Calcimimetics and CaSR signaling in CKD-MBD: bone-immune-vascular crosstalk and therapeutic potential

Chronic kidney disease (CKD) disrupts mineral metabolism, skeletal remodeling, vascular homeostasis, and immune regulation, producing the systemic phenotype of CKD-mineral and bone disorder (CKD-MBD) together with chronic inflammation and impaired host defense. Osteoimmunology provides a framework for understanding how bone cells, immune cells, and vascular cells interact through shared mediators such as RANKL, osteoprotegerin, NF-kappaB, NFATc1, inflammatory cytokines, fibroblast growth factor 23 (FGF23), Wnt inhibitors, and phosphate-dependent osteogenic signaling pathways. The calcium-sensing receptor (CaSR) is a class C G protein-coupled receptor that regulates parathyroid hormone (PTH) secretion and can signal through Gαq/11, Gαi/o, Gα12/13, and beta-arrestin-dependent pathways. CaSR expression and/or calcium-sensing responses have been described in bone cells, selected immune-lineage cells, and vascular smooth muscle cells, suggesting that CaSR may participate in bone-immune-vascular communication. Calcimimetics, including cinacalcet, etelcalcetide, and evocalcet, are established CaSR-targeting therapies for secondary hyperparathyroidism in dialysis patients. Their best-validated actions are PTH suppression and improvement of calcium-phosphate biochemical control; clinical and experimental studies also support reductions in FGF23, selected bone-turnover markers, and vascular calcification measures. This review critically evaluates the pharmacology of calcimimetics and their potential osteoimmune relevance in CKD-MBD. We emphasize established clinical effects while distinguishing them from mechanistic hypotheses, including direct NLRP3 inflammasome suppression, Th17/Treg rebalancing, macrophage M1-to-M2 polarization, osteocyte connexin-43/DAMP regulation, and hematopoietic niche restoration, which remain insufficiently validated in human CKD. We propose an integrated bone-vascular-immune framework and identify biomarker-guided and precision-medicine strategies for future calcimimetic research.