Association of Denosumab Therapy with Tooth Root Resorption

PROJECT SUMMARY/ABSTRACT Tooth root resorption mediated by osteoclasts (OCs)/odontoclasts is a normal physiologic process required for the exfoliation of primary teeth to make space for the eruption of permanent teeth. However, root resorption of permanent teeth is pathological. Multiple External Cervical Root Resorption (MECRR) is an aggressive form of pathologic root resorption that affects multiple teeth at the cemento-enamel junction. The precise etiology of MECRR remains unknown, and MECRR lesions are often detected incidentally during routine dental exams. They are resistant to interventions, resulting in significant tooth loss. Our preliminary data indicate a critical link between denosumab (DMAb) therapy and MECRR. DMAb therapy appears to initiate MECRR, and its discontinuation leads to a rapid progression of MCERR. DMAb is an antiresorptive medication used to treat osteoporosis, bone metastases, and fibrous dysplasia. DMAb inhibits receptor activator of nuclear factor-κB ligand (RANKL), thereby preventing OC formation, function, and survival. To date, the direct causal role of DMAb in MECRR initiation and progression remains unknown. The objective of this proposal is to elucidate the causal role of DMAb in MECRR using clinical and pre-clinical models. Our central hypothesis is that prolonged DMAb therapy increases MECRR susceptibility, and its cessation accelerates MECRR progression due to a rebound OC effect. This hypothesis will be tested using two complementary Specific Aims that leverage clinical, animal, and in vitro studies. In Aim 1, through clinical study we will measure the prevalence, association strength, and risk factors for MECRR. In Aim 2, through murine studies we will establish the causal role of DMAb therapy in MECRR susceptibility and how its cessation accelerates MECRR. The proposed research is significant as it addresses a critical knowledge gap in the pathogenesis of MECRR. By providing mechanistic insights into the initiation and progression of MECRR, our study aims to advance scientific knowledge and transform clinical practices. This research will help identify patients at risk for DMAb-related MECRR and inform novel preventive and therapeutic strategies. Moreover, our findings will have broader implications for understanding OC dysfunction in other conditions such as osteoporosis, bone metastases, and fibrous dysplasia.