1. Introduction
Medication-related osteonecrosis of the jaw (MRONJ) is an uncommon and potentially serious adverse side effect of antiresorptive and antiangiogenic agents [ 1 ]. It can cause chronic pain, infection, dysfunction, and disfigurement and can affect the quality of life of affected individuals [ 2 , 3 ]. The vast majority of cases of MRONJ are associated with antiresorptive agents including bisphosphonates, denosumab, and more recently romosozumab [ 4 – 7 ]. A notably smaller number of cases are associated with the use of antiangiogenic agents, both in individuals who also take antiresorptive drugs and in those who are antiresorptive drugs-naïve [ 8 ]. MRONJ can develop in approximately 7% of cancer patients taking high-potency bisphosphonates or high-dose denosumab and about 0.01–0.1% of those with osteoporosis using low-potency oral bisphosphonates or low-dosage denosumab [ 1 , 9 – 12 ]. The use of antiangiogenic agents in combination with antiresorptive drugs is known to increase the risk of MRONJ development [ 13 ]; however, little is known regarding the incidence and prevalence of antiangiogenic-related MRONJ in antiresorptive drugs-naïve individuals. Antiangiogenic inhibitors have been increasingly used in the management of a range of malignancies including ovarian cancer, metastatic renal cell cancer, breast cancer, colorectal cancer, non-small-cell lung cancer (NSCLC), and glioblastoma multiforme [ 14 ]. Antiangiogenic inhibitors can be categorised into three major groups based on their mechanism of action: anti-VEGF monoclonal antibody (e.g., bevacizumab), VEGF decoy receptors or VEGF-Trap (e.g., aflibercept), and small molecule tyrosine kinase inhibitors (TKI) that block the VEGF receptors downstream signaling pathways (e.g., sunitinib, cabozantinib, and sorafenib) [ 15 ] ( Table 1 ). Additionally, the mammalian target of rapamycin (mTOR) inhibitors also seems to have antiangiogenic effects by inhibiting the production of VEGF and platelet-derived growth factors (PDGF) [ 16 – 18 ].
The number of patients developing MRONJ associated with antiangiogenic inhibitors or a combination of antiangiogenics and antiresorptive drugs has been growing over the last few years [ 8 , 13 , 19 , 20 ]. The purpose of the present study is to provide a comprehensive review of the published reports of MRONJ associated with antiangiogenic agents in patients with no history of antiresorptive therapies.
2. Materials and Methods
2.1. Literature Search Strategy
A literature search was conducted to identify clinical trials, case reports, and case series on MRONJ associated with antiangiogenic treatment in antiresorptive drugs-naïve individuals using MEDLINE via PubMed (up to December 2017), EMBASE (from 1980 to December 2017), and Web of Science (from 1900 to December 2017). The search strategy used the following keywords: “osteonecrosis,” “jaw osteonecrosis,” “jaw bone necrosis,” “oral osteonecrosis,” “antiangiogenic,” “angiogenesis inhibitors,” “antineoplastic agents,” “antiangiogenic activity,” “antiangiogenic therapy,” “chemotherapy,” and “targeted therapy.” The references of retrieved articles were manually searched in order to identify additional relevant articles and abstracts. The search included articles published in English and other languages. Inclusion criteria were patients developing MRONJ associated with antiangiogenic agents based on the definition of MRONJ proposed by the special committee on MRONJ of the American Association of Oral and Maxillofacial Surgeons (AAOMS) in 2014 [ 1 ]. Patients with history of radiotherapy involving the jaw bones and patients having previous history or concurrent use of antiresorptive therapy were excluded.
3. Results
3.1. Search Results
A total of 4,597 articles were retrieved by the initial search, including literature reviews, duplicate articles, clinical trials, and case reports with bisphosphonates and antiangiogenic treatment. The flow chart of review process to identify studies included and excluded is shown in Figure 1 . Following screening the articles, we identified 28 articles describing 35 cases of MRONJ meeting the aforementioned inclusion criteria. Of these 28 publications, 26 papers were published in English, one was published in Italian, and one was published in Japanese. These 35 reported MRONJ cases were related to previous history of treatment with bevacizumab (14 cases), aflibercept (5 cases), sunitinib (3 cases), cabozantinib (2 cases), sorafenib (1 case), temsirolimus (1 case), everolimus (1 case), dasatinib (1 case), and multiple antiangiogenic agents (7 cases) ( Table 2 ).
All 35 patients were reported to have developed MRONJ associated with at least one antiangiogenic agent and without a history of treatment with antiresorptive drugs. There were 19 males (54.29%) and 14 males (40%). The mean age of patients was 59.06 years (range: 33–80 years). The underlying diseases that required treatment with antiangiogenic agents included metastatic renal cell cancer (10 patients, 28.57%) followed by metastatic colorectal cancer (6 patients, 17.14%), metastatic breast cancer (5 patients, 14.29%), and other cancers (14 patients, 40%).
The most common presenting symptom was pain to the mandible/maxilla (12 patients, 34.29%) whereas 8 individuals (22.86%) reported no notable symptoms. The remaining patients had a variety of presenting complaints including mild discomfort to the mandible (1 patient, 2.86%), spontaneous teeth loss (1 patient, 2.86%), gingival bleeding (1 patient, 2.86%), and limited mouth opening together with submandibular swelling (1 patient, 2.86%). Moreover, there were 6 patients (17.14%) presenting with multiple symptoms including pain to the jaw, halitosis, spontaneous tooth loss, ulceration, difficulty in chewing, and paraesthesia. Regarding clinical characteristics of MRONJ, 32 patients (91.43%) had intraoral frank bone exposure, while the other three patients had nonexposed MRONJ. Mandible was the most common area of MRONJ development (29 patients, 82.86%), whereas four patients (11.43%) developed MRONJ in the maxilla.
Fourteen patients (40%) were exposed to bevacizumab, followed by aflibercept (5 patients, 14.29%), sunitinib (3 patients, 8.57%), cabozantinib (2 patients, 5.71%), sorafenib (1 patient, 2.86%), temsirolimus (1 patient, 2.86%), everolimus (1 patient, 2.86%), dasatinib (1 patient, 2.86%), and multiple antiangiogenic agents (7 patients, 20%). Regarding the routes of drug administration, antiangiogenic medications were administered intravenously in 21 patients (60.00%), while 12 patients (34.29%) were given antiangiogenic therapy orally. Two patients (5.71%) were given the combination of intravenous administration and oral administration. The mean duration of intravenous and oral antiangiogenic therapy before MRONJ development was 6.49 months (range: 0.23–36; SD = 1.82; 95% CI: 2.67–10.30) and 16.72 months (range: 1–60; SD = 6.42; 95% CI: 2.59–30.84), respectively. Patients with MRONJ also received a variety of concomitant medications including chemotherapy, hormone therapy, corticosteroids, antihypertensive drugs, antidepressants, and gastrointestinal medications.
Additional risk factors for MRONJ were reported in 21 patients, with dental extraction being the most prominent factor (13 patients, 37.14%). Other factors included history of mucosal trauma from dentures, chronic infection/inflammation to the tooth-bearing alveolar bone (periodontal disease), and insertion of osteointegrated dental implants (8 patients, 22.86%). The mean time to MRONJ diagnosis after tooth extraction was 3.09 months (range: 0.23–8; SD = 1.13; 95% CI: 0.40–5.77).
Regarding the management of MRONJ, seventeen patients (48.57%) were managed with surgical procedures alone or combined with medications (antibiotic therapy, antimicrobial mouthwash) and interruption of antiangiogenic agents. 16 patients did not receive surgery (45.71%), with antiangiogenic agents being discontinued in 7 cases. There was no active intervention reported in one patient. Most surgical interventions (11 patients) were minimally invasive procedures including smoothening of exposed bone, local flap coverage, removal of superficial necrotic bone, soft tissue debridement, and bone curettage, whereas 6 patients underwent major surgery such as bone decortication, resection of necrotic bone with local flap coverage, segmental osteotomy, and block resection. The outcomes of therapy were reported for 29 patients (82.8%), whereas no information was provided for the other 6 cases. 18 patients out of these 29 (62%) were reported to have disease resolution, while 11 patients showed persistent bone exposure. Disease resolution was described as complete mucosal coverage/no evidence of exposed bone in 13 cases, whereas no clear description was provided for the remaining 5 cases. Of note, one patient who experienced disease resolution to the left side of the mandible eventually developed a new area of MRONJ to the right mandible. The mean time from MRONJ diagnosis to complete healing was 6.75 months (range months: 1.84–22; SD = 2.47; 95% CI: 0.90–12.59). The data of 35 reported cases with MRONJ associated with antiangiogenics are summarised in Table 3 .
4. Discussion
The present study is the first comprehensive review upon MRONJ in patients treated with antiangiogenics in the absence of bone-modulating therapy.
We present data from 35 patients with different metastatic cancers who developed MRONJ following antiangiogenic treatments. All individuals were antiresorptive drugs-naïve. We have identified a number of differences between MRONJ associated with antiangiogenic agents and MRONJ associated with antiresorptive drugs. Our data showed a sex ratio of 4 : 5 (F : M) and an age range of 33–80 years (mean: 59.06 years), compared to sex ratio of 3 : 2 and age range of 42–90 years (mean 66 years) reported for antiresorptive drugs-associated MRONJ [ 50 – 52 ]. There also seem to be differences in the prevalence of MRONJ in these two populations. The reported prevalence of MRONJ in patients who had been treated with intravenous bevacizumab alone for the treatment of advanced breast cancer was 0.2%, which was lower than that of MRONJ associated with intravenous antiresorptive agents (7%) [ 11 , 19 ]. However, it is important to note that the prevalence of MRONJ related to antiangiogenic agents may also depend on the epidemiology of underlying malignancies that require antiangiogenic therapy.
The clinical presentations of MRONJ associated with antiangiogenics also seem to be different from MRONJ due to antiresorptive agents. Approximately up to 25% of MRONJ cases related to antiresorptive medications can present without frank bone exposure [ 53 ], whereas most of the patients in the present review had clear evidence of bone exposure (91.43%). However, the number of patients with nonexposed MRONJ might be underestimated, since until 2014 MRONJ could only be diagnosed in individuals with clinical evidence of exposed bone as per AAOMS definition [ 53 , 54 ].
With respect to the presenting complaints and location, they appear to be similar in two populations. The majority of patients with antiangiogenic-related MRONJ in this study experienced pain to the jaw, which is also the most common complaint in patients with MRONJ associated with antiresorptive agents [ 51 , 55 ]. In the present study, most MRONJ cases associated with antiangiogenic therapy tended to occur in the mandible more frequently than in the maxilla, similar to those with antiresorptive drugs-induced MRONJ [ 50 , 52 ].
A number of additional risk factors were identified in the present review including dental extraction, the use of denture, periodontal infection, and dental implant. Almost 40% of reported cases in this study were predominantly preceded by tooth extraction, which is similar to those with antiresorptive drugs-related MRONJ [ 50 , 56 ].
There is a slight difference with respect to underlying malignancies between two populations. Patients with antiresorptive drugs-associated MRONJ showed the previous history of multiple myeloma, metastatic breast cancer, and metastatic prostate cancer, whereas those with MRONJ related to antiangiogenic medications in our review were mainly diagnosed with metastatic renal cell cancer, followed by metastatic colorectal cancer and metastatic breast cancer as demonstrated in Table 3 [ 52 ].
Although there was no consistent pattern in the time to MRONJ development in this review, the average time for developing MRONJ among patients with either intravenous or oral antiangiogenics was shorter than the average time to MRONJ onset in those treated with antiresorptive drugs. The mean time to event for intravenous and oral antiangiogenic agents in this study was 6.5 and 16.71 months, respectively, while it was reported to be approximately 1.8 and 3 years for bisphosphonate therapy [ 12 , 57 ].
Patients with metastatic malignancy may receive a number of anticancer drugs simultaneously. In this review, we found that seven of the reported cases received more than one antiangiogenic agent in their treatment history [ 32 , 44 – 49 ]. Of these patients, some were given different antiangiogenics at the same time, while others received these agents at different time points. The development of MRONJ is usually associated with the latest antiangiogenic agent used by the patient; however, one cannot exclude the fact that the antiangiogenic agents previously used by these patients might have contributed to it.
We included in this review two cases of MRONJ associated with new TKIs, namely, pazopanib in combination with axitinib ( n = 1) and dasatinib ( n = 1) [ 32 , 49 ]. According to the Food and Drug Administration's Adverse Event Reporting System (FAERS), pazopanib and axitinib have been associated with the development of MRONJ in 10 and 9 individuals, respectively; however, as data regarding concurrent or previous medication were not available in FAERS documentation [ 58 ], it is difficult to conclude whether these individuals were indeed antiresorptive drugs-naïve. Therefore, we decided not to include these 19 cases in our review.
With regard to the management of MRONJ, approximately half of the individuals with MRONJ associated with antiangiogenics (48.57%) were managed surgically, which is similar to those with bisphosphonate-related MRONJ [ 11 , 52 ]. However, the prognosis of antiangiogenic-related MRONJ appears to be better than that of individuals developing MRONJ associated with antiresorptive agents. We observed a 62% rate of disease resolution in those where outcomes were reported as opposed to approximately 50% reported in the literature for MRONJ associated with antiresorptive agents [ 56 , 59 , 60 ]. It is possible that the higher rate of disease resolution might be related to the shorter half-life of antiangiogenics [ 61 , 62 ], as well as the lower cumulative dosages [ 63 ]. Moreover, the average time to resolution for MRONJ associated with antiangiogenics appears to be shorter than antiresorptive drugs-induced MRONJ (6.75 months, range: 1.84–22 months versus 8.2 months, range: 0.2–25.6 months) [ 55 ].
In this comprehensive review, we excluded a number of potential antiangiogenic-related MRONJ cases due to a lack of adequate clinical information. For example, the 2012 report on aflibercept by the US Food and Drug Administration (FDA) described 3 aflibercept-treated bisphosphonate-naïve patients who developed MRONJ; however, none of these patients were added to the present review as one had jaw bone exposure for less than 8 weeks and no information was provided for the other two cases [ 64 ]. Furthermore, in a pivotal BOLERO-2 trial, MRONJ has been described in 2 patients in the experimental arm (everolimus-exemestane) and 1 patient in the control arm (exemestane), with one of three patients to receive bisphosphonate treatment [ 65 ]. However, there was no evidence to show whether the patient with a history of bisphosphonate treatment was in the experimental arm or control arm. More recently, Antonuzzo et al. [ 66 ] reported the first case with MRONJ potentially associated with regorafenib, one of the tyrosine kinase inhibitors, in an antiresorptive drugs-naïve individual. Although MRONJ appeared 22 months after regorafenib treatment, Fusco et al. [ 67 ] have noted that some details such as the use of other medications prior to regorafenib treatment, dosing, and the time on medication are still missing. This medication is usually used as a third or further line of treatment of metastatic colorectal cancer. Therefore, it is also worth knowing whether this patient has received other well-documented antiangiogenic medications such as bevacizumab and aflibercept prior to regorafenib. If this is the case, bevacizumab or aflibercept possibly might contribute to the development of MRONJ rather than regorafenib alone. Another patient with gastrointestinal stromal tumours (GISTs) receiving imatinib monotherapy presented with pain and exposed bone at lower right mandible after having the tooth removed for 5 weeks. The patient was treated with debridement of necrotic bone and antibiotic and then was discharged. Unfortunately, there was no further information about this patient [ 68 ]. The duration of persistent bone exposure in this case was not mentioned if it was longer than 8 weeks. Therefore, available data seems not to be enough to classify this case as MRONJ according to the definition of MRONJ [ 1 ] and to confirm the association between MRONJ and imatinib. In addition to the above reported cases, Hopp et al. [ 69 ] reported one patient with necrotic bone exposure after the 2-year intravitreal injections of bevacizumab for treatment of retinal vascular thrombosis without notable dental risk factors or use of bisphosphonates. After the patient experienced pain to the mandible, the lesion was completely healed by antibiotics treatment within 8 weeks. Therefore, this case seems not to be correlated with the definition of MRONJ formulated by the AAOMS in 2014 [ 1 ].
It is important to highlight that another case of oral soft tissues complication associated with bevacizumab was also reported by Magremanne et al. [ 70 ]. Although this case was included in previous reviews regarding cases of MRONJ associated with antiangiogenic agents, there was no evidence of osteonecrosis of the jaw and also the necrotic area seemed to be limited only to oral soft tissues. This reported case does not meet the definition of MRONJ and hence it was excluded from this review.
5. Conclusion
There remains incomplete information regarding the cases of antiangiogenic-related MRONJ in antiresorptive-naïve individuals reported in the literature. It is therefore difficult to draw any conclusion regarding the epidemiology and the characteristics of MRONJ in this patient population. Within the limitation of available data, we have identified a number of differences between MRONJ associated with antiangiogenics and MRONJ related to antiresorptive drugs including demographic characteristics, prevalence, the underlying malignant disease, time to the onset, and time to resolution. Considering that the list of antiangiogenic inhibitors that have potential to increase the risk of MRONJ development is increasing, further prospective and well-designed research is warranted to confirm our findings and increase knowledge and understanding of the disease.
Acknowledgments
Professor Stefano Fedele received salary support from the NIHR UCLH Biomedical Research Centre.
Conflicts of Interest
The authors have no conflicts of interest to declare.
1 Ruggiero S. L. Dodson T. B. Fantasia J. American association of oral and maxillofacial surgeons position paper on medication-related osteonecrosis of the jaw—2014 update Journal of Oral and Maxillofacial Surgery 2014 72 10 1938 1956 10.1016/j.joms.2014.04.031 25234529
2 Hinchy N. V. Jayaprakash V. Rossitto R. A. Osteonecrosis of the jaw - Prevention and treatment strategies for oral health professionals Oral Oncology 2013 49 9 878 886 2-s2.0-84883135340 10.1016/j.oraloncology.2013.06.008 23890929
3 Capocci M. Romeo U. Guerra F. Medication-related osteonecrosis of the jaws (MRONJ) and quality of life evaluation: A pilot study La Clinica Terapeutica 2017 168 4 e253 e257 2-s2.0-85023197902 10.7417/T.2017.2015 28703840
4 Marx R. E. Pamidronate (Aredia) and zoledronate (Zometa) induced avascular necrosis of the jaws: a growing epidemic Journal of Oral and Maxillofacial Surgery 2003 61 9 1115 1117 10.1016/S0278-2391(03)00720-1 2-s2.0-0042861578 12966493
5 Stopeck A. T. Lipton A. Body J. Denosumab compared with zoledronic acid for the treatment of bone metastases in patients with advanced breast cancer: a randomized, double-blind study Journal of Clinical Oncology 2010 28 35 5132 5139 10.1200/JCO.2010.29.7101 2-s2.0-79551568488 21060033
6 Uyanne J. Calhoun C. C. Le A. D. Antiresorptive drug-related osteonecrosis of the jaw Dental Clinics of North America 2014 58 2 369 384 10.1016/j.cden.2013.12.006 2-s2.0-84896346446 24655528
7 Cosman F. Crittenden D. B. Adachi J. D. Romosozumab treatment in postmenopausal women with osteoporosis The New England Journal of Medicine 2016 375 16 1532 1543 2-s2.0-84992145944 10.1056/NEJMoa1607948 27641143
8 Hamadeh I. S. Ngwa B. A. Gong Y. Drug induced osteonecrosis of the jaw Cancer Treatment Reviews 2015 41 5 455 464 10.1016/j.ctrv.2015.04.007 2-s2.0-84937512136 25913713
9 Bagan J. Scully C. Sabater V. Jimenez Y. Osteonecrosis of the jaws in patients treated with intravenous bisphosphonates (BRONJ): A concise update Oral Oncology 2009 45 7 551 554 2-s2.0-67449096723 10.1016/j.oraloncology.2009.01.002 19251474
10 Reid I. R. Osteonecrosis of the jaw—who gets it, and why? Bone 2009 44 1 4 10 10.1016/j.bone.2008.09.012 2-s2.0-57549103742 18948230
11 Kühl S. Walter C. Acham S. Pfeffer R. Lambrecht J. T. Bisphosphonate-related osteonecrosis of the jaws—a review Oral Oncology 2012 48 10 938 947 10.1016/j.oraloncology.2012.03.028 2-s2.0-84866373893 22525606
12 Malden N. Lopes V. An epidemiological study of alendronate-related osteonecrosis of the jaws. A case series from the south-east of Scotland with attention given to case definition and prevalence Journal of Bone and Mineral Metabolism 2012 30 2 171 182 2-s2.0-84859824848 10.1007/s00774-011-0299-z 21858474
13 Fusco V. Porta C. Saia G. Osteonecrosis of the Jaw in Patients with Metastatic Renal Cell Cancer Treated with Bisphosphonates and Targeted Agents: Results of an Italian Multicenter Study and Review of the Literature Clinical Genitourinary Cancer 2015 13 4 287 294 2-s2.0-84936985160 10.1016/j.clgc.2014.12.002 25586958
14 De Falco S. Antiangiogenesis therapy: an update after the first decade Korean Journal of Internal Medicine 2014 29 1 1 11 10.3904/kjim.2014.29.1.1 2-s2.0-84894632560 24574826 PMC3932378
15 Al-Husein B. Abdalla M. Trepte M. DeRemer D. L. Somanath P. R. Antiangiogenic therapy for cancer: an update Pharmacotherapy 2012 32 12 1095 1111 10.1002/phar.1147 2-s2.0-84871556175 23208836 PMC3555403
16 Del Bufalo D. Ciuffreda L. Trisciuoglio D. Antiangiogenic potential of the mammalian target of rapamycin inhibitor temsirolimus Cancer Research 2006 66 11 5549 5554 2-s2.0-33745242315 10.1158/0008-5472.CAN-05-2825 16740688
17 Yuan R. Kay A. Berg W. J. Lebwohl D. Targeting tumorigenesis: development and use of mTOR inhibitors in cancer therapy Journal of Hematology & Oncology 2009 2, article 45 10.1186/1756-8722-2-45 2-s2.0-72849150434 PMC2775749 19860903
18 Moriya M. Yamada T. Tamura M. Antitumor effect and antiangiogenic potential of the mTOR inhibitor temsirolimus against malignant pleural mesothelioma Oncology Reports 2014 31 3 1109 1115 2-s2.0-84896705342 10.3892/or.2013.2948 24378576
19 Guarneri V. Miles D. Robert N. Bevacizumab and osteonecrosis of the jaw: Incidence and association with bisphosphonate therapy in three large prospective trials in advanced breast cancer Breast Cancer Research and Treatment 2010 122 1 181 188 2-s2.0-77953534421 10.1007/s10549-010-0866-3 20361252
20 Wynn R. L. Bevacizumab (Avastin): An anti-angiogenic drug associated with osteonecrosis of the jaw General dentistry 2011 59 6 410 413 2-s2.0-84856428677 22313910
21 Yoo S. Y. Kwon S. M. Angiogenesis and its therapeutic opportunities Mediators of Inflammation 2013 2013 11 10.1155/2013/127170 127170 2-s2.0-84894589746 PMC3745966 23983401
22 The U.S. Food and Drug Administration. FDA approved drug products 2017, https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm?event=overview.process&ApplNo=021986
23 Estilo C. L. Fornier M. Farooki A. Carlson D. Bohle G. III Huryn J. M. Osteonecrosis of the jaw related to bevacizumab Journal of Clinical Oncology 2008 26 24 4037 4038 2-s2.0-50549088915 10.1200/JCO.2007.15.5424 18711196
24 Greuter S. Schmid F. Ruhstaller T. Thuerlimann B. Bevacizumab-associated osteonecrosis of the jaw Annals of Oncology 2008 19 12 2091 2092 2-s2.0-56749177288 10.1093/annonc/mdn653 18977851 PMC2733125
25 Serra E. Paolantonio M. Spoto G. Mastrangelo F. Tetè S. Dolci M. Bevacizumab-related osteneocrosis of the jaw International Journal of Immunopathology and Pharmacology 2009 22 4 1121 1123 2-s2.0-76349114265 10.1177/039463200902200429 20074477
26 Brunamonti Binello P. Bandelloni R. Labanca M. Buffoli B. Rezzani R. Rodella L. F. Osteonecrosis of the jaws and bevacizumab therapy: A case report International Journal of Immunopathology and Pharmacology 2012 25 3 789 791 2-s2.0-84868022117 10.1177/039463201202500328 23058032
27 Bettini G. Blandamura S. Saia G. Bedogni A. Bevacizumab-related osteonecrosis of the mandible is a self-limiting disease process BMJ Case Reports 2012 2012 2-s2.0-84920834302 10.1136/bcr-2012-007284 PMC4543697 23093510
28 Dişel U. Beşen A. A. Özyilkan Ö. Er E. Canpolat T. A case report of bevacizumab-related osteonecrosis of the jaw: Old problem, new culprit Oral Oncology 2012 48 2 p. -e3 2-s2.0-84856331700 10.1016/j.oraloncology.2011.07.030 21865077
29 Sato M. Ono F. Yamamura A. Onochi S. A case of osteonecrosis of the jaw during treatment by bevacizumab for sigmoid colon cancer Journal of Japanese Society of Gastroenterology 2013 110 4 655 659 2-s2.0-84877299816 23558129
30 Fusco V. Fasciolo A. Gaino R. Bevacizumab-related osteonecrosis of jaw in a rectal cancer patient never treated with bisphosphonates Ann Stomatol 2014 5 2 p. 31
31 Tzermpos F. Ismail A. Pavli M. Tosios K. I. Osteonecrosis of the mandible in a patient with lung adenocarcinoma undergoing anti-angiogenic therapy with bevacizumab Oral Surgery 2016 9 1 40 46 2-s2.0-84956731919 10.1111/ors.12153
32 Abel Mahedi Mohamed H. Nielsen C. E. Schiodt M. Medication related osteonecrosis of the jaws associated with targeted therapy as monotherapy and in combination with antiresorptives. A report of 7 cases from the Copenhagen Cohort Oral Surgery, Oral Medicine, Oral Pathology, Oral Radiology, and Endodontology 2018 125 2 157 163 10.1016/j.oooo.2017.10.010 29221983
33 Ponzetti A. Pinta F. Spadi R. Jaw osteonecrosis associated with aflibercept, irinotecan and fluorouracil: Attention to oral district TUMORI 2016 102 S74 S77 2-s2.0-84995459577 10.5301/tj.5000405 26350200
34 Mawardi H. Enzinger P. McCleary N. Osteonecrosis of the jaw associated with ziv-aflibercept Journal of Gastrointestinal Oncology 2016 7 6 E81 E87 2-s2.0-85006965732 10.21037/jgo.2016.05.07 28078129 PMC5177584
35 Zarringhalam P. Brizman E. Shakib K. Medication-related osteonecrosis of the jaw associated with aflibercept British Journal of Oral and Maxillofacial Surgery 2017 55 3 314 315 2-s2.0-85007494453 10.1016/j.bjoms.2016.11.315 27923511
36 Nicolatou-Galitis O. Migkou M. Psyrri A. Gingival bleeding and jaw bone necrosis in patients with metastatic renal cell carcinoma receiving sunitinib: Report of 2 cases with clinical implications Oral Surgery, Oral Medicine, Oral Pathology, Oral Radiology, and Endodontology 2012 113 2 234 238 2-s2.0-84862535407 10.1016/j.tripleo.2011.08.024 22669112
37 Fleissig Y. Regev E. Lehman H. Sunitinib related osteonecrosis of jaw: a case report Oral Surgery, Oral Medicine, Oral Pathology, Oral Radiology, and Endodontology 2012 113 3 e1 e3 10.1016/j.tripleo.2011.06.023 2-s2.0-84862524211 22676833
38 Melloni C. Tuttolomondo A. Anfosso A. Calamia C. Clemente F. D. Cordova A. Sunitinib related osteonecrosis of the jaw (SURONJ): a rare occurrence? European Journal of Plastic Surgery 2016 39 2 161 162 2-s2.0-84930175372 10.1007/s00238-015-1112-3
39 Tempia Valenta G. Marino R. Erovigni F. Pentenero M. Gandolfo S. Mandibular osteonecrosis related to cabozantinib 2012 1:40 Abstracts of the 11th Biennial Congress of the European Association of Oral Medicine
40 Marino R. Orlandi F. Arecco F. Gandolfo S. Pentenero M. Osteonecrosis of the jaw in a patient receiving cabozantinib Australian Dental Journal 2015 60 4 528 531 2-s2.0-84957871204 10.1111/adj.12254 25474298
41 Garuti F. Camelli V. Spinardi L. Bucci L. Trevisani F. Osteonecrosis of the jaw during sorafenib therapy for hepatocellular carcinoma TUMORI 2016 102 S69 S70 2-s2.0-84995480906 10.5301/tj.5000504 27079903
42 Parti V. Ortega C. Aglietta M. Caso clinico di Osteonecrosi da inibitore di m-TOR Abstract Convegno Osteonecrosi dei mascellari (ONJ): ruolo della Rete Oncologica del Piemonte e della Valle d'Aosta 10.1016/S1359-6349(07)70650-X
43 Yamamoto D. Tsubota Y. Utsunomiya T. Osteonecrosis of the jaw associated with everolimus: A case report Molecular and Clinical Oncology 2017 6 2 255 257 10.3892/mco.2016.1100 28357105 PMC5351763
44 Agostino N. M. Gingrich R. Drabick J. J. Bevacizumab demonstrates prolonged disease stabilization in patients with heavily pretreated metastatic renal cell carcinoma: A case series and review of the literature Advances in Urology 2010 2-s2.0-77956754451 10.1155/2010/687043 687043 PMC2913531 20721275
45 Koch F. P. Walter C. Hansen T. Jäger E. Wagner W. Osteonecrosis of the jaw related to sunitinib Journal of Oral and Maxillofacial Surgery 2011 15 1 63 66 2-s2.0-79951859614 10.1007/s10006-010-0224-y 20401503
46 Santos-Silva A. R. Belizário Rosa G. A. Castro Júnior G. D. Dias R. B. Prado Ribeiro A. C. Brandão T. B. Osteonecrosis of the mandible associated with bevacizumab therapy Oral Surgery, Oral Medicine, Oral Pathology, Oral Radiology, and Endodontology 2013 115 6 e32 e36 2-s2.0-84878304679 10.1016/j.oooo.2013.02.001 23567260
47 Pakosch D. Papadimas D. Munding J. Kawa D. Kriwalsky M. S. Osteonecrosis of the mandible due to anti-angiogenic agent, bevacizumab Journal of Oral and Maxillofacial Surgery 2013 17 4 303 306 10.1007/s10006-012-0379-9 2-s2.0-84888128134 23242941
48 Jung T.-Y. Osteonecrosis of jaw after antiangiogenic agent administration in a renal cell carcinoma patient Oral and Maxillofacial Surgery Cases 2017 3 2 27 33 2-s2.0-85019156985 10.1016/j.omsc.2017.03.001
49 Patel V. Sproat C. Kwok J. Tanna N. Axitinib-related osteonecrosis of the jaw Oral Surgery, Oral Medicine, Oral Pathology, Oral Radiology, and Endodontology 2017 2-s2.0-85029416450 10.1016/j.oooo.2017.08.003 28918879
50 Woo S. B. Hellstein J. W. Kalmar J. R. Systematic review: bisphosphonates and osteonecrosis of the jaws Annals of Internal Medicine 2006 144 10 753 756 10.7326/0003-4819-144-10-200605160-00009 2-s2.0-33646836925 16702591
51 Otto S. Schreyer C. Hafner S. Bisphosphonate-related osteonecrosis of the jaws - Characteristics, risk factors, clinical features, localization and impact on oncological treatment Journal of Cranio-Maxillo-Facial Surgery 2012 40 4 303 309 2-s2.0-84860696738 10.1016/j.jcms.2011.05.003 21676622
52 Filleul O. Crompot E. Saussez S. Bisphosphonate-induced osteonecrosis of the jaw: a review of 2,400 patient cases Journal of Cancer Research and Clinical Oncology 2010 136 8 1117 1124 10.1007/s00432-010-0907-7 2-s2.0-77954577009 20508948 PMC11828172
53 Fedele S. Bedogni G. Scoletta M. Up to a quarter of patients with osteonecrosis of the jaw associated with antiresorptive agents remain undiagnosed British Journal of Oral and Maxillofacial Surgery 2014 10.1016/j.bjoms.2014.09.001 25282593
54 Ruggiero S. L. Dodson T. B. Assael L. A. Landesberg R. Marx R. E. Mehrotra B. American association of oral and maxillofacial surgeons postion paper on bisphosphonate-related osteonecrosis of the jaws Journal of Oral and Maxillofacial Surgery 2009 67 5, supplement 1 2 12 10.1016/j.joms.2009.01.009 2-s2.0-64649105333 19371809
55 Saad F. Brown J. E. Van Poznak C. 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 Annals of Oncology 2012 23 5 1341 1347 10.1093/annonc/mdr435 2-s2.0-84860467736 21986094
56 Campisi G. Fedele S. Fusco V. Pizzo G. Di Fede O. Bedogni A. Epidemiology, clinical manifestations, risk reduction and treatment strategies of jaw osteonecrosis in cancer patients exposed to antiresorptive agents Future Oncology 2014 10 2 257 275 2-s2.0-84893820808 10.2217/fon.13.211 24490612
57 Palaska P. K. Cartsos V. Zavras A. I. Bisphosphonates and time to osteonecrosis development The Oncologist 2009 14 11 1154 1166 2-s2.0-75449117669 10.1634/theoncologist.2009-0115 19897878
58 Zhang X. Hamadeh I. S. Song S. Osteonecrosis of the Jaw in the United States Food and Drug Administration's Adverse Event Reporting System (FAERS) Journal of Bone and Mineral Research 2016 31 2 336 340 2-s2.0-84959482616 10.1002/jbmr.2693 26288087
59 van den Wyngaert T. Claeys T. Huizing M. T. Vermorken J. B. Fossion E. Initial experience with conservative treatment in cancer patients with osteonecrosis of the jaw (ONJ) and predictors of outcome Annals of Oncology 2009 20 2 331 336 10.1093/annonc/mdn630 2-s2.0-60549109454 18953067
60 Lazarovici T. S. Yahalom R. Taicher S. Elad S. Hardan I. Yarom N. Bisphosphonate-realted osteonecrosis of the jaws: a single-center study of 101 patients Journal of Oral and Maxillofacial Surgery 2009 67 4 850 855 10.1016/j.joms.2008.11.015 2-s2.0-62649163689 19304045
61 Gordon M. S. Margolin K. Talpaz M. Phase I safety and pharmacokinetic study of recombinant human anti-vascular endothelial growth factor in patients with advanced cancer Journal of Clinical Oncology 2001 19 3 843 850 2-s2.0-0035253739 10.1200/JCO.2001.19.3.843 11157038
62 Oudard S. Beuselinck B. Decoene J. Albers P. Sunitinib for the treatment of metastatic renal cell carcinoma Cancer Treatment Reviews 2011 37 3 178 184 2-s2.0-79952005493 10.1016/j.ctrv.2010.08.005 20817406
63 Fusco V. Santini D. Armento G. Tonini G. Campisi G. Osteonecrosis of jaw beyond antiresorptive (bone-targeted) agents: new horizons in oncology Expert Opinion on Drug Safety 2016 15 7 925 935 2-s2.0-84965053887 10.1080/14740338.2016.1177021 27074901
64 FDA report FDA report on aflibercept: Center for drug evaluation and research 2012 100 141 Clin Rev. Aflibercept/Zaltrap. Application number 125418Orig1s000, p. 99
65 Gnant M. Baselga J. Rugo H. S. Effect of everolimus on bone marker levels and progressive disease in bone in BOLERO-2 Journal of the National Cancer Institute 2013 105 9 654 663 2-s2.0-84877305137 10.1093/jnci/djt026 23425564 PMC6430494
66 Antonuzzo L. Lunghi A. Giommoni E. Brugia M. Di Costanzo F. Regorafenib also can cause osteonecrosis of the jaw Journal of the National Cancer Institute 2016 108 4 2-s2.0-84964819856 10.1093/jnci/djw002 djw002 26857267
67 Fusco V. Campisi G. Numico G. Migliorati C. A. Santini D. Bedogni A. RE: Regorafenib Also Can Cause Osteonecrosis of the Jaw Journal of the National Cancer Institute 2016 108 9 2-s2.0-84989189613 10.1093/jnci/djw155 djw155 27390045
68 Viviano M. Rossi M. Cocca S. A rare case of osteonecrosis of the jaw related to imatinib Journal of the Korean Association of Oral and Maxillofacial Surgeons 2017 43 2 p. 120 10.5125/jkaoms.2017.43.2.120 PMC5410424 28462197
69 Hopp R. N. Pucci J. Santos-Silva A. R. Jorge J. Osteonecrosis after administration of intravitreous bevacizumab Journal of Oral and Maxillofacial Surgery 2012 70 3 632 635 2-s2.0-84859932479 10.1016/j.joms.2011.02.104 21757280
70 Magremanne M. Lahon M. De Ceulaer J. Reychler H. Unusual bevacizumab-related complication of an oral infection Journal of Oral and Maxillofacial Surgery 2013 71 1 53 55 2-s2.0-84871225112 10.1016/j.joms.2012.03.022 22705223