From the Guidelines
Calcitriol, the active form of vitamin D (1,25-dihydroxyvitamin D3), works through a complex mechanism to regulate calcium and phosphate homeostasis in the body, primarily by binding to vitamin D receptors (VDRs) in target tissues and regulating gene transcription. The mechanism of action of calcitriol involves its production in the kidneys through hydroxylation of 25-hydroxyvitamin D by the enzyme 1α-hydroxylase 1. Once formed, calcitriol acts as a steroid hormone, binding to VDRs in target tissues, including the intestine, bone, and kidneys.
Key Mechanisms of Action
- In the intestine, calcitriol increases calcium and phosphate absorption by upregulating calcium transport proteins like TRPV6 and calbindin 1.
- In bone, it promotes mineralization by stimulating osteoblast differentiation and regulating osteoclast activity through RANKL expression.
- In the kidneys, calcitriol reduces calcium excretion while promoting phosphate excretion.
- It also provides negative feedback to the parathyroid glands, suppressing parathyroid hormone (PTH) secretion when calcium levels are adequate.
Clinical Implications
The comprehensive mechanism of calcitriol allows it to maintain proper calcium-phosphate balance, which is essential for bone health, neuromuscular function, and various cellular processes throughout the body. Understanding the mechanism of action of calcitriol is crucial for its effective use in the management of conditions like X-linked hypophosphataemia, where it is used alongside phosphate supplements to counter calcitriol deficiency and prevent secondary hyperparathyroidism 1.
Evidence-Based Practice
The most recent and highest quality evidence supports the use of calcitriol in the management of bone metabolism and disease, particularly in chronic kidney disease and X-linked hypophosphataemia 1. This evidence highlights the importance of calcitriol in regulating calcium and phosphate homeostasis and its role in preventing complications associated with disturbed mineral metabolism.
From the FDA Drug Label
The two known sites of action of calcitriol are intestine and bone. A calcitriol receptor-binding protein appears to exist in the mucosa of human intestine. Additional evidence suggests that calcitriol may also act on the kidney and the parathyroid glands. Calcitriol is the most active known form of vitamin D3 in stimulating intestinal calcium transport
The mechanism of action of Calcitriol (1,25-Dihydroxyvitamin D3) is to:
- Stimulate intestinal calcium transport
- Act on bone, kidney, and parathyroid glands Key aspects of its mechanism include:
- Binding to a receptor-binding protein in the intestinal mucosa
- Regulation of calcium and phosphorus metabolism at target tissues 2 2
From the Research
Mechanism of Action of Calcitriol
The mechanism of action of calcitriol (1,25-Dihydroxyvitamin D3) involves its binding to the vitamin D receptor (VDR), which regulates the transcription of target genes 3, 4, 5, 6, 7.
- Calcitriol stimulates intestinal calcium and phosphate absorption, maintaining sufficient concentrations of these ions in the extracellular fluids necessary for normal mineralization of bone matrix 4, 5, 7.
- It also exerts important functions in regulating bone metabolism, suppressing pre-osteoblasts and activating mature osteoblasts 3.
- The interaction between calcitriol and VDR increases the efficiency of intestinal absorption of calcium and phosphate, with serum phosphate levels influencing calcitriol and fibroblast growth factor 23 (FGF23) levels 5.
- Calcitriol regulates immune and inflammatory response, cell turnover, cell differentiation, renin production, and reduces proteinuria 3.
Regulation of Mineral Metabolism
Calcitriol plays a crucial role in regulating mineral metabolism, including:
- Stimulating calcium and phosphate absorption in the intestine 4, 5, 7
- Regulating parathyroid hormone (PTH) synthesis and FGF23 production 3, 5, 6
- Maintaining phosphate homeostasis, which is essential for preventing hyperphosphatemia and hypophosphatemia 5
Biological Actions
The biological actions of calcitriol are mediated by its binding to VDR, which is present in a large variety of cells 3, 4, 6, 7.
- Calcitriol localizes specifically in the nucleus, where it interacts with VDR to bring about transcription of specific genes that code for calcium and phosphorus transport proteins 7.
- The molecular mechanism of calcium transport in villus cells involves the induction of specific genes, including the calcium-binding protein 7.