Abstract

Bone metastasis (BM) are the most severe and prevalent consequences of prostate cancer (PC) affecting more than 80% of patients with advanced PC. PCBM generate pain, pathological fractures, and paralysis. As modern therapies increase survival, more patients are suffering from these catastrophic consequences of PCBM. Radiographically, PCBM are predominantly osteosclerotic, but the mechanisms of abnormal bone formation, and how this "more and new" bone is related to fractures is unclear. In this study, we conducted a comprehensive analysis on a cohort of 76 cadaveric PCBM samples and 12 from non-PC donors as control. We used -CT to determine three-dimensional organization and quantify bone characteristics, quantitative backscattering electron microscopy to characterize mineral content and details in bone structure, nano indentation to determine mechanical properties, and we finalize with histological and immunohistochemical analysis of bone structure and composition. We define 4 phenotypes of PCBM, osteolytic, mixed lytic-sclerotic, and two subgroups of osteosclerotic lesions, those with residual trabeculae, and others without residual trabeculae. The osteosclerotic lesions are characterized by the presence of abnormal bone within the trabeculae surfaces and intertrabecular spaces. This abnormal bone is characterized by higher lacunae density, abnormal lacunae morphology and orientation. However, we observed no significant difference between this irregular bone and residual trabeculae in terms of mineral content, hardness, and elastic modulus at micron-scale. The collagen matrix of this abnormal bone presents with irregular organization and is accompanied by increased proteoglycan and phosphorylated glycoprotein content. These characteristics suggests the presence of woven bone in PCBM. However, the lack of subsequent bone remodelling, absence of lamellar bone deposition on its surface, absence of markers of matrix vesicles but evidence of alkaline phosphatase dominated mineralization and collagen-III structure, set up differences from woven bone, while the role of PC cells in inducing this irregular bone phenotype remains unclear.