New insights into molecular and cellular mechanisms of zoledronate in human osteosarcoma

Osteosarcoma is the most common primary malignant tumor of the skeleton in teenagers and young adults and continues to confer a generally poor prognosis in patients who do not respond to chemotherapy or who present with metastatic diseases at diagnosis. The nitrogen-containing zoledronate, the third generation bisphosphonate (BP), effectively inhibits osteoclastic bone resorption and is widely utilized in the treatment of metabolic and metastatic bone diseases nowadays. Owing to an acceptable safety profile and tolerability, zoledronate is the only BP currently approved for the prevention and treatment of skeletal relevant events in patients with metastatic bone lesions, especially bone metastases from advanced renal cell carcinoma and prostate cancer, and breast cancer, due to all solid malignancy. Moreover, zoledronate possesses diverse anti-osteosarcoma properties and may have potential to become an adjunctive treatment for high-grade osteosarcoma to enhance survival rates and to obliterate complications of the chemotherapy. Herein we highlighted the pharmacology of BPs and its underlying molecular mechanisms in osteoclasts and various cancer cells. We further provided the available literature on in vitro studies to illustrate the new insights into the intracellular molecular mechanisms of zoledronate in human osteosarcoma cell lines and in vivo animal models that led to the development and regulatory approval of zoledronate in patients with human osteosarcoma. This review also addresses clinical trials to focus on the efficacy of zoledronate on human osteosarcoma.