Vitamin D3 · Evidence-First Fact Sheet

Vitamin D3 (cholecalciferol) is a secosteroid hormone precursor with meta-analysis-supported evidence for bone mineral density, daily-dose respiratory immune support, VITAL autoimmune and telomere findings, and depressive symptom scores. FDA and EFSA authorized health claims are cited with conditions.

Quick Summary

Vitamin D3 (cholecalciferol) is a fat-soluble secosteroid hormone precursor that the body can synthesize endogenously through skin exposure to UVB sunlight and obtain through diet (fatty fish, egg yolks, fortified dairy) or supplementation. Its active metabolite calcitriol binds the vitamin D receptor (VDR) to regulate over 900 genes — influencing calcium-phosphorus balance, bone mineralization, immune regulation, and cellular differentiation. Vitamin D3 has one of the deepest evidence bases of any dietary nutrient, with multiple large meta-analyses and the 25,871-participant VITAL trial supporting roles in bone mineral density, daily-dose respiratory infection prevention, autoimmune disease incidence reduction, leukocyte telomere protection, and depressive symptom support. Importantly, several large trials have returned negative or mixed results — including no fracture reduction in healthy adults (LeBoff 2022 NEJM), no cardiovascular outcome reduction, and loss of autoimmune protection two years after discontinuation. Vitamin D3 also holds FDA and EFSA authorized health claims for osteoporosis risk reduction and (in the EU) 60+ falls — the highest density of authorized claims in the supplement category. Vitamin D deficiency is highly prevalent: NHANES data report 22% of US adults with moderate deficiency and 41% with insufficiency. Pregnant, lactating, and pediatric populations, individuals with kidney disease or sarcoidosis, and those on thiazide diuretics or digoxin should consult a healthcare provider before starting supplementation.

Overview · What is Vitamin D3?

Vitamin D3 (cholecalciferol · CAS 67-97-0 · molecular formula C₂₇H₄₄O · PubChem CID 5280795) is a fat-soluble secosteroid prohormone — structurally a "broken-ring" steroid in which the B-ring of the cyclopentanoperhydrophenanthrene skeleton is opened. This distinguishes vitamin D3 from animal-derived vitamin D2 (ergocalciferol · from yeast/fungi) and gives it its uniquely high binding affinity to the vitamin D binding protein (DBP) and the vitamin D receptor (VDR).

Vitamin D3 is unique among "vitamins" because the human body can synthesize it endogenously: when 7-dehydrocholesterol in skin keratinocytes absorbs UVB photons (290-315 nm), it isomerizes to previtamin D3, which thermally converts to cholecalciferol over hours. Dietary sources include fatty fish (salmon · mackerel · sardines), cod liver oil, egg yolks, beef liver, and foods fortified with vitamin D3 (milk · plant-milk alternatives · breakfast cereals · orange juice in some markets). Supplemental vitamin D3 is produced by UVB irradiation of 7-dehydrocholesterol derived from lanolin (sheep's wool) or, in plant-based formulations, from lichen.

Once absorbed or synthesized, vitamin D3 undergoes two sequential hydroxylations: first by hepatic CYP2R1 to 25-hydroxyvitamin D (25(OH)D) — the circulating storage form with a 2-3 week half-life and the standard clinical biomarker of vitamin D status — and then by renal (or local tissue) CYP27B1 to 1,25-dihydroxyvitamin D (calcitriol), the biologically active hormone.

Vitamin D deficiency is globally common. A 2022 NHANES analysis of 71,685 US adults reported 2.6% with severe deficiency (serum 25(OH)D <25 nmol/L), 22% with moderate deficiency (25-50 nmol/L), and 41% with insufficiency (50-75 nmol/L) — leaving only 34.5% with sufficient status. Women, non-Hispanic Black adults, 20-29 year-olds, and winter-month measurements were associated with the highest deficiency rates.

This page is part of ASXAN's evidence-first educational hub and does not constitute a purchase recommendation.

Mechanism of Action

Vitamin D3's biological activity arises from a well-characterized hormonal signaling network — distinctively, the mechanistic evidence base in humans is among the strongest of any dietary nutrient, with serum 25(OH)D directly measurable and the VDR pathway extensively mapped. The following mechanisms are central:

VDR-mediated gene transcription (classical pathway). Calcitriol binds VDR, heterodimerizes with the retinoid X receptor (RXR), binds vitamin D response elements (VDREs) in gene promoters, and regulates the transcription of more than 900 genes. Key targets include the calcium-binding protein calbindin, the antimicrobial peptide cathelicidin (LL-37 / CAMP), bone matrix proteins (osteocalcin), the Treg lineage transcription factor FOXP3, and the feedback enzyme CYP24A1 that degrades excess calcitriol to maintain hormone homeostasis.

Calcium-phosphorus axis. Calcitriol upregulates intestinal calbindin and the TRPV6 channel, increasing dietary calcium absorption to approximately 30%; it promotes renal phosphate reabsorption in the proximal tubule; and it modulates osteoblast RANKL expression to indirectly regulate osteoclast activity. Low vitamin D status triggers secondary hyperparathyroidism (PTH ↑), driving bone resorption to maintain serum calcium — the proximal mechanism connecting vitamin D status to long-term bone mineral density.

Cathelicidin (LL-37) upregulation — innate immunity. Calcitriol-VDR directly binds the cathelicidin antimicrobial peptide (CAMP) gene promoter, upregulating LL-37 synthesis in macrophages and neutrophils and enhancing pathogen clearance against respiratory bacteria and viruses. This is the molecular basis for the daily-dose respiratory infection signals reported in the Martineau 2017 IPD and Jolliffe 2025 stratified meta-analyses (§4.2).

Immune balance and Treg induction. Calcitriol suppresses Th1 / Th17 polarization (decreasing IFN-γ and IL-17) and promotes FOXP3+ regulatory T-cell differentiation, supporting peripheral immune tolerance. This immunoregulatory shift is the proposed mechanism underlying the 22% autoimmune disease incidence reduction observed in the VITAL trial (Hahn 2022 BMJ, §4.3).

NF-κB signaling inhibition and anti-inflammatory effects. Calcitriol-VDR suppresses IκB kinase activity, blocking p65 nuclear translocation and downregulating IL-6, TNF-α, and CRP — dampening chronic low-grade inflammation across tissues.

Cell differentiation and apoptosis regulation. Calcitriol modulates cyclin-dependent kinase inhibitors (p21, p27) and the Bcl-2 family, influencing cellular differentiation and apoptosis pathways. In human RCT data, this mechanism translates to a modest signal on cancer-related mortality (Ruiz-García 2023 daily dosing OR 0.90) but not to cancer incidence reduction — a distinction that must be preserved (§4 and §4.6).

A distinguishing feature of vitamin D3 versus most other dietary bioactives is that direct human mechanistic evidence is extensive — serum 25(OH)D is a gold-standard clinical biomarker, VDR genetic polymorphisms have been mapped to outcomes, and VITAL sub-studies have measured leukocyte telomere length and immune cell phenotypes directly in supplemented humans. Mechanism narratives below therefore require fewer "based on preclinical" qualifiers than is typical for carotenoid or botanical ingredients.

References: PMID 36308775 (Kazemian 2023, BMD), PMID 35082139 (Hahn 2022, autoimmune mechanism), PMID 28202713 (Martineau 2017, respiratory mechanism), PMID 40409468 (Zhu 2025, telomere).

Evidence-Based Benefits

Each benefit below opens with an evidence tier label following NIH-ODS conventions: meta-analysis-supported > rct-supported > emerging > preclinical-major. Effect sizes, sample sizes, and study designs are reported as published — no values are inferred. Disease-related research populations are described as such; vitamin D3 is not characterized as a treatment for any disease.

Inside the VITAL Trial · America's Largest Vitamin D RCT

Multiple benefit sections below reference findings from the VITAL trial (VITamin D and OmegA-3 TriaL), the largest randomized controlled trial of vitamin D supplementation conducted to date. VITAL randomized 25,871 US adults (men ≥50 years · women ≥55 years) to a 2×2 factorial design: vitamin D3 2000 IU/day vs placebo, and marine omega-3 fatty acids 1 g/day vs placebo, with a median follow-up of 5.3 years. VITAL has generated multiple sub-study publications spanning autoimmune disease, fractures, telomere length, cardiovascular outcomes, and mood-related endpoints. Throughout this fact sheet, VITAL findings are cited transparently — including studies where vitamin D3 demonstrated benefit (Hahn 2022 BMJ autoimmune · Zhu 2025 AJCN telomere) and studies where it did not (LeBoff 2022 NEJM fracture · Costenbader 2024 2-year discontinuation follow-up). The VITAL sub-study cluster is described under each relevant heading rather than collected in one place, so that each benefit area can be read in its full evidence context.

Bone Mineral Density and Fracture Risk

Evidence Tier: meta-analysis-supported

Educational notice: Osteoporosis (ICD-10 M81 / M80) is a clinical diagnosis requiring medical evaluation and management. The data below evaluate vitamin D3's effects on bone mineral density and fracture-related outcomes; for individuals with diagnosed osteopenia, osteoporosis, or prior fragility fracture, vitamin D3 supplementation may be one component of a medically directed care plan — not a substitute for it. Consult your healthcare provider for personalized bone health assessment.

A 2023 systematic review and meta-analysis of 39 RCTs (Kazemian et al., Nutrition Reviews, screened from 6,409 records) reported that vitamin D3 supplementation across the 400-7000 IU/day range significantly increased bone mineral density at the lumbar spine (standardized mean difference 0.06) and femoral neck (SMD 0.25), with a positive dose-response relationship and concurrent reductions in parathyroid hormone (PTH).

A 2022 meta-analysis of 32 RCTs (Kong et al., Endocrinology and Metabolism) further established that daily dosing of 800-1000 IU/day produced concurrent reductions in both fracture risk and fall risk, while intermittent high-dose regimens (e.g., monthly bolus dosing) were not effective. This daily-versus-bolus distinction is one of the most reproducible findings in the vitamin D literature.

The VITAL ancillary fracture sub-study (LeBoff 2022 NEJM) evaluated total fractures, non-vertebral fractures, and hip fractures in 25,871 generally healthy midlife and older adults assigned to vitamin D3 2000 IU/day or placebo for a median of 5.3 years. There was no significant reduction in total fracture, non-vertebral fracture, or hip fracture incidence versus placebo. Importantly, the VITAL cohort was a generally healthy population not selected for vitamin D deficiency, baseline 25(OH)D levels were largely sufficient, and the trial was not designed to require concurrent calcium supplementation — three factors that distinguish it from the Kong 2022 meta-analytic context.

These data support vitamin D3's role in maintaining bone mineral density and — particularly when combined with calcium and especially in adults with low baseline vitamin D status — fracture and fall risk reduction. They do not support fracture prevention as a uniform benefit in healthy adults already replete in vitamin D, and the LeBoff 2022 NEJM finding is reported transparently rather than omitted.

Authorized health claim references. The US FDA has authorized, under 21 CFR 101.72, the health claim that adequate calcium and vitamin D throughout life, as part of a well-balanced diet, may reduce the risk of osteoporosis (with claim wording conditions including ≥10% Daily Value of calcium per serving and vitamin D content disclosure). The European Food Safety Authority (EFSA) has authorized, under Regulation (EU) No 432/2012 and Commission Regulation (EU) No 1228/2014 Article 14, a disease risk reduction claim that adequate intake of calcium and vitamin D may reduce the loss of bone mineral in postmenopausal women (claim conditions: ≥1200 mg calcium and ≥20 μg / 800 IU vitamin D per day in women aged 50+). These are among the small number of supplement-related claims to have received formal regulatory authorization in either jurisdiction; they are presented here as a regulatory reference, not as a recommendation that supplementation alone will prevent or reverse bone disease in any individual.

References: PMID 36308775 (Kazemian 2023, Nutrition Reviews), PMID 35504603 (Kong 2022, Endocrinology and Metabolism), PMID 35939577 (LeBoff 2022, NEJM — fracture sub-study transparency).

Daily-Dose Respiratory Infection Prevention

Evidence Tier: meta-analysis-supported

Educational notice: Acute respiratory infections — including influenza, the common cold, COVID-19, and other viral and bacterial respiratory illnesses — are medical conditions. Vitamin D3 supplementation is not authorized as a treatment, cure, or specific preventive therapy for any named respiratory illness. The data below describe research findings on supplementation patterns and infection risk.

A 2017 individual participant data (IPD) meta-analysis of 25 RCTs with 11,321 participants (Martineau et al., BMJ) reported that vitamin D supplementation produced an adjusted odds ratio of 0.88 for acute respiratory tract infection across the full pooled population. Benefit was substantially larger in subgroups: participants with baseline 25(OH)D below 25 nmol/L receiving daily or weekly dosing had OR 0.58. Notably, bolus dose regimens were not effective.

A 2025 updated stratified-aggregate meta-analysis of 43 RCTs with 49,320 participants (Jolliffe et al., Lancet Diabetes & Endocrinology) — which incorporated the largest single trial published since the 2017 IPD (a 15,804-participant Norwegian trial) — found a non-significant overall effect (RR 0.99) but a statistically significant effect in the daily-dosing subgroup (RR 0.92) and identified the 400-1200 IU/day dose range as the optimal protective band. The shift in pooled point estimate between 2017 and 2025 highlights that vitamin D's respiratory effect is most reproducible in deficient populations and with daily (not intermittent) dosing — a refinement of, rather than contradiction to, the earlier IPD signal.

These data support a role for daily vitamin D3 supplementation in the 400-1200 IU/day range — particularly in individuals with low baseline 25(OH)D — in maintaining respiratory immune resilience. They do not support claims that vitamin D3 "prevents," "treats," or "cures" influenza, the common cold, COVID-19, or any other named respiratory illness. Individuals concerned about respiratory infection should consult their healthcare provider regarding evidence-based preventive measures including vaccination and routine medical care.

References: PMID 28202713 (Martineau 2017, BMJ IPD), PMID 39993397 (Jolliffe 2025, Lancet Diabetes & Endocrinology).

Autoimmune Disease Incidence — VITAL Findings and the Discontinuation Caveat

Evidence Tier: rct-supported

Educational notice: Autoimmune diseases — including rheumatoid arthritis (ICD-10 M05/M06), autoimmune thyroid disease (E06), psoriasis (L40), multiple sclerosis (G35), type 1 diabetes (E10), and autoimmune hematologic disorders — are clinical diagnoses that require medical management. The data below report research findings on autoimmune disease incidence in supplemented research populations. Vitamin D3 is not characterized here as a treatment or cure for any autoimmune condition; individuals with diagnosed autoimmune disease should not modify their treatment regimen without consulting their rheumatologist or other treating specialist.

The VITAL trial randomized 25,871 generally healthy US adults (men ≥50 years · women ≥55 years) to vitamin D3 2000 IU/day or placebo (and, in a 2×2 factorial design, to marine omega-3 1 g/day or placebo) for a median of 5.3 years. The pre-specified ancillary endpoint of total incident autoimmune disease — covering rheumatoid arthritis, autoimmune thyroid disease, psoriasis, polymyalgia rheumatica, and others — showed a 22% reduction in the vitamin D3 arm versus placebo (Hahn 2022 BMJ, hazard ratio 0.78, 95% CI 0.61-0.99). This remains one of the largest randomized signals on autoimmune disease incidence in the supplement literature.

The 2024 VITAL follow-up study (Costenbader et al., Arthritis & Rheumatology) continued passive surveillance in 21,592 of the original VITAL participants for an additional two years after randomized treatment ended. In this extension period, the protection against autoimmune disease incidence from daily vitamin D3 was no longer statistically significant, while the benefit from daily marine omega-3 fatty acids remained significant. This finding suggests that vitamin D3's autoimmune-protective effect may require continuous supplementation rather than persisting after discontinuation. We report this caveat transparently rather than reporting only the original 2022 randomized result.

These data support vitamin D3 supplementation as a research-supported nutritional approach to maintaining healthy immune balance in midlife and older adults — most consistently when supplementation is continuous. They do not establish vitamin D3 as a treatment for any autoimmune disease, and the discontinuation caveat is integral to interpreting the VITAL evidence.

References: PMID 35082139 (Hahn 2022, BMJ — VITAL autoimmune primary), PMID 38272846 (Costenbader 2024, Arthritis & Rheumatology — 2-year discontinuation follow-up).

Leukocyte Telomere Length — VITAL Sub-Study Signal

Evidence Tier: rct-supported

A 2025 sub-study of VITAL (Zhu et al., American Journal of Clinical Nutrition) measured leukocyte telomere length by quantitative PCR in 2,571 blood samples from 1,031 participants at baseline and after 4 years of randomized treatment. Participants in the vitamin D3 2000 IU/day arm showed reduced telomere shortening by approximately 0.14 kilobases (~140 base pairs) compared with the placebo arm — equivalent to delaying roughly three years of cellular aging when benchmarked against typical adult telomere attrition rates. The marine omega-3 arm did not show a comparable effect.

Telomere length is widely studied as a biomarker of cellular aging; it is not itself a disease endpoint, and a single biomarker change does not translate directly into lifespan, healthspan, or specific disease outcomes. This finding is reported here as a mechanistically suggestive signal from one of the few large randomized trials to measure telomere length directly in supplemented humans — one component of the broader VITAL sub-study program rather than a standalone basis for any therapeutic claim.

References: PMID 40409468 (Zhu 2025, American Journal of Clinical Nutrition — VITAL telomere sub-study).

Depressive Symptom Scores in Adult Research Populations

Evidence Tier: meta-analysis-supported

Educational notice: Depression and major depressive disorder (ICD-10 F32-F33) are clinical diagnoses that require professional evaluation and care. The data below evaluate vitamin D3 supplementation's effect on depressive symptom scores measured by validated rating scales in research populations; they do not establish vitamin D3 as a treatment, cure, or substitute for evidence-based antidepressant therapy. Individuals experiencing persistent low mood, depressive symptoms, or any mental health concern should consult a qualified mental health provider.

A 2024 dose-response meta-analysis of 31 RCTs with 24,189 participants (Ghaemi et al., Psychological Medicine) reported that each additional 1000 IU/day of vitamin D3 supplementation was associated with a standardized mean difference of -0.32 (95% CI -0.43 to -0.22) in depressive symptom scores. The effect was larger in participants with elevated depressive symptoms at baseline (SMD -0.57) and tended to be more pronounced in short-term (≤8-week) trials.

A 2023 systematic review and meta-analysis (Mikola et al., Critical Reviews in Food Science and Nutrition) — including a subgroup analysis of 7 RCTs in participants with major depressive disorder — also reported modest improvements in depressive symptom scales across general adult populations and in the MDD subgroup, with the authors noting that doses of approximately 2000 IU/day or higher were associated with the more consistent symptom-score signals.

These data support the position that vitamin D3 supplementation may favorably influence depressive symptom rating scales in adult research populations, particularly those with elevated baseline symptoms. They do not support characterizing vitamin D3 as an "antidepressant," a "natural alternative to antidepressant medication," or a treatment for major depressive disorder. The appropriate framing for consumer-facing reporting is supportive effects on mood-related markers in research settings.

References: PMID 39552387 (Ghaemi 2024, Psychological Medicine — dose-response MA), PMID 35816192 (Mikola 2023, Critical Reviews in Food Science and Nutrition).

Pregnancy Notice · High-Stakes YMYL Section

Educational notice for pregnancy. Pregnancy is a high-stakes nutritional and medical period. Always consult your healthcare provider before starting, stopping, or changing any supplement during pregnancy or lactation. The 2024 Cochrane systematic review of vitamin D supplementation in pregnancy (Palacios et al., CD008873.pub5) reassessed previously included trials under updated trustworthiness criteria and found that only 9 of the 30 originally included studies passed the new criteria; one trial was retracted and 20 were moved to "awaiting classification." Effect estimates on maternal and neonatal outcomes from the remaining trials are weaker and more uncertain than earlier Cochrane summaries suggested. Vitamin D status during pregnancy should be assessed and managed by a qualified obstetric provider, not on the basis of any general educational content. See /lifestyles/pregnancy/ for the broader pregnancy nutrition educational overview. Vitamin D3 is not characterized here as preventing preeclampsia, gestational diabetes, preterm birth, or any other named pregnancy complication.

References: PMID 39077939 (Palacios 2024, Cochrane Database of Systematic Reviews CD008873.pub5).

Dosage

Most clinical evidence for vitamin D3 uses oral doses in the range of 400-2000 IU/day (10-50 μg/day), taken with a fat-containing meal to support absorption (vitamin D3 is fat-soluble). Daily dosing has been repeatedly shown to outperform intermittent high-dose (weekly · monthly · annual bolus) regimens across respiratory, fracture, and mortality endpoints — this is one of the most reproducible findings in the vitamin D literature and should anchor any dosing decision.

Typical validated dose ranges by use case, based on published RCT and meta-analytic data:

Direction Validated dose Typical onset Source
Bone mineral density / bone health 800-2,000 IU/day (with ≥1,200 mg/day calcium) Continuous supplementation Kazemian 2023 · Kong 2022
Daily-dose respiratory immune support 400-1,200 IU/day (daily, not bolus) Continuous supplementation Martineau 2017 IPD · Jolliffe 2025
Autoimmune incidence (VITAL profile) 2,000 IU/day (continuous) ≥5 years Hahn 2022 · Costenbader 2024 (discontinuation caveat)
Leukocyte telomere protection 2,000 IU/day ≥4 years Zhu 2025 VITAL telomere sub-study
Depressive symptom scores in research populations ≥2,000 IU/day 8-24 weeks (short-term effects observed) Ghaemi 2024 · Mikola 2023
Fall risk reduction in adults aged 60+ 800-1,000 IU/day Continuous supplementation EFSA Art.14 · Kong 2022

Key dosing principle. The daily-versus-bolus distinction is critical: across the 2017 Martineau IPD (respiratory), the 2022 Kong meta-analysis (bone), the 2023 Ruiz-García meta-analysis (mortality), and the 2025 Jolliffe stratified meta-analysis (respiratory), daily dosing in the modest 400-2000 IU/day range has consistently outperformed weekly, monthly, or annual bolus regimens — sometimes by a wide margin, and sometimes with bolus regimens showing no benefit or even adverse signals. Where supplementation is initiated, daily dosing is strongly preferable.

Regulatory framework — four jurisdictions.

Market RDI / RDA Tolerable Upper Intake (UL) Authorized health claims
US FDA 800 IU/day (Daily Value) 4,000 IU/day (IOM 2011) 21 CFR 101.72 authorized health claim: "adequate calcium and vitamin D throughout life, as part of a well-balanced diet, may reduce the risk of osteoporosis" (with specified conditions including ≥10% DV calcium per serving)
EU EFSA 600 IU/day (adequate intake) · 200 IU/day (NRV) 4,000 IU/day Regulation 432/2012 Article 13 authorizes multiple nutrition function claims (contribution to normal bone, teeth, immune function, muscle function, calcium and phosphorus absorption, and cell division). Article 14 authorizes disease risk reduction claims for adequate calcium + vitamin D and bone mineral loss in postmenopausal women (≥1,200 mg Ca + ≥20 μg / 800 IU vitamin D / day) and for reduced risk of falls in adults aged 60+ (≥20 μg / 800 IU vitamin D / day)
CN NMPA 400 IU/day (ages 18-49) · 600 IU/day (≥50) 2,000 IU/day NMPA permits "supplements vitamin D" and certain health food function categories (e.g., supports immune function) under the registered health food framework; specific claim wording requires product-level NMPA approval
BR ANVISA 200 IU/day (RDI) 2,000 IU/day ANVISA positive list recognizes vitamin D's role in calcium and phosphorus absorption; disease-specific claims are not permitted in product labeling

Individual response varies. Consult a healthcare provider for personalized dosage assessment, particularly if you take medication, are pregnant or lactating, have kidney disease, granulomatous disease (sarcoidosis · tuberculosis), or any chronic condition.

Safety and Drug Interactions

Vitamin D3 has an excellent safety profile and a long history of use in fortified foods (>90 years). It is FDA GRAS and listed in the United States Pharmacopeia (USP) as a Cholecalciferol monograph article. The Institute of Medicine established the adult tolerable upper intake level (UL) at 4,000 IU/day (IOM 2011); the Endocrine Society's 2011 clinical practice guideline considered short-term doses up to 10,000 IU/day tolerable in clinical contexts. The VITAL trial's 5.3-year administration of 2,000 IU/day in 25,871 adults reported no increased risk of hypercalcemia or kidney stones — the largest long-term human safety dataset for vitamin D3 supplementation at this dose to date.

Toxicity threshold. Sustained intake above approximately 10,000 IU/day, or serum 25(OH)D above 150 ng/mL (375 nmol/L), is associated with increased risk of hypercalcemia (presenting as nausea, constipation, polyuria, or nephrocalcinosis). Vitamin D toxicity is rare in clinical practice and has been reported most often in the context of mislabeled over-the-counter products containing far higher doses than declared, or in unsupervised mega-dosing.

Drug interactions.

Contraindications and special caution populations.

Pregnancy and lactation. The IOM recommended dietary allowance during pregnancy and lactation is 600 IU/day; the American College of Obstetricians and Gynecologists (ACOG) recognizes 1,000-2,000 IU/day as a safe supplementation range during pregnancy where indicated. The 2024 Cochrane systematic review (Palacios et al.) reported that — among the 9 of 30 originally included trials that passed updated trustworthiness criteria — vitamin D supplementation during pregnancy may improve some maternal and neonatal outcomes, with the trustworthiness caveat explicitly noted (see §4.6 and the §4-Pregnancy notice above). Pregnant or lactating individuals should consult their obstetric or primary care provider before initiating, modifying, or discontinuing vitamin D supplementation.

References: PMID 35082139 (Hahn 2022 VITAL safety endpoints), PMID 39077939 (Palacios 2024 Cochrane).

ASXAN Sources

Vitamin D3 is a globally produced ingredient with a well-developed manufacturing base. ASXAN Group sources vitamin D3 through established global supply networks under group-level quality control (third-party identity testing · potency analysis · heavy metal and contaminant screening) and does not maintain a proprietary synthetic-biology production pipeline for vitamin D3 — in contrast to ASXAN's astaxanthin and fucoxanthin platforms, where dedicated synthetic-biology fermentation and microalgal cultivation routes are developed in-house. This educational hub does not sell finished consumer products.

References

All PMIDs verified by cross-source PubMed search on 2026-05-23. Effect sizes are reported as published. The Scita upstream evidence document includes the full extraction provenance and the NutriCodex T0-Vitamin-D3 vault cross-reference.

Bone Health (§4.1)

  1. PMID 36308775 · Kazemian E et al. (2023) · "Effect of supplemental vitamin D3 on bone mineral density: a systematic review and meta-analysis" · Nutrition Reviews · MA of 39 RCTs · BMD SMD 0.06 lumbar / 0.25 femoral neck · dose-response
  2. PMID 35504603 · Kong SH et al. (2022) · "Effect of Vitamin D Supplementation on Risk of Fractures and Falls According to Dosage and Interval: A Meta-Analysis" · Endocrinology and Metabolism · MA of 32 RCTs · 800-1000 IU/day daily optimal
  3. PMID 35939577 · LeBoff MS et al. (2022) · "Supplemental Vitamin D and Incident Fractures in Midlife and Older Adults" · New England Journal of Medicine · VITAL ancillary fracture sub-study n=25,871 · total and hip fracture not significantly reduced in generally healthy adults

Respiratory Immune (§4.2)

  1. PMID 28202713 · Martineau AR et al. (2017) · "Vitamin D supplementation to prevent acute respiratory tract infections: systematic review and meta-analysis of individual participant data" · BMJ · IPD MA of 25 RCTs n=11,321 · adjusted OR 0.88 overall · OR 0.58 in deficient + daily-dosing subgroup
  2. PMID 39993397 · Jolliffe DA et al. (2025) · "Vitamin D supplementation to prevent acute respiratory infections: systematic review and meta-analysis of stratified aggregate data" · Lancet Diabetes & Endocrinology · 43 RCTs n=49,320 · daily-dose subgroup RR 0.92 · 400-1200 IU/day optimal

Autoimmune (§4.3)

  1. PMID 35082139 · Hahn J et al. (2022) · "Vitamin D and marine omega-3 fatty acid supplementation and incident autoimmune disease: VITAL randomized controlled trial" · BMJ · VITAL n=25,871 · D3 2000 IU/day × 5.3 y · HR 0.78 (autoimmune incidence -22%)
  2. PMID 38272846 · Costenbader KH et al. (2024) · "Vitamin D and Marine n-3 Fatty Acids for Autoimmune Disease Prevention: Outcomes Two Years After Completion of a Double-Blind, Placebo-Controlled Trial" · Arthritis & Rheumatology · D3 autoimmune effect no longer statistically significant 2 years after discontinuation · omega-3 effect persisted

Telomere (§4.4)

  1. PMID 40409468 · Zhu H et al. (2025) · "Vitamin D3 and marine omega-3 fatty acids supplementation and leukocyte telomere length: 4-year findings from the VITamin D and OmegA-3 TriaL (VITAL) randomized controlled trial" · American Journal of Clinical Nutrition · VITAL sub-study n=1,031 · 2,571 blood samples qPCR · D3 reduced telomere shortening by ~140 bp over 4 years

Depressive Symptoms (§4.5)

  1. PMID 39552387 · Ghaemi S et al. (2024) · "The effect of vitamin D supplementation on depression: a systematic review and dose-response meta-analysis of randomized controlled trials" · Psychological Medicine · 31 RCTs n=24,189 · per 1000 IU/day SMD -0.32 · symptomatic subgroup SMD -0.57
  2. PMID 35816192 · Mikola T et al. (2023) · "The effect of vitamin D supplementation on depressive symptoms in adults: A systematic review and meta-analysis of randomized controlled trials" · Critical Reviews in Food Science and Nutrition · adult populations + MDD subgroup 7 RCTs

Negative / Mixed Findings and Other (§4.6 and §3 context)

  1. PMID 37111028 · Ruiz-García A et al. (2023) · "Vitamin D Supplementation and Its Impact on Mortality and Cardiovascular Outcomes: Systematic Review and Meta-Analysis of 80 Randomized Clinical Trials" · Nutrients · n=163,131 · all-cause mortality OR 0.95 (p=0.013 borderline) · cancer-related mortality OR 0.90 (daily dosing) · cancer incidence NS · CV outcomes NS
  2. PMID 39178988 · Petrelli F et al. (2024) · "Vitamin D3 and cancer risk in healthy subjects: An umbrella review of systematic review and meta-analysis" · Clinical Nutrition ESPEN · head-and-neck / breast / colorectal / lung directions described as "highly suggestive but not conclusive"
  3. PMID 39525782 · Mirza AMW et al. (2024) · "Effect of vitamin D supplementation on cardiovascular outcomes: an updated meta-analysis of RCTs" · Annals of Medicine and Surgery · MACE / MI / HF / CV death / all-cause mortality all NS

Pregnancy and T2DM (Educational Context Only)

  1. PMID 39077939 · Palacios C et al. (2024) · "Vitamin D supplementation for women during pregnancy" · Cochrane Database of Systematic Reviews · CD008873.pub5 · 30 trials reassessed under updated trustworthiness criteria · only 9 passed
  2. PMID 39355942 · Chen W et al. (2024) · "Efficacy of vitamin D supplementation on glycaemic control in type 2 diabetes: An updated systematic review and meta-analysis of randomized controlled trials" · Diabetes, Obesity and Metabolism · MA in T2DM patients · HbA1c / fasting plasma glucose / insulin resistance markers improved (cited here for academic context only; not a basis for any T2DM-specific recommendation)

Epidemiology (§2)

  1. PMID 36263304 · Cui A et al. (2022) · "Prevalence, trend, and predictor analyses of vitamin D deficiency in the US population, 2001-2018" · Frontiers in Nutrition · NHANES n=71,685 · severe deficiency 2.6% · moderate deficiency 22% · insufficiency 41% · sufficient 34.5%

Regulatory References (not counted in PMID total)

← All Ingredients