Multiscale Characterization of Skeletal Properties in Diabetes and Chronic Kidney Disease

Chronic kidney disease (CKD) affects 15% of Americans and dramatically increases their risk of skeletal fractures and fracture-related mortality. The progression of CKD is marked by abnormal biochemistries including disrupted mineral homeostasis and elevated parathyroid hormone (PTH). High PTH is linked to the bone alterations seen in CKD including cortical porosity and altered turnover. To mitigate the effects of sustained elevations in PTH, dialysis patients are commonly given calcimimetics which act by sensitizing the calcium-sensing receptor on parathyroid chief cells, lowering PTH synthesis and secretion. While calcimimetics are suggested to reduce fracture risk in dialysis patients, little is known about how these drugs impact bone tissue properties or whether they can be implemented in early CKD to prevent CKD-induced bone deterioration. Therefore, understanding how calcimimetics alter bone quality may reveal new strategies to prevent fractures in patients with CKD. While CKD represents a major global health crisis, nearly half of all CKD patients also have diabetes. Diabetes disrupts numerous physiologic systems and independently increases fracture risk by lowering bone mass and quality. Therefore, we have two major objectives in this work. Firstly, we developed a method for analyzing bone composition and material properties in a spatially resolved manner and found that calcimimetics increase mineral crystallinity and stiffness in newly formed periosteal bone while increasing relative mineralization, stiffness, and hardness in perilacunar bone. Further, we found that these properties depended on distance from the osteocyte lacunar wall. Secondly, we developed a novel combined murine model of type 1 diabetes and CKD which revealed a unique combination of detriments in structural and tissue-level bone microarchitecture, mechanical properties, and fracture toughness. Taken together, this work represents a thorough investigation of how diabetes and CKD alter bone quality on multiple scales and how calcimimetics improve bone quality in localized regions in early CKD.