(A) The PTH/1,25(OH)₂D axis. The principal function of the PTH/1,25(OH)₂D axis is to regulate calcium homeostasis. Decrements in serum calcium levels stimulate PTH secretion by the PTG, which targets the kidney to reduce urinary calcium excretion, stimulate 1^α-hydroxylase activity, and enhance the fractional excretion of phosphate (PO₄), and targets bone to increase the efflux of calcium and phosphate. The resulting increase in 1,25(OH)₂D targets the gastrointestinal tract to increase dietary absorption of calcium, which suppresses PTH. (B) The FGF23/Klotho axis. FGF23 produced by bone principally targets the kidney, leading to reductions in serum phosphate and 1,25(OH)₂D levels by stimulating the fractional excretion of phosphate and reducing 1^α-hydroxylase activity. The receptor for FGF23 in the kidney is a Klotho:FGFR1 complex located in the distal tubule. There may be a distal-to-proximal feedback mechanism that mediates the effects of FGF23 on the proximal tubule. FGF23 also decreases the kidney expression of Klotho, which diminishes renal tubular calcium reabsorption via its interactions with transient receptor potential cation channel, subfamily V, member 5 (TRPV5). FGF23 may also directly target the PTG to reduce PTH secretion. FGF23 is the principal phosphaturic hormone and may function to counter the hypercalcemic and hyperphosphatemic effects of excess 1,25(OH)₂D through reductions in PTH and elevations in FGF23 levels.