Osteonecrosis of the Jaw with Zoledronic Acid Treatment

SUMMARY: OsteoNecrosis of the Jaw (ONJ) is defined as progressive bone destruction in the maxillofacial region resulting in exposed bone, or bone that can be probed through an intraoral or extraoral fistula (or fistulae) in the maxillofacial region and that does not heal within 8 weeks, occurring in a patient who has received a Bone-Modifying Agent (BMA) or an angiogenic inhibitor agent and with no history of head and neck radiation. The condition may involve the mandible or the maxilla and can be challenging to treat and can cause significant pain, impacting patients quality of life. The true incidence ONJ is unknown.

Bone Modifying Agents that have been linked with ONJ principally include bisphosphonates such as Zoledronic acid and Pamidronate and Rank Ligand inhibitor, Denosumab. BMAs are an integral part of cancer management and have essential roles in supportive oncology for the treatment of hypercalcemia of malignancy and bone metastases, and prevention of Skeletal-Related Events (SREs) such as pathologic fractures and reduce the need for radiation or surgical intervention. BMAs disrupt the bone remodeling cycle by reducing osteoclast survival and function.

The SWOG Cancer Research Network designed this trial to prospectively assess the incidence of and predictive factors associated with OsteoNecrosis of the Jaw (ONJ), in patients with cancer receiving Zoledronic acid. The Primary objective was to prospectively assess the cumulative incidence of ONJ at 3 years. SWOG S0702 is a multicenter, prospective observational cohort study which enrolled 3491 patients with Metastatic Bone Disease (MBD) with either limited or no prior exposure to Bone Modifying Agents, who had received Zoledronic acid (ZOMETA®) within 30 days of registration. The median patient age was 63 years of whom 32% had breast cancer, 17% had myeloma, 20% had prostate cancer, 19% had lung cancer, and 12% had other malignancies. A baseline dental examination was performed in 65% of the patients. Over 65% of patients reported no alcohol use, 12% were current smokers and complete or partial dentures were observed in 22% of patients. The Primary end point was the diagnosis of confirmed ONJ, defined as an area of exposed bone in the maxillofacial region that had been present for at least 8 weeks in a patient receiving or previously exposed to a bisphosphonate, and who had not had radiotherapy to the craniofacial region. A suspected case of ONJ was defined by the same ONJ criteria but present for less than 8 weeks. All suspected and confirmed cases of ONJ were adjudicated by the study team. The median follow up was 3 years.

The cumulative incidence of confirmed ONJ at year 1 was 0.8%, at year 2 was 2% and at year 3 was 2.8%. The cumulative incidence at 3 years was highest in patients with myeloma (4.3%) and lowest in those with breast cancer (2.4%). ONJ risk was higher among patients with planned Zoledronic acid dosing intervals of less than 5 weeks versus those with planned intervals of 5 weeks or longer (cumulative incidence 3.2% versus 0.7%; P=0.009). ONJ risk was higher among patients with any dentures (cumulative incidence, 5% versus 2.9%; P=0.02) and removable dentures (cumulative incidence 6.5% versus 3%; P=0.03), and were about twice as likely to experience ONJ compared with patients without any dentures or without removable dentures, respectively. A higher rate of ONJ was associated with fewer total number of teeth (less than 25 versus more than 25), with a 3 year ONJ incidence of 4.4% versus 2.4% respectively (HR=0.51; P=0.006). Current smokers were more likely to experience ONJ than patients who were not current smokers (3.7% versus 2.4%; P=0.02)

The authors concluded that this prospective study of patients treated with Zoledronic acid provides clinicians with critical information about the overall risk and risk factors for developing ONJ. The authors added that when clinically appropriate, consideration should be given to use of Zoledronic acid dosing intervals of greater than 5 weeks to reduce the risk of ONJ.

Association of Osteonecrosis of the Jaw With Zoledronic Acid Treatment for Bone Metastases in Patients With Cancer. Van Poznak CH, Unger JM, Darke AK, JAMA Oncol. Published online December 17, 2020. doi:10.1001/jamaoncol.2020.6353.