Bisphosphonates (BPs) are widely used as antiresorptive drugs. However, one of most potent BPs, zoledronic acid (ZA) can cause BP-related osteonecrosis of the jaws (BRONJ) with a poorly understood pathophysiology. The aim of this study was to find a clue for the development of BRONJ by evaluating the cytotoxic effects of ZA on osteoblasts and examining the action mechanism of ZA on osteoclast differentiation. Jaw bone osteoblasts (JB-OBs), long bone osteoblasts (LB-OBs), and bone marrow macrophages (BMMs) were isolated from Balb/C mouse. Osteoblasts were treated with ZA at increasing doses (0.01, 0.1, 1, 5, 10, 50, and 100 μM) for 7 days. The cytotoxic effects of ZA appeared from day 3 at high dose of 50 and 100 μM with increase of apoptosis in both types of osteoblasts, of which JB-OBs were more sensitive than LB-OBs. Western blotting showed increased expression of apoptotic markers, p21 and p53 at 50 μM of ZA. BMMs were pretreated with various concentrations (0, 0.01, 0.1, and 1 μM) of ZA for 1 h before stimulating with receptor activator of nuclear factor-κB ligand, the osteoclast differentiation factor. ZA attenuates osteoclast differentiation by suppressing the development of multinuclear cells. ZA decreased the transcriptional expression of osteoclast transcription factor, NFATc1 as well as ATP6v0d2 gene which was involved in cell-cell fusion during osteoclastogenesis. These findings revealed that ZA at high dose induces apoptosis, more apparently in JB-OBs than LB-OBs, and attenuates osteoclast differentiation, suggesting that chronic administration of ZA might exert adverse effect on bone metabolism.
17 - 20 May 2014
European Calcified Tissue Society