2025 Volume 40 Issue 1 Pages 43-53
Osteosarcoma (OS) is a prevalent primary malignant bone tumor, and many patients with OS experience severe pain. Bisphosphonates, such as zoledronic acid (ZA), reduce bone resorption and pain. However, further clinical pharmacological usefulness for ZA in the pathology of OS has not yet been elucidated. In this study, we generated a mouse model of bone cancer pain by transplanting mouse OS cells into the femoral bone marrow cavity of mice and examined the effects of ZA treatment on persistent pain and survival under OS conditions. We found that in vivo treatment with ZA significantly relieved pain and extended the survival of mice bearing OS cells. Using human iPS cell–derived sensory neurons and human OS cells, in vitro treatment of the supernatant obtained from activated sensory neurons with human OS cells significantly suppressed the anti–cancer effect of cisplatin. Moreover, the supernatant obtained from activated sensory neurons dramatically increased NF–κB–related tumor–promoting signals in OS cells and the enhanced cell migration ability of OS cells. Under these conditions, the suppression of cisplatin–induced anti–cancer effects, the increased expression of NF–κB–related tumor–promoting factors and the increased migration activity of OS cells were inhibited by the co–treatment with ZA. These findings suggest that ZA may suppress severe pain associated with OS progression and induce significant recovery from OS–induced cancer aggravation. Furthermore, the combination of ZA with anti–cancer drugs may pave the way for new therapies against osteosarcoma.
