Vitamin D

Vitamin D is a fat-soluble secosteroid hormone precursor essential for calcium and phosphate homeostasis, skeletal mineralization, and multiple extraskeletal functions including immune modulation and cell differentiation. Unlike most vitamins, the primary source in most populations is endogenous skin synthesis from cholesterol under UVB exposure, with dietary and supplemental intake secondary.

Biochemistry

The two major forms are vitamin D2 (ergocalciferol) from UV-irradiated ergosterol in plants and fungi, and vitamin D3 (cholecalciferol) from UVB photolysis of 7-dehydrocholesterol in skin. Both are biologically inactive precursors requiring sequential hydroxylation: CYP2R1 in the liver produces 25-hydroxyvitamin D (calcidiol), and CYP27B1 primarily in the kidney produces 1,25-dihydroxyvitamin D (calcitriol), the active hormone. Calcitriol binds the vitamin D receptor (VDR), a nuclear hormone receptor regulating transcription of hundreds of target genes.

Calcium and bone homeostasis

The classical endocrine function of vitamin D is maintenance of serum calcium and phosphate at concentrations supporting bone mineralization. Calcitriol acts at three principal sites: (1) intestinal epithelium, upregulating TRPV6 calcium channel and calbindin for active calcium absorption; (2) kidney, enhancing distal tubular calcium reabsorption; (3) bone, mobilizing calcium in conjunction with parathyroid hormone. Severe deficiency produces rickets in children (impaired growth plate mineralization) and osteomalacia in adults (defective bone matrix mineralization).

Requirements

The 2011 NAM DRI report set RDAs of 600 IU/day for ages 1-70 and 800 IU/day for age 71+, with a Tolerable Upper Intake Level of 4000 IU/day. The Endocrine Society position statement recommends higher intakes for patients at risk of deficiency. Serum 25(OH)D is the accepted marker; NAM defines sufficiency as ≥20 ng/mL (≥50 nmol/L), while the Endocrine Society recommends ≥30 ng/mL (≥75 nmol/L). These thresholds continue to be debated.

Deficiency epidemiology

Vitamin D insufficiency (25(OH)D <20 ng/mL) affects approximately 20-25% of US adults, with higher rates in individuals with darker skin pigmentation (melanin reduces UVB skin synthesis efficiency), those with limited sun exposure, older adults, obese individuals (sequestration in adipose tissue), and populations at higher latitudes during winter. Supplementation is broadly recommended for these higher-risk groups.

Extraskeletal effects and RCT evidence

Observational studies have associated low 25(OH)D with virtually every chronic disease studied — cardiovascular, cancer, autoimmune, infectious, psychiatric. Large-scale randomized trials have produced more modest results: the VITAL trial (Manson et al., NEJM 2019) tested 2000 IU/day D3 in 25,871 adults and found no significant effect on the primary composite cancer or cardiovascular endpoints, though certain secondary outcomes (cancer mortality over follow-up, autoimmune disease incidence) showed modest benefit. Similar patterns have emerged for respiratory infection prevention, falls prevention, and diabetes progression — observational associations generally exceed RCT effect sizes.

Dietary sources

Per USDA FoodData Central: salmon (wild) 400-1000 IU per 100 g, salmon (farmed) 100-400 IU, mackerel 340 IU, tuna 230 IU, sardines 190 IU per 100 g, cod liver oil 1360 IU per tablespoon, egg yolk 40 IU per large egg, UV-exposed mushrooms 400-1000 IU per 100 g. Fortified foods in the US supply: milk 100 IU per 8 oz, some fortified plant milks and orange juice 100-150 IU per 8 oz, fortified breakfast cereals 40-100 IU per serving.

Supplementation guidance

Vitamin D3 is generally preferred over D2 due to longer half-life and more efficient raising of serum 25(OH)D. Typical supplementation ranges are 1000-2000 IU/day for general maintenance or 4000-5000 IU/day for established deficiency correction, titrated against periodic 25(OH)D measurement. Toxicity (hypercalcemia) from supplementation is rare at intakes below 10,000 IU/day over extended periods but can occur.