Supportive Care in Cancer

, Volume 27, Issue 2, pp 383–394 | Cite as

Osteonecrosis of the jaw related to non-antiresorptive medications: a systematic review

  • Ourania Nicolatou-GalitisEmail author
  • Maria Kouri
  • Erofili Papadopoulou
  • Emmanouil Vardas
  • Dimitra Galiti
  • Joel B. Epstein
  • Sharon Elad
  • Giuseppina Campisi
  • Nikolaos Tsoukalas
  • Kivanc Bektas-Kayhan
  • Winston Tan
  • Jean-Jacques Body
  • Cesar Migliorati
  • Rajesh V. Lalla
  • for the MASCC Bone Study Group
Review Article



The reporting of osteonecrosis of the jaw (ONJ) related to anticancer agents without known antiresorptive properties (non-antiresorptives), such as antiangiogenics, tyrosine kinase inhibitors, mammalian target of rapamycin inhibitors, immune checkpoint inhibitors, and cytotoxic chemotherapy is increasing.


To review characteristics of ONJ in cancer patients receiving non-antiresorptives.


A systematic review of the literature between 2009 and 2017 was conducted by the Bone Study Group of MASCC/ISOO.


Of 6249 articles reviewed and from personal communication, 42 ONJ cases related to non-antiresorptives were identified. No gender predilection was noted. Median age was 60 years and ONJ stage 2 was most common, with predilection for posterior mandible. Exposed bone, pain, and infection were common at diagnosis. In comparison to bone targeting agents (BTAs), radiology, histology, and management were similar, with medication often discontinued. Delayed diagnosis (median 8 weeks) was noted.

Important differences included earlier time to ONJ onset (median 20 weeks), absence of trigger event (40%), and greater likelihood of healing and shorter healing time (median 8 weeks) as compared to BTA-related ONJ. Gastrointestinal cancers predominated, followed by renal cell carcinomas compared to breast, followed by prostate cancers in BTA-related ONJ, reflecting different medications.


Data about non-antiresorptive-related ONJ is sparse. This type of ONJ may have better prognosis compared to the BTA-related ONJ, suggested by greater likelihood of healing and shorter healing time. However, the delay in diagnosis highlights the need for more education. This is the first attempt to characterize ONJ associated with different non-antiresorptives, including BRAF and immune checkpoint inhibitors.


Bone resorption Cytotoxic chemotherapy Immune checkpoint inhibitors Inhibitors of angiogenesis mTOR inhibitors Tyrosine kinase inhibitors BRAF inhibitors Osteonecrosis of the jaw 



We thank the MASCC Board for the opportunity to work on this project, within the Bone Study Group.

Compliance with ethical standards

Conflict of interest

Ourania Nicolatou-Galitis and Cesar Migliorati have received consultant fee from AMGEN. Maria Kouri, Erofili Papadopoulou, Emmanouil Vardas, Dimitra Galiti, Joel Epstein, Sharon Elad, Giuseppina Campisi, Nikolaos Tsoukalas, Kivanc Bektas-Kayhan, Winston Tan, Jean-Jacques Body, and Rajesh Lalla declare no conflict of interest.


  1. 1.
    Ruggiero SL, Dodson TB, Fantasia J, Goodday R, Aghaloo T, Mehrotra B, O’Ryan F (2014) American Association of Oral Maxillofacial Surgeons position paper on medication-related osteonecrosis of the jaw-2014 update. J Oral Maxillofac Surg 72:1938–1956CrossRefGoogle Scholar
  2. 2.
    Stopek AT, FizaZi K, Body JJ, Brown JE, Carducci M, Diel I et al (2016) Safety of long-term denosumab therapy: results from the open label extension phase of two phase 3 studies in patients with metastatic breast and prostate cancer. Support Care Cancer 24:447–455CrossRefGoogle Scholar
  3. 3.
    Schiodt M, Vadhan-Raj S, Chambers MC, Nicolatou-Galitis O, Politis C, Coropciuc R, Fedele S, Jandial D, Zhang J et al (2018) A multicenter case registry study on medication-related osteonecrosis of the jaw in patients with advanced cancer. Support Care Cancer 26:1905–1915CrossRefGoogle Scholar
  4. 4.
    Van Cann T, Loyson T, Verbiest A, Clement OM, Bechter O, Willems L et al (2018) Incidence of medication-related osteonecrosis of the jaw in patients treated with bone resorption inhibitors and vascular endothelial growth factor receptor tyrosine kinase inhibitors. Support Care Cancer 26:869–878CrossRefGoogle Scholar
  5. 5.
    Fung PPL, Bedogni G, Bedogni A, Petrie A, Porter S, Campisi G, Bagan J, Fusco V, Saia G, Acham S, Musto P, Petrucci MT, Diz P, Colella G, Mignogna MD, Pentenero M, Arduino P, Lodi G, Maiorana C, Manfredi M, Hallberg P, Wadelius M, Takaoka K, Leung YY, Bonacina R, Schiødt M, Lakatos P, Taylor T, de Riu G, Favini G, Rogers SN, Pirmohamed M, Nicoletti P, GENVABO Consortium, Fedele S (2017) Time to onset of bisphosphonate-related osteonecrosis of the jaws: a multicenter retrospective cohort study. Oral Dis 23:477–483CrossRefGoogle Scholar
  6. 6.
    Pilanci KN, Alco G, Ordu C, Sarsenov D, Celebi F, Erdogan Z, Agacayak F, Ilgun S, Tecimer C, Demir G, Erlp Y, Okkan S, Ozmen V (2015) Is administration of trastuzumab an independent risk factor for developing osteonecrosis of the jaw among metastatic breast cancer patients under zoledronic acid treatment? Medicine 94:e671. CrossRefPubMedPubMedCentralGoogle Scholar
  7. 7.
    Gaudin E, Seidel L, Bacevic M, Rompen E, Lambert F (2015) Occurrence and risk indicators of medication-related osteonecrosis of the jaw after dental extraction: a systematic review and meta-analysis. J Clin Periodontol 42:922–932CrossRefGoogle Scholar
  8. 8.
    McGowan K, McGowan T, Ivanovski S (2017). Risk factors for medication-related osteonecrosis of the jaws: a systematic review. Oral Dis 1-10. doi:
  9. 9.
    Pimolbutr K, Porter S, Fedele S (2018). Osteonecrosis of the jaw associated with antiangiogenics in antiresorptive-naïve patient: a comprehensive review of the literature BioMed Res Int Article ID 8071579, doi:
  10. 10.
    Fusco V, Santini D, Armento G, Tonini G, Campisi G (2016) Osteonecrosis of the jaw beyond antiresorptive (bone-targeted) agents: new horizons in oncology. Expert Opin Drug Saf 15(7):925–935CrossRefGoogle Scholar
  11. 11.
    Nicolatou-Galitis O, Papadopoulou E, Sarri T, Boziari P, Karayanni A, Kyrtsonis MC. Repousis P, Barbounis V, Migliorati C (2011). Osteonecrosis of the jaw in oncology patients treated with bisphosphonates: prospective experience of a dental oncology referral center. Oral Surg Oral Med Oral Pathol Oral Radiol 112:195–202Google Scholar
  12. 12.
    Vardas E, Coward T, Papadopoulou E, Nicolatou-Galitis O (2014) Dental extractions as the major local risk factor of bisphosphonates related jaw osteonecrosis in cancer therapy. A systematic review. Mediterranean Oncol J-MOJ 1:26–33Google Scholar
  13. 13.
    Fedele S, Porter SR, D’Aiuto F, Aljohani S, Vesconi P, Mafredi M, Arduino PG, Broccoletti R, Musciotto A, Di Fede O, Lazarovici TS, Campisi G (2010) Nonexposed variant of bisphosphonate-associated osteonecrosis of the jaw: a case series. Am J Med 123:1060–1064CrossRefGoogle Scholar
  14. 14.
    Bedogni A, Fusco V, Agrillo A, Campisi G (2012) Learning from experience. Proposal of a refined definition and staging system for bisphosphonate-related osteonecrosis of the jaw (BRONJ). Oral Dis 18:621–623CrossRefGoogle Scholar
  15. 15.
    Schiodt M, Reibel J, Oturai P, Kofod T (2014) Comparison of nonexposed and exposed bisphosphonate-induced osteonecrosis of the jaws: a retrospective analysis from the Copenhagen cohort and a proposal for an updated classification system. Oral Surg Oral Med Oral Pathol Oral Radiol 117:204–213CrossRefGoogle Scholar
  16. 16.
    Papadopoulou E, Nicolatou-Galitis O, Razis E, et al (2017). Localized alveolar bone disease prior to dental extraction in cancer patients treated with antiresorptives: an early stage of osteonecrosis of the jaw (ONJ)? [oral presentation]. Presented at the Multinational Association of Supportive Care in Cancer congress, 22–24 June 2017. Washington DC, USA 2017Google Scholar
  17. 17.
    Troeltzsch M, Woodlock T, Kriegelstein S, Steiner T, Messlinger K, Mar T (2012) Physiology and pharmacology of nonbisphopshonate drugs implicated in osteonecrosis of the jaw. J Can Dent Assoc 78:c85PubMedGoogle Scholar
  18. 18.
    Bowen JM, Elad S, Hutchins RD, Lalla RV (2013) Methodology for the MASCC/ISOO mucositis clinical practice guideline update. Support Care Cancer 21:303–308CrossRefGoogle Scholar
  19. 19.
    Hadorn DC, Baker D, Hodges JS, Hicks N (1996) Rating the quality of evidence for clinical practice guidelines. J Clin Epidemiol 49:749–754CrossRefGoogle Scholar
  20. 20.
    Somerfield MR, Padberg JJ, Pfister DG, Bennett CL, Recht A, Smith TJ, Weeks JC, Winn RJ, Durant JR (2000) ASCO clinical practice guiedlines: process, progress, pitfalls, and prospects. Classic Pap Curr Comments 4:881–886Google Scholar
  21. 21.
    Owosho AA, Scordo M, Yom SK, Randazzo J, Chapman PB, Huryn JM, Estilo CL (2015) Osteonecrosis of the jaw a new complication related to ipilimumab. Oral Oncol 51:e100–e101. CrossRefPubMedPubMedCentralGoogle Scholar
  22. 22.
    Mahedi Mohamed HA, Nor Nielsen CE, Schiodt M (2018) Medication related osteonecrosis of the jaws associated with targeted therapy as monotherapy and in combination with anti-resorptives. A report of seven cases from the Copenhagen ONJ cohort. Oral Surg Oral Med Oral Pathol Oral Radiol 125:157–163. CrossRefGoogle Scholar
  23. 23.
    Aghaloo TL, Tetradis S (2017) Osteonecrosis of the jaw in the absence of antiresorptive or antiangiogenic exposure: a series of 6 cases. J Oral Maxillofac Surg 75:129–142CrossRefGoogle Scholar
  24. 24.
    Omarini C, Filieri ME, Depenni R, Grizzi G, Cascinu S, Piacentini F (2017). Osteonecrosis of the jaw in a breast cancer patient treated with everolimus and a single dose of zoledronic acid. The Breast J 1–2. doi:
  25. 25.
    Viviano M, Rossi M, Cocca S (2017) A rare case of osteonecrosis of the jaw related to imatinib. J Korean Assoc Oral Maxillofac Surg 43:120–124. CrossRefPubMedPubMedCentralGoogle Scholar
  26. 26.
    Erovigni F, Gambino A, Cabras M, Fasciolo A, Bianchi SD, Bellini E, Fusco V (2016) Delayed diagnosis of osteonecrosis of the jaw (ONJ) associated with bevacizumab therapy in colorectal cancer patients: report of two cases. Dent J 4:39.
  27. 27.
    Yamamoto D, Tsubota Y, Utsunomiya T, Sueoka N, Ueda A, Endo K, Yoshikawa K, Kon M (2017) Osteonecrosis of the jaw associated with everolimus: a case report. Mol Clin Oncol 6:255–257. CrossRefPubMedGoogle Scholar
  28. 28.
    Zarringhalam P, Brizman E, Shakib K (2017) Medication-related osteonecrosis of the jaw associated with aflibercept. Br J Oral Maxillofac Surg 55:314–315. CrossRefPubMedGoogle Scholar
  29. 29.
    Patel V, Sproat C, Kwok J, Tanna N (2017) Axitinib-related osteonecrosis of the jaw. Oral Surg Oral Med Oral Pathol Oral Radiol 124:e257–e260CrossRefGoogle Scholar
  30. 30.
    Antonuzzo L, Lunghi A, Giommoni E, Brugia M, Di Costanzo F (2016) Regorafenib also can cause osteonecrosis of the jaw. J Natl Cancer Inst 108:djw002.
  31. 31.
    DeSeza CR, Appugoumder S, Haberland C, Johnson MP (2016) Osteonecrosis of the jaw in association with cutaneous T-cell lymphoma. J Oral Maxillofac Surg 74:292–301CrossRefGoogle Scholar
  32. 32.
    Garuti F, Camelli V, Spinardi L, Bucci L, Trevisani F (2016) Osteonecrosis of the jaw during sorafenib therapy for hepatocellular carcinoma. Tumori 102(Suppl 2):S69–S70. CrossRefGoogle Scholar
  33. 33.
    Mawardi H, Enzinger P, McCleary N, Manon R, Villa A, Treister N, Woo S-B (2016) Osteonecrosis of the jaw associated with ziv-aflibercept. J Gastrointest Oncol 7:e81–e87. CrossRefPubMedPubMedCentralGoogle Scholar
  34. 34.
    Melloni C, Tuttolomondo A, Anfosso A, Calamia C, Clemente FD, Cordova A (2016) Sunitinib related osteonecrosis of the jaw (SURONJ): a rare occurrence? Eur J Plast Surg 39:161–162CrossRefGoogle Scholar
  35. 35.
    Nicolatou-Galitis O, Galiti D, Moschogianni M, Sachanas S, Edwards BJ, Migliorati CA, Pangalis G (2016) Osteonecrosis of the jaw in a patient with acute myeloid leukemia, who received azacitidine. J Cancer Metasta Treat 2:220–223CrossRefGoogle Scholar
  36. 36.
    Ponzetti A, Pinta F, Spadi R, Mecca C, Fanchini L, Zanini M, Ciuffreda L, Racca P (2016) Jaw osteonecrosis associated with aflibercept, irinotecan and fluorouracil: attention to oral district. Tumori 102(Suppl 2):S74–S77. CrossRefGoogle Scholar
  37. 37.
    Marino R, Orlandi F, Arecco F, Gandolfo S, Pentenero M (2015) Osteonecrosis of the jaw in a patient receiving cabozantinib. Austr Dental J 60:528–531. CrossRefGoogle Scholar
  38. 38.
    Kim DW, Jung Y-S, Park H-S, Jung H-D (2013) Osteonecrosis of the jaw related to everolimus: a case report. Br J Oral Maxillofac Surg 51:e302–e304. CrossRefPubMedGoogle Scholar
  39. 39.
    Nicolatou-Galitis O, Razis E, Galiti D, Vardas E, Tzerbos F, Labropoulos S (2013) Osteonecrosis of the jaw in a patient with chronic myelogenous leukemia receiving imatinib - a case report with clinical implications. Forum Clin Oncol 4:29–33Google Scholar
  40. 40.
    Pakosch D, Papadimas D, Munding J, Kawa D, Kriwalsky MS (2013) Osteonecrosis of the mandible due to anti-angiogenic agent, bevacizumab. Oral Maxillofac Surg 17:303–306. CrossRefPubMedGoogle Scholar
  41. 41.
    Santos-Silva AR, Rosa GAB, de Castro JG, Dias RB, Ribeiro ACP, Brandão TB (2013) Osteonecrosis of the mandible associated with bevacizumab therapy. Oral Surg Oral Med Oral Pathol Oral Radiol 115:e32–e36CrossRefGoogle Scholar
  42. 42.
    Bettini G, Blandamura S, Saia G, Bedogni A (2012) Bevacizumab-related osteonecrosis of the mandible is a self-limiting disease process. BMJ Case Rep 2012:bcr2012007284. CrossRefPubMedPubMedCentralGoogle Scholar
  43. 43.
    Brunamonti Binello P, Bandelloni R, Labanca M, Buffoli B, Rezzani R, Rodella LF (2012) Osteonecrosis of the jaws and bevacizumab therapy: a case report. Int J Immunopathol Pharmacol 25:789–791CrossRefGoogle Scholar
  44. 44.
    Disel U (2012) A case report of bevacizumab-related osteonecrosis of the jaw: old problem, new culprit. Oral Oncol 48:e2–e3. CrossRefPubMedGoogle Scholar
  45. 45.
    Fleissig Y, Regev E, Lehman H (2012) Sunitinib related osteonecrosis of jaw: a case report. Oral Surg Oral Med Oral Pathol Oral Radiol 113:e1–e3CrossRefGoogle Scholar
  46. 46.
    Infante-Cossio P, Lopez-Martin JC, Gonzelez-Gardero E, Martinez-de-Fuentes R, Casas-Fernadez-Tejerina A (2012) Osteonecrosis of the maxilla associated with cancer chemotherapy in patients wearing dentures. J Oral Maxillofac Surg 70:1587–1592CrossRefGoogle Scholar
  47. 47.
    Nicolatou-Galitis O, Migkou M, Psyrri A, Bamias A, Pectasides D, Economopoulos T, Raber-Durlacher JE, Dimitriadis G, Dimopoulos MA (2012) Gingival bleeding and jaw bone necrosis in patients with metastatic renal cell carcinoma receiving sunitinib: report of 2 cases with clinical implications. Oral Surg Oral Med Oral Pathol Oral Radiol 113:234–238. CrossRefPubMedGoogle Scholar
  48. 48.
    Koch FP, Walter C, Hansen T, Jäger E, Wagneret W (2011) Osteonecrosis of the jaw related to sunitinib. Oral Maxillofac Surg 15:63–66. CrossRefPubMedGoogle Scholar
  49. 49.
    Serra E, Paolantonio M, Spoto G, Mastrangelo F, Tete S, Dolci M (2009) Bevacizumab-related osteneocrosis of the jaw. Int J Immunopathol Pharmacol 22(4):1121–1123CrossRefGoogle Scholar
  50. 50.
    Estilo CL, Fornier M, Farooki A, Carlson D, Bohle G III, Huryn JM (2008) Osteonecrosis of the jaw related to bevacizumab. JCO 26:4037–4038CrossRefGoogle Scholar
  51. 51.
    Greuter S, Schmid F, Ruhstaller T, Thuerlimann B (2008) Bevacizumab-associated osteonecrosis of the jaw. Ann Oncol 19:2091–2092CrossRefGoogle Scholar
  52. 52.
    Hallmer F, Bjornland T, Nicklasson A, Becktor JP, Andersson G (2014) Osteonecrosis of the jaw in patients treated with oral and intravenous bisphosphonates: experience in Sweden. Oral Surg Oral Med Oral Pathol Oral Radiol 118:202–208CrossRefGoogle Scholar
  53. 53.
    Fortuna G, Ruoppo E, Pollio A, Aria M, Adamo D, Leuci S, Dell’Aversana Orabona G, Mignogna MD (2012) Multiple myeloma vs. breast cancer patients with bisphopshonates-related osteonecrosis of the jaws: a comparative analysis of response to treatment and predictors of outcome. J Oral Pathol Med 41:222–228CrossRefGoogle Scholar
  54. 54.
    Ramaglia L, Guida A, Iorio-Siciliano V, Cuozzo A, Blasi A, Sculean A (2018). Stage-specific therapies of medication-related osteonecrosis of the jaws: a systematic review and meta-analysis of the drug suspension protocol. Clin Oral Invest 597-615, doi:
  55. 55.
    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. Internat J Dent article ID 452737,
  56. 56.
    Nicolatou-Galitis O, Razis E, Galiti D, Galitis E, Labropoulos S, Tsimpidakis A, Sgouros J, Karampeazis A, Migliorati C (2015) Periodontal disease preceding osteonecrosis of the jaw (ONJ) in cancer patients receiving antiresorptives alone or combined with targeted therapies: report of 5 cases and literature review. Oral Surg Oral Med Oral Pathol Oral Radiol 120:699–706CrossRefGoogle Scholar
  57. 57.
    Otto S, Pautke C, Jurado OM< Nehrbass D, Stoddart MJ, Ehrenfeld M, Zeiter S (2017). Further development of the MRONJ minipig large animal model. J Cranio-maxillo-Facial Surg 45:1503–1514Google Scholar
  58. 58.
    Coropciuc RG, Grisar K, Aerden T, Schol M, Schoenaers J, Politis C (2017) Medication-related osteonecrosis of the jaw in oncological patients with skeletal metastases: conservative treatment is effective up to stage 2. Br J Oral Maxillofac Surg 55:787–792CrossRefGoogle Scholar
  59. 59.
    Oken MM, Creech RH, Tormey DC, Horton J (1982) Toxicity and response criteria of the eastern cooperative oncology group. Am J Clin Oncol 5:649–655CrossRefGoogle Scholar
  60. 60.
    Tanna N, Steel C, Stagnell S, Bailey E (2017) Awareness of medication related osteonecrosis of the jaws (MRONJ) amongst general dental practitioners. Br Dental J 222:121–125CrossRefGoogle Scholar
  61. 61.
    Kim JW, Jeong SR, Kim SJ, Kim YS (2016) Perceptions of medical doctors on bisphosphonate-related osteonecrosis of the jaw. BMC Oral Health 16:92. CrossRefPubMedPubMedCentralGoogle Scholar
  62. 62.
    Taguchi A, Shiraki M, Sugimoto T, Ohta H, Soen S, Japan Osteoporosis S (2016) Lack of cooperation between physicians and dentists during osteoporosis treatment may increase fractures and osteonecrosis of the jaw. Curr Med Res Opin 32:1261–1268CrossRefGoogle Scholar
  63. 63.
    Nicolatou-Galitis O, Migliorati C. (2018) Osteonecrosis of the jaw (ONJ) in patients who receive bone targeting agents (BTAs): the power of e-learning. ecancermedicalscience. 12Google Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2018

Authors and Affiliations

  • Ourania Nicolatou-Galitis
    • 1
    Email author
  • Maria Kouri
    • 1
  • Erofili Papadopoulou
    • 1
  • Emmanouil Vardas
    • 1
  • Dimitra Galiti
    • 1
  • Joel B. Epstein
    • 2
  • Sharon Elad
    • 3
  • Giuseppina Campisi
    • 4
  • Nikolaos Tsoukalas
    • 5
  • Kivanc Bektas-Kayhan
    • 6
  • Winston Tan
    • 7
  • Jean-Jacques Body
    • 8
  • Cesar Migliorati
    • 9
  • Rajesh V. Lalla
    • 10
  • for the MASCC Bone Study Group
  1. 1.Dental SchoolNational and Kapodistrian University of AthensAthensGreece
  2. 2.Samuel Oschin Comprehensive Cancer InstituteCedars-Sinai Health System, Los Angeles CA and City of Hope National Medical CenterDuarteUSA
  3. 3.Eastman Institute for Oral HealthUniversity of Rochester Medical CenterRochesterUSA
  4. 4.Sector of Oral Medicine “V. Margiotta”, Department Di.Chir.On.SUniversity of PalermoPalermoItaly
  5. 5.Consultant Medical Oncologist, Oncology DepartmentVeterans Hospital (NIMTS)AthensGreece
  6. 6.Faculty of Dentistry, Department of Oral and Maxillofacial SurgeryIstanbul UniversityIstanbulTurkey
  7. 7.Hematology/Oncology, Mayo Clinic FloridaJacksonvilleUSA
  8. 8.CHU BrugmannUniversité Libre de BruxellesBrusselsBelgium
  9. 9.Department of Oral and Maxillofacial Diagnostic SciencesUniversity of Florida College of DentistryGainesvilleUSA
  10. 10.Section of Oral MedicineUniversity of Connecticut School of Dental MedicineFarmingtonUSA

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