Clinical, Radiographic, and Biomarker Characterization of Multiple Myeloma Patients with Bisphosphonate Associated Osteonecrosis of the Jaw.
Authors: Raje Noopur , Woo Sook-Bin , Hande Karen , Yap Jeffrey T. , Richardson Paul G. , Vallet Sonia , Treister Nathaniel , Hideshima Teru , Tai Yu-Tzu , Chhetri Shweta , Connell Brendan , Szot-Barnes Agnieszka , Tian Mei , Schlossman Robert L. , Weeler Edie , Munshi Nikhil C. , Van Den Abbeele Annick D. , Anderson Kenneth C. 
Published: October 2019

Abstract
Osteonecrosis of the jaw (ONJ) is a recently described entity observed in patients with a history of aminobisphosphonate use. To date nearly 400 patients with ONJ have been reported in literature and this number continues to rise. However,prospective characterization of ONJ is lacking. We here characterize ONJ clinically and radiographically using multiple imaging modalities including panorex films, CAT scans, magnetic resonance imaging (MRI), FDG-PET scans, and NaF-PET bone scans in 11 patients with multiple myeloma (MM). Moreover, bone turnover and remodelling markers in these patients were analyzed prospectively in order to gain insights into the pathophysiology of ONJ. Eleven patients between the ages of 57 and 81 yrs were included. There were 8 men and 3 women, and 6 patients presented with Durie Salmon stage III disease. Patients were treated with various combinations of conventional and novel agents, including stem cell transplantation (4/11). Patients received either pamidronate (n=3), zolendronic acid (n=4), or both agents sequentially (n=4). The mean duration of bisphosphonate (BP) therapy was 38.7 months (range: 9–81 months). All patients were examined independently by 2 oral medicine physicians, and clinical data was validated on 2 separate dental visits. Six of 11 patients had mandibular lesions, 3 had lesions in the maxilla, and 2/11 patients had lesions in both the maxilla and mandible. Plain and panorex filmsdemonstrated a mottled appearance with increased radiolucency at the site of ONJ.This was associated with an increase in both glucose metabolism and mineralization at sites of ONJ, as measured with the maximum standardized uptake value (SUVmax) on FDG and NaF-PET scans, respectively. However, one patient with increased uptake on NaF-PET did not have increased glucose metabolism with FDG-PET. The target-to-background ratio of SUVmax for NaF-PET scans was significantly greater than FDG-PET suggesting that NaF-PET may have greater sensitivity than FDG-PET in confirming a diagnosis of ONJ. Several markers of bone turnover and remodelling were measured including serum calcium, vitamin D (25-OH), urinary N telopeptides, bone alkaline phosphatase (BAP), osteopontin, MIP 1a, RANK-L, osteoprotegrin, and DKK. Transcriptional profiling on peripheral blood mononuclear cells (PBMCs) using the Affymetrix U133Plus 2.0 gene chip was also performed in all 11 patients and compared with those of 10 MM patients on BP therapy without ONJ and 5 normal donors. These correlative studies will be presented and provide insights into the pathophysiology of ONJ. Importantly these studies both define clinical and radiographic features on ONJ, but also identify biomarkers to be evaluated in future prospective studies of BP therapy and ONJ.