Combination Therapy with Zoledronic Acid and Parathyroid Hormone Improves Bone Architecture and Strength following a Clinically-Relevant Dose of Stereotactic Radiation Therapy for the Local Treatment of Canine Osteosarcoma in Athymic Rats

PLoS One. 2016 Jun 22;11(6):e0158005. doi: 10.1371/journal.pone.0158005. eCollection 2016.

Abstract

Clinical studies using definitive-intent stereotactic radiation therapy (SRT) for the local treatment of canine osteosarcoma (OSA) have shown canine patients achieving similar median survival times as the current standard of care (amputation and adjuvant chemotherapy). Despite this, there remains an unacceptable high risk of pathologic fracture following radiation treatment. Zoledronic acid (ZA) and parathyroid hormone (PTH) are therapeutic candidates for decreasing this fracture risk post-irradiation. Due to differing mechanisms, we hypothesized that the combined treatment with ZA and PTH would significantly improve bone healing more than ZA or PTH treatment alone. Using an orthotopic model of canine osteosarcoma in athymic rats, we evaluated bone healing following clinically-relevant doses of radiation therapy (12 Gy x 3 fractions, 36 Gy total). Groups included 36 Gy SRT only, 36 Gy SRT plus ZA, 36 Gy SRT plus ZA and PTH, 36 Gy SRT plus PTH, and 36 Gy SRT plus localized PTH treatment. Our study showed significant increases in bone volume and increased polar moments of inertia (in the distal femoral metaphysis) 8 weeks after radiation in the combined (ZA/PTH) treatment group as compared to radiation treatment alone. Histomorphometric analysis revealed evidence of active mineralization at the study endpoint as well as successful tumor-cell kill across all treatment groups. This work provides further evidence for the expanding potential indications for ZA and PTH therapy, including post-irradiated bone disease due to osteosarcoma.

MeSH terms

  • Animals
  • Bone and Bones / diagnostic imaging
  • Bone and Bones / pathology*
  • Calcification, Physiologic
  • Combined Modality Therapy
  • Diphosphonates / therapeutic use*
  • Dogs
  • Dose-Response Relationship, Radiation
  • Drug Therapy, Combination
  • Female
  • Imidazoles / therapeutic use*
  • Luminescence
  • Osteosarcoma / drug therapy*
  • Osteosarcoma / radiotherapy*
  • Parathyroid Hormone / therapeutic use*
  • Rats, Nude
  • Stereotaxic Techniques*
  • Tartrate-Resistant Acid Phosphatase / metabolism
  • Time Factors
  • X-Ray Microtomography
  • Zoledronic Acid

Substances

  • Diphosphonates
  • Imidazoles
  • Parathyroid Hormone
  • Zoledronic Acid
  • Tartrate-Resistant Acid Phosphatase

Grant support

Supported by a Cancer Supercluster Grant from Colorado State University’s Flint Animal Cancer Center.