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Bisphosponate-related osteonecrosis of the jaw (ONJ) has been reported in the literature since 2003,1,2 with more than 90% of the events attributed to treatment with bisphosphonate agents, such as zoledronic acid (Zometa) and pamidronate, which are used to treat hypercalcemia of malignancy and to reduce the risk of skeletal-related events due to bone metastases.3– 5 Patients with ONJ generally present with exposed necrotic bone that does not heal for 6–8 weeks, often leading to significant morbidity. The pathogenic mechanism for osteonecrosis is unclear, but, in addition to inhibiting bone resorption, preclinical data have demonstrated thrombotic microangiopathy and potent inhibition of angiogenesis,6 which may lead to avascular necrosis and poor wound healing after dental procedures.

Angiogenesis is a critical step in tumor growth, and agents that block neovascularization by targeting vascular endothelial growth factor (VEGF) or its receptor (VEGFR) have been used successfully for a variety of solid tumors. Bevacizumab (Avastin) is a monoclonal antibody that inhibits angiogenesis by binding to VEGF,7 and sorafenib (Nexavar) is a multiple-kinase inhibitor that inhibits several intracellular and cell-surface kinases, including VEGFR.8 Osteonecrosis of the jaw or femoral heads has been increasingly recognized in patients treated with antiangiogenic therapies, even without concurrent bisphosphonate use.9–12 Previous data on combining bisphosphonates with antiangiogenic agents are conflicting, with some reports indicating a similar risk of ONJ compared with the use of bisphosphonates alone13,14 and others showing significantly higher rates (18% vs 1% with bisphosphonates alone).15.16

In this paper, we describe the case of a patient with metastatic prostate cancer and a history of ONJ from use of zoledronic acid who developed a mandibular fracture while he was off zoledronic acid for 15 months but undergoing treatment with paclitaxel and bevacizumab plus sorafenib on a clinical trial. The case may help explain the temporal relationship between therapy and the occurrence of jaw fracture, as well as the link between ONJ and the risk of fractures with sequential use of bisphosphonates and antiangiogenic agents. ...

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