ABSTRACT More than 10 million Americans are affected by osteoporosis, and an estimated 40 million Americans are at risk of osteoporosis from decreased bone mass. In addition to primary osteoporosis affecting post-menopausal women and the elderly, secondary osteoporosis from conditions such as plasma cell disorders, lupus and hyperparathyroidism also increases the risk of skeletal fractures. The spine is a prevalent site for osteoporotic fractures resulting in substantial morbidity due to debilitating consequences such as pain and immobility. Current diagnostic approach for osteoporosis evaluation such as dual-energy x-ray absorptiometry (DXA) lack the spatial resolution to characterize trabecular microarchitecture, a crucial marker of bone quality. Considering the high socioeconomic burden related to skeletal fragility, there is an unmet clinical need to develop a quantitative bone characterization technique that can comprehensively measure cortical and trabecular microstructures in vivo. Photon-counting detector (PCD) CT has been recently introduced for clinical use. We have demonstrated numerous technical and clinical benefits of PCD-CT for musculoskeletal imaging. A single PCD-CT scan offers both high spatial resolution (110 µm) and spectrally resolved x-ray data which are beneficial for characterizing trabecular morphometry and volumetric bone density. The long-term goal of our work is to extract imaging biomarkers of bone quality for routine assessment of skeletal fragility and guide timely initiation and monitoring of pharmacologic therapies in patients at high risk of osteoporotic fractures. The objective of this proposal is to demonstrate the clinical utility of PCD-CT in characterizing bone quality in the vertebrae of patients undergoing pharmacologic therapy for osteoporosis. We propose to meet this objective by first developing and validating a quantitative spine PCD-CT imaging methodology using cadavers and compare the results to a high-resolution reference standard (micro-CT) in Aim 1, and clinically translate the imaging methodology in Aim 2 to demonstrate in vivo bone quantification in osteoporotic patients. The significance of our proposed technique is that it will enable accurate characterization of bone quality on a clinically available CT system for direct or opportunistic bone quality assessment.