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.

12 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.

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