High dose zoledronic acid increases ischemia-reperfusion damage of the liver

Zoledronic acid (ZA), a nitrogen-containing bisphosphonate, has been reported to exhibit a protective effect against cancers and prevent bone fractures. It also induces apoptosis by increasing proinflammatory cytokines and oxidative stress. Oxidative stress increases significantly during ischemia-reperfusion (IR) injury. The liver is highly sensitive to IR injury. In this study, we aim to investigate whether high-dose ZA treatment affects the liver during IR.

We used twenty-one Sprague-Dawley male rats in our study, and they were subdivided randomly into three groups, each containing seven rats. A single dose of 100 μg/kg ZA was administered via the intraperitoneal route in the ZA group. Forty-eight hours after the ZA administration, infrarenal abdominal aortic cross ligation was performed on the ZA and IR groups. After 2 hours of ischemia, 2 hours of reperfusion was applied.

The malondialdehyde (MDA) level of the control group was significantly lower than the IR (p = 0.006) and ZA (p<0.001) groups. However, the superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPx) values of the control group were significantly higher than the values of the IR group (p<0.05, p<0.001, and p<0.05) and ZA group (p = 0.002, p<0.001, and p<0.001). Caspase-3 activity was significantly higher in the IR group as compared to the control group (p<0.001). The caspase-3 activity in the ZA group, on the other hand, was higher than both the control (p<0.001) and IR groups (p<0.001).

High-dose ZA may exacerbate liver injury during IR by increasing reactive oxygen species production and apoptosis.