Exposing human epithelial cells to zoledronic acid can mediate osteonecrosis of jaw: an in vitro model

Abstract

Osteonecrosis of the jaw (ONJ) is a chronic complication of bisphosphonate therapy, mainly when intravenous, in cancer patients with bone metastases and myeloma. Its pathophysiology is not yet fully elucidated; in particular, the molecular/cellular events triggering ONJ remain unclear. This complication could result from the effect of bisphosphonates released from bone into the soft-tissues, or from osteolysis induced by soft-tissues directly exposed to bisphosphonates. This research investigated the possibility that ONJ may be evocated by changes induced in osteoblast activity by factors released by soft-tissue cells exposed to zoledronic acid. An 'in vitro' model was used, in which human osteoblast-like MG-63 cells were grown in medium conditioned by human keratinocytes NCTC 2544, exposed or not to zoledronic acid (5 or 50 μM); 5 μM zoledronic acid was also directly administered to MG-63 cells. In NCTC 2544 cells, zoledronic acid decreased proliferation via decreased hydroxy-3-methyl-glutaryl-CoA reductase, suggesting that a decrease in healing capability can occur in case of injury. An increased pro-inflammatory potential was also observed. Osteoblasts grown in medium conditioned in the presence of zoledronic acid showed decreased proliferation and osteogenic properties, and increased ability to induce osteoclast differentiation and inflammatory process. Zoledronic acid directly administered to MG-63 modulated only some parameters and in a lesser extent. The research evidenced, for the first time, the direct involvement of epithelial cells in zoledronic acid-triggered molecular mechanisms leading to osteonecrosis of the jaw, by modulating both osteoblast and osteoclast properties.