Improving bone mass and quality in comorbid diabetes and chronic kidney disease

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PROJECT SUMMARY Diabetes and chronic kidney disease (CKD) consistently rank among the top ten chronic conditions in the United States in terms of prevalence and mortality. US veterans develop diabetes and CKD at an alarming rate, and comorbidity is twice as common in veterans compared with the general population. Both diseases put patients at increased risk of fracture and when fractures occur, patients are at a greater risk of death compared to other populations. Treatments for skeletal disease typically address deficits in either bone mass or tissue quality, which may be insufficient in cases of combined CKD and diabetes where there are known deficits in both. Despite their increasing comorbidity and well-established detrimental impacts on the skeleton, their skeletal interaction remains unexplored due to a lack of combined disease animal models and routine exclusion of patients with diabetes and/or CKD from clinical drug trials. The goal of this project is to study skeletal interactions between diabetes and CKD and to identify effective combination skeletal treatments. Using our novel combined model of diabetes and CKD, we will test the central hypothesis that increasing bone mass while concurrently improving tissue quality using combined therapies will increase bone mechanical strength, improve fracture resistance, and reverse adverse skeletal effects of late-stage diabetes+CKD. To achieve this goal, we will use our novel combined model of diabetes and CKD to investigate molecular, biochemical, and compositional changes coupled with multiscale structural and mechanical properties. Aim 1 will investigate the effects of combined disease as a function of age of onset and disease duration. Our lab has established a combined model of diabetes (streptozotocin) and CKD (adenine) that uniquely alters skeletal properties in young mice. 4 experiments will be used, inducing disease in either young or aged mice, and then allowing disease to progress for a short or longer duration. Key outcomes will include longitudinal insulin and glucose monitoring, HbA1c, insulin and glucose tolerance tests, pancreatic beta cell mass, and renal biochemistries. Skeletal outcomes will include biochemical markers of turnover and disease, structural imaging, bone formation/resorption histology, and a suite of multiscale mechanical and compositional properties. These experiments will clarify how diabetes and CKD impact the skeleton as a function of sex, age, and disease duration. In Aim 2, we will determine the skeletal impacts of treatment in late-stage disease utilizing mechanical loading (to improve bone mass) and Raloxifene (RAL – to improve tissue hydration and quality). We have shown that RAL, an FDA-approved agent for treating bone, specifically benefits bone material properties in a cell- and estrogen-independent manner. End points will be the same as those in Aim 1, including colocalized Raman spectroscopy and nanoindentation to characterize the mineral and collagen properties/mechanics of bone formed during the interventions compared with older bone. To increase translational value in Aim 3, we will determine the effects of pharmaceutical polytherapies initiated in late-stage combined diabetes and CKD. This work will challenge the idea that the effect of combined disease on the skeleton is equal to the sum of the parts and will have a positive impact in our at risk-veteran population by providing new ways to prevent or treat skeletal deficits associated with diabetes and CKD.