Making a Case for Defining Osteonecrosis of the Jaw

During the past decade, osteonecrosis of the jaw (ONJ) has come to the attention of the dental and medical communities, first as a phenomenon, then as an uncommon occurrence seen primarily in patients with cancer receiving osteoclast inhibition with high-potency bisphosphonates (Van Poznak, 2006; Khosla et al., 2007; Ruggiero et al., 2009). Since ONJ has been seen in association with bisphosphonates, some have called it ‘bisphosphonate-related osteonecrosis of the jaw’ (BRONJ). Approximately 3 years after ONJ had come to the attention of healthcare professionals, a working definition was created, and it included that the affected individual had exposure to bisphosphonate therapy but not radiation to the head and neck region, and that the lesion was present for 8 weeks or more (Khosla et al., 2007; Ruggiero et al., 2009). This definition can be used to separate ONJ from osteomyelitis and osteoradionecrosis (ORN). The etiology of ONJ remains unknown, and much work is being done to improve our understanding of its pathophysiology, as well as to identify risk factors. This issue of the Journal of Dental Research includes 2 important case-control studies that aid in defining clinical factors associated with ONJ. Both case-control studies utilized a similar definition of ONJ, in that bisphosphonate exposure was not required for the cases, and radiation therapy to the head and neck was not an exclusion criterion. The case-control study by Barasch et al., performed in the Practice-based Research Network (PBRN) by the Collaboration on Networked Dental and Oral Health Research Collaborative Group, included patients from New York City, Seattle (WA), Portland (OR), and Birmingham (AL) [{"type":"clinical-trial","attrs":{"text":"NCT01130389","term_id":"NCT01130389"}}NCT01130389] (Barasch et al., 2011). In this study, “ONJ was defined as maxillary or mandibular exposed bone of any size that clinically appears necrotic, without regard to duration or cause.” This definition is more broad than that posed by the American Society for Bone and Mineral Research (ASBMR) (Khosla et al., 2007) and the American Association of Oral and Maxillofacial Surgeons (AAOMS) (Ruggiero et al., 2009) and could capture cases of ORN or other diagnoses as well. The paper by Fellows et al. estimated the incidence of, and risk factors for, ONJ within 2 large health maintenance organizations participating in the Dental PBRN, Health Partners of Minnesota (HP) and Kaiser Permanente Northwest (KPNW), which includes Oregon and Southwest Washington (Fellows et al., 2011). The KPNW population could potentially overlap with those in the Barasch study population. This study “defined ONJ as a clinically diagnosed exposed necrotic lesion in the mandible or maxilla”, which is similar to the other PBRN study. The Table outlines the findings of both case-control studies. Table Risks Associated with the Development of Osteonecrosis of the Jaw It is reassuring that these 2 case-control studies generally concur regarding risk factors for ONJ. These risks include bisphosphonate use, cancer, radiation therapy to the head and neck, osteoporosis, and, to some extent, the use of steroids. The Barasch paper also included dental extractions as a significant risk factor. These results support earlier reports where the majority of ONJ cases have occurred in patients with metastatic cancer involving the bone who have been receiving high-potency intravenous bisphosphonates, and with ONJ often occurring in association with dental extractions (Zahrowski, 2010). By including patients who have had radiation therapy to the head and neck in the 2 case-control reports, the cases labeled as ONJ may reflect ORN. The cases of exposed, necrotic bone associated with radiation therapy demonstrated the continued need for vigilance in oral care prior to head and neck radiotherapy. It is less clear whether these radiation-associated cases add to the understanding of the diagnosis of ONJ, as defined by ASBMR and AAOMS. Case-control studies can provide data, within a limited time frame, on previous exposures of interest. Case-control methodology has pointed the way to significant scientific advancements, including the link between tobacco use and lung cancer (Doll and Hill, 1950). Barasch et al. conclude that their case-control study supports a link between bisphosphonates and ONJ. The osteoclast inhibitor, denosumab, a monoclonal anti-RANKL antibody, has been shown to have a risk for ONJ similar to that of zoledronic acid when used in patients with cancer involving the bone. Through adverse event reporting in 3 Phase III studies of 5677 patients with cancer randomized to either denosumab 120 mg subcutaneously or zoledronic acid 4 mg intravenously monthly, 89 adjudicated cases of ONJ were identified. Cases of ONJ were defined by an area of exposed bone in the jaw persisting for more than 8 weeks in patients without prior craniofacial radiation to the jaws. ONJ occurred in 1.8% of the patients treated with denosumab and 1.3% with zoledronic acid (P = 0.13). The majority of patients with ONJ had a history of tooth extraction, poor oral hygiene, or use of a dental appliance (Brown et al., 2010). Hence, bisphosphonates are not the sole class of drug that appears to associate with the development of this condition. ONJ occurring in the setting of a non-bisphosphonate raises questions of whether the definition of ONJ, as put forward by both the ASBMR (Khosla et al., 2007) and the AAOMS (Ruggiero et al., 2009), warrants revision, since these definitions of ONJ include exposure to bisphosphonates. The observation that ONJ occurs with another potent osteoclast inhibitor, denosumab, supports the hypothesis that ONJ may be due to dysfunction in a bone remodeling mechanism. Also in support of this hypothesis is the recent report of ONJ healing in response to teriparatide therapy in an osteoporotic 88-year-old woman who had ONJ that developed in the setting of alendronate use (Cheung and Seeman, 2010). Of note, the teriparatide FDA labeling warns against the use of this anabolic agent in patients with bone metastases. Clinical and pre-clinical studies are ongoing in an attempt to elucidate the mechanism of ONJ. In fewer than 10 years, our understanding of ONJ has progressed considerably, and these 2 case-control studies add to the expanding knowledge base. However, these studies highlight the continued need for re-assessing the parameters we use to define the condition we call ONJ. A clear definition of ONJ is critical to making the diagnosis and to evaluating means of detecting, treating, and/or preventing the condition.