Risk profile for antiangiogenic agent-related osteonecrosis of the jaws

Caminha, Raquel D’Aquino Garcia; Chicrala, Gabriela Moura; Soares Júnior, Luiz Alberto Valente; Santos, Paulo Sérgio da Silva

doi:10.31744/einstein_journal/2019RW4628

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Review • EINSEinstein (São Paulo) 17 (3) • 2019 • https://doi.org/10.31744/einstein_journal/2019RW4628 copy

Risk profile for antiangiogenic agent-related osteonecrosis of the jaws

Authorship SCIMAGO INSTITUTIONS RANKINGS

ABSTRACT

To establish the profile of patients who developed antiangiogenic agent-related osteonecrosis of the jaws, and identify the treatments currently used in dental management. We searched the PubMed^®/Medline^® and Scopus databases using the words “osteonecrosis AND antiangiogenic therapy”, with the following inclusion criteria: articles published in English, case reports, available online, and for an unlimited period. Of the 209 articles retrieved, 18 were selected, for a total of 19 case reports, since one article included two cases that met the inclusion criteria for this study. Medication-related osteonecrosis of the jaws is characterized by exposure of necrotic bone in the oral cavity that does not heal over a period of 8 weeks in patients with no previous history of radiation therapy. Antiangiogenic drugs are indicated in the treatment of certain tumors, since they stop the formation of new blood vessels, controlling tumor growth and the chance of metastasis. Dental prevention is essential in patients who will be put on antiangiogenic agents, to minimize the risk for osteonecrosis.

Keywords:
Osteonecrosis; Dental care; Metastatic neoplasm; Angiogenesis inhibitors; Antineoplastic agents

Article (country)	Sex, age	Location	Signs and symptoms	Imaging findings	Histological features	Drug/dose
Estilo et al.⁽¹1. Estilo CL, Fornier M, Farooki A, Carlson D, Bohle G 3rd, Huryn JM. Osteonecrosis of the jaw related to bevacizumab. J Clin Oncol. 2008;26(24):4037-8.⁾ (United States) Case 1	Female, 51	Left mandible (lingual)	EB (1x1mm), normal ST, no evidence of infection, discomfort	NR	Devitalized bone, bacteria (Actinomyces) and inflammatory cells	Bevacizumab (inhibitor -VEGF), 15mg/kg, 3 weeks, total of 8 doses
Dişel et al.⁽²2. Dişel U, Beşen AA, Özyılkan Ö, Er E, Canpolat T. A case report of bevacizumab-related osteonecrosis of the jaw: old problem, new culprit. Oral Oncol. 2012; 48(2):e2-3.⁾ (Turkey)	Male, 51	Right mandible	EB (3×3mm), ulcerated and necrotic ST, no evidence of infection, fistula and abscess, pain, difficulty masticating	PR and CT: sclerotic bone lesion	Osteonecrosis, bacteria (Actinomyces)	Bevacizumab (inhibitor -VEGF) 5mg/kg, 6 cycles/2 weeks
Brunamoti Binello et al.⁽³3. Brunamonti Binello P, Bandelloni R, Labanca M, Buffoli B, Rezzani R, Rodella LF. Osteonecrosis of the jaws and bevacizumab therapy: a case report. Int J Immunopathol Pharmacol. 2012;25(3):789-91.⁾ (Italy)	Male, 47	Left mandible (lingual)	EB, edema with moderate mucosal exudate, trismus, pain, left-sided lower lip paresthesia	PR: no significant findings; CT: bone loss; BS: increased uptake	NR	Bevacizumab (inhibitor -VEGF),15mg/kg/ 6 months/8 doses
Erovigni et al.⁽⁴4. Erovigni F, Gambino A, Cabras M, Fasciolo A, Bianchi SD, Bellini E, et al. Delayed Diagnosis of Osteonecrosis of the Jaw (ONJ) Associated with Bevacizumab Therapy in Colorectal Cancer Patients: Report of Two Cases. Dent J (Basel). 2016;4(4):E39.⁾ (Italy) Case 1	Male, 79	Left mandible (mylohyoid line)	EB (3×1m), ulcerated and necrotic ST, fistula, asymptomatic	CBCT: sclerotic lesion in the cortical bone, and alveolar residue with no sequestration images	NR	Bevacizumab (inhibitor-VEGF), dose NR
Erovigni et al.⁽⁴4. Erovigni F, Gambino A, Cabras M, Fasciolo A, Bianchi SD, Bellini E, et al. Delayed Diagnosis of Osteonecrosis of the Jaw (ONJ) Associated with Bevacizumab Therapy in Colorectal Cancer Patients: Report of Two Cases. Dent J (Basel). 2016;4(4):E39.⁾ (Italy) Case 2	Male, 60	Left mandible (lingual)	EB (1cm), pain and gingival lesion	PR: no signs of osteolysis, only the alveolar profile; CT: 7mmx4mm cortical bone lesion	NR	Bevacizumab (inhibitor -VEGF), 5mg/kg/day/14 days (8 cycles/4 months)
Ponzetti et al.⁽⁵5. Ponzetti A, Pinta F, Spadi R, Mecca C, Fanchini L, Zanini M, et al. Jaw osteonecrosis associated with aflibercept, irinotecan and fluorouracil: attention to oral district. Tumori. 2016;102(Suppl 2):S74-7. Review.⁾ (Italy)	Female, 64	Right mandible	Non-traumatic avulsion of two teeth with purulent secretion, symptoms NR	PR and CT: multiple foci of osteonecrosis of the jaws	NR	Aflibercept (inhibitor -VEGF), dose NR
Jung⁽⁶6. Jung TY. Osteonecrosis of jaw after antiangiogenic agent administration in a renal cell carcinoma patient. Oral and Maxillofacial Surgery Cases. 2017; 3(2):27-33.⁾ (Korea)	Female, 62	Right and left mandible	EB around implants on the right and left sides, with pus drainage, gingival bleeding and edema, pain	PR and CT: fracture lines/bone sequestration in both regions; BS: bilateral uptake compatible with osteomyelitis	Acute osteomyelitis	Pazopanib (TKi), 6 months
Pakosch et al.⁽⁸8. Pakosch D, Papadimas D, Munding J, Kawa D, Kriwalsky MS. Osteonecrosis of the mandible due to anti-angiogenic agent, bevacizumab. Oral Maxillofac Surg. 2013;17(4):303-6.⁾ (Germany)	Female, 53	Left mandible (lingual)	EB (15×3 mm), fistula due to B and L, inflamed and ulcerated ST, abscess, pain and edema	PR and CBCT: osteolysis with two punctiform radiodense areas, due to foreign bodies, ST emphysema, fragmented cancellous bone, opacity of the right maxillary sinus	Chronic osteomyelitis with bone marrow fibrosis and necrotic bone	Bevacizumab (inhibitor -VEGF) and sorafenib (MKi), dose NR
Greuter et al.⁽⁹9. Greuter S, Schmid F, Ruhstaller T, Thuerlimann B. Bevacizumab-associated osteonecrosis of the jaw. Ann Oncol. 2008;19(12):2091-2.⁾ (Switzerland)	Female, 63	Left maxilla	Fistula, pain, trigeminal neuralgia	PR and CT: sinusitis and osteonecrosis	Osteonecrosis	Bevacizumab (inhibitor -VEGF), dose NR
Serra et al.⁽¹⁰10. Serra E, Paolantonio M, Spoto G, Mastrangelo F, Tete S, Dolci M. Bevacizumab-related osteneocrosis of the jaw. Int J Immunopathol Pharmacol. 2009; 22(4):1121-3.⁾ (Italy)	Male, 64	Left mandible	EB in the alveolar region, pain	PR and CT: area of bone necrosis	Necrotic bone, bacteria and inflammatory cells	Bevacizumab (inhibitor -VEGF), 7.5mg/kg, 8g
Koch et al.⁽¹¹11. Koch FP, Walter C, Hansen T, Jager E, Wagner W. Osteonecrosis of the jaw related to sunitinib. Oral Maxillofac Surg. 2011;15(1):63-6.⁾ (Sweden)	Male, 59	Left mandible	EB (10mm), normal ST, pain	DVT: area of hypodense bone with no sequestration	Necrotic bone, bacteria (Actinomyces)	Sorafenib (TKi), sunitinib (TKi) 50mg/day
Bettini et al.⁽¹²12. Bettini G, Blandamura S, Saia G, Bedogni A. Bevacizumab-related osteonecrosis of the mandible is a self-limiting disease process. BMJ Case Rep. 2012;2012. pii:bcr2012007284.⁾ (Italy)	Female, 57	Left mandible	EB (6x3cm) reaching basal bone; severe periodontal disease, periodontal abscess in the right posterior region, pain and halitosis	BS: focal and persistent uptake suggestive of bone infection. CT: bone sequestration	Osteonecrosis, inflammatory infiltrate and few blood vessels	Bevacizumab (inhibitor -VEGF), 945mg IV/21 days
Nicolatou-Galitis et al.⁽¹³13. Nicolatou-Galitis O, Migkou M, Psyrri A, Bamias A, Pectasides D, Economopoulos T, et al. 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. 2012; 113(2):234-8.⁾ (Greece) Case 2	Female, 64	Left mandible (lingual)	EB, inflamed ST, superior central incisors present with periodontal disease, pain	PR: no obvious radiological changes or bone disease	NR	Sunitinib (TKi), 50mg/day
Hopp et al.⁽¹⁴14. Hopp RN, Pucci J, Santos-Silva AR, Jorge J. Osteonecrosis after administration of intravitreous bevacizumab. J Oral Maxillofac Surg. 2012;70(3):632-5.⁾ (Brazil)	Male, 58	Left mandible (lingual)	EB (5x5mm), normal ST, regional teeth with no pulp/periodontal abnormalities, pain	EX: absence of periapical/periodontal problems	Necrotic bone and bacteria	Bevacizumab (inhibitor -VEGF), 2.5mg (intravitreal)
Fleissig et al.⁽¹⁵15. Fleissig Y, Regev E, Lehman H. Sunitinib related osteonecrosis of jaw: a case report. Oral Surg Oral Med Oral Pathol Oral Radiol. 2012;113(3):e1-3.⁾ (Israel)	Male, 58	Right mandible	EB (small area), inflamed ST, limited pus drainage, enlarged submandibular lymph nodes; pain and limited mouth opening	PR: incomplete bone remodeling in the alveolar region; CT: irregular alveolar cortical margin at 38	Necrotic bone and bacteria	Sunitinib (TKi), 50mg, once a day/4 consecutive weeks followed by 2 weeks off drugs
Magremanne et al.⁽¹⁶16. Magremanne M, Lahon M, De Ceulaer J, Reychler H. Unusual bevacizumab-related complication of an oral infection. J Oral Maxillofac Surg. 2013;71(1): 53-5⁾ (Belgium)	Male, 49	Left mandible	EB from the angle to the midline of the mandible, submandibular edema reaching the clavicle, partial necrosis of the mental nerve and facial artery, pain	PR: absence of periapical/periodontal lesions; CT: infiltration; ST, no evidence of necrosis	Necrotic tissues, inflammatory infiltrate, hemorrhagic necrosis and local thrombosis	Bevacizumab inhibitor -VEGF), 10mg/kg, single dose
Santos-Silva et al.⁽¹⁷17. Santos-Silva AR, Belizário GA, Castro Júnior GD, Dias RB, Prado Ribeiro AC, Brandão TB. Osteonecrosis of the mandible associated with bevacizumab therapy. Oral Surg Oral Med Oral Pathol Oral Radiol. 2013;115(6):e32-6.⁾ (Brazil)	Male, 61	Left mandible (lingual)	EB (1x1cm), normal ST, pain	PR: area of destroyed bone with discontinuity of the external oblique line; CT: lesion-associated loss of integrity and erosion of the underlying cortical bone	NR	Bevacizumab(inhibitor -VEGF) IV (10mg/kg every other week)
Marino et al.⁽¹⁸18. Marino R, Orlandi F, Arecco F, Gandolfo S, Pentenero M. Osteonecrosis of the jaw in a patient receiving cabozantinib. Aust Dent J. 2015;60(4):528-31.⁾ (Italy)	Female, 51	Left mandible	Inflammation, infection with pus drainage, asymptomatic	PR: incomplete bone remodeling; CT: cortical irregularity and sclerotic reaction	Atypical bone necrosis	Cabozantinib (TKi), 175mg/day
Garuti et al.⁽¹⁹19. Garuti F, Camelli V, Spinardi L, Bucci L, Trevisani F. Osteonecrosis of the jaw during sorafenib therapy for hepatocellular carcinoma. Tumori. 2016; 102(Suppl 2):S69-70.⁾ (Italy)	Male, 74	Right mandible (body region)	EB with no infection/sequestration, gingival lesion	CBCT: lytic area in the contralateral mandibular body (right side), at the site of prior tooth extraction (October 2014)	NR	Sorafenib (TKi), 400mg/day

Article (country)	Time to lesion onset	Underlying disease	Triggering factor	Treatment	Associated treatments	Comorbidities	Outcome
Estilo et al.⁽¹1. Estilo CL, Fornier M, Farooki A, Carlson D, Bohle G 3rd, Huryn JM. Osteonecrosis of the jaw related to bevacizumab. J Clin Oncol. 2008;26(24):4037-8.⁾ (United States) Case 1	1 week	Breast cancer, ST metastasis	Spontaneous	EB smoothing, 0.12% CLXMW, discontinuation of bevacizumab and capecitabine	Doxorubicin, cyclophosphamide, letrozole, paclitaxel, chest X-ray and capecitabine	NR	A few weeks later: CH
Disel et al.⁽²2. Dişel U, Beşen AA, Özyılkan Ö, Er E, Canpolat T. A case report of bevacizumab-related osteonecrosis of the jaw: old problem, new culprit. Oral Oncol. 2012; 48(2):e2-3.⁾ (Turkey)	2 weeks	Sigmoid colon cancer, metastasis	Spontaneous	Curettage and dressing	Fluorouracil, leucovorin and oxaliplatin	NR	NR
Brunamonti Binello et al.⁽³3. Brunamonti Binello P, Bandelloni R, Labanca M, Buffoli B, Rezzani R, Rodella LF. Osteonecrosis of the jaws and bevacizumab therapy: a case report. Int J Immunopathol Pharmacol. 2012;25(3):789-91.⁾ (Italy)	10 months	Cancer of the parotid gland, bone metastasis	Eruption	EB removal, antibiotic therapy (amoxicillin + clavulanate)	Epirubicin, cisplatin	NR	Death
Erovigni et al.⁽⁴4. Erovigni F, Gambino A, Cabras M, Fasciolo A, Bianchi SD, Bellini E, et al. Delayed Diagnosis of Osteonecrosis of the Jaw (ONJ) Associated with Bevacizumab Therapy in Colorectal Cancer Patients: Report of Two Cases. Dent J (Basel). 2016;4(4):E39.⁾ (Italy) Case 1	3 years	Colon cancer, lung metastasis	Tooth extraction	LPLT, antibiotic therapy (amoxicillin + clavulanate and meropenem) and 0.2% CLXMW	Capecitabine, oxaliplatin, leucovorin, oxaliplatin, RT in the lung region, mitomycin and bisphosphonates (after BRONJ)	HTN and prostatic hyperplasia	6 months later: CH
Erovigni et al.⁽⁴4. Erovigni F, Gambino A, Cabras M, Fasciolo A, Bianchi SD, Bellini E, et al. Delayed Diagnosis of Osteonecrosis of the Jaw (ONJ) Associated with Bevacizumab Therapy in Colorectal Cancer Patients: Report of Two Cases. Dent J (Basel). 2016;4(4):E39.⁾ (Italy) Case 2	8 months	Renal cancer, lung and brain metastases	Tooth extraction	Antibiotic therapy (amoxicillin + clavulanate and meropenem) and 0.12% CLXMW	Leucovorin, oxaliplatin and pelvic RT	NR	Death
Ponzetti et al.⁽⁵5. Ponzetti A, Pinta F, Spadi R, Mecca C, Fanchini L, Zanini M, et al. Jaw osteonecrosis associated with aflibercept, irinotecan and fluorouracil: attention to oral district. Tumori. 2016;102(Suppl 2):S74-7. Review.⁾ (Italy)	After cycle 11	Colon cancer, liver metastasis	Atraumatic avulsion of 2 teeth	LPLT and discontinuation of chemotherapy	Cetuximab, capecitabine, oxaliplatin, raltitrexed and leucovorin	HTN and chronic periodontitis	Death
Jung⁽⁶6. Jung TY. Osteonecrosis of jaw after antiangiogenic agent administration in a renal cell carcinoma patient. Oral and Maxillofacial Surgery Cases. 2017; 3(2):27-33.⁾ (Korea)	7 weeks	Kidney cancer	NR	Removal of implants and bone sequestration, placement of a fixation plate, antibiotic therapy (3^rd generation cefalexin), discontinuation of everolimus (treatment with pazopanib had already finished)	Everolimus	NR	Interrupted follow-up
Pakosch et al.⁽⁸8. Pakosch D, Papadimas D, Munding J, Kawa D, Kriwalsky MS. Osteonecrosis of the mandible due to anti-angiogenic agent, bevacizumab. Oral Maxillofac Surg. 2013;17(4):303-6.⁾ (Germany)	During the 3-month treatment	Pancreatic cancer	Abscess	Removal of EB, abscess drainage, antibiotic therapy (amoxicillin + clavulanate), chemotherapy discontinuation, 0.12% CLXMW. NGT to prevent trauma	Gemcitabine, erlotinib, folinic acid, 5-FU, oxaliplatin and paclitaxel	NR	2 months later: CH
Greuter et al.⁽⁹9. Greuter S, Schmid F, Ruhstaller T, Thuerlimann B. Bevacizumab-associated osteonecrosis of the jaw. Ann Oncol. 2008;19(12):2091-2.⁾ (Switzerland)	1 month	Breast cancer	Tooth extraction	Removal of EB, maxillary sinus drainage	Liposomal doxorubicin	NR	3 weeks later: CH
Serra et al.⁽¹⁰10. Serra E, Paolantonio M, Spoto G, Mastrangelo F, Tete S, Dolci M. Bevacizumab-related osteneocrosis of the jaw. Int J Immunopathol Pharmacol. 2009; 22(4):1121-3.⁾ (Italy)	1 week	Lung cancer, bone metastasis	Tooth extraction	Removal of EB, antibiotic therapy (amoxicillin + clavulanate), 0.2% CLXMW	Cisplatin and gemcitabine	NR	2 weeks later: initiated treatment with zoledronic acid. PH
Koch et al.⁽¹¹11. Koch FP, Walter C, Hansen T, Jager E, Wagner W. Osteonecrosis of the jaw related to sunitinib. Oral Maxillofac Surg. 2011;15(1):63-6.⁾ (Sweden)	1.5 year	Kidney cancer, ST metastasis	Tooth extraction	Removal of EB	Interferon, viblastin, ramipril, HCT, metoprolol and hyroxin	HTN and hyperthyroidism	Healing
Bettini et al.⁽¹²12. Bettini G, Blandamura S, Saia G, Bedogni A. Bevacizumab-related osteonecrosis of the mandible is a self-limiting disease process. BMJ Case Rep. 2012;2012. pii:bcr2012007284.⁾ Italy	1 month	Lung cancer, lymph node metastasis	Atraumatic avulsion of 2 teeth	Removal of implants, antibiotic therapy (amoxicillin + clavulanate, lincomycin)	Gemcitabine, cisplatin and corticosteroids	No comorbidities	2 weeks later: healing
Nicolatou-Galitis et al.⁽¹³13. Nicolatou-Galitis O, Migkou M, Psyrri A, Bamias A, Pectasides D, Economopoulos T, et al. 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. 2012; 113(2):234-8.⁾ (Greece) Case 2	4 years	Kidney cancer, lung metastasis	Potential trauma of the inferior dental implant	Antibiotic therapy: amoxicillin, CLXMW, discontinuation of sunitinib	Prednisolone	Hypothyroidism and cutaneous vasculitis	3 months later: CH
Hopp et al.⁽¹⁴14. Hopp RN, Pucci J, Santos-Silva AR, Jorge J. Osteonecrosis after administration of intravitreous bevacizumab. J Oral Maxillofac Surg. 2012;70(3):632-5.⁾ (Brazil)	2 years	Retinal vein thrombosis	Spontaneous	Bone curettage, antibiotic therapy (clindamycin), 0.12% CLXMW	NR	HTN, gout and retinal vein thrombosis	3 weeks later: CH
Fleissig et al.⁽¹⁵15. Fleissig Y, Regev E, Lehman H. Sunitinib related osteonecrosis of jaw: a case report. Oral Surg Oral Med Oral Pathol Oral Radiol. 2012;113(3):e1-3.⁾ (Israel)	6 months	Kidney cancer	Tooth extraction	Antibiotic therapy: (amoxicillin + clavulanate) temporary discontinuation of sunitinib	NR	Hypothyroidism and osteoporosis	6 weeks later: PH
Magremanne et al.⁽¹⁶16. Magremanne M, Lahon M, De Ceulaer J, Reychler H. Unusual bevacizumab-related complication of an oral infection. J Oral Maxillofac Surg. 2013;71(1): 53-5⁾ (Belgium)	2 weeks	Glioblastoma	Tooth extraction	Antibiotic therapy (clindamycin, meropenem), CLXMW, ST debridement, facial artery ligation; dressing: gauze with povidone. Use of NET for feeding	Temozolomide, RT and corticosteroids	NR	4 weeks later: CH
Santos-Silva et al.⁽¹⁷17. Santos-Silva AR, Belizário GA, Castro Júnior GD, Dias RB, Prado Ribeiro AC, Brandão TB. Osteonecrosis of the mandible associated with bevacizumab therapy. Oral Surg Oral Med Oral Pathol Oral Radiol. 2013;115(6):e32-6.⁾ (Brazil)	55 weeks	Kidney cancer, lymph node metastasis	Spontaneous	Temporary discontinuation of bevacizumab and tensirolimus, 0.12% CLXMW	Tensirolimus IV (25 mg/week)	HTN	3 months later: CH
Marino et al.⁽¹⁸18. Marino R, Orlandi F, Arecco F, Gandolfo S, Pentenero M. Osteonecrosis of the jaw in a patient receiving cabozantinib. Aust Dent J. 2015;60(4):528-31.⁾ (Italy)	3 months	Thyroid cancer, liver metastasis	Tooth extraction	Segmental ostectomy, debridement, antibiotic therapy, 0.2% CLXMW.	5-FU, dacarbazine, RT, levothyroxine, calcitriol, vitamin D3, duloxetine propranolol, lansoprazol and loperamide	NR	4-year control: CH
Garuti et al.⁽¹⁹19. Garuti F, Camelli V, Spinardi L, Bucci L, Trevisani F. Osteonecrosis of the jaw during sorafenib therapy for hepatocellular carcinoma. Tumori. 2016; 102(Suppl 2):S69-70.⁾ (Italy)	1 month	Liver cancer, recurrence	Tooth extraction	Discontinuation of sorafenib	Furosemide, potassium canrenoate, bisoprolol, allopurinol, tamsulosin, hydroxychloroquine, vitamin D and sertraline	Hepatitis C and aortic artery stenosis	Death

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[1] Corresponding author: Paulo Sérgio da Silva Santos, Rua Dr. Octavio Pinheiro Brisolla, 9-75 – Vila Universitária, Zip code: 17012-901 - Bauru, SP, Brazil. Phone: (55 14) 3235-8000 E-mail: paulosss@fob.usp.br