Osteoporosis and fracture risk have largely been regarded as heritable diseases of bone loss in the aged population. However, recent discoveries have demonstrated that heritable variability in bone morphology and tissue quality can contribute to bone fragility throughout life. Building upon these findings, we have applied an integrated systems biology and engineering approach to uncover the biological (and ultimately genetic) factors influencing fragility, such as variability in skeletal growth, tissue quality, and bone functionality. Previous work has focused on identifying sets of adult morphological and compositional bone traits that predispose one to either fracture susceptibility or resistance. This work investigated how "at-risk" trait sets are linked to variability in the biology of skeletal growth and functional adaptation. Studying the femoral growth of genetically distinct inbred mice, we have shown that genotype-specific variability in sets of adult traits, and thus whole bone functionality (i.e., strength, stiffness, and fragility), results from genetically defined patterns of periosteal and endosteal growth, and mineral accrual. Importantly, these studies also identified that femoral growth patterns co-vary with measures of tissue quality in adulthood and throughout growth. Thus, growth patterns and tissue composition appear to be co-adapted during growth leading to the construction of sets of bone traits that are well adapted to loading conditions. However, such co-adaption also resulted in the co-variance of tissue brittleness and morphological fitness, thereby explaining how variability in whole bone fragility might arise. Lastly, this research identified several genotype-specific properties of bone cells, at the tissue and population levels, that influenced how clinically relevant variability in growth patterns may arise. These insights from the growth of the mouse skeleton should provide new targets for clinically investigating the genetics of bone fragility and fracture risk.