PROJECT SUMMARY / ABSTRACT Extremes of bone turnover are common in patients with chronic kidney disease (CKD), a population with exceptionally high fracture risk. Medical management of fracture risk in CKD requires assessment of bone turnover. Bone turnover assessment is important because either high or low bone turnover can lead to low bone mass and fracture risk, but treatment in these two bone turnover scenarios are diametrically opposite. There are now FDA approved medications that can either decrease (e.g. bisphosphonates) or increase (e.g. teriparatide) bone turnover, but these must be used carefully in CKD to avoid exacerbating fracture risk. The gold standard measurement of bone turnover in CKD requires bone biopsy and histomorphometry, which is invasive, expensive, and not widely available. While blood biomarkers can give insights to bone turnover in the general population, these biomarkers are cleared from the body by the kidneys, and therefore are uniformly elevated and disassociated with bone turnover rates in CKD patients. Clinically available bone imaging modalities quantify bone mass, but cannot determine bone turnover rates. Thus, a particularly important clinical need is to identify novel methods to assess bone turnover rates non-invasively in CKD patients. Such innovations would immediately impact clinical practice to prevent fractures in CKD. High resolution peripheral quantitative computed tomography (HR-pQCT) can image bone in fine detail with low radiation dose. Cross-sectional and longitudinal HR-pQCT studies typically characterize bone density and microstructure, but like other bone imaging modalities, do not quantify bone turnover. We propose non-invasive ‘virtual bone biopsy’ for assessment of CKD turnover metrics through the application of time-lapse HR-pQCT. In time-lapse HR-pQCT, data obtained serially over a period of interest are processed to identify and quantify specific areas of new bone formation and resorption, enabling the direct measurement of bone formation rate, bone resorption rate, and total bone turnover. These measurements can be obtained for the integral volume or within trabecular or cortical compartments. We aim to compare time-lapse HR-pQCT to the gold-standard, tetracycline labeled histomorphometry by biopsy, and to determine the sensitivity and specificity of time-lapse HR-pQCT for assessment of turnover status in a CKD population. In addition, we propose to obtain repeat HR-pQCT time-lapse data longitudinally to determine whether time-lapse HR-pQCT can monitor changes in turnover in response to therapy. The data generated here will be used to design follow-on clinical trials testing whether treatment guided by time-lapse HR- pQCT can decrease fracture risk compared to usual care in CKD patients.