Various pathways of zoledronic acid against osteoclasts and bone cancer metastasis: a brief review

Zoledronic acid (ZA) is one of the most important and effective class of anti-resorptive drug available among bisphosphonate (BP), which could effectively reduce the risk of skeletal-related events, and lead to a treatment paradigm for patients with skeletal involvement from advanced cancers. However, the exact molecular mechanisms of its anticancer effects have only recently been identified. In this review, we elaborate the detail mechanisms of ZA through inhibiting osteoclasts and cancer cells, which include the inhibition of differentiation of osteoclasts via suppressing receptor activator of nuclear factor kappa B ligand (RANKL)/receptor activator of nuclear factor kappa B (RANK) pathway, non-canonical Wnt/Ca2+/calmodulin dependent protein kinase II (CaMKII) pathway, and preventing of macrophage differentiation into osteoclasts, in addition, induction of apoptosis of osteoclasts through inhibiting farnesyl pyrophosphate synthase (FPPS)-mediated mevalonate pathway, and activation of reactive oxygen species (ROS)-induced pathway. Furthermore, ZA also inhibits cancer cells proliferation, viability, motility, invasion and angiogenesis; induces cancer cell apoptosis; reverts chemoresistance and stimulates immune response; and acts in synergy with other anti-cancer drugs. In addition, some new ways for delivering ZA against cancer is introduced. We hope this review will provide more information in support of future studies of ZA in the treatment of cancers and bone cancer metastasis.