Biological constraints that limit compensation of a common skeletal trait variant lead to inequivalence of tibial function among healthy young adults.

Having a better understanding of how complex systems like bone compensate for the natural variation in bone width to establish mechanical function will benefit efforts to identify traits contributing to fracture risk. Using a collection of pQCT images of the tibial diaphysis from 696 young adult women and men, we tested the hypothesis that bone cells cannot surmount the nonlinear relationship between bone width and whole bone stiffness to establish functional equivalence across a healthy population. Intrinsic cellular constraints limited the degree of compensation, leading to functional inequivalence relative to robustness, with slender tibias being as much as two to three times less stiff relative to body size compared with robust tibias. Using Path Analysis, we identified a network of compensatory trait interactions that explained 79% of the variation in whole-bone bending stiffness. Although slender tibias had significantly less cortical area relative to body size compared with robust tibias, it was the limited range in tissue modulus that was largely responsible for the functional inequivalence. Bone cells coordinately modulated mineralization as well as the cortical porosity associated with internal bone multicellular units (BMU)-based remodeling to adjust tissue modulus to compensate for robustness. Although anecdotal evidence suggests that functional inequivalence is tolerated under normal loading conditions, our concern is that the functional deficit of slender tibias may contribute to fracture susceptibility under extreme loading conditions, such as intense exercise during military training or falls in the elderly. Thus, we show the natural variation in bone robustness was associated with predictable functional deficits that were attributable to cellular constraints limiting the amount of compensation permissible in human long bone. Whether these cellular constraints can be circumvented prophylactically to better equilibrate function among individuals remains to be determined.