Analysis of Risedronate Analog on Extraction Socket Healing in Mice

Medication-related osteonecrosis of the jaw (MRONJ) is a severe adverse effect associated with anti-resorptive medications like nitrogen-containing bisphosphonates (N-BPs), particularly zoledronate (ZOL). This study aimed to investigate whether a BP analog with high bone affinity but minimal anti-resorptive activity, NE-58051, could induce MRONJ-like lesions in a mouse model.

Female C57BL/6J mice (n=6 per group) were administered ZOL (250 μg/kg intravenously, twice weekly) for one or two weeks, or NE-58051 (250 μg/kg intravenously, twice weekly) for two weeks. Two weeks after initiation of study, the bilateral first molars were extracted. Mice were euthanized after a total duration of four weeks. Histological assessments evaluated necrotic bone area and osteoclast activity at extraction sites. Serum tartrate-resistant acid phosphatase isoform 5b (TRAcP-5b) levels were measured.

Mice treated with ZOL for two weeks exhibited significant increases in empty osteocytic lacunae and necrotic bone area compared to the saline group, indicating the development of MRONJ-like lesions. NE-58051-treated mice did not show significant differences in necrotic bone area or osteoclast activity compared to controls. No significant differences were observed in serum TRAcP-5b levels among all groups.

High bone affinity without potent inhibition of bone resorption does not induce MRONJ-like lesions in mice. These findings suggest that the potent anti-resorptive activity of N-BPs is a key factor in MRONJ development, highlighting the importance of bone turnover suppression in the pathogenesis of this condition.