SUMMARY Cortical bone porosity is a major determinant of bone strength. In fact, age-related increases in cortical porosity account for more than 75% of the concomitant reduction in cortical bone strength. Further, our group and others have found that increased cortical porosity is associated with elevated fracture prevalence in patients with type 2 diabetes (T2D). Despite the biomechanical importance of cortical porosity, the biological drivers of cortical pore expansion are unknown. Filling this knowledge gap will elucidate appropriate cellular targets for drug development to prevent or reverse pathological pore development and the associated skeletal fragility. The biological systems influencing pore expansion can be revealed by visualizing the content of cortical pore space. Our team has developed innovative magnetic resonance imaging (MRI)-based acquisition and processing techniques to visualize vasculature and fat within cortical pores, both of which have been implicated in pore expansion. We propose to detect new pore space formed over the course of a longitudinal skeletal imaging study, identify the content of that new pore space, and in this way determine the biological system(s) driving development of the new pore space. The proposed parent study is an ongoing longitudinal study of cortical pore development in the context of T2D. The aim of the parent study is to quantify longitudinal changes in cortical porosity in patients with T2D and in healthy controls. Further, the parent study applies our MRI-based pore content visualization technique to the baseline time-point of the study (only) to compare pore content between T2D and healthy cohorts and to evaluate associations between pore content and clinical evaluations of vascular health and fat metabolism. The parent study does not include MRI at the follow-up visit, and therefore will not be able to answer the question: In T2D and healthy controls, is the vascular system, the marrow fat, or both responsible for increased cortical porosity over time? In this ancillary study, we will add the MRI-based pore content visualization to the follow-up visit of the parent study. We will directly image the content of pores that develop and/or expand over the 2-year follow-up period, and in this way reveal the mechanisms associated with pore space expansion. By leveraging the parent study we capture a well- characterized cohort, with all necessary clinical and imaging data already acquired, with the exception of the follow-up MRI. This application meets the time sensitivity requirement of the funding announcement: in order to efficiently leverage the established parent study cohort, the pore content visualization technique must be added by early 2020. This work will identify the biological systems driving increased porosity associated with aging and T2D, as well as potential drug targets for the prevention or reversal of age- and T2D-related pathological porosity and bone fragility, laying the groun...