Medication-Related Osteonecrosis of the Jaw: a Brief Review, Treatment and Practical Guidelines for Dentists

Ioana-Aurița Albu-Stan 1 , Daniel-Emil Albu 2 , Diana Cerghizan 1 , Lia Yero Eremie 1 , Kinga Jánosi 1 , Monica Baloș 1  and Constantin Copotoiu 3
  • 1 University of Medicine and Pharmacy, , Tîrgu Mureș, Romania
  • 2 Department of Orthopedic Surgery and Traumatology I, County Emergency Clinical Hospital, Tîrgu Mureș, Romania
  • 3 Department of Surgery, University of Medicine and Pharmacy, Tîrgu Mureș, Romania


Osteonecrosis of the jaws is a complication after treatment with antiresorptive drugs. Bisphosphonates (BPs) are widely used to treat conditions with bone metastases of malignant tumors such as multiple myeloma, breast cancer, prostatic cancer, as well as hypercalcemia of malignancy, osteoporosis, Paget’s disease, and osteogenesis imperfecta. Denosumab is an antiresorptive agent that is used for the treatment of osteoporosis or metastatic bone diseases. These antiresorptive agents improve the quality of life of patients by increasing strength and bone mineral density, and reducing the risk of bone fractures. More than a decade had passed since the first publication of this pathology, and the occurrence of the disease, its pathophysiology, and proper treatment methods are still not fully elucidated. Prevention is critical in medication-related osteonecrosis of the jaw, because the treatment is difficult, and there are no universally accepted treatment protocols. There is an accepted approach of palliation of symptoms and controlling the associated infections. Treatment may follow one of three procedures: conservative management of pain, conservative or extensive (segmental) surgery, depending on the disease stage.

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

  • 2. Ruggiero SL, Dodson TB, Assael LA, Landesberg R, Marx RE, 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(5suppl):2-12.

  • 3. Ruggiero SL, Dodson TB, 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. Nussbaum SR, Younger J, Vandepol CJ, et al. Single-dose intravenous therapy with pamidronate for the treatment of hypercalcemia of malignancy: Comparison of 30-, 60-, and 90-mg dosages. Am J Med. 1993;95:297-304.

  • 5. Hortobagyi GN, Theriault RL, Lipton A, et al. Long-term prevention of skeletal complications of metastatic breast cancer with pamidronate. Protocol 19 Aredia Breast Cancer Study Group. J Clin Oncol. 1998;16:2038-2044.

  • 6. Saad F, Gleason DM, Murray R, et al. Long-term efficacy of zoledronic acid for the prevention of skeletal complications in patients with metastatic hormone-refractory prostate cancer. J Natl Cancer Inst. 2004;96:879-882.

  • 7. Berenson JR, Hillner BE, Kyle RA, et al. American society of clinical oncology clinical practice guidelines: The role of bisphosphonates in multiple myeloma. J Clin Oncol. 2002;20:3719-3736.

  • 8. Delmas PD. The use of bisphosphonates in the treatment of osteoporosis. Curr Opin Rheumatol. 2005;17:462-466.

  • 9. Medical economics. Physicians’ Desk Reference. 57th ed. Montvale, NJ: Medical Economics; 2003.

  • 10. Delmas PD, Meunier PJ. The management of Paget’s disease of bone. N Engl J Med. 1997;336:558-566.

  • 11. Delmas PD. Clinical potential of RANKL inhibition for the management of postmenopausal osteoporosis and other metabolic bone diseases. J Clin Densitom. 2008;11:325-338.

  • 12. Fizazi K, Carducci M, Smith M, et al. Denosumab versus zoledronic acid for treatment of bone metastases in men with castration-resistant prostate cancer: A randomised, double-blind study. Lancet. 2011;377:813-822.

  • 13. Tenore G, Palaia G, Gaimari G, et al. Medication-Related Osteonecrosis of the Jaws (MRONJ): Etiological update. Senses Sci. 2014;1:147-152.

  • 14. Barasch A, Cunha-Cruz J, Curro FA, et al. Risk factors for osteonecrosis of the jaws: a case-control study from the CONDOR dental PBRN. J Dent Res. 2011;90:439-444.

  • 15. Zervas K, Verrou E, Teleioudis Z, et al. Incidence, risk factors and management of osteonecrosis of the jaw in patients with multiple myeloma: a single-centre experience in 303 patients. Br J Haematol. 2006;134:620-623.

  • 16. Hoff AO, Toth BB, Altundag K, et al. Frequency and risk factors associated with osteonecrosis of the jaw in cancer patients treated with intravenous bisphosphonates. J Bone Miner Res. 2008;23:826-836.

  • 17. 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;27:5356-5362.

  • 18. Badros A, Weikel D, Salama A, et al. Osteonecrosis of the jaw in multiple myeloma patients: clinical features and risk factors. J Clin Oncol. 2006;24:945-952.

  • 19. Kyrgidis A, Vahtsevanos K, Koloutsos G, et al. Bisphosphonate-related osteonecrosis of the jaws: a case-control study of risk factors in breast cancer patients. J Clin Oncol. 2008;26:4634-4638.

  • 20. Aguiar BD, Bohn SU, Cabrera Suarez MA, Aguiar MJ. Assessment of renal toxicity and osteonecrosis of the jaws in patients receiving zoledronic acid for bone metastasis. Ann Oncol. 2007;18:556-560.

  • 21. Lesclous P, Abi NS, Carrel JP, et al. Bisphosphonate-associated osteonecrosis of the jaw: a key role of inflammation? Bone. 2009;45:843-852.

  • 22. Tsao C, Darby I, Ebeling PR, et al. Oral health risk factors for bisphosphonate-associated jaw osteonecrosis. J Oral Maxillofac Surg. 2013;71:1360-1366.

  • 23. Jadu F, Lee L, Pharoah M, Reece D, Wang L. A retrospective study assessing the incidence, risk factors and comorbidities of pamidronate-related necrosis of the jaws in multiple myeloma patients. Ann Oncol. 2007;18:2015-2019.

  • 24. Thumbigere-Math V, Tu L, Huckabay S, et al. A retrospective study evaluating frequency and risk factors of osteonecrosis of the jaw in 576 cancer patients receiving intravenous bisphosphonates. Am J Clin Oncol. 2012;35:386-392.

  • 25. 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;23:1341-1347.

  • 26. Diz P, Lopez-Cedrun JL, Arenaz J, Scully C. Denosumab-related osteonecrosis of the jaw. J Am Dent Assoc. 2012;143:981-984.

  • 27. Papapoulos S, Chapurlat R, Libanati C, et al. Five years of denosumab exposure in women with postmenopausal osteoporosis: results from the first two years of the FREEDOM extension. J Bone Miner Res. 2012;27:694-701.

  • 28. Lacey DL, Boyle WJ, Simonet WS, et al. Bench to bedside: elucidation of the OPG-RANK-RANKL pathway and the development of denosumab. Nat Rev Drug Discov. 2012;11:401.

  • 29. Coleman RE, Major P, Lipton A, et al. Predictive value of bone resorption and formation markers in cancer patients with bone metastases receiving the bisphosphonate zoledronic acid. J Clin Oncol. 2005;23:4925.

  • 30. Stewart AF. Clinical practice. Hypercalcemia associated with cancer. N Engl J Med. 2005;352:373.

  • 31. Stopeck AT, Lipton A, Body JJ, et al. Denosumab compared with zoledronic acid for the treatment of bone metastases in patients with advanced breast cancer: a randomized, double-blind study. J Clin Oncol. 2010;28:5132.

  • 32. Henry DH, Costa L, Goldwasser F, et al. Randomized, double-blind study of denosumab versus zoledronic acid in the treatment of bone metastases in patients with advanced cancer (excluding breast and prostate cancer) or multiple myeloma. J Clin Oncol. 2011;29:1125.

  • 33. Kimmel DB. Mechanism of action, pharmacokinetic and pharmacodynamic profile, and clinical applications of nitrogen-containing bisphosphonates. J Dent Res. 2007;86:1022.

  • 34. Baron R, Ferrari S, Russell RG. Denosumab and bisphosphonates: different mechanisms of action and effects. Bone. 2011;48:677.

  • 35. Suzuki K, Takeyama S, Sakai Y, Yamada S, Shinoda H. Current topics in pharmacological research on bone metabolism: inhibitory effects of bisphosphonates on the differentiation and activity of osteoclasts. J Pharmacol Sci. 2006;100:189.

  • 36. Ito M, Amizuka N, Nakajima T, Ozawa H. Ultrastructural and cytochemical studies on cell death of osteoclasts induced by bisphosphonate treatment. Bone. 1999;25:447.

  • 37. Marx R. Oral and intravenous bisphosphonate induced osteonecrosis of the jaws: history, etiology, prevention, and treatment. 2nd ed. New Malden: Quintessence Publishing; 2007.

  • 38. Marx RE, Sawatari Y, Fortin M, Broumand V. Bisphosphonate-induced exposed bone (osteonecrosis/osteopetrosis) of the jaws: risk factors, recognition, prevention, and treatment. J Oral Maxillofac Surg. 2005;63:1567.

  • 39. Hansen T, Kunkel M, Weber A, et al. Osteonecrosis of the jaws in patients treated with bisphosphonates—Histomorphologic analysis in comparison with infected osteoradionecrosis. J Oral Pathol Med. 2006;35:155.

  • 40. Pabst AM, Ziebart T, Ackermann M, Konerding MA, Walter C. Bisphosphonates’ antiangiogenic potency in the development of bisphosphonate-associated osteonecrosis of the jaws: influence on microvessel sprouting in an in vivo 3D Matrigel assay. Clin Oral Investig. 2014;18:1015.

  • 41. McLeod NM, Brennan PA, Ruggiero SL. Bisphosphonate osteonecrosis of the jaw: a historical and contemporary review. Surgeon. 2012;10:36.

  • 42. Reid IR, Bolland MJ, Grey AB. Is bisphosphonate-associated osteonecrosis of the jaw caused by soft tissue toxicity? Bone. 2007;41:318.

  • 43. Dimopoulos MA, Kastritis E, Bamia C, et al. Reduction of osteonecrosis of the jaw (ONJ) after implementation of preventive measures in patients with multiple myeloma treated with zoledronic acid. Ann Oncol. 2009;20:117-120.

  • 44. Vandone AM, Donadio M, Mozzati M, et al. Impact of dental care in the prevention of bisphosphonate-associated osteonecrosis of the jaw: A single-center clinical experience. Ann Oncol. 2012;23:193-200.

  • 45. Khan AA, Morrison A, Hanley DA, et al. Diagnosis and management of osteonecrosis of the jaw: a systematic review and international consensus. J Bone Miner Res. 2015;30:3-23.

  • 46. Lerman MA, Xie W, Treister NS, Richardson PG, Weller EA, Woo SB. Conservative management of bisphosphonate-related osteonecrosis of the jaws: staging and treatment outcomes. Oral Oncol. 2013;49:977-983.

  • 47. Melea PI, Melakopoulos I, Kastritis E, Tesseromatis C, Margaritis V, Dimopoulos MA. Conservative treatment of bisphosphonate-related osteonecrosis of the jaw in multiple myeloma patients. Int J Dent. 2014;2014:427273.

  • 48. Vescovi P, Merigo E, Meleti M, Manfredi M, Fornaini C, Nammour S. Conservative surgical management of stage I bisphosphonate-related osteonecrosis of the jaw. Int J Dent. 2014;2014:107690.

  • 49. Romeo U, Galanakis A, Marias C, et al. Observation of pain control in patients with bisphosphonate-induced osteonecrosis using low level laser therapy: Preliminary results. Photomed Laser Surg. 2011;29:447-452.

  • 50. Wutzl A, Biedermann E, Wanschitz F, Seemann R, Klug C, Baumann A. Treatment results of bisphosphonate-related osteonecrosis of the jaws. Head Neck. 2008;30:1224-1230.

  • 51. Vescovi P, Merigo E, Meleti M, Manfredi M, Guidotti R, Nammour S. Bisphosphonates-related osteonecrosis of the jaws: a concise review of the literature and a report of a single-centre experience with 151 patients. J Oral Pathol Med. 2012;41:214-221.

  • 52. Martins MA, Martins MD, Lascala CA, Curi MM, Migliorati CA, Tenis CA. Association of laser phototherapy with PRP improves healing of bisphosphonate-related osteonecrosis of the jaws in cancer patients: a preliminary study. Oral Oncol. 2012;48:79-84.

  • 53. Rugani P, Acham S, Kirnbauer B, Truschnegg A, Obermayer-Pietsch B, Jakse N. Stage-related treatment concept of medication-related osteonecrosis of the jaw-a case series. Clin Oral Investig. 2015;19:1329-38.

  • 54. Carlson ER, Basile JD. The role of surgical resection in the management of bisphosphonate-related osteonecrosis of the jaws. J Oral Maxillofac Surg. 2009;67(5Suppl):85-95.

  • 55. Brauner E, Guarino G, Jamshir S, et al. Evaluation of highly porous dental implants in postablative oral and maxillofacial cancer patients: A prospective pilot clinical case series report. Implant Dent. 2015;24:631-637.

  • 56. Seth R, Futran ND, Alam DS, Knott PD. Outcomes of vascularized bone graft reconstruction of the mandible in bisphosphonate-related osteonecrosis of the jaws. Laryngoscope. 2010;120:2165-71.

  • 57. Pompa G, Bignozzi I, Cristalli MP, Quaranta A, Di Carlo S. Bisphosphonates and Osteonecrosis of the jaw: The oral surgeon’s perspective. Eur J Inflamm. 2012;101:11-23.

  • 58. Agrillo A, Filiaci F, Ramieri V, Riccardi E, Quarato D, Rinna C. Bisphosphonate-related osteonecrosis of the jaw (BRONJ): 5 year experience in the treatment of 131 cases with ozone therapy. Eur Rev Med Pharmacol Sci. 2012;16:1741–1747.

  • 59. Gonzálvez-García M, Rodríguez-Lozano FJ, Villanueva V, Segarra-Fenoll D, Rodríguez-González MA, Oñate-Sánchez R. Cell therapy in bisphosphonate-related osteonecrosis of the jaw. J Craniofac Surg. 2013;24:e226–e228.

  • 60. Cella L, Oppici A, Arbasi M, Moretto M, Piepoli M, Vallisa D. Autologous bone marrow stem cell intralesional transplantation repairing bisphosphonate related osteonecrosis of the jaw. Head Face Med. 2011;7:16.

  • 61. Curi MM, Cossolin GS, Koga DH, Zardetto C, Christianini S, Feher O. Bisphosphonate-related osteonecrosis of the jaws--an initial case series report of treatment combining partial bone resection and autologous platelet-rich plasma. J Oral Maxillofac Surg. 2011;69:2465–2472.

  • 62. Cheung A, Seeman E. Teriparatide therapy for alendronate-associated osteonecrosis of the jaw. N Engl J Med. 2010;363:2473–2474.

  • 63. Neuprez A, Rompen E, Crielaard JM, Reginster JY. Teriparatide therapy for denosumab-induced osteonecrosis of the jaw in a male osteoporotic patient. Calcif Tissue Int. 2014;95:94-96.


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