Phenotypic integration contributes to skeletal functionality and fragilit

Increased risk of bone fracture is generally attributed to the reduced load-bearing capacity associated with small cross-sectional size or mass. Previous studies in inbred mice demonstrated that phenotypic integration among bone traits is critical for establishing long bone functionality by compensating for genetic variants that compromise skeletal size, mass, and strength. However, phenotypic integration also contributes to fracture susceptibility by giving rise to trait sets that were more damageable and brittle. We set out to better understand how phenotypic integration creates sets of bone traits that are functional for daily activities, but contribute to skeletal fragility. An examination of young adult human tibiae revealed that the biological concepts observed in the mouse femur translate to the human skeleton. Slender tibiae compensated for small size by increasing cortical thickness and mineralization. This phenotypic integration produced functional structures, but increases in mineralization resulted in a more brittle and damageable material that would be expected to perform poorly under extreme load conditions (e.g., military training or falling). By combining a systems based approach with a newly developed network theory analysis, we found that phenotypic integration is not limited to long bones, but also affects corticocancellous skeletal sites like the vertebral body. Phenotypic integration among cortical and trabecular traits compensated for genetic variants affecting skeletal size and mass in a manner that created functional load transfer networks in mouse vertebrae. Smaller vertebrae relative to body size would have been unable to support daily loads (i.e., not functional) without increasing tissue mineral density and the relative amounts of cortical and trabecular bone. However, increases in mineral content may increase fracture risk under extreme loading. Together, these results have great clinical significance because they provide two new areas of focus in studying skeletal fragility: (1) sets of traits arising from phenotypic integration that may be susceptible to fracture under challenging physiological conditions and (2) genetic or environmental variants that disrupt the biological processes involved in phenotypic integration and thus affect functionality. By understanding genetic variation in the interaction among sets of traits, our understanding of the genetic basis of skeletal functionality and fragility can be improved.