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Vitamin D

Vitamin D is a prohormone and a non-essential, fat-soluble vitamin that can be synthesized in the skin following UV exposure. (149)(435) Vitamin D3 (cholecalciferol) and vitamin D2 (ergocalciferol) are the naturally occurring forms found in supplements, though synthetic vitamin D analogs are also available. (415) Supplementation is often used to establish sufficient vitamin D levels, which typically correlates with the prevention and treatment of a wide variety of health conditions.

The Institute of Medicine (IOM) uses the following 25-hydroxyvitamin D (25(OH)D) levels as indicators of vitamin D health status:

Deficiency: <12 ng/ml (<30 nmol/L)
Insufficiency: 12-20 ng/ml (30-50 nmol/L)
Sufficiency: >20 ng/ml (>50 nmol/L)
High: >50 ng/ml (>125 nmol/L)
Increased risk of adverse effects: > 60ng/ml (>150 nmol/L) (189)

Other authorities, including the American Geriatrics Society, the Endocrine Society, and the International Osteoporosis Foundation, recommend 25(OH)D levels >30 ng/ml (>75 nmol/L) for optimal vitamin D status to reduce risk of falls and fractures in the older population. Further, adverse effects from excess vitamin D may only become prevalent if blood levels reach >100 ng/ml (>250 nmol/L). (18)(105)(177)

Not be confused with:

Calcidiol (25(OH)D3)
Calcitriol (1,25-dihydroxyvitamin D3)
Doxercalciferol (1-α-hydroxyergocalciferol)
Ercalcidiol (25(OH)D2)
Ercalcitriol (1,25-dihydroxyvitamin D2)
Falecalcitriol (F6-1α,25-dihydroxyvitamin D3)
Maxacalcitol (22-oxacalcitriol)
Paricalcitol (19-Nor-1,25-dihydroxyvitamin D2)

Main uses

Bone and musculoskeletal disorders
Cardiovascular disorders
Chronic pain
Fractures and falls
Kidney disorders
Immune and inflammatory disorders
Metabolic disorders
Neurological disorders
Prenatal health
Psychological disorders
Respiratory disorders
Thyroid disorders

Formulations

Form	Bioavailability and supplement sources
Vitamin D2 (ergocalciferol)	Follows similar absorption pattern to D3, with food and supplements being equally well absorbed, but is not as effective in raising vitamin D status as D3 (284)(415) Supplement sources: mushrooms (84)(282)
Vitamin D3 (cholecalciferol)	More effective than D2 for raising vitamin D status due to its greater half-life; possibly more potent than D2 due to higher affinity of its metabolites for the vitamin D receptor (284)(415) Supplement sources: lanolin (secreted from the sweat glands of sheep) & lichen (155)(176)

Dosing & administration

Addison’s disease
General outcomes from A-level evidence	No data currently available.
Dosing & administration	4,000 IU (as D3) per day for 3 months to adults with low vitamin D status
Outcomes	↓ late-activated Th and Tc cells ↑ monocytes (325)
Class of evidence	C

All-cause mortality
General outcomes from A-level evidence	↓ risk of all-cause mortality by 6-11% by D3, but not D2 or vitamin D analogs; may need to be provided with calcium in the elderly (63)(95)(349) Reduction in risk may increase to 26% within 5 year follow-ups with interventions targeting individuals with low vitamin D statuses (75)
Dosing & administration	300-2,000 IU (average of ~500 IU) per day, ongoing
Outcomes	↓ risk of all-cause mortality by 7% with ordinary vitamin D intake (37)
Class of evidence	A
Dosing & administration	800 IU per day (as D3) for a minimum of 3 years, particularly for females younger than 80 and vitamin D insufficiency
Outcomes	↓ risk for all-cause mortality by 6% (475)
Class of evidence	A

Allergic rhinitis
General outcomes from A-level evidence	No data currently available.
Dosing & administration	50,000 IU (as vitamin D pearl) per week with concomitant cetirizine for 8 weeks to adults with vitamin D deficiency
Outcomes	↓ symptom severity for rhinorrhea, nasal itching, sneezing, and postnasal drip after 8 weeks but not after 4 weeks compared with cetirizine alone Note: suggests that vitamin D levels may need adequate time to replenish before symptom relief (42)
Class of evidence	B
Dosing & administration	1,000 IU per day with concomitant grass pollen immunotherapy for 5 months to children
Outcomes	↓ nasal, asthmatic, and combined symptom scores compared with immunotherapy alone (200)
Class of evidence	B

Alzheimer’s disease prevention
General outcomes from A-level evidence	No data currently available.
Dosing & administration	50,000 IU (as D3) per week for 8 weeks to older adults with vitamin D insufficiency
Outcomes	↓ plasma amyloid-β, implying reduced brain amyloid-β (290)
Class of evidence	C

Asthma
General outcomes from A-level evidence	↓ incidence of exacerbations needing corticosteroid treatment by 26-37% and odds of hospitalization, particularly in Px with vitamin D deficiency (204)(274) Use of vitamin D may be particularly effective in reducing the relative risk of asthma exacerbation in children by 59-74% (352)(445)
Dosing & administration	500-2,000 IU per day to children with asthma
Outcomes	↑ relative risk of asthma exacerbation by 59% (335)
Class of evidence	A
Dosing & administration	500-1,200 IU (as D3) per day, or 60,000 IU per month with or without adjunct to children for 4-6 months
Outcomes	↓ the relative risk of exacerbation by 83%, ATAQ scores, the number of exacerbations, time to control, severity of asthma, and need for steroids or emergency visits compared with budesonide or placebo alone ↑ peak expiratory flow rate compared with budesonide or placebo alone; prevents declines in 25(OH)D (264)(420)(450)
Class of evidence	B
Dosing & administration	200,000 IU (as D3) followed by monthly 100,000 IU for ~1-3 years to older adults
Outcomes	↑ FEV1 in chronic smokers with or without asthma/COPD (373)(388)
Class of evidence	B
Dosing & administration	100,000 IU (one intramuscular bolus dose) followed by 50,000 IU (oral) per week for 24 weeks to adults and children using inhaled corticosteroids (ICS) or ICS with long-acting β-agonists
Outcomes	↓ FEV1 after 8 weeks compared with ICS or ICS/ β-agonists alone (28)
Class of evidence	C
Dosing & administration	400,000 IU (as D3) single dose to patients with nonatopic asthma
Outcomes	↓ eosinophil levels only in Px with more severe airway inflammation (106)
Class of evidence	C

Asthma development prevention
General outcomes from A-level evidence	↓ risk of development of offspring wheezing by 19% with prenatal supplementation (97)(421)
Dosing & administration	2,800-4,400 IU (as D3) during pregnancy (from 10-26 weeks gestation)
Outcomes	↓ risk of asthma/wheezing by 25% in offspring by the age of 3, particularly when ingested by mothers with > 30ng/ml 25(OH)D levels; Note: reduced risk does not continue by 6 years of age (77)(255)(358)(439)
Class of evidence	A
Dosing & administration	400 IU per day until 6 months of age to infants
Outcomes	↓ relative risk of recurrent wheezing by the age of 12 months (173)
Class of evidence	B

Attention deficit hyperactivity disorder (ADHD)
General outcomes from A-level evidence	Small overall improvements in inattention, hyperactivity, and behavior scores when adjunct to methylphenidate (141)
Dosing & administration	2,000-3,000 IU per day, or 50,000 IU per week adjunct to methylphenidate for 8-12 weeks to children and young teenagers with vitamin D insufficiency
Outcomes	↓ ADHD evening symptoms, inattention score, and inattention, hyperactivity/impulsivity, & combination type subscale scores ↑ cognitive functional domains for inattention, opposition, hyperactivity, and impulsivity (109)(126)(297)
Class of evidence	B

Autism spectrum disorder
General outcomes from A-level evidence	No data currently available.
Dosing & administration	2,000 IU (as D3) per day for 5-12 months to children
Outcomes	↓ irritability, hyperactivity (by 12 months ↑ self-care (by 5 months) (221)(285)
Class of evidence	B

Blood pressure
General outcomes from A-level evidence	↓ SBP & DBP in healthy Px older than 50 with vitamin D deficiency and possibly in obese Px with deficiency (151)(169) Note: Vitamin D supplementation does not generally have meaningful effects on CVD risk factors including blood pressure, vascular function, or inflammatory and lipid markers (485)
Dosing & administration	800 IU per day (as D3) for 6 months to healthy Px older than age of 50
Outcomes	↓ SBP (~1.5-4 mmHg) & DBP (~1.2-2.2 mmHg) Note: concomitant calcium may elevate BP (151)
Class of evidence	A

Cardiovascular disease (CVD)
General outcomes from A-level evidence	↓ endothelial dysfunction via improvements in flow-mediated dilation in protocols longer than 16 weeks and with higher baseline blood pressure, FBG, insulin, and insulin resistance ↑ insulin sensitivity, and HDL-C (318)(399) Note: Vitamin D supplementation does not generally have meaningful effects on CVD risk factors including blood pressure, vascular function, or inflammatory and lipid markers (485)
Dosing & administration	60,000 IU (as D3) per month for 4 months to African-American adults
Outcomes	↑ flow-mediated dilation (165)
Class of evidence	B

Chronic kidney disease (CKD)
General outcomes from A-level evidence	↓ mortality with vitamin D or analogs in observational studies but not RCTs, pulse-wave velocity, proteinuria, FBG, and parathyroid hormone (212)(262)(368)(446)(477) ↑ flow-mediated dilation with D3 or paricalcitol (119) Note: supplementation may reduce relative risk for composite infection during long-term dialysis by 41%, but may also increase relative risk for hypercalcemia (401)(446)
Dosing & administration	300,000 IU (as D3) single dose with re-administration after 8 weeks to nondiabetic stage 3-4 CKD adults
Outcomes	↑ flow-mediated dilation ↓ parathyroid hormone, pulse-wave velocity, IL-6, intact fibroblast growth factor-23, E-selectin, ICAM-1, VCAM-1, total and bone-specific alkaline phosphatase, & serum C-terminal cross-linked collagen type I telopeptides (93)(235)(236)(449)
Class of evidence	B
Dosing & administration	40,000-50,000 IU (as D2 or D3) per week for 8-12 weeks, followed by 50,000 IU bi-weekly for the remainder of 1 year
Outcomes	↓ parathyroid hormone (particularly in Px with secondary hyperparathyroidism), MCP-1 , & proteinuria (during the first 12 weeks) (16)(17)(273)(403)
Class of evidence	B
Dosing & administration	800 IU (as D3) with 1,200 mg calcium per day for 2 years to older women with moderate CKD
Outcomes	↓ rate of BMD loss, & parathyroid hormone (72)
Class of evidence	B
Dosing & administration	Infants: 600 IU (as D2) per day for 3-month replenishing phase followed by 400 IU per day for 9-month maintenance phase to infants; Children > 1: replenishment phase dosing may be stratified by vitamin D status: 2,000 IU (~15-30 ng/ml), 4,000 IU (~15-5 ng/ml), 8,000 IU (<5 ng/ml), followed by 2,000 IU per day for 9 months
Outcomes	↓ progression of secondary hyperparathyroidism (384)
Class of evidence	B
Dosing & administration	1,000-2,500 IU per day (as D2) for 5-10 months to vitamin D deficient children
Outcomes	Normalizes sclerostin and Klotho (bone and metabolic biomarkers but elevates fibroblast growth factor 23) (249)
Class of evidence	C

Chronic obstructive pulmonary disease (COPD)
General outcomes from A-level evidence	↓ rate of moderate-severe exacerbations only in vitamin D deficient Px (204)
Dosing & administration	200,000 IU (as D3) as optional single administration, followed 100,000 IU once a month for 6-18 months to Px with severe COPD
Outcomes	↑ exacerbation rate by 43% in Px with severe vitamin D deficiency (<10 ng/mL) only ↑ FEV1 particularly in chronic smokers May improve inspiratory muscle strength, O2 uptake and muscular performance during rehabilitation programs (179)(247)(388)(463)
Class of evidence	B
Dosing & administration	120,000 IU (as D3) bi-monthly for 12 months to adults
Outcomes	↓ moderate/severe exacerbation in Px with vitamin D insufficiency (275)
Class of evidence	B
Dosing & administration	50,000 IU (as D3) per week for 8 weeks, followed by once per month for 4 months
Outcomes	↓ QoL by end of 8th week, but no changes in exacerbation (12)
Class of evidence	B

Chronic pain (musculoskeletal)
General outcomes from A-level evidence	↓ mean chronic pain scores across a variety of conditions by improving vitamin D status, (443)(459) though evidence is conflicting (139)(400)
Dosing & administration	100,000-150,000 IU (as D3) optional bolus dose which can be repeated after 6 weeks, or 4,000 IU can be provided per day for 3-4 months to overweight/obese Px with low back pain
Outcomes	↓ pain and disability scores particularly in Px with vitamin D deficiency by 6th week, need for analgesic rescue therapies, TNF-ɑ, & PGE2 (74)(144)(370)
Class of evidence	B
Dosing & administration	50,000 IU (as D2) weekly for 8-16 weeks, then monthly for 8-16 weeks in addition to daily 400 IU (as D3) and 1,000mg of calcium to women with aromatase inhibitor-induced musculoskeletal pain
Outcomes	↓ pain scores by 8th week Maintained BMD (346)
Class of evidence	B

Chronic urticaria
General outcomes from A-level evidence	↓ disease activity (417)
Dosing & administration	4,000 IU (as D3) per day adjunct to triple therapy (cetirizine, ranitidine, and montelukast) for 12 weeks
Outcomes	↓ urticaria symptom severity score by 40%, which was primarily due to reduced body distribution & number of days with hives compared with lower doses of vitamin D (600 IU) (355)
Class of evidence	C
Dosing & administration	60,000 IU (as D3) per week for 4 weeks adjunct to antihistamines and corticosteroids
Outcomes	↓ visual analog score and itch scores to a greater extent than vitamin D alone, or adjunct therapies alone (345)
Class of evidence	C

Corticosteroid-induced osteoporosis
General outcomes from A-level evidence	↓ the loss of lumbar bone mineral density more than no treatment or calcium alone, but not as effective as bisphosphonates or fluoride. Greatest effects may be observed with use of vitamin D3, or analogs, and concomitant calcium (19)(20)(107)(178)(351)
Dosing & administration	600-800 IU per day with 1,000-1,200 mg calcium to adults using glucocorticoids for more than 3 months and who are at low risk for fractures, and with bisphosphonate if at moderate-high risk
Outcomes	↓ risk of fracture (78)
Class of evidence	A
Dosing & administration	600 IU per day with 1,000 mg calcium to children using glucocorticoids for more than 3 months
Outcomes	↓ risk of fracture (78)
Class of evidence	A
Dosing & administration	400-800 IU (as D3) per day with 500-1,000 mg calcium to children using corticosteroids for renal diseases
Outcomes	Improves BMD compared to Px only using corticosteroids (162)
Class of evidence	A

Critical illness mortality
General outcomes from A-level evidence	↓ odds of mortality by 30%, (338) though evidence is conflicting (242)
Dosing & administration	540,000 IU (as D3) once, then monthly doses of 90,000 IU for 5 months
Outcomes	↓ risk of hospital mortality by 44% in Px with severe vitamin D deficiency, but does not extend to 6-month mortality (21)
Class of evidence	B

Cystic fibrosis
General outcomes from A-level evidence	Note: no clinical benefit reported (131)
Dosing & administration	250,000 IU (as D3) once to adults
Outcomes	↓ TNF-ɑ by 50%, & IL-6 by 64.5% (trend) (159)
Class of evidence	C
Dosing & administration	50,000 IU (D3) per week for 12 weeks to adults with vitamin D insufficiency
Outcomes	↓ lactococcus species in gut and airways Note: higher prevalence of pathogenic bacteria may exist in reduced states of vitamin D status (213)
Class of evidence	C
Dosing & administration	5,000 IU to children younger than 16, or ~7,000 IU (as D2 or D3) to Px older than 16 per day for 3 months
Outcomes	↑ functional vital capacity, changes in lung function positively correlated with response to raising vitamin D status ↓ IL-8, CD279 (PD-1) expression on CD4+ & CD8+ T cells, and frequency of CD8+ T cells co-expressing CD38 and human leukocyte antigen (HLA-DR) (332)(333)
Class of evidence	C
Dosing & administration	1,000 IU (as D3) per day for 3 months to children with CF and chronic Pseudomonas aeruginosa pulmonary infection
Outcomes	↓ IL-23 in breath (314)
Class of evidence	C

Dental caries
General outcomes from A-level evidence	↓ relative risk of dental caries by 47% in children, particularly under the age of 13 (185)
Dosing & administration	800 IU (as D3) per day (median dose), or 3,750 IU (as D2) to children, ongoing
Outcomes	↓ relative risk of dental caries by 47%, particularly under the age of 13 (185)
Class of evidence	A

Depression
General outcomes from A-level evidence	↓ symptoms in Px with clinically significant depression, but not in Px without clinically significant depression, (377)(424) though evidence is conflicting (156)(250)
Dosing & administration	800 IU per day to adults, ongoing
Outcomes	↓ symptoms with similar effectiveness as antidepressant medications when doses improve vitamin D status (395)
Class of evidence	A
Dosing & administration	4,000 IU per day, or 20,000-40,000 IU per week for 3-12 months to Px with mild-moderate depressive symptoms
Outcomes	↓ Beck Depression Inventory scores (206)(315)
Class of evidence	B
Dosing & administration	1,500 IU (as D3) per day with fluoxetine, or 50,000 IU per week for 8 weeks to adults with major depressive disorder and vitamin D deficiency
Outcomes	↓ Depression scores to a greater extent than fluoxetine alone after 4 weeks, serum insulin, HOMA-IR, & β cell function ↑ total antioxidant capacity, & glutathione levels (224)(375)
Class of evidence	C

Diabetic foot ulcer
General outcomes from A-level evidence	No data currently available.
Dosing & administration	50,000 IU bi-weekly for 12 weeks in Px with grade 3 ulcers
Outcomes	↓ ulcer length, width, depth, & erythema rate, insulin, HOMA-IR, HBA1C, total cholesterol, LDL-C, total-C:HDL-C ratio, hs-CRP, erythrocyte sedimentation rate, & malondialdehyde ↑ insulin sensitivity (347)
Class of evidence	B

Diabetic nephropathy
General outcomes from A-level evidence	↑ urine protein, and inflammation via albumin excretion rate, hs-CRP, TNF-α, and IL-6; Effects were equivalent between vitamin D3 and analogs regardless of dose or duration, (434)(469) though some evidence conflicts (112)
Dosing & administration	50,000 IU (as D3) per week for 8 weeks
Outcomes	↓ FBG, HOMA-IR, TNF-α, IL-6, proteinuria, TGs, LDL, & total cholesterol (46)(128)
Class of evidence	B
Dosing & administration	50,000 IU (as D3 intramuscularly) per month for 6 months
Outcomes	↓ urinary albumin:creatinine ratio, & renin ↑ glomerular filtration rate, & HDL (256)(257)
Class of evidence	C
Dosing & administration	800-4,000 IU (as D3) per day for 3-6 months to Px with T2D
Outcomes	↑ microalbuminuria, KL-40, MCP-1, IL-6, insulin, & HOMA-IR (184)(316)
Class of evidence	C

Diabetic neuropathy
General outcomes from A-level evidence	↓ pain scores (452)
Dosing & administration	50,000 IU (as D3) weekly for 8 weeks to Px with T2D, neuropathy and vitamin D deficiency
Outcomes	↓ neuropathy symptom score (382)
Class of evidence	B

Fall prevention
General outcomes from A-level evidence	↓ odds for falls by 13-22% and rate of falls by 28% especially in the elderly ambulatory or institutionalized population (58)(59)(83)(289)(305) Note: use of vitamin D for fall prevention is still controversial as some high level evidence exists showing only showing benefit for reducing risk and rate of falls in individuals with low vitamin D status, while others show no benefit regardless of vitamin D status, treatment protocol, or residency. (69)(146) It may be important to note that there is some evidence that annual high-dose vitamin D may also increase the rate of falls (163)
Dosing & administration	700-1,000 IU per day with 1,000 mg calcium for minimum of 6 months to older adults, especially if institutionalized
Outcomes	↓ relative risk of falls by ~15% (with 200-1,000 IU) but by 19-20% with >700 IU, rate of falls by 30-46% when using adjunct calcium (87)(210)(441)
Class of evidence	A

Fibromyalgia
General outcomes from A-level evidence	No data currently available.
Dosing & administration	2,400 IU (as D3) per day to Px with 25(OH)D levels of <24 ng/ml or 1,200 IU to Px with 24-32 ng/ml for 5 months
Outcomes	↓ perception of pain (436)
Class of evidence	C

Gestational diabetes
General outcomes from A-level evidence	↑ risk of developing gestational diabetes by 49%, infant hyperbilirubinemia by 60%, polyhydramnios by 83%, and need for maternal or infant hospitalization by 87%, FBG, insulin, HOMA-IR, HOMA-𝛃, glycated haemoglobin, total cholesterol, LDL, & hs-CRP (8)(196)(313)(321)(354)(457) ↑ insulin sensitivity, HDL (196)(457) Note: supplementation does not consistently improve individual measures of glycemic control or progression of diabetes across all meta-analyses
Dosing & administration	50,000 IU (as D3) once every 2-3 weeks with or without 1,000mg calcium per day, over 2 months to pregnant women
Outcomes	↓ FBG, insulin, HOMA-IR, total cholesterol, LDL, HBA1C, rate of caesarean section, maternal & infant hospitalization, infant macrosomia, hyperbilirubinemia, & polyhydramnios ↑ insulin sensitivity, HDL, HDL ratio, total antioxidative capacity, & GSH; Prevents rises in malondialdehyde (31)(32)(214)(455)(468)
Class of evidence	B
Dosing & administration	700 IU with 100 mg calcium per day at the start of pregnancy until delivery
Outcomes	↓ risk of developing gestational diabetes (472)
Class of evidence	C
Dosing & administration	4,000 IU (as D3) per day for 6 months to women who are 6-48 months postpartum and were formerly diagnosed with gestational diabetes
Outcomes	↑ basal pancreatic 𝛃-cell function as measured by the disposition index (456)
Class of evidence	C

Hashimoto’s thyroiditis (HT)
General outcomes from A-level evidence	↑ thyroid peroxidase & thyroglobulin antibody titers after 6 months (431)
Dosing & administration	50,000-60,000 IU per week, or 1,000-2,000 IU per day adjunct to levothyroxine for 1- 6 months to Px with vitamin D deficiency
Outcomes	↓ thyroid peroxidase antibody, & thyroglobulin antibody titers, and TSH (88)(90)(233)(387)
Class of evidence	C
Dosing & administration	4,000 IU with 200 μg of selenomethionine per day for 1 year to euthyroid women with HT
Outcomes	↓ thyroid peroxidase and thyroglobulin antibody titers ↑ SPINA-GT index (232)
Class of evidence	C

Heart failure
General outcomes from A-level evidence	↓ TNF-ɑ, CRP, & parathyroid hormone (202)(353) ↑ QoL related outcomes in chronic heart failure (432) Note: Vitamin D supplementation does not generally have meaningful effects on CVD risk factors including blood pressure, vascular function, or inflammatory and lipid markers (485)
Dosing & administration	4,000 IU per day to adolescents or adults
Outcomes	↓ left ventricular end-diastolic diameter ↑ left ventricular ejection fraction (98)(470)
Class of evidence	A
Dosing & administration	2000-4,000 IU (as D3) with or without 500 mg calcium per day for 6-36 months to adults with vitamin D deficiency
Outcomes	↑ left ventricular ejection fraction particularly in patients older than 50, & IL-10 ↓ left ventricular end-diastolic, end-systolic diameter, parathyroid hormone, renin activity, & renin concentration Prevented significant rises in TNF-ɑ, but no differences in heart failure survival rates (101)(369)(371)(438)(484)
Class of evidence	B
Dosing & administration	10,000-50,000 IU (as D3) per day, or 300,000 IU as bolus dose followed by 50,000 IU per month for 6 months to Px with vitamin D insufficiency or deficiency
Outcomes	↑ short term physical function (3 months), QoL scores, b-type natriuretic peptide ↓ aldosterone, parathyroid hormone, & hs-CRP (men) (73)(299)(418)
Class of evidence	B
Dosing & administration	1,000 IU (as D3) per day for 12 weeks to infants with chronic congestive heart failure
Outcomes	↓ heart failure score, heart rate, left ventricular end-diastolic & end-systolic diameters, myocardial performance index, parathyroid hormone, IL-6, TNF-ɑ ↑ left ventricular ejection fraction %, fraction shortening %, E-A wave ratio, & IL-10 Effects occur by 6 weeks but may reverse post-intervention (381)
Class of evidence	B

Heart failure prevention
General outcomes from A-level evidence	Note: Vitamin D supplementation does not generally have meaningful effects on CVD risk factors including blood pressure, vascular function, or inflammatory and lipid markers (485)
Dosing & administration	800 IU (as D3) per day with 1,000 mg of calcium ongoing (for 1-7 years) in older adults
Outcomes	↓ relative risk of cardiac failure by 25-37% compared with no vitamin D particularly in individuals with low-risk based on pre-existing risk factors such as coronary heart diseases, diabetes or hypertension (117)(132)
Class of evidence	B

Hepatitis C virus
General outcomes from A-level evidence	↑ efficacy of antiviral therapy response rate by 30% after 24 weeks of therapy, particularly in hepatitis C virus genotype 1, (225) and in Px achieving 30 ng/ml vitamin D status (425)
Dosing & administration	60,000 IU (vitamin D status: 20-30 ng/ml), 80,000 IU (10-20 ng/mL), or 100,000 IU (<10 ng/mL) (as D2) in two divided doses per week for 6 weeks to adults with low vitamin D status
Outcomes	↓ Interferon gamma-induced protein 10 (IP-10), enzyme dipeptidyl peptidase-4 (DPP IV), TGF-β1, & TIMP1 ↑ MMP2 & MMP9 (228)(229)
Class of evidence	B
Dosing & administration	1,000-2,000 IU (as D3) per day adjunct to interferon and ribavirin therapy to Px with hepatitis C (1b, 2-3 genotypes) for 1-10 months to adults or children
Outcomes	↓ viral load ↑ efficacy of antiviral therapy on early and sustained viral response rate (36)(127)(308)(317)(428)(458)
Class of evidence	C

Human immunodeficiency virus (HIV)
General outcomes from A-level evidence	Note: vitamin D supplementation may not have an impact on musculoskeletal outcomes in HIV (326)
Dosing & administration	4,000-7,000 IU (as D3) per day or 20,000 IU (as D2) per week with 600-1,000 mg of calcium per day, adjunct to antiretroviral therapy for 3-12 months to children and adults
Outcomes	↓ viral load, & bone loss from antiretroviral therapy; ↑ naive T-helper cell percentage, CD4%, and neuromuscular motor skills (76)(320)(396)(397)
Class of evidence	B
Dosing & administration	120,000 IU (as D3) per month adjunct to antiretroviral therapy for 1-2 years to children and young adults
Outcomes	↓ CD4 & CD8 activation/exhaustion, CD14+CD16+ inflammatory monocytes, procollagen type 1 aminoterminal propeptide & B-CrossLaps (bone turnover markers), and carotid artery thickness (71)(123)(124)(125)
Class of evidence	C
Dosing & administration	400 IU (as D3) with 1,000 mg calcium per day adjunct to antiretroviral therapy and alendronate therapy for 12 weeks to adults
Outcomes	Improves BMD in lumbar spine, hip and trochanter (286)
Class of evidence	C
Dosing & administration	200,000 IU (as D3) single bolus dose to Px with vitamin D insufficiency
Outcomes	↑ MIP-1β & cathelicidin (240)
Class of evidence	C

Hypercholesterolemia
General outcomes from A-level evidence	↓ total cholesterol, LDL, & triglycerides in Px with vitamin D insufficiency and at high risk for CVD (114)
Dosing & administration	2,000 IU (as D3) per day for 6 months adjunct to statins
Outcomes	↓ total cholesterol and TGs after 6 months, particularly in Px with vitamin D status of <30 ng/ml (339)
Class of evidence	B

Hypertension
General outcomes from A-level evidence	↓ SBP & DBP in Px older than 50 with vitamin D deficiency, and vitamin D3/D2 may be more effective than analogs (151)(169)(437) Note: While low vitamin D status may be associated with higher risk for hypertension, supplementation may not consistently result in reduced blood pressure (465)
Dosing & administration	800 IU per day (as D3) for a minimum of 6 months to overweight and obese Px older than age of 50 with vitamin D deficiency
Outcomes	↓ SBP (~3.5-6.6 mmHg) & DBP (~1.7-3.1 mmHg) Note: concomitant calcium may elevate BP. Individuals not meeting these characteristics concurrently may not experience reductions in BP (151)(169)
Class of evidence	A
Dosing & administration	2,800-4,000 IU (as D3) per day for 2-6 months in Px with vitamin D insufficiency or deficiency
Outcomes	↓ augmentation index, augmentation pressure, HBA1C, & aldosterone (160)(161)(244)(462)
Class of evidence	B
Dosing & administration	2,000 IU per day adjunct to nifedipine for 6 months to Px with grade I-II essential hypertension
Outcomes	↓ SBP (~6.2-7.1 mmHg) and DBP (~4.2-5.7 mmHg) (91)
Class of evidence	B

Hypocalcemia post-thyroidectomy
General outcomes from A-level evidence	↓ odds of temporary symptomatic and biochemical hypocalcemia, the need for administration of intravenous calcium, when administered as D3 or analogs combined with calcium as compared with no treatment, or calcium treatment alone (15)(23)(365)(366)
Dosing & administration	400-800 IU (as D3) with 600-3,000 mg calcium per day post-operatively day for up to 1 week
Outcomes	↓ incidence of symptomatic hypocalcemia, requirement for intravenous calcium administration and length of hospital stay Note: calcitriol supplementation may be more effective than native D3 if hypocalcemia is already onset (94)(238)(334)
Class of evidence	C

Immune function
General outcomes from A-level evidence	↓ immune function via IL-2, IgA, & IgG in preterm infants (453)
Dosing & administration	800-1,000 IU per day to preterm infants
Outcomes	↑ immune function via IL-2, IgA, & IgG (453)
Class of evidence	A
Dosing & administration	1,000-5,000 IU (as D3) per day, 20,000-40,000 IU per week, or 140,000 IU per month or 3-12 months to adults
Outcomes	↓ CD4+ T-cell activation, IL-5, & IL-6 ↑ regulatory T cell counts & percentage, salivary IgA & cathelicidin secretion rate during stress, and tetanus toxoid-specific IgA vaccination efficiency (65)(80)(168)(230)(337)(372)
Class of evidence	B
Dosing & administration	2,000-4,400 IU (as D3) per day, or 35,000 IU per week during 2nd-3rd trimesters of pregnancy
Outcomes	↑ GM-CSF, IFN-γ, IL-1β, IL-6, IL-8, IL-10, TNF-α, TLRP2, TLRP9 & IL17A gene expression in cord blood mononuclear cells in response to innate or mitogenic stimuli and T-cell stimulation ↓ intracellular macrophage LL-37 peptides; Provides modulatory effect on Th1 & Th2 responses (11)(180)(343)(464)
Class of evidence	B

Inflammatory bowel disease (IBD)
General outcomes from A-level evidence	No data currently available.
Dosing & administration	400-1,000 IU (as D3) with 500-1,000 mg calcium per day adjunct to bisphosphonate or sodium fluoride therapy, for 1-3.5 years to osteoporotic adults with IBD
Outcomes	↑ BMD regardless of corticosteroids or IBD activity (3)(45)(227)(386)(392)(426)(427)
Class of evidence	B
Dosing & administration	300,000 IU (as D3 injection) single administration to ulcerative colitis patients with low vitamin D status
Outcomes	↓ Beck Depression Inventory scores, TNF-α, IFN-γ, IL12p70 , hs-CRP, & eosinophil sedimentation rate ↑ cathelicidin gene expression (378)(379)(380)
Class of evidence	B
Dosing & administration	1,000-10,000 IU (as D2 or D3) per day for 6-12 months
Outcomes	↑ disease activity scores, relapse rates, depression & anxiety scores, CRP, IL-6 , CD80 expression, IL-10, and IL-1β synthesis ↑ QoL scores, & CD4+ t cell proliferation Note: effects on IL-6 levels are conflicting (44)(50)(207)(216)(307)(322)(323)
Class of evidence	C

Influenza prevention
General outcomes from A-level evidence	No data currently available.
Dosing & administration	1,200-2,000 IU per day for 2-4 months during influenza season to infants, children, or adolescents
Outcomes	↑ relative risk of influenza infection, duration of fever, cough, wheezing, and viral loads Note: supplementation may provide greatest benefit within 1st month (419)(420)(478)
Class of evidence	B
Dosing & administration	100,000 IU (as D3) every 15 days for 3 months to elderly adults with vitamin D insufficiency before influenza vaccination
Outcomes	↓ Th1:Th2 ratio at vaccination timepoint, andTNF-ɑ, & IL-6 one month after vaccination ↑ TFG-β one month after vaccination (152)
Class of evidence	C

Metabolic syndrome
General outcomes from A-level evidence	No data currently available.
Dosing & administration	4,000 IU per day for up to 8 weeks
Outcomes	↓ von willebrand factor (406)
Class of evidence	A
Dosing & administration	50,000 IU (as D3) per week for 3-4 months to vitamin D insufficient or deficient Px
Outcomes	↓ insulin, HOMA-IR, cMETS, TGs, IL-6, parathyroid hormone ↑ serum 25(OH)D (219)(362)(363)
Class of evidence	B
Dosing & administration	2,000 IU per day for 3 months to adults engaging in endurance exercise
Outcomes	↑ total cholesterol, & LDL-C (130)
Class of evidence	B

Multiple sclerosis (MS)
General outcomes from A-level evidence	No data currently available.
Dosing & administration	10,000-50,000 IU (as D3) every 5-7 days for 3-12 months adjunct to IFN-β therapy to relapsing-remitting MS patients
Outcomes	↓ mental health, Montreal Cognitive Assessment & BVMT-delayed Recall scores, IL-10 within 3 months, central memory & naive CD4(+) T cells by 6 months, and TGF-β by 12 months ↑ relative risk of relapse by 68%, rate of new MRI lesions, and PBMC proliferation by 12 months, and IL-17 synthesis by CD(+) T cells, & proportion of effector memory CD4(+) T cells by 6 months (7)(34)(35)(102)(111)(186)(226)(389)(393)
Class of evidence	B
Dosing & administration	1,000 IU (as D3) per day with 800mg calcium, or 300,000 IU (as D3 injection) per month for 6 months adjunct to IFN-β therapy
Outcomes	↓ lymphocyte proliferation ↑ IL-10 & TGF-β1 (263)(300)
Class of evidence	B

Muscle strength and functional capacity
General outcomes from A-level evidence	No data currently available.
Dosing & administration	1,000 IU per day for 3 months to postmenopausal women with vitamin D insufficiency
Outcomes	↑ handgrip strength (4)
Class of evidence	A
Dosing & administration	800-1,000 IU per day to adults older than 60 not on exercise interventions
Outcomes	↑ lower-limb strength ↓ postural sway, & time to stand up test (304)
Class of evidence	A
Dosing & administration	2,000 IU (as D3) for 8-12 weeks to athletes with low vitamin D status
Outcomes	↑ muscle strength (92)
Class of evidence	A
Dosing & administration	800-1,000 IU with or without 600-1,000 mg calcium per day for 3-24 months in community-dwelling older adults
Outcomes	↑ lower limb strength ↓ body sway, time to stand up test, and falls May prevent declines in muscular strength over long periods of time when combined with exercise (25)(330)(447)(481)
Class of evidence	B

Osteoarthritis
General outcomes from A-level evidence	No data currently available.
Dosing & administration	2,000 IU per day to Px with knee osteoarthritis
Outcomes	↓ pain and dysfunction scores (143)
Class of evidence	A
Dosing & administration	60,000 IU (as D3) per day for 10 days, then 50,000-60,000 IU per month for 1-2 years to Px with knee osteoarthritis and vitamin D insufficiency
Outcomes	↓ knee pain & dysfunction by a small clinically relevant extent, and progression of effusion-synovitis volume (367)(433)
Class of evidence	B

Osteoporosis and fracture prevention
General outcomes from A-level evidence	No data currently available.
Dosing & administration	700-1,000 IU per day with 1,000-1,200 mg calcium to elderly individuals
Outcomes	↓ relative risk of hip fractures by 16-33%, non-vertebral fractures by 14-23%, & any fracture by 5-19% May prevent losses of bone mineral density (51)(60)(61)(62)(70)(85)(87)(192)(306)
Class of evidence	A
Dosing & administration	400-800 IU per day with 1,000-1,200 mg calcium to elderly individuals
Outcomes	↓ relative risk of any fracture by 6-8%, & hip fracture by 16% (115)(454)
Class of evidence	A

Parathyroid hormone
General outcomes from A-level evidence	No data currently available.
Dosing & administration	3,000 IU per day with 600-1,200 mg calcium per day for at least 1 year to healthy Px without conditions that affect vitamin D metabolism
Outcomes	↓ parathyroid hormone, particularly with low baseline vitamin D status and in overweight or obese populations (301)
Class of evidence	A
Dosing & administration	700-1,000 IU with or without 500 mg calcium per day to overweight and obese adults
Outcomes	↓ parathyroid hormone (261)
Class of evidence	A

Parkinson’s disease (PD)
General outcomes from A-level evidence	↓ risk of PD by 28 (383) ↑ vitamin D status, which is inversely correlated to risk of PD, but supplementation may not alter motor function (480)
Dosing & administration	10,000 IU with 1,000 mg calcium per day for 16 weeks to older adults
Outcomes	Improves balance only in younger cohorts (ages 52-66) (174)
Class of evidence	B
Dosing & administration	1,200 IU (as D3) per day for 1 year
Outcomes	↓ relative progression of PD by 17% but no changes in disease severity (405)
Class of evidence	B

Pneumonia
General outcomes from A-level evidence	No effect as adjuvant therapy in pediatric pneumonia (103)(303)(451)
Dosing & administration	100,000 IU (as D3) single dose after course of antibiotics to children or infants (ages 1-36 months) with non-severe or severe pneumonia
Outcomes	↓relative risk of pneumonia episode recurrence by 58% ↑ number of days without recurrence of pneumonia (271)
Class of evidence	B

Polycystic ovarian syndrome (PCOS)
General outcomes from A-level evidence	↑ follicular development and regularity of menstrual cycles in adjunct with metformin, and total antioxidative capacity (9)(129)(385) ↓ FBG, HOMA-IR, HOMA-β, TGs, parathyroid hormone, hs-CRP, MDA, total testosterone, total cholesterol, & LDL (9)(39)(241)(288)(448) Note: other studies show no effect on metabolic or hormonal dysregulation (167)(201)(328), but effects on individual biomarkers vary between most studies.
Dosing & administration	4,000 IU per day, ongoing
Outcomes	↓ FBG, & HOMA-IR (241)
Class of evidence	A
Dosing & administration	50,000 IU (as D3) every 1-2 weeks with or without 1,000 mg calcium per day for 2-3 months
Outcomes	↓ interval between menstrual periods, Ferriman-Gallwey score, TGF-β1:soluble endoglin ratio, FBG, insulin, HOMA-IR, HOMA-β, total cholesterol, LDL, VLDL, TGs, hs-CRP, MDA, anti-Müllerian hormone, & vascular endothelial growth factor ↑ insulin sensitivity, adiponectin, total antioxidative capacity, & GSH Note: the addition of weight loss intervention can further improve anthropometric measures and the regularity of menstrual cycles than supplementation alone, while the addition of calcium improves biomarkers to a greater extent than vitamin D alone (30)(104)(133)(190)(191)(194)(268)(342)(376)
Class of evidence	B
Dosing & administration	3,200-4,000 IU per day for 3 months
Outcomes	↓ FBG, insulin, HOMA-IR, TGs, total cholesterol, LDL, VLDL, total:HDL cholesterol ratio, total testosterone, free androgen index, hirsutism, hs-CRP, alanine aminotransferase, & hyaluronic acid ↑ sex hormone-binding globulin, & total antioxidative capacity (134)(198)(199)
Class of evidence	B
Dosing & administration	300,000 IU (as D3 injection) 2 months prior to infertile women with PCOS undergoing intrauterine insemination
Outcomes	↑ endometrial proliferation (29)
Class of evidence	B
Dosing & administration	400 IU per day with 1,000 mg calcium adjunct to metformin therapy for 3 months to infertile women with PCOS
Outcomes	↑ number of dominant follicles (344)
Class of evidence	C

Postpartum depression
General outcomes from A-level evidence	No data currently available.
Dosing & administration	2,000 IU (as D3) to pregnant women from 26-28 weeks gestation until childbirth
Outcomes	↓ depression scores at weeks 38-40 of gestation, and at weeks 4 & 8 postpartum (423)
Class of evidence	C

Pre-eclampsia risk
General outcomes from A-level evidence	↓ relative risk of pre-eclampsia by 50-53% when supplemented during pregnancy with or without calcium, by correcting low vitamin D levels (188)(223)(321) Note: the best effect with concomitant calcium may occur with fewer than 18 weeks of supplementation (ie. based on a 38 week gestation pregnancy, initiation of concomitant calcium may be most effective after the 20th week of gestation) (223)
Dosing & administration	50,000 IU (as D3) biweekly, or 200 IU per day with 500-1,000mg calcium per day for 9-12 weeks (from 20-32 weeks of gestation) to women at risk for pre-eclampsia
Outcomes	↓ FBG, insulin, HOMA-IR, & TGs ↑ insulin sensitivity, HDL, GSH, & total antioxidative capacity (33)(215)(364)
Class of evidence	B
Dosing & administration	4,000 IU (as D3) per day during pregnancy
Outcomes	↓ relative risk of pre-eclampsia development by 7% compared with Px treated with 400 IU, but had a slightly higher incidence in intrauterine growth restriction and pre-eclampsia events (13)
Class of evidence	C

Prediabetes
General outcomes from A-level evidence	↓ risk of progression to type 2 diabetes, FBG, HBA1C, impaired glucose tolerance (2-hour glucose tolerance test), & HOMA-IR but effects can be moderated by age, co-administration of calcium, vitamin D status and the duration of the intervention (170)(294)(336)(460) Note: supplementation does not consistently improve individual measures of glycemic control or progression of diabetes across all meta-analyses (374)(409)
Dosing & administration	2,000-3,500 IU per day for approximately 6 months to individuals with prediabetes
Outcomes	↓ risk of progression to type II diabetes by 16%, FBG, HBA1C, & HOMA-IR (170)
Class of evidence	A
Dosing & administration	50,000-60,000 IU (as D3) weekly for 3 months, then monthly for 3-12 months, or 2,000-6,000 IU per day for 4-6 months to adults with vitamin D deficiency
Outcomes	↑ reversal to normal glycemic indices, insulin sensitivity, β-cell function, & miR-152 (microRNA) ↓ rate of progression towards diabetes, insulin resistance, TNF-ɑ, IL-6, miR-7 & miR-192 (122)(138)(248)(310)(311)
Class of evidence	B
Dosing & administration	50,000 IU (as D2), per week for 12 months to adults with vitamin D insufficiency or deficiency
Outcomes	Attenuates impairment in glucose intolerance and raises left atrial volume (43)(86)
Class of evidence	B
Dosing & administration	15,000 IU (as D3) or 20,000 IU (as D2) per week for 3 months
Outcomes	↑ waist circumference, & SBP Note: HOMA-IR decreased in Px with low vitamin D status, and D3 was more effective to reduce waist circumference than D2 (309)
Class of evidence	C

Premenstrual syndrome (PMS)
General outcomes from A-level evidence	↓ symptom severity of PMS (1)(26)
Dosing & administration	2,000 IU every 2nd day for 12 weeks, or 50,000 IU (as D3) every 1-2 weeks for 9-16 weeks to women with vitamin D deficiency
Outcomes	↓ prevalence of PMS & dysmenorrhea, mean PMS symptom scores, including nervousness, anxiety, fatigue, breast tenderness, bloating, headaches, backache, nausea, vomiting, diarrhea, job/social activity absence scores, IL-12, & IL-10 ↑ normalization of menstrual cycle length, & total antioxidative capacity (2)(41)(171)
Class of evidence	B
Dosing & administration	200,000 IU single administration followed by bi-weekly use of 25,000 IU for 4 months to adolescents and young women (ages 15-21) with severe vitamin D deficiency
Outcomes	↓ anxiety, irritability, sadness, crying, & relationship disturbance scores (410)
Class of evidence	C

Preterm birth and low birthweight
General outcomes from A-level evidence	↓ relative risk of preterm birth by 40%, risk of delivering low birthweight (<2,500 g) infants by 45-60% , and risk of small for gestational age by 31% when supplemented during pregnancy (283)(321)(412)(479) ↑ mean birthweight by ~103-107 grams, birth length by 0.22-0.3 cm, and head circumference by 0.19 cm (140)(283)(327) Note: supplementation during pregnancy with calcium may increase the risk of preterm birth by 52% (321)
Dosing & administration	600-2,000 IU per day during pregnancy
Outcomes	↓ relative risk of small for gestational age by 28-40%, & fetal or neonate mortality relative risk by 65% ↑ mean birthweight by ~58-75 grams (55)(358)
Class of evidence	A
Dosing & administration	800-1,000 IU per day to preterm infants
Outcomes	↑ body length gain, head circumference, & immune function (IL-2, IgA, & IgG) (453)
Class of evidence	A
Dosing & administration	200-1,000 IU (as D3) per day to very-low birthweight infants for 4 weeks to 6 months
Outcomes	↑ BMD, weight, & limb circumference ↓ proportion of stunted growth infants, alkaline phosphatase, parathormone, & incidence of skeletal hypomineralization (22)(234)(281)
Class of evidence	B

Respiratory tract infection (RTI) prevention
General outcomes from A-level evidence	↓ odds of RTI event in children and adults by 42% and 12-36%, respectively, and relative risk of developing an RTI in offspring with prenatal supplementation (52)(89)(97)(276) Effects may be strongest with daily or weekly administration compared with large bolus doses, and when baseline 25(OH)D is <25 nmol/L (52)(276)(277) Note: some evidence shows no preventative effect in healthy populations (272)(429)
Dosing & administration	2,000 IU per day for 2-18 months to adults or children
Outcomes	↓ incidence of RTI events and relative risk in all populations by 12% (277)
Class of evidence	A
Dosing & administration	4,000 IU (as D3) per day for 1 year to patients with antibody deficiency or increased RTI susceptibility
Outcomes	↓ risk of RTI, the number of RTIs experienced, & total infectious score by 23-25%, for ears, sinuses, malaise, odds of antibiotics use by 63.5%, and presence of bacterial or fungal pathogens ↑ time to first RTI (53)(54)
Class of evidence	B
Dosing & administration	10,000-14,000 IU per week for 2-8 months to children, adolescents, or young adults
Outcomes	↓ incidence of non-influenza respiratory virus infections in children and adolescents, viral load, & relative risk of lab-confirmed URTI by 56% in young adults (153)(258)
Class of evidence	B
Dosing & administration	500 IU (as D3) per day for 6 months to Px with inflammatory bowel disease
Outcomes	↓ relative risk of URTI by 49%, and by 64% in Px with low initial vitamin D status Note: ulcerative colitis symptoms may worsen (27)
Class of evidence	B
Dosing & administration	100,000 IU (as D3) per month for 12 months to older long-term care residents
Outcomes	↓ incidence of acute respiratory infection Note: higher doses were associated with higher rates of falls (147)
Class of evidence	B
Dosing & administration	2,000 IU (as D3) per day from 27 weeks gestation to pregnant mothers until birth, and 800 IU per day to infants from birth until 6 months of age
Outcomes	↓ incidence and number of acute respiratory infections of infants after the supplementation period (157)
Class of evidence	B
Dosing & administration	5,000 IU (as D3) per day for 4 weeks to athletes with vitamin D insufficiency training in the winter
Outcomes	↑ 25(OH)D possessing an inverse relationship with total and individual symptoms (runny nose, sneezing & cough) of upper respiratory tract infections (208)
Class of evidence	C

Rheumatoid arthritis (RA)
General outcomes from A-level evidence	↓ relative risk of incidence by 24% and may modulate pain perception and immune parameters at high doses (49)(391)
Dosing & administration	500 IU (as D3) with 1,000 mg calcium per day for 3-48 months adjunct to corticosteroid or triple disease‐modifying anti‐rheumatic drug (DMARD) therapy
Outcomes	↓ pain score by 3rd month compared with DMARD and calcium alone; Prevents long-term losses in BMD from corticosteroid use (79)(154)
Class of evidence	B
Dosing & administration	50,000 IU (as D3) per week for 6 months to Px with controlled RA in remission with vitamin D insufficiency
Outcomes	↓ absolute risk of recurring flare-ups by 10%, or relative risk by 36%, which was clinically, but not statistically significant (110)
Class of evidence	B
Dosing & administration	300,000 IU (as D3) single administration adjunct to corticosteroids and methotrexate
Outcomes	Standard therapy improves disease activity, pain, global health, & health assessment questionnaire scores, CRP, ESR, & IL-23 but D3 further improves the global health score (81)
Class of evidence	C

Rickets
General outcomes from A-level evidence	↓ risk to develop nutritional rickets (486)
Dosing & administration	400 IU per day to infants
Outcomes	Recommended as a broad strategy to prevent rickets by achieving ~50 nmol/L vitamin D status (486)
Class of evidence	A
Dosing & administration	300,000-600,000 IU or 10,000 IU/kg (as D3 injection) single administration, or 20,000-60,000 IU per week combined with daily calcium for 4-12 weeks to infants and children with nutritional rickets
Outcomes	↑ calcium, phosphate, vitamin D levels, & improvement in radiological measures ↓ alkaline phosphatase, parathyroid hormone Note: single injection or regular high dose therapy may be equally effective, though conflicting evidence exists for the overt risk of hypercalcemia (6)(10)(239)(296)(298)(390)(411)
Class of evidence	C
Dosing & administration	200 IU per day for 8 weeks to preterm infants
Outcomes	Provides equal efficacy to prevent rickets as 400 IU (14)
Class of evidence	C

Seasonal affective disorder (SAD)
General outcomes from A-level evidence	No data currently available.
Dosing & administration	400-800 IU (as D3) for 5 days in later winter to healthy subjects
Outcomes	positive affect (243)
Class of evidence	C
Dosing & administration	100,000 IU (as D2) single dose in Px with low vitamin D status
Outcomes	Improved depression scores at the one-month followup (148)
Class of evidence	C
Dosing & administration	2,800 IU per day for 3 months to adults
Outcomes	No effect on SAD symptoms demonstrated (136)
Class of evidence	C

Sexual dysfunction
General outcomes from A-level evidence	No data currently available.
Dosing & administration	300,000 IU (as intramuscular D3) single administration which is repeated after 4 weeks in women with vitamin D insufficiency
Outcomes	↑ Female Sexual Functioning Index score at week 4 & 8 ↓ Beck Depression score, independently from changes in sexual function (197)
Class of evidence	C

Sickle cell disease
General outcomes from A-level evidence	No data currently available.
Dosing & administration	4,000-7,000 IU (as D3) per day for 12 weeks or 12,000 IU per month for up to 2 years to children and young adults with vitamin D insufficiency and/or a history of respiratory events
Outcomes	↑ fetal hemoglobin ↓ hsCRP, percentage of Px with high platelet counts within 12 weeks, & rate of respiratory illness by 50% in 2nd year (120)(246)
Class of evidence	C
Dosing & administration	50,000 IU (as D2) per week for 2 months, then bi-weekly for 10 months with 1,000 mg calcium per day for the whole year to adults with vitamin D deficiency
Outcomes	↑ BMD (5)
Class of evidence	C
Dosing & administration	240,000-600,000 IU (as D3) based on body weight, in divided weekly doses, over 6 weeks, alongside 200IU per day with 500mg calcium for 6 months to children with chronic pain and vitamin D deficiency or insufficiency
Outcomes	↓ number of days with pain ↑ physical activity quality of life scores, and 25(OH)D levels (319)
Class of evidence	C

Sleep
General outcomes from A-level evidence	No data currently available.
Dosing & administration	50,000 IU bi-weekly for 8 weeks to adults with sleep disorders
Outcomes	↑ sleep latency ↑ sleep quality, & duration (265)
Class of evidence	B

Systemic lupus erythematosus (SLE)
General outcomes from A-level evidence	↓ fatigue scores, inflammation, endothelial dysfunction, and possibly anti-dsDNA positivity (a marker for SLE disease activity) though the effects on disease activity are inconsistent (135)(394)(474)
Dosing & administration	25,000-50,000 IU (as D3) per week for 6-24 months to Px with SLE or juvenile-onset SLE using glucocorticoids and immunosuppressants
Outcomes	↑ trabecular numbers, & total T-regulatory cells via higher CD4+CD45RA+CCR7- T-cells ↓ trabecular separation, CD8+CD28- T-cells, IFN-γ:IL-4 ratio in CD8+ T-cells Improves systemic lupus erythematosus disease activity index, and the European consensus lupus activity measurement & fatigue scores (253)(254)
Class of evidence	B
Dosing & administration	5,000 IU (as D3) per day for 16 weeks to SLE Px with vitamin D deficiency
Outcomes	↑ flow mediated dilation with improved vitamin D status (211)
Class of evidence	C

Testosterone
General outcomes from A-level evidence	Some evidence indicates benefit on testosterone concentrations but evidence is conflicting in men (181)(416)
Dosing & administration	3,332 IU per day for one year to healthy overweight men with low vitamin D status in a weight reduction program
Outcomes	↑ total, bioactive, and free testosterone compared to baseline but not placebo (331)
Class of evidence	B
Dosing & administration	2,000 IU (as D3) per day for one year to overweight or obese postmenopausal women with low vitamin D status on a weight reduction program
Outcomes	↑ free and bioavailable testosterone with successful vitamin D repletion (bioavailable estradiol and sex hormone-binding globulin also decreased and increased respectively) (279)
Class of evidence	B

Tooth loss
General outcomes from A-level evidence	No data currently available.
Dosing & administration	700 IU (as D3) per day with 500 mg calcium for 3 years in older adults
Outcomes	↑ risk of losing one or more teeth by 50-60% if consuming more than 1,000 mg calcium per day (231)
Class of evidence	B

Tuberculosis (TB)
General outcomes from A-level evidence	↑ proportion of conversion of sputum smear and culture from positive to negative, positive chest radiographic outcomes, & lymphocyte counts as combination therapy (442) May accelerate sputum smear or culture conversion but might only be effective in Px with the TaqI TT genotype of the vitamin D receptor or for multidrug-resistant TB (158)(203)(404)(466) Note: evidence on culture or smear conversion effectiveness is inconsistent (430)(444)
Dosing & administration	5,000-10,000 IU per day, or 100,000 IU (as D3) bi-weekly adjunct to anti-TB therapy for 2-4 months
Outcomes	↑ proportion of sputum conversion by 4th week, sputum smear conversion speed, resolution of lymphopenia, monocytosis, hypercytokinemia, hyperchemokinaemia, & the initiation of the killing of Mycobacterium tuberculosis by macrophages within 1 week ↓ primary tuberculosis score by 2nd month, antigen-stimulated proinflammatory cytokine response, and the suppressive effect of TB therapy on antigen-stimulated production of IL-4, CC chemokine ligand 5, & IFN-α Note: enhanced sputum conversion speed may only be improved in Px with the TaqI TT genotype of the vitamin D receptor (48)(100)(278)(291)(292)(312)
Class of evidence	B
Dosing & administration	600-800 IU (as D3) per day adjunct to anti-TB therapy for 2-6 months
Outcomes	↑ height growth ↓ relative risk of tuberculin skin test conversion by 59% (but not reaching statistical significance), & the incidence of anti-TB therapy induced liver disorders (142)(166)
Class of evidence	B
Dosing & administration	600,000 IU (as D3 injection) once and repeated after 1 month adjunct to anti-TB therapy
Outcomes	↑ IFN-γ secretion in response to Mycobacterium tuberculosis in Px with vitamin D deficiency, & weight gain ↓ residual disease (number of diseased areas and reduced cavity size) (360)
Class of evidence	B

Type I diabetes
General outcomes from A-level evidence	↓ odds of developing type I diabetes by 29% with early life supplementation (116)(483)
Dosing & administration	2,000-4,000 IU, or 70 IU/kg of bodyweight (as D3) per day for 3-18 months with insulin therapy to adults or children
Outcomes	↑ T regulatory cells, particularly in men, T regulatory cell suppressive capacity, & chemokine ligand 2 ↓ cumulative incidence of progression to undetectable fasting & stimulated C-peptide Improves insulin demands & HBA1C (66)(137)(414)
Class of evidence	B

Type II diabetes
General outcomes from A-level evidence	↓ glycemic, lipid and inflammatory parameters including FBG, HBA1C, insulin and insulin resistance, total cholesterol, LDL, CRP & TNF-α (145)(182)(193)(245)(302)(359)(440) Note: effects on glycemic control, lipid parameters and chronic low-grade inflammation are inconsistent across meta-analyses and conflicting meta-analyses widely exist. Parameters seem to be modulated by many factors including baseline vitamin D status, baseline glycemic, lipid & inflammatory levels, ethnicity, age, and BMI, for example.
Dosing & administration	500-4,000 IU per day, ongoing for a minimum of 3 months
Outcomes	↓ risk of developing type II diabetes by 13% compared with lower doses lower than 500 IU, FBG, insulin resistance, HBA1C, total cholesterol, LDL, & hs-CRP ↑ insulin sensitivity Note: TGs may only decrease with doses lower than 2,000 IU. Establishing vitamin D status of >25 ng/ml reduces risk of developing type II diabetes by 43% compared with individuals with <14 ng/ml (170)(193)(252)(293)(295)(461)
Class of evidence	A

Vaginal atrophy
General outcomes from A-level evidence	May improve growth and differentiation of vaginal epithelial cells, pH, and reduce dryness in menopausal women (350)
Dosing & administration	1,000 IU (vitamin D vaginal suppository) every night before bed for 8 weeks to postmenopausal women
Outcomes	↓ vaginal pH, & genitourinary atrophy symptom scores such as pain, dryness and paleness ↑ Vaginal Maturation Index, number of superficial cells (222)(341)
Class of evidence	B

Weight loss
General outcomes from A-level evidence	↓ BMI, body fat, and waist circumference, but may not affect weight loss in overweight and obese populations (175)(329)
Dosing & administration	2,000 IU (as D3) per day with reduced-calorie diet and exercise intervention for 1 year in postmenopausal women with vitamin D insufficiency
Outcomes	↑ weight, waist circumference, body fat percentage, CRP only in women who replenish vitamin D status above 32 ng/ml, & IL-6 in women losing at least 5% body weight (121)(280)
Class of evidence	B
Dosing & administration	400-1,000 IU (as D3) with 1,000 mg calcium per day, ongoing to postmenopausal women
Outcomes	↓ fat mass & parathyroid hormone within 3 months, and the likelihood of small (1-3 kg) or moderate (>3 kg) weight gains by 11% in women with lower calcium intake at baseline over the course of 7 years (82)(361)
Class of evidence	B
Dosing & administration	125-200 IU per day or 50,000 IU (as D3) per week with 600-1,200 mg calcium per day for 3-4 months to overweight and obese subjects on an energy-restricted diet
Outcomes	↓ weight, BMI, total fat mass, fat percentage, visceral fat mass & area, waist circumference, FBG, PTH, TGs, LDL, total cholesterol:LDL ratio, LDL:HDL ratio, & monocyte chemoattractant protein-1; Improvements in body weight, fat mass and lipid intake may be more prominent in subjects with lowest baseline calcium intake (259)(266)(267)(402)(482)
Class of evidence	B

Adverse effects

Adverse effects reported with vitamin D supplementation include nausea, vomiting, upset stomach, diarrhea, constipation, rashes, itchiness, allergic reactions, cardiovascular events, pain, cancer, and mortality. However, meta-analyses demonstrate that there are no significant effects associated with long term administration of doses of 4000 IU or less in adults. (270)

Vitamin D supplementation can increase the risk of hypercalcemia, hypercalciuria, and gastrointestinal (GI) events when used in conjunction with calcium supplementation. (38)(270) Single doses up to 200,000 IU can be administered in healthy, elderly populations without side effects, though GI complaints have been reported in some subjects. Doses greater than 500,000 IU have been reported to increase fracture risk, increase GI discomfort, and alter biochemical markers. (218) Vitamin D toxicity has been reported in mega-doses ranging from 2,220,000 to 6,360,000 IU, administered in an attempt to correct deficiencies. (217)

Pharmacokinetics

Absorption

Vitamin D is primarily synthesized (80%) in the skin upon the exposure of 7-dehydrocholecalciferol to UV light from the sun.
When ingested orally, vitamin D is released from food and fatty matrices in the stomach and absorbed in the jejunum and ileum of the stomach.
Vitamin D3 and D2 are thought to be absorbed by enterocytes through incorporation into micelles and chylomicrons.
At low concentrations, enzymatic transport is likely the primary uptake mechanism. At high concentrations, passive diffusion may dominate. (284)

Distribution

CYP27B1, the enzyme responsible for the conversion of vitamin D to its active form, can be found in many tissues and cells throughout the body, thereby promoting vitamin D’s widespread physiological actions. (96)(172)
CYP27B1 is primarily found in the kidneys, but extrarenal sites include the GI tract, macrophages, monocytes, osteoblasts, osteoclasts, placenta, skin, and vasculature. (96)(172)(422)
Vitamin D3 is stored in adipose tissue with a half-life of two days, while the active form’s half-life is three weeks. (220)

Metabolism

Vitamin D is metabolized by vitamin D hydroxylases, particularly by CYP2R1 to form calcidiol, but CYP2D11 and CYP2D25 may also be used in this function.
25(OH)D3 is the primary form of vitamin D that circulates in the blood and is used as a measure of vitamin D status.
25(OH)D3 can be further hydroxylated by CYP27B1 in the kidneys to calcitriol, the active form of vitamin D.
However, 25-hydroxyvitamin D3 24 hydroxylase (CYP24), also found in the kidneys, can metabolize calcitriol to 1,24,25(OH)3D3. Subsequent oxidation of this metabolite results in the production of calcitroic acid, which is readily excreted.
Importantly, CYP27B1 can also be found in the placenta, monocytes, and macrophages, which may promote vitamin D’s active effects in placental development and in the regulation of the immune system. (96)

Excretion

Calcitroic acid is excreted in the urine or used in bile.
Similarly, other vitamin D metabolites such as 1,25(OH)2D may proceed through the C23 lactone pathway for excretion or use in bile. (56)(205)

View our vitamin D metabolism infographic.