Ultra-high Resolution pQCT as a Biomarker of Bone Strength in Osteoporosis Trials

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DESCRIPTION (provided by applicant): Osteoporosis, a disease of interest to NIAMS, is a very common disorder of aging. Measurement of bone mineral density (BMD) by dual energy x-ray absorptiometry (DXA) has important limitations in diagnosis of osteoporosis, prediction of fracture, and assessment of response to therapies to reduce fracture risk. As osteoporosis is also characterized by microarchitectural deterioration, in vivo assessment of trabecular and cortical bone microarchitecture, may improve upon DXA in these functions. In response to the NIAMS Clinical Trial Outcomes Instrument Development Grant Program, we will evaluate a new noninvasive imaging technology, ultra high-resolution peripheral quantitative computed tomography (HR-pQCT), as a biomarker of bone strength in patients with and without fracture. The Xtreme CT (Scanco Medical AG, Basserdorf, Switzerland), with a resolution of 80-100 urn, permits separate measurements of cortical and trabecular compartments, distinguishes ultra-structural details of trabecular microarchitecture, and yields datasets that can be subjected to finite element analysis (FEA) modeling to assess bone strength. We hypothesize that HR-pQCT will assess fracture status and bone strength more accurately than DXA. We will test this hypothesis in a cross sectional study that compares the utility of DXA and HR-pQCT to classify fracture status in women over age 60. As declining kidney function commonly accompanies aging and could contribute to fracture risk, we will also assess its impact on the ability of HR-pQCT and DXA to classify fracture status. A subset will have iliac crest bone biopsies to compare measures of microarchitecture and strength from HR-pQCT to similar measures assessed by micro-CT of biopsy specimens. The 3 Specific Aims are: 1. To evaluate the utility of HR-pQCT measurements of bone mass and microarchitecture for classification of fracture status. 2. To evaluate the utility of FEA of HR-pQCT images, a computational approach to assess mechanical competence, for classification of fracture status. 3. In a subset of participants, to correlate measures of bone mass, microarchitecture, and strength performed by HR-pQCT to similar measures performed on biopsy specimens. This research may support the future use of HR-pQCT as a registrable outcome in clinical trials that test therapies for osteoporosis. As fractures are associated with considerable morbidity and excess mortality, this research has high relevance to public health.