ABSTRACT Chronic kidney disease (CKD) affects one in seven individuals in the US and significantly increases fracture risk. While CKD occurs in patients of all ages, the prevalence is highest in the aged, with nearly 40% of individuals over age 65 having some form of CKD yet the interaction of CKD and aging is understudied. CKD primarily affects cortical bone in the form of cortical porosity, which is inversely related to bone mechanical properties and fracture. In CKD and aging, mechanical properties of bone are also compromised at the tissue level. Targeting both cortical porosity and material properties will be important for reducing bone fragility in CKD. Previous research on cortical porosity has focused on preventing pore formation while research on porosity reversal (infilling) is lacking. We have shown that pore infilling occurs following potent suppression of parathyroid hormone (PTH) in young animals with CKD-induced cortical porosity. Because osteoblast function is known to be compromised with age, it is unclear whether infilling would be compromised in aged CKD or if it would necessitate anabolic drug treatment with an agent such as anti-sclerostin antibody (romosozumab). Further, it remains unknown if the bone that forms during pore infilling, in either young or aged animals, is of sufficient quality to improve bone mechanical properties. Thus, the global hypothesis of this proposal is that PTH suppression alone is insufficient to promote cortical pore infilling with normal bone matrix in aging bone and that it will require both PTH suppression and anabolic stimulation. This hypothesis will be assessed in two Aims: Specific Aim 1. Determine the isolated effect of PTH suppression or anabolic drug therapy compared to their combination for promoting cortical pore infilling in young and aged CKD. Young and aged (16 and 66 weeks of age) male and female C57BL/6J mice will be fed a diet containing adenine to induce CKD and cortical porosity. Animals will then serve as untreated (controls) or receive 4 weeks of PTH-suppression drug treatment (cinacalcet, in diet), anabolic drug treatment (romosozumab), or both combined. Key outcomes will include high-resolution computer tomography imaging, histology, and gene expression. Specific Aim 2. Define the mechanical and material properties of the infilled bone. Tissue from Aim 1 will be assessed for mechanical properties of the newly formed bone within the cortical pores using Raman spectroscopy and nanoindentation. Whole bone mechanical properties will be assessed by multiple testing methods. Importantly, the proposed studies provide a fertile training environment in which the applicant can expand understanding of bone, aging, and chronic kidney disease within an existing translational collaborative team. The mentoring team of Dr. Allen (skeletal biology), Dr. White (mineral metabolism), Dr. Wallace (bone mechanics), and Dr. Moe (nephrology) have an established track record of mentorship to augment...