Dr. Moyad highlights what has been learned about vitamin D in urology

"This is my passion—the area of diet, lifestyle empowerment, and dietary supplements: the good, the bad, the indifferent," says Mark A. Moyad, MD, MPH.

Mark Moyad, MD, MPH, is the Jenkins/Pomkempner Director of Complementary Alternative Medicine in the Department of Urology at the University of Michigan Medical Center. In this interview, Moyad discusses the history of vitamin D in urology as well as the advancements that were made in vitamin D last year based on findings from the recent VITamin D and OmegA-3 TriaL (VITAL) (NCT01169259).

Could you describe your own career interests?

I am Dr. Mark Moyad, MD, MPH. I am the Jenkins/Pomkempner Director of Complementary Alternative Medicine in the Department of Urology at the University of Michigan Medical Center. I have been doing that for 25+ years. I can't believe it. I think it's one of the longest running areas of education and research in over-the-counter complementary medicine globally. We've been teaching all over the United States and countless countries.

Long story short, I started very early. I started at college with my first paper, it was in nutrition. Then in public health, I was a part of interviewing over 150 patients who were impacted by the [adverse] effects of a supplement. That was in the 1990s, it was called eosinophilia-myalgia syndrome.

I quickly learned that there is this exploding area called supplements and over-the-counter products, and we don't get education in it. This is where I was publishing. This is where my interests were. I even did consultation at the University of Michigan in my first several years with a lot of individuals. This is my passion—the area of diet, lifestyle empowerment, and dietary supplements: the good, the bad, the indifferent.

After doing the [American Urological Association] (AUA) classes, the AUA updates, 150+ publications, 16 books, this is basically what I do and where I spend my time, and I love it. It's the greatest possible job in the world because there's this beautiful space of over-the-counter supplementation. Bringing objectivity to it has not been easy, but it's been a pleasure on my part and the colleagues I've worked with throughout the globe.

Today, I know we're going to talk about vitamin D, but this is very much in the wheelhouse. Vitamin D is one of the biggest sellers over the past decade over the counter. Every over-the-counter company sells some version of vitamin D. My background easily transitioned into the idea that some of the biggest trials going on right now are in vitamin D. A number of medical disciplines, especially urology, needed somebody to translate what was going on, so here we are.

What is the history of vitamin D trials in urology?

I always like to give props to all the giants of urology whose shoulders we're stepping on. The [Selenium and Vitamin E Cancer Prevention Trial] (SELECT) (NCT00006392) was one of the largest dietary supplement studies in the world and published some of their results in 2011. That was a urology trial that was trying to look at vitamin E and selenium to see if it would reduce the risk of prostate cancer. The reason I think a lot of people don't know about the trial, even though it was one of the largest in the world ever done, primarily done in the United States, was they didn't find a benefit to selenium and vitamin E to prevent prostate cancer. In fact, there was some suggestion from that trial that vitamin E as a supplement might increase the risk of prostate cancer.¹ That was the biggest surprise.

Since that time, there have been a lot of little studies going on, but we've been waiting for something very large to give us some idea of another supplement. It was vitamin E and selenium in 2011-2012. There was a lot of hype about it. People were very excited. They lost their excitement in urology about it, but then along came vitamin D.

Vitamin D has probably been argued or advertised that it does "everything under the sun for you,” no pun intended, that it makes breakfast for you, that it cures you of all these diseases. What we needed was a group of individuals to come along, like happened in the SELECT trial, and do a massive study.

The Boston/Harvard group did that, along with a sponsorship by the [National Institutes of Health]. It was probably the most rigorous trial in US history to see if vitamin D could prevent a variety of medical conditions, primarily cardiovascular disease and cancer.

So, after the SELECT trial was finished, the vitamin D trial started to launch. The interventions just finished several years ago. Now what you're starting to see is just an avalanche of publications coming out from this largest vitamin D prevention study ever done.

On the vitamin D side, they were doing 2000 international units (IU) vs placebo. It was a placebo-controlled trial. It was done so well. They should give a class on how well this study was done. It was very objective, and it's not easy in the world of over-the-counter [supplements] or other areas to say that you got an objective study. The idea was to find out what it does here. It's touching upon urology now in terms of part of the study.

What advancements in vitamin D were made in 2022?

In 2022, we have been waiting to get this treasure trove of information of what does vitamin D do and what doesn't it do. To cut to the chase, in 2022, we learned that for a lot of things that people thought vitamin D would cure or take care of, it turned out to be not so true. That's also the story of vitamin E in urology. The idea was that it could do a lot of things, but it turned out if it can do some things, it's a very small pool of things that it can do. It can be beneficial, but for most things, it's indifferent.

That's what we learned in 2022, that for a variety of areas, including—can you imagine this—reducing the risk of fractures. Vitamin D is associated with bone health.

Now, the individuals in this trial were straightforward—generally healthy, midlife to older individuals. If you're a man 50 and older, you can get in the trial, and if you're a woman 55 and older, you could get into the trial. About half men, half women, and very strong minority group representation. They were prepared to put together an amazing trial, and they did.

You get over 25,000 individuals randomized. They're going to take the intervention versus placebo for a little bit more than 5 years. What we've learned is for most of the end points thus far, including the prevention of cancer and including the prevention of cardiovascular disease, it didn't work any better than placebo.² That's important to know. It really is. We thought there was the potential there to have a strong ability to prevent a variety of different conditions.

The big story in the past few years is it doesn't seem to prevent heart disease, and it doesn't seem to prevent cancer. What's going to happen in 2023, is that after this interview, we're going to learn more about the urologic cancers. Was there any potential impact in prostate, for example? I'm hoping they also look at bladder cancer. I'm hoping they look at a variety of urologic end points. We're starting to learn what vitamin D does and what it doesn't do well.

I think this is incredibly important. Even though most of the end points had been negative and found no benefit, I think there are a couple of findings that we've learned in 2022 that surprised me. Finding number 1 is they went and did a secondary analysis of the cancer prevention data with vitamin D. What it seemed to suggest, and they're studying this further, is that for individuals with a healthier BMI [body mass index], the vitamin D dosage might have had the ability to reduce the risk of aggressive cancer.³ There are a lot of subgroups and a lot of things being teased out, but there's a suggestion that if you're of a healthier weight, that vitamin D at this fairly low dosage (2000 IU per day) might reduce the risk of being diagnosed with an advanced cancer.

The reason why they're going to pursue that further is it has been argued for a long time that the more adipose tissue a patient or an individual carries—vitamin D is a fat-soluble vitamin—that a lot of the vitamin D that's in the bloodstream then goes into the adipose tissue and is sequestered there and not utilized. Is it possible that a person of a healthier weight or BMI is more sensitive to the benefits of Vitamin D? It's possible.

How this translates into urology is not just when they look at this in cancer, but when they look looked in terms of women and urinary incontinence. The suggestion there again was women who had a healthier weight or BMI, vitamin D had a suggestive benefit in that urologic category.⁴ They're going to test that further.

All this stuff is going on, and that's why I was asked to write this editorial⁵, to try to bring all this together. Let me go back to the main findings. A couple of main findings for any clinicians and investigators, anybody from the public [reading] this, we're learning that for many of the end points, vitamin D didn't work any better than placebo at this dosage. We learned that it didn't reduce the risk of cancer and cardiovascular disease, which was the primary intention. We're learning though of a healthier BMI that might be more sensitive to the beneficial effects of vitamin D. That's interesting, and that includes looking at some areas like female incontinence.

I think the most surprising thing and the reason why you have to do these studies, is that there was a fairly strong suggestion—and this was an ancillary study in 2022—that vitamin D might reduce the risk of autoimmune disease. That was a surprise. Not a shocker, but a surprise. The Harvard team and some of the investigators, if you look online, they are already talking about this possibility with patients. They feel like that was a strong enough signal—and you'll see in the medical journals—that this should be at least discussed at some of the autoimmune clinics. Not if you already have autoimmune disease, like LUPUS or rheumatoid arthritis, that it can slow the progression, but if you are at high risk for autoimmune disease. We don't have a single preventive pill that I'm aware of that is also of low cost, just to simply prevent an autoimmune condition.

In the LUPUS clinic and other places, this has been a discussion already in the clinical practice. It could turn out that the greatest story of 2022 is that vitamin D didn't do the things that some people thought it would do, but in the area of prevention, in terms of preventing autoimmune disease, if that turns out to be true, that is a massive, massive homerun. An incredible finding, if it turns out to be true as they continue to investigate it. It was statistically significant. It was a strong enough signal to continue to pursue that.

A large part of the vitamin D hype was the fact that almost every cell in the human body has a vitamin D receptor, including all the immune cells. There has been a thought that vitamin D, when you get adequate intakes—not too much, not too low—that it can help control immune response. The immune response becomes more robust when you need it, and when you don't need it, it's not so robust, but it doesn't turn on you, like an autoimmune disease does. In 2022, that's a lot to digest. In 2022, you have to remember in my world, that's more in my opinion that we've learned about vitamin D than in my entire 30 years collectively. I think it's an incredible finding if that turns out to be true. That's where we are in 2022 with vitamin D.

Clinicians have asked me [and] I get notes from the public that say, 'Well, should I discuss the idea of taking 2000 international units of vitamin D with my clinician, and if I'm higher risk for autoimmune disease?' The answer is absolutely, this should be discussed.

I think part of the shame of these supplement trials is they don't get labeled as phase 1, 2, [or] 3. When you do a drug study and you pass a phase 3 trial, you can get FDA approval. We all know that, and I think the public knows that. We don't have that for supplements, but we do have trials that are the equivalent of a phase 3 trial in the pharmaceutical world. The VITAL trial with over 25,000 individuals randomized was so robust in its methodology, that that's a phase 3 trial. I think the information coming from it is important enough to know overall.

I'll tell you something else we've learned in 2022. This is part of the papers, because I've written a variety of teaching papers on vitamin D in a variety of urology journals. What we also learned is that there's this severe [misconception] out there in vitamin D that more is better. What we learned in the trial, and I think a lot of clinicians are learning this, is that when vitamin D started to get hot 10 years ago, it started to get added back to all sorts of foods. All the plant-based milks, a lot of them are fortified now with vitamin D. Almost all of your multivitamins have doubled their amount. People are being exposed to more vitamin D than ever. It was very rare in this study of generally healthy people throughout the United States to find someone who was deficient from a blood test. That's why people have to be careful, because what may have been a deficiency 10 years ago, because of all this fortification, and all these people taking all these pills with vitamin D in it, there are a lot of people who are doing quite well.

References

1. Klein EA, Thompson Jr. IM, Tangen CM, et al. Vitamin E and the risk of prostate cancer: the Selenium and Vitamin E Cancer Prevention Trial (SELECT). JAMA. 2011;306(14):1549-56. doi:10.1001/jama.2011.1437

2. Chou SH, Murata EM, Yu C, et al. Effects of vitamin D3 supplementation on body composition in the VITamin D and OmegA-3 TriaL (VITAL). J Clin Endocrinol Metab. 2021;106(5):1377-1388. doi:10.1210/clinem/dgaa981

3. Manson JE, Cook NR, Lee I, et al. Vitamin D supplements and prevention of cancer and cardiovascular disease. N Engl J Med. 2019;380(1):33-44. doi:10.1056/NEJMoa1809944

4. Markland AD, Vaughan C, Huang A, et al. Effect of vitamin D supplementation on urinary incontinence in older women: ancillary findings from a randomized trial. Am J Obstet Gynecol. 2022;226(4):535.e1-535.e12. doi:10.1016/j.ajog.2021.10.017

5. Moyad MA. Vitamin D and the vital need for more VITALs: seeking causation amidst escalating association, inflammation, and supplementation. J Urol. 2023;209(1):29-31. doi:10.1097/JU.0000000000003036