Osteoporosis is a significant public health concern. Currently half of Americans over 50 will experience an osteoporotic fracture, with occurrences expected to increase as the population ages. By 2025, osteoporotic fractures will have an estimated cost of $25.3 billion. Furthermore, morbidity and mortality increases following all major fractures. It is widely understood that compromised bone strength is the underlying

pathophysiology of osteoporosis. Currently, bone mineral density is the basis for diagnosis and is the primary target for osteoporosis therapy. Although bone mineral density is an important clinical tool, it only explains up to 55 % of fractures. Fundamentally, bone strength has two interconnected, but distinct, components:​ quantity and quality. While bone mineral density reflects quantity, bone quality reflects morphology and matrix composition properties. The study and clinical translation of bone-matrix quality has been stymied by an incomplete understanding of its genetic basis.

To bridge this gap in knowledge, multiple approaches were employed to investigate the genetic control of bone-matrix quality. First, a classical population genetics approach was used to determine the extent to which bone-matrix quality variation was explained by genetic variation. A genetically diverse cohort of inbred mice demonstrated that genetic background accounts for most of the variation in bone-matrix quality. Furthermore, parameters of bone-matrix quality were associated with mechanical properties of bone after accounting for mass and geometry. Next, a systems genetics approach was used on a murine model of estrogen deficiency, which mimics human post-menopausal bone loss. Constructing weighted gene regulatory networks, putative regulatory genes were identified under homeostatic and pathologic conditions.

These results suggest that bone matrix quality is influenced by genetics and participates in maintaining tissue-level mechanical properties. Furthermore, identifying putative regulatory genes is clinically significant as they are presumptive targets for developing novel therapeutics. Altogether, this body of work establishes the foundation for prospective studies further exploring the mechanisms and therapeutic potential of bonematrix quality.