DESCRIPTION (provided by applicant): Chronic kidney disease-mineral and bone disorder (CKD-MBD) results in complex skeletal and metabolic phenotypes. Because of this, patients with advanced kidney disease have an increased risk of fractures. In patients with age-related bone loss, bone mineral density (BMD) estimates are a helpful predictor of fracture development. In CKD, however, the picture is unclear. While it may be of use, the presence of other metabolic derangements indicate that bone quality likely plays a greater role in the pathogenesis of CKD-related fractures than in those associated with age-related bone loss. Current treatment in patients with CKD-MBD is focused on suppressing elevations in parathyroid hormone. This is accomplished by calcitriol supplementation. While the effect of calcitriol in osteoporotic patients has been studied, its impact on bone quality and fracture risk n CKD patients is currently unknown. Also, recent analyses suggest that raloxifene, a selective estrogen receptor modulator, might be a useful intervention for patients with late stage kidney disease. This is supported by beneficial renal outcomes in patients on raloxifene as well as evidence demonstrating an additional non-cellular mechanism by which to improve bone quality. So, we hypothesized that CKD leads to alterations in bone quality that can be corrected by raloxifene and its combination with calcitriol. This will be tested through the use of a slowly progressive model of CKD-MBD, the Cy/+ rat. This study will compare the quality of skeletal tissue (independently of mass) in normal and Cy/+ rats. This will be accomplished by examining bones from 30-week-old rats for changes in bone quality. Specifically, outcomes will include tissue-level mechanical properties, mineralization, collagen composition (cross-linking, morphology, and mechanics), and bone matrix hydration (MRI). We expect rats with CKD to display lower bone strength, lower mineralization, lower collagen stiffness, lower matrix-bound water, and higher non-enzymatic cross-linking of collagen. The second major goal is to examine the effects of raloxifene on bone abnormalities present in Cy/+ rats. 25-week-old animals will be treated for 5 weeks (equivalent to one bone remodeling cycle). Primary outcomes will be determined by skeletal analyses (histology, microCT, bone density, mechanical testing, and bone quality measures), though the biochemical, renal, and vascular components of CKD-MBD will be assessed as well. Gene expression analyses will be performed to begin to identify signaling pathways involved in changes in biomechanical bone quality. We predict that raloxifene will improve the mechanical properties of bone by improving bone quality, while calcitriol will improve mechanical properties by increasing bone mass. Combination therapy should exceed all other treatments by positively impacting both quality and mass. An understanding of the detrimental impact of CKD on bone quality is a crucial step in preventing fractures in these patients. This study provides an important step in achieving this goal by examining these changes and their potential corrections in a rat model with the spontaneous and progressive development of chronic kidney disease.

PUBLIC HEALTH RELEVANCE: Chronic kidney disease is a growing worldwide epidemic. Patients exhibit an increased risk of severely debilitating and life-threatening bone fractures. This study will examine the unknown impact of CKD on the quality of bone and the use of raloxifene as a potential therapy to prevent these devastating outcomes.