A recent review led by Dr. Mike Allan questioned whether vitamin D supplementation improves health outcomes, concluding that “enthusiasm for a vitamin D panacea should be tempered.”[1] However, the review ignores several important findings while voicing a biased interpretation of scientific literature.

We have all seen this too many times before, media headlines consumed by whatever appears to be controversial or conflicting with current beliefs. “Should You Hug Your Dog?” an article published by New York Times warns readers that hugging dogs increases their stress levels.[2] “A Glass of Red Wine is the Equivalent to an Hour at the Gym, Says New Study,” the Huffington Post reported.[3]  Now, media headlines report, “Everything You’ve Read About Vitamin D is Wrong” by How Stuff Works.[4] While these titles may elicit readers, they take a step backwards for science.

A recent review evaluated ten different beliefs about vitamin D. The review deemed vitamin D as non-beneficial for most of the topics, ranging from multiple sclerosis to depression. In doing so, the review neglected scientific evidence to push their controversial opinion into the media. The Vitamin D Council felt that it was our obligation, as a public health non-profit, to address some of these topics and to put an end to spreading misleading information. Let’s take a look at a few of the topics that we found most deceptive.

Respiratory tract infections

The review concluded, “Vitamin D supplementation does not prevent or reduce RTIs in western populations.” Yet, two of the three meta-analyses that they referenced actually showed that vitamin D supplementation significantly reduced respiratory tract infections.

The first meta-analysis by Bergman and colleagues included 11 randomized controlled trials (RCTs), the gold standard of research, with a total of 5,660 people.[5] The average supplementation regimen was 1600 IU daily with a dose interval ranging from 24 hours to three months. The meta-analysis discovered that vitamin D supplementation resulted in a significant 33% reduction in respiratory tract infections. They also found that, as one would expect, daily dosing provided a larger protective effect compared to bolus dosing. However, the review believed the study’s population was too diverse to consider the findings valid.

The second meta-analysis consisted of seven RCTs and a total of 4827 men and women ranging from 1.75 years to 63 years old. The analysis suggested that vitamin D supplementation did not significantly reduce the incidence of respiratory infections.[6] Though, some important limitations should be considered. The supplementation regimens widely varied. Two studies used quarterly vitamin D supplementation with 100,000 IU and 200,000 IU. The other five studies included a supplementation regimen ranging from 400-6800 IU daily. Despite the variability in age and vitamin D doses, the reviewers considered this meta-analysis as high quality and as the only meta-analysis fit valid for its findings. However, as many of us know, studies that involve bolus dosing (especially those that are as infrequent as quarterly boluses) do not produce significant results. This is because, as Bergman’s meta-analysis pointed out, daily dosing is much more effective.

Lastly, a meta-analysis of five RCTs conducted by Dr. Charan and colleagues discovered that vitamin D supplementation reduced the risk of respiratory tract infections by 42%.[7] The dose of vitamin D ranged from 400 IU/day to 2,000 IU/day and one study used a single dose of 100,000 IU per day. Again, one would not expect significant results from a trial that uses bolus dosing.

While the meta-analyses results are somewhat conflicting, the majority (2/3) clearly suggest that vitamin D supplementation prevents respiratory tract infections. The review dismisses the two positive studies, stating that the heterogeneous study populations make the studies “unreliable.” However, the negative study possessed several weaknesses, which one could argue make the study less reliable than the other two. But Dr. Allan decided to ignore these weaknesses, illustrating his underlying bias.

Depression and Mental Well-Being

The researchers from the review summarized the scientific literature on depression by stating, “Vitamin D supplementation does not improve mental wellbeing scores in the general population without clear depression, even when 25-OHD levels are low.”

They went on to state, “Vitamin D supplementation in patients with depression has conflicting, poor quality evidence and cannot be recommended.”

Unfortunately, the researchers hold somewhat valid points for this topic; studies have produced conflicting results.

The review included three meta-analyses. The first meta-analysis consisted of seven RCTs and found a small non-significant reduction in depressive symptoms.[8] The second meta-analysis was comprised of six RCTs and concluded that there was insufficient evidence that vitamin D supplementation can improve mood.[9] Finally, the third meta-analysis involved 15 RCTs.[10] The conclusion stated, “Studies with biological flaws were mainly inconclusive, with the meta-analysis demonstrating a statistically significant worsening in depression by taking Vitamin D supplements (-1.1 CI -0.7, -1.5). Vitamin D supplementation (≥800 IU daily) was somewhat favorable in the management of depression in studies that demonstrate a change in vitamin levels, and the effect size was comparable to that of anti-depressant medication.”

After the publication of these meta-analyses, a new RCT produced insightful results.[11] The RCT consisted of a control group that remained deficient throughout the eight week trial, allowing researchers to fully assess the benefits of achieving healthy vitamin D levels in comparison to remaining deficient. The vitamin D levels increased from a baseline level of 8 ng/ml to a final level of 30 ng/ml. The severity of depression significantly improved in the vitamin D group in comparison to the placebo group (p = 0.04).

Although the recent RCT provides hope to individuals who endure the hardships accompanied by depression, further research is needed before we can definitively state that vitamin D helps depression.

Multiple sclerosis

The review stated their consensus of available studies on MS and vitamin D, “vitamin D supplementation does not appear to provide a clinical benefit in the treatment of MS.” Research shows otherwise:

• Safety and immunologic effects of high- vs low-dose cholecalciferol in multiple sclerosis.[12]

In this RCT, the researchers compared the effects of daily supplementation of 10,800 IU to 800 IU among 40 patients with relapse remitting MS. They found that high doses were not only safe, but also effective in reducing the proportion of a specific type of immune system cell that is involved in the MS disease progression.

• Vitamin D receptor retinoid X receptor heterodimer signaling regulates oligodendrocyte progenitor cell differentiation[13]

Research conducted from the MS Society Cambridge Centre for Myelin Repair revealed that vitamin D receptor protein pairs with a protein called the RXR gamma receptor, known to be involved in the repair of myelin sheath. MS causes the body’s own immune system to attack and damage myelin, leading to disrupted messages sent to the brain and spinal cord. Researchers found that by adding vitamin D to brain stem cells where the RXR gamma proteins were present, the production of myelin creating cells called oligodendrocytes increased by 80%. When the vitamin D receptor was blocked, the RXR gamma protein alone was incapable of stimulating the production of oligodendrocytes. Although this research took place in a laboratory, the findings still prove to be monumental for MS.

The lead researcher of the study, Professor Robin Franklin, stated the study’s potential implications, “For years scientists have been searching for a way to repair damage to myelin. So far, the majority of research on vitamin D has looked at its role in the cause of the disease. This work provides significant evidence that vitamin D is also involved in the regeneration of myelin once the disease has started.”

• Vitamin D and Risk of Multiple Sclerosis: A Mendelian Randomization Study[14]

A Mendelian randomization study assessed the genotypes of approximately 39,000 people, some with MS and some without. They found that people with genetically low vitamin D levels were more likely to have MS compared to those who are not genetically predisposed to low vitamin D levels; so much so that  they found that if the individual’s vitamin D level was about 6 ng/ml lower than the others in the group, they had twice the risk of developing MS. It’s important to acknowledge that Mendelian randomization studies are equally as strong if not stronger than randomized controlled trials.

• Effect of high dose vitamin D intake on interleukin-17 levels in multiple sclerosis: a randomized, double-blind, placebo-controlled clinical trial[15]

A RCT consisting of 94 patients diagnosed with relapsing remitting MS were randomized into two groups. One group received 50,000 IU of vitamin D3 every five days for 12 weeks, while the other group received a dummy pill. Serum interleukin 17 (IL-17), a critical protein involved in the inflammatory response in MS, was measured at the beginning and end of the trial. At baseline, the IL-17 levels were 56 pg/ml and 30 pg/ml in the intervention and placebo groups, respectively. After 12 weeks, IL-17 levels were 58 pg/ml and 46 pg/ml in the intervention and placebo groups, respectively.This indicated that vitamin D3 supplementation prevented the increase of IL-17 levels in comparison to the placebo group.

Mortality

“The effects of vitamin D on mortality are not consistently statistically significant,” the review suggests. However, 100% of the included meta-analyses (7/7) showed that vitamin D3 reduced mortality. Six of the seven meta-analyses found that vitamin D3 reduced mortality significantly. The meta-analyses’ total of participants included ranged from 30,716 to 95,286.

The review argues against vitamin D’s role in mortality due to a lack of research, “Trial sequential analysis suggests that optimum sample size of 130,005 participants has not been reached.” However, the review failed to acknowledge one of the most conclusive studies regarding vitamin D and mortality. The study, conducted by Lindqvist and colleagues,[16] followed nearly 30,000 Swedish women for 20 years with the goal of determining the association between sun exposure and mortality. The researchers discovered that the mortality rate among women who avoided the sun doubled compared to those with the highest sun exposure. In addition, there was a dose dependent inverse relationship between sun exposure and all-cause mortality. While this study did not specifically look at vitamin D status, sun exposure is directly linked to vitamin D status. The reduction in mortality is likely attributed to increased vitamin D production.

The review’s conclusion contradicts the findings from every study that was included in the review. Once again, the author’s opinion overruled logic and scientific evidence.

Cancer

The relationship between vitamin D and cancer has gained much interest in recent years due to vitamin D’s ability to help regulate cell division and cell apoptosis. However, the understanding of vitamin D’s role is still considered in its infancy. Within the past year, over three million dollars in research grants have been allocated to vitamin D treatment in cancer. With this funding, researchers hope to provide answers and treatments for cancer.

Currently, limited clinical trials exist that evaluate the effects of vitamin D supplementation in cancer.[17] The review mentioned a frequently cited RCT on the topic, which found that supplementing with vitamin D and calcium resulted in a statistically significant 60% reduced risk of developing cancer in comparison to placebo. The study, which was published in the journal American Society for Clinical Nutrition, lasted for four years and included 1,179 post-menopausal women. A third of the women received 1,400-1,500 mg calcium, a third received calcium and 1,100 vitamin D3 daily and a third received placebo.

The review dismissed this study by stating, “The trial, however, had many limitations: industry-funded…unclear allocation concealment, small number of events reported…and outcome was patient reporting of new onset cancers.” First off, the RCT stated, “None of the authors were affiliated in any way with an entity involved with the manufacture or marketing of vitamin D.” Secondly, while the cancers were self-reported, the researchers avoided the possibility of recall bias by examining the medical records to confirm the diagnosis. The study also stated that the women were randomly divided into three groups, which eliminates the idea that the women were strategically placed into groups as implied by stating the study had “unclear allocation concealment.” Lastly, the results reached statistical significance of p = 0.013, meaning that there was a 1.3% probability of no relationship existing between vitamin D and calcium supplementation and cancer. To neglect the available research due to trivial study limitations, which are found within the majority of studies, is simply ignorant.

The review does admit, “There is relatively consistent evidence from observational studies of an association between lower vitamin D levels and an elevated risk of cancer.” However, despite the accumulated scientific evidence that supports vitamin D supplementation for cancer prevention and treatment, Dr. Allan concluded, “Vitamin D supplementation does not reduce the incidence of cancer.”

It’s important to acknowledge that vitamin D supplementation has been proven to prevent and aid in treating a wide range of conditions, many of which were not discussed in the study, such as migraines, psoriasis, Crohn’s disease and lupus.

One must also understand that vitamin D supplementation will not cure all ailments. However, if one is deficient in vitamin D, it increases the risk for developing many health conditions. Our bodies evolved alongside of sunlight, making thousands of units of vitamin D within minutes of sun exposure. In today’s world, we spend most of our days inside, and when we do go outside, we smother our bodies in sunscreen, which blocks the production of vitamin D. This has left many of us vitamin D deficient, and we now face the consequences.

This review understated the detrimental effects of vitamin D deficiency on the general population. The review itself stated, “Over the past decade, more than 1600 studies have been conducted on vitamin D.” Just because a single review counters the majority of past research, does not make the other 1,599 studies invalid as the media implies with titles like “Everything You’ve Read About Vitamin D is Wrong.”

We understand that most individuals do not have the time to sort through all of the available research. That’s why the Vitamin D Council exists, to provide readers with the facts. If you ever have any questions about vitamin D or recent media headlines, we ask that you send us an email at [email protected]. All of us here at the Vitamin D Council are more than happy to help dispel the misinformation from the media and navigate your way through the abundance of research available.

Citation

Tovey, A & Cannell, JJ. Should vitamin D enthusiasm be “tempered”? The Vitamin D Council Blog & Newletter, 2016.

Sources

^[1] Allan GM et al. Vitamin D: A Narrative Review Examining the Evidence for Ten Beliefs. J Gen Intern Med, 2016

[2] Hauser, C. “Should You Hug Your Dog?” The New York Times, 2016. 

[3] Sitch, M. “A Glass Of Red Wine Is The Equivalent To An Hour At The Gym, Says New Study.”The Huffington Post. 2016

[4] Whitbourne, K. “Everything You’ve Read About Vitamin D Is Wrong.” HowStuffWorks, 2016.

[5] Bergman P et al. Vitamin D and Respiratory Tract Infections: A Systematic Review and Meta-Analysis of Randomized Controlled Trials. PLoS One, 2013.

[6] Mao S et al. Vitamin D supplementation and risk of respiratory tract infections: a meta-analysis of randomized controlled trials. Scand J Infect Dis, 2013.

[7] Charan J et al. Vitamin D for prevention of respiratory tract infections: A systematic review and meta-analysis. J Pharmacol Pharmacother, 2012.

[8] Shaffer J et al. Vitamin D supplementation for depressive symptoms: a systematic review and meta-analysis of randomized controlled trials. Psychosom Med, 2016.

[9] Li G. et al. Efficacy of vitamin D supplementation in depression in adults: a systematic review protocol. Syst Rev, 2013.

[10] Spedding S. et al. Vitamin D and Depression: A Systematic Review and Meta-Analysis Comparing Studies with and without Biological Flaws. Nutrients, 2014.

[11] Sepehrmanesh Z. et al. Vitamin D Supplementation Affects the Beck Depression Inventory, Insulin Resistance, and Biomarkers of Oxidative Stress in Patients with Major Depressive Disorder: A Randomized, Controlled Clinical Trial. J Nutr, 2016.

[12] Sotirchos ES. et al. Safety and immunologic effects of high- vs low-dose cholecalciferol in multiple sclerosis. Neurology, 2016.

[13] De la Fuente AG. et al. Vitamin D receptor-retinoid X receptor heterodimer signaling regulates oligodendrocyte progenitor cell differentiation. J Cell Biol, 2015.

[14] Mokry LE. et al. Vitamin D and Risk of Multiple Sclerosis: A Mendelian Randomization Study. PLoS, 2016.

[15] Toghianifar N. et al. Effect of high dose vitamin D intake on interleukin-17 levels in multiple sclerosis: a randomized, double-blind, placebo-controlled clinical trial. J Neuroimmunol, 2015.

[16] Lindqvist PG. et al. Avoidance of sun exposure is a risk factor for all-cause mortality: results from the Melanoma in Southern Sweden cohort. J Intern Med, 2014.

[17] Lappe J. et al. Vitamin D and calcium supplementation reduces cancer risk: results of a randomized trial. American Society for Clinical Nutrition, 2007.