Assessing and improving bone quality in chronic kidney disease

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 DESCRIPTION (provided by applicant): Chronic kidney disease-mineral and bone disorder (CKD-MBD) patients have increased fracture risk, have a higher risk of fracture-related mortality, and are difficult to treat due to CKD's metabolic complexity. Furthermore, standard practices for monitoring fracture risk (i.e. bone mineral density, BMD) have limitations in this patient population. Currently, treatment for CKD-MBD patients is primarily focused on suppressing elevated parathyroid hormone, as can be accomplished with a calcimimetic. Cinacalcet, an FDA approved calcimimetic, effectively reduces parathyroid hormone, slows bone turnover and increases bone mass, yet it only modestly reduces fracture risk. This suggests a defect in bone quality, not just bone loss, is contributing to CKD fragility, and this notion is supported by recent evidence of alterations in collagen cross-linking and matrix hydration in CKD bone. Preliminary data collected for this study found evidence of bone microdamage, another important factor of bone quality which is previously unstudied in CKD. Microdamage is known to interact with porosity, thus the combination of these issues may have significant impact on CKD fragility. In summary, normalizing fracture risk in these patients will likely require more than simply suppressing bone loss; the bone quality must also be treated. We hypothesize that the quality of CKD bone can be improved using a combination treatment of calcimimetic, to reduce parathyroid hormone and bone loss, and raloxifene, a selective estrogen receptor modulator drug for osteoporosis recently revealed to have direct positive effects on bone tissue quality. We will test this hypothesis using a slowly progressive model of CKD-MBD, the Cy/+ rat. This study will first quantify the extent of skeletal microdamage in the bones of 30 and 35-week old CKD rats in comparison to their normal, age-matched littermates. We expect CKD to cause progressively increasing accumulation of cortical porosity and microdamage, with interactions occurring between microcracks and porosity. Next, the ability of combination calcimimetic and raloxifene treatment to improve measures of bone quantity and quality will be tested. Cy/+ rats will be treated from 25 to 35 weeks of age with vehicle, raloxifene, calcimimetic, or both drugs. Primary outcomes will be determined by skeletal analyses (microdamage, histology, microCT, bone density, mechanical testing, and resistance to fatigue), though the treatments' effects on the biochemical and renal components of CKD-MBD will be assessed as well. We predict that raloxifene will improve the mechanical properties of bone by improving bone quality and reducing microdamage formation, while calcimimetic treatment will improve mechanical properties by increasing bone mass and reducing porosity. Combination therapy should exceed both single 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 spontaneous and progressive development of CKD.