Vitamin D-insufficient, bisphosphonate-treatment rats developed osteonecrosis of the jaw

Although bisphosphonate treatment in the management of malignant neoplasms that reside in or metastasize to bone was initially considered to be without major side effects, there have been an increasing number of cases of osteonecrosis of the jaw (ONJ) attributed to these drugs. The UCLA Weintraub Center ONJ Research Consortium has recognized that coincidental vitamin D insufficiency may potentially increase susceptibility to develop bisphosphonate-related ONJ. OBJECTIVE: The aim of this study was to ascertain the effect of coincident vitamin D insufficiency and bisphosphonate treatment on the generation of osteonecrosis in the rat alveolar bone. METHODS: Male 8-week old rats were placed in vitamin D-deficient environment for 2 weeks and received injections through tail vein a bolus of zoledronate (35 μg/Kg) every 2 weeks for 5 weeks. Controls received vehicle injection. One week after the first injection, maxillary molars were extracted unilaterally. Four weeks after tooth extraction, the rat was subjected to micro positron emission tomography (μPET), followed by euthanasia and the maxillary tissue collection for micro-computed tomography (μCT) and histological examination. RESULTS: The vitamin D-insufficient rats showed the prolonged retention of osteoclasts at the healing alveolar bone and significantly delayed bone wound healing in the extraction socket. Zoledronate injection to vitamin D-insufficient rats resulted in the generation of partially exposed necrotic bone fragments, which mirror human ONJ lesions. μPET showed the abnormal accumulation of ¹⁸F-fluorodeoxyglucose tracer at the sites of ONJ lesions of vitamin D-insufficient, zoledronate-treatment rats, suggesting that extensive chronic inflammation at the healing oral mucosa and alveolar bone was a prerequisite for development of ONJ. CONCLUSION: This study has, for the first time, recapitulated human ONJ in an animal model and suggests that vitamin D insufficiency-induced secondary hyperparathyroidism and dysregulation of innate immunity may play the role in the pathogenesis of ONJ. (Supported by the Oppenheimer Foundation)