Abstract
The pathogenesis of secondary hyperparathyroidism (2HPT) is explained by the trade-off hypothesis: a reduction in renal function increases parathyroid hormone (PTH) secretion, which stimulates urinary phosphate (P) excretion and prevents hyperphosphatemia in compensation for metabolic bone disease. Dietary treatment with P binder can inhibit parathyroid hyper-function and prevent bone lesions, which indicates that P retention underlies the pathogenesis and pathophysiology of 2HPT. In addition, the administration of cinacalcet hydrochloride (cinacalcet) decreases blood P levels by inhibiting the mobilization of P from the bone in association with decreased PTH secretion in patients on dialysis. In contrast, the reduction in PTH induced by cinacalcet increases blood P levels with decreased urinary P excretion and also causes severe hypocalcemia in pre-dialysis patients with chronic kidney disease (CKD). Thus, PTH should be increased in order to prevent both hyperphosphatemia and hypocalcemia. Moreover, eliminating the effect of fibroblast growth factor-23 (FGF23) with a neutralizing antibody increases blood P, Ca, and 1,25(OH)2 vitamin D3[1,25(OH)2D3] levels and decreases blood PTH levels in CKD rats with 2HPT. Therefore, FGF23 prevents the incidence of hyperphosphatemia in a coordinated manner with PTH and also lowers 1,25(OH)2D3 production, thereby increasing PTH secretion. The long-term neutralization of FGF23 in CKD rats improves bone histology but accelerates vascular calcification and increases mortality. Hence, elevated FGF23 in CKD is considered to prevent vascular calcification in compensation for metabolic bone disease. Furthermore, the decreased expression of receptors for Ca, 1,25(OH)2D3, and FGF23 reported in the parathyroid gland and reduction in renal α-klotho may contribute to the early pathogenesis and progression of 2HPT.
