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Prostate cancer (PCa) frequently metastasizes to the bone, generally inducing osteoblastic alterations that increase bone brittleness. Although there is growing interest in the management of the physical capability of patients with bone metastasis, the mechanism underlying the impairment of bone mechanical function remains unclear. The alignment of both collagen fibrils and biological apatite (BAp) c-axis, together with bone mineral density, is one of the strongest contributors to bone mechanical function. In this study, we analyzed the bone microstructure of the mouse femurs with and without PCa cell inoculation. Histological assessment revealed that the bone-forming pattern in the PCa-bearing bone was non-directional, resulting in a spongious structure, whereas that in the control bone was unidirectional and layer-by-layer, resulting in a compact lamellar structure. The degree of preferential alignment of collagen fibrils and BAp, which was evaluated by quantitative polarized microscopy and microbeam X-ray diffraction, respectively, were significantly lower in the PCa-bearing bone than in the control bone. Material parameters including Young's modulus and toughness, measured by the three-point bending test, were simultaneously decreased in the PCa-bearing bone. Specifically, there was a significant positive correlation between the degree of BAp c-axis orientation and Young's modulus. In conclusion, the impairment of mechanical function in the PCa-bearing bone is attributable to disruption of the anisotropic microstructure of bone in multiple phases. This is the first report demonstrating that cancer bone metastasis induces disruption of the collagen/BAp alignment in long bones, thereby impairing their mechanical function.

Recently, there have been remarkable advances in medical techniques for regenerating bone defects. To determine the degree of bone regeneration, it is essential to develop a new method that can analyze microstructure and related mechanical function. Here, quantitative analysis of the orientation distribution of biological apatite (BAp) crystallites by a microbeam X-ray diffractometer system is proposed as a new index of bone quality for the evaluation of regenerated bone microstructure. Preferential alignment of the BAp c-axis in the rabbit ulna and skull bone, regenerated by controlled release of basic fibroblast growth factor (bFGF) was investigated. The BAp c-axis orientation was evaluated by the relative intensity between the (002) and (310) diffraction peaks, or the three-dimensional texture for the (002) peak. It was found that new bone in the defects was initially produced without preferential alignment of the BAp c-axis, and subsequently reproduced to recover towards the original alignment. In other words, the BAp density recovered prior to the BAp orientation. Perfect recovery of BAp alignment was not achieved in the ulna and skull defects after 4 weeks and 12 weeks, respectively. Apparent recovery of the macroscopic shape and bio-mineralization of BAp was almost complete in the ulna defect after 4 weeks. However, an additional 2 weeks was required for complete repair of BAp orientation. It is finally concluded that orientation distribution of BAp crystallites offers an effective means of evaluating the degree of microstructural regeneration, and also the related mechanical function, in regenerated hard tissues.

Preferential orientation of biological apatite (Ap) crystallites in typical calcified tissues of rabbit ulna, rabbit skull, and monkey dentulous mandible was investigated using a microbeam X-ray diffractometer, with a beam spot of 100 microm in diameter, to clarify relationship between the Ap orientation and mechanical function. Preferential alignment of the c-axis of the biological Ap was evaluated by the relative intensity between (002) and (310) diffraction peaks. Preferential alignment of biological Ap in each calcified tissue varied depending on the shape and stress condition in vivo; that is, the c-axes of biological Ap in the rabbit ulna and the rabbit skull bone were preferentially observed as a one-dimensional orientation along the longitudinal axis and a two-dimensional orientation along the surface, respectively. Precise analysis of the preferential alignment along the skull surface showed an elliptical distribution of the c-axis of biological Ap elongating along the suture inside the skull surface of both lamina exterior and interior. The c-axis of biological Ap in a monkey dentulous mandible basically aligned along the mesiodistal direction in the flat bone, but this alignment changed along the normal direction to the flat bone surface parallel to the biting direction near the tooth, due to the force of mastication. It was concluded that the microscale measurement of biological Ap texture is one of the useful new methods for evaluating mechanical function and stress distribution in vivo in calcified tissues.