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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 Deficiency in Children and Its Management: Review of Current Knowledge and Recommendations

Author/s: 
Misra, M., Pacaud, D., Petryk, A., Collett-Solberg, P. F., Kappy, M.

Given the recent spate of reports of vitamin D deficiency, there is a need to
reexamine our understanding of natural and other sources of vitamin D, as well as
mechanisms whereby vitamin D synthesis and intake can be optimized. This state-of-the-art report from the Drug and Therapeutics Committee of the Lawson Wilkins
Pediatric Endocrine Society was aimed to perform this task and also reviews recommendations for sun exposure and vitamin D intake and possible caveats associated
with these recommendations. Pediatrics 2008;122:398–417

The effect of high-dose vitamin D supplementation on serum vitamin D levels and milk calcium concentration in lactating women and their infants

Author/s: 
Basile, L. A., Taylor, S. N., Wagner, C. L., Horst, R. L., Hollis, B. W.

Objective: Improve vitamin D status in lactating women and their recipient infants, and measure breast milk calcium concentration [Ca] as a function of vitamin D regimen.

Design/methods: Fully breastfeeding mothers were randomized at 1 month postpartum to 2000 (n = 12) or 4000 (n = 13) IU/day vitamin D for 3 months to achieve optimal vitamin D status [serum 25(OH)D > or =32 ng/mL (80 nmol/L)]. Breast milk [Ca], maternal and infant serum 25(OH)D and serum Ca, and maternal urinary Ca/Cr ratio were measured monthly.

Results: Mothers were similar between groups for age, race, gestation, and birth weight. 25(OH)D increased from 1 to 4 months in both groups (mean +/- SD): +11.5 +/- 2.3 ng/mL for group 2000 (p = 0.002) and +14.4 +/- 3.0 ng/mL for group 4000 (p = 0.0008). The 4000 IU/day regimen was more effective in raising both maternal and infant serum levels and breast milk antirachitic activity than the 2000 IU/day regimen. Breast milk [Ca] fell with continued lactation through 4 months in the 2000 and 4000 IU groups. Decline in breast milk [Ca] was not associated with vitamin D dose (p = 0.73) or maternal 25(OH)D (p = 0.94). No mother or infant experienced vitamin D-related adverse events, and all laboratory parameters remained in the normal range.

Conclusion: High-dose vitamin D was effective in increasing 25(OH)D levels in fully breastfeeding mothers to optimal levels without evidence of toxicity. Breast milk [Ca] and its decline in both groups during 1 to 4 months were independent of maternal vitamin D status and regimen. Both the mother and her infant attained improved vitamin D status and maintained normal [Ca].

A predictive equation to guide vitamin D replacement dose in patients

Author/s: 
Singh, G., Bonham, A. J.

Background: Vitamin D is essential for bone health and probably the health of most nonskeletal tissues. Vitamin D deficiency is widespread, and recommended doses are usually inadequate to maintain healthy levels. We conducted a retrospective observational study to determine whether the recommended doses of vitamin D are adequate to correct deficiency and maintain normal levels in a population seeking health care. We also sought to develop a predictive equation for replacement doses of vitamin D.

Methods: We reviewed the response to vitamin D supplementation in 1327 patients and 3885 episodes of vitamin D replacement and attempted to discern factors affecting the response to vitamin D replacement by conducting multiple regression analyses.

Results: For the whole population, average daily dose resulting in any increase in serum 25-hydroxyvitamin D level was 4707 IU/day; corresponding values for ambulatory and nursing home patients were 4229 and 6103 IU/day, respectively. Significant factors affecting the change in serum concentrations of 25-hydroxyvitamin D, in addition to the dose administered, are (1) starting serum concentration of 25-hydroxyvitamin D, (2) body mass index (BMI), (3) age, and (f) serum albumin concentration. The following equation predicts the dose of vitamin D needed (in international units per day) to affect a given change in serum concentrations of 25-hydroxyvitamin D: Dose = [(8.52 - Desired change in serum 25-hydroxyvitamin D level) + (0.074 × Age) - (0.20 × BMI) + (1.74 × Albumin concentration) - (0.62 × Starting serum 25-hydroxyvitamin D concentration)]/(-0.002). Analysis of the dose responses among 3 racial groups-white, black, and others-did not reveal clinically meaningful differences between the races. The main limitation of the study is its retrospective observational nature; however, that is also its strength in that we assessed the circumstances seen in usual health care setting.

Conclusions: The recommended daily allowance for vitamin D is grossly inadequate for correcting low serum concentrations of 25-hydroxyvitamin D in many adult patients. About 5000 IU vitamin D3/day is usually needed to correct deficiency, and the maintenance dose should be ≥2000 IU/day. The required dose may be calculated from the predictive equations specific for ambulatory and nursing home patients.

Effect of Vitamin D3 Supplements on Development of Advanced Cancer: A Secondary Analysis of the VITAL Randomized Clinical Trial

Author/s: 
Chandler, P.D., Chen, W.Y., Ojala, O.N.

Importance  Epidemiologic and trial data suggest that vitamin D supplementation may reduce metastatic cancer and cancer mortality, reflecting shared biological pathways.

Objective  To follow up on the possible reduction in cancer death in the Vitamin D and Omega-3 Trial (VITAL) with an evaluation of whether vitamin D reduces the incidence of advanced (metastatic or fatal) cancer and an examination possible effect modification by body mass index.

Design, Setting, and Participants  VITAL is a randomized, double-blind, placebo-controlled, 2 × 2 factorial clinical trial of vitamin D3 (cholecalciferol, 2000 IU/d) and marine omega-3 fatty acids (1 g/d). This multicenter clinical trial was conducted in the United States; participants included men aged 50 years or older and women aged 55 years or older who were free of cancer and cardiovascular disease at baseline. Randomization took place from November 2011 through March 2014, and study medication ended on December 31, 2017. Data for this secondary analysis were analyzed from November 1, 2011, to December 31, 2017.

Interventions  Vitamin D3 (cholecalciferol, 2000 IU/d) and marine omega-3 fatty acids (1 g/d) supplements.

Main Outcomes and Measures  For the present analysis, the primary outcome was a composite incidence of metastatic and fatal invasive total cancer, because the main VITAL study showed a possible reduction in fatal cancer with vitamin D supplementation and effect modification by body mass index (BMI; calculated as weight in kilograms divided by height in meters squared) for total cancer incidence reduction for individuals with normal BMI, but not for individuals with overweight or obesity. Secondary analyses included examination of BMI (<25, 25 to < 30, and ≥30) as effect modifiers of the observed associations.

Results  Among 25 871 randomized VITAL participants (51% female; mean [SD] age, 67.1 [7.1] years), 1617 were diagnosed with invasive cancer over a median intervention period of 5.3 years (range, 3.8-6.1 years). As previously reported, no significant differences for cancer incidence by treatment arm were observed. However, a significant reduction in advanced cancers (metastatic or fatal) was found for those randomized to vitamin D compared with placebo (226 of 12 927 assigned to vitamin D [1.7%] and 274 of 12 944 assigned to placebo [2.1%]; HR, 0.83 [95% CI, 0.69-0.99]; P = .04). When stratified by BMI, there was a significant reduction for the vitamin D arm in incident metastatic or fatal cancer among those with normal BMI (BMI<25: HR, 0.62 [95% CI, 0.45-0.86]) but not among those with overweight or obesity (BMI 25-<30: HR, 0.89 [95% CI, 0.68-1.17]; BMI≥30: HR, 1.05 [95% CI, 0.74-1.49]) (P = .03 for interaction by BMI).

Conclusions and Relevance  In this randomized clinical trial, supplementation with vitamin D reduced the incidence of advanced (metastatic or fatal) cancer in the overall cohort, with the strongest risk reduction seen in individuals with normal weight.

Trial Registration  ClinicalTrials.gov Identifier: NCT01169259

Pharmacologic and Nonpharmacologic Therapies in Adult Patients With Exacerbation of COPD: A Systematic Review

Author/s: 
Dobler, CC, Morrow, AS, Farah, MH, Beuschel, B, Majzoub, AM, Wilson, ME, Hasan, B, Seisa, MO, Daraz, L, Prokop, LJ, Murad, MH, Wang, Z

Objectives. To synthesize existing knowledge about the effectiveness and harms of pharmacologic and nonpharmacologic treatments for exacerbations of chronic obstructive pulmonary disease (ECOPD).

Data sources. Embase®, Epub Ahead of Print, In-Process & Other Non-Indexed Citations, MEDLINE® Daily, MEDLINE, Cochrane Central Registrar of Controlled Trials, Ovid Cochrane Database of Systematic Reviews, and Scopus from database inception to January 2, 2019.

Review methods. We included randomized controlled trials (RCTs) that evaluated pharmacologic intervention or nonpharmacologic interventions for ECOPD. The strength of evidence (SOE) was graded for critical final health outcomes.

Results. We included 98 RCTs (13,401 patients, mean treatment duration 9.9 days, mean followup 3.7 months). Final health outcomes, including mortality, resolution of exacerbation, hospital readmissions, repeat exacerbations, and need for intubation, were infrequently evaluated and often showed no statistically significant differences between groups. Antibiotic therapy increases the clinical cure rate and reduces the clinical failure rate regardless of the severity of ECOPD (moderate SOE). There is insufficient evidence to support a particular antibiotic regimen. Oral and intravenous corticosteroids improve dyspnea and reduce the clinical failure rate (low SOE). Despite the ubiquitous use of inhaled bronchodilators in ECOPD, we found only a small number of trials that assessed lung function tests, and not final health outcomes. The evidence is insufficient to support the effect of aminophyllines, magnesium sulfate, mucolytics, inhaled corticosteroids, inhaled antibiotics, 5-lipoxygenase inhibitor, and statins on final health outcomes. Titrated oxygen reduces mortality compared with high flow oxygen (low SOE). Low SOE suggested benefit from some nonpharmacologic interventions such as chest physiotherapy using vibration/percussion/massage or breathing technique (on dyspnea), resistance training (on dyspnea and quality of life), early pulmonary rehabilitation commenced before hospital discharge during the initial most acute phase of exacerbation rather than the convalescence period (on dyspnea) and whole body vibration training (on quality of life). Vitamin D supplementation may improve quality of life (low SOE).

Conclusions. Although chronic obstructive pulmonary disease is a common condition, the evidence base for most interventions in ECOPD remains limited. Systemic antibiotics and corticosteroids are associated with improved outcomes in mild and moderate to severe ECOPD. Titrated oxygen reduces mortality. Future research is required to assess the effectiveness of several emerging nonpharmacologic and dietary treatments.

Keywords 
copd chronic obstructive pulmonary disease therapy randomized control trial systematic review

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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