Zoledronic acid suppresses lung metastases and prolongs overall survival of osteosarcoma-bearing mice

Cancer. 2005 Dec 1;104(11):2522-9. doi: 10.1002/cncr.21530.


Background: Although there is no doubt that bisphosphonates (BPs), specific inhibitors of osteoclasts, are beneficial for the treatment of bone metastases, their effects on visceral metastases are unclear. The effect of zoledronic acid (ZOL) was examined in vivo on lung metastasis progression and animal survival, and in vitro on the cellular mechanisms involved.

Methods: An animal model of lung metastasis was developed in C3H/He mice inoculated intravenously with a spontaneous murine osteosarcoma POS-1 cell line. Lung metastasis was determined at the time of autopsy. ZOL was assessed in vitro on POS-1 cell proliferation, cell cycle progression, and caspase-1 and -3 activities.

Results: The overall survival in five independent experiments (two series treated with ZOL 0.1 mg/kg twice a week, and three series with 0.1 mg/kg five times a week) showed a significant increase of the actuarial survival: 0.422 +/- 0.07 in ZOL-treated animals versus 0.167 +/- 0.07 in controls (P = 0.036). Lung metastases were absent in all ZOL-treated mice that survived more than 21 days postinjection as revealed by macroscopic and histologic analysis. In vitro, a 48-hour incubation with 10 microM ZOL inhibited POS-1 cell line proliferation associated with cell cycle arrest in S-phase. In addition, ZOL induced a weak increase of caspase-3 activity, but not caspase-1.

Conclusion: We demonstrate that ZOL exerts a direct antitumor effect on POS-1 cells in vitro, significantly diminishes osteosarcoma-induced lung metastasis in vivo, thereby prolonging survival of POS-1-inoculated animals.

MeSH terms

  • Animals
  • Bone Density Conservation Agents / therapeutic use*
  • Bone Neoplasms / drug therapy*
  • Bone Neoplasms / mortality
  • Bone Neoplasms / pathology
  • Diphosphonates / therapeutic use*
  • Disease Models, Animal
  • Imidazoles / therapeutic use*
  • Lung Neoplasms / mortality
  • Lung Neoplasms / secondary*
  • Male
  • Mice
  • Mice, Inbred C3H
  • Osteosarcoma / drug therapy*
  • Osteosarcoma / mortality
  • Osteosarcoma / pathology
  • Survival Analysis
  • Zoledronic Acid


  • Bone Density Conservation Agents
  • Diphosphonates
  • Imidazoles
  • Zoledronic Acid