A hundred years of debate about vitamin D

Summer is here and many people can’t wait to start “taking vitamin D,” which is more popular than ever, even though it isn’t really a vitamin or even a single substance, but rather a hormonal system that we absorb from the sun. Research and public interest in vitamin D deficiencies have grown over the last 10 years. “They [health care providers] request blood tests for vitamin D levels for no reason. When they learn that a patient has low levels of vitamin D, then they prescribe treatment and even more blood tests,” said Ricardo González, a family physician and director of the San Fermín Health Center in Madrid. “Many people call it the ‘sunshine vitamin’ and want to check vitamin D levels as part of other routine blood tests. But not many people want to take vitamin supplements when their levels are low. Tests for vitamin D levels should only be done for people with risk factors, and they should only take supplements if needed,” he said.

August 1, 2022 will mark 100 years since biochemists Elmer McCollum and Marguerite Davis published a study in the Journal of Biological Chemistry that reported their discovery of vitamins A and B, and another substance “that helps build calcium.” They would ultimately give this new substance a name–vitamin D–a misnomer since vitamins are defined as essential compounds that our bodies cannot synthesize. However, the skin does produce vitamin D photochemically when ultraviolet-B (UV-B) irradiates a cholesterol precursor in our bodies.

We now know that this system is essential for bone health and the metabolism of calcium and phosphates. Vitamin D deficiency is a global health problem primarily caused by insufficient sun exposure, which provides more than the 90% of the vitamin D our bodies need. This deficiency is estimated to affect more than a billion people, especially the elderly, and some call it a pandemic. The remaining 10% of the vitamin D that our bodies need is obtained by consuming oily fish such as tuna, salmon, or mackerel and, to a lesser extent, eggs and mushrooms. Recently, genetically modified tomatoes have been engineered to increase their vitamin D content.

“Had we lived centuries ago, we all would have sufficient levels of vitamin D. But since we are no longer diurnal creatures, and because we wear clothes and don’t do much outdoor exercise, it’s almost impossible to get all the vitamin D we need from the sun. We have to get it through our food,” said Esteban Jódar, an endocrinologist with Quirónsalud Madrid University Hospital and a professor at European University. To get enough sun without risking premature aging of the skin or melanoma, Jódar recommends, “15 minutes of outdoor exercise in the morning and 15 in the afternoon with bare arms and legs.” However, in Spain and other countries north of the 35th parallel, the amount of UV-B radiation synthesized by the skin drops in winter and spring. Diet can compensate for this deficiency if basic foods like bread, milk, and dairy products are vitamin D-fortified like they are in the Nordic countries. But in other countries where these foods are not fortified, “we see a paradox that, despite having more sun, [vitamin D] levels are lower than in Nordic countries,” said Jódar.

When Carmen Madrigal, a pediatrician at the Doctor Morante Health Center in Santander (Spain), checks vitamin D levels in children, she says, “they are usually just right. But if they live in apartments and cities, they’ll get little sun, especially in winter, because many of their extracurricular activities are indoors.” Unlike some of her colleagues, she does not recommend dispensing with the sunscreen for children because, “that doesn’t seem very smart. But it’s difficult to know for sure if you’re doing the right thing,” she said.

As in many aspects of biomedicine, there are few certainties about vitamin D, some areas of consensus, and much debate among the experts. José Manuel Quesada, a retired endocrinologist and researcher at the Maimónides Biomedical Research Institute of Córdoba (Spain), has dedicated his life to this field of study. “What do we mean when we say vitamin D?” he asks, rhetorically. He says this ambiguous term encompasses several compounds that form the endocrine system of vitamin D, similar to that of other steroid hormones. One compound consists of two nutrients–cholecalciferol or vitamin D3. This is what our skin synthesizes from UV-B, and what we also get from certain foods. The other consists of ergocalciferol or vitamin D2, which is found in certain plants, yeasts, and mushrooms. These produce a prohormone called calcifediol (25 hydroxyvitamin D3)–the compound measured by blood tests–and calcitriol or active hormone, the last link in the system.

Although there is still some disagreement, experts have established a normal range for calcifediol levels: between 30 and 70 ng/ml (nanograms per milliliter). Levels below 20 ng/ml indicate an insufficiency, and levels below 10 ng/ml indicate a deficiency. Jódar, who is a member of the Mineral and Bone Metabolism Group of the Spanish Society of Endocrinology and Nutrition (Sociedad Española de Endocrinología y Nutrición - SEEN), says that supplements should only be taken by people with levels below 30 ng/ml and who have risk factors, such as institutionalized elderly patients, pregnant and lactating women, and people suffering from obesity, diabetes, osteoporosis, and other chronic diseases. Healthy individuals should take supplements only if they have levels below 20 ng/ml. In studies mostly conducted in wealthy countries, 88% of the population exhibits some level of vitamin D insufficiency, and almost 7% exhibit a serious deficiency. SEEN found that in Spain, 80% of adults under 65, 100% of adults over 65, and 40% of minors have vitamin D levels below 20 ng/ml.

Although minor insufficiencies do not produce symptoms, lack of vitamin D is associated with multiple pathologies, such as autoimmune disorders, infectious and cardiovascular diseases, and diabetes. It can lead to osteoporosis and, in extreme cases, produces a severe softening of the bones called rickets in children and osteomalacia in adults, both of which are rare in Spain. If so many people have vitamin D deficiencies, why hasn’t this led to epidemics of these diseases? From a primary care perspective, Ricardo González says that “the deficit indicated by the analytical data doesn’t correspond to the clinical picture.” Madrigal agrees. “We no longer see rickets, which was common during my father’s lifetime,” said the retired pediatrician. In 2016, the New England Journal of Medicine (NEJM) published a study titled, “Vitamin D deficiency: is there really a pandemic?” in which several US specialists argued that setting the minimum normal level of vitamin D at 20 ng/ml encompasses many healthy people. The study also concluded that too many screening tests are performed and that supplements are unnecessarily prescribed. The authors of the study believe that a more appropriate minimum normal level would be 12.5 ng/ml, which would encompass less than 6% of their compatriots.

SEEN does not recommend measuring calcifediol in people with no risk factors, nor does it advocate systematic supplementation with pharmacological preparations in adults under 50 to improve bone health. There is no evidence supporting the use of supplements to obtain benefits when other pathologies are present. “There are very few high-quality studies of cases in which administration of vitamin D successfully alleviated a condition. Most of the existing studies have been incorrectly designed,” said Jódar. “All the trials done in the last 100 years have been poorly designed,” concurs Quesada. He claims that vitamin D has been studied as if it were a drug, not a nutrient, and the trials are done with people that have normal vitamin D levels, so administering more vitamin D will not improve anything.

Research on vitamin supplementation has yielded mixed results. In 1980, a study published in the International Journal of Epidemiology suggested that vitamin D supplements might protect against colon cancer after finding that mortality was higher in places with less natural light, such as large cities and rural areas at high latitudes. Another study published recently in Nutrients, hypothesized that, “many experimental studies in cultured cells and animal models have described a wide range of anticancer effects,” but added the disclaimer that “clinical trials have provided limited support for this hypothesis.”

A 2019 study published in the NEJM concluded that supplements did not decrease the incidence of invasive cancer or cardiovascular events. Other research published in The BMJ medical trade journal found a protective effect against acute respiratory infections, especially in those with significant [vitamin D] deficits. Quesada studied its effect on coronavirus infections and concluded that low levels of calcifediol are associated with an increased risk of COVID-19 infection, severity, and mortality. But both the National Institutes of Health (NIH) in the US and the National Institute for Health and Care Excellence (NICE) in the UK state that taking vitamin D alone to prevent or treat COVID-19 is not justified. However, a recent systematic review in the Journal of Clinical Endocrinology and Metabolism determined that vitamin D supplements do reduce the risk of hip fracture, although “high-risk individuals, such as the elderly, institutionalized patients, and people with low vitamin D levels, may benefit the most.”

Considering all the uncertainty and conflicting research, Quesada believes that we should follow the Nordic example and supplement basic foods with vitamin D for the whole population, in the same way that iodine is added to salt to help the thyroid function properly. “While all this research is going on to determine whether having good levels of calcifediol prevents cancer, cardiovascular disease, or falls, let’s get the entire population up to adequate vitamin D levels,” said Quesada.