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. The parathyroid gland expresses both the VDR and CYP27B1, so that endogenous production of 1,25(OH)2D within the parathyroid gland may be more important for the regulation of PTH secretion than serum levels of 1,25(OH)2D. This provides yet another negative feedback loop. In patients with chronic renal failure who frequently are deficient in producing 1,25(OH)2D due in part to elevated FGF23 levels, loss of this 1,25(OH)2D-mediated feedback loop coupled with impaired phosphate excretion and intestinal calcium absorption 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 hyperparathyroidism 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. However, the rise in FGF23 in the early stages of renal failure remains unexplained and is not due to increases in either 1,25OH)2D or phosphate, and appears not to be under the same feedback control as operates under normal physiologic conditions.
A number of hormones modulate the actions of PTH, FGF23, and vitamin D in regulating bone mineral homeostasis. Compared with that of PTH, FGF23, and vitamin D, the physiologic impact of such secondary regulation on bone mineral homeostasis is minor. However, in pharmacologic amounts, several of these hormones, including calcitonin, glucocorticoids, and estrogens, have actions on bone mineral homeostatic mechanisms that can be exploited therapeutically.
The calcitonin secreted by the parafollicular cells of the mammalian thyroid is a single-chain peptide hormone with 32 amino acids and a molecular weight of 3600. A disulfide bond between positions 1 and 7 is essential for biologic activity. Calcitonin is produced from a precursor with a molecular weight of 15,000. The circulating forms of calcitonin are multiple, ranging in size from the monomer (molecular weight 3600) to forms with an apparent molecular weight of 60,000. Whether such heterogeneity includes precursor forms or covalently linked oligomers is not known. Because of its chemical heterogeneity, calcitonin preparations are standardized by bioassay in rats. Activity is compared to a standard maintained by the British Medical Research Council (MRC) and expressed as MRC units.
Human calcitonin monomer has a half-life of about 10 minutes. Salmon calcitonin has a longer half-life of 40–50 minutes, making it more attractive as a therapeutic agent. Much of the clearance occurs in the kidney by metabolism; little intact calcitonin appears in the urine.