Introduction

Zoledronic acid (ZA) is a third-generation bisphosphonate with high affinity for areas of bone resorption. Preclinical studies have investigated its role as an anti-neoplastic agent, both independently and synergistically, with radiation therapy (RT). ZA+RT act synergistically in numerous human neoplastic cell lines. The exact mechanism of ZA’s radiosensitization has not been fully elucidated. It may also have immunomodulatory effects on the tumor microenvironment, including tumor-associated macrophages.

Methods

We investigated cell viability and apoptosis in canine osteosarcoma (OS) cells treated with ZA+RT: 0, 2, 4, and 8 Gy of RT and 10-fold increases of ZA. Secondly, we evaluated cell cycle arrest at 0, 4, 24, and 48 hours post ZA, to decipher an ideal neo-adjuvant timepoint. Finally, we treated 20 dogs with naturally occurring OS with 0.1 mg/kg ZA IV 24 hours prior to receiving 8 Gy of RT (once weekly fraction x 4 weeks).

Results

Apoptosis was significantly increased, and viability decreased in ZA+RT treated canine OS cells. Preliminary data showed ZA treatment shifts cells from G1 to S phase. Twenty dogs were prospectively treated with ZA+RT and had MST of 254 days; dogs receiving adjuvant carboplatin (n=11, MST 444 days) had significantly longer MST compared to dogs that did not (n=9, MST 211 days, p=0.02). Two out of 20 dogs (10%) developed pathologic fracture.

Conclusion

With clinically acceptable survival times noted in our canine OS patients and a low fracture rate, ZA+RT is an appropriate treatment for non-surgical candidates. Future studies should evaluate the immune role ZA+RT play in both human and canine OS.

Funding Information

Intramural funds.