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Chapter: Basic & Clinical Pharmacology : Agents That Affect Bone Mineral Homeostasis

Interaction of PTH, FGF23, & Vitamin D

A summary of the principal actions of PTH, FGF23, and vitamin D on the three main target tissues—intestine, kidney, and bone—is presented in Table 42–2.

INTERACTION OF PTH, FGF23, & VITAMIN D

A summary of the principal actions of PTH, FGF23, and vitamin D on the three main target tissues—intestine, kidney, and bone—is presented in Table 42–2. The net effect of PTH is to raise serum calcium and reduce serum phosphate; the net effect of FGF23 is to decrease serum phosphate; the net effect of vitamin D is to raise both. Regulation of calcium and phosphate homeostasis is achieved through important feedback loops. Calcium is one of two principal regulators of PTH secretion. It binds to a novel ion recognition site that is part of a Gq protein-coupled receptor called the calcium-sensing receptor (CaSR) that employs the phosphoinositide second messenger system to link changes in the extracellular cal-cium concentration to changes in the intracellular free calcium. As serum calcium levels rise and activate this receptor, intracellular calcium levels increase and inhibit PTH secretion. This inhibi-tion by calcium of PTH secretion, along with inhibition of renin and atrial natriuretic factor secretion, is the opposite of the effect in other tissues such as the beta cell of the pancreas, in which calcium stimulates secretion. Phosphate regulates PTH secretion directly and indirectly by forming complexes with calcium in the serum. Because it is the ionized free concentration of extracellular calcium that is detected by the parathyroid gland, increases in serum phos-phate levels reduce the ionized calcium, leading to enhanced PTH secretion. 


Such feedback regulation is appropriate to the net effect of PTH to raise serum calcium and reduce serum phosphate levels. Likewise, both calcium and phosphate at high levels reduce the amount of 1,25(OH)2D produced by the kidney and increase the amount of 24,25(OH)2D produced.

High serum calcium works directly and indirectly by reducing PTH secretion. High serum phosphate works directly and indirectly by increasing FGF23 levels. Since 1,25(OH)2D raises serum calcium and phosphate, whereas 24,25(OH)2D has less effect, such feedback regulation is again appropriate. 1,25(OH)2D directly inhibits PTH secretion (independent of its effect on serum calcium) by a direct inhibitory effect on PTH gene transcription. This pro-vides yet another negative feedback loop. In patients with chronic renal failure who frequently are deficient in producing 1,25(OH)2D, loss of this 1,25(OH)2D-mediated feedback loop coupled with impaired phosphate excretion and intestinal calcium absorption often leads to secondary hyperparathyroidism. The ability of 1,25(OH)2D to inhibit PTH secretion directly is being exploited with calcitriol analogs that have less effect on serum calcium because of their lesser effect on intestinal calcium absorption. Such drugs are proving useful in the management of secondary hyperparathy-roidism accompanying chronic kidney disease and may be useful in selected cases of primary hyperparathyroidism. 1,25(OH)2D also stimulates the production of FGF23. This completes the negative feedback loop in that FGF23 inhibits 1,25(OH)2D production while promoting hypophosphatemia, which in turn inhibits FGF23 production and stimulates 1,25(OH)2D production.


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Basic & Clinical Pharmacology : Agents That Affect Bone Mineral Homeostasis : Interaction of PTH, FGF23, & Vitamin D |


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