Ingredient review —Vitamin D
What is it?
Description
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)
Vitamin D3 (cholecalciferol)
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
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
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
Class of evidence
b
Dosing & administration
200,000 IU (as D3) followed by monthly 100,000 IU for ~1-3 years to older adults
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
Dosing & administration
2,800-4,400 IU (as D3) during pregnancy (from 10-26 weeks gestation)
Outcomes
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
Class of evidence
b
Autism spectrum disorder
Blood pressure
General outcomes from A-level evidence
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
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)
Dosing & administration
300,000 IU (as D3) single dose with re-administration after 8 weeks to nondiabetic stage 3-4 CKD adults
Outcomes
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
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
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)
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
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
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
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
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
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
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
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
Dosing & administration
50,000 IU (as D3) per week for 8 weeks
Class of evidence
b
Dosing & administration
50,000 IU (as D3 intramuscularly) per month for 6 months
Class of evidence
c
Diabetic neuropathy
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
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)
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
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
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
Dosing & administration
>4,000 IU per day to adolescents or adults
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
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
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
Class of evidence
b
Hepatitis C virus
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
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
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
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
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
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
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
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
Dosing & administration
400-800 IU (as D3) with 600-3,000 mg calcium per day post-operatively day for up to 1 week
Outcomes
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
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
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
Class of evidence
b
Dosing & administration
300,000 IU (as D3 injection) single administration to ulcerative colitis patients with low vitamin D status
Outcomes
Class of evidence
b
Dosing & administration
1,000-10,000 IU (as D2 or D3) per day for 6-12 months
Outcomes
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
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
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
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
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
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
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)
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
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)
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
Class of evidence
b
Dosing & administration
3,200-4,000 IU per day for 3 months
Outcomes
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
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
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
Class of evidence
b
Dosing & administration
50,000 IU (as D2), per week for 12 months to adults with vitamin D insufficiency or deficiency
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)
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
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
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
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)
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
Class of evidence
b
Dosing & administration
10,000-14,000 IU per week for 2-8 months to children, adolescents, or young adults
Outcomes
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)
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
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
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
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)
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
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
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)
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
Class of evidence
b
Dosing & administration
600-800 IU (as D3) per day adjunct to anti-TB therapy for 2-6 months
Outcomes
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
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
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
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
Class of evidence
b
Weight loss
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
Class of evidence
b
Dosing & administration
400-1,000 IU (as D3) with 1,000 mg calcium per day, ongoing to postmenopausal women
Outcomes
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.
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