BioMed Research International
Volume 2018 (2018), Article ID 8071579, 14 pages
https://doi.org/10.1155/2018/8071579

Review Article

Osteonecrosis of the Jaw Associated with Antiangiogenics in Antiresorptive-Naïve Patient: A Comprehensive Review of the Literature

Kununya Pimolbutr,1,2 Stephen Porter,¹ and Stefano Fedele1,3

¹UCL Eastman Dental Institute, London, UK
²Department of Oral Medicine and Periodontology, Faculty of Dentistry, Mahidol University, Bangkok, Thailand
³NIHR University College London Hospitals Biomedical Research Centre, London, UK

Correspondence should be addressed to Stefano Fedele; s.fedele@ucl.ac.uk

Received 29 December 2017; Accepted 7 March 2018; Published 23 April 2018

Academic Editor: Adriana Bigi

Copyright © 2018 Kununya Pimolbutr et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract.

Objectives. To review the available literature on medication-related osteonecrosis of the jaw (MRONJ) associated with antiangiogenics in antiresorptive-naïve individuals. Methods. A literature search was performed using MEDLINE via PubMed, EMBASE, and Web of Science in December 2017. Results. We identified reports describing a total of 35 antiresorptive drugs-naïve patients who developed antiangiogenic-related MRONJ. The mean age of these patients was 59.06 years and the F : M ratio was 4 : 5. The most common underlying disease was metastatic renal cell cancer. Pain to the mandible was the most common complaint (34.29%) and the majority of patients presented with bone exposure. The mean duration of intravenous and oral antiangiogenics before MRONJ development was 6.5 and 16.72 months, respectively. The most common additional risk factor was dental extraction (37.14%). Almost half of the MRONJ patients (48.57%) received surgical treatment. 18 patients (62.06%) were reported to have disease resolution within an average time of 6.75 months. Conclusion. MRONJ associated with antiangiogenic therapy in antiresorptive-naïve patients is a rare but potentially serious adverse effect. Available data suggests that there might be notable differences between MRONJ associated with antiangiogenics and antiresorptives; however, further prospective well-designed studies are required.

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].

Table 1: Approved antiangiogenic medications [14, 15, 21, 22].

Approved antiangiogenic drugs

Anti-VEGF monoclonal antibody
Indications for use

Bevacizumab
Metastatic colorectal cancer

Non-small-cell lung cancer

Glioblastoma multiforme

Metastatic renal cell cancer

Macular degeneration

Metastatic HER2 negative breast cancer

Persistent, recurrent, and metastatic cervical cancer

Platinum-resistant recurrent epithelial ovarian, fallopian tube or primary peritoneal cancer

VEGF decoy receptor (VEGF-Trap)
Indications for use

Aflibercept
Metastatic colorectal cancer

Tyrosine kinase inhibitors
Indications for use

Sorafenib
Metastatic renal cell cancer

Hepatic cancer (hepatocellular carcinoma)

Sunitinib
Metastatic renal cell carcinoma

Gastrointestinal stromal tumour

Pancreatic neuroendocrine tumour

Cabozantinib
Medullary thyroid cancer

Erlotinib
Non-small-cell lung cancer

Pancreatic cancer

Axitinib
Metastatic renal cell cancer

Pegaptanib
Macular degeneration

Ranibizumab
Macular degeneration

Pazopanib
Metastatic renal cell cancer

Soft tissue sarcoma

Vandetanib
Medullary thyroid cancer

Regorafenib
Metastatic colorectal cancer

Gastrointestinal stromal tumour

Imatinib
Chronic myeloid leukemia

Renal cell cancer

Gastrointestinal stromal tumour

Dasatinib
Philadelphia chromosome-positive (Ph+) chronic

myeloid leukemia (CML)

Chronic phase Ph+ CML

Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (Ph+ ALL)

Mammalian target of rapamycin inhibitors (mTOR inhibitors)
Indications for use

Temsirolimus
Renal cell cancer

Everolimus
Advanced breast cancer

Advanced renal cell cancer

Pancreatic neuroendocrine tumour

Tuberous sclerosis complex

Subependymal giant cell astrocytoma

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).

Table 2: Previously reported cases of MRONJ associated with antiangiogenic medications .

Number
Authors
Age
Sex
Diagnosis of cancer
Treatment and concurrent medications
Antiangiogenic agents
Symptoms
Clinical presentation
Site of MRONJ
Time to MRONJ
Predisposing factors
Management of MRONJ
Outcomes
Definition of disease resolution

Estilo et al. [23]
51
F
Metastatic breast cancer
Mastectomy
Chest wall resection
Chest wall radiation
Doxorubicin
Cyclophosphamide
Letrozole
Paclitaxel
Capecitabine
Bevacizumab
15 mg/kg
every 3 weeks
(total 8 doses)
Jaw discomfort
Bone exposure
Mandible
18 weeks
after starting bevacizumab
None
Surgical treatment
(smoothen exposed bone)
Chlorhexidine mouthwash 0.12%
Interruption of bevacizumab
Disease resolution (few weeks)
Developed new MRONJ lesion (right mandible)
Complete mucosal coverage

Estilo et al. [23]
33
F
Glioblastoma multiforme
Surgical resection
Radiotherapy
Temozolomide
Bevacizumab
15 mg/kg
every 2 weeks
Jaw pain
(gingival pain)
Bone exposure
Mandible
11 weeks
after starting bevacizumab
None
None
Persistent bone exposure
(3 months)
—

Greuter et al. [24]
63
F
Metastatic breast cancer
Liposomal-doxorubicin
Bevacizumab
Maxillary pain
Bone exposure
Maxilla
2 months
after starting bevacizumab
Extraction due to dental infection
(1 month)
Surgical treatment
Disease resolution
Not specified

Serra et al. [25]
64
M
Metastatic non-small-cell lung cancer
Pneumectomy
Lymph node ablation
Cisplatin
Gemcitabine
Bevacizumab
7.5 mg/kg
Jaw pain
Bone exposure
Mandible
1 week
after starting bevacizumab
Extraction
(1 week)
Surgical treatment
(local flap coverage)
Amoxicillin with clavulanate
Chlorhexidine mouthwash 0.2%
Persistent bone exposure
(3.5 months)
—

Guarneri et al. [19]
NA
NA
Metastatic breast cancer
Docetaxel
Bevacizumab
7.5 mg/kg or
15 mg/kg every 3 weeks
NA
Bone exposure
Mandible
7 months
after starting bevacizumab
None
Surgical treatment
(mandible decortication, tooth extraction)
Interruption of bevacizumab
Disease resolution
(6 months)
Complete mucosal coverage

Guarneri et al. [19]
NA
NA
Metastatic breast cancer
Docetaxel
Bevacizumab
7.5 mg/kg or
15 mg/kg every 3 weeks
NA
Bone exposure
NA
2 months
after starting bevacizumab
None
NA
NA
—

Brunamonti
Binello et al. [26]
47
M
Adenocarcinoma of parotid gland
Surgical treatment
Epirubicin
Cisplatin
Bevacizumab
15 mg/kg
(total 8 doses in
6 months)
Jaw pain, paraesthesia
Bone exposure
Mandible
16 months
after starting bevacizumab
Symptomatic eruption of lower third molar
Surgical treatment
(removed necrotic bone)
Amoxicillin with clavulanate
Metronidazole
Persistent bone exposure
(7 months)
—

Bettini et al. [27]
57
F
Metastatic non-small-cell lung cancer
Gemcitabine
Cisplatin
Corticosteroid
Bevacizumab
945 mg/21 days
4 cycles
Jaw pain,
halitosis, tooth loss
Bone exposure
Mandible
2 months
after starting bevacizumab
Periodontal infection
Amoxicillin with clavulanate
Lincomycin (for 7 days)
Disease resolution
Complete mucosal coverage

Dişel et al. [28]
51
M
Metastatic colon cancer
5-Fluorouracil
Leucovorin
Oxaliplatin
Bevacizumab
5 mg/kg
every 2 weeks
Jaw pain, ulcer, difficulty in chewing
Bone exposure
Mandible
NA
None
Surgical treatment
(bone curettage)
NA
—

Sato et al.
[29]
67
M
Metastatic sigmoid colon cancer
Surgical treatment
Oxaliplatin
Leucovorin
Irinotecan
5-Fluorouracil
Bevacizumab
Jaw pain
Nonexposed MRONJ
Maxilla
3 months
after starting bevacizumab
Extraction
(1 month)
Surgical treatment
(removal of necrotic tissue)
Antibiotics
Disease resolution
Complete mucosal coverage

Fusco et al. [30]
60
M
Metastatic rectal cancer
Surgical treatment
Radiotherapy
5-Fluorouracil
Leucovorin
Irinotecan
Oxaliplatin
Bevacizumab
Jaw pain
Bone exposure
Mandible
9 months
after starting bevacizumab
Extraction
(8 months)
Antibiotics
Chlorhexidine mouthwash
NA
—

Tzermpos et al. [31]
69
M
Metastatic non-small-cell lung cancer
Carboplatin
Docetaxel
Cortisone
Bevacizumab
15 mg/kg
every 3 weeks
Jaw pain, discomfort, paraesthesia
Bone exposure
Mandible
3 years
after starting bevacizumab
Denture
Surgical treatment
(surgical debridement)
Amoxicillin
Metronidazole
Chlorhexidine mouthwash 0.12%
Interruption of bevacizumab
Disease resolution (8 weeks)
Complete mucosal coverage

Abel Mahedi
Mohamed
et al. [32]
55
F
Non-small-cell lung cancer
Corticosteroids
Bevacizumab
Asymptomatic
Bone exposure
Maxilla
1.5 months after starting bevacizumab
Extraction
Conservative treatment
Disease resolution
Not specified

Abel Mahedi
Mohamed
et al. [32]
66
M
Glioblastoma multiforme
Corticosteroids
Bevacizumab
Pain
Nonexposed MRONJ
Mandible
1.5 months after starting bevacizumab
Trauma
Conservative treatment
(antibiotic treatment)
Disease resolution
Not specified

Ponzetti et al. [33]
64
F
Metastatic colorectal cancer
5-Fluorouracil
Irinotecan
Aflibercept
Spontaneous teeth loss with purulent discharge
Bone exposure
Mandible
22 weeks
after starting
aflibercept
Periodontal infection
Laser treatment
Persistent bone exposure
—

Mawardi et al. [34]
43
M
Metastatic colorectal cancer
5-Fluorouracil
Leucovorin
Irinotecan
Aflibercept
Jaw pain
Bone exposure
Mandible
32 weeks after starting aflibercept
None
Amoxicillin
Chlorhexidine mouthwash
Persistent bone exposure
(1.5 months)
—

Mawardi et al. [34]
63
M
Metastatic carcinoid cancer
NA
Aflibercept
Asymptomatic
Bone exposure
Mandible
46 weeks after starting aflibercept
None
Amoxicillin with clavulanate
Chlorhexidine mouthwash
Persistent bone exposure (2.5 months)
—

Mawardi et al. [34]
51
M
Metastatic esophageal cancer
5-Fluorouracil
Leucovorin
Oxaliplatin
Aflibercept
Jaw pain
Bone exposure
Mandible
14 weeks after starting aflibercept
Extraction
(2 weeks)

Amoxicillin
Chlorhexidine mouthwash
Nonsurgical sequestrectomy
Persistent bone exposure (2 months)
-

Zarringhalam et al. [35]
47
M
Metastatic colorectal, peritoneum, liver, and pelvic cancer
None
Aflibercept
Asymptomatic
Bone exposure
Mandible
4 weeks after starting aflibercept
None
Surgical treatment
(smoothen sharp exposed bone)
Persistent bone exposure (12 weeks)
—

Nicolatou-Galitis
et al. [36]
64
F
Metastatic renal cell cancer
Nephrectomy
T4 replacement therapy
Prednisolone
(50 mg/day)
Sunitinib
50 mg/day for 4 weeks on and 2 weeks off (for 4 years)
Jaw pain
Bone exposure
Mandible
4 years
after starting sunitinib
Denture
Amoxicillin
Chlorhexidine mouthwash
Azithromycin
Interruption of sunitinib
Disease resolution (3 months)
Complete mucosal coverage

Fleissig et al. [37]
58
F
Metastatic renal cell cancer
Nephrectomy
Thyroxin sodium
Sunitinib 50 mg/day for 4 weeks on and
2 weeks off
Limited mouth opening, submandibular swelling, pain
Bone exposure
Mandible
10 months
after starting sunitinib
Extraction
(8 months)
Amoxicillin with clavulanate (IV)
PenG (IV) for 6 weeks and oral amoxicillin for 6 weeks
Interruption of sunitinib
Disease resolution (18 weeks)
Complete mucosal coverage

Melloni et al. [38]
62
M
Metastatic renal cell cancer
NA
Sunitinib 50 mg/day for 4 weeks on and
2 weeks off
Jaw pain and infected lesion to the cutaneous side of the jaw
Bone exposure
Mandible
5 years
after starting sunitinib
None
Surgical treatment
(surgical sequestrectomy, ablation of necrotic bone, and local flap coverage)
Amoxicillin with clavulanate
Ofloxacin
Interruption of sunitinib
Disease resolution (12 months)
Complete mucosal coverage

Tempia Valenta
et al. [39]
51
F
Medullary thyroid cancer
NA
Cabozantinib
NA
Bone exposure
Mandible
6 months
after starting cabozantinib
Extraction
Surgical treatment
(surgical debridement)
Amoxicillin and clavulanate
Chlorhexidine mouthwash 0.2%
Disease resolution (22 months)
Not specified

Marino et al. [40]
51
F
Medullary thyroid cancer
Thyroidectomy
5-Fluorouracil
Dacarbazine
Radiotherapy
Levothyroxine
Calcitriol
Vitamin D3
Duloxetine
Propranolol
Lansoprazole
Loperamide
Cabozantinib
(175 mg/day)
Asymptomatic
Bone exposure
Mandible
3 months
after starting cabozantinib
Extraction due to dental infection
(3 months)

Surgical treatment
(segmental ostectomy and tooth extraction)
Amoxicillin and clavulanate
Chlorhexidine mouthwash 0.2%
Disease resolution
Complete mucosal coverage

Garuti et al. [41]
74
M
Metastatic hepatocellular carcinoma
Furosemide
Potassium canrenoate
Bisoprolol
Allopurinol
Tamsulosin
Hydroxychloroquine
Vitamin D
Sertraline
Sorafenib
400 mg/day
Asymptomatic
Nonexposed MRONJ
Mandible
3 months after starting sorafenib
None
Interruption of sorafenib
Persistent bone exposure
(3 months)
—

Abel Mahedi
Mohamed
et al. [32]
53
F
Acute lymphoblastic leukemia

Corticosteroids
Dasatinib
Pain
Bone exposure
Mandible
5 months after starting dasatinib
Extraction
Surgical treatment (block resection)
Disease resolution
Not specified

Parti et al. [42]
60
M
Metastatic renal cell cancer
Nephrectomy
Prostatectomy
Temsirolimus
25 mg every week

NA
Bone exposure
Mandible
3 months
after starting
temsirolimus
Extraction
(3 months)
Interruption of temsirolimus
NA
—

Yamamoto
et al. [43]
80
F
Metastatic breast cancer
Capecitabine
Tamoxifen
Fulvestrant
Exemestane
Everolimus
Jaw pain, localised heat, tenderness
Bone exposure
Mandible
2 months after starting everolimus
None
Interruption of everolimus
Persistent bone exposure (2 months)
—

Agostino et al. [44]
73
M
Metastatic renal cell cancer
Nephrectomy
(1) Sunitinib
50 mg/day for 4 weeks of 6-week cycle
(2) Temsirolimus 25 mg every week
(3) Bevacizumab 10 mg/kg every two weeks
NA
NA
NA
12 months
after starting
bevacizumab
NA
Interruption of bevacizumab
NA
—

Koch et al. [45]
59
M
Metastatic renal cell cancer
Nephrectomy
Interferon
Vinblastine
Ramipril
Hydrochlorothiazide
Metoprolol
I-Thyroxin
(1) Sorafenib
(2) Sunitinib
50 mg/day for
4 weeks and then sunitinib
37.5 mg/day
Asymptomatic
Bone exposure
Mandible
51 months
after starting
sunitinib
Extraction
(2 months)
Surgical treatment
(ablation of necrosis and local flap coverage)
Disease resolution
Complete mucosal coverage

Santos-Silva et al. [46]
61
M
Metastatic renal cell cancer
Nephrectomy
Hydrochlorothiazide
Captopril
(1) Bevacizumab
10 mg/kg every 2 weeks
(2) Temsirolimus
25 mg every week
Jaw pain
Bone exposure
Mandible
55 weeks
after starting
bevacizumab and temsirolimus
None
Chlorhexidine mouthwash 0.12%
Interruption of bevacizumab and temsirolimus
Disease resolution (3 months)
The absence of exposed necrotic bone

Pakosch et al. [47]
53
F
Pancreatic cancer
Surgical treatment
Gemcitabine
Leucovorin
5-Fluorouracil
Oxaliplatin
Paclitaxel
Erlotinib
(1) Bevacizumab
(2) Sorafenib
Jaw pain
Bone exposure
Mandible
4 months
after starting bevacizumab and sorafenib
Denture
Surgical treatment
(decortication),
Amoxicillin with clavulanate
Chlorhexidine mouthwash
Solcoseryl
Interruption of bevacizumab and chemotherapy
Disease resolution (2 months)
Complete mucosal coverage

Jung [48]
62
F
Renal cell cancer
Nephrectomy
(1) Pazopanib
(2) Everolimus
Gingival bleeding and sore gum
Bone exposure
Mandible
7 weeks after starting everolimus
Dental implant
Cephalosporin
Surgical treatment
(sequestrectomy and internal fixation)
Disease resolution
Complete mucosal coverage

Patel et al. [49]
67
M
Metastatic renal cell cancer
Nivolumab
Amlodipine
Ramipril
Levetiracetam
Dexamethasone
Lansoprazole
Morphine
Metoclopramide
Amiodarone
Cholecalciferol
(1) Pazopanib
(2) Axitinib
Asymptomatic
Bone exposure
Maxilla
1 months after starting axitinib
None
Hydrogen peroxide mouthwash
NA
—

Abel Mahedi
Mohamed
et al. [32]
70
M
Renal cell cancer
Corticosteroids
(1) Sunitinib
(2) Everolimus
Asymptomatic
Bone exposure
Mandible
10 months after starting sunitinib, everolimus was commenced
Extraction
Conservative treatment
Persistent bone exposure
—

NA: not available.

Figure 1: Flow chart of the study selection process.

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.

Table 3: Summary of data of reported cases of antiangiogenic-related MRONJ ().

Age (years, range)

    Mean
59.06 (33–80)

Gender (, %)

    Male
19 (54.29%)

    Female
14 (40.00%)

    NA
2 (5.71%)

Diagnosis of cancers (, %)

    Metastatic renal cell cancer
10 (28.57%)

    Metastatic colorectal cancer
6 (17.14%)

    Metastatic breast cancer
5 (14.29%)

    Other cancers
14 (40.00%)

        Metastatic non-small-cell lung cancer
4

        Glioblastoma multiforme
2

        Medullary thyroid cancer
2

        Malignant parotid tumour
1

        Pancreatic cancer
1

        Metastatic hepatocellular carcinoma
1

        Metastatic carcinoid cancer
1

        Metastatic oesophageal cancer
1

Presenting complaints (, %)

    Jaw pain
12 (34.29%)

    Jaw pain with other complaints
6 (17.14%)

    Asymptomatic
8 (22.86%)

    Jaw discomfort
1 (2.86%)

    Spontaneous teeth loss
1 (2.86%)

    Limited mouth opening and submandibular area swelling
1 (2.86%)

    Gingival bleeding
1 (2.86%)

    NA
5 (14.29%)

Clinical presentation (, %)

    Bone exposure MRONJ
32 (91.43%)

    Nonexposed MRONJ
3 (8.57%)

Location

    Mandible
29 (82.86%)

    Maxilla
4 (11.43%)

    NA
2 (6.67%)

Types of antiangiogenic agents (, %)

    Bevacizumab
14 (40%)

    Aflibercept
5 (14.29%)

    Sunitinib
3 (8.57%)

    Cabozantinib
2 (5.71%)

    Sorafenib
1 (2.86%)

    Temsirolimus
1 (2.86%)

    Everolimus
1 (2.86%)

    Dasatinib
1 (2.86%)

    Multiple antiangiogenic agents
7 (20.00%)

Route of antiangiogenic administrations (, %)

    Intravenous administration
21 (60.00%)

    Oral administration
12 (34.29%)

    Combination of intravenous administration and oral administration
2 (5.71%)

Time to MRONJ (months, 95% CI)

    Intravenous antiangiogenics
6.49 (2.67–10.30)

    Oral antiangiogenics
16.72 (2.59–30.84)

Predisposing factors (, %)

    Extraction
13 (37.14%)

    Periodontal disease
3 (8.57%)

    Minor trauma from use of denture
4 (11.43%)

    Dental implant
1 (2.86%)

    Mean time to MRONJ after extraction (months, 95% CI)
3.09 (0.40–5.77)

Management of MRONJ (, %)

    Surgical treatment
17 (48.57%)

        Minimally invasive surgical procedures
11

        Major surgical procedures
6

    Nonsurgical treatment
16 (45.71%)

    No treatment
1 (2.86%)

    NA
1 (2.86%)

Treatment outcomes (, %)

    Disease resolution
18 (62.06%)

    Mean time to resolution (months, 95% CI)
6.75 (0.90–12.59)

    Incomplete resolution
11 (37.93%)

    NA
6

NA: not available.

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 () and dasatinib () [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.

Conflicts of Interest

The authors have no conflicts of interest to declare.

Acknowledgments

Professor Stefano Fedele received salary support from the NIHR UCLH Biomedical Research Centre.

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