cases. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2010; 110: 463-469.

  58. Melloni C, Tuttolomondo A, Anfosso A, Calamia C, Clemente F D, Cordova A. Sunitinib related osteonecrosis of the jaw (SURONJ): a rare occurrence? Eur J Plast Surg 2016; 39: 161-162.

  59. Guillet M, Walter T, Scoazec J Y, Vial T, Lombard-Bohas C, Dumortier J. Sorafenib-Induced Bilateral Osteonecrosis of Femoral Heads. J Clin Onco 2010; DOI: 10.1200/JCO.2009.23.4252.

  60. Guarneri V, Miles D, Robert N, Diéras V, Glaspy J, Smith I. Bevacizumab and osteonecrosis of the jaw: incidence and association with bisphosphonate therapy in three large prospective trials in advanced breast cancer. Breast Cancer Res Treat 2010; 122: 181-188.

  61. Pakosch D, Papadimas D, Munding J, Kawa D, Kriwalsky M S. Osteonecrosis of the mandible due to anti-angiogenic agent, bevacizumab. J Oral Maxillofac Surg 2013; 17: 303-306.

  62. Lescaille G, Coudert A E, Baaroun V et al. Clinical study evaluating the effect of bevacizumab on the severity of zoledronic acid-related osteonecrosis of the jaw in cancer patients. Bone 2014; 58: 103-107.

  63. Allegra A, Oteri G, Alonci A et al. Association of osteonecrosis of the jaws and POEMS syndrome in a patient assuming rituximab. J Craniomaxillofac Surg 2014; 42: 279-282.

  64. Subramanian G, Quek S Y P. Comment on Narváez et al.: Lack of response to teriparatide therapy for bisphosphonate-associated osteonecrosis of the jaw. Osteoporosis Int 2013; 24: 735-736.

  65. Weigert K L, Lewgoy J, Mazzoleni D S, Franco F R, Enriconi L, Sasso J H. Rituximab and Osteonecrosis of The Jaws: Case Study. Oral Surg Oral Med Oral Pathol Oral Radiol 2014; DOI: 10.1016/j.oooo.2013.12.203.

  66. Bagan J V, Bagan L, Poveda R, Scully C. Mitoxantrone as a contributing factor in medication-related osteonecrosis of the jaws. Int J Oral Maxillofac Surg 2016; 45: 377-379.

  67. Tanna N, Steel C, Stagnell S, Bailey E. Awareness of medication related osteonecrosis of the jaws (MRONJ) among general dental practitioners. Br Dent J 2017; 222: 121-125.

  68. Lau J, Ng L, Siddiqi A, Zafar S. Paediatric Dentists Treating Children on Bisphosphonates: A Cross-Sectional Questionnaire-Based Study. Ped Dent 2019; 41: 3-8.

  69. Scottish Dental Clinical Effectiveness Programme. Oral Health Management of Patients at Risk of Medication-related Osteonecrosis of the Jaw. 2017. Available online at http://www.sdcep.org.uk/published-guidance/medication-related-osteonecrosis-of-the-jaw/ (accessed May 2020).

Download references

Author information

Authors and Affiliations

  1. General Dentist, School of Dentistry and Oral Health, Griffith University, Queensland, 4222, Australia

    Nupur Kanwar

  2. Director of Clinical Education (Dentistry), Senior Lecturer, General Dental Practice, School of Dentistry and Oral Health, Griffith University Queensland, 4222, Australia

    Mahmoud M. Bakr

  3. Senior Lecturer, Oral and Maxillofacial Surgery, School of Dentistry and Oral Health, Griffith University, Queensland, 4222, Australia

    Mohammed Meer

  4. Department of Periodontics, School of Dentistry and Oral Health, Griffith University, Queensland, 4222, Australia

    Allauddin Siddiqi

Authors
  1. Nupur Kanwar
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Mahmoud M. Bakr
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Mohammed Meer
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Allauddin Siddiqi
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Allauddin Siddiqi.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Kanwar, N., Bakr, M., Meer, M. et al. Emerging therapies with potential risks of medicine-related osteonecrosis of the jaw: a review of the literature. Br Dent J 228, 886–892 (2020). https://doi.org/10.1038/s41415-020-1642-3

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41415-020-1642-3

This article is cited by

Search

Advanced search

Quick links