Research into the health effects associated with vitamin D continued to be strong in 2014. The number of publications with vitamin D in the title or abstract listed at pubmed.gov increased from 3,119 in 2011 to 3,919 in 2014. Seven vitamin D researchers (listed after this report) worked together to pick the 20 papers in 2014 that made the most contribution to understanding the health effects of vitamin D in 2014.

Papers are not in priority order, but instead grouped by type of study. For the purpose of this article “vitamin D” in the blood is a measurement of 25-hydroxyvitamin D or 25(OH)D.

Do randomized controlled trials work for vitamin D?

No one refutes the fact that vitamin D is beneficial to the skeletal system. There are many studies (randomized controlled trials [RCT] and also epidemiological) that support this hypothesis. What is at odds is whether or not vitamin D is beneficial to the non-skeletal system. There are many observational (epidemiological, or association) studies that show vitamin D is beneficial, and many RCTs that show it isn’t. Does that mean that vitamin D does not aid in disease prevention? Or does it mean that the RCT model does not work for nutrients?

Randomized Control Trials in 2014

A vitamin D trial in the UK in which patients with chronic obstructive pulmonary disease (COPD) were given 120,000 IU vitamin D3 every two months for a year found that vitamin D3 supplementation was protective against moderate or severe exacerbation in those with baseline 25(OH)D concentrations < 50 nmol/L (20 ng/mL) but not for those with concentrations > 50 nmol/L. Vitamin D3 supplementation had no effect on upper respiratory infections. This is consistent with previous RCTs that used high doses at infrequent intervals, every 2 months in this case; however other trials that used an adequate dose given daily have shown reduction in upper respiratory tract infections.

Vitamin D promotes vascular regeneration [Wong, 2014]

This study demonstrated that vitamin D improved cardiovascular disease. The German team investigated this effect several ways. They showed that supplementation with 4000 IU/day of vitamin D3 increased the number of circulating angiogenic myeloid cells, which promote growth and vascular regeneration necessary for a healthy cardiovascular system. A similar result was found in a mouse model, which also demonstrated restoration of impaired angiogenesis (new vessel formation) function. They also examined the mechanisms by which vitamin D acted.

Vitamin D and depression: a systematic review and meta-analysis comparing studies with and without biological flaws. [Spedding, 2014]

This paper reported on a statistical average of many studies of vitamin D RCTs without methodological flaws and found that vitamin D supplementation resulted in a statistically significant improvement in clinical depression. However, the same analysis of vitamin D RCTs with methodological flaws found a statistically significant worsening of depression. The major flaws identified included not increasing 25(OH)D concentrations and not measuring baseline or final 25(OH)D concentrations. Vitamin D supplementation of > 800 IU/d was somewhat favorable in the management of depression.

A post hoc (conducted after the study was completed) analysis of a vitamin D RCT involving 644 Australian residents aged 60-84 years found a significant reduction in prescribed antibiotics if they were over the age of 70 years and taking 60,000 IU of vitamin D3 monthly compared with the placebo groups. The effect was not significant for those < 70 years of age. This study suggests that taking an average of 2000 IU/day vitamin D3 reduces the risk of infections, most likely respiratory infections, in older adults.

Observational studies of Vitamin D

Observational studies provide some of the strongest evidence to date for beneficial health outcomes related to vitamin D. Observational studies measure vitamin D status and health outcomes for every participant. Blood samples are taken at the time of enrollment and people are followed for several years. Vitamin D is said to be effective if positive health outcomes result.

This paper was a review of observational and RCT studies that showed a correlation between vitamin D and specific mortality outcomes. One conclusion was that supplementation with vitamin D3 significantly reduces overall mortality among older adults. They used data from 73 cohort studies (849,412 participants) and 22 RCTs (30,716 participants). In the RCTs, all cause mortality rate was reduced by 11% for vitamin D3 supplementation but increased by 4% for vitamin D2 supplementation. In addition, their meta-analysis of cancer-specific incidence and mortality rates comparing those who started in the lowest third of vitamin D blood concentrations against those in the highest third suggests that vitamin D may have a much stronger impact on survival after developing cancer than on reducing the risk of developing cancer to start with.

An analysis of 32 observational studies found that as 25(OH)D concentrations increased from 13 nmol/L (5 ng/ml) to 90 nmol/L (36 ng/ml) there is a linear reduction in all-cause mortality. At concentrations greater than 90 nmol/L (36 ng/ml), no further improvement was observed. This finding is important in that it did not find any evidence for a U-shaped relationship showing higher risk for both low and high 25(OH)D concentrations as has been reported in some studies. Furthermore, the risk for all-cause mortality rate for those with 25(OH)D concentration < 25 nmol/L (10 ng/mL) was 1.9 compared to that for those with concentrations > 100 nmol/L (40 ng/mL).

A study in New York found that 25(OH)D concentration and age were the only independent predictors of response to the highly fatal Clostridium difficile-associated diarrhea (CDAD). Subjects with 25(OH)D concentration < 53 nmol/L (21 ng/mL) were 4.75 times more likely to fail to resolve CDAD after 30 days than subjects with 25(OH)D concentrations > 75 nmol/L (30 ng/mL). This is an important finding since CDAD rates are increasing due to antibiotic resistant strains of CD.

Avoidance of sun exposure is a risk factor for all-cause mortality: results from the MISS cohort [Lindqvist, 2014]

An observational study in Sweden involving 29,518 women followed for up to 20 years with 2,545 reported deaths found that the mortality rate for those who avoided sun exposure was approximately twice as high as those who were most exposed to the sun. This difference explained 3% of all deaths and is important since UVB doses in Sweden are generally low and virtually absent for six months of the year. Production of vitamin D may explain most of the differences between sun exposure amounts, although other beneficial effects of solar UV exist, such as release of nitric oxide resulting in reduction of blood pressure, as well as vitamin D-independent effects on the immune system.

25-Hydroxyvitamin D in the range of 20 to 100 ng/ml and incidence of kidney stones [Nguyen, 2014]

GrassrootsHealth (510c3) initiated a voluntary reporting project called D*action. There are over 7,000 in the cohort, of which 2,012 have reported their data for a median of 19 months. In this cohort, there has been no evidence of an association of 25(OH)D and kidney stones. What was a risk factor for kidney stones in this study was high body mass index. This study counters the Women’s Health Initiative study that reported an elevated risk of kidney stones for women taking 400 IU/d vitamin D3 and 1500 mg/d calcium.

An observational study involving 520,000 participants in the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort, of which 138 developed hepatocellular carcinoma (HCC) or liver cancer, found that higher levels of 25(OH)D reduced incidence of HCC. Each 10 nmol/L (4 ng/mL) increase in 25(OH)D concentration was associated with a 20% average decrease in risk of HCC. The large number of participants in the study with a very small number of cases indicates the difficulty of demonstrating the beneficial effect of vitamin D for the rare cancers. The authors noted that the result did “not change after adjustment for biomarkers of preexisting liver damage, nor chronic infection with hepatitis B or C viruses.”

A study in Ireland and Scotland involving 1,598 patients with stage I to III colorectal cancer, found that 25(OH)D concentrations (measured approximately 15 weeks after diagnosis of colorectal cancer) were associated with survival rates. Those in the highest third of 25(OH)D concentrations with a median concentration of 51 nmol/L (20 ng/mL) compared to the lowest third with a median concentration of 10 nmol/L (4 ng/mL) had a 32% lower risk of cancer-specific mortality rate and a 30% lower risk of all-cause mortality rate over a ten-year follow-up period. This study provides support for the idea that people diagnosed with cancer should raise their 25(OH)D concentration to above a minimum of 50 nmol/L (20 ng/mL),

Two meta-analyses found significantly increased cancer survival rates with higher concentration of 25(OH)D at time of diagnosis. For breast cancer, results from five studies found that those with 25(OH)D concentration of 75 nmol/L (30 ng/mL) had half the 5-20 year mortality rate as those with a lower concentration of 30 nmol/L (12 ng/mL).

In this meta-analysis for colorectal cancer, results from four studies found that those with 25(OH)D concentration of 80 nmol/L (32 ng/mL) had 60% of the 6-20 year mortality rate as those with 45 nmol/L (18 ng/mL).

Two papers reported that those with low 25(OH)D concentrations had increased risk of developing vascular dementia and Alzheimer’s disease. This first one is from Denmark. A study involving 418 people followed for 30 years found a 25% increased risk of Alzheimer’s disease and a 22% increased risk of vascular dementia for those with baseline 25(OH)D concentration < 25 nmol/L (10 ng/ml) compared to > 50 nmol/L (20 ng/ml)

Vitamin D and the risk of dementia and Alzheimer disease [Littlejohns, 2014]

In this second paper on dementia and Alzheimer disease, a study in the United States involving 1,658 participants followed for 5.6 years found a 125% increased risk of Alzheimer’s disease for those with severely deficient 25(OH)D levels (< 25 nmol/L (10 ng/mL)), and a 53% increased risk for those with deficient levels ( ≥ 25 to < 50 nmol/L) compared to participants with sufficient concentrations ( ≥ 50 nmol/L (20 ng/mL)).

Pregnancy

There is considerable interest in the role of vitamin D during pregnancy. In a reanalysis of results from two maternal vitamin D supplementation trials conducted in South Carolina, it was found that: “(1) maternal vitamin D status closest to delivery date was more significantly associated with preterm birth, suggesting that later intervention as a rescue treatment may positively impact the risk of preterm delivery, and (2) a serum concentration of 100 nmol/L (40ng/mL) in the 3rd trimester was associated with a 47% reduction in preterm births.”

A study in Australia compared maternal 25(OH)D concentration at 18 weeks’ pregnancy with outcomes of the children years later. The authors found that “maternal vitamin D deficiency during pregnancy was associated with impaired lung development in 6-year-old offspring, neurocognitive difficulties at age 10, increased risk of eating disorders in adolescence, and lower peak bone mass at 20 years.”

A review of vitamin D supplementation and 25(OH)D concentrations during pregnancy found vitamin D reduces the risk of pre-eclampsia. For 25(OH)D concentration, the combined risk reduction was 48% with higher level circulating vitamin D. For vitamin D RCTs, the combined risk reduction was 34% for vitamin D supplementation vs. a placebo. This review provides further support for the importance of vitamin D supplementation and raising 25(OH)D concentrations during pregnancy.

Randomization

An approach recently being applied to evaluating whether vitamin D can be considered causally linked to health outcomes is Mendelian randomization analysis. In this approach, genetic variants known to be affected by vitamin D are compared to health outcomes. The advantage of this approach is that the results should be independent of baseline 25(OH)D concentrations, which vary over time. The disadvantage is that only a few factors are considered and the most important ones affecting 25(OH)D concentrations may not be included.

In a study involving 95,766 white participants of Danish descent, genetic variations of DHCR7 (related to vitamin D synthesis) and CYP2R1 (hepatic 25-hydroxylation), which slightly lower plasma 25(OH)D concentrations over the lifetime of the subjects, were examined. As 25(OH)D increased, significant reductions were found for all-cause, cancer and other mortality rates, but not for cardiovascular mortality. These results are interesting, but the method is not strong enough to rule out a protective role of vitamin D in reducing risk of cardiovascular disease. Some regard this approach as particularly weak, since the serum 25(OH)D concentration depends much more in the general population upon solar exposure than upon genes.

Most vitamin D RCTs were based on guidelines designed for pharmaceutical drugs where the only source of the agent is the medication in the trial, and there is a linear dose-response relation between the agent and the outcome. Dr. Heaney asserts that neither assumption is valid for vitamin D trials.

Instead, vitamin D trials should:

Start with an understanding of the 25(OH)D concentration-health outcome relationship. What are we expecting to find?

Measure 25(OH)D concentrations of prospective trial participants and only enroll those with values near the low end of the relation.

Supplement with enough vitamin D to raise 25(OH)D concentrations to near the upper end of the relation.

Measure 25(OH)D concentrations throughout the trial.

Optimize the status of other nutrients related to vitamin D so that vitamin D is the only limiting factor in the response.

Unfortunately, many of the ongoing vitamin D trials have not been designed with these or similar guidelines in mind. As a result, it may be some time before vitamin D RCTs will be able to provide adequate evidence to confirm or refute the findings of observational studies for non-skeletal diseases.

Conclusion

Research on the health benefits of solar UVB exposure and vitamin D continues at a rapid pace. We appear to be in the middle of the golden age of vitamin D research, a period with much progress in understanding the effects of UVB exposure and vitamin D for a large range of health outcomes. We are shifting from discovery to evaluation of previous findings and testing the role of vitamin D in prevention and treatment of various diseases.

While many of the findings from ecological and observational studies are strong, it appears that health systems and policy makers are awaiting results from large on-going RCTs before they accept UVB exposure and vitamin D as valid factors for health. Unfortunately, most of the RCTs currently underway and due to be completed before the end of the decade, including large-scale RCTs in several countries, have not been properly designed, so they may not shed light on vitamin D’s preventive powers. Thus, it may be another decade before the true health benefits of vitamin D and sunlight are accepted. Meanwhile, various types of research will continue and it will be up to individuals and their health care providers to evaluate the available evidence and act accordingly.

Andrew W. Saul, Ph.D. (USA), Editor and contact person. Email: [email protected] This is a comments-only address; OMNS is unable to respond to individual reader emails. However, readers are encouraged to write in with their viewpoints. Reader comments become the property of OMNS and may or may not be used for publication.

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