Thursday, May 13, 2010

Vitamin D: Does Too Much Incur Worse Pain?

Vitamin DA new study raises questions about the harms versus benefits of high-dose vitamin D supplementation in preventing painful falls and fractures. However, as much as anything, this study is a lesson in how consumers of research need to more closely examine and be more critical of published evidence.

Writing in the Journal of the American Medical Association (JAMA), Kerrie Sanders, PhD, and colleagues from the University of Melbourne, Australia, recount a randomized controlled study in which 1,131 women (aged ≥ 70 years) were orally administered a once-yearly dose of 500,000 IU vitamin D3 [Sanders et al. 2010]. An equivalent number of women (n=1,123) received placebo. Contrary to expectations, those receiving vitamin D had a significantly greater incidence of painful falls and bone fractures, compared with the placebo group, and the largest increases occurred within 3 months of dosing.

It had been anticipated that the annual megadose of vitamin D3 would improve patient compliance with the treatment regimen and favorable effects on muscle and bone health would result in reduced falls and fractures. The contrary findings suggest a failure of vitamin D to be of benefit. However, a thoughtful editorial in the same edition of JAMA offers several sensible alternate explanations [Dawson-Hughes and Harris 2010]:
  1. One possibility is that such a large single dose of vitamin D3 (500,000 IU) may have triggered natural protective mechanisms within the body to more rapidly metabolized the major active form of vitamin D [that is, calcitriol or 1,25(OH)2D, which is formed from 25(OH)D]. This phenomenon had been observed in animal experiments in which ultra-high dosing (75,000 IU/week) negated the benefits of vitamin D supplementation.

  2. A second possibility is that vitamin D supplementation was indeed beneficial in reducing chronic pain, improving physical performance, and elevating mood, which have all been demonstrated in prior research. Consequently, the women in this study may have had increased mobility leading to greater opportunity for falls. Sanders and colleagues did not assess such effects of vitamin D in their study.

  3. Third, vitamin D has been shown to benefit the immune system, potentially resulting in fewer common infections such as colds. Women in the vitamin D group may have had less “down time” due to such illness during the course of the study, thereby increasing their opportunity for falls and fractures. Again, this was not examined.
In the study by Sanders et al., most subjects were at the least vitamin D insufficient at baseline [25(OH)D < 30 ng/mL on average]. The 500,000 IU megadose of oral D3 produced more than a 100% spike in 25(OH)D levels at 1 month post-dosing, which quickly decreased by the 2nd month to about 55% above baseline, and further declined during the remaining 10 months to about 30 ng/mL on average (which is an acceptable level). Corresponding to this, however, there was a 31% increase in falls and 53% increase in fractures within the first 3 months, compared with 13% and 18% increases, respectively, after 3 months.

COMMENTS: Sanders and colleagues acknowledge that increased falls and fractures have not been found in numerous other studies using lower-dose and more frequent vitamin D supplementation. They concede that the high serum levels of vitamin D and/or metabolites resulting from megadose administration, with subsequent sharp decreases in those levels, or both, might have been harmful. Furthermore, they note, the short-term spike in 25(OH)D levels found in their study could occur with other high-dose supplementation regimens. Indeed, this is probably the primary and most important message of this study, which, unfortunately, is buried in the report.

The editorial authors similarly note that this study “raises the possibility that infrequent high doses of vitamin D are counterproductive,” which is not to say that vitamin D supplementation is not of value for musculoskeletal health and ameliorating associated painful conditions. Rather, they question the value of the common clinical practice of treating vitamin D-deficient patients with high loading doses of D3 at the outset of repletion (typically 50,000 IU weekly or twice weekly for 6 to 8 weeks).

In fact, there is no way in nature for the human body to acquire such high doses — whether 50,000 or 500,000 IU — at one time, either from sunlight or food sources. And, research has not yet fully revealed how the body might physiologically process and/or benefit from such megadose supplements. Therefore, our prior recommendation of 2,000+ IU D3/day [see full report] or up to 5,000 IU D3/day in some cases [noted in this blogpost] may be a more reasonable and natural, albeit possibly slower-acting, alternative for vitamin D supplementation in those persons who would benefit. However — important caveat here — the long-term effectiveness and safety of vitamin D supplementation is still under investigation, so proper monitoring would be advisable in persons taking such supplements.

>Dawson-Hughes B, Harris SS. High-dose vitamin D supplementation: Too much of a good thing? [editorial. JAMA. 2010;303(18):1861-1862 [
> Sanders KM, Stuart AL, Williamson EJ, et al. Annual high-dose oral vitamin D and falls and fractures in older women: A randomized controlled trial. JAMA. 2010;303(18):1815-1822 [full article here].