dosing, it employed an extremely unphysiological approach to replacement therapy. A comparable approach in the field of clinical endocrinology would be to treat hypothyroid patients with a single dose of 12,000 µg l-thyroxine once every three months. Such a regimen would be both ineffective and dangerous. As the half-life of 25(OH)D is approximately four times that of thyroxine, the two regimens just described (yearly for vitamin D and quarterly for thyroxine) are exactly equivalent. It is not surprising, therefore, that the outcomes of such a vitamin D study are not representative of the outcomes that would have been produced by the same dose had it been given on a daily basis (which would have averaged about 1,370 IU/day).
In a similar vein, the IOM panel undoubtedly noted that, for certain endpoints (mostly non-skeletal), apparent benefit waned at the highest percentiles of a particular population’s distribution of 25(OH)D values—and, in some reports, even reversed.30,31
Vieth has insightfully
explained that this is due to wide annual variations in serum 25(OH)D concentrations, and has shown why this oscillation nullifies any apparent benefit.32
been the case in the study using 500,000 IU once yearly.29
Exactly such wide annual oscillation also would have Vieth noted
that annual oscillations of more than a few ng/ml are unphysiologic and described their effect well in advance of the IOM panel’s deliberations, but whether the panel was aware of his work is not clear.
The panel certainly should, however, have been aware of the fact that both outdoor summer workers in temperate latitudes and people living in the tropics have 25(OH)D values in the range the IOM considered suspect (40–60 ng/ml), and yet do not exhibit any apparent untoward effects. In fact, one of the most powerful arguments for requirements
1. Ross AC, Manson JE, Abrams SA, et al., The 2011 report on dietary reference intakes for calcium and vitamin D from the Institute of Medicine: what clinicians need to know, J Clin Endocrinol Metab, 2011;96:53–8.
IOM (Institute of Medicine), Dietary Reference Intakes for Calcium and Vitamin D, Washington, DC: The National Academies Press, 2011.
3. Holick MF, Binkley NC, Bischoff-Ferrari HA, et al., Endocrine Society, Evaluation, treatment, and prevention of vitamin D deficiency: an Endocrine Society clinical practice guideline, J Clin Endocrinol Metab, 2011;96:1911–30.
4. Boucher BJ, The 2010 recommendations of the American Institute of Medicine for daily intakes of vitamin D, Public Health Nutr, 2011;14:740.
5. Giovannucci E, Vitamin D, how much is enough and how much is too much? Public Health Nutr, 2011;14:740–1.
6. Gorham ED, Garland CF, Vitamin D and the limits of randomized controlled trials, Public Health Nutr, 2011;14: 741–3.
7. Cannell J, Era or error? Public Health Nutr, 2011;14:743. 8. Norman AW, Vitamin D nutrition is at a crossroads, Public Health Nutr, 2011;14:744–5.
9. Grant WB, The Institute of Medicine did not find the vitamin D-cancer link because it ignores UV-B dose studies, Public Health Nutr, 2011;14:745–6.
10. Schwalfenberg GK, Whiting SJ, A Canadian response to the 2010 Institute of Medicine vitamin D and calcium guidelines, Public Health Nutr, 2011;14:746–8.
11. Hollis BW, Wagner CL, The vitamin D requirement during human lactation: the facts and IOM’s ‘utter’ failure, Public Health Nutr, 2011;14:748–9.
12. Heaney RP, Finding the appropriate referent for vitamin D, Public Health Nutr, 2011;14:749–50.
13. Holick MF, The D-batable Institute of Medicine report: a D-lightful perspective, Endocr Prac, 2011;7:143–9.
14. Heaney RP, Holick MF, Why the IOM recommendations for vitamin D are deficient, J Bone Miner Res, 2011;26:455–67.
higher than those currently recommended by the IOM is that, during the evolution of human physiology, daily vitamin D inputs from solar UV-B radiation would certainly have been in excess of 10,000 IU, with serum 25(OH)D values well above 40 ng/ml. Since these are the conditions to which human physiology has been adapted by natural selection, it has been argued that such values should be taken as the starting point in setting recommendations for the intake of contemporary humans, with the burden of proof shifted to those who propose that lower values are either adequate or safe.12
In summary, the IOM recommendations are internally inconsistent, and both the RDA and the 25(OH)D blood level declared by the IOM to be ‘adequate’ are low, in the first case by approximately six-fold and in the second by about two-fold. Further, the panel’s insistence on evidence from RCTs to establish particular benefits is itself inappropriate.33,34
may seem a retrogressive statement in today’s climate, which applies indiscriminately the criteria of evidence-based medicine to all interventions; however, nutrients are not drugs, and consuming them at levels plausibly available from the environment is not an intervention. All nutrients are efficacious, i.e., essential for health—by definition. Inadequate intake of a particular nutrient leads to dysfunction or disease. This much is a given. To associate a particular nutrient with a particular disease is equivalent to stating that low intake produces or worsens the disease concerned. Such a hypothesis cannot ethically be tested in humans using the RCT design. Even if a particular association turns out not to be causal, the control group in such a trial will have received an inadequate intake and hence will have experienced some disease or dysfunction, if not the one being specifically tested. Continued insistence on RCT-level evidence will guarantee not certainty, but stagnation. n
15. Trivedi DP, Doll R, Khaw KT, Effect of four monthly oral vitamin D3 (cholecalciferol) supplementation on fractures and mortality in men and women living in the community: randomised double blind controlled trial, BMJ, 2003;326:469.
16. Grant AM, Avenell A, Campbell MK, et al., RECORD Trial Group, Oral vitamin D3 and calcium for secondary prevention of low-trauma fractures in elderly people (Randomised Evaluation of Calcium Or vitamin D, RECORD): a randomised placebo-controlled trial, Lancet, 2005;365:1621–8.
17. Porthouse J, Cockayne S, King C, et al., Randomised controlled trial of calcium and supplementation with cholecalciferol (vitamin D3) for prevention of fractures in primary care, BMJ 2005;330:1003.
18. Jackson RD, LaCroix AZ, Gass M, et al., Calcium plus vitamin D supplementation and the risk of fractures, N Engl J Med, 2006;354:669–83.
19. Bischoff-Ferrari HA, Willett WC, Wong JB, et al., Fracture prevention with vitamin D supplementation: a meta-analysis of randomized controlled trials, JAMA, 2005;293:2257–64.
20. Bischoff-Ferarri HA, Willett WC, Wong JB, et al., Prevention of nonvertebral fractures with oral vitamin D and dose dependency: a meta-analysis of randomized controlled trials, Arch Intern Med, 2009;169(6):551–61.
21. Bischoff-Ferrari HA, Dawson-Hughes B, Baron JA, et al., Calcium intake and hip fracture risk in men and women: a meta-analysis of prospective cohort studies and randomized controlled trials, Am J Clin Nutr, 2007;86:1780–90.
22. Bischoff-Ferrari HA, Dawson-Hughes B, Platz A, et al., Effect of high-dosage cholecalciferol and extended physiotherapy on complications after hip fracture, Arch Intern Med, 2010;170:813–20.
23. Heaney RP, Dowell MS, Hale CA, et al., Calcium absorption varies within the reference range for serum 25-hydroxyvitamin D, J Am Coll Nutr, 2003;22:142–6. 24. Shapses SA, Kendler DL, Robson R, et al., Effect of
alendronate and vitamin D3 on fractional calcium absorption in a double-blind, randomized, placebo-controlled trial in
postmenopausal osteoporotic women, J Bone Miner Res, 2011;26:1836–44.
25. Priemel M, von Domarus C, Klatte TO, et al., Bone mineralization defects and vitamin D deficiency: histomorphometric analysis of iliac crest bone biopsies and circulating 25-hydroxyvitamin D in 675 patients, J Bone Miner Res, 2010;25:305–12.
26. Need AG, Horowitz M, Morris HA, et al., Seasonal change in osteoid thickness and mineralization lag time in ambulant patients, J Bone Miner Res, 2007;22:757–61.
27. Garland CF, French CB, Baggerly LL, et al., Vitamin D supplement doses and serum 25-hydroxyvitamin D in the range associated with cancer prevention, Anticancer Res, 2011;31:607–12.
28. Heaney RP, Davies KM, Chen TC, et al., Human serum 25-hydroxy-cholecalciferol response to extended oral dosing with cholecalciferol, Am J Clin Nutr, 2003;77:204–10.
29. Sanders KM, Stuart LA, Williamson AJ, et al., Annual high dose oral vitamin D and falls and fractures in older women, JAMA, 2010;303(18):1815–22.
30. McGrath JJ, Eyles DW, Pedersen CB, et al., Neonatal vitamin D status and risk of schizophrenia, Arch Gen Psychiatry, 2010;67(9):889–94.
31. Tuohimaa P, Tenkanen L, Ahonen M, et al., Both high and low levels of blood vitamin D are associated with a higher prostate cancer risk: a longitudinal, nested case-control study in the Nordic countries, Int J Cancer, 2004;108:104–8.
32. Vieth R, Enzyme kinetics hypothesis to explain the U-shaped risk curve for prostate cancer vs. 25-hydroxyvitamin D in Nordic countries, Int J Cancer, 2004;111:468.
33. Blumberg J, Heaney RP, Huncharek M, et al., Evidence-based criteria in the nutritional context, Nutr Rev, 2010;68:478–84. (Appendix: Amplification on certain of the points discussed in the paper [online only]).
34. Heaney RP, Weaver CM, Blumberg J, EBN (Evidence-Based Nutrition) Ver. 2.0. Nutr Today, 2011;46:22–6.
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