The worthlessness of vitamin D is mildly exaggerated

DYNOMIGHT best topics follow about For a while there, many people thought vitamin D was magical—that it could improve bones, the heart, infections, cancer, heart disease, longevity, even mental health. But among people I respect, opinion is now overwhelmingly that taking vitamin D does nothing unless you’re severely deficient. The central argument is that while vitamin D levels are correlated with ~all positive health outcomes, when you actually test vitamin D supplements against placebo in randomized trials, nothing ever happens. That’s what I used to think, too. But I’ve come to think the skeptics have over-corrected. Yes, randomized trials have shown the magical correlations are not causal. But if you start with non-insane expectations, the trials look like weak but positive evidence. And if you consider what we know about biology and evolution, I think the balance of evidence tips pretty clearly in the direction that people with low-ish levels would be wise to supplement. Am I certain that vitamin D is beneficial for people with low-ish levels? Absolutely not! But I claim that’s the best bet given the limits of our knowledge. The classical view: Boring bone vitamin Most vitamins are “ingredients” that the body uses to do stuff. Vitamin D is more like a “signal” that the body uses to communicate with itself about what to do.1 The classical “endocrine” story of vitamin D is that your body uses it to tell your guts to take in more calcium from food. If you don’t get enough vitamin D, then you have calcium problems. That’s all you really need to know about the classical view. But if you enjoy gawking at biology’s complexity, I recommend this diagram and the following three paragraphs: Ready for science? OK: Almost all the cells in your body make provitamin D.2 Usually, this is all converted to cholesterol, but your skin cells leave some sitting around. When UVB light hits those skin cells, provitamin D is transformed (physically by the light itself) into previtamin D and then (by heat) into vitamin D. This diffuses from the skin cells into blood vessels.

There it binds to a protein3 and starts circulating in the blood, where it is joined by vitamin D from food.4 Eventually, the liver converts it into more-stable storage vitamin D. It also soaks in and out of fat and muscle tissue, which acts as a slow-release reservoir. Now, a fun fact: If calcium levels in your blood get too low, then your heart will stop working and you will die. To avoid this, you have parathyroid glands in your neck that sense when calcium is getting low, and release parathyroid hormone into the blood. This tells your bones to release some of their stored calcium. It also tells your kidneys to convert some of the storage vitamin D from your blood into active vitamin D. And when that gets to your guts, they try to absorb more calcium from food. So what happens if you don’t get enough vitamin D? Well, your body is not going to let calcium levels drop too low, because your body is designed to avoid death. Parathyroid hormone will still get secreted, and it will still tell your bones to scavenge calcium. But without vitamin D, your guts never get the signal to gather extra calcium from food. So the body scavenges a lot of calcium from your bones, and you end up with weak bones, which is bad. Now here’s the thing: In this story, only active vitamin D actually does anything. The kidneys make this on demand in response to calcium levels, not in response to storage vitamin D levels. General opinion is that as long as the blood has above ~25 nmol/L of storage vitamin D, then the kidneys have no trouble making active vitamin D.5 Furthermore, survey data suggests that only ~2% of the population has levels below that threshold. This suggests that for ~98% of people, supplementing vitamin D should do approximately nothing. The correlation view: Magical mystery cure Rickets is a terrible disease that involves soft bones, stunted growth, and skeletal deformities. It’s probably been with us since ancient times, but it became common in the West after the industrial revolution. In 1890, a Scottish missionary named Theobald Palm observed that rickets was common in smog-ridden UK cities but almost unheard of in sunny countries with poor sanitation, suggesting sunlight itself was the issue.

This contributed to the discovery that rickets could be cured with UV light or cod-liver oil, and eventually the discovery of vitamin D. In 1941, Apperly noticed that the amount of sunlight in different US states was positively correlated with skin cancer but inversely correlated with overall cancer mortality.6 He gave this charming graph: Apperly never mentions vitamin D, presumably because he thought it was a boring bone vitamin. Things took off in 1980, when Cedric and Frank Garland published, “Do Sunlight and Vitamin D Reduce the Likelihood of Colon Cancer?” Seemingly unaware of Apperly, they gave a similar, but uglier, graph: They point out that regional diets (like meat and fiber) didn’t seem to explain this pattern. Instead, they propose a mechanistic story: Sunlight ↓ Vitamin D ↓ Adequate calcium in blood ↓ Reduced inflammation of epithelial cells in the colon ↓ Less colon cancer (It’s always inflammation.) This paper was rejected many times before finally being published. I wish I could find an un-gated copy to link to, because it would have made a magnificent blog post.7 Following that paper, there was an explosion of work that found negative correlations between sunlight (or latitude) and other types of cancers as well as blood pressure, diabetes, and multiple sclerosis. Then people started measuring vitamin D in blood. In 1989, the Garlands and collaborators found blood samples takin in 1974 from 25,000 people. They found that 34 of those people had since gotten colon cancer. They matched these with 67 demographically similar people and measured vitamin D levels in the stored blood samples for all 101 people. Among that group, people with vitamin D levels below 50 nmol/L got colon cancer more than three times as often as people with higher levels. Again, many similar studies followed. These linked higher vitamin D levels to better outcomes in cardiovascular disease, diabetes, obesity, infectious disease, Parkinson’s, and mood disorders. While results were mixed for non-colorectal cancer incidence, higher vitamin D levels predicted better survival of many cancers. Amazingly, all-cause mortality was roughly 30% lower for those at the 75th percentile of vitamin D levels compared to the 25th.

Vitamin D was looking like a miracle. But how could it do all that stuff if it was just a boring bone vitamin? Meanwhile in biology While all these correlations were being discovered, we learned that the body doesn’t just use vitamin D for bone stuff. In 1969, we discovered the vitamin D receptor that active vitamin D binds to in the gut and bones. And in the 1980s came a shock: Almost all cells in the body have vitamin D receptors. These seem to do different things in different tissues. In the pancreas, they support insulin secretion. In immune cells, they boost antimicrobial peptides and reduce inflammation. In neurons, they influence proliferation and differentiation. So… What? When calcium drops and the kidneys put out active vitamin D, does every part of the body start doing different unrelated stuff? In the late 1990s, we cloned the gene for the enzyme that the kidneys use to convert storage vitamin D to active vitamin D. Soon came another shock: This enzyme also exists in tons of other cells, including immune cells, the heart, the skin, the prostate, the breast, and colon. (Another win for the Garlands.) So it’s not just the kidneys making active vitamin D to trigger the gut. Cells everywhere are making their own active vitamin D and using it to trigger vitamin D receptors in neighboring cells, or even inside the same cell.8 This often has little to do with calcium or bones.9 So: The kidneys use vitamin D as a boring bone hormone. As long as the blood contains at least ~25 nmol/L of storage vitamin D, the kidneys don’t care. They create the same amount of active vitamin D, in response to calcium levels. But now cells everywhere are using storage vitamin D. To do god-knows-what. With god-knows-what sensitivity to circulating vitamin D levels. And remember how only active vitamin D does anything? That’s wrong. In the mid-1970s, we learned that storage vitamin D also binds to the vitamin D receptor. The affinity is 100-1000× lower, but have ~1000× more in your blood. So maybe circulating levels of storage vitamin D themselves matter, independently of how much active vitamin D gets made?

If that’s not confusing enough, people also noticed that while active vitamin D levels in the blood aren’t correlated with storage vitamin D (above ~25 nmol/L), levels of parathyroid hormone (the thing your parathyroid glands use to tell your kidneys to make active vitamin D) seem to decline as levels of storage vitamin D rise from ~25 to 50 or 75 nmol/L. Huh?10 On the one hand, all this makes the idea that vitamin D could be a miracle more plausible. On the other hand, this is getting complicated. And do we really believe that raising your vitamin D levels from the 25th to the 75th percentile could reduce your risk of death from any cause by thirty percent? Maybe we should try giving people vitamin D and see what happens. Then came the RCTs There have been many randomized trials. The “right” thing to do in such cases is to look at meta analyses that carefully combine all the data. We’ll get to those. But they conceal a lot of important nuance about what actually happens on the ground during these trials. So let’s start by going over the three main “megatrials”. The Women’s Health Initiative (WHI) trial came out in 2006 and is still the largest vitamin D trial ever done. This took 36,000 postmenopausal American women and assigned half to take 400 IU daily with calcium and the other half to placebo.11 After seven years, here’s what happened:12 Outcome (WHI trial) Hazard ratio Fractures 0.97 (0.91 to 1.03) Cancer 0.97 (0.91 to 1.04) Cancer mortality 0.90 (0.77 to 1.05) CVD mortality 0.94 (0.78 to 1.12) All-cause mortality 0.92 (0.83 to 1.01) Kidney stones 1.17 (1.02 to 1.34) (The hazard ratio is the ratio of the rate that something happens in the treatment vs. placebo groups. So, a number less than one suggests a benefit to taking vitamin D, while a number larger than one suggests a harm. The numbers in parentheses show a 95% confidence interval.)