Effects of Low-Dose Combination Therapy of Zoledronate and Dexamethasone on Post-Tooth Extraction Socket Healing: A Pre-Clinical Study in Mice

Introduction: Pharmaceutical agents targeting distinct therapeutic pathways can exert disparate influences on bone metabolism, notably exemplified by nitrogen-containing bisphosphonates and glucocorticoids. Objective: This investigation sought to elucidate the effects of a low-dose administration of zoledronate (ZL) combined with dexamethasone (DX), on post-tooth extraction sockets healing in a murine model. Mothodology: Forty young male C57BL/6J mice were assigned to four distinct groups through weight-stratified randomization: Control (C) - 0.9% saline solution, ZL - 0.05 mg/kg ZL, DX - 5 mg/kg DX, and ZL+DX - combined regimen of 0.05 mg/kg ZL and 5 mg/kg DX. All substances were delivered via intraperitoneal on a weekly basis, commencing four weeks before right upper incisor extraction and continuing up to 7 and 30 days after the extraction of the right upper incisor tooth, when blood was collected for biochemical analysis of bone markers, and the maxillae were removed and prepared for microcomputed analysis for the trabecular architecture in the healing sockets, and for the confectioning of histological slices to be stained with hematoxylin and eosin, and immunohistochemistry for TRAP and Runx2. Results: Histopathology and microCT unveiled that DX administration correlated with impaired bone formation, manifesting as reduced bone volume/total volume (BV/TV) and trabecular thickness (Tb.Th). Conversely, ZL exposure disrupted bone viability. However, the combination of both demonstrated enhanced maturation in bone remodeling at day 30. Notably, DX treatment elicited a notable reduction in serum calcium and phosphate levels, concomitant with a decline in total TRAP. Runx-2+ cells were significantly elevated in the Control group at day 7 compared to ZL and DX-ZL, and at day 30 compared to ZL. Conclusions: Collectively, our findings elucidated that the co-administration of low doses of ZL and DX in young male mice augmented the recuperative processes in post-extraction sockets when juxtaposed with either agent in isolation. Nevertheless, further comprehensive inquiry is needed to delineate the precise underlying mechanisms in a more controlled experimental context.