Caloric Restriction Diet Attenuates Systemic Bone Fragility after Radiotherapy

Abstract

Bone fragility is a well-documented long-term side effect of radiotherapy, which currently has no preventative treatments. In this study, we applied a caloric restriction (CR) diet to attenuate both local and systemic bone loss after irradiation (RTx) in an established female Balb/c mouse model (4 consecutive daily doses of 5 Gy to the right hindlimb only). CR mice were tapered down to a 30% reduced calorie diet (RTx/CR) one week before irradiation, while regular diet (RD) mice received food ad libitum (RTx/RD). Unirradiated (sham) mice received either a 30% CR diet (SH/CR) or received food ad libitum (SH/RD). Irradiated, contralateral, and unirradiated hindlimbs were evaluated at 2, 4, and 8 weeks postirradiation using micro-computed tomography (μCT) to assess bone morphology and 3-point bending to quantify femur strength. Histological analysis of irradiated and unirradiated tibiae was performed to examine general bone tissue cytology and serum biomarker analysis was performed using terminal blood draw samples. After treatment, femur strength and metaphyseal bone quantity was decreased in irradiated and contralateral femora of RTx/RD mice compared to SH/RD femurs; this finding is consistent with previous studies. RTx/CR mice had positive effects when compared to RTx/RD mice, including increased strength relative to body mass in both the irradiated and contralateral limb, increased trabecular bone mass, and decreased marrow adiposity. However, a number of adverse effects were also observed, including a significant decrease in body mass and decreased cortical bone. Overall, CR shows promise as a preventative treatment for postirradiated bone fragility, yet questions remain to be addressed in future studies. Ideal diet duration, impact to normal tissue, and mechanism of action must be explored to better understand the clinical implication of a CR diet.