Introduction

The anti-angiogenic agent, bevacizumab, is an established component of cancer therapy. Since 2003, reports of bisphosphonate-related osteonecrosis have been increasing [1, 2], following infections, oral surgical interventions, long-term intake of corticosteroids or chemotherapy being reported to increase the risk of osteonecrosis. Studies have shown that anti-angiogenic agents can increase the risk for osteonecrosis, particularly when combined with bisphosphonates. Anti-angiogenic agents are being prescribed with increasing frequency to inhibit vascular endothelial growth factor (VEGF) [3–6] and may increase the risk of osteonecrosis of the jaw.

Case report

A 53-year-old female patient was referred to our department with a painful area of bone exposure in the left posterior lingual mandible with an area of 15 × 3 mm mainly located on the alveolar crest. The bone appeared necrotic with fistulae to the vestibular and lingual regions, and the surrounding tissue revealed signs of inflammation (Fig. 1).

Fig. 1
figure 1

Bone exposure in the left posterior lingual mandible

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The history from the patient revealed pancreatic carcinoma, which had been diagnosed 16 months before the referral. Palliative surgery was performed, and the patient was subsequently treated with gemcitabine (Gemzar®, Lilly Deutschland) and erlotinib (Tarceva®, Roche) from March 2009 until August 2009 and with folinic acid, 5-fluorouracil and oxaliplatin) from September 2009 until January 2010. A combination of paclitaxel (Taxol®, Bristol-Myers Squibb GmbH), bevacizumab (Avastin®, Roche) and sorafenib (Nexavar®, Bayer AG) was administered from February 2010 until May 2010.

At this time, the patient developed a swelling in the left mandible, and her dentist drained an abscess in region 036 and prescribed an oral antibiotic. Due to the persistence of the swelling, chemotherapy was discontinued, and the patient was referred to our clinic. Up to this time, she had worn a total prosthesis in the lower jaw and an overdenture prosthesis in the upper jaw.

Cone beam computer tomography revealed osteolysis of the left mandible with two punctiform areas of radiodensity, composed of foreign bodies, appearing in the left posterior mandible. Emphysema was observed in the surrounding soft tissue, and the cancellous bone was fragmented. Furthermore, a unilateral opacity of the maxillary sinus was observed on the right side (Fig. 2).

Fig. 2
figure 2

Cone beam computer tomography revealed osteolysis of the left mandible

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Decortication was performed in the area of osteonecrosis, wherein the bone was soft; the surrounding soft tissue was carefully closed, and a biopsy of the bone was taken intraoperatively. Pathological analysis verified the clinical diagnosis of osteonecrosis of the posterior lingual mandible, showing chronic osteomyelitis with fibrosis of the bone marrow and areas of devitalised necrotic bone. An infiltration of cancer was excluded (Fig. 3 a, b). The patient was administered with amoxicillin and clavulanic acid (Augmentin®, HEXAL AG) 2.2 gr, 1:1:1 intravenously and chlorhexidine 0.12 % (Hexoral®, Pfizer CHC GmbH) as an oral rinse. A nasogastric tube was inserted to avoid postoperative, mechanical disturbance of the wound (Fig. 4). A wound healing deficit was observed after the operation with dehiscence and exposed bone in the place of the original lesion, which measured approximately 10 mm in diameter. Due to a slow response, chemotherapy was stopped after consulting the oncologist, and the wound healing was treated conservatively. After 2 months of conservative treatment with daily lavage, local debridement and administration of a cream (Solcoseryl®, Meda Pharma Gmbh & Co. KG), tissue repair was evident, and no exposed bone was visible (Fig. 5).

Fig. 3
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a, b Pathological analysis presenting fibrosis of the bone marrow and areas of devitalised necrotic bone

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Fig. 4
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Postoperative orthopantomogram of the patient with nasogastric tube

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Fig. 5
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Two months after treatment, tissue repair was evident, and no exposed bone was visible

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Discussion

Osteonecrosis is defined as a non-healing wound of the bone, which arises because of dental extractions or oral surgical interventions, either spontaneously or due to poor oral hygiene [3], and is often associated with bisphosphonate therapy [1, 4, 7]. Bisphosphonate-induced osteonecrosis is a non-inflammatory drug side effect [8], wherein the mandible is affected more frequently than the upper jaw [9]. This effect could be attributed to the relatively poor vascularisation of the mandible compared to the maxilla.

The incidence of osteonecrosis in tumour patients is 11 % or lower, and this complication is often associated with the intake of bisphosphonates [4]. Bisphosphonates block angiogenesis by modulating cell proliferation and lower VEGF levels [7]. Infections, oral surgical interventions, long-term intake of corticosteroids or chemotherapy are risk factors for osteonecrosis. Often osteonecrosis originates after local infections which can be caused by tooth extractions, dental medical treatments or pressure sores from prostheses [10].

Above all, the intake of bisphosphonates is often associated with osteonecrosis of the jaw. Studies show that anti-angiogenic agents can raise the risk for osteonecrosis, particularly when combined with bisphosphonates [1, 11]. Additionally, increased risk is also observed with therapy with sunitinib, a tyrosine kinase inhibitor possessing an anti-angiogenic effect, which is administered for osteomyelitis of the lower jaw [5].

In the current report, we describe a case of osteonecrosis in a cancer patient treated with bevacizumab without any prior bisphosphonate exposure. Osteonecrosis of the lower jaw [4, 6] due to bevacizumab therapy has been described in the literature, with the first case being described by Estilo in 2008 [12].

Bevacizumab is a humanised monoclonal IgG1 antibody, which works as an angiogenesis inhibitor of all endothelial growth factors and is prescribed for the treatment of advanced cancer. The above-mentioned wound healing defects, haemorrhage, thromboembolic complications, arterial hypertension and proteinuria constitute some of the side effects of bevacizumab [3, 6, 13].

In the case presented above, osteonecrosis was caused by interference in angiogenesis [3, 4]. Our patient underwent an incision and surgical drainage in the area of the necrotic bone. Furthermore, the patient developed a mouth ulcer as a side effect after treatment with gemcitabine, erlotinib, 5-fluorouracil, oxaliplatin and paclitaxel. The vulnerable mucosa represents another risk factor for bone exposure [1]. Studies have shown that the intake of bisphosphonates and such anti-angiogenic agents as bevacizumab is associated with increased incidence of osteonecrosis [1, 11].

Bevacizumab may increase the risk for osteonecrosis of the jaw while it modulates angiogenesis and inhibits the vascular endothelial growth factor [3, 4], which plays an important role in the differentiation and formation of bone [8]. Clinicians involved in the care of patients receiving anti-angiogenic agents should be aware that inhibition of VEGF might compromise the vascularisation of the jaw and lead to healing complications, especially after trauma, as in the case of tooth extraction. With increasing numbers of anti-angiogenic therapeutic agents entering clinical practice, further studies are needed to investigate any possible correlation between bevacizumab and osteonecrosis.