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.

Ryan C Curtis,Keith W Condon,E J Ehrhart,Sara E Gookin,Nicole P Ehrhart,Seth W Donahue,James T Custis,Carlos M Isales

doi:10.1371/journal.pone.0158005

Ryan C Curtis, Keith W Condon + Show 6 more

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https://doi.org/10.1371/journal.pone.0158005

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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.

Highlights

Osteosarcoma (OSA) is the most common primary bone tumor in dogs, accounting for approximately 85% of all bone cancers [1]
Trabecular bone volume was not increased with parathyroid hormone (PTH) treatment in controls. These results suggest the increased bone volume seen with combination therapy (ZA/PTH) for the irradiated femurs is primarily due to the Zoledronic acid (ZA) treatment
Using an orthotopic model of canine osteosarcoma in athymic rats, we found combination therapy (ZA/PTH) increased bone volume and polar moment of inertia as compared to stereotactic radiation therapy (SRT) alone

Summary

Introduction

Osteosarcoma (OSA) is the most common primary bone tumor in dogs, accounting for approximately 85% of all bone cancers [1]. Osteosarcoma is the most frequently diagnosed primary bone tumor in people and shares many similarities with its canine counterpart [2]. It is a locally aggressive tumor with a high rate of metastasis, typically to the lungs [3]. Due to the goals of therapy, palliative protocols are well tolerated by normal tissues, but never achieve a biologically effective dose (BED) sufficient for long-term tumor control [5,6,7,8]. Definitive-intent radiation therapy, relying solely upon conventional fractionation for normal tissue sparing, fails to achieve a BED sufficient for local tumor control [9]. By achieving significant tumor cell death and maximizing survival time, SRT can be considered for definitive-intent therapy

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