Phosphate drives skeletal abnormalities in Klotho-deficient mice

Chronic kidney disease-mineral and bone disorder (CKD-MBD) is characterized by complex alterations in mineral metabolism and endocrine regulation. Although phosphate retention is a hallmark of advanced CKD-MBD, its contribution to skeletal abnormalities remains elusive. Here, we investigated the role of phosphate in bone pathology using Klotho-deficient mice, a model of severe phosphate retention. These mice exhibited hyperphosphatemia and elevated circulating levels of calciprotein particles (CPPs), colloidal complexes of calcium phosphate that mediate phosphate toxicity. They also showed increased circulating sclerostin, an inhibitor of bone formation, and reduced parathyroid hormone (PTH) levels. These systemic abnormalities were associated with skeletal defects that partially recapitulate those observed in CKD-MBD patients, including impaired mineralization, disrupted bone remodeling, increased trabecular bone mass, and osteoid accumulation. Treatment with a phosphate binder reduced serum levels of phosphate, CPP, and sclerostin and markedly improved skeletal abnormalities without restoring PTH levels. Notably, phosphate binder treatment reduced cortical bone area and thickness, indicating that phosphate is essential for skeletal growth. Together, these findings suggest that phosphate retention is a major contributor to skeletal abnormalities in Klotho-deficient mice, highlighting a dual role of phosphate as both a pathogenic factor and an essential nutrient for skeletal integrity and supporting further investigation of phosphate-lowering strategies in CKD-MBD.