Bench to Bedside: Animal Models of Radiation Induced Musculoskeletal Toxicity

Abstract

Ionizing radiation is a critical aspect of current cancer therapy. While classically mature bone was thought to be relatively radio-resistant, more recent data have shown this to not be the case. Radiation therapy (RT)-induced bone loss leading to fracture is a source of substantial morbidity. The mechanisms of RT likely involve multiple pathways, including changes in angiogenesis and bone vasculature, osteoblast damage/suppression, and increased osteoclast activity. The majority of bone loss appears to occur rapidly after exposure to ionizing RT, with significant changes in cortical thickness being detectable on computed tomography (CT) within three to four months. Additionally, there is a dose–response relationship. Cortical thinning is especially notable in areas of bone that receive >40 gray (Gy). Methods to mitigate toxicity due to RT-induced bone loss is an area of active investigation. There is an accruing clinical trial investigating the use of risderonate, a bisphosphonate, to prevent rib bone loss in patients undergoing lung stereotactic body radiation therapy (SBRT). Additionally, several other promising therapeutic/preventative approaches are being explored in preclinical studies, including parathyroid hormone (PTH), amifostine, and mechanical loading of irradiated bones.

Animal Models for Radiotherapy Research: All (Animal) Models Are Wrong but Some Are Useful

“…This approach was combined with single-photon emission computed tomography (SPECT) imaging for the functional assessment of early region-specific radiation-induced liver damage. The review from Farris et al [ 11 ] covers current preclinical studies aimed at investigating the biological basis of radiation-induced musculoskeletal toxicity, another major source of morbidity in patients receiving radiotherapy. Furthermore, Pazzaglia and colleagues [ 12 ] provide a comprehensive review of the mechanisms and therapeutic implications of neurocognitive decline following radiotherapy, with an emphasis on radiation-induced stem cell injury and its functional consequences.…”

Should Postoperative Radiation for Long Bone Metastases Cover Part or All of the Orthopedic Hardware? Results of a Large Retrospective Analysis

“…Although one concern with the use of large field radiation might be higher rates of hardware failure, we found that this commonly occurred in the setting of local recurrence (11 of 17). While RT can lead to hardware failure by impairing bone repair and remodeling [9,10], previous data support the finding that failure is highly correlated with recurrence [11], therefore emphasizing tumor control as the primary objective.…”

Relations Between Bone Quantity, Microarchitecture, and Collagen Cross‐links on Mechanics Following In Vivo Irradiation in Mice

“…Thus, it is possible that there are more significant systemic effects taking place in our model. It is also possible that our model is conservative with respect to clinical applicationswith a dose larger than 5 Gy applied locally to the surrounding bone tissue, the bone quantity, quality, microarchitecture, and collagen structure may be further degraded (20) such that they contribute to the increased risk in fracture (80) . Despite these limitations, our results suggest implications with respect to future studies on spaceflight and clinical irradiation.…”

“…It is also possible that our model is conservative with respect to clinical applications—with a dose larger than 5 Gy applied locally to the surrounding bone tissue, the bone quantity, quality, microarchitecture, and collagen structure may be further degraded ( 20 ) such that they contribute to the increased risk in fracture. ( 80 )…”