Two inbred rat strains that differ substantially in hip fragility

One approach to identifying the genetic influences on skeletal phenotypes involves the creation and genetic mapping of a population of the second filial (F2) offspring derived from a cross of two inbred strains of rodents. The two inbred strains should be chosen based upon a large difference in the phenotype of interest, e.g., bone fragility. We found previously that considerable variation exists in fragility phenotypes among inbred strains of rats, and the phenotypic variation was site specific. In particular, two inbred rat strains, Copenhagen 2331 (COP) and Dark Agouti (DA), were found to differ significantly in femoral neck geometry and strength. The aim of this study was to further characterize hip fragility in COP and DA rats at 6 months of age using peripheral quantitative computed tomography (pQCT), microcomputed tomography (mCT), and biomechanical tests. COP rats had a significantly wider femoral head (P = 0.04) and neck (P = 0.007), significantly larger bone area and cortical bone area in femoral neck (P = 0.03 and P = 0.02, respectively), significantly greater total bone mineral content (BMC) and cortical BMC in femoral neck (P = 0.01 and P = 0.001, respectively), and 65% greater femoral neck cross-sectional moment of inertia (P = 0.02), as compared with DA rats. As a result, COP rats had 22% higher ultimate force (Fu), 68% higher ultimate displacement (du), and 81% higher work to failure (U) than DA rats in the femoral neck biomechanical test (P = 0.04, P = 0.01, and P = 0.02, respectively). The biomechanical properties for the femoral midshaft and lumbar vertebrae were virtually the same in the two rat strains, suggesting a hip-specific genetic effect on bone strength. These data indicate that significant phenotypic variation at the femoral neck site exists between these two inbred strains, and COP rats appear to have genes that specifically enhance the femoral neck structural properties and strength. Therefore these two inbred strains, COP with DA, may facilitate effective genetic studies of hip fragility.