Local irradiation alters bone morphology and increases bone fragility in a mouse model

Abstract

Insufficiency fracture following radiation therapy (RTx) is a challenging clinical problem and typical bone mass measures fail to predict these fractures. The goals of this research were to develop a mouse model that results in reduced bone strength following focal irradiation, quantify morphological and strength changes occurring over time, and determine if a positive correlation between bone morphology and strength is retained after irradiation. Right hind limbs of 13 week-old female Balb/c mice were irradiated (5 or 20 Gy) using a therapeutic X-ray unit. Left limbs served as control. Animals were euthanized at 2, 6, 12, or 26 weeks. Axial compression tests of the distal femur were used to quantify whole bone strength. Specimen-specific, non-linear finite element (FE) analyses of the mechanical tests were performed using voxel-based meshes with two different material failure models: a linear bone density-strength relationship and a non-linear 'embrittled' relationship. Radiation resulted in a dose dependent increase in cortical bone density and marked loss of trabecular bone, measured using micro-CT. An early (2 week) increase in bone volume was associated with an increase in bone strength following irradiation; at 12 weeks there was a loss of bone strength despite higher bone volume for irradiated limbs. There was a positive correlation between bone volume bone and strength in control (r²=0.63) but not irradiated femora (r²=0.08). FE analysis with a constant strain failure model resulted in improved prediction of bone strength for irradiated limbs (r²=0.34) and this was improved further with the embrittled material model (r²=0.46). In summary, focal irradiation leads to substantial changes in bone morphology and strength with time, where there is a decreased bone strength following irradiation in the face of increasing bone mass; FE models with a non-linear embrittled material model were most successful in simulating these experimental findings.