Immunosuppression and insufficient followup in vitamin D studies

One of the abiding weaknesses of studies on the effects of vitamin D on health is that researchers simply do not follow subjects consuming the secosteroid for a sufficient period of time. Instead, they tend to track subjects over the course of weeks, months, or one or two years, during the period of time when study participants are usually feeling the palliative effects of the steroid.

This practice is a mistake as it does not account for the long-term immunosuppressive effects of a steroid. For example, the U-shaped relationship between vitamin D levels and long-term outcome in large cohort ¹⁾

The effects of vitamin D in various doses is only in this century becoming apparent.

In the February 2016 edition of JAMA Internal Medicine attention is drawn to two studies showing an increase in falls associated with high doses of vitamin D.

A Cautionary Tale of Vitamin Supplements Retold

A previous RCT4 in women of the same age showed that 500 000 IU of vitamin D per year achieved serum 25(OH)D levels of at least 30 ng/mL in most participants but significantly increased risk of falls by 15% and fractures by 26%.

Steven R. Cummings, MD; Douglas P. Kiel, MD, MPH; Dennis M. Black, PhD, in Vitamin D Supplementation and Increased Risk of Falling

People who consume vitamin D through supplements or food are suppressing their innate immune response.²⁾ In the absence of a robust immune response, fewer bacteria killed. As a consequence, inflammation declines as does the amount of toxins released into the tissues. This contributes to symptom relief and feelings of temporary well-being. Without knowing anything else, researchers might erroneously conclude that supplementing with vitamin D is therapeutic.

At a certain point, however, consuming the secosteroid starts to have an effect on those symptoms which researchers typically focus their attention. A person's pathogen load increases to the point such that it cannot be offset by a mitigated immune response. This tipping point occurs at different times for different patient groups. For someone who is young and has a robust immune response, it may take decades for chronic pathogens to escalate to the point where they become symptoms of disease. On the other hand, the time to experience a negative effect for a person who is sick with a chronic disease or elderly (and presumably has a higher bacterial load), is relatively shorter.

The failure to appreciate the molecular metabolism of vitamin D has unfortunate repercussions when it comes to interpreting the data for epidemiological studies.

There are a number of studies, too many to review in the context of this article. Generally speaking, research noting a therapeutic effect of vitamin D tend to be short-term or in patients whose immune systems are yet to be suppressed.

A study out of Creighton University recently received attention, because the researchers found that vitamin D might lower the incidence of colorectal cancer.³⁾ The length of the observation: only four years.

Jacques Rossouw at the National Institutes of Health criticized the finding. His group conducted a similar study that tracked the effects of vitamin D in a larger cohort (36,282 vs. 1,179 subjects) over a longer period of time (seven vs. four years).⁴⁾

In our study we found absolutely no indication of an effect of calcium or vitamin D [on cancer] — zero. And that’s over a seven-year period. It was a much larger study and a much longer study.

Jacques Rossouw, in a comment to the press

A 2000 study found that five patients confined to wheelchairs with severe weakness and fatigue were able to walk after supplementing with 300,000 IU’s of vitamin D, (150 times higher than the U.S. Institute of Medicine of the National Academy of Sciences' tolerable upper intake level) over a period of six weeks. But the patients were not “cured,“ and no follow-up study was conducted published on the group. Based on what is known about vitamin D metabolism, these patients were simply feeling the effect of a temporary decrease in cytokine and toxin release that resulted after the high levels of vitamin D completely shut down their innate immune systems. In fact, one of the patients actually died in the weeks during which vitamin D was administered.⁵⁾

Those researchers, which have followed subjects who have supplemented with vitamin D over the course of decades, have found that the secosteroid does have harmful effects and especially in patients with chronic disease.

One 2004 study found a clear association between high-dose vitamin D supplementation in infancy and an increased risk of atopy, allergic rhinitis, and asthma later in life.⁶⁾ Those subjects given higher levels of vitamin D during infancy were found to suffer from higher levels of atopy, rhinitis and asthma. However the results were not apparent until the research team checked back with them at 31 years of age.

According to another group of researchers, patients consuming vitamin D are significantly more likely to have greater volumes of brain lesions, indicating regions of damage that can increase risk of cognitive impairment, dementia, depression and death. Vitamin D intake – mean 341 IU and maximum intake 1014 IU – was the only variable that retained a significant correlation with the brain lesions when analyzed by a multivariate analysis.⁷⁾ In this case, the negative effective could be easily documented, because the subjects were older (average age 71) and presumably had a longer period to build up their pathogenic load.

It is worth noting that studies of certain other classes of steroids, substances which are nearly biochemically identical to vitamin D, have opted to focus on the long-term harm the drugs cause. One study of anabolic steroids is typical. Graham et al documented how rates of cardiovascular disease are significantly higher in former users.⁸⁾ The study's authors sensibly chose to study subjects only after at least 20 years of previous or current use.

A 2010 study found that Danish neonates with the highest measurable levels of 25-D had a two-fold elevated risk of developing schizoprhenia. The relationship was not explained by a wide range of potential confounding or interacting variables.⁹⁾ This result is consistent with the explanation that higher rates of disease were caused by the immunosuppressive effects of heavy supplementation with vitamin D.

CorticosteroidsA first-line treatment for a number of diseases. Corticosteroids work by slowing the innate immune response. This provides some patients with temporary symptom palliation but exacerbates the disease over the long-term by allowing chronic pathogens to proliferate., which have a more profound effect on the immune system as well, have a well-documented effect in increasing symptoms of disease if not disease itself. One study found that disease relapse was significantly higher in patients trying to ease their dose of Prednisone.¹⁰⁾

Supplementation and Fracture Incidence in Community-Dwelling Older Adults: A Systematic Review and Meta-analysis.

Results A total of 33 randomized trials involving 51 145 participants fulfilled the inclusion criteria. There was no significant association of calcium or vitamin D with risk of hip fracture compared with placebo or no treatment (calcium: RR, 1.53 [95% CI, 0.97 to 2.42]; ARD, 0.01 [95% CI, 0.00 to 0.01]; vitamin D: RR, 1.21 [95% CI, 0.99 to 1.47]; ARD, 0.00 [95% CI, −0.00 to 0.01]. There was no significant association of combined calcium and vitamin D with hip fracture compared with placebo or no treatment (RR, 1.09 [95% CI, 0.85 to 1.39]; ARD, 0.00 [95% CI, −0.00 to 0.00]). No significant associations were found between calcium, vitamin D, or combined calcium and vitamin D supplements and the incidence of nonvertebral, vertebral, or total fractures. Subgroup analyses showed that these results were generally consistent regardless of the calcium or vitamin D dose, sex, fracture history, dietary calcium intake, and baseline serum 25-hydroxyvitamin D concentration. JAMA 2017;318(24) Abstract

Conclusions and Relevance In this meta-analysis of randomized clinical trials, the use of supplements that included calcium, vitamin D, or both compared with placebo or no treatment was not associated with a lower risk of fractures among community-dwelling older adults. These findings do not support the routine use of these supplements in community-dwelling older people. JAMA 2017;318(24)Abstract

In a CBS interview on video (17 March, 2015) Dr David Agus discussed the finding that vitamin D was useless for lowering blood pressure. Supplementation was also found to be associated with more cancer and heart disease. “Nobody should be taking it…that's the data” said the doctor, who also drew attention to increased risk of bone fracture and kidney stone.

view Dr Agus

Two recent publications challenge the belief that 25(OH)D levels greater than 30 ng/mL are optimal for bone health. In a randomized, placebo-controlled trial, high-dose, once-yearly vitamin D therapy increased the incidence of fractures and falls. The second study reported that high-dose vitamin D did not reduce levels of parathyroid hormone or bone resorption among adults with 25(OH)D levels less than 32 ng/mL at baseline. It is time to question whether serum 25(OH)D levels of 30 ng/mL or greater are necessary for all individuals. ¹¹⁾

Blood vitamin D levels were associated with a risk of metabolic syndrome in cross-sectional studies but not in longitudinal studies. ¹²⁾

Evidence does not support the use of vitamin D supplementation for the prevention of cancer, respiratory infections or rheumatoid arthritis. Similarly, evidence does not support vitamin D supplementation for the treatment of multiple sclerosis and rheumatoid arthritis or for improving depression/mental well-being. Regular testing of 25-hydroxyvitamin D is generally not required, and mega-doses (≥300,000 IU) appear to increase harms. Much of the evidence is at high risk of bias, with multiple flaws, including analyses of secondary endpoints, small and underpowered studies, inconsistent results and numerous other issues. Therefore, enthusiasm for a vitamin D panacea should be tempered.¹³⁾

New evidence indicates that both high and low 25(OH)D levels may be associated with increased health risks.¹⁴⁾

Despite a few hundred systematic reviews and meta-analyses, highly convincing evidence of a clear role of vitamin D does not exist for any outcome, but associations with a selection of outcomes are probable.¹⁵⁾