Bone Fragility: Time to Address the Matrix.

Mechanical failure of bone - not bone density - is the primary clinical concern for skeletal disorders and diseases. Bone mass and density are major contributors to whole bone strength, which is why therapeutics that regulate bone volume by altering resorption and formation are so effective. However, there are limits to the increases in bone mass and density achieved with existing therapeutics and challenges in maintaining gains after treatment is suspended. This perspective focuses on a major contributor to whole bone strength that is not directly addressed by existing therapeutics: the quality of bone extracellular matrix as measured by matrix mechanical properties. We review studies showing: a) whole bone strength is much more sensitive to variation in bone matrix quality than to bone mass/density, b) bone matrix quality varies in humans in ways sufficient to influence whole bone strength, and c) interventions may alter bone matrix quality with minimal effects on bone mass/density. A major limitation to discovering methods for improving bone matrix quality is that most preclinical studies focus on bone formation and bone density/mass and do not measure or report bone matrix mechanical properties. Identifying mechanisms that enhance bone matrix quality will require faster and more precise biomechanical assessments of bone matrix and studies specifying the molecular mechanisms that regulate the composition of bone extracellular matrix. While there are many observational reports of differences in bone matrix among individuals, here we argue it is time to go beyond observational studies and consider bone matrix as an attractive therapeutic target.