Temporal changes in bone mass and mechanical properties in a murine model of tumor osteolysis

Pathological fracture is a devastating complication of osteolytic bone metastases. The progression of osteolysis and its effect on bone fracture risk are poorly understood. The goal of this study was to determine the temporal changes in bone strength following tumor inoculation in a preclinical model of tumor osteolysis. In addition, a predictive model was developed between non-invasive radiographic measures and bone strength. The right femora of female nude mice were injected with breast cancer cells; the left limb served as a sham-operated control. Radiographs and DEXA scans were obtained at the time of surgery and at 3, 6, and 9 weeks. Groups of mice were euthanized at each time point for mechanical assessment. Micro-CT analysis was performed on a sub-set of mice with advanced state disease to quantify bone loss. Radiographs documented an increase in tumor osteolysis over time, with 58% of the mice showing signs of osteolysis at 3 weeks, 75% at 6 weeks, and 81% at 9 weeks. BMD measurements revealed a 21.6% increase from baseline in the controls whereas tumor-injected femora failed to increase in BMD over the same time course. Tumor-bearing limbs exhibited statistically significant decreases in torque at failure (86%), energy to failure (88%), and initial stiffness (94%) compared to the controls. Both lysis scores and BMD measurements proved to be modest predictors of mechanical strength, accounting for approximately 73% and 41% of variation in torque at failure, respectively. Micro-CT analysis revealed decreases in both total bone volume in the distal femur (31%) and metaphyseal fractional trabecular bone (89%). We have shown that non-invasive radiographic techniques provide a useful tool for monitoring the progression of tumor osteolysis and for predicting the mechanical strength of tumor-bearing bones in this model. By integrating non-invasive measures of tumor osteolysis and fracture risk, we have validated a clinically relevant platform for evaluating new therapeutic approaches for preserving and/or restoring bone affected by metastatic disease.