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Endocrinology, Metabolism and Clinical Nutrition

Bone Biomechanical Performance

Over 2 million low trauma fractures occur annually in the US. A woman’s lifetime low trauma fracture risk approaches 50%, and 1 year mortality following hip fracture approaches 25%. Low trauma fractures are therefore a leading cause of morbidity, mortality, and health care spending.

The Blank lab has a long-standing interest in the genetic basis of variation in bone’s biomechanical performance. 3-point bending tests, along with supporting imaging, biochemistry, genotyping, and gene expression data allow us to obtain a comprehensive understanding of what makes bones differ in how hard they are to break. A key concept is that there are multiple aspects of biomechanical performance; they are all important and each is distinct from the others. Stiffness is a measure of how much a bone deforms in response to applied force or load. Strength is a measure of how much force a bone can absorb before fracturing. Ductility (the opposite of brittleness) is a measure of how much a bone will bend before it fractures. All of these can be measured in the 3-point bending test. Ultimately, three different domains determine a bone’s mechanical behavior—the detailed composition of its tissue, its size, and its shape.

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3 Point Bending Test. The test setup is shown schematically on the left. An Actual test is shown on the right.

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Parameters extracted from a 3 point bending test. Displacement of the crosshead, reflecting downward motion of the bone, is shown on the X axis. Load applied to the bone is shown on the Y axis. The stiffness of the bone is the slope of the elastic region. Other mechanical parameters are labeled in the image.

Approximately 70% of the variation in bone properties can be attributed to genetics. We have used the general approach described above to map quantitative trait loci (QTLs) for bone biomechanical performance and construct new congenic mouse strains in which these have been isolated. Many medically important traits, including fracture susceptibility are controlled by multiple, interacting genes as well as the environment. By relating trait values to genotype, it is possible to detect the contributions of chromosome regions and specific genes to the trait.

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Micro-CT scans of femora from HcB-8 and HcB-23 male mice. Note the difference in size and shape. Scale bar = 1 mm.

We recently completed a collaborative study with Denise Ney to determine the contributions of genotype and diet to reduced biomechanical performance in a mouse model of phenylketonuria (PKU). We found that the mice with PKU have a global defect in biomechanical performance, regardless of diet. We further found that the amino acid diet used to treat PKU impairs bone growth, while a novel diet attenuates the impact of the restricted diet.

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Representative load displacement curves for a normal mouse (blue) and a mouse with PKU (red). The mouse with PKU has lesser stiffness, lesser strength, lesser ductility, and absorbs less energy prior to fracture.

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Cross-sections through the femoral mid-diaphysis of mice fed the indicated diets.