Background : Osteonecrosis of the jaw occurs in patients receiving high doses of intravenous nitrogen-containing bisphosphonates in the course of their supportive cancer therapy. The exact pathomechanisms are elusive and questions of paramount importance remain unanswered. Recent studies indicate toxic effects of bisphosphonates on different cell types, apart from osteoclast inhibition. Since multipotent stem cells and osteoblasts play important roles in the processes of wound healing and bone regeneration, the aim of this study was to investigate the effects of different bisphosphonate derivatives and dose levels combined with varying pH-levels on mesenchymal stem cells and osteoblasts in vitro .
Materials and methods : The effect of two nitrogen containing bisphosphonates (zoledronate and ibandronate) and one non-nitrogen containing bisphosphonate (clodronate) on mesenchymal stem cells (hMSC) and osteoblasts (HOB) was tested at different concentrations of the two N-BPs and equimolar concentrations of clodronate at different pH-values (7.4, 6.7). Cell viability and activity was analyzed by WST-assay. Cell motility was investigated by means of scratch wound assays and visualized using time-lapse microscopy.
Results : Zoledronate and ibandronate showed a dose- and pH-dependent cellular toxicity. Increasing concentrations of both N-BPs and acidic milieus led to a significant decrease in cell viability and activity ( p < 0.01), with more pronounced effects for zoledronate. In contrast, equimolar concentrations of clodronate did not affect the cell survival or activity significantly, apart from the effect of pH reduction itself, which was also detectable in controls without bisphosphonates.
Conclusion : We conclude that high concentrations of nitrogen-containing bisphosphonates and local inflammation associated pH changes might play a key role in the pathogenesis of ONJ in patients receiving high doses of nitrogen containing bisphosphonates due to malignant diseases.
Key words: bisphosphonate; bisphosphonate-related osteonecrosis of the jaw; acadic milieu; pH