Zoledronic acid and radiation: toxicity, synergy or radiosensitization?

Abstract

Zoledronic acid (Z) is a bisphosphonate used in hypercalcaemia-related cancer, in complications for bone metastasis and in postmenopausal osteoporosis and it has been related to osteoradionecrosis, especially when associated with radiation to the head and neck structures. To determine the radiosensitization capacity of zoledronic acid in the combined treatment with ionizing radiation (IR) by evaluating its genotoxic and cytotoxic capacities in non-tumoral cells. The genotoxic effect of Z was studied by means of the micronucleus test in cytokinesis-blocked cells of human lymphocytes irradiated before and after a 2Gy irradiation, while the cytotoxic effect was studied by a cell viability test in the PNT2 cell line before and after exposure to different X-ray doses (0-20Gy) in four groups (Z alone, radiation alone, Z+IR and IR+Z). A dose-dependent and time-dependent cytotoxic effect of Z and IR on PNT2 cells in vitro (p>0.001) was demonstrated. With the concentrations recommended for humans, the combined treatment had a more pronounced effect than individual treatments (p<0.001). The effect was synergic (CI<1), increasing the Z enhancement ratio (2.6) and sensitization factor (56%); the effect of Z was always greater after IR exposure. In the genotoxic effect, only the administration of Z after irradiation (IR+Z) increased chromosome damage (p<0.001) and the sensibilization factor (35.7%). High concentrations of Z are toxic, but the concentrations recommended for clinical practice in humans give it the characteristics of a radiosensitization agent, whose effect is even greater when administered after IR.