Sotirios Tetradis, DDS, PhD
UCLA School of Dentistry
Amgen, Inc.: Consultant/Advisory Board, Research Grant includes principal investigator, collaborator or consultant and pending grants as well as grants already received
Statement of the Problem: Medication Related Osteonecrosis of the Jaw (MRONJ is a rare, but severe side effect of anti-resorptive medications that presents as exposed bone in the maxillofacial region lasting for at least 8 weeks. Although it was initially described in 2003 and 2004, the molecular changes that precede clinical bone exposure remain poorly understood. Current knowledge has shown that systemic anti-resorptive treatment in conjunction with local risk factors, such as tooth extraction or periodontal/periapical disease can lead to ONJ development. While these findings are important, they do not explain the early, molecular changes that occur prior to bone exposure. Utilizing experimental periodontitis (EP), here we aim to investigate the early submucosal changes that precede clinical MRONJ development.
Materials and Methods: An animal model of MRONJ utilizing EP was used in mice treated with Zoledronic Acid (ZA), a potent bisphosphonate, and OPG-Fc, a RANK-L inhibitor. Animals were pre-treated for 1 week with ZA or OPG-Fc, after which EP was induced in the maxillary second molar of all animals. Animals were euthanized 1 week, 2 weeks, and 4 weeks following EP induction. 36 animals (12 Veh, 12 ZA, and 12 OPG-Fc) were used for each timepoint. Animals were evaluated radiographically for alveolar bone loss and periosteal bone formation. Histologically, animals were evaluated for clinical bone exposure, epithelial-crest distance, empty osteocytic lacunae, and osteonecrotic area. Immunofluorescent analysis was employed to assess vasculature changes, levels of vascular endothelial growth factor A (VEGF-A), vascular cell adhesion protein-1 (VCAM-1), hypoxia, oxidative stress, and apoptosis. One way ANOVA was used to detect changes among groups.
Results: Anti-resorptive treatment inhibited periodontal bone loss, and led to increased levels of empty osteocytic lacunae and osteonecrosis. Overall, an inhibition of arteriole and venule network was seen in animals treated with both anti-resorptives. Increased levels of VEGF-A and VCAM-1 were noted around the ligated area. Hypoxia, oxidative stress, and apoptosis levels were high through the duration of the experiment in animals treated with anti-resorptives.
Conclusions: These data point to subclinical vasculature and structural disturbances that affect levels of oxidative stress, hypoxia, and apoptosis around areas of developing ONJ.