VITAMIN D















  • 1 ng/ml of vitamin D = 2.5 nmol/L
  • Reference [4]
Endocrine Society recommendations on serum 25-hydroxyvitamin D levels
Level (ng/ml) Range
< 20 Deficiency
20 - 29 Insufficiency
≥ 30 Normal


  • 1 ng/ml of vitamin D = 2.5 nmol/L
  • Reference [7]
NAM recommendations on serum 25-hydroxyvitamin D levels
Level (ng/ml) Recommendations
< 12 Associated with vitamin D deficiency, which can lead to rickets in infants and children and osteomalacia in adults
12 - 19 Some people are potentially at risk of inadequacy
20 - 50 Generally considered adequate for bone and overall health in healthy individuals
> 50 Linked to potential adverse effects, particularly when > 60 ng/mL







  • 1 mcg of vitamin D = 40 IU
  • Recommendations assume minimal sun exposure
  • Recommended intake is the same for men and women
  • Reference [7]
NAM recommended daily dietary allowance for vitamin D
Age Vitamin D
0 - 12 months 400 IU (10 mcg)
1 - 70 years 600 IU (15 mcg)
> 70 years 800 IU (20 mcg)
Pregnant or lactating 600 IU (15 mcg)






  • Reference: Manufacturer's PI
Vitamin D supplements
Cholecalciferol (Vitamin D3)
  • Dosage forms: Comes in many OTC products in numerous strengths
  • Dosing: RDA for vitamin D in most adults is 600 - 800 IU/day. See also deficiency treatment regimens.
  • Other: Found in oily fish, egg yolks, and fortified foods
Ergocalciferol (Vitamin D2)
  • Dosage forms: Comes in many OTC products in numerous strengths. Also available in prescription form as a 50,000 IU capsule.
  • Dosing: RDA for vitamin D in most adults is 600 - 800 IU/day. See also deficiency treatment regimens.
  • Other: Found in salmon, egg yolks, mushrooms, and fortified foods
Active (analog) vitamin D products
Calcitriol (Rocaltrol®)
  • Dosage forms (prescription only)
    • Capsule: 0.25, 0.50 mcg
    • Solution: 1 mcg/ml | Comes in 15 ml bottle
    • Generic available | Costs < $50/month
  • Dosing:
  • Other
    • Active form of vitamin D. Does not require metabolism.
    • FDA-approved for secondary hyperparathyroidism in predialysis and dialysis CKD patients. Also approved for hypoparathyroidism in patients with postsurgical hypoparathyroidism, idiopathic hypoparathyroidism, and pseudohypoparathyroidism.
Doxercalciferol (Hectorol®)
  • Dosage forms (prescription only)
    • Capsule: 0.50, 1.0, 2.5 mcg
    • Injection: 2 mcg/ml | Comes in single-dose and multiple-dose vials
    • Generic capsule available | Costs $50 - $150/month
  • Dosing
  • Other
    • Doxercalciferol is converted in the liver to 1α,25-(OH)2D2, an active metabolite that does not require kidney metabolism
    • FDA-approved for treatment of secondary hyperparathyroidism in adult patients with Stage 3 or Stage 4 CKD and adult patients with CKD on dialysis
Paricalcitol (Zemplar®)
  • Dosage forms (prescription only)
    • Capsule: 1, 2, 4 mcg
    • Generic capsule available | Costs $50 - $150/month
  • Dosing
  • Other
    • Paricalcitol is a synthetic version of calcitriol. It does not require metabolism to become active.
    • FDA-approved for prevention and treatment of secondary hyperparathyroidism in patients ≥ 10 years old with Stage 3, 4, or 5 CKD and patients with CKD on dialysis



Asthma
Vitamin D3 vs Placebo to Prevent Asthma Exacerbations in Children, JAMA (2020) [PubMed abstract]
  • Design: Randomized placebo-controlled trial (N=192 | length = median 332 days) in asthmatics aged 6 - 16 years with vitamin D levels of 10 - 30 ng/ml (mean 22.6 ng/ml) and at least one severe asthma exacerbation in the previous year
  • Treatment: Vitamin D3 4000 IU/day vs Placebo
  • Primary outcome: Time to a severe asthma exacerbation
  • Results:
    • Primary outcome: Vitamin D3 - 240 days, Placebo - 253 days (p=0.63)
    • The trial was terminated early due to futility
  • Findings: Among children with persistent asthma and low vitamin D levels, vitamin D3 supplementation, compared with placebo, did not significantly improve the time to a severe asthma exacerbation. The findings do not support the use of vitamin D3 supplementation to prevent severe asthma exacerbations in this group of patients.
Vitamin D vs Placebo for Prevention of Wheezing in Premature Black Infants, JAMA (2018) [PubMed abstract]
  • Design: Randomized controlled trial (N=300, length - 12 months) in black infants born 28 - 36 weeks gestation
  • Treatment: Open-label multivitamin until they were consuming 200 IU/d of cholecalciferol from formula or fortifier added to human milk, after which they received either 400 IU/d of cholecalciferol until 6 months of age adjusted for prematurity (sustained supplementation) or placebo (diet-limited supplementation)
  • Primary outcome: Recurrent wheezing by 12 months' adjusted age
  • Results:
    • Primary outcome: Vitamin D - 31.1%, Placebo - 41.8% (diff 10.7%, 95%CI [-27.4% to -2.9%])
  • Findings: Among black infants born preterm, sustained supplementation with vitamin D, compared with diet-limited supplementation, resulted in a reduced risk of recurrent wheezing by 12 months' adjusted age. Future research is needed to better understand the mechanisms and longer-term effects of vitamin D supplementation on wheezing in children born preterm.
Vitamin D vs Placebo in Pregnant Women to Prevent Wheezing in Offspring, JAMA (2016) [PubMed abstract]
  • Design: Randomized placebo-controlled trial (N=623 | length = 3 years) in pregnant women who were 24 weeks pregnant
  • Treatment: Vitamin D3 2400 IU/day vs Placebo from pregnancy week 24 to 1 week postpartum. All women received Vitamin D3 400 IU/day throughout pregnancy
  • Primary outcome: Percentage of offspring with persistent wheeze in the first 3 years of life
  • Results:
    • Primary outcome: Vitamin D - 16%, Placebo - 20% (p=0.16)
  • Findings: The use of 2800 IU/d of vitamin D3 during the third trimester of pregnancy compared with 400 IU/d did not result in a statistically significant reduced risk of persistent wheeze in the offspring through age 3 years. However, interpretation of the study is limited by a wide CI that includes a clinically important protective effect.
Vitamin D vs Placebo in Pregnant Women for Prevention of Asthma/Wheezing in Offspring JAMA (2016) [PubMed abstract]
  • Design: Randomized placebo-controlled trial (N=881 | length = 3 years) in pregnant women who were 10 - 18 weeks pregnant and at high risk of having children with asthma
  • Treatment: Vitamin D3 4000 IU/day vs Placebo. All women received Vitamin D3 400 IU/day throughout pregnancy.
  • Primary outcomes: Parental report of physician-diagnosed asthma or recurrent wheezing through 3 years of age
  • Results:
    • Primary outcome: Vitamin D - 24.3%, Placebo - 30.4% (p=0.051)
  • Findings: In pregnant women at risk of having a child with asthma, supplementation with 4400 IU/d of vitamin D compared with 400 IU/d significantly increased vitamin D levels in the women. The incidence of asthma and recurrent wheezing in their children at age 3 years was lower by 6.1%, but this did not meet statistical significance; however, the study may have been underpowered. Longer follow-up of the children is ongoing to determine whether the difference is clinically important.
Results from Six-years of Follow-up, NEJM (2020) [PubMed abstract]
    • The children from the study above were followed through the age of 6 years, and results for the primary outcome are given below
  • Results:
    • Primary outcome: Vitamin D - 43.5%, Placebo - 45.9% (p=0.25)
  • Findings: Vitamin D supplementation during the prenatal period alone did not influence the 6-year incidence of asthma and recurrent wheeze among children who were at risk for asthma
Vitamin D3 vs Placebo to Prevent Exacerbation in Asthmatics with Vitamin D Level < 30 ng/ml, JAMA (2014) [PubMed abstract]
  • Design: Randomized placebo-controlled trial (N=408 | length = 28 weeks) in adults with symptomatic asthma and vitamin D level < 30 ng/ml
  • Treatment: Vitamin D3 100,000 IU once followed by 4000 IU/day vs Placebo
  • Primary outcome: The primary outcome was time to first asthma treatment failure (a composite outcome of decline in lung function and increases in use of beta agonists, systemic corticosteroids, and health care)
  • Results:
    • Primary outcome: Vitamin D - 28%, Placebo 29% (p=0.57)
  • Findings: Vitamin D3 did not reduce the rate of first treatment failure or exacerbation in adults with persistent asthma and vitamin D insufficiency. These findings do not support a strategy of therapeutic vitamin D3 supplementation in patients with symptomatic asthma.

Autoimmune disease
Vitamin D3 vs Placebo for the Prevention of Autoimmune Disease, BMJ (2022) [PubMed abstract]
  • Design: Secondary analysis of the VITAL study, a randomized placebo-controlled trial (N=25,871 | length = median 5.3 years) in healthy men ≥ 50 years and women ≥ 55 years
  • Treatment: Vitamin D3 2000 IU/day vs Placebo. The study had another factor that involved fish oil.
  • Primary outcome: All incident autoimmune diseases confirmed by medical record review: rheumatoid arthritis, polymyalgia rheumatica, autoimmune thyroid disease, psoriasis, and all others
  • Results:
    • Primary outcome: Vitamin D3 - 0.95%, Placebo - 1.2% (p=0.05)
  • Findings: Vitamin D supplementation for five years, with or without omega 3 fatty acids, reduced autoimmune disease by 22%, while omega 3 fatty acid supplementation with or without vitamin D reduced the autoimmune disease rate by 15% (not statistically significant). Both treatment arms showed larger effects than the reference arm (vitamin D placebo and omega 3 fatty acid placebo).

Cancer
High-dose vs Low-dose Vitamin D3 for Advanced or Metastatic Colorectal Cancer, JAMA (2019) [PubMed abstract]
  • Design: Randomized controlled trial (N=139 | length = 22.9 months) in patients with advanced or metastatic colorectal cancer
  • Treatment: High-dose vitamin D3 (8000 IU/d followed by 4000 IU/day) vs Standard-dose Vitamin D3 (400 IU/day)
  • Primary outcome: Progression-free survival (PFS) assessed by the log-rank test and a supportive Cox proportional hazards model
  • Results:
    • Primary outcome: High-dose - 13 months, Standard dose - 11 months (p=0.07)
  • Findings: Among patients with metastatic CRC, addition of high-dose vitamin D3, vs standard-dose vitamin D3, to standard chemotherapy resulted in a difference in median PFS that was not statistically significant, but with a significantly improved supportive hazard ratio. These findings warrant further evaluation in a larger multicenter randomized clinical trial.
Vitamin D vs Placebo for Secondary Prevention of Gastrointestinal Cancers, JAMA (2019) [PubMed abstract]
  • Design: Randomized placebo-controlled trial (N=417 | length = 3.5 years) in Japanese patients diagnosed with stage I to III gastrointestinal cancer
  • Treatment: Vitamin D3 2000 IU once daily vs Placebo
  • Primary outcome: Relapse-free survival time to relapse or death
  • Results:
    • 5-year relapse-free survival: Vitamin D - 77%, Placebo - 69% (p=0.18)
  • Findings: Among patients with digestive tract cancer, vitamin D supplementation, compared with placebo, did not result in significant improvement in relapse-free survival at 5 years.
VITAL study - Vitamin D vs Placebo for the Primary Prevention of Cancer, NEJM (2018) [PubMed abstract]
  • Design: Randomized placebo-controlled trial (N=25,871; length - 5.3 years) in healthy men ≥ 50 years and women ≥ 55 years with no history of cancer
  • Treatment: vitamin D3 2000 IU once daily vs Placebo. The study had another factor that involved fish oil.
  • Results:
    • Primary outcome: Vitamin D - 793 cases, Placebo - 824 (HR 0.96, 95%CI [0.88 - 1.06])
  • Primary outcome: Invasive cancer of any type
  • Findings: Supplementation with vitamin D did not result in a lower incidence of invasive cancer or cardiovascular events than placebo
Effect of vitamin D and Calcium Supplementation on Cancer Incidence in Older Women: A Randomized Clinical Trial. - JAMA (2017) [PMID 28241355]
  • Design: Randomized placebo-controlled trial (N=2303, length=4 years)
  • Primary outcome: The primary outcome was the incidence of all-type cancer (excluding nonmelanoma skin cancers), which was evaluated using Kaplan-Meier survival analysis and proportional hazards modeling.
  • Results:
    • Primary outcome: Vitamin D - 3.89%, Placebo - 5.58% (p=0.06)
  • Findings: Among healthy postmenopausal older women with a mean baseline serum 25-hydroxyvitamin D level of 32.8 ng/mL, supplementation with vitamin D3 and calcium compared with placebo did not result in a significantly lower risk of all-type cancer at 4 years. Further research is necessary to assess the possible role of vitamin D in cancer prevention.
Vitamin D + Aspirin + Calcium vs Placebo for the Secondary Prevention of Colorectal Adenomas, Gastroenterology (2016) [PubMed abstract]
  • Design: Randomized placebo-controlled trial (N=1107 | length = 3 years) in patients with 1 or more sporadic adenoma(s) removed from the colon or rectum
  • Treatment: Calcitriol 0.5 mcg + Aspirin 75 mg + Calcium carbonate 1250 mg once daily vs Placebo
  • Primary outcome: Adenoma recurrence assessed by colonoscopy after 3 years
  • Results:
    • Primary outcome: There were no differences between groups in the rate of recurrence (OR 0.95, 95%CI [0.61-1.48]), adverse effects, or secondary outcomes
  • Findings: In a prospective study, the combination of calcitriol, aspirin, and calcium carbonate did not prevent recurrence of colorectal adenomas over a 3-year period. The negative results might be owing to the effects of smoking or low doses of the tested agents.
Vitamin D vs Placebo for the Secondary Prevention of Colorectal Adenomas, NEJM (2015) [PubMed abstract]
  • Design: Randomized placebo-controlled trial (N=2259 | length = 3 - 5 years) in patients with recently diagnosed adenomas and no known colorectal polyps remaining after complete colonoscopy
  • Treatment: Vitamin D3 1000 IU once daily vs Placebo. There was another factor in the study that involved calcium carbonate.
  • Primary outcome: Adenomas diagnosed in the interval from randomization through the anticipated surveillance colonoscopy
  • Results:
    • Primary outcome: Vitamin D - 42.8%, Placebo - 42.7% (RR 0.99, 95%CI [0.89 - 1.09])
  • Findings: Daily supplementation with vitamin D3 (1000 IU), calcium (1200 mg), or both after removal of colorectal adenomas did not significantly reduce the risk of recurrent colorectal adenomas over a period of 3 to 5 years.

COPD
Vitamin D vs Placebo for the Prevention of COPD Exacerbations, Annals of Internal Medicine (2012) [PubMed abstract]
  • Design: Randomized placebo-controlled trial (N=182 | length = 1 year) in patients with COPD
  • Treatment: Vitamin D 100,000 IU every 4 weeks vs Placebo for one year
  • Primary outcome: Time to first COPD exacerbation
  • Results:
    • Primary outcome: The median time to first exacerbation did not significantly differ between the groups (HR 1.1, 95%CI [0.82 to 1.56], p=0.41), nor did exacerbation rates, FEV(1), hospitalization, quality of life, and death
  • Findings: High-dose vitamin D supplementation in a sample of patients with COPD did not reduce the incidence of exacerbations. In participants with severe vitamin D deficiency at baseline, supplementation may reduce exacerbations.

Critically ill patients
Vitamin D3 vs Placebo in Critically ill, Vitamin D-deficient patients, NEJM (2019) [PubMed abstract]
  • Design: Randomized placebo-controlled trial (N=1360 | length = 90 days) in critically ill, vitamin D-deficient patients who were at high risk for death
  • Treatment: Enteral vitamin D3 540,000 IU one time vs Placebo
  • Primary outcome: 90-day all-cause, all-location mortality
  • Results:
    • Primary outcome: Vitamin D3 - 23.5%, Placebo - 20.6% (p=0.26)
  • Findings: Early administration of high-dose enteral vitamin D3 did not provide an advantage over placebo with respect to 90-day mortality or other, nonfatal outcomes among critically ill, vitamin D-deficient patients.
Vitamin D3 vs Placebo in Critically ill Patients with Vitamin D deficiency (2014) [PubMed abstract]
  • Design: Randomized placebo-controlled trial (N=492 | length = 6 months) in critically ill adult white patients with vitamin D deficiency
  • Treatment: Vitamin D3 540,000 IU once followed by 90,000 IU once monthly for 5 months vs Placebo
  • Primary outcome: Hospital length of stay
  • Results:
    • Primary outcome (median): Vitamin D - 20.1 days, Placebo 19.3 days (p=0.98)
  • Findings: Among critically ill patients with vitamin D deficiency, administration of high-dose vitamin D3 compared with placebo did not reduce hospital length of stay, hospital mortality, or 6-month mortality. Lower hospital mortality was observed in the severe vitamin D deficiency subgroup, but this finding should be considered hypothesis generating and requires further study.

Depression
Vitamin D3 vs Placebo for Prevention of Depression in Adults Older than 50 Years, JAMA (2020) [PubMed abstract]
  • Design: Randomized placebo-controlled trial (N=18,353 | length = median 5.3 years) in adults ≥ 50 years old without depression at baseline
  • Treatment: Cholecalciferol 2000 IU/day vs Placebo. There was another arm of the trial where patients were randomized to fish oil or placebo.
  • Primary outcome: The primary outcomes were the risk of depression or clinically relevant depressive symptoms (total of incident and recurrent cases) and the mean difference in mood scores (8-item Patient Health Questionnaire depression scale [PHQ-8]; score range, 0 points [least symptoms] to 24 points [most symptoms]
  • Results:
    • Risk of depression or clinically relevant depressive symptoms: Vitamin D3 - 12.9/1000 person-years, Placebo - 13.3/1000 person-years (p=0.62)
    • No significant differences were observed between treatment groups for change in mood scores over time (mean difference 0.01 points)
  • Findings: Among adults aged 50 years or older without clinically relevant depressive symptoms at baseline, treatment with vitamin D3 compared with placebo did not result in a statistically significant difference in the incidence and recurrence of depression or clinically relevant depressive symptoms or for change in mood scores over a median follow-up of 5.3 years. These findings do not support the use of vitamin D3 in adults to prevent depression.

Diabetes and diabetes prevention
Vitamin D3 vs Placebo for Prevention of Diabetes in Prediabetics, NEJM (2019) [PubMed abstract]
  • Design: Randomized placebo-controlled trial (N=2423 | length = 2.5 years) in adults with prediabetes
  • Treatment: Vitamin D3 4000 IU/day vs Placebo
  • Primary outcome: New-onset diabetes
  • Results:
    • Primary outcome: Vitamin D3 - 9.39%/year, Placebo - 10.66%/year (p=0.12)
  • Findings: Among persons at high risk for type 2 diabetes not selected for vitamin D insufficiency, vitamin D3 supplementation at a dose of 4000 IU per day did not result in a significantly lower risk of diabetes than placebo.
Vitamin D3 vs Placebo for Prevention of Kidney Disease in Type 2 Diabetes, JAMA (2019) [PubMed abstract]
  • Design: Randomized placebo-controlled trial (N=1312 | length = 5 years) in adults with type 2 diabetes
  • Treatment: Vitamin D3 2000 IU/day vs Placebo. The study had another factor that involved omega-3 fatty acids.
  • Primary outcome: Change in glomerular filtration rate estimated from serum creatinine and cystatin C (eGFR) from baseline to year 5
  • Results:
    • Primary outcome (decrease in GFR): Vitamin D3 - 12.3 ml/min, Placebo - 13.1 (difference 0.9, 95%CI [-0.7 to 2.5])
  • Findings: Among adults with type 2 diabetes, supplementation with vitamin D3 or omega-3 fatty acids, compared with placebo, resulted in no significant difference in change in eGFR at 5 years. The findings do not support the use of vitamin D or omega-3 fatty acid supplementation for preserving kidney function in patients with type 2 diabetes.
Vitamin D3 vs Placebo for the Prevention of Type 2 Diabetes, JCEM (2016) [PubMed abstract]
  • Design: Randomized placebo-controlled trial (N=511 | length = 5 years) in patients with prediabetes
  • Treatment: Vitamin D3 20,000 IU every week vs Placebo for 5 years
  • Primary outcome: Progression to type 2 diabetes
  • Results:
    • Primary outcome: Vitamin D - 40.2%, Placebo - 43.9% (p=0.45)
  • Findings: In subjects without vitamin D deficiency, vitamin D supplementation is unlikely to prevent progression from prediabetes to diabetes. Very large studies with inclusion of vitamin D-deficient subjects will probably be needed to show such a putative effect.

Falls
Vitamin D vs Control for Falls in Elderly Adults, Ann Intern Med (2020) [PubMed abstract]
  • Design: Randomized response-adaptive controlled trial (N=688 | length = 2 years) in patients ≥ 70 years with elevated fall risk and 25-hydroxyvitamin D level of 10 - 29 ng/ml
  • Treatment: An initial phase of the trial determined that vitamin D3 1000 IU/day was more likely to offer a benefit than a dose of 2000 or 4000 IU/day. Patients then received either vitamin D3 200 IU/day (control) or 1000 IU/day.
  • Primary outcome: Time to first fall or death over 2 years
  • Results:
    • Primary outcome: There was no significant difference between those receiving 200 IU and 1000 IU (HR 0.94, 95%CI [0.76 to 1.15], p=0.54)
  • Findings: In older persons with elevated fall risk and low serum 25-(OH)D levels, vitamin D3 supplementation at doses of 1000 IU/d or higher did not prevent falls compared with 200 IU/d. Several analyses raised safety concerns about vitamin D3 doses of 1000 IU/d or higher.
Vitamin D vs Placebo for the Secondary Prevention of Falls in Older Women, JAMA Intern Med (2015) [PubMed abstract]
  • Design: Randomized placebo-controlled trial (N=409 | length = 2 years) in home-dwelling women 70 to 80 years old with at least one fall during the previous year
  • Treatment: Vitamin D 800 IU/day vs Placebo. The study had another factor that involved open-label exercise.
  • Primary outcome: Monthly reported falls
  • Results:
    • Primary outcome: Vitamin D - 132/100 person-years, Placebo - 118.2/100 person-years
  • Findings: The rate of injurious falls and injured fallers more than halved with strength and balance training in home-dwelling older women, while neither exercise nor vitamin D affected the rate of falls. Exercise improved physical functioning. Future research is needed to determine the role of vitamin D in the enhancement of strength, balance, and mobility.

Heart disease
VITAL study - Vitamin D vs Placebo for the Primary Prevention of Heart Disease, NEJM (2018) [PubMed abstract]
  • Design: Randomized placebo-controlled trial (N=25,871 | length - 5.3 years) in healthy men ≥ 50 years and women ≥ 55 years with no history of CVD
  • Treatment: Vitamin D3 2000 IU once daily vs Placebo. The study had another factor that involved fish oil.
  • Primary outcome: Composite of myocardial infarction, stroke, or death from cardiovascular causes
  • Results:
    • Primary outcome: Vitamin D - 396 events, Placebo - 409 events (HR 0.97 95%CI [0.85 - 1.12])
  • Findings: Supplementation with vitamin D did not result in a lower incidence of invasive cancer or cardiovascular events than placebo
Vitamin D3 vs Placebo for Prevention of CVD, JAMA (2017) [PubMed abstract]
  • Design: Randomized placebo-controlled trial (N=5108, length - 3.3 years) in patients recruited from a primary care setting
  • Treatment: Vitamin D3 200,000 IU on time followed by 100,000 IU monthly vs Placebo
  • Primary outcome: Number of participants with incident CVD and death
  • Results:
    • Primary outcome: Vitamin D - 11.8%, Placebo - 11.5% (HR 1.02 95%CI [0.87 - 1.20])
  • Findings: Monthly high-dose vitamin D supplementation does not prevent CVD. This result does not support the use of monthly vitamin D supplementation for this purpose. The effects of daily or weekly dosing require further study.
Vitamin D3 vs Placebo in Heart Failure J Am Coll Cardiol (2016) [PubMed abstract]
  • Design: Randomized placebo-controlled trial (N=229 | length = 12 months) in patients with chronic heart failure and vitamin D deficiency
  • Treatment: Vitamin D3 4,000 IU once daily vs Placebo for 1 year
  • Primary outcome: Change in 6-minute walk distance between baseline and 12 months
  • Results:
    • Primary outcome: One year of high-dose vitamin D3 supplementation did not improve 6-min walk distance at 1 year
  • Findings: One year of 100μg daily 25-OH vitamin D3 supplementation does not improve 6-minute walk distance but has beneficial effects on LV structure and function in patients on contemporary optimal medical therapy. Further studies are necessary to determine whether these translate to improvements in outcomes.

Infections
High-dose Vitamin D3 vs Placebo for Patients Hospitalized with COVID, JAMA (2021) [PubMed abstract]
  • Design: Randomized placebo-controlled trial (N=240 | length = until discharge) in patients hospitalized with moderate to severe COVID
  • Treatment: Single oral dose of vitamin D3 200,000 IU vs Placebo
  • Primary outcome: Length of stay, defined as the time from the date of randomization to hospital discharge
  • Results:
    • Primary outcome (median length of stay): Vitamin D3 - 7 days, Placebo - 7 days (p=0.62)
    • In-hospital mortality: Vitamin D3 - 7.6%, Placebo - 5.1% (p=0.43)
    • Mean baseline 25-hydroxyvitamin D level: 20.9 ng/ml
    • 25-hydroxyvitamin D level after treatment: Vitamin D3 - 44.4 ng/ml, Placebo 19.8 ng/ml
  • Findings: Among hospitalized patients with COVID-19, a single high dose of vitamin D3, compared with placebo, did not significantly reduce hospital length of stay. The findings do not support the use of a high dose of vitamin D3 for treatment of moderate to severe COVID-19.
Vitamin D vs Placebo for Prevention of Tuberculosis in Children, NEJM (2020) [PubMed abstract]
  • Design: Randomized placebo-controlled trial (N=8851 | length = 3 years) in children (6 - 13 years) living in Mongolia who were negative for TB
  • Treatment: Vitamin D 14,000 IU once weekly vs Placebo for 3 years
  • Primary outcome: Positive QuantiFERON-TB Gold test at the end of the 3-year treatment period
  • Results:
    • Primary outcome: Vitamin D - 3.6%, Placebo 3.3% (p=0.42)
    • Average vitamin D level at end of trial: Vitamin D - 31 ng/ml, Placebo - 10.7 ng/ml
  • Findings: Vitamin D supplementation did not result in a lower risk of tuberculosis infection, tuberculosis disease, or acute respiratory infection than placebo among vitamin D–deficient schoolchildren in Mongolia
Vitamin D3 400 IU/day vs 1200 IU/day for Bone Strength and Infections, JAMA Pediatrics (2018) [PubMed abstract]
  • Design: Randomized controlled trial (N=975 | length - 24 months) in healthy term infants
  • Treatment: Vitamin D3 400 IU/day vs 1200 IU/day from age 2 weeks to 24 months
  • Primary outcome: Primary outcomes were bone strength and incidence of parent-reported infections at 24 months
  • Results:
    • Primary outcome (infections): Incidence rates of parent-reported infections did not differ between groups (incidence rate ratio 1.00, 95%CI [0.93-1.06])
  • Findings: A vitamin D3 supplemental dose of up to 1200 IU in infants did not lead to increased bone strength or to decreased infection incidence. Daily supplementation with 400 IU vitamin D3 seems adequate in maintaining vitamin D sufficiency in children younger than 2 years.
Vitamin D3 400 IU/day vs 2000 IU/day for Prevention of Viral Upper Respiratory Infections, JAMA (2017) [PubMed abstract]
  • Design: Randomized controlled trial (N=703 | length - 6.2 months) in children aged 1 - 5 years
  • Treatment: Vitamin D3 2000 IU/day vs 400 IU/day for a minimum of 4 months
  • Primary outcome: Number of laboratory-confirmed viral upper respiratory tract infections based on parent-collected nasal swabs over the winter months
  • Results:
    • Primary outcome (average infections): 2000 IU - 1.05, 400 IU - 1.03 (p=0.71)
  • Findings: Among healthy children aged 1 to 5 years, daily administration of 2000 IU compared with 400 IU of vitamin D supplementation did not reduce overall wintertime upper respiratory tract infections. These findings do not support the routine use of high-dose vitamin D supplementation in children for the prevention of viral upper respiratory tract infections.
Vitamin D3 vs Placebo for Prevention of Upper Respiratory Infections in Adults, JAMA (2012) [PubMed abstract]
  • Design: Randomized placebo-controlled trial (N=322 | length = 18 months) in healthy adults
  • Treatment: Vitamin D3 200,000 IU once monthly for 2 months followed by 100,000 IU monthly thereafter vs Placebo
  • Primary outcome: Number of upper respiratory tract infection episodes
  • Results:
    • Primary outcome (average per person): Vitamin D - 3.7, Placebo - 3.8 (RR 0.97, 95%CI [0.85-1.11])
  • Findings: In this trial, monthly administration of 100,000 IU of vitamin D did not reduce the incidence or severity of URTIs in healthy adults
Vitamin D3 vs Placebo for Prevention of Pneumonia in High-risk Infants, Lancet (2012) [PubMed abstract]
  • Design: Randomized placebo-controlled trial (N=3046 | length = 18 months) in children aged 1 - 11 months who were living in in Kabul, Afghanistan
  • Treatment: Vitamin D3 100,000 IU every 3 months vs Placebo
  • Primary outcome: First or only episode of radiologically-confirmed pneumonia
  • Results:
    • Primary outcome: Vitamin D - 0.145/child/year, Placebo - 0.137/child/year (p=0.476)
  • Findings: Quarterly bolus doses of oral vitamin D(3) supplementation to infants are not an effective intervention to reduce the incidence of pneumonia in infants in this setting

Mortality
Vitamin D3 vs Placebo for Overall Mortality in Australians 60 Years and Older, Lancet Diabetes Endocrinol (2022) [PubMed abstract]
  • Design: Randomized placebo-controlled trial (N=21,315 | length = median of 5.7 years) in Australians 60 years and older
  • Treatment: Vitamin D3 60,000 IU once monthly vs Placebo for 5 years
  • Primary outcomes: All-cause mortality
  • Results:
    • Primary outcome: Vitamin D3 - 5.3%, Placebo - 5.1% (p=0.47)
    • In exploratory analyses excluding the first 2 years of follow-up, those randomly assigned to receive vitamin D had a numerically higher hazard of cancer mortality than those in the placebo group (HR 1·24 [95% CI 1·01-1·54]; p=0·05)
    • In 4441 blood samples collected from randomly sampled participants (N=3943) during follow-up, mean serum 25-hydroxy-vitamin D concentrations were 30.8 ng/ml in the placebo group and 46 ng/ml in the vitamin D group
  • Findings: Administering vitamin D3 monthly to unscreened older people did not reduce all-cause mortality. Point estimates and exploratory analyses excluding the early follow-up period were consistent with an increased risk of death from cancer. Pending further evidence, the precautionary principle would suggest that this dosing regimen might not be appropriate in people who are vitamin D-replete.

Osteoarthritis
Vitamin D3 vs Placebo for Symptomatic Knee Osteoarthritis, JAMA (2016) [PubMed abstract]
  • Design: Randomized placebo-controlled trial (N=413 | length = 24 months) in patients with symptomatic knee osteoarthritis and low vitamin D (12.5-60 nmol/L)
  • Treatment: Vitamin D3 50,000 IU once monthly vs Placebo for 2 years
  • Primary outcomes: Change in tibial cartilage volume (assessed with MRI) and change in WOMAC pain score (0 [no pain] to 500 [worst pain]) from baseline to month 24
  • Results:
    • Primary outcome: There were no significant differences in annual change of tibial cartilage volume or WOMAC pain score
  • Findings: Among patients with symptomatic knee osteoarthritis and low serum 25-hydroxyvitamin D levels, vitamin D supplementation, compared with placebo, did not result in significant differences in change in MRI-measured tibial cartilage volume or WOMAC knee pain score over 2 years. These findings do not support the use of vitamin D supplementation for preventing tibial cartilage loss or improving WOMAC knee pain in patients with knee osteoarthritis
Vitamin D3 vs Placebo for Symptomatic Knee Osteoarthritis, JAMA (2013) [PubMed abstract]
  • Design: Randomized placebo-controlled trial (N=146 | length = 2 years) in patients with symptomatic knee osteoarthritis
  • Treatment: Vitamin D3 2000 IU once daily vs Placebo. Doses were escalated to elevate serum levels to more than 36 ng/mL.
  • Primary outcomes: Knee pain severity (WOMAC pain scale, 0 - 20: 0, no pain; 20, extreme pain), and cartilage volume loss measured by MRI
  • Results:
    • Primary outcome: There were no significant differences in knee pain at any time. The percentage of cartilage volume decreased by the same extent in both groups.
  • Findings: Vitamin D supplementation for 2 years at a dose sufficient to elevate 25-hydroxyvitamin D plasma levels to higher than 36 ng/mL, when compared with placebo, did not reduce knee pain or cartilage volume loss in patients with symptomatic knee osteoarthritis.

Osteoporosis/bone health/growth
Vitamin D3 vs Placebo for Prevention of Fractures in Elderly Adults, Lancet Diabetes Endocrinol (2023) [PubMed abstract]
  • Design: Randomized placebo-controlled trial (N=20,326 | length = median 5.1 years) in adults aged 60 - 84 years living in Australia
  • Treatment: Vitamin D3 60,000 IU once monthly vs Placebo
  • Primary outcome: Any fracture
  • Results:
    • Primary outcome (total fractures): Vitamin D3 - 5.6%, Placebo - 5.9% (HR 0·94 [95% CI 0·84-1·06])
  • Findings: These findings do not support concerns that bolus doses of vitamin D administered monthly increase fracture risk. Long-term supplementation might reduce the incidence of total fractures, but additional research is needed to clarify this effect.
Vitamin D3 vs Placebo for Prevention of Fractures in Healthy Adults, NEJM (2022) [PubMed abstract]
  • Design: Ancillary study of the VITAL study, a randomized placebo-controlled trial (N=25,871 | length = median 5.3 years) in healthy men ≥ 50 years and women ≥ 55 years
  • Treatment: Vitamin D3 2000 IU/day vs Placebo
  • Primary outcome: Incident total, nonvertebral, and hip fractures
  • Results:
    • Primary outcome (incident fracture): Vitamin D3 - 5.9%, Placebo - 6.0% (p=0.70)
    • Primary outcome (nonvertebral fracture): Vitamin D3 - 5.6%, Placebo - 5.7% (p=0.50)
    • Primary outcome (hip fracture): Vitamin D3 - 0.44%, Placebo - 0.43% (p=0.96)
  • Findings: Vitamin D3 supplementation did not result in a significantly lower risk of fractures than placebo among generally healthy midlife and older adults who were not selected for vitamin D deficiency, low bone mass, or osteoporosis
Vitamin D3 vs Placebo for Bone Mineral Density in Healthy Adults, J Bone Miner Res (2020) [PubMed abstract]
  • Design: Subgroup analysis (N=771) of the VITAL study, a randomized placebo-controlled trial (N=25,871 | length = median 5.3 years) in healthy men ≥ 50 years and women ≥ 55 years
  • Treatment: Vitamin D3 2000 IU/day vs Placebo
  • Primary outcome: Two-year changes in areal (a) BMD at the spine, hip, and whole body determined by dual-energy X-ray absorptiometry (DXA)
  • Results:
    • Primary outcome: Supplemental vitamin D3 versus placebo had no effect on 2-year changes in aBMD at the spine (0.33% vs 0.17% | p=0.55), femoral neck (-0.27% vs -0.68% | p=0.16), total hip (-0.76% vs -0.95% | p=0.23), or whole body (-0.22% vs -0.15% | p=0.60)
  • Findings: Supplemental vitamin D3 versus placebo for 2 years in general healthy adults not selected for vitamin D insufficiency did not improve BMD or structure
Comparison of 3 daily doses of Vitamin D3 for BMD measurements, JAMA (2019) [PubMed abstract]
  • Design: Randomized controlled trial (N=311 | length = 3 years) in community-dwelling adults without osteoporosis
  • Treatment: Vitamin D3 400 IU vs 4000 IU vs 10000 IU once daily
  • Primary outcome: Co-primary outcomes were total volumetric BMD at radius and tibia, assessed with high resolution peripheral quantitative computed tomography, and bone strength (failure load) at radius and tibia estimated by finite element analysis
  • Results:
    • Percent decrease in radial volumetric BMD: 400 IU - 1.2%, 4000 IU - 2.4%, 10,000 IU - 3.5%
  • Findings: Among healthy adults, treatment with vitamin D for 3 years at a dose of 4000 IU per day or 10 000 IU per day, compared with 400 IU per day, resulted in statistically significant lower radial BMD; tibial BMD was significantly lower only with the 10 000 IU per day dose. There were no significant differences in bone strength at either the radius or tibia. These findings do not support a benefit of high-dose vitamin D supplementation for bone health; further research would be needed to determine whether it is harmful.
Vitamin D3 vs Placebo to Prevent Bone Loss in Elderly Black Women, J Bone Miner Res (2018) [PubMed abstract]
  • Design: Randomized placebo-controlled trial (N=260 | length = 3 years) in healthy black American women ≥ 60 years old
  • Treatment: Vitamin D3 adjusted to maintain serum 25(OH)D > 30 ng/ml vs Placebo
  • Primary outcome: Change in BMD
  • Results:
    • Primary outcome (% BMD decline): Vitamin D - 1.7%, Placebo - 2.5% (p=0.08)
  • Findings: The rate of bone loss with serum 25(OH)D above 30 ng/ml is comparable to the rate of loss with serum 25(OH)D at the Recommended Dietary Allowance (RDA) of 20 ng/ml. Black Americans should have the same exposure to vitamin D as white Americans.
Vitamin D vs Placebo for Infant Growth in Pregnancy and Lactation, NEJM (2018) [PubMed abstract]
  • Design: Randomized placebo-controlled trial (N=1164) in pregnant women who were 17 - 24 weeks gestation
  • Treatment: Vitamin D supplementation (4 different regimens) vs Placebo
  • Primary outcome: Infants' length-for-age z scores at 1 year according to WHO child growth standards
  • Results:
    • Primary outcome: Among 1164 infants assessed at 1 year of age, there were no significant differences across groups in the mean length-for-age z scores
  • Findings: In a population with widespread prenatal vitamin D deficiency and fetal and infant growth restriction, maternal vitamin D supplementation from midpregnancy until birth or until 6 months post partum did not improve fetal or infant growth.
Vitamin D3 400 IU v 1200 IU for Bone Strength and Infection Prevention in Healthy Infants, JAMA Pediatrics (2018) [PubMed abstract]
  • Design: Randomized controlled trial (N=489 | length = 24 months) in healthy term infants
  • Treatment: Vitamin D3 400 IU/day vs Vitamin D3 1200 IU/day from age 2 weeks to 24 months
  • Primary outcomes: Bone strength and incidence of parent-reported infections at 24 months
  • Results:
    • Primary outcome: There was no significant difference in bone strength measures or parent-reported infections between groups
  • Findings: A vitamin D3 supplemental dose of up to 1200 IU in infants did not lead to increased bone strength or to decreased infection incidence. Daily supplementation with 400 IU vitamin D3 seems adequate in maintaining vitamin D sufficiency in children younger than 2 years.
Vitamin D3 vs Placebo in Pregnant Women for Newborn Bone Mass, Lancet Diabetes Endo (2016) [PubMed abstract]
  • Design: Randomized placebo-controlled trial (N=569) in pregnant women at < 17 weeks gestation and with vitamin D levels of 25 - 100 nmol/L
  • Treatment: Vitamin D3 1000 IU once daily vs Placebo
  • Primary outcome: Neonatal whole-body bone mineral content, assessed within 2 weeks of birth by DXA
  • Results:
    • Primary outcome: Vitamin D - 61.6 grams, Placebo - 60.5 grams (p=0.21)
  • Findings: Supplementation of women with cholecalciferol 1000 IU/day during pregnancy did not lead to increased offspring whole-body BMC compared with placebo, but did show that 1000 IU of cholecalciferol daily is sufficient to ensure that most pregnant women are vitamin D replete, and it is safe. These findings support current approaches to vitamin D supplementation in pregnancy. Results of the ongoing MAVIDOS childhood follow-up study are awaited.
Vitamin D3 800 IU/day vs Vitamin D3 50,000 IU twice monthly vs Placebo for Musculoskeletal Health in Women (2015) [PubMed abstract]
  • Design: Randomized placebo-controlled trial (N=230 | length = 1 year) in postmenopausal women ≤ 75 years with baseline 25(OH)D levels of 14 through 27 ng/mL and no osteoporosis
  • Treatment: Vitamin D3 800 IU/day vs Vitamin D3 50,000 IU twice monthly vs Placebo
  • Primary outcomes: 1-year change in total fractional calcium absorption using 2 stable isotopes, bone mineral density and muscle mass using dual energy x-ray absorptiometry, Timed Up and Go and five sit-to-stand tests, functional status, and physical activity
  • Results:
    • Primary outcomes: Besides a slight increase in calcium absorption in the 50,000 IU group, there was no significant difference in any other outcome between groups
  • Findings: High-dose cholecalciferol therapy increased calcium absorption, but the effect was small and did not translate into beneficial effects on bone mineral density, muscle function, muscle mass, or falls. We found no data to support experts' recommendations to maintain serum 25(OH)D levels of 30 ng/mL or higher in postmenopausal women. Instead, we found that low- and high-dose cholecalciferol were equivalent to placebo in their effects on bone and muscle outcomes in this cohort of postmenopausal women with 25(OH)D levels less than 30 ng/mL.
Vitamin D3 vs Placebo for Secondary Prevention of Fracture in Elderly Patients, Lancet (2005) [PubMed abstract]
  • Design: Randomized placebo-controlled trial (N=5292 | length = 24 - 62 months) in patients ≥ 70 years who were mobile before developing a low-trauma fracture
  • Treatment: Vitamin D3 800 IU/day vs Calcium 1000 mg/day vs Calcium + Vitamin D3 vs Placebo
  • Primary outcome: New low-energy fractures
  • Results:
    • Primary outcome: Vitamin D3 - 15.8%, Calcium - 14.4%, Vitamin D + Calcium - 14.1%, Placebo - 14.7% (all comparisons nonsignificant)
  • Findings: The findings do not support routine oral supplementation with calcium and vitamin D3, either alone or in combination, for the prevention of further fractures in previously mobile elderly people

Overall health/Physical fitness
Vitamin D, Fish oil, and Exercise for a Variety of Health Outcomes in Elderly Patients, JAMA (2020) [PubMed abstract]
  • Design: Randomized, 2 X 2 X 2 factorial, placebo-controlled trial (N=2157 | length = 3 years) in adults ≥ 70 years old with no major health events in the last 5 years
  • Treatment: Patients were randomly assigned to Vitamin D3 2000 IU/day vs Placebo, Fish oil 1 gram/day vs Placebo, and Strength-training exercise program vs None
  • Primary outcome: The 6 primary outcomes were change in systolic and diastolic blood pressure, Short Physical Performance Battery, Montreal Cognitive Assessment, and incidence rates of nonvertebral fractures and infections over 3 years.
  • Results:
    • Primary outcome: Overall, there were no statistically significant benefits of any intervention individually or in combination for the 6 end points at 3 years
  • Findings: Among adults without major comorbidities aged 70 years or older, treatment with vitamin D3, omega-3s, or a strength-training exercise program did not result in statistically significant differences in improvement in systolic or diastolic blood pressure, nonvertebral fractures, physical performance, infection rates, or cognitive function. These findings do not support the effectiveness of these 3 interventions for these clinical outcomes.
Vitamin D3 vs Placebo for Physical Fitness in Healthy Elderly Black Women, J Clin Endocrinol Metab (2019) [PubMed abstract]
  • Design: Randomized placebo-controlled trial (N=260 | length = 3 years) in healthy elderly black women with vitamin D levels between 20 - 65 nmol/L
  • Treatment: Vitamin D3 with dose adjusted to maintain serum 25(OH)D > 75 nmol/L vs Placebo
  • Primary outcome: Prevention of decline in physical performance measures
  • Results:
    • There were no substantial differences between the placebo and active vitamin D3 groups with respect to the temporal patterns observed for any of the performance measures
  • Findings: There is no benefit of maintaining serum 25(OH)D > 75 nmol/L in preventing the decline in physical performance in healthy black American women