Mechanism of Action of Vitamin D Supplementation in Infants
Primary Metabolic Pathway
Vitamin D supplementation in infants works through a two-step hydroxylation process that ultimately enables calcium and phosphorus absorption necessary for skeletal mineralization and growth. 1
The mechanism unfolds as follows:
First hydroxylation occurs in the liver, where ingested vitamin D (ergocalciferol or cholecalciferol) is converted to 25-hydroxyvitamin D [25(OH)D], the major circulating form used to assess vitamin D status 1, 2
Second hydroxylation occurs in the kidneys, where 25(OH)D is converted to 1,25-dihydroxyvitamin D [1,25(OH)₂D₃], the biologically active hormone form 1, 3
Parathyroid hormone regulates this renal conversion, making the kidney the critical control point for vitamin D activation 1
Cellular and Molecular Actions
Once activated, vitamin D functions as a steroid hormone rather than a true vitamin:
1,25-dihydroxyvitamin D binds to vitamin D receptors (VDRs) present in the nuclei of target cells, particularly in calcium-regulating tissues 3, 2
The vitamin D-receptor complex translocates to the nucleus and interacts with DNA responsive elements, regulating the transcription of over 1,200 genes 4, 2
This gene regulation stimulates production of calcium and phosphorus transport proteins in the intestinal epithelium, though only calcium-binding protein has been definitively identified as vitamin D-dependent 3
Physiological Effects Critical for Infants
The activated vitamin D hormone achieves three primary functions essential for infant skeletal development:
Stimulates intestinal calcium and phosphorus absorption in the small intestine, which is the primary mechanism for maintaining adequate mineral levels 1, 3
Mobilizes calcium and phosphate from bone when needed to maintain serum concentrations, though this requires parathyroid hormone for bone and kidney effects 3
Increases renal reabsorption of calcium in the distal tubules, conserving calcium that would otherwise be lost in urine 1, 3
Clinical Significance in Infants
The net result elevates serum calcium and phosphorus to supersaturating levels required for proper bone mineralization, preventing rickets, osteomalacia, and hypocalcemic tetany 3. This is particularly critical in infants because:
There is a 10-24 hour time lag between vitamin D administration and initiation of biological action, due to the necessity of hepatic and renal metabolism 1
Breast milk provides insufficient vitamin D (generally less than 25-78 IU per liter), placing exclusively breastfed infants at high risk without supplementation 5
Each 100 IU/day increase in vitamin D supplementation is associated with an average 1.92 nmol/L increase in achieved 25(OH)D concentration, though with considerable individual variation 6
Beyond Skeletal Health
While calcium regulation remains the primary established function, emerging evidence suggests broader roles:
Most cells in the body possess vitamin D receptors and can produce 1,25-dihydroxyvitamin D locally, suggesting autocrine and paracrine functions beyond calcium metabolism 4, 7
Vitamin D may modulate immune function, cell growth regulation, and cardiovascular health, though high-quality evidence for supplementation benefits in these areas remains insufficient in infants 2, 4
Critical Dosing Considerations
For term infants, 400 IU daily supplementation is recommended starting at hospital discharge, as this dose reliably raises 25(OH)D concentrations above the sufficiency threshold of 50 nmol/L (20 ng/mL) without risk of toxicity 2, 5, 8
Preterm infants require higher doses of 200-1,000 IU/day (80-400 IU/kg/day) due to increased metabolic demands and limited hepatic reserves 2, 9, 8
Common Pitfall
Do not confuse the mechanism of nutritional vitamin D supplementation with active vitamin D analogs (calcitriol, alfacalcidol)—these bypass normal metabolic regulation and are inappropriate for treating nutritional deficiency, as they do not build hepatic 25(OH)D stores and carry higher risk of hypercalcemia 5, 4