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Vitamin D Research: A Round-Up

by Berkeley Wellness  

Vitamin D has certainly kept a lot of researchers busy, as seen by the plethora of research published in recent years.

Observational studies: generating hypotheses

The great majority of the studies done on vitamin D have been observational. That is, they follow a group of people over time to see how factors such as vitamin D (intake or blood levels) correlate with increased or decreased risk of developing certain diseases or conditions. Such studies identify associations rather than prove cause and effect.

Here are just some of the conditions (beyond bone diseases) that have been linked to low vitamin D in observational studies: arthritis, asthma, various cancers (notably colorectal), emphysema, cognitive decline and dementia, coronary artery disease, depression, diabetes, fibromyalgia, gum disease, heart failure, hypertension, infections (such as colds, flu, and pneumonia), infertility, inflammatory bowel diseases, multiple sclerosis, muscle weakness (causing falls), obesity, Parkinson’s disease, and psoriasis. Some studies link vitamin D levels to disease prevention, others to improved disease treatment or prognosis.

Clinical trials: putting D to the test

There have been far fewer randomized, double-blind, placebo-controlled clinical trials on vitamin D, except for ones focusing on its effect on bone health. Such studies are the “gold standard” in evaluating treatments or preventive measures and establishing causality. In the case of vitamin D, supplements are usually compared to a placebo (dummy pill). Overall, clinical trials have been less likely to find benefits than the observational studies—a common scenario with scientific research.

The biggest and best clinical trials on vitamin D have focused on bone health, and even here the results have been somewhat inconsistent. That’s not surprising because clinical trials on D vary widely in many ways—notably in the amount of the vitamin tested, the dosing regimen, the age and health of the subjects, whether they consumed adequate calcium, their initial blood levels of vitamin D (if this was even measured), and whether the amount taken was enough to raise blood levels to the optimal range (however that was defined).

Nearly all of the clinical trials on vitamin D for potential non-skeletal benefits have been relatively small and short and thus preliminary. Many were limited by the fact that they did not measure baseline levels of vitamin D (supplements are unlikely to benefit people who already have adequate blood levels) or used low doses of D that were unlikely to raise low blood levels adequately.

That’s why everyone has been eagerly awaiting the results of several long, large, well-designed clinical trials testing high doses of vitamin D for a wide range of outcomes that are underway. In November 2018, first results were published from the Vitamin D and Omega-3 Trial (VITAL), which has involved more than 25,000 people who took 2,000 IU of vitamin D a day or a placebo (and/or omega-3 pills) for an average of five years; the endpoints of the first two VITAL studies were cancer and heart disease. Other important clinical trials on vitamin D are still underway. And the VITAL researchers are continuing to follow the participants’ incidence of cardiovascular disease and cancer. Also in progress are additional VITAL analyses looking at a long list of other endpoints, such as diabetes, cognition, bone health, depression, asthma, infections, and autoimmune disorders. So we’ll be hearing a lot more VITAL news about vitamin D (and omega-3s) in the next few years.

Dueling reviews and analyses

In recent years there have also been hundreds of systematic research reviews and meta-analyses on vitamin D, involving millions of people. Meta-analyses combine data from many smaller observational studies or clinical trials to achieve greater statistical power. Such analyses tend to generate lots of publicity, even though they add no new data and reshuffle similar sets of studies. Moreover, depending on how the studies are selected for inclusion and then analyzed, they often reach conflicting conclusions and cause controversy.

Many reviews and meta-analyses have focused on vitamin D, usually combined with calcium, for bone health and fracture prevention and have produced conflicting conclusions. For instance, in 2013, a review and meta-analysis in the Lancet concluded that the supplements do not helpkeep bones strong in the general population and thus are unnecessary. In contrast, an updated review by the Cochrane Collaboration in 2014 concluded that vitamin D, along with calcium, does help protect bones, at least in frail older people.In 2016, a panel of experts from the National Osteoporosis Foundation conducted a meta-analysis on eight well-designed clinical trials and found that calcium plus vitamin D supplementation produced a 30 percent reduction in hip fractures and a 15 percent reduction in total fractures. But then in 2017, a review and meta-analysis in theJournal of the American Medical Associationconcluded that the supplements do not reduce fracture risk in community-dwelling adults.

Many observational studies and clinical trials on vitamin D in older people have included data on mortality rates. Most reviews and meta-analyses of such studies suggest that vitamin D helps prolong lives, though clinical trials generally find a more modest benefit than observational studies.

As if that wasn’t enough, a so-called “umbrella review” of research on vitamin D appeared in BMJ in 2015. It included 107 systemic reviews and 74 meta-analyses on vitamin D and looked at 137 conditions or other outcomes. Its conclusion: Nearly all of the proposed benefits remain uncertain, primarily because of a lack of large, well-designed clinical trials.

Originally published March 2015; updated December 2018.