PTH and FGF23 Exert Interdependent Effects on Renal Phosphate Handling: Evidence From Patients With Hypoparathyroidism and Hyperphosphatemic Familial Tumoral Calcinosis Treated With Synthetic Human PTH 1–34

Abstract

Parathyroid hormone (PTH) and fibroblast growth factor 23 (FGF23) both influence blood phosphate levels by regulating urinary phosphate reabsorption. Clinical data suggest that adequate renal phosphate handling requires the presence of both FGF23 and PTH, but robust evidence is lacking. To investigate whether the phosphaturic effects of PTH and FGF23 are interdependent, 11 patients with hypoparathyroidism, which features high blood phosphate in spite of concomitant FGF23 elevation, and 1 patient with hyperphosphatemic familial tumoral calcinosis (HFTC), characterized by deficient intact FGF23 action and resulting hyperphosphatemia, were treated with synthetic human PTH 1–34 (hPTH 1–34). Biochemical parameters, including blood phosphate, calcium, intact FGF23 (iFGF23), nephrogenic cAMP, 1,25(OH)2 vitamin D (1,25D), and tubular reabsorption of phosphate (TRP), were measured at baseline and after hPTH 1–34 treatment. In patients with hypoparathyroidism, administration of hPTH 1–34 increased nephrogenic cAMP, which resulted in serum phosphate normalization followed by a significant decrease in iFGF23. TRP initially decreased and returned to baseline. In the patient with HFTC, hPTH 1–34 administration also increased nephrogenic cAMP, but this did not produce changes in phosphate or TRP. No changes in calcium were observed in any of the studied patients, although prolonged hPTH 1–34 treatment did induce supraphysiologic 1,25D levels in the patient with HFTC. Our results indicate that PTH and FGF23 effects on phosphate regulation are interdependent and both are required to adequately regulate renal phosphate handling. Published 2021. This article is a U.S. Government work and is in the public domain in the USA.

High bone turnover and hyperparathyroidism after surgery for tumor-induced osteomalacia: A case series

“…Although, cFGF23 has remained mildly elevated, iFGF23 was normal. As recently described, both PTH and FGF23 independently lower TmP/GFR but both are required for normalcy of renal phosphate handling ( McKenna et al, 2021 ; Ovejero et al, 2021 ). It is possible that residual secondary hyperparathyroidism in case 1 accounts for lowering of TmP/GFR rather than residual tumor.…”

“…Tumor-induced osteomalacia (TIO) is a rare paraneoplastic syndrome, which is associated with phosphaturic mesenchymal tumors (PMT), resulting in an acquired form of severe chronic hypophosphatemia that leads to osteomalacia in adults ( Ryan et al, 1984 ; Minisola et al, 2017 ). Most cases are caused by excess tumoral production of fibroblast growth factor 23 (FGF23), one of the factors that regulates phosphate excretion ( McKenna et al, 2021 ; Ovejero et al, 2021 ). Increased circulating FGF23 in TIO inhibits sodium-dependent phosphate co-transporters (NaPi2a) on the luminal surface of the proximal renal tubule, which results in reduced phosphate reabsorption.…”

Combined treatment by burosumab and a calcimimetic can ameliorate hypophosphatemia due to excessive actions of FGF23 and PTH in adult XLH with tertiary hyperparathyroidism: A case report

“…The relationship between FGF23 and PTH on the phosphaturic effect is unclear at present. A recent clinical study concluded that the phosphaturic effects of FGF23 and PTH were interdependent, with both required to adequately regulate renal phosphate handling ( 18 ). The authors showed that the administration of human PTH 1-34 normalized the serum phosphate level, followed by a significant decrease in FGF23 in 11 patients with hypoparathyroidism, which is characterized by a high serum phosphate level despite concomitant FGF23 elevation ( 18 ).…”

“…A recent clinical study concluded that the phosphaturic effects of FGF23 and PTH were interdependent, with both required to adequately regulate renal phosphate handling ( 18 ). The authors showed that the administration of human PTH 1-34 normalized the serum phosphate level, followed by a significant decrease in FGF23 in 11 patients with hypoparathyroidism, which is characterized by a high serum phosphate level despite concomitant FGF23 elevation ( 18 ). Furthermore, two cases of XLH with tertiary hyperparathyroidism were reported to have a normalized TmP/GFR upon being rendered hypoparathyroidism by total parathyroidectomy but still showed the marked elevation of FGF23 ( 19 , 20 ).…”

Phosphate Metabolism and Pathophysiology in Parathyroid Disorders and Endocrine Tumors

“…FGF-23 is elevated by chronic hyperphosphatemia [ 30 ]. A very recent and well-conducted clinical study [ 31 ] has shed light on the interdependent physiology of PTH and FGF-23 in patients with hypoparathyroidism. Since both FGF-23 and PTH are phosphaturic hormones, it was anticipated that patients with hypoparathyroidism, treated with synthetic human PTH (1-34), would serve as an optimal model to clarify which of either hormone would have a prominent role over the other in determining phosphate excretion.…”