The primary transporter of vitamin D and its metabolites in the bloodstream is vitamin D-binding protein (DBP). DBP is a glycoprotein produced by the liver and it binds over 85% of 1,25-hydroxyvitamin D and 24,25-dihydroxyvitamin D. Only 0.4% of 1,25-dihydroxyvitamin D circulates freely as a hormone due to its binding to other proteins. DBP serves as a carrier for the highly lipophilic vitamin D in the blood, acting as a reservoir that protects against vitamin D deficiency.

The actions of 1,25-dihydroxyvitamin D are primarily mediated through its binding to the nuclear vitamin D receptor (VDR). The VDR is part of the nuclear hormone receptor family and functions as a ligand-dependent transcription factor. It forms a heterodimer with the retinoid X receptor (RXR) and binds to specific DNA sequences known as vitamin D response elements. Thus, the main role of 1,25-dihydroxyvitamin D is to regulate gene expression in its target tissues, including the small intestine, bone, kidneys, and parathyroid gland.

The genomic effects of 1,25-dihydroxyvitamin D, mediated by the VDR, occur over a period of hours to days. However, 1,25-dihydroxyvitamin D also has rapid effects that occur within seconds to minutes. For example, it rapidly stimulates calcium absorption in the duodenum. The VDR is also present in the cell plasma membrane and is associated with rapid signaling pathways involving G proteins and phosphatidylinositol-3'-kinase. Recent advancements in molecular modeling have led to the development of ligands that specifically bind to the nuclear or membrane-localized VDR, allowing for selective treatment of disorders related to the rapid or slow actions of 1,25-dihydroxyvitamin D using synthetic vitamin D analogues.

The regulation of calcium (Ca++) and phosphate (Pi) levels in the body involves the actions of parathyroid hormone (PTH) and 1,25-dihydroxyvitamin D on the small intestine, bone, and parathyroid glands. More details on the renal handling of calcium can be found in Chapter 36.

Calcitonin is a peptide hormone produced by the medullary cells, or C-cells, of the thyroid gland. Its secretion is positively regulated by serum calcium levels through the calcium-sensing receptor (CaSR). The calcitonin receptor is expressed in osteoclasts, where calcitonin acts rapidly and directly to inhibit bone resorption. However, in humans, calcitonin does not play a major role in regulating serum calcium levels. This is supported by the fact that excessive production or complete absence of calcitonin (e.g., following thyroidectomy) does not significantly affect serum calcium levels. More potent forms of calcitonin, such as salmon calcitonin, have been used therapeutically as anti-resorptive agents in the treatment of Paget's disease (characterized by excessive osteoclastic bone resorption) and osteoporosis. Calcitonin also serves as a useful histochemical marker for medullary thyroid cancer.
Vitamin D and its metabolites circulate in blood primarily bound to vitamin D–binding protein (DBP). DBP is a serum glycoprotein that is synthesized by the liver. DBP binds more than 85% of 1,25-hydroxyvitamin D and 24,25-dihydroxyvitamin D. Because of binding to other proteins, only 0.4% of 1,25-dihydroxyvitamin D circulates as free hormone. DBP transports the highly lipophilic vitamin D in blood and provides a reservoir of vitamin D that protects against vitamin D deficiency.
1,25-Dihydroxyvitamin D Receptor 1,25-Dihydroxyvitamin D exerts its actions primarily through binding to the nuclear vitamin D receptor (VDR), which is a member of the nuclear hormone receptor family. The VDR is a ligand-dependent transcription factor that binds to cognate DNA sequences (vitamin D response elements) as a heterodimer with the retinoid X receptor (RXR). Thus the primary action of 1,25-dihydroxyvitamin D is to regulate gene expression in its target tissues, including the small intestine, bone, kidneys, and parathyroid gland.
The genomic actions of 1,25-dihydroxyvitamin D mediated by the VDR occur over a period of hours to days. 1,25-Dihydroxyvitamin D also has rapid effects (seconds to minutes). For example, 1,25-dihydroxyvitamin D rapidly induces absorption of Ca++ by the duodenum. The VDR is also expressed in the plasma membrane of cells and is linked to rapid signaling pathways (e.g., G proteins, phosphatidylinositol-3′-kinase). Current molecular modeling has led to development of ligands that specifically bind
Hormonal Regulation of Calcium and Phosphate Metabolism to the nuclearversus the membrane-localized VDR, paving the way for selective treatment of disorders related to the rapid versus slow actions of 1,25-dihydroxyvitamin D with synthetic vitamin D analogues.
Regulation of [Ca++] and [Pi] by Small Intestine and Bone
An overview of the regulation of [Ca++] and Pi] by the action of PTH and 1,25-dihydroxyvitamin D on the small intestine, bone, and parathyroid glands is summarized in
Table 40.2 and in the following paragraphs. For details on renal handling of Ca++ , consult
Chapter 36.
Calcitonin isapeptidehormoneproducedbythemedullarycells,orC-cells,ofthethyroidgland.Calcitoninsecretionispositivelyregulatedbyserum[Ca++]viatheCaSR.Thecalcitoninreceptorisexpressedinosteoclasts,wherecalcitoninactsrapidlyanddirectlytoinhibitboneresorption.However,inhumans,calcitonindoesnotappeartoplayamajorroleinregulatingserumCa.Insupportofthisview,productionofexcesscalcitoninorcompleteabsenceofcalcitonin(e.g.,followingthyroidectomy)doesnotperturbserumCalevels.Morepotentformsofthehormone(e.g.,salmoncalcitonin)havebeenusedtherapeuticallyasanantiresorptiveinthetreatmentofPaget’s disease (characterizedbyexcessiveosteoclasticboneresorption)andinosteoporosis.Calcitoninisalsoausefulhistochemicalmarkerofmedullarythyroidcancer.