Interactions Between Aging and Chronic Kidney Disease on the Skeleton

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.

Year	Entry
2022	Tippen SP, Metzger CE, Swallow EA, Sacks SA, Wallace JM, Allen MR. The combination of aging and chronic kidney disease leads to an exacerbated cortical porosity phenotype. Bone. January 2022;154:116228.
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Year

Entry

2022

Tippen SP, Metzger CE, Swallow EA, Sacks SA, Wallace JM, Allen MR. The combination of aging and chronic kidney disease leads to an exacerbated cortical porosity phenotype. Bone. January 2022;154:116228.

1994

Kanis JA, Melton LJ III, Christiansen C, Johnston CC, Khaltaev N. The diagnosis of osteoporosis. J Bone Miner Res. August 1994;9(8):1137-1141.

2021

Tippen SP, Noonan ML, Ni P, Metzger CE, Swallow EA, Sacks SA, Chen NX, Thompson WR, Prideaux M, Atkins GJ, Moe SM, Allen MR, White KE. Age and sex effects on FGF23-mediated response to mild phosphate challenge. Bone. May 2021;146:115885.

2009

Li X, Ominsky MS, Warmington KS, Morony S, Gong J, Cao J, Gao Y, Shalhoub V, Tipton B, Haldankar R, Chen Q, Winters A, Boone T, Geng Z, Niu Q-T, Ke HZ, Kostenuik PJ, Simonet WS, Lacey DL, Paszty C. Sclerostin antibody treatment increases bone formation, bone mass, and bone strength in a rat model of postmenopausal osteoporosis. J Bone Miner Res. April 2009;24(4):578-588.

2020

Creecy A, Uppuganti S, Girard MR, Schlunk SG, Amah C, Granke M, Unal M, Does MD, Nyman JS. The age-related decrease in material properties of BALB/c mouse long bones involves alterations to the extracellular matrix. Bone. January 2020;130:115126.