Metabolic analyses of bisphosphonate–related osteonecrosis of the jaw in rats

Objectives: We have previously reported the development of osteonecrosis in the jaw (ONJ) of vitamin D insufficient rats received intravenous (IV) bisphosphonate treatments. However, rats received either the vitamin D deficient diet or IV bisphosphonate treatments alone did not show the sign of ONJ. The objective of this study was to characterize the bone metabolic activity of the rat ONJ model. Methods: Female 4-week old rats were placed in vitamin D-deficient environment and received injections through tail vein a bolus of bisphosphonate (zoledronate, 35 µg/Kg) every 2 weeks. Controls received vehicle injection. Four weeks after starting the vitamin D-deficient environment, maxillary molars were extracted unilaterally. Four weeks after tooth extraction, the rat was subjected to 2 sets of micro positron emission tomography (µPET) using 18F-ion tracer and 18F-labeled fluorodeoxyglucose (18F-FDG). The micro computed tomography (µCT) image was concurrently obtained for each rat. Results: The µPET/µCT data indicated the accumulation of 18F-ions at the maxillary alveolar bone of non-extraction side as well as contralateral tooth extraction site, suggesting the significant bone remodeling activity. However, the bone remodeling rate of ONJ lesions was equivalent to that of the control extraction sites. 18F-FDG accumulates in the area of high glucose metabolism such as inflammation. The µPET/µCT data revealed that ONJ lesions showed the abnormal accumulation of 18F-FDG tracer, which was significantly higher than that of controls (p<0.05). Conclusion: Our data indicate that while bone remodeling metabolic activity was not altered, the increased 18F-FDG accumulation may suggest the extensive chronic inflammation at the healing oral mucosa and alveolar bone in the ONJ lesion. This study has recapitulated human ONJ in an animal model and further suggests that vitamin D deficiency-induced dysregulation of innate immunity may be involved in the pathogenesis of ONJ. (Supported by the Stein/Oppenheimer Foundation)