Increased bone strength is associated with improved bone microarchitecture in intact female rats treated with strontium ranelate: A finite element analysis study

Strontium ranelate has been previously shown to act on bone metabolism and to be effective in postmenopausal osteoporosis treatment by preventing vertebral and non-vertebral fractures. Animal studies explicitly demonstrated that bone strength was improved with strontium ranelate treatment, but the contribution of either improved bone microarchitecture or intrinsic quality of the bone tissue is not clear. Therefore, the purpose of this research was to address this issue by using the unique capability of finite element (FE) analysis to integrate both intrinsic bone quality properties from nano-indentation and microarchitecture measured by micro-computed tomography (μCT). The two groups included intact female Fischer rats fed a normal diet (controls, N = 12) or a diet containing strontium ranelate (900 mg/kg/day; N = 12) for a period of 104 weeks. The L5 vertebra was scanned by μCT and a morphological analysis of the vertebral body was performed. Subsequently, those μCT data were the basis of FE models with added virtual endcaps that simulated axial compression tests. The FE models were solved with the vertebral bodies only and repeated with the vertebral processes intact. In the initial stages, the intrinsic bone properties were kept constant between the control and the treated animals in order to independently study the impact of microarchitectural changes on bone strength. Morphological data indicated a significant improvement in bone microarchitecture associated with strontium ranelate compared to controls, including a 40% (p < 0.01) higher trabecular thickness, a 28% (p < 0.01) higher cortical thickness, and no significant change in the number of trabeculae (p = 0.56). The poor correlation of bone strontium content against bone volume fraction (BV/TV) (R2 = 0.013, p = 0.74) and BMD (R2 = 0.153, p = 0.23) indicated that the morphological data were not biased by the presence of strontium in bone. The FE simulations demonstrated a 22% (p < 0.01) increase of stiffness and 29% (p < 0.01) increase in strength compared to controls. The magnitudes were greater, but the relative differences were similar when the entire intact vertebra was modeled compared to the vertebral body alone. Adjusting the FE models to account for differences in intrinsic bone tissue quality between control and treated animals resulted in an even higher bone strength with strontium ranelate. Furthermore, load transfer in strontium ranelate treated animals shifted from an equal distribution between cortical and trabecular compartments to more load being supported by the trabecular bone (a shift of 8%, p < 0.02). Tissue-level stresses were reduced on average (− 7%, p < 0.01) and more homogeneously distributed. Together, these findings indicated that, independently from bone strontium content, microarchitectural adaptations played a major role in the increased bone strength associated with strontium ranelate exposure and that the changes in load distribution resulted in patterns that were more favorable to resisting fracture.

Research Highlights
► Bone quality in rats treated with strontium ranelate.
► Analysis based on micro-CT and the finite element method.
► Microarchitecture was improved independent of bone strontium content.
► Both microarchitecture and intrinsic bone quality lead to improved strength.
► Patterns of load distribution were more favorable to resisting fracture.