As a clinician, you probably understand the pathophysiology of vitamin D deficiency well. But here are four things you may not know about the evolving role of this hormone in the treatment and prevention of disease.

The Role of Rickets

You certainly know vitamin D deficiency can lead to osteopenia and osteoporosis, as well as osteomalacia. You’re probably also aware it has been implicated in various nonskeletal conditions — hypertension, hypercholesterolemia, multiple sclerosis, rheumatoid arthritis, and some carcinomas. But among the various vitamin D-related illnesses, rickets enjoys the longest history of being recognized as a distinct disease, having been documented as early as the mid-17th century.

While real progress toward preventing this notorious, debilitating disease would unfold in the early 20th century, serendipity was a major factor in elucidating vitamin D, whereas the pathophysiology of rickets remained hidden for some time.

“People in the sanatoria were feeding liver to patients and curing rickets in the 1920s, without knowing about the vitamin D being the reason,” said Daniel Bikle, MD, PhD, a leading expert in bone endocrinology and a professor emeritus in the Departments of Medicine and Dermatology at the University of California San Francisco. “Subsequently, there were a couple of groups that identified vitamin D.”

A Shared History…With Rat Poison?

The main group doing rickets research in the 1920s was based at the University of Wisconsin-Madison, but they had help from the discovery in 1913 by Elmer McCollum and Marguerite Davis that cod liver oil contained a fat-soluble substance, which they called “fat-soluble A,” was needed for growth, not only of bones but also of various other tissues.

The names get tricky, because 1 year earlier, Casimir Funk, a biochemist at the Lister Institute of Preventive Medicine in London, England, had coined the word “vitamin” — short for “vital amine” — whose absence led to diseases he was studying: beriberi, scurvy, and pellagra.

The connection with this trio should make sense if you know your B vitamins. Some of them are amines — notably thiamine (which prevents beriberi) and niacinamide (which prevents pellagra). But as for these water-soluble coenzymes getting stuck with the letter B — despite Funk coming up with the word “vitamin” in 1912, while the Wisconsin fat-soluble non-amine was discovered later — that’s simply because the Wisconsin researchers took A, whereas Funk did not take any letter.

As it turned out, the “fat-soluble A” was more than one compound. In 1922, McCollum found heating or oxidizing the substance destroyed its ability to support various aspects of growth but preserved whatever it was that prevented rickets. Thus, the destroyed compound came to be called vitamin A, and the other compound was called “antirachitic factor,” later known as vitamin D.

After 2 years, McCollum’s colleague at Wisconsin, the biochemist Harry Steenbock, found irradiating certain foods — such as mushrooms, plant-based products, and cow’s milk — with ultraviolet (UV) light could boost their levels of vitamin D. We now know UV light had this effect because the foods contained precursor compounds: ergosterol in the mushrooms and plants and 7-dehydrocholesterol in the milk.

To be sure, ergocalciferol and cholecalciferol are not 1,25-dihydroxyvitamin D, the active compound, whose synthesis requires two hydroxylation steps — one in the liver, the next in the kidney. Understanding the hydroxylation steps and the distinction between 1,25-dihydroxyvitamin D and its precursors would take two generations of researchers at Wisconsin, funded by what came to be known as the Wisconsin Alumni Research Foundation (WARF). If WARF sounds familiar, it’s because research funded by the group ultimately led to the name of the drug warfarin — an inhibitor of the recycling of vitamin K epoxide back to active vitamin K — and its use as a rodenticide in the late 1940s, then as a human anticoagulant starting in the 1950s, when it began saving numerous lives, including that of President Dwight D. Eisenhower.

The discovery of warfarin itself was serendipitous. Back in the 1930s, cattle were dying from a hemorrhagic condition linked to moldy sweet clover hay on which they were feeding. After a farmer went to Madison to bring the crisis to the attention of WARF researchers, they isolated the hemorrhage-inducing compound, dicoumarol, which was later modified into the drug that was named for the foundation. Dicoumarol, meanwhile, had a direct impact on warfarin’s trade name, Coumadin.

Clues From the Sanatoria

Hypertension, hypercholesterolemia, multiple sclerosis, rheumatoid arthritis, and cancer all are hot topics today related to vitamin D. But hints that the substance had widespread effects in the body were evident a century ago, when it was still called antirachitic factor.

“In the 1920s, the sanatoria would bring tuberculosis patients up to a mountaintop or somewhere, and they had them sunbathe,” Bikle said. “It was one of the curative means; it seemed to help, and they didn’t know why it helped.”

Modern-day research supports the idea that vitamin D was the reason sunlight was helpful against tuberculosis. The connection between vitamin D and immunology is fairly obvious today for the simple reason that immune cells, such as macrophages and T and B lymphocytes, have vitamin D receptors.

Bone demineralization is associated particularly with aging and disease, but it is also a major issue in human spaceflight. Even relatively brief periods of weightlessness can lead to significant bone loss, with NASA reporting that bone density drops by between 1% and 1.5% in the course of a 4- to 6-month mission.

Imagine getting selected as an astronaut not only because you have two doctoral degrees and a pile of science publications taller than Olympus Mons but also because you’re as fit as an Olympian athlete. Then you train for 10 years to travel to Mars, you leave Earth with the DEXA scan of a healthy 45-year-old, but you arrive back on Earth 2 years later with the bone mineral density of a 90-year-old and the risk for a hip fracture that goes with it.

Such a scenario is why, as with bone loss on Earth, the space medicine angle on bone has emphasized weight-bearing exercise, bisphosphonates, and vitamin D.

Bikle advised NASA on space bone endocrinology back in the 1980s and helped conduct some of the first studies of the effects of weightlessness on the skeleton.

“We worked a fair amount with what we called the hindlimb suspension model,” Bikle recalled, referring to a widely used technique to offload weight from rodents as a model for offloading from human weight-bearing sites, such as the femoral neck. “We found that rats lose about 15% of their bone density over a 2-week period. These were long bones, and they don’t lose bone in the head or the forelimbs.”

Interestingly, Bikle and his colleagues found levels of 1,25-dihydroxyvitamin D declined with hindlimb unloading.

“This big drop in 1,25 vitamin D levels occurred without much change in calcium or parathyroid hormones, and those were the days when we weren’t able to study this in any sophisticated way, because we hadn’t yet cloned the 1-hydroxylase in the kidney, which we did subsequently,” he said.

When researchers infused the animals with active vitamin D, on the hypothesis that it would protect their bones, they were surprised to find the opposite occurred. “In concert with research of other groups, this was the time of the big realization that too much 1,25 vitamin D causes osteomalacia, inhibiting bone formation,” in rodents with hindlimb suspension, he said.

As you read this, NASA’s Project Artemis II is months away from sending humans back to the Moon after more than 52 years of limiting astronauts to low Earth orbit, so research on the effects of microgravity on bones is poised to accelerate. Stay tuned for more surprises about the role of vitamin D.

David Warmflash, MD, has been a contributor to Medscape Medical News on various topics since 2019.