Zoledronic acid delays wound healing of the tooth extraction socket, inhibits oral epithelial cell migration, and promotes proliferation and adhesion to hydroxyapatite of oral bacteria, without causing osteonecrosis of the jaw, in mice

Nitrogen-containing bisphosphonates such as zoledronic acid (ZOL) and pamidronate have been widely and successfully used for the treatment of cancer patients with bone metastases and/or hypercalcemia. Accumulating recent reports have shown that cancer patients who have received these bisphosphonates occasionally manifest bisphosphonate-related osteonecrosis of the jaw (BRONJ) following dental treatments, including tooth extraction. However, little is known about the pathogenesis of BRONJ to date. Here, to understand the underlying pathogenesis of BRONJ, we examined the effects of ZOL on wound healing of the tooth extraction socket using a mouse tooth extraction model. Histomorphometrical analysis revealed that the amount of new bone and the numbers of blood vessels in the socket were significantly decreased in ZOL-treated mice compared to control mice. Consistent with these results, ZOL significantly inhibited angiogenesis induced by vascular endothelial growth factor in vivo and the proliferation of endothelial cells in culture in a dose-dependent manner. In contrast, etidronate, a non-nitrogencontaining bisphosphonate, showed no effects on osteogenesis and angiogenesis in the socket. ZOL also suppressed the migration of oral epithelial cells, which is a crucial step for tooth socket closure. In addition, ZOL promoted the adherence of Streptococcus mutans to hydroxyapatite and the proliferation of oral bacteria obtained from healthy individuals, suggesting that ZOL may increase the bacterial infection. In conclusion, our data suggest that ZOL delays wound healing of the tooth extraction socket by inhibiting osteogenesis and angiogenesis. Our data also suggest that ZOL alters oral bacterial behaviors. These actions of ZOL may be relevant to the pathogenesis of BRONJ.