MO554: Roxadustat Improves Renal Osteodystrophy by Dual Regulating Bone Remodeling

Abstract

Abstract BACKGROUND AND AIMS Renal osteodystrophy (ROD) is a complication of chronic kidney disease (CKD) resulting in increased susceptibility to fractures. Therefore, developing effective drugs to prevent and treat ROD is vital. Accumulating evidence suggested stabilization of hypoxia-inducible factor-1α (HIF-1α) could promote bone formation. Roxadustat is a novel HIF stabilizer to treat renal anemia in CKD patients. This study aims to investigate the effects of roxadustat on bone remodeling using a CKD rat model. METHOD A total of 24 8-week-old male Sprague–Dawley rats were divided into three groups (n = 8/group): the normal group (Normal), CKD group and CKD + Roxadustat group. For induction of CKD, the diet containing 0.5% (w/w) adenine was given to the rats for the first 4 weeks. Roxadustat (10 mg/kg, by gavage) was given every other day from the third week of CKD induction for 4 weeks. Then blood was collected to test hemoglobin (Hb) concentrations, serum levels of creatinine (Cr), calcium (Ca), phosphorus (P), intact parathyroid hormone (iPTH) and bone turnover markers including bone alkaline phosphatase (BAP), osteocalcin (OCN) and tartrate-resistant acid phosphatase 5b (TRACP-5b). Left femurs were subjected to micro-computed tomography (micro-CT) to evaluate bone mineral density (BMD), bone volume/total volume (BV/TV), trabecular number (Tb.N), trabecular thickness (Tb.Th) and trabecular separation (Tb.Sp). Left tibiae were collected to calculate osteoclast surface/bone surface (Oc.S/BS), osteoclast number/bone surface (N.Oc/BS), osteoblast surface/bone surface (Ob.S/BS) and osteoblast number/bone surface (N.Ob/BS). One-way analysis of variance followed by Tukey HSD post hoc test was used for comparisons. P < 0.05 was statistically significant. RESULTS CKD rats exhibited remarkably higher serum Cr, P, iPTH, TRACP-5b levels and obviously lower Hb and serum Ca levels compared with the normal group. Whereas roxadustat treatment significantly decreased iPTH, TRACP-5b and increased Hb, BAP and OCN levels in CKD rats. CKD induced remarkably decreased BMD, BV/TV, Tb.N, Tb.Th and dramatically increased Tb.Sp compared with the normal group. However, roxadustat treatment improved these changes in CKD rats. CKD rats had increased Oc.S/BS, N.Oc/BS, Ob.S/BS and N.Ob/BS compared with the normal group. Roxadustat decreased Oc.S/BS, N.Oc/BS but further increased Ob.S/BS and N.Ob/BS in CKD rats. CONCLUSION Roxadustat alleviated bone loss and bone microstructure deterioration of CKD rats by promoting bone formation and inhibiting bone resorption.