Osteonecrosis of the jaw related to non-antiresorptive medications: a systematic review
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.
KeywordsBone 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.
- 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.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.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. https://doi.org/10.1097/MD.0000000000000671 CrossRefPubMedPubMedCentralGoogle Scholar
- 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: https://doi.org/10.1111/odi.12708
- 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: https://doi.org/10.1155/2018/8071579
- 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.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
- 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.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
- 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.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. https://doi.org/10.1016/j.oraloncology.2015.08.014 CrossRefPubMedPubMedCentralGoogle Scholar
- 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. https://doi.org/10.1016/j.oooo.2017.10.010 CrossRefGoogle Scholar
- 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: https://doi.org/10.1111/tbj.12808
- 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. https://doi.org/10.3390/dj4040039
- 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. https://doi.org/10.1093/jnci/djw002
- 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
- 44.Disel U (2012) A case report of bevacizumab-related osteonecrosis of the jaw: old problem, new culprit. Oral Oncol 48:e2–e3. https://doi.org/10.1016/j.oraloncology.2011.07.030 CrossRefPubMedGoogle Scholar
- 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. https://doi.org/10.1016/j.tripleo.2011.08.024 CrossRefPubMedGoogle Scholar
- 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.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: https://doi.org/10.1007/s00784-017-2325-6
- 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, https://doi.org/10.1155/2014/452737
- 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.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
- 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