Interactions Between Aging and Chronic Kidney Disease on the Skeleton

Abstract

In the US, 15% of adults have chronic kidney disease (CKD). While CKD occurs across all ages, the prevalence is highest in the aged, with ~40% of individuals over age 65 having some form of CKD. CKD and aging are each independently associated with higher fracture risk, and thus overlaying CKD in the aging population presents an additive fracture risk. Cortical porosity is a central tenet underlying skeletal fragility and occurs in CKD and aging. Previous research on cortical porosity has focused on preventing pore formation, while research on pore reversal (infilling) is lacking. Pore infilling is dependent on proper osteoblast function, and previous research has shown that infilling is possible in young mice. However, it is unclear whether infilling is possible in aging mice due to aging-associated osteoblast dysfunction. Therefore, we proposed that aging animals with CKD may require both suppression of CKD-induced elevations in parathyroid hormone (PTH) and anabolic therapy to infill cortical pores. Romosozumab, a humanized monoclonal sclerostin antibody, uses PTH-independent mechanisms to increase osteoblast activity, making it an attractive therapeutic for CKD. CKD was induced by feeding aging (78-week) male mice 0.2% adenine for six weeks followed by two weeks of maintenance on control diet for a total study duration of eight weeks of CKD; mice were then treated with calcium water, romosozumab, or the combination and their effectiveness in improving skeletal quantity and quality was evaluated. Romosozumab treatment was associated with higher trabecular bone volume, lower cortical porosity, and higher mechanical properties compared to control animals. Combination treatment also resulted in benefits to trabecular bone volume and mechanical properties. These results demonstrate that both romosozumab alone and when combined with PTH suppression can be effective at improving bone microarchitecture and mechanical properties in aged individuals with CKD who are at high risk of fracture.