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).
Still, as we've concluded previously, the evidence overall supports supplementation with vitamin D and calcium for bone health for people with inadequate intakes. This was confirmed in July 2014 in an updated review by the Cochrane Collaboration that focused on fracture risk. Vitamin D also helps maintain muscle function and balance, which can help prevent fractures by reducing the risk of falls in older people.
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 is eagerly awaiting the results of several long, large, well-designed clinical trials testing high doses of vitamin D for non-skeletal outcomes that are underway. For instance, the Vitamin D and Omega-3 Trial (VITAL) from Harvard involves more than 25,000 people who are taking 2,000 IU of vitamin D a day (and/or omega-3 pills or a placebo) for an average of five years; the endpoints are cancer and heart disease. First results are expected in 2017; those from three other important trials won’t come out until 2020. Why haven’t such trials been done until now? Largely because they are so expensive, and there are no drug companies to fund them. The Harvard study will reportedly cost $22 million, funded by taxpayer dollars from the National Institutes of Health.
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 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 early 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.