Systemic Treatments Impact Bone Quality in a Preclinical Model of Mixed Femoral Metastases.

Abstract

Skeletal metastases disrupt bone remodeling, compromising mechanical integrity and increasing fracture risk. Cancer therapies can further influence bone quality. This study aimed to evaluate the impact of systemic cancer therapies (docetaxel (DTX) and zoledronic acid (ZA)) on bone quality in a preclinical model of mixed femoral metastases. Mixed metastases were induced in 5-6-week-old athymic male rats via intracardiac injection of luciferase-transfected ACE-1 canine prostate cancer cells (day 0). Healthy and inoculated rats were randomly assigned to receive no treatment, DTX (5 mg/kg), or ZA (60 μg/kg) on day 10. Tumor development was confirmed with bioluminescence imaging (day 14 and 21). Animals were euthanized on day 21. Bilateral femora were excised and underwent μCT scanning. Trabecular bone in the left femora was segmented for microstructural analysis. The left distal femora were then cut to 1 cm length and stained with barium sulfate for high-resolution μCT imaging to assess microdamage. The cut femora were then loaded to failure under axial compression. The right femora were processed for histology to evaluate bone histoarchitecture and verify tumor presence. DTX, despite lower bone mineral density, bone volume fraction, and trabecular number, showed reduced microdamage accumulation and improved load to failure in inoculated animals. ZA improved microstructural parameters, reduced damage volume fraction, and enhanced load to failure compared to inoculated untreated animals. These findings highlight the differential impact of cancer therapies on the quality of healthy and metastatic bone. Understanding these effects is essential for optimizing treatment strategies and minimizing skeletal complications secondary to skeletal metastases.