title: Zoledronic acid protects against osteosarcoma-induced bone destruction but lacks efficacy against pulmonary metastases in a syngeneic rat model.
abstract: Osteosarcoma (OS) is the most common primary malignant tumor of bone in children and adolescents. In spite of successful control of the primary tumor, death from lung metastasis occurs in more than a third of patients. To investigate the efficacy of zoledronic acid (ZOL) on the development, progression and metastatic spread of OS, we used a rat model of OS, with features of the disease similar to human patients, including spontaneous metastasis to lungs. Rat OS cells were inoculated into the tibial marrow cavity of syngeneic rats. OS development was associated with osteolysis mixed with new bone formation, adjacent to the periosteum and extended into the surrounding soft tissue. Metastatic foci in the lungs formed 3-4 weeks postcancer cell transplantation. Treatment with a clinically relevant dose of ZOL was initiated 1 week after tumors were established and continued once weekly or as a single dose. ZOL preserved the integrity of both trabecular and cortical bone and reduced tumor-induced bone formation. However, the overall tumor burden at the primary site was not reduced because of the persistent growth of cancer cells in the extramedullary space, which was not affected by ZOL treatment. ZOL treatment failed to prevent the metastatic spread of OS to the lungs. These findings suggest that ZOL as a single agent protects against OS-induced bone destruction but lacks efficacy against pulmonary metastases in this rat model. ZOL may have potential value as an adjuvant therapy in patients with established OS.
authors.affiliation: University of Adelaide, The Royal Adelaide Hospital, Adelaide, South Australia, Australia.
authors.forename: Agatha
authors.initials: A
authors.lastname: Labrinidis
authors.forename: Shelley
authors.initials: S
authors.lastname: Hay
authors.forename: Vasilios
authors.initials: V
authors.lastname: Liapis
authors.forename: David M
authors.initials: DM
authors.lastname: Findlay
authors.forename: Andreas
authors.initials: A
authors.lastname: Evdokiou
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D050071:Bone Density Conservation Agents / Q000494:pharmacology*; D001859:Bone Neoplasms / Q000473:pathology / Q000517:prevention & control*; D001862:Bone Resorption / Q000209:etiology / Q000473:pathology / Q000517:prevention & control*; D020169:Caspases / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D004164:Diphosphonates / Q000494:pharmacology*; D007093:Imidazoles / Q000494:pharmacology*; D008175:Lung Neoplasms / Q000188:drug therapy / Q000473:pathology* / Q000556:secondary; D008297:Male; D012516:Osteosarcoma / Q000473:pathology / Q000517:prevention & control*; D051381:Rats; D011916:Rats, Inbred F344; D000077211:Zoledronic Acid
chemical_list: D050071:Bone Density Conservation Agents; D004164:Diphosphonates; D007093:Imidazoles; D000077211:Zoledronic Acid; D020169:Caspases