Osteonecrosis of the jaw (ONJ) occurs in up to 18% of patients being treated with bisphosphonates due to bone metastases.1 Recent evidence suggests that bevacizumab, a new antiangiogenic drug, could alone induce ONJ and that the combination of both drugs can increase the risk for ONJ.2,3 We present herein a case of ONJ attributed to bevacizumab in a patient with advanced lung cancer, and we review the recent understanding on this subject.

A 57-year-old male was diagnosed with non-small-cell lung cancer. At the time of the diagnosis, the patient presented bone metastases in the right femur and iliac bone, and he received palliative radiotherapy combined with 4mg of intravenous zoledronic acid once a month. At the same time, combined chemotherapy was begun with cisplatin (75mg/m2) and paclitaxel (75mg/m2) every 3 weeks. After completing 3 cycles, treatment with bevacizumab was added at a dose of 15mg/kg every 3 weeks up to a total of 8 cycles. While the patient received this new treatment for 3 weeks, he reported low-grade fever with pain in the right jaw and painless swelling of the right eyelid. The patient used dentures and had mentioned no recent history of oral or dental surgery. Upon examination, we observed an area of uncovered bone at the back of the right jaw measuring 1.8cm×0.5cm, which had a necrotic appearance with inflammation of the surrounding soft tissue (Fig. 1). The samples obtained with a swab of the area of the necrotic bone were negative for bacteria. Maxillofacial CT ruled out metastatic disease. The administration of bevacizumab and bisphosphonates was suspended, and the patient was treated with ampicillin-sulbactam 3 times a day for 21 days, while using mouthwash with 0.2% chlorhexidine. We observed remission of the inflammation and facial edema and an improvement, although without complete coverage of the exposed alveolar bone. As no other obvious cause was identified, we continued to presume that the most likely origin of the lesion was related to the medication (bevacizumab).

Fig. 1.

Area of the uncovered bone at the back of the right jaw (black arrow).

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ONJ is a slowly developing process (over the course of 6 weeks) that is characterized by the exposure of the mandibular or maxillary bone in patients treated with bisphosphonates. Several risk factors have been identified, such as the administration of nitrogenous bisphosphonates, a prolonged treatment period, the concomitant use of corticosteroids, dental surgery and trauma caused by artificial dentures. However, its exact production mechanism is still not clear. Two main hypotheses have been suggested: osteoclast inhibition induced by the bisphosphonates and excessive suppression of bone metabolism and its antiangiogenic properties.1

Vascular endothelial growth factor is overexpressed in different human tumors and it is also essential for osteogenic differentiation and bone formation. Bevacizumab, a monoclonal antibody that targets VEGF, exerts an intense anti-tumor effect, but, in combination with bisphosphonates, it induces ONJ with greater frequency (16%).2,4 In addition, treatment with bevacizumab alone has been related with ONJ in few case presentations.3

Osteonecrosis may also be caused by local radiotherapy, chemotherapy with corticosteroid content, diabetes, renal osteodystrophy vasculitis or peripheral vascular disease.1 In the present case, bevacizumab seems to be the product responsible for the lesion, and this is supported by the time association observed between the start of the administration of this drug and the appearance of the ONJ (12 weeks after starting administration). A possible synergic effect of the bisphosphonates could not be ruled out. Nevertheless, in that case one would have expected the presence of more evident clinical manifestations of ONJ before initiating the administration of bevacizumab. Microtrauma caused by artificial dentures of the patient may have also played a role by affecting the local microvascular integrity.

To date, no treatment has been established as being the most effective. Medical ozone (O3) administered in an oily suspension may be a promising treatment, but the approach that is currently used is conservative.5 Proper oral hygiene, preventative measures and the avoidance of invasive dental interventions should be a part of standard patient care before initiating treatment with bevacizumab.