NMA: Nonprescription Medicines Academy

Vitamin D Roundup

January 28th, 2013

The past few months have seen a flurry of articles describing possible consequences of low serum 25-hydroxyvitamin D3 (25[OH] vitamin D) levels and possible benefits of vitamin D supplementation. Findings from 11 of these articles are summarized below.

1. Low Levels of Vitamin D Associated With Increased Cardiovascular Disease Risk
A meta-analysis of 19 prospective studies published from 1966 through February 2012 found a generally linear, inverse association between cardiovascular disease (CVD) risk and circulating 25(OH) vitamin D concentrations ranging from 20 to 60 nmol/L.

The primary analysis included a total of 6,123 CVD cases from 65,994 participants. In a comparison of the lowest with the highest 25(OH) vitamin D categories, the pooled relative risk was 1.52 (95% CI, 1.30–1.77) for total CVD, 1.42 (95% CI, 1.19–1.71) for CVD mortality, 1.38 (95% CI, 1.21–1.57) for coronary heart disease, and 1.64 (95% CI, 1.27–2.10) for stroke. These associations remained strong and significant when analyses were limited to studies that excluded participants with baseline CVD and were better controlled for season and confounding.

The dose–response curve between 25(OH) vitamin D and CVD risk indicated that the association was generally linear across the range of concentrations from 20 to 60 nmol/L, with a relative risk of 1.03 (95% CI, 1.00–1.06) per 25-nmol/L decrement in 25(OH) vitamin D.

Circ Cardiovasc Qual Outcomes. 2012;5:819-29. Epub 2012 Nov 13.

2. Low Levels of Vitamin D Associated With Increased Risk of Ischemic Heart Disease, Myocardial Infarction, and Early Death
The highest powered general population study to date found stepwise increases in risk of ischemic heart disease, myocardial infarction, and early death with stepwise decreasing plasma 25(OH) vitamin D levels.

The Copenhagen City Heart Study is a prospective study of the general population of Copenhagen, Denmark, initiated in 1976–1978 with follow-up examinations in 1981–1983, 1991–1994, and 2001–2003. The current analysis included data for 10,170 women and men. Baseline plasma 25(OH) vitamin D levels were measured in 1981–1983; during the subsequent 29 years of follow-up, 3,100 participants developed ischemic heart disease, 1,625 developed myocardial infarction, and 6747 died.

Decreasing plasma 25(OH) vitamin D concentrations were associated with increasing risk of ischemic heart disease, myocardial infarction, and early death as a function of seasonally adjusted percentile categories [P for trend, 2×10(−4)−3×10(−53)]. When participants with plasma 25(OH) vitamin D levels at the 1st to 4th percentile (<5 nmol/L) were compared with participants at the 50th to 100th percentile (>50 nmol/L), the multivariable adjusted risk was increased by 40% (95% CI, 14%–72%) for ischemic heart disease, by 64% (25%–114%) for myocardial infarction, by 57% (38%–78%) for early death, and by 81% (40%–135%) for fatal ischemic heart disease/myocardial infarction.

The authors also conducted a meta-analysis of 18 general population studies published through January 2012, representing 82,982 participants and 8,376 ischemic heart disease events. Compared with participants in the highest quartile of plasma 25(OH) vitamin D levels, participants in the lowest quartile had a 39% increased risk of ischemic heart disease (95% CI, 25%–54%) in a random effects model and a 33% increased risk (95% CI, 28%–38%) in a fixed effect model. In a separate meta-analysis of 17 general population studies with a total of 77,155 participants and 15,447 deaths, the corresponding risk of early death was increased by 46% (31%–64%, random effect) and by 35% (30%–42%, fixed effect).

Arterioscler Thromb Vasc Biol. 2012;32:2794-802. Epub 2012 Aug 30.

3. Low Levels of Vitamin D May Increase Risk of Insulin-Requiring Diabetes
In a nested case-control study using serum collected from U.S. military service members, individuals with lower serum 25(OH) vitamin D concentrations had a greater risk of insulin-requiring diabetes than those with higher concentrations.

The study population encompassed 1,000 consecutive new cases of insulin-requiring diabetes and1,000 healthy controls matched to each case on blood-draw date (± 2 days), age (± 3 months), length of service (± 30 days), and sex. The median elapsed time between serum collection and first diagnosis of diabetes was 1 year (range, 1 month to 10 years).

The risk of insulin-requiring diabetes was 3.5 times higher in individuals with the lowest serum 25(OH) vitamin D concentrations compared to those with the highest. Odds ratios for insulin-requiring diabetes by quintile of serum 25(OH) vitamin D, from lowest to highest, were 3.5 (95% CI, 2.0–6.0), 2.5 (1.5–4.2), 0.8 (0.4–1.4), 1.1 (0.6–2.8) and 1.0 (reference) (ptrend <0.001). The quintiles—based on fifths using serum 25(OH) vitamin D concentration in the controls—were <43 nmol/L (median 28 nmol/L), 43–59 nmol/L (median 52), 60–77 nmol/L (median 70), 78–99 nmol/L (median 88), and ≥100 nmol/L (median 128).

Diabetologia. 2012;55:3224-7. Epub 2012 Sep 7.

4. Low Levels of Vitamin D Linked to Alzheimer’s Disease
The results of a systematic review and meta-analysis designed to examine the association between serum 25(OH) vitamin D concentrations and cognitive function and dementia in adults suggest that lower serum 25(OH) vitamin D concentrations are associated with poorer cognitive function and a higher risk of Alzheimer’s disease.

The systematic review encompassed English-language studies with a comparative group published through August 2010. A total of 37 studies met the inclusion criteria. Sufficient data were available to conduct two meta-analyses. The first compared the mean serum 25(OH) vitamin D concentration between an Alzheimer’s disease group and a control group. Individuals with Alzheimer’s disease had lower serum 25(OH) vitamin D concentrations compared to those without Alzheimer’s disease; the mean difference was −15.0 nmol/L (95% CI, −26.2 to −3.9 nmol/L). The second meta-analysis compared mean Mini-Mental State Examination (MMSE) scores for participants with serum 25(OH) vitamin D concentrations <50 nmol/L to scores for participants with values ≥50 nmol/L. MMSE scores were lower in individuals with lower serum 25(OH) vitamin D concentrations; the mean difference in was 1.2 (95% CI, 0.5–1.9), but there was statistically significant heterogeneity.

The authors concluded that these results provide sufficient evidence to warrant further investigation of a possible cause and effect relationship between vitamin D and cognitive impairment.

Neurology. 2012;79:1397-405.

5. Low Levels of Vitamin D Associated With Non-Migraine Headache
Data from the sixth survey of the Tromsø Study (Tromsø 6) conducted in Norway in 2007–2008 show an association between low serum 25(OH) vitamin D concentrations and non-migraine headache. No association was found between serum 25(OH) vitamin D and migraine.

The Tromsø Study is an epidemiologic, prospective study of health problems and chronic diseases. The current analysis is based on data from questionnaires returned by 11,614 participants. The data were stratified according to smoking status and analyzed with regard to migraine and non-migraine headache. Adjustments were done for age, body mass index (BMI), gender, season, chronic diseases, education, physical exercise, and alcohol consumption.

Non-migraine headache was associated with low serum 25(OH) vitamin D concentrations, with an odds ratio of 1.31 (95% CI, 1.14–1.49; P <0.005) in the lowest quartile vs the highest quartile. The association remained statistically significant after adjusting for possible confounders (odds ratio 1.20; 95% CI, 1.04–1.39; P <0.05). Nonetheless, the authors cautioned that this finding may still reflect lifestyle rather than causality, and further studies are needed.

Headache. 2012;52:1499-1505. Epub 2012 Sep 13.

6. Low Levels of Vitamin D Prevalent in Overweight and Obese Children
Data from the 2003-2006 National Health and Nutrition Examination Survey (NHANES) suggest that vitamin D deficiency is highly prevalent in overweight and obese children.

The study sample included 12,292 children 6 to 18 years of age. As part of the NHANES data collection, serum 25(OH) vitamin D levels were measured in venous blood samples drawn in mobile examination centers according to standardized protocols; body height and weight were measured directly. Vitamin D deficiency was defined as a serum 25(OH) vitamin D concentration <20 ng/mL. Children were classified as healthy weight, overweight, obese, or severely obese by using recommended age-specific and gender-specific body mass index (BMI)-percentile cut points. Associations between BMI-percentile classification and vitamin D deficiency were examined after adjustment for relevant confounders.

The prevalence of vitamin D deficiency was 21% (95% CI, 20%–22%) in healthy weight children, 29% (27%–31%) in overweight children, 34% (32%–36%) in obese children, and 49% (45%–53%) in severely obese children. The prevalence of vitamin D deficiency in severely obese white, Latino, and African-American children was 27% (3%–51%), 52% (36%–68%), and 87% (81%–93%), respectively. Overweight, obese, and severely obese children had significantly greater adjusted odds of vitamin D deficiency, compared with healthy weight children.

Modifiable, independent risk factors for vitamin D deficiency were identified among both overweight and obese/severely obese children. Possible interventions suggested by the authors include drinking at least 2 to 3 cups per day of vitamin D-fortified milk, restricting TV/computer use to ≤2 hours per day, and being physically active ≥2 hours per week.

Pediatrics. 2013;131:e152 -61. Epub 2012 Dec 24.

7. Lower Levels of Vitamin D Associated With Longevity
Among participants in the Leiden Longevity Study, familial longevity was associated with lower serum 25(OH) vitamin D levels and a reduced frequency of allelic variation in the CYP2R1 gene, which predisposes people to high vitamin D levels.

The Leiden Longevity Study (based at Leiden University Medical Center in the Netherlands) was designed to identify genetic and phenotypic markers related to familial longevity. Families were included if at least two long-lived siblings were still alive and met the age criteria (at least 89 years of age for men and 91 years of age for women). Because it is difficult to include proper controls for this older age group, the nonagenarians’ offspring were asked to participate and serve as cases; the offspring are known to have a low prevalence of age-related diseases and an increased propensity to reach old age. The partners of the offspring were asked to participate as environment-matched controls.

The current analysis included data from 380 families, focusing on 1,038 offspring and 461 partner controls. The researchers assessed anthropometric characteristics, 25(OH) vitamin D levels, parathyroid hormone levels, dietary vitamin D intake, and single nucleotide polymorphisms (SNPs) associated with vitamin D levels. Age, sex, body mass index, month during which blood sampling was performed, dietary and supplemental vitamin D intake, and creatinine levels were included as possible confounding factors.

Linear regression analysis revealed that the offspring had significantly lower levels of vitamin D (64.3 nmol/L) compared with controls (68.4 nmol/L; p = 0.002), independent of possible confounding factors. There was no difference in the levels of parathyroid hormone between groups. Compared with controls, the offspring had a lower frequency of a genetic variant in the CYP2R1 gene (rs2060793) (p = 0.04). The difference in vitamin D levels between offspring and controls persisted over the wo most prevalent genotypes of this SNP.

According to the authors, the results cast doubt on the causal nature of previously reported associations between low levels of vitamin D and age-related diseases and mortality.

CMAJ. 2012;184:E963-8. Epub 2012 Nov 5.

8. On the One Hand: Vitamin D Supplementation May Reduce Disease Burden in Patients With Frequent Respiratory Tract Infections
In a prospective, randomized, double-blind, placebo-controlled trail conducted in Sweden, vitamin D3 supplementation reduced symptoms and antibiotic consumption among patients with an increased susceptibility to respiratory tract infections.

Adult patients (18 to 75 years of age) at the Immunodeficiency Unit of Karolinska University Hospital were eligible for the study if they had more than 42 days with respiratory tract symptoms during a 12-month period prior to study inclusion. A total of 140 patients were randomized to daily treatment with 4,000 IU vitamin D3 or placebo for 12 months. Participants kept a diary in which they recorded symptoms from the respiratory tract, ears, and sinuses; treatment with antibiotics; numbers of bacterial cultures; times and reasons of visits to hospitals; frequency of travelling abroad; and adherence to study treatment. The primary outcome was a composite infectious score that included symptoms from the respiratory tract, ears, and sinuses; malaise; and use of antibiotics. Each parameter gave 1 point per day.

The composite infectious score was significantly lower among patients in the vitamin D group (202 points) than the placebo group (249 points). After adjustment for potential confounders, the relative score was 0.771 (95% CI, 0.604–0.985; p = 0.04), corresponding to a 23% reduction.

BMJ Open. 2012;2:e001663. http://bmjopen.bmj.com/content/2/6/e001663.long.

9. On the Other Hand: Vitamin D Supplementation Has No Effect on Upper Respiratory Tract Infections
In a randomized, double-blind, placebo-controlled trial involving 322 healthy adults, monthly administration of 100,000 IU vitamin D did not reduce either the incidence or severity of upper respiratory tract infections (URTIs). This result remained unchanged when the analysis included winter season or baseline serum 25(OH) vitamin D levels.

The trial was conducted in Christchurch, New Zealand, between February 2010 and November 2011. Participants were randomly assigned to treatment or placebo groups. The treatment group received an initial dose of 200,000 IU oral vitamin D3, followed by 200,000 IU 1 month later, then 100,000 IU monthly for a total of 18 months; the placebo group followed an identical dosing regimen. The primary end point was number of URTI episodes. Secondary end points were duration of URTI episodes, severity of URTI episodes, and number of days of missed work due to URTI episodes.

The mean baseline serum 25(OH) vitamin D concentration for all participants was 29 ± 9 ng/mL. Vitamin D supplementation resulted in an increase in serum 25(OH) vitamin D levels that was maintained at greater than 48 ng/mL throughout the study.

A total of 593 URTI episodes were reported among participants in the treatment group, vs 611 in the placebo group. There were no statistically significant differences in the number of URTIs per participant (mean, 3.7 per person in the vitamin D group and 3.8 per person in the placebo group; risk ratio, 0.97; 95% CI, 0.85–1.11), number of days of missed work as a result of URTIs (mean, 0.76 days in each group; risk ratio, 1.03; 95% CI, 0.81–1.30), duration of symptoms per episode (mean, 12 days in each group; risk ratio, 0.96; 95% CI, 0.73–1.25), or severity of URTI episodes.

JAMA. 2012;308:1333-9.

10. Vitamin D Supplementation Not Helpful for Knee Osteoarthritis
Vitamin D supplementation for 2 years proved to be no better than placebo in reducing knee pain or cartilage volume loss in 146 older adult patients (mean age 62.4 ± 8.5 years) with symptomatic knee osteoarthritis.

Participants in this single center, double-blind clinical trial were randomized to receive daily treatment with oral cholecalciferol 2,000 IU or placebo, with subsequent dose escalation in increments of 2,000 IU at 4, 8, and 12 months as needed to elevate the serum 25(OH) vitamin D concentration to >36 ng/mL. Primary outcomes were knee pain severity (Western Ontario and McMaster Universities [WOMAC] pain scale, 0–20: 0, no pain; 20, extreme pain) and cartilage volume loss measured by magnetic resonance imaging. Secondary end points included physical function, knee function (WOMAC function scale, 0–68: 0, no difficulty; 68, extreme difficulty), cartilage thickness, bone marrow lesions, and radiographic joint space width.

Serum 25(OH) vitamin D levels increased by a mean of 16.1 ng/mL (95% CI, 13.7–18.6) in the treatment group and 2.1 ng/mL (95% CI, 0.5–3.7) in the placebo group (P <0.001). Knee pain decreased in both groups, by a mean of −2.31 units (95% CI, −3.24 to −1.38) in the treatment group and −1.46 units (95% CI, −2.33 to −0.60) in the placebo group. No significant differences were seen at any time. The percentage of cartilage volume decreased by the same extent in both groups (mean, −4.30; 95% CI, −5.48 to −3.12 vs mean, −4.25; 95% CI, −6.12 to −2.39) (P = 0.96). There were no differences in any of the secondary clinical end points.

JAMA. 2013;309:155-62.

11. Vitamin D Supplementation May Reduce Risk for Dental Caries
A systematic review and meta-analysis of 24 controlled clinical trials encompassing 2,827 children found a 47% reduction in risk for dental caries with vitamin D supplementation. The pooled relative-rate estimate of supplemental vitamin D was 0.53 (95% CI, 0.43–0.65). No robust differences were identified between the caries-preventive effects of vitamin D2 (median dose 3,750 IU), vitamin D3 (median dose 800 IU), and ultraviolet radiation (Prob > F = 0.22).

However, the authors could conclude only with low certainty (using the criteria for certainty established by the U.S. Preventive Services Task Force) that vitamin D in childhood may reduce the incidence of dental caries. Nearly all (22) of the trials predated modern clinical trial design; the relative-rate estimates of the 24 trials exhibited significant heterogeneity (P <0.0001); and there was evidence of significant publication bias (P <0.001).

Nutr Rev. 2012 Nov 9. [Epub ahead of print]