title: Zoledronic Acid: Pleiotropic Anti-Tumor Mechanism and Therapeutic Outlook for Osteosarcoma.
abstract: 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.
  
  
  
  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.
  
  
  
  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.
authors.affiliation: Department of Orthopaedics, Shanghai Key Laboratory of Orthopaedic Implant, Shanghai Ninth People's Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, 200011, China.|Department of Orthopaedics, The Second Xiangya Hospital, Central South University, Changsha, Hunan, 410011, China.
authors.forename: Zhengxiao
authors.initials: Z
authors.lastname: Ouyang
authors.affiliation: Department of Orthopaedics, Shanghai Key Laboratory of Orthopaedic Implant, Shanghai Ninth People's Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, 200011, China.
authors.forename: Haowei
authors.initials: H
authors.lastname: Li
authors.affiliation: Department of Orthopaedics, Shanghai Key Laboratory of Orthopaedic Implant, Shanghai Ninth People's Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, 200011, China.
authors.forename: Zanjing
authors.initials: Z
authors.lastname: Zhai
authors.affiliation: School of Pathology and Laboratory Medicine, The University of Western Australia, Perth, WA 6009, Australia.
authors.forename: Jiake
authors.initials: J
authors.lastname: Xu
authors.affiliation: School of Pharmacy, Bldg 306, Curtin University, Bentley 6102, Australia.
authors.forename: Crispin R
authors.initials: CR
authors.lastname: Dass
authors.affiliation: Department of Orthopaedics, Shanghai Key Laboratory of Orthopaedic Implant, Shanghai Ninth People's Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, 200011, China.
authors.forename: An
authors.initials: A
authors.lastname: Qin
authors.affiliation: Department of Orthopaedics, Shanghai Key Laboratory of Orthopaedic Implant, Shanghai Ninth People's Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, 200011, China.
authors.forename: Kerong
authors.initials: K
authors.lastname: Dai
mesh_terms: D020533:Angiogenesis Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D001859:Bone Neoplasms / Q000188:drug therapy*; D002454:Cell Differentiation / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D006801:Humans; D066298:In Vitro Techniques; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000556:secondary*; D012516:Osteosarcoma / Q000188:drug therapy*; D000077211:Zoledronic Acid / Q000494:pharmacology* / Q000627:therapeutic use
chemical_list: D020533:Angiogenesis Inhibitors; D000077211:Zoledronic Acid
keywords: Bisphosphonate; bone; osteolysis; osteosarcoma; pulmonary metastasis; zoledronic acid