High-dose vitamin D: negative results from a randomized clinical trial

Data from a recently published, Canadian, clinical trial of high-dose vitamin D as a method to strengthen bones in healthy adults who do not have osteoporesis have had significant and unexpectedly negative results.

The paper by Burt et al., just published in the Journal of the American Medical Association (and summarized on the MedPage Today web site), reports data from a total of 311 otherwise healthy, adult patients.

The patients were randomized to receive one of three daily doses of vitamin D (25-hydroxyvitamin D) for a total of 3 years:

  • 400 IU per day (n = 109)
  • 4,000 IU per day (n = 100)
  • 10,000 IU per day (n = 102)

Calcium supplements were also provided to participants with a dietary calcium intake of < 1,200 mg per day. No one was randomized to a placebo instead of a daily dose of vitamin D.

The core result of the paper was that not one of the three doses of vitamin D prevented bone loss, and — furthermore — there was actually a decline in the radial volumetric bone mineral density (BMD) that increased with the dose of vitamin D over a 3-year period compared to baseline levels:

  • For patients randomized to 400 IU, the loss in BMD was -1.2 percent.
  • For patients randomized to 4,000 IU, the loss was -2.4 percent.
  • For patients randomized to 10,000 IU, the loss was -3.5 percent.

The authors conclude that:

Among healthy adults, treatment with vitamin D for 3 years at a dose of 4,000 IU per day or 10,000 IU per day, compared with 400 IU per day, resulted in statistically significant lower radial BMD; tibial BMD was significantly lower only with the 10,000 IU per day dose. There were no significant differences in bone strength at either the radius or tibia. These findings do not support a benefit of high-dose vitamin D supplementation for bone health.

It has long been argued by some that giving patients with prostate cancer very high doses of vitamin D would be beneficial to their bone health and minimize bone loss. While this paper by Burt et al. cannot be said to disprove such arguments, it should be noted that it causes the hypothesis to be called further into question. It should also be noted that Burt et al. were expecting a very different result, which was that high doses of vitamin D would be beneficial in preventing bone loss in otherwise healthy patients. This turned out very clearly not to be the case!

Once again, this is a paper that clearly demonstrates the importance of seeking and obtaining level 1 evidence for hypotheses that may seem — to many — to be “obvious”. The human body is a very complex organism; it will always tend to respond to treatment in ways that are balanced back toward the “normal”. In this particular case, the use of high doses of vitamin D appear to have come with higher levels of risk than benefit over a period of 3 years.

Your sitemaster is not surprised by this finding. He has long expressed concerns about the use of very high doses of vitamin D and the suggestion that these were necessarily beneficial in the management of prostate cancer.

18 Responses

  1. I wonder what kind of vitamin D was used. I’ve read that vitamin D3 is the preferred form.

  2. You need to include Vitamin K2 for good bone results.

  3. I always ask — but is this plausible?
    MedPage Today discusses the plausibility of these findings

    “One possible explanation for these findings could be related to an increase in plasma marker of bone resorption (CTx) paired with suppression of parathyroid hormone. This was particularly true among the highest 10,000 IU/day group who saw sharp decline in parathyroid hormone levels, as well as a sharp increase in plasma CTx levels during the first 18 months of being on high-dose vitamin D, according to the authors.

    “High-dose vitamin D without extra calcium supplementation has been associated with increased levels of the active vitamin D metabolite 1,25(OH)2 vitamin D (calcitriol), and an increase in CTx,” they explained. On the other hand, high doses of vitamin D can also suppress parathyroid hormone levels either by directly impacting parathyroid cells or also by bolstering intestinal calcium absorption.”

    This RCT supports a major Mendelian randomization study that found “Genetic predisposition to lower levels of vitamin D and estimated calcium intake from dairy sources were not associated with fracture risk.”

    Also, the dose-dependent effect (higher doses were more damaging than lower doses) increases the plausibility of this being a real effect.

    It’s worth noting that vitamin D, unlike other vitamins, is a steroid. Steroids tend to interact and to have wide-ranging effects in humans. Overwhelming our steroid-control systems with massive doses of any one steroid is bound to have unintended consequences.

  4. So what kind of calcium was used? I assume limestone … calcium carbonate garbage. Of course, no magnesium, no vitamin K-2, nor boron which are all cofactors of D3. Why do a good study when we can do a garbage one and ask for more research money, right? Common sense doesn’t apply in government or in “scientific studies”.

  5. Not surprising. Most self-prescribed supplementing has failed to be proven to be beneficial — period.

  6. Study does not address the need for vitamin K-2 combined with D3 to direct calcium from blood to bones.

  7. What are considered high doses of vitamin D and what are the negative results?

  8. What race was the study?

  9. Why didn’t they supplement with vitamin K-2 as well? It’s useful to move calcium into bones instead of arteries. See here.

  10. Ray — Calcium citrate. Vitamin K may increase risk for prostate cancer. Vitamins and minerals should come from diet, not pills. Your body is smarter than you are about taking what it needs. People should only supplement when blood levels are lower than what is required for good health.

    Tony Crispino — Couldn’t agree more.

    Tony and Nc — Blocking vitamin K may decrease risk of prostate cancer; so does supplementing it increase risk? Why chance it? Just eat green, leafy vegetables. See here.

    Gail — Read it! Higher doses led to lower BMD

    Tonyafells — They were a random sample of Canadians.

  11. This is the second study in September 2019 which found that 10,000 IU vitamin D alone does not improve bone health. Many successful studies, however, have added one or more of the following: magnesium, protein, exercise, vitamin K (see here).

  12. Henry:

    There is a big difference between a randomized clinical trial (RCT) and the kinds of observational studies you are referring to. Observational studies are only useful for hypothesis generation.

  13. Allen:

    The concept of using evidence of efficacy in medicine has been around since before the first written words in hieroglyphics on papyrus or stone. In its present instantiation, Evidence Based Medicine (EBM) was codified in ’93 in a Cochrane Collaboration. Since then, the Big Pharma have bastardized EBM with the gold standard (randomized, double-blind, placebo-controlled) RCTs as the only acceptable qualification for recommended use of a medical intervention. This has effectively turned the concept of EBM on its head, relegating observational studies to the lowest form of medical evidence not worthy of recommendation for use. There is something very wrong with this picture.

    As an example, I would point out that the parachute has been indicated as a means of preventing death from severe trauma during gravity accelerated descents from disabled aircraft in flight since its first use in 1911. That was when Grant Morton made the first parachute jump from an airplane, a Wright Model B Flyer.

    I would further point out that parachutes have been widely accepted by all military pilots and later by sports aviation enthusiasts ever since. Moreover, parachutes have been mandated in all ejection seat equipped tactical military jets. That said, there has never been a randomized, blinded, and placebo-controlled trial of the parachute. Hmmm …. Wonder why that is?

    The same goes for the use of 100% oxygen as indicated to treat hypoxia, its use in unpressurized aircraft flying above 10,000 feet msl – an FAA requirement, or its use in pressurized space suits worn by astronauts during EVA. And then there’s penicillin as indicated for bacterial infections, insulin as indicated for the treatment of insulin-dependent diabetes mellitus (type I diabetes) and whole blood as indicated for hemorrhaging due to trauma or surgery. None of these interventions went through a gold standard RCT, yet all are universally accepted as being lifesaving.

    Why should vitamin D3 be any different. It’s a USP. It’s been an integral part of the human genome and physiology throughout its evolution and before. There have been zero deaths attributed to vitamin D3 in the 23-year history of the FDAs Adverse Events Reporting System (FAERS). We cannot say this for aspirin.

    So, as it stands today, all new pharmaceuticals must go through a regimented FDA process with gold standard Phase 1 and Phase 2 testing costing hundreds of millions of dollars and up to 12 years before approval for human use – Right? Vitamin D3 is not a pharmaceutical …

    If this is the only way to go … what about vaccines? They receive FDA approval in a matter of days. What is wrong with that picture?

  14. Dear CrusaderDriver:

    I am sorry to have to tell you that the idea that vaccines “receive FDA approval in a matter of days” is completely fallacious. They have to undergo extremely rigorous RCTs.

    You also need to appreciate that numerous therapeutic products were approved for clinical use in the past (e.g., aspirin and oxygen) because we had enormous amounts of data showing their efficacy and safety prior to the development of current standards determine NOT by “Big Pharma” but by organizations like the Food and Drug Administration and the European Medicines Agency. “Evidence Based Medicine” is NOT based solely on the potential value of large randomized, double-blind clinical trials at all. If it was, we would never get any drugs approved for truly rare disorders.

    What is important is that if you want to take vitamin D3. you are at complete liberty to do so. It appears to be relatively safe in the vast majority of people at reasonable dose levels. However, the question of whether it is effective and safe in the management of prostate cancer at defined dose levels is a very different question. That has never been proven.

  15. Dear CrusaderDriver,

    The first RCT I know of was conducted by James Lind in 1747. He proved that citrus could prevent and cure scurvy. Since then, RCTs have become the gold standard for proving safety and efficacy. All patients should want drugs proven to be safe and effective. What good is a medicine that cures a disease by killing its host? Men with prostate cancer also have to be concerned with interactions with other drugs and with masking of biomarkers. Big Pharma would certainly prefer to NOT spend millions on RCTs, but we rightly require them to. Where there is no profit potential to tempt Big Pharma, we sometimes pool our resources to conduct RCTs ourselves, as we did in the SELECT RCT that proved that Vitamin E caused prostate cancer, and brought into question the popular abuse of antioxidant supplements.

  16. Dear Sitemaster and Allen, Interesting responses on a fascinating topic. Let me start by saying as a vitamin D3 researcher for the last 10 years, I think we’re in substantial agreement in many areas on the topic of using vitamin D3 to control a growing number of medical conditions. My concern with the Canadian study in question is the results indicate several likely flaws. For starters, taking this study’s results at face value, that there was a loss of BMD across all three vitamin D3 dosing groups, flies in the face of evolution. If these results were true, we would be little more than a mass of protoplasmic ooze on the floor with no skeletal system. Vitamin D3 genomic sequences have played an essential role in the human genome and long before. The effects of vitamin D3 likely date back to the Cambrian period and explosion that started 543 million years ago where vitamin D3 related genomic sequences enabled multi-celled animals to mineralize an exoskeleton and appendages from calcium and phosphorus in sea water. If we’re in agreement on this point, I’ll elucidate the Canadian study’s likely flaws. (1) vitamin D3 is not a monotherapy. Optimum vitamin D3 pharmacokinetics and pharmacodynamics require the cofactors: magnesium, zinc, boron, vitamin A (retinol), the vitamin B complex, the vitamin K2 complex and the N-3 PUFAs (there are others). Nutritional studies of nutrients like vitamin D3 are messy, as cofactors are needed for optimum pharmacokinetics and pharmacodynamics. Accordingly, treating vitamin D3 like a pharmaceutical without its cofactors is a sure recipe to conclude the null hypothesis or worse. (2) The fundamental macromolecular building blocks of bone include calcium, phosphorus and collagen peptides. In simple terms, you don’t build a brick wall with just sand and water. This study assumed the results of a questionnaire to determine if participants obtained the IOM suggested RDA of 1200 mg/day calcium from dietary sources. If questionnaire results indicated a dietary intake of calcium was less than the 1200 mg/day RDA, they were provided supplemental calcium. To my way of thinking, this was a risky assumption. To sum up these points, participants in all three arms of this study should have been provided with the vitamin D3 cofactors, dicalcium phosphate and collagen peptide supplements. That way the only variable in question, would be the vitamin D3 dose.

    Sitemaster, I suspect the confusion over “vaccine approval” is a matter of semantics and context. I was referring to pandemic vaccines. The WHO states the typical pandemic influenza vaccine manufacturing process and timeline as approximately five to six months for the first supplies of approved vaccine to become available once a new strain of influenza virus with pandemic potential is identified and isolated. The actual approval for release takes a matter of a few days to as long as 3 to 4 weeks. The classic phase 1, phase 2 and phase 3 RCTs required by pharmaceuticals don’t really start for a pandemic vaccine until after it has been released for use. The 2009 H1N1 pandemic vaccine is good example.

    This is likely why the pharmaceutical industry paid their minions on K street handsome sums to buy legislation in ’86 that indemnifies vaccine manufacturers so they cannot be sued for injury or wrongful deaths due to vaccine side effects.

    I’m not an anti-vaccer, but I am a pragmatist with a degree in chemistry with lots of bio-chem and instrumental analysis circa ’67 from the UW, Seattle. There are no silver bullets for viral infections. Only our immune system can beat down a virus. That’s why I try to keep my immune system strong and healthy with lots of vitamin D3 (≥10,000 IU/day) its cofactors and lots of vitamin C ≥ 4 to 6 grams/day. That said, it’s likely I’m alive today because of vaccines. I received the Salk polio vaccine in ’54. By then three of my classmates had been stricken with polio. We didn’t find out until later that we’d been participants in the Francis Field Trial of the Salk polio vaccine. What had my classmates and our families concerned was the Salk polio vaccine made by Cutter and Wyeth labs. It had not been completely inactivated, allowing live polio virus into more than 100,000 doses of vaccine with 250 confirmed cases of polio before it was pulled from the market. As a Naval Officer and fighter Pilot I spent most of the ’70s deployed to SW Asia so was vaccinated for everything under the sun. Later in the ‘90s while working for OAS on a two-month counter drug effort in South America, I received even more vaccinations prior to working along the Amazon river from Iquitos, Peru through Leticia and Tabatinga, in the Tri-Border region and down to Manaus, Brazil.

    I don’t know if you’ve ever checked, but the list of excipients and adjuvants approved for use in today’s vaccines reads like the 2nd witch’s line from Shakespeare’s Macbeth…

    “Eye of newt, and toe of frog,
    Wool of bat, and tongue of dog,
    Adder’s fork, and blind-worm’s sting,
    Lizard’s leg, and howlet’s wing,–
    For a charm of powerful trouble,
    Like a hell-broth boil and bubble.”

    You can find an extensive list of approved vaccine excipients that include preservatives, antibiotics, genetic material (cell culture sources), salts, stabilizers and adjuvants to help stimulate a stronger immune response at the following CDC link.


  17. Sitemaster, Allen,

    I somehow left off the closing argument on the flawed study so here it is.

    … Finally, there was no pertinent discussion, tracking or correlating changes in the calcium homeostatic analytes, serum 25(OH)D3, calcium and PTH. Calcium homeostasis dictates insufficient calcium in the gut triggers 1,25(OH)2D3 to pull calcium from bones through resorption by osteoclasts to maintain serum calcium within its normal reference range. Accordingly, it’s a no brainer that the increased calcium kinetics associated with the increase in vitamin D3 dose from 400 IU/day to 4,000 IU/day and on to 10,000 IU/day coupled with a complete lack of the vitamin D3 cofactors and inadequate BMD and BMC building blocks: calcium, phosphorus and collagen in the gut, accounted for the increased loss of BMD across the three arms of this vitamin D3 study.

  18. Dear CrusaderDriver:

    The urgent need for vaccines when we are faced with a new pandemic with a high risk for short-term mortality (or the resurgence of an old pandemic in a new form) is very different from the situation with the most common vaccines. The people most at risk from such a pandemic may be absolutely over the moon about the availability of any form of product that might ameliorate their risk under such circumstances. Perhaps if you lived in Wuhan, you might have a rather different perspective on the urgent need for some form of vaccine against coronavirus. I should also point out that all vaccines developed under such circumstances are still considered investigational by regulatory authorities, and the results of administration of every dose of such vaccines are carefully tracked for efficacy and safety purposes.

    With regard to the polio vaccines, I think you may have your facts wrong. The first successful demonstration of a polio vaccine was by Hilary Koprowski in 1950, with a live attenuated virus which people drank. This Kaprowski vaccine was never approved in the US, The injectable, inactivated Salk vaccine was developed a few years later and was approved for commercial use in the US in 1955. My memory is that I was given this vaccine in the UK in 1956 or 1957. The oral Sabin vaccine was developed and came into commercial use in 1961 (and I distinctly remember my much younger brother being given this because I didn’t think it was fair that he got his orally and I had had to have an injection).

    In the development of all vaccines, the critical question is whether the benefits associated with administration of products like this to millions of people with all of their individual variations in their biological and immunological systems in the interests of the public health outweigh the risks for the small number of people who can clearly show that they have adverse effects from such vaccinations. I freely admit that I am generally a “pro-vaccine” person, but I do recognize that they aren’t perfect. There are no perfect vaccines, drugs, biologics, etc. Even many natural foodstuffs are seriously problematic for some people. They all come with side effects in at least a few people. The vaccines, drugs, and biologics never work exactly as intended in 100% of the people to whom they are administered. And they may have very serious side effects in some percentage of the populations to whom they are given.

    With regard to what goes into some of the vaccines used today, I am not a vaccine developer. I am also neither a vaccine regulator nor a public health expert. I was, however, at one time a communications advisor to the Pubic Health Laboratory Service in the UK. I leave thatthe development, regulation, and use of vaccines to those with expertise in the relevant fields. I also leave flying planes to those trained to fly them. However, sometimes planes still crash and sometimes vaccines don’t work perfectly in every patient who is given one. We live in an imperfect world.

    What any of this has to do with your personal willingness to take very high doses of vitamin D3, I have no idea. I have never taken any form of vitamin or other supplement over the long term. I am nearly 72 years of age, and I am generally in very good health. Furthermore, I have a 250-year-long family history in which many of my direct antecedents lived into their 90s. Most of them, as far as I am aware, never used meaningful amounts of supplements like vitamins either. Indeed, most of them wouldn’t even have had such products available to them. That doesn’t mean that I think anyone should necessarily follow my guidance. It simply confirms the fact that human biology is extremely complex and there are very few rules that apply with equal levels of seriousness to all people. Even heavy smoking doesn’t lead to mortality in some people, just as some people get lung cancer even though they never smoke at all.

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