Vitamin D Beyond Bone Health: Immune Modulation and Gene Expression

Vitamin D's role in calcium homeostasis and bone mineralization is well established. Less widely appreciated is the extent to which vitamin D functions as a steroid hormone with regulatory effects on over 200 genes across nearly every tissue type.

Beyond the Skeleton

The vitamin D receptor (VDR) is expressed in immune cells, intestinal epithelium, pancreatic beta cells, cardiomyocytes, neurons, and numerous other cell types. This distribution suggests functions far beyond calcium metabolism.

Key non-skeletal roles include:

• Innate immunity: Vitamin D upregulates cathelicidin (LL-37), an antimicrobial peptide critical for defense against bacterial and viral pathogens
• Adaptive immunity: Modulation of T-helper cell differentiation, favoring regulatory T cells over inflammatory Th17 responses
• Insulin secretion: VDR expression in beta cells suggests a role in glucose homeostasis
• Cardiovascular function: Association with endothelial function and vascular smooth muscle regulation

The Measurement Problem

Standard assessment relies on serum 25-hydroxyvitamin D (25(OH)D), which reflects circulating vitamin D status. However, this may not capture tissue-level vitamin D availability, which depends on:

• Local conversion of 25(OH)D to the active form 1,25(OH)2D by tissue-specific 1-alpha-hydroxylase
• VDR polymorphisms that affect receptor sensitivity
• Magnesium status, which is required for vitamin D metabolism at multiple steps

This complexity means that a "normal" serum level may be functionally insufficient in some individuals, and supplementation trials using serum 25(OH)D as the sole outcome marker may underestimate tissue-specific effects.

Supplementation Considerations

The evidence supports maintaining serum 25(OH)D above 30 ng/mL (75 nmol/L) for most adults, with some researchers arguing for 40–60 ng/mL for optimal immune function. Key practical points:

• Vitamin D3 (cholecalciferol) is preferred over D2 (ergocalciferol) for sustained elevation
• Co-administration with fat improves absorption
• Magnesium sufficiency is a prerequisite for vitamin D metabolism
• Individual dose–response varies considerably; testing is more useful than standardized dosing

The broader point is that vitamin D deficiency is not merely a skeletal issue — it represents a systemic hormonal deficit with implications across multiple organ systems.