Metzger, Corinne E.Kittaka, MizuhoLaPlant, Alec N.Ueki, YasuyoshiAllen, Matthew R.2024-06-212024-06-212024-01-14Metzger CE, Kittaka M, LaPlant AN, Ueki Y, Allen MR. Inhibition of RANKL improves the skeletal phenotype of adenine-induced chronic kidney disease in mice [published correction appears in JBMR Plus. 2024 May 08;8(6):ziae059. doi: 10.1093/jbmrpl/ziae059]. JBMR Plus. 2024;8(2):ziae004. Published 2024 Jan 14. doi:10.1093/jbmrpl/ziae004https://hdl.handle.net/1805/41705Skeletal fragility and high fracture rates are common in CKD. A key component of bone loss in CKD with secondary hyperparathyroidism is high bone turnover and cortical bone deterioration through both cortical porosity and cortical thinning. We hypothesized that RANKL drives high bone resorption within cortical bone leading to the development of cortical porosity in CKD (study 1) and that systemic inhibition of RANKL would mitigate the skeletal phenotype of CKD (study 2). In study 1, we assessed the skeletal properties of male and female Dmp1-cre RANKLfl/fl (cKO) and control genotype (Ranklfl/fl; Con) mice after 10 wk of adenine-induced CKD (AD; 0.2% dietary adenine). All AD mice regardless of sex or genotype had elevated blood urea nitrogen and high PTH. Con AD mice in both sexes had cortical porosity and lower cortical thickness as well as high osteoclast-covered trabecular surfaces and higher bone formation rate. cKO mice had preserved cortical bone microarchitecture despite high circulating PTH as well as no CKD-induced increases in osteoclasts. In study 2, male mice with established AD CKD were either given a single injection of an anti-RANKL antibody (5 mg/kg) 8 wk post-induction of CKD or subjected to 3×/wk dosing with risedronate (1.2 μg/kg) for 4 wk. Anti-RANKL treatment significantly reduced bone formation rate as well as osteoclast surfaces at both trabecular and cortical pore surfaces; risedronate treatment had little effect on these bone parameters. In conclusion, these studies demonstrate that bone-specific RANKL is critical for the development of high bone formation/high osteoclasts and cortical bone loss in CKD with high PTH. Additionally, systemic anti-RANKL ligand therapy in established CKD may help prevent the propagation of cortical bone loss via suppression of bone turnover.en-USAttribution 4.0 InternationalChronic kidney diseaseCortical porosityPTHRANKLArticle