Osteonecrosis of the jaw and bevacizumab therapy

Osteonecrosis of the jaw (ONJ) initially came to attention through case reporting. It appears to occur in 1–18% of patients with metastatic bone disease treated with bisphosphonate therapy [1, 2] and is seen less frequently in patients treated with bisphosphonates for osteoporosis or Paget's Disease of Bone [3]. ONJ is seen uncommonly in patients with early stage breast cancer treated with bisphosphonates as was demonstrated in the recent metaanalysis of breast cancer adjuvant bisphosphonate studies where the incidence of ONJ was 0.24% [4]. ONJ may be uncommon, but it is clinically significant to the patient, medical, and dental communities [5]. Risk factors for developing ONJ appear to be bisphosphonate exposure, cancer and its therapies (possibly including antiangiogenesis therapies), bone invasive dental procedures, lifestyle, and behaviors [6, 7]. There are many potential mechanisms of ONJ (Table 1). The etiology of ONJ is presently unknown.

Table 1.

Potential mechanisms of ONJ [19]

Inhibition of bone remodeling	Compromised bone microenvironment functioning affecting bone remodeling and repair
Vascular	Antiangiogenic affects delaying wound healing and/or affecting micro-infarction in bone and/or soft tissues
Infection and inflammation	Microorganisms of the oral cavity promoting cell death in the bone and/or oral soft tissues
Genetic predisposition	Genetic polymorphisms affecting drug metabolism, excretion, or drug targets within pathways of bone metabolism and/or wound healing
Drug interactions	Drug interactions between chemotherapy and bisphosphonate selectively promoting cell death

Osteonecrosis of the jaw appears to occur most frequently in patients cancer treated with high potency nitrogen-containing bisphosphonates [6], and many of the leading hypotheses for the mechanism behind ONJ relate to potential affects of the bisphosphonates. The main effect of bisphosphonate therapy is osteoclast inhibition, and over suppression of bone metabolism has been proposed as a mechanism involved in the development of ONJ [6]. There are evolving data demonstrating that the bisphosphonates may have additional affects including altering cell migration, invasion, adhesion, apoptosis, and synergizing with antitumor cytotoxic drugs, as well as decreasing angiogenesis [8]. The antiangiogenic effects of bisphosphonates are of particular interest in regard to ONJ due to the importance of neo-vascularization in wound healing. Dental extraction is a risk factor for ONJ, and healing after bone invasive surgeries or mucosal trauma requires revascularization. It is possible that interrupting the normal healing process increases the risk for ONJ. In line with the hypothesis that ONJ is of vascular origin is that avascular necrosis of the hip and osteoradionecrosis are both conditions of necrotic bone associated with vascular disruption [9]. Angiogenesis and ONJ have been linked by the case reports of ONJ occurring in patients treated with antitumor therapies targeting vascular endothelial growth factor. Guarneri et al. [10] provide an excellent presentation of the ONJ case reports involving patients treated with bevacizumab or sunitinib and the rationale for performing their analysis of bevacizumab in patients with locally recurrent or metastatic breast cancer (LR/MBC).

Guarneri et al. investigated the databases of three clinical trials, AVADO, RIBBON-1, and ATHENA, where bevacizumab was studied in LR/MBC. Analysis was performed comparing the incidence of ONJ in patients receiving bevacizumab versus placebo and in patients with and without bisphosphonate exposure. A thorough analysis was performed of the data available; however, there are limitations to the research. As acknowledged by the authors, the case report forms for these three clinical trials did not include detailed assessment of oral health and were limited to the NCI CTCAE 3.0 toxicity assessments. The limitations of assessing ONJ using data from pharmacovigilance reporting and the contrasts between pharmacovigilance data and prospective epidemiologic research have been highlighted in the recent literature [11, 12]. Rare toxicities are likely to be underreported using techniques similar to those used by Guarneri et al., given that the clinical trials analyzed were not specifically designed to address these events.

The data from the review of ONJ adverse events in the 3,560 patients treated with bevacizumab in AVADO, RIBBON-1 and ATHENA are reassuring in that the incidence of ONJ does not appear to be greater then expected for the population of patients with MBC receiving systemic antitumor therapy. ONJ in this population is often estimated at 0.8–12% [13] and a recent longitudinal cohort study in patients with breast cancer demonstrated the crude incidence of ONJ to be 3.1% [14]. The overall incidence of ONJ in patients treated with bevacizumab in AVADO, RIBBON-1 and ATHENA was 0.3–0.4% [10]. In those patients receiving bevacizumab and bisphosphonate therapy the incidence was slightly higher at 0.9–2.4%. The incidence of ONJ was not statistically different in patients receiving bevacizumab and chemotherapy for LR/MBC compared to those receiving chemotherapy alone, with or without concurrent bisphosphonate therapy. These data are consistent with the Memorial Sloan-Kettering Cancer Center retrospective analysis of 1,711 patients with cancer where the incidence of ONJ was 0% in patients treated with bevacizumab without bisphosphonate and 2% in those treated with bevacizumab and bisphosphonate [15]. This frequency of ONJ is consistent with recent reports from two Phase III randomized, placebo controlled, clinical trials comparing zoledronic acid to denosumab in the management of metastatic bone disease where the incidence of ONJ was 1–2% and with both zoledronic acid and denosumab [16, 17]. The true incidence of ONJ is unknown.

To prospectively define the incidence of ONJ in patient with metastatic bone disease receiving zoledronic acid, the Southwest Oncology Group registry study S0702, NCT00874211, will assess the cumulative incidence of ONJ at 3 years. Secondary objectives of S0702 are to prospectively gather data on the clinical presentation, natural history, and risk factors for developing ONJ, as well as define patient-related outcomes and explore potential mechanisms of ONJ through the development of a specimen and imaging bank for correlative studies. The Cancer and Leukemia Group B study of patients with metastatic bone disease receiving zoledronic acid dosed either monthly or every 3 months will also generate data on ONJ (CALGB-70604; NCT00869206), along with other studies (NCT00434447, NCT00601068, NCT00869206). Preclinical studies are ongoing to aid in defining the pathogenesis of ONJ. These include investigating angiogenesis and its relationship to ONJ by assessing the vasculature in the oral mucosa of a rat model treated with zoledronic acid in the setting of tooth extraction and in assessing alterations of vasculature reconstitution in the setting of suppression of angiogenesis and hypoxia-related gene expression [18].

Osteonecrosis of the jaw is an uncommon problem that is not well understood. However, in the past few years the field has progressed, primarily through case reports, epidemiologic studies, and the evolving preclinical models. The data generated by Guarneri et al. are clinically relevant and will aid in ONJ risk assessment in both the medical and dental offices. It is reassuring to see the bevacizumab does not appear to significantly increase the risk of ONJ in patients with LR/MBC treated with chemotherapy, with or without bisphosphonates. However, caution must be exercised until additional data are generated. In caring for patients with metastatic breast cancer, the clinician is faced with the need to manage patients in advance of adequate data and a complete understanding of ONJ. Ongoing clinical and basic science studies will add to the understanding of the mechanism, risks, and therapy for ONJ. In the interim, although disruption of angiogenesis could be a factor in the pathogenesis of ONJ, bevacizumab therapy does not appear to be a strong risk factor in the development of ONJ.