Vitamin D3 (Cholecalciferol) | Supplementopedia

Overview

Vitamin D₃ (cholecalciferol) is a fat-soluble secosteroid hormone.

Robust clinical and epidemiologic data link adequate vitamin D₃ status (serum 25-hydroxy-vitamin D ≥ 30 ng/mL) with several health outcomes:

Bone health: Enhances intestinal calcium absorption, reducing the risk of osteomalacia, rickets, and osteoporosis-related fractures.
Immune function: Modulates innate and adaptive immunity; deficiency is linked to increased respiratory infections and, in some trials, reduced severity of viral illnesses.
Musculoskeletal performance: Improves muscle strength and balance, lowering fall risk in older adults.
Metabolic health: Observational studies associate higher vitamin D levels with improved insulin sensitivity and lower incidence of type-2 diabetes, though causality remains under investigation.
Cognitive and mood regulation: Low serum 25-OH-D is correlated with higher rates of depression and cognitive decline; supplementation shows modest benefit in mood scores for deficient individuals.
All benefits are strongest when baseline levels are insufficient.

After cutaneous synthesis or oral intake, vitamin D₃ is hydroxylated in the liver to 25-hydroxy-vitamin D (calcidiol).
The kidney then converts calcidiol to the biologically active 1,25-dihydroxy-vitamin D (calcitriol) via 1α-hydroxylase (CYP27B1).
Calcitriol binds the intracellular vitamin D receptor (VDR), a ligand-activated transcription factor.
The VDR-retinoid X-receptor heterodimer binds vitamin-D responsive elements (VDREs) in DNA, regulating expression of >300 genes involved in:
- Calcium transport (e.g., TRPV6, calbindin)
- Immune modulation (e.g., cathelicidin, IL-10)
- Cell proliferation/differentiation
This genomic pathway, together with rapid non-genomic signaling (e.g., MAPK activation), underlies its effects on bone mineralization, immune cell function, and endocrine regulation.

Recommended daily allowances (RDA) for adults are 600–800 IU (15–20 µg) of vitamin D₃.
Many clinical guidelines recommend 1,000–2,000 IU (25–50 µg) for adults with limited sun exposure.
Therapeutic re-pletion of deficiency commonly uses 2,000–5,000 IU/day for 8–12 weeks, then a maintenance dose of 1,000–2,000 IU/day.
Higher doses (10,000 IU/day) are occasionally used under medical supervision for severe deficiency.
Vitamin D is best taken with a meal containing fat to enhance absorption.
Special considerations:
- Osteoporosis patients often receive 800–1,200 IU plus calcium.
- Obese individuals may require 1.5–2× higher doses due to sequestration in adipose tissue.
- Pediatric doses are lower (400–1,000 IU).
Consistent daily intake is preferred over intermittent mega-doses, which have been linked to increased fall risk in the elderly.

Vitamin D₃ is generally safe.
Toxicity is rare and usually occurs at sustained intakes >10,000 IU/day, leading to hypercalcemia, nephrolithiasis, and vascular calcification.
Common adverse effects at high doses include nausea, polyuria, and weakness.
Contraindications include hyperparathyroidism, sarcoidosis, or granulomatous diseases (e.g., tuberculosis) where extrarenal 1α-hydroxylase activity is elevated.
Drug interactions:
- Thiazide diuretics and vitamin A excess may potentiate hypercalcemia.
- Glucocorticoids and anticonvulsants can increase vitamin D catabolism, requiring higher doses.
Pregnant and lactating women can safely use 600–2,000 IU/day.
Patients with chronic kidney disease, hypercalcemia, or active granulomatous disease should avoid high-dose supplementation without physician oversight.

Vitamin D₃ (cholecalciferol) is a sterol-like molecule with the IUPAC name (3S,5Z,7E)-9,10-sec-cholesta-5,7-diene-3-ol.
Molecular formula: C₂₇H₄₄O
Molecular weight: 384.64 g mol⁻¹
Its structure consists of:
- A broken B-ring (secosteroid)
- A 3-β-hydroxyl group
- A conjugated diene (C5–C6 and C7–C8)
- A side chain (C-19 carbon) ending in a saturated alkyl chain.
The molecule is highly lipophilic (logP ≈ 8).
It is insoluble in water but soluble in organic solvents and lipid matrices, which underlies its absorption with dietary fat.
The 3-hydroxyl group is the key functional group for VDR binding after conversion to the active 1α-hydroxylated form.

Vitamin D₃ is primarily derived from lanolin (wool wax) of sheep.
- The precursor 7-dehydrocholesterol is extracted, purified, and UV-irradiated to produce cholecalciferol.
Alternative sources include fish oil and lichen (the latter for vegan-friendly products).
Most commercial supplements are synthesized via photochemical conversion of 7-dehydrocholesterol to cholecalciferol, followed by purification steps (e.g., chromatography) to achieve >98 % purity.
Quality considerations include:
- Verification of potency (via HPLC)
- Absence of heavy metals or residual solvents
- Stability (protect from light and heat)
Third-party testing (e.g., USP, NSF) helps assure consistency, especially for high-dose formulations.