Background: Osteosarcoma is considered the most frequent primary bone malignancy.
Lung metastasis is the leading cause of death and the most consistent factor for predicting negative
patient outcome in osteosarcoma. Third-generation nitrogen-containing bisphosphonates, such as
zoledronic acid, have been shown to reduce osteolysis induced by bone metastasis and exhibit
highly selective localization and retention in bone, thus making them attractive agents in the treatment
of bone metastasis. Studies have shown that zoledronic acid exerts pleiotropic anti-tumor effects
against osteosarcoma cells in vitro, including anti-proliferative, anti-angiogenic, and immunomodulatory
effects. However, the efficacy of zoledronic acid against primary tumor growth and
pulmonary metastasis of osteosarcoma is controversial, which has limited its clinical application.
Objective: The present review summarizes the controversial effects of zoledronic acid on primary tumor
burden and pulmonary metastases in osteosarcoma. We also analyze the clinical effectiveness of zoledronic
acid alone and in combination with chemotherapeutic drugs for the treatment of osteosarcoma.
Conclusion: Zoledronic acid exhibits diverse anti-tumor effects in osteosarcoma in vitro, however,
the in vivo effect is still controversial. Further preclinical and clinical studies are needed to clarify
the effects of zoledronic acid in osteosarcoma.