Chronic kidney disease (CKD) patients are at an alarming risk of fracture-related mortality. The progression of CKD is marked by abnormal biochemistries including disrupted mineral homeostasis and elevated parathyroid hormone (PTH), or hyperparathyroidism (HPT). Chronic HPT is currently thought to be responsible for the dramatic loss of bone mass and increased fracture risk in CKD patients, and thus patients have PTH levels monitored to determine their fracture risk. Further, these patients are commonly given PTH-lowering drugs including calcimimetics. These drugs act by sensitizing the calcium-sensing receptor in parathyroid chief cells, lowering their PTH secretion. While these drugs have been shown to reduce fracture risk in CKD patients on dialysis, there is little known about their effect on bone mass and quality. Interestingly, CKD patients with normal bone mass and controlled PTH levels remain at an increased fracture risk. Thus, there is a critical gap in our understanding of what skeletal properties dictate bone strength in both the disease process and treatment of CKD bone disorder. Recently, there has been increasing recognition of the role of bone quality in determining overall bone strength. Bone quality refers to a combination of bone architecture, chemical composition of the bone matrix, and the resulting whole bone and tissue-level mechanical properties. To date, however, measures of bone quality in the setting of CKD and calcimimetic treatment have not been spatially matched, or colocalized, in bone samples of known tissue age. Based on the above scientific premise, the goal of this proposal is to test the hypothesis that calcimimetic drugs reduce fracture risk by improving bone quality. Specifically, this study will, in addition to measuring changes in bone architecture, spatially match measures of matrix composition and tissue-level mechanical properties before and after calcimimetic treatment.
The first Aim i s to determine the effects of calcimimetic treatment on matrix composition and mechanical properties in the Cy/+ rat, a slowly progressive model of CKD. This will be accomplished by running colocalized Raman spectroscopy to determine matrix composition and nanoindentation to determine tissue-level mechanical properties on rat femur sections. Fluorescent labels will be given before and after treatment to identify regions of bone formed at each time point and to control for tissue age. Outcomes will include semi-quantitative measurements of mineral and matrix content, crystallinity, and carbonate content as well as measurements of tissue hardness and stiffness. For the second Aim, a similar study will be accomplished using transiliac crest bone biopsies from CKD patients with severe HPT. Specimens will again be controlled for tissue age and will undergo colocalized Raman spectroscopy and nanoindentation. Data from the above Aims will allow us to generate novel correlations between alterations in bone matrix properties and tissue-level mechanics, helping us begin filling the critical gap in our understanding of CKD bone disease. Additionally, because this study navigates between the laboratory and clinic, it provides an excellent opportunity for a physician-scientist in training.
Chronic kidney disease (CKD) patients are at an alarming risk of fracture-related mortality and is a growing medical concern in the United States. This study aims to determine the skeletal properties that determine bone fragility in the setting of CKD and to examine whether calcimimetic treatment reverses CKD-induced changes in bone quality. Such knowledge would fill a critical gap in our understanding of CKD bone disease and enhance our ability to design treatments to specifically increase bone quality in CKD patients.
