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Vitamin D for Prevention of Disease

Author/s: 
Eva S Liu, Andrew M Davis, Sherri-Ann M Burnett-Bowie

Vitamin D regulates bone homeostasis,1 and epidemiologic studies suggest that lower vitamin D levels may be associated with increased risk of RTIs, cardiovascular disease, malignancy, and metabolic disorders.2,3 Increased awareness of possible health benefits associated with higher 25(OH)D levels has resulted in widespread vitamin D testing and supplementation in the general US population. Nonetheless, there is no consensus on a threshold value below which people should be offered vitamin D supplementation.3,4 In 2021, the US Preventive Services Task Force reported that there was insufficient evidence to recommend routine screening of asymptomatic adults for vitamin D deficiency.4 Rates of marked vitamin D deficiency (25[OH]D ≤12 ng/mL) vary by race and ethnicity, with higher rates in non-Hispanic Asian (8%), non-Hispanic Black (18%), and Hispanic (6%) people compared with non-Hispanic White people (2%).3

Keywords 
guideline nutrition vitamin D Disease Prevention

The Women’s Health Initiative Randomized Trials and Clinical Practice

Author/s: 
Manson, J.E., Crandall, C.J., Rossouw, J.E.

Importance: Approximately 55 million people in the US and approximately 1.1 billion people worldwide are postmenopausal women. To inform clinical practice about the health effects of menopausal hormone therapy, calcium plus vitamin D supplementation, and a low-fat dietary pattern, the Women's Health Initiative (WHI) enrolled 161 808 postmenopausal US women (N = 68 132 in the clinical trials) aged 50 to 79 years at baseline from 1993 to 1998, and followed them up for up to 20 years.

Observations: The WHI clinical trial results do not support hormone therapy with oral conjugated equine estrogens plus medroxyprogesterone acetate for postmenopausal women or conjugated equine estrogens alone for those with prior hysterectomy to prevent cardiovascular disease, dementia, or other chronic diseases. However, hormone therapy is effective for treating moderate to severe vasomotor and other menopausal symptoms. These benefits of hormone therapy in early menopause, combined with lower rates of adverse effects of hormone therapy in early compared with later menopause, support initiation of hormone therapy before age 60 years for women without contraindications to hormone therapy who have bothersome menopausal symptoms. The WHI results do not support routinely recommending calcium plus vitamin D supplementation for fracture prevention in all postmenopausal women. However, calcium and vitamin D are appropriate for women who do not meet national guidelines for recommended intakes of these nutrients through diet. A low-fat dietary pattern with increased fruit, vegetable, and grain consumption did not prevent the primary outcomes of breast or colorectal cancer but was associated with lower rates of the secondary outcome of breast cancer mortality during long-term follow-up.

Conclusions and relevance: For postmenopausal women, the WHI randomized clinical trials do not support menopausal hormone therapy to prevent cardiovascular disease or other chronic diseases. Menopausal hormone therapy is appropriate to treat bothersome vasomotor symptoms among women in early menopause, without contraindications, who are interested in taking hormone therapy. The WHI evidence does not support routine supplementation with calcium plus vitamin D for menopausal women to prevent fractures or a low-fat diet with increased fruits, vegetables, and grains to prevent breast or colorectal cancer. A potential role of a low-fat dietary pattern in reducing breast cancer mortality, a secondary outcome, warrants further study.

Keywords 
vitamin D calcium menopause Menopausal women Women's Health

Reduce unnecessary routine vitamin D testing

Author/s: 
Singer, Alexander G., McChesney, Christopher

Laura is a 40-year-old engineer of eastern European ancestry who presents to your office to request testing of her vitamin D levels. She generally wears sunscreen in the summer and wears sun-protective clothing year round. She is fairly healthy, eating a balanced diet high in fresh fruits and vegetables, but experiences migraines for which she takes triptans for rescue about 4 times per year. She and her partner own a house in a middle-class neighbourhood where they live with their son. Laura informs you that her mother has been taking vitamin D supplements for many years based on her doctor’s recommendations to improve her bone health. Additionally, Laura tells you that her neighbour, a nurse about her age, recently had her vitamin D levels checked and they were “very low,” so she has considered starting vitamin D supplementation.

Laura is hoping that by testing her vitamin D levels she will know how much supplementation she needs to take to protect her from COVID-19, cancer, and fractures as she gets older. Laura is worried that her levels might be low because she avoids direct sunlight and is concerned that she may be missing an easy opportunity to improve her health with supplementation she can afford.

Keywords 
vitamin D vitamins

Vitamin D supplementation to prevent acute respiratory tract infections: systematic review and meta-analysis of individual participant data

Author/s: 
Martineau, AR, Jolliffe, DA, Hooper, RL, Greenberg, L, Aloia, JF, Bergman, P, Dubnov-Raz, G, Esposito, S, Ganmaa, D, Ginde, AA, Goodall, EC, Grant, CC, Griffiths, CJ, Janssens, W, Laaksi, I, Manaseki-Holland S, Mauger D, Murdoch DR, Neale R, Rees JR, Simpson S Jr, Stelmach, I, Kumar, GT, Urashima, M", CA Jr

Objectives To assess the overall effect of vitamin D supplementation on risk of acute respiratory tract infection, and to identify factors modifying this effect.

Design Systematic review and meta-analysis of individual participant data (IPD) from randomised controlled trials.

Data sources Medline, Embase, the Cochrane Central Register of Controlled Trials, Web of Science, ClinicalTrials.gov, and the International Standard Randomised Controlled Trials Number registry from inception to December 2015.

Eligibility criteria for study selection Randomised, double blind, placebo controlled trials of supplementation with vitamin D3 or vitamin D2 of any duration were eligible for inclusion if they had been approved by a research ethics committee and if data on incidence of acute respiratory tract infection were collected prospectively and prespecified as an efficacy outcome.

Results 25 eligible randomised controlled trials (total 11 321 participants, aged 0 to 95 years) were identified. IPD were obtained for 10 933 (96.6%) participants. Vitamin D supplementation reduced the risk of acute respiratory tract infection among all participants (adjusted odds ratio 0.88, 95% confidence interval 0.81 to 0.96; P for heterogeneity <0.001). In subgroup analysis, protective effects were seen in those receiving daily or weekly vitamin D without additional bolus doses (adjusted odds ratio 0.81, 0.72 to 0.91) but not in those receiving one or more bolus doses (adjusted odds ratio 0.97, 0.86 to 1.10; P for interaction=0.05). Among those receiving daily or weekly vitamin D, protective effects were stronger in those with baseline 25-hydroxyvitamin D levels <25 nmol/L (adjusted odds ratio 0.30, 0.17 to 0.53) than in those with baseline 25-hydroxyvitamin D levels ≥25 nmol/L (adjusted odds ratio 0.75, 0.60 to 0.95; P for interaction=0.006). Vitamin D did not influence the proportion of participants experiencing at least one serious adverse event (adjusted odds ratio 0.98, 0.80 to 1.20, P=0.83). The body of evidence contributing to these analyses was assessed as being of high quality.

Conclusions Vitamin D supplementation was safe and it protected against acute respiratory tract infection overall. Patients who were very vitamin D deficient and those not receiving bolus doses experienced the most benefit.

Systematic review registration PROSPERO CRD42014013953.

Keywords 
vitamin D respiratory tract infections dietary supplements

Association between vitamin D supplementation and mortality: systematic review and meta-analysis

Author/s: 
Zhang, Y., Fang, F., Tang, J., Jia, L., Feng, Y., Xu, P., Faramand, A.

Abstract

OBJECTIVE:

To investigate whether vitamin D supplementation is associated with lower mortality in adults.

DESIGN:

Systematic review and meta-analysis of randomised controlled trials.

DATA SOURCES:

Medline, Embase, and the Cochrane Central Register from their inception to 26 December 2018.

ELIGIBILITY CRITERIA FOR SELECTING STUDIES:

Randomised controlled trials comparing vitamin D supplementation with a placebo or no treatment for mortality were included. Independent data extraction was conducted and study quality assessed. A meta-analysis was carried out by using fixed effects and random effects models to calculate risk ratio of death in the group receiving vitamin D supplementation and the control group.

MAIN OUTCOME MEASURES:

All cause mortality.

RESULTS:

52 trials with a total of 75 454 participants were identified. Vitamin D supplementation was not associated with all cause mortality (risk ratio 0.98, 95% confidence interval 0.95 to 1.02, I2=0%), cardiovascular mortality (0.98, 0.88 to 1.08, 0%), or non-cancer, non-cardiovascular mortality (1.05, 0.93 to 1.18, 0%). Vitamin D supplementation statistically significantly reduced the risk of cancer death (0.84, 0.74 to 0.95, 0%). In subgroup analyses, all cause mortality was significantly lower in trials with vitamin D3 supplementation than in trials with vitamin D2 supplementation (P for interaction=0.04); neither vitamin D3 nor vitamin D2 was associated with a statistically significant reduction in all cause mortality.

CONCLUSIONS:

Vitamin D supplementation alone was not associated with all cause mortality in adults compared with placebo or no treatment. Vitamin D supplementation reduced the risk of cancer death by 16%. Additional large clinical studies are needed to determine whether vitamin D3 supplementation is associated with lower all cause mortality.

STUDY REGISTRATION:

PROSPERO registration number CRD42018117823.

Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.

Keywords 
cancer cancer mortality vitamin D Vitamin D3 supplimentation

Vitamin D and diabetic foot ulcer: a systematic review and meta-analysis

Author/s: 
Dai, Jiezhi, Jiang, Chaoyin, Chen, Hua, Chai, Yimin

We aimed to evaluate the association between vitamin D deficiency and diabetic foot ulcer (DFU) in patients with diabetes. Pubmed, EMBASE, BIOSIS, the Cochrane Library, and Web of Knowledge, last updated in July 2018, were searched. We assessed eligible studies for the association between vitamin D deficiency and DFU in diabetic patients. The mean difference (MD) or the odds ratio (OR) was calculated for continuous or dichotomous data respectively. Data were analyzed by using the Cochrane Collaboration’s RevMan 5.0 software. Seven studies that involved 1115 patients were included in this study. There were significantly reduced vitamin D levels in DFU (MD −13.47 nmol/L, 95%CI −16.84 to −10.10; P  =  0.34, I2 = 12%). Severe vitamin D deficiency was significantly associated with an increased risk of DFU (OR 3.22, 95%CI 2.42−4.28; P  = 0.64, I2 = 0%). This is the first meta-analysis demonstrating the association between serum vitamin D levels and DFU. Severe vitamin D deficiency is significantly associated with an increased risk of DFU.

Keywords 
diabetes complications risk factors diabetes vitamin D

Vitamin D supplementation to prevent acute respiratory infections: individual participant data meta-analysis.

Author/s: 
Martineau, Adrian R., Jolliffe, David A., Greenberg, Lauren, Aloia, John F., Bergman, Peter, Dubnov-Rax, Gal, Esposito, Susanna, Ganmaa, Davaasambuu, Ginde, Adit A., Goodall, Emma C., Grant, Cameron C., Janssens, Wim, Jensen, Megan E., Kerley, Conor P., Laaksi, Ilkka, Manaseki-Holland, Semira, Mauger, David, Murdoch, David R., Neale, Rachel, Rees, Judy R., Simpson, Steve Jr., Stelmach, Iwona, Kumar, Geeta Trilok, Mitsuyoshi, Urashima, Camargo, Carlos A. Jr., Griffiths, Christopher J., Hooper, Richard L.

BACKGROUND:

Randomised controlled trials (RCTs) exploring the potential of vitamin D to prevent acuterespiratory infections have yielded mixed results. Individual participant data (IPD) meta-analysis has the potential to identify factors that may explain this heterogeneity.

OBJECTIVES:

To assess the overall effect of vitamin D supplementation on the risk of acute respiratory infections (ARIs) and to identify factors modifying this effect.

DATA SOURCES:

MEDLINE, EMBASE, the Cochrane Central Register of Controlled Trials (CENTRAL), Web of Science, ClinicalTrials.gov and the International Standard Randomised Controlled Trials Number (ISRCTN) registry.

STUDY SELECTION:

Randomised, double-blind, placebo-controlled trials of supplementation with vitamin D3 or vitamin D2 of any duration having incidence of acute respiratory infection as a prespecified efficacy outcome were selected.

STUDY APPRAISAL:

Study quality was assessed using the Cochrane Collaboration Risk of Bias tool to assess sequence generation, allocation concealment, blinding of participants, personnel and outcome assessors, completeness of outcome data, evidence of selective outcome reporting and other potential threats to validity.

RESULTS:

We identified 25 eligible RCTs (a total of 11,321 participants, aged from 0 to 95 years). IPD were obtained for 10,933 out of 11,321 (96.6%) participants. Vitamin D supplementation reduced the risk of ARI among all participants [adjusted odds ratio (aOR) 0.88, 95% confidence interval (CI) 0.81 to 0.96; heterogeneity p < 0.001]. Subgroup analysis revealed that protective effects were seen in individuals receiving daily or weekly vitamin D without additional bolus doses (aOR 0.81, 95% CI 0.72 to 0.91), but not in those receiving one or more bolus doses (aOR 0.97, 95% CI 0.86 to 1.10; p = 0.05). Among those receiving daily or weekly vitamin D, protective effects of vitamin D were stronger in individuals with a baseline 25-hydroxyvitamin D [25(OH)D] concentration of < 25 nmol/l (aOR 0.30, 95% CI 0.17 to 0.53) than in those with a baseline 25(OH)D concentration of ≥ 25 nmol/l (aOR 0.75, 95% CI 0.60 to 0.95; p = 0.006). Vitamin D did not influence the proportion of participants experiencing at least one serious adverse event (aOR 0.98, 95% CI 0.80 to 1.20; p = 0.83). The body of evidence contributing to these analyses was assessed as being of high quality.

LIMITATIONS:

Our study had limited power to detect the effects of vitamin D supplementation on the risk of upper versus lower respiratory infection, analysed separately.

CONCLUSIONS:

Vitamin D supplementation was safe, and it protected against ARIs overall. Very deficient individuals and those not receiving bolus doses experienced the benefit. Incorporation of additional IPD from ongoing trials in the field has the potential to increase statistical power for analyses of secondary outcomes.

Keywords 
vitamin D dietary supplements respiratory infections

Vitamin D to prevent exacerbations of COPD: systematic review and meta-analysis of individual participant data from randomised controlled trials

Author/s: 
Jolliffe, David. A, Greenberg, Lauren, Hooper, Richard L., Mathyssen, Carolien, Rafiq, Rachida, de Jongh, Renate T., Camargo, Carlos A., Griffiths, Christopher J., Janssens, Wim, Martineau, Adrian R.

BACKGROUND:

Randomised controlled trials (RCTs) of vitamin D to prevent COPDexacerbations have yielded conflicting results.Individual participant data meta-analysis could identify factors that explain this variation.

METHODS:

PubMed, Embase, the Cochrane Central Register of Controlled Trials and Web of Science were searched from inception up to and including 5 October 2017 to identify RCTs of vitamin D supplementation in patients with COPD that reported incidence of acute exacerbations. Individual participant data meta-analysis was performed using fixed effects models adjusting for age, sex, Global Initiative for Chronic Obstructive Lung Disease spirometric grade and trial.

RESULTS:

Four eligible RCTs (total 560 participants) were identified; individual participant datawere obtained for 469/472 (99.4%) participants in three RCTs. Supplementation did not influence overall rate of moderate/severe COPD exacerbations (adjusted incidence rate ratio (aIRR) 0.94, 95% CI 0.78 to 1.13). Prespecified subgroup analysis revealed that protective effects were seen in participants with baseline 25-hydroxyvitamin D levels <25 nmol/L (aIRR 0.55, 95% CI 0.36 to 0.84) but not in those with baseline 25-hydroxyvitamin D levels ≥25 nmol/L (aIRR 1.04, 95% CI 0.85 to 1.27; p for interaction=0.015). Vitamin D did not influence the proportion of participants experiencing at least one serious adverse event (adjusted OR 1.16, 95% CI 0.76 to 1.75).

CONCLUSIONS:

Vitamin D supplementation safely and substantially reduced the rate of moderate/severe COPD exacerbations in patients with baseline 25-hydroxyvitamin D levels <25 nmol/L but not in those with higher levels.

TRIAL REGISTRATION NUMBER:

CRD42014013953.

Keywords 
chronic obstructive pulmonary disease vitamin D
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