Vitamin D: some perspective please
BMJ 2012; 345 doi: https://doi.org/10.1136/bmj.e4695 (Published 19 July 2012) Cite this as: BMJ 2012;345:e4695
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The editorial that argues that hypovitaminosis 25OHD is an effect rather than cause of disease, is supported by other authors. It might be easier to understand and recognise when looking at Vitamin D not as a Vitamin, but rather as a steroid hormone, produced and used on demand, with possible side effects, and kinetics more like other steroid hormones.
ref:
Proal AD, Albert PJ, Marshall TG: Autoimmune Disease and the Human Metagenome. in Metagenomics of the Human Body; Ed. Nelson, K; pub Springer, 2011. ISBN: 978-1-4419-7088-6
Preprint from http://autoimmunityresearch.org/preprints/Proal_MHB_Chapter_preprint.pdf
Proal AD, Albert PJ, Blaney GP, Lindseth IA, Benediktsson C, Marshall TG: Immunostimulation in the Era of the Metagenome. Cell Mol Immunol. 2011 Jan 31.
Preprint from http://autoimmunityresearch.org/preprints/Proal2010CellularMolecularImmu...
Competing interests: No competing interests
I noticed when reading the JAMA 2010 paper referenced [1] that although the authors conclude that “annual oral administration of high-dose cholecalciferol resulted in an increased risk of falls and fractures” the statistics reported don’t quite agree: Once the analysis was adjusted for calcium intake the P values show non significance for fractures, but the increased risk of falls did remain statistically significant. I think therefore, it might have been more accurate to draw the conclusion that high dose annual administration of vitamin D increased falls risk. The authors of the JAMA 2010 paper also note that the increase in falls was largely observed in the three months immediately following the large annual dose of Vitamin D. Interestingly among the claims of non bone vitamin D mechanisms is the proposal that Vitamin D has an effect on the renin-angiotensin system [2]; could this maybe have contributed to increased falls following the large dose? Wouldn’t then a trial be needed to see whether spreading this dose out to say monthly reduced this risk of falls following the high dose?
I use this to illustrate my point that I am in no doubt that many many more high quality RCTs need to be done but my concern is that because vitamin D is not a novel chemical entity that can command a lucrative patent from pharmaceutical companies I am not confident that the studies required will happen in any great hurry.
I think therefore we have a responsibility as guideline writers to look at the existing evidence and come to some recommendations about daily supplementation that balances safety with efficacy, that are logical, based on the evidence available to us now accepting that we will inevitably have to review our evidence base constantly as more is learned about vitamin D. We must balance being over cautious with the risk of not acting on the current evidence, even if it isn’t a RCT.
[1] Sanders KM, Stuart AL, Williamson EJ, Simpson JA, Kotowicz MA, Young D, Nicholson GC: Annual high-dose oral vitamin D and falls and fractures in older women: a randomized controlled trial. JAMA 2010, 303(18):1815-1822.
[2]Li, Y.C., Kong, J., Wei, M., Chen, Z.F., Liu, S.Q. and Cao, L.P. (2002) 1,25-Dihydroxyvitamin D(3) is a negative endocrine regulator of the renin-angiotensin system. J Clin Invest 110: 229 238.
Competing interests: No competing interests
I am not a doctor, but I am moved to respond to Harvey's editorial.
Obviously the Precautionary Principle is a worthy path to follow in many ways, but a great number of people like myself are living under considerable risks to health caused by past medical treatments, past environmental factors--and we have been instructed to cover up in the sun for at least the past 20 years. Was there considerable and lengthy research before this advice was given?
We live in a world where the ballparks are not equal.
It is disturbing to discover accidentally, when you are in your middle age that the extensive treatment you had as a child for cancer gives you the same risks of breast cancer as those with the breast cancer gene. Chest radiotherapy to a young child also substantially increases the risk of other cancers, heart disease, and early mortality. Obviously we are trying to change the statistics--and when so much warning has been given out for years to avoid the sun, waiting years for more conclusive evidence on vitamin D supplementation seems a gamble too far.
I live in Scotland--I garden and walk dogs daily, and am very much an outdoors person, yet was still found to be, like the majority, deficient in Vit D on blood test. This was only discovered after I had had to have a mastectomy for breast cancer. As a consequence of the childhood radiotherapy I had and its long term effects, treatment choices for subsequent malignant neopasms are very limited. But I am of course extremely fortunate because I learnt of the risks and could catch the cancer early. Very many of my compatriots have not been so lucky--they have lived under very much increased risks and kept out of the sun.
I have just sat on the SIGN Guideline group trying to improve long term health outcomes for child cancer survivors--a group who are in effect in many ways guinea pigs in themselves. How ironic that this group--who face some of the most severe health challenges of any other group of patients--are bombarded with messages to always cover up in the sun--even after protracted spells in hospital when no sun can touch their skin. In past decades they might have been sent to sanitoriums to bask in the sun as much as possible-which is after all a natural response to the sun for those living in a cloudy country. I have certainly found considerable benefit to energy levels in taking vitamin D, and for any cancer survivor this alone is a great thing, allowing more exercise, lifting mood, and helping weight control. For the vast majority it would appear the risks far outweigh any negative effect.
The most puzzling aspect of this vitamin D debate for me is that many of those doctors arguing against vit D supplementation have apparently permanently bronzed faces. Supplementation is needed for many ordinary people as holidays abroad are now outwith beyond their financial reach.
Competing interests: No competing interests
In their timely and provocative editorial on vitamin D [1] Harvey and Cooper fail to consider the fundamental possibility, supportive to their view, that hypovitaminosis D is the consequence rather than cause of disease. We have recently completed a study which has unequivocally shown that serum 25-hydroxy vitamin D (25OHD) is a negative acute phase reactant. We measured serum C-reactive protein (CRP) and 25OH-D before and two days after elective knee or hip surgery in 30 patients. Following surgery the mean (SD) serum CRP increased [5.0 (5.5) vs 116.0 (81.2) mg/L; p <0.0001] whereas serum 25OH-D decreased [56.2 (30.3) vs 46.0 (27.6) nmol/L; p <0.0006]. These results are consistent with two other studies reporting a rapid and marked fall in serum 25OH-D during a systemic inflammatory response [2,3].
These studies, however, appear to directly conflict with other studies reporting no change in serum 25OHD for up to 90 days after an inflammatory insult [4,5]. Initial serum samples in these studies [4,5] were, however, all collected after the inflammatory insult by which time serum 25OHD is already likely to be at a nadir [2,3]. A unifying explanation for the apparently conflicting data from these studies is that there is a rapid and dramatic decrease in serum 25OH-D following an inflammatory insult which persists for at least 3 months.
Serum 25OHD is a negative acute phase reactant and this has implications for acute and chronic diseases. Firstly, serum 25OHD is an unreliable biomarker of vitamin D status following an acute inflammatory insult. Secondly, we suggest that hypovitaminosis D may be the consequence rather than the widely purported cause of a myriad of chronic diseases [1].
REFERENCES
1. Harvey NC, Cooper C. Vitamin D: some perspectives please. BMJ 2012;345:e4695
2. Reid D, Toole BJ, Knox S, et al. The relation between acute changes in the systemic inflammatory response and plasma 25-hydroxyvitamin D concentrations after elective knee arthroplasty. Am J Clin Nutr 2011;93:1006–11
3. Louw JA, Werbeck A, Louw ME, Kotze TJ, Cooper R, Labadarios D. Blood vitamin concentrations during the acute-phase response. Crit Care Med 1992;20:934-41
4. Newens K, Filteau S, Tomkins A. Plasma 25-hydroxyvitamin D does not vary over the course of a malarial infection. Trans Roy Soc Trop Med Hyg 2006;100:41–4
5. Barth JH, Field HP, Mather AN, Plein S. Serum 25 hydroxy-vitamin D does not exhibit an acute phase reaction after acute myocardial infarction. Ann Clin Biochem 2012;49:399-401.
Competing interests: No competing interests
Professor Harvey has misinterpreted my comments on his editorial in his statement “that vitamin D, as "an integral biological component” of the human body, does not warrant the same level of supporting evidence as would a pharmacological agent” [1]. What I stated was “However, vitamin D is not a pharmaceutical drug but, rather, a compound that has been an integral biological component since before man appeared on earth. The need for vitamin D was the driving force for change in skin pigmentation as man moved out of Africa. Thus, the criteria for evidence-based medicine may not be applicable. In fact, other criteria have been proposed including the criteria for causality in a biological system and those for evidence based nutrition.” [2]. The implication of his comment is that randomized controlled trials (RCTs) are superior to observational, ecological, and laboratory study evidence. RCTs are thought by many to be required to demonstrate the benefits of vitamin D without risk. However, RCTs with vitamin D are very difficult to conduct for a number of reasons including other sources of vitamin D, lack of knowledge of the time of life when vitamin D has important effects on many health outcomes, the fact that those enrolled in the studies should be chosen based on an understanding of the serum 25-hydroxyvitamin D [25(OH)D] concentration-health outcome relation, and that serum 25(OH)D concentrations should be measured after supplementation. Ref. 3 discusses some of these problems. Unfortunately, many of the vitamin D RCTs to date were not conducted with these considerations in mind. As a result, there are few RCTs demonstrating significant health benefits. In addition to those mentioned in [2], a recent meta-analysis of RCTs of vitamin D supplementation for fracture reduction found “By quartiles of actual intake, reduction in the risk of fracture was shown only at the highest intake level (median, 800 IU daily; range, 792 to 2000), with a 30% reduction in the risk of hip fracture (hazard ratio, 0.70; 95% CI, 0.58 to 0.86) and a 14% reduction in the risk of any nonvertebral fracture (hazard ratio, 0.86; 95% CI, 0.76 to 0.96).” [4].
Meta-analyses of observational studies are considered nearly as strong as RCTs. Meta-analyses have found significant inverse correlations between serum 25(OH)D concentrations and incidence of colorectal [5] and breast [6] cancer, diabetes and cardiovascular disease [7], and all-cause mortality rate [8,9].
Large observational studies have found significant inverse correlations between serum 25(OH)D concentration and cardiovascular disease [10,11]. A large-scale observational study in Israel found significantly higher all-cause mortality rates for those with serum 25(OH)D concentrations below 50 nmol/l [12]. A modest-sized observational study found a highly significant increased risk for acute viral respiratory infection for those with serum 25(OH)D concentrations below 95 nmol/l [13].
A recent treatment study using 4000 IU/d vitamin D3 for men with low-grade prostate cancer found regression of number of tumors in 55% of the participants, compared to 20% in a historical control group [14].
Ecological studies of solar UVB and cancer incidence and/or mortality rates have consistently found significant inverse correlations for about 15 types of cancer in studies from Australia, China, France, Japan, Nordic countries, and the United States [15,16].
Another way to consider the evidence is to look at the reviews by vitamin D experts. Several such recent reviews endorsed oral intakes up to 2000 or more IU/d vitamin D3 and serum 25(OH)D concentrations up to 100 nmol/l [17-19].
Early man spent much time in the sun with large amounts of skin exposed to the sun. Skin pigmentation adapted to changing solar UV doses as man migrated out of Africa [20]. Some modern day pastoral Africans have serum 25(OH)D concentrations above 100 nmol/l [21]. Many people today cover up when in the sun, but spend much of their time indoors. Taking vitamin D supplements compensates for lack of sun exposure. Those who think the current evidence of beneficial effects of vitamin D is strong are encouraged to obtain vitamin D from natural or artificial UVB or from oral intake of supplements or food.
References
1.Harvey NC. Vitamin D: some perspective please: Authors' response to Grant and Rhein. BMJ 31 July 2012
2. Grant WB. The health benefits of vitamin D are well supported. BMJ. 23 July 2012.
3. Lappe JM, Heaney RP. Why randomized controlled trials of calcium and vitamin D sometimes fail. Dermatoendocrin. 2012;4(2) epub
4. Bischoff-Ferrari HA, Willett WC, Orav EJ, Lips P, Meunier PJ, Lyons RA, et al. A pooled analysis of vitamin D dose requirements for fracture prevention. N Engl J Med. 2012;367:40-9.
5. Yin L, Grandi N, Raum E, Haug U, Arndt V, Brenner H. Meta-analysis: longitudinal studies of serum vitamin D and colorectal cancer risk. Aliment Pharmacol Ther. 2009;30:113-25.
6. Yin L, Grandi N, Raum E, Haug U, Arndt V, Brenner H. Meta-analysis: Serum vitamin D and breast cancer risk. Eur J Cancer. 2010;46:2196-2205.
7. Parker J, Hashmi O, Dutton D, Mavrodaris A, Stranges S, Kandala NB, et al. Levels of vitamin D and cardiometabolic disorders: systematic review and meta-analysis. Maturitas. 2010;65:225-36.
8. Zittermann A, Iodice S, Pilz S, Grant WB, Bagnardi V, Gandini S. Vitamin D deficiency and mortality risk in the general population: A meta-analysis of prospective cohort studies. Am J Clin Nutr. 2012;95:91-100.
9. Schöttker B, Ball D, Gellert C, Brenner H. Serum 25-hydroxyvitamin D levels and overall mortality. A systematic review and meta-analysis of prospective cohort studies. Ageing Res Rev. 2012 Feb 16. [Epub ahead of print]
10. Anderson JL, May HT, Horne BD, Bair TL, Hall NL, Carlquist JF, et al. Relation of vitamin D deficiency to cardiovascular risk factors, disease status, and incident events in a general healthcare population. Am J Cardiol. 2010;106:963-8.
11. Vacek JL, Vanga SR, Good M, Lai SM, Lakkireddy D, Howard PA. Vitamin D deficiency and supplementation and relation to cardiovascular health. Am J Cardiol. 2012;109:359-63.
12. Saliba W, Barnett O, Rennert HS, Rennert G. The Risk of All-Cause Mortality Is Inversely Related to Serum 25(OH)D Levels. J Clin Endocrinol Metab. 2012 May 30. [Epub ahead of print]
13. Sabetta JR, DePetrillo P, Cipriani RJ, Smardin J, Burns LA, Landry ML. Serum 25-hydroxyvitamin D and the incidence of acute viral respiratory tract infections in healthy adults. PLoS One. 2010;5:e11088.
14. Marshall DE, Savage SJ, Garrett-Mayer E, Keane TE, Hollis BW, Host RL, et al. Vitamin D3 supplementation at 4000 international units per day for one year results in a decrease of positive cores at repeat biopsy in subjects with low-risk prostate cancer under active surveillance. J Clin Endocrinol Metab. 2012;97:2315-24.
15. Grant WB. Ecological studies of the UVB–vitamin D–cancer hypothesis; review. Anticancer Res. 2012;32:223-36.
16. Grant WB. Role of solar UV irradiance and smoking in cancer as inferred from cancer incidence rates by occupation in Nordic countries. Dermatoendocrinol. 2012;4(2) epub
17. Souberbielle JC, Body JJ, Lappe JM, Plebani M, Shoenfeld Y, Wang TJ, et al. Vitamin D and musculoskeletal health, cardiovascular disease, autoimmunity and cancer: Recommendations for clinical practice. Autoimmun Rev 2010;9:709-15.
18. Holick MF, Binkley NC, Bischoff-Ferrari HA, Gordon CM, Hanley DA, Heaney RP, et al. Evaluation, treatment, and prevention of vitamin D deficiency: an Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab, 2011 Jul;96(7):1911-30.
19. Holick MF, Binkley NC, Bischoff-Ferrari HA, Gordon CM, Hanley DA, Heaney RP, et al. Guidelines for preventing and treating vitamin D deficiency and insufficiency revisited. J Clin Endocrinol Metab. 2012;97:1153-8.
20. Jablonski NG, Chaplin G. Colloquium paper: human skin pigmentation as an adaptation to UV radiation. Proc Natl Acad Sci U S A. 2010;107 Suppl 2:8962-8.
21. Luxwolda MF, Kuipers RS, Kema IP, Janneke Dijck-Brouwer DA, Muskiet FA. Traditionally living populations in East Africa have a mean serum 25-hydroxyvitamin D concentration of 115 nmol/l. Br J Nutr. 2012 Jan 23:1-5. [Epub ahead of print]
Competing interests: I receive funding from the UV Foundation (McLean, VA), Bio-Tech Pharmacal (Fayetteville, AR), the Vitamin D Council (San Luis Obispo, CA), the Vitamin D Society (Canada), and the Sunlight Research Forum (Veldhoven).
In defence of his suggestion that vitamin D, as "an integral biological component” of the human body, does not warrant the same level of supporting evidence as would a pharmacological agent, Grant[1] quotes two randomised controlled trials demonstrating that vitamin D, notably in combination with calcium supplementation, reduces the risk of cancer[2, 3]. Indeed a recent meta-analysis showed that the combination of vitamin D and calcium is associated with a reduction in all-cause mortality[4]; interestingly these benefits were not observed with the use of vitamin D alone, suggesting that it might be the calcium rather than the vitamin D which is important, and thus hardly providing the definitive evidence of vitamin D’s protective effects. Furthermore, across a wide range of health outcomes, there are many negative observational and interventional studies of vitamin D supplementation alone to counter the positive studies presented by Grant[5-13].
Although Rhein[14] correctly points out that one of the conclusions of the study by Sai et al[15] was that, based partly on relationships between concentrations of serum calcidiol and bone turnover markers, 50 nmol per litre was a reasonable threshold, there have been few studies using this definition; given the widely disparate estimates based on PTH concentrations, such data should be interpreted with caution. Our key point, in conjunction with the bone histomorphometry results from Priemel et al[16], was that a low serum calcidiol level does not necessarily equate to disease.
Whilst the current evidence base suggests that modest levels of vitamin D supplementation are unlikely to do harm, there are very few data on long-term outcomes, in particular those in the offspring following maternal supplementation. Given the current enthusiasm for widespread supplementation, sometimes at substantial daily doses[17], even a small risk of an adverse effect at the individual level could be associated with considerable morbidity in the population. The whole-scale adoption of hormone replacement therapy, followed by its equally dramatic fall from grace, provides a salutary lesson here. Quite apart from any potential adverse effects, such as the already observed increase in fracture risk following high-dose supplementation[18], there is real concern about the marked rise in serum 25(OH)-vitamin D measurements[19], the apparent confusion amongst the public and physicians as to the interpretation of these results, and the consequent labelling of healthy individuals with a medical condition.
In contrast to Grant, we do not feel that the general lack of regulation surrounding food supplementation is a justification for a superficial assessment of the benefits of vitamin D, and maintain that further high-quality work is needed.
Reference List
1. Grant WB: The health benefits of vitamin D are well supported. BMJ 2012, ePub.
2. Lappe JM, Travers-Gustafson D, Davies KM, Recker RR, Heaney RP: Vitamin D and calcium supplementation reduces cancer risk: results of a randomized trial. AmJClinNutr 2007, 85(6):1586-1591.
3. Bolland MJ, Grey A, Gamble GD, Reid IR: Calcium and vitamin D supplements and health outcomes: a reanalysis of the Women's Health Initiative (WHI) limited-access data set. Am J Clin Nutr 2011, 94(4):1144-1149.
4. Rejnmark L, Avenell A, Masud T, Anderson F, Meyer HE, Sanders KM, Salovaara K, Cooper C, Smith HE, Jacobs ET et al: Vitamin D with Calcium Reduces Mortality: Patient Level Pooled Analysis of 70,528 Patients from Eight Major Vitamin D Trials. J Clin Endocrinol Metab 2012.
5. Annweiler C, Allali G, Allain P, Bridenbaugh S, Schott AM, Kressig RW, Beauchet O: Vitamin D and cognitive performance in adults: a systematic review. Eur J Neurol 2009, 16(10):1083-1089.
6. Bath-Hextall FJ, Jenkinson C, Humphreys R, Williams HC: Dietary supplements for established atopic eczema. Cochrane Database Syst Rev 2012, 2:CD005205.
7. Buttigliero C, Monagheddu C, Petroni P, Saini A, Dogliotti L, Ciccone G, Berruti A: Prognostic role of vitamin d status and efficacy of vitamin D supplementation in cancer patients: a systematic review. Oncologist 2011, 16(9):1215-1227.
8. Chung M, Lee J, Terasawa T, Lau J, Trikalinos TA: Vitamin D with or without calcium supplementation for prevention of cancer and fractures: an updated meta-analysis for the U.S. Preventive Services Task Force. Ann Intern Med 2011, 155(12):827-838.
9. Ferguson JH, Chang AB: Vitamin D supplementation for cystic fibrosis. Cochrane Database Syst Rev 2012, 4:CD007298.
10. George PS, Pearson ER, Witham MD: Effect of vitamin D supplementation on glycaemic control and insulin resistance: a systematic review and meta-analysis. Diabet Med 2012, 29(8):e142-150.
11. Pittas AG, Chung M, Trikalinos T, Mitri J, Brendel M, Patel K, Lichtenstein AH, Lau J, Balk EM: Systematic review: Vitamin D and cardiometabolic outcomes. Ann Intern Med 2010, 152(5):307-314.
12. Sinclair D, Abba K, Grobler L, Sudarsanam TD: Nutritional supplements for people being treated for active tuberculosis. Cochrane Database Syst Rev 2011(11):CD006086.
13. Straube S, Derry S, Moore RA, McQuay HJ: Vitamin D for the treatment of chronic painful conditions in adults. Cochrane Database Syst Rev 2010(1):CD007771.
14. Rhein HM: Re: Vitamin D: some perspective please. BMJ 2012, ePub.
15. Sai AJ, Walters RW, Fang X, Gallagher JC: Relationship between vitamin D, parathyroid hormone, and bone health. J ClinEndocrinolMetab 2011, 96(3):E436-E446.
16. Priemel M, von DC, Klatte TO, Kessler S, Schlie J, Meier S, Proksch N, Pastor F, Netter C, Streichert T et al: Bone mineralization defects and vitamin D deficiency: histomorphometric analysis of iliac crest bone biopsies and circulating 25-hydroxyvitamin D in 675 patients. JBone MinerRes 2010, 25(2):305-312.
17. Hollis BW, Wagner CL: Vitamin D and Pregnancy: Skeletal Effects, Nonskeletal Effects, and Birth Outcomes. Calcif Tissue Int 2012.
18. Sanders KM, Stuart AL, Williamson EJ, Simpson JA, Kotowicz MA, Young D, Nicholson GC: Annual high-dose oral vitamin D and falls and fractures in older women: a randomized controlled trial. JAMA 2010, 303(18):1815-1822.
19. Bilinski K, Boyages S: The rise and rise of vitamin D testing. BMJ 2012, 345:e4743.
Competing interests: No competing interests
In pointing out that claims for vitamin D exceed available evidence, Harvey and Cooper [1] neglect to mention psychiatric disorders. In this domain, too, enthusiasts tend to over-interpret deficiency and uncritically promote supplementation as a panacea. Despite the hype, evidence of vitamin D’s importance to mental health is accumulating. For example, follow-up of a Finnish birth cohort showed that boys receiving vitamin D supplements during the first year of life had a decreased risk of developing schizophrenia in adolescence and young adulthood [2]. Consistent with this, we observed a striking association of vitamin D deficiency with schizophrenia in a New Zealand inpatient sample, particularly among Maori [3]. Irrespective of its role in the pathophysiology of schizophrenia, vitamin D deficiency is likely to exacerbate elevated metabolic and cardiovascular risks in this population [4], emphasising the links between mental and physical health.
1. Harvey NC, Cooper C: Vitamin D: some perspective please. BMJ 2012, 345:e4695.
2. McGrath J, Saari K, Hakko H, Jokelainen J, Jones P, Järvelin M-R, Chant D, Isohanni M: Vitamin D supplementation during the first year of life and risk of schizophrenia: a Finnish birth cohort study. Schizophrenia Research 2004, 67:237-245.
3. Menkes DB, Lancaster K, Grant M, Marsh RW, Dean P, du Toit SA: Vitamin D status of psychiatric inpatients in New Zealand's Waikato region. BMC Psychiatry 2012, 12:68.
4. Pittas AG, Chung M, Trikalinos T, Mitri J, Brendel M, Patel K, Lichtenstein AH, Lau J, Balk EM: Systematic review: Vitamin D and cardiometabolic outcomes. Ann Intern Med 2010, 152:307-314.
Competing interests: No competing interests
The editorial by Harvey claims that the evidence for beneficial effects of vitamin D for non-bone outcomes is based largely on observational studies and needs to be verified by randomized controlled trials (RCTs).1 He bases his claim with reference to evidence based medicine. However, vitamin D is not a pharmaceutical drug but, rather, a compound that has been an integral biological component since before man appeared on earth. The need for vitamin D was the driving force for change in skin pigmentation as man moved out of Africa.2 Thus, the criteria for evidence-based medicine may not be applicable. In fact, other criteria have been proposed including the criteria for causality in a biological system3 and those for evidence based nutrition.4
It is instructive to examine the evidence that vitamin D reduces the risk of cancer with respect to the three criteria. There have been two successful RCTs with vitamin D and calcium. One, using 1100 IU/d vitamin D3 and 1450 mg/c calcium found a 77% reduction in all-cancer incidence between the ends of the first and fourth years.5 The second was a reanalysis of the Women’s Health Initiative, which used 400 IU/d vitamin D3 plus 1500 mg/d calcium. It found that considering only those participants who had not used personal vitamin D or calcium supplements prior to enrolling in the study, risk of breast cancer was reduced significantly by 14-20% and that for colorectal cancer nonsignificantly by 17%.6
The important Hill criteria for vitamin D and cancer include strength of association, consistency, biological gradient, plausibility, and experiment.3 These criteria have been applied to many types of cancer7 and breast cancer in particular.8 The inverse correlation between serum 25-hydroxyvitamin D [25(OH)D] and breast and colorectal cancer is strong.9 The results are stronger for case-control studies than for nested case-control studies from cohort studies since serum 25(OH)D concentrations change with time.10 As to consistency, both the observational studies9 and the ecological studies of solar UVB doses11 have been very consistent, the latter for about 15 types of cancer. The ultraviolet B-vitamin D-cancer hypothesis was proposed in 1980 based on an ecological study.12 No mechanism other than vitamin D production has been proposed to explain the findings. The mechanisms whereby vitamin D reduces risk of cancer are well known.13-15 As to experiment, there are the two RCTs as well as ecological studies11 and observational studies of cancer survival with respect to serum 25(OH)D concentration at time of diagnosis, reviewed in.16
There are other RCTs reporting health benefits of vitamin D including influenza,17 pregnancy outcomes,18 and all-cause mortality rate (with calcium).19 RCTs with vitamin D are very difficult to conduct properly, as noted in a recent review.20 Some of the problems include not selecting subjects with vitamin D deficiency, not using doses high enough to move serum 25(OH)D concentrations along the 25(OH)D-health outcome relation, not measuring serum 25(OH)D concentration after supplementation, and interference from other sources of vitamin D.8,17 In addition, there is the possibility that RCTs might not be performed at the period of life when vitamin D would be most protective against the health outcome in question. For example, a multicountry ecological study of diet and cancer incidence and mortality rates identified dietary animal products and fat as important risk factors for many types of cancer.21 This finding was disputed for many years until cohort studies with younger women confirmed the finding.22
Thus, there is strong evidence that vitamin D reduces risk of several adverse health outcomes, although the evidence may not rise to the level required for pharmaceutical drugs. However, risk of adverse effects of vitamin D at doses up to 10,000 IU/d has not been documented,23,24 so there is no harm in taking vitamin D supplements. There are many potential benefits of vitamin D supplementation,25 so supplementation should be encouraged. Hopefully the RCTs will confirm the beneficial findings of solar UVB and vitamin D from ecological, observational and laboratory studies in the near future.
References
1.Harvey NC. Vitamin D: some perspective please. BMJ 2002;345:e4695.
2. Jablonski NG. The evolution of human skin colouration and its relevance to health in the modern world. J R Coll Physicians Edinb 2012;42:58-63.
3. Hill AB. The environment and disease: Association or causation? Proc R Soc Med 1965;58:295-300.
4. Blumberg J, Heaney RP, Huncharek M, Scholl T, Stampfer M, Vieth R, et al. Evidence-based criteria in the nutritional context. Nutr Rev 2010;68:478-84.
5. Lappe JM, Travers-Gustafson D, Davies KM, Recker RR, Heaney RP. Vitamin D and calcium supplementation reduces cancer risk: results of a randomized trial. Am J Clin Nutr 2007;85:1586-91.
6. Bolland MJ, Grey A, Gamble GD, Reid IR. Calcium and vitamin D supplements and health outcomes: a reanalysis of the Women's Health Initiative (WHI) limited-access data set. Am J Clin Nutr 2011;94:1144-9.
7. Grant WB. How strong is the evidence that solar ultraviolet B and vitamin D reduce the risk of cancer? An examination using Hill’s criteria for causality. Dermatoendocrin 2009;1:17-24.
8. Mohr SB, Gorham ED, Alcaraz JE, Kane CI, Macera CA, Parsons JE, et al. Does the evidence for an inverse relationship between serum vitamin D status and breast cancer risk satisfy the Hill criteria? Dermatoendocrin 2012;4(2) epub
9. Grant WB. Relation between prediagnostic serum 25-hydroxyvitamin D level and incidence of breast, colorectal, and other cancers. J Photochem Photobiol B 2010;101:130–6.
10. Grant WB. Effect of interval between serum draw and follow-up period on relative risk of cancer incidence with respect to 25-hydroxyvitamin D level; implications for meta-analyses and setting vitamin D guidelines. Dermatoendocrinol 2011;3:199-204.
11. Grant WB. Ecological studies of the UVB–vitamin D–cancer hypothesis; review. Anticancer Res 2012;32:223-36.
12. Garland CF, Garland FC. Do sunlight and vitamin D reduce the likelihood of colon cancer? Int J Epidemiol 1980;9:227-31.
13. Garland CF, Gorham ED, Mohr SB, Garland FC. Vitamin D for cancer prevention: Global perspective. Ann Epi 2009;19:468-83.
14. Fleet JC, Desmet M, Johnson R, Li Y. Vitamin D and cancer: a review of molecular mechanisms. Biochem J 2012;441:61-76.
15. Krishnan AV, Trump DL, Johnson CS, Feldman D. The role of vitamin D in cancer prevention and treatment. Rheum Dis Clin North Am 2012;38:161-78.
16. Grant WB, Peiris AN. Differences in vitamin D status may account for unexplained disparities in cancer survival rates between African and White Americans. Dermatoendocrinol 2012;4(2): Epub
17. Urashima M, Segawa T, Okazaki M, Kurihara M, Wada Y, Ida H. Randomized trial of vitamin D supplementation to prevent seasonal influenza A in schoolchildren. Am J Clin Nutr 2010;91:1255-60.
18. Hollis BW, Johnson D, Hulsey TC, Ebeling M, Wagner CL. Vitamin D supplementation during pregnancy: double-blind, randomized clinical trial of safety and effectiveness. J Bone Miner Res 2011;26:2341-57.
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Competing interests: I receive funding from the UV Foundation (McLean, VA), Bio-Tech Pharmacal (Fayetteville, AR), the Vitamin D Council (San Luis Obispo, CA), the Vitamin D Society (Canada), and the Sunlight Research Forum (Veldhoven).
Harvey and Cooper pose the question of how to define vitamin D deficiency in their editorial "Vitamin D: some perspective please".(1) However, I think this question has an answer: most biochemists, endocrinologists, general physicians and vitamin D experts appear to agree that serum 25(OH)D levels should be 50 nmol/l (20 ng/ml) or above. (2) Harvey and Cooper even quote a study looking at the relationship of PTH and 25(OH)D but don't seem to realise that the study concludes: "Vitamin D insufficiency should be defined as serum 25(OH)D less than 20 ng/ml (50 nmol/liter) as it relates to bone." (3)
From a Scottish perspective four out of five inhabitants have 25(OH)D levels below 50 nmol/l, due to latitude and climate (4-7) For bone health alone people living in Scotland are well advised to raise their vitamin D - levels either by taking supplements or sunbathing.
Harvey and Cooper rightly point out that the UK government has advised all pregnant women to take 400 IU vitamin D daily but that there is poor update of this advice. However it should have also been pointed out that this amount is actually insufficient to raise adults' blood level to 50 nmol/l, needed for bone health. This is the case in Scotland for the general population(6) as well as for pregnant women. (8)
Adults and pregnant women living in Scotland should be advised to consider taking decent sized supplements (2000 IU have been suggested) (9).
1. Harvey NC, Cooper C. Vitamin D: some perspective please. Editorial. BMJ 2012;345:e4695
2. Institute of Medicine (2011) Dietary Reference Intakes for Calcium and Vitamin D. Washington, DC: National Academies Press.
3. Sai AJ, Walters RW, Fang X, Gallagher JC. Relationship between vitamin D, parathyroid hormone, and bone health. J Clin Endocrinol Metab2011;96:E436-46
4. Hyppönen E, Power C. Hypovitaminosis D in British adults at age 45 y: nationwide cohort study of dietary and lifestyle predictors. Am J Clin Nutr 2007 Mar; 85(3):860-8.
5. Macdonald HM, Mavroeidi A, Fraser WD, Darling AL, Black AJ, Aucott L, O'Neill F, Hart K, Berry JL, Lanham-New SA, Reid DM. Sunlight and dietary contributions to the seasonal vitamin D status of cohorts of healthy postmenopausal women living at northerly latitudes: a major cause for concern? Osteoporos Int 2011; 22(9):2461-72.
6. Zgaga L, Theodoratou E, Farrington SM, et al. Diet, environmental factors, and lifestyle underlie the high prevalence of vitamin D deficiency in healthy adults in Scotland, and supplementation reduces the proportion that are severely deficient. J Nutr 2011; 141(8):1535-42.
7. Rhein HM. Vitamin D deficiency is widespread in Scotland. BMJ 2008 Jun 28; 336(7659):1451.
8. Holmes VA, Barnes MS, Alexander HD, McFaul P and Wallace JMW. Vitamin D deficiency and insufficiency in pregnant women: a longitudinal study. British Journal of Nutrition. 2009;102: 876–81
9. Vitamin D supplementation: Recommendations for Canadian mothers and infants. Canadian Paediatric Society (CPS). Paediatr Child Health 2007;12(7):583-9
Competing interests: No competing interests
Re: Vitamin D: some perspective please
We follow with interest the ongoing debate regarding vitamin D and its effect on various aspects of health. We agree that there is a need for well-designed studies as highlighted by the editorial in July by Nicholas Harvey and Cyrus Cooper. However, in the present situation where paediatricians are having to practise with a lack of robust data in some key areas relating to vitamin D and bone health, the British Paediatric and Adolescent Bone Group (the membership of which comprises most of the paediatricians in the United Kingdom with a specialist interest in children’s metabolic bone disease) has produced a position statement that is based on the current expert opinion within the group. This statement has been circulated to and has the support of the British Society of Paediatric Radiology and the Child Protection and Nutrition Committees of the Royal College of Paediatrics and Child Health.
“Vitamin D deficiency position statement – British Paediatric and Adolescent Bone Group.
There is currently considerable clinical and research interest regarding vitamin D deficiency. We are aware of a number of clinical guidelines relating to this topic that provide different criteria for the definition of what is a sufficient level of vitamin D. These different criteria have caused some confusion and may influence clinical decisions regarding management of a child or adolescent.
It is the current opinion of the British Paediatric and Adolescent Bone Group that the definition of vitamin D deficiency relates only to the impact of vitamin D on the skeleton. As such vitamin D deficiency should be regarded as a plasma level of 25 hydroxyvitamin D of less than 25 nmol/l (10 ng/ml) with vitamin D insufficiency being a level between 25 and 50 nmol/l (10-20 ng/ml) and vitamin D sufficiency as a level greater than 50 nmol/l. Our practice in general is to use these thresholds although we recognise that the evidence base in children and adolescents is limited.
In the context of unexplained fractures in infancy it is our opinion that unless there is radiological evidence of rickets using conventional x-ray techniques and biochemical evidence of rickets i.e. abnormal blood levels of calcium, phosphate, alkaline phosphatase or parathyroid hormone that the level of 25 hydroxyvitamin D is not relevant to the causation of the fractures.
We would emphasise the importance of ensuring that vitamin D supplementation is taken by vulnerable groups of individuals at risk of vitamin D deficiency as recommended by the Chief Medical Officers for Health for the UK (www.dh.gov.uk/health/2012/02/advice-vitamin-d/). In the context of child health this is all pregnant or breastfeeding women and all infants and children from the age of six months until the age of five years. We would also recommend that exclusively breastfed infants receive vitamin D supplements from soon after birth.”
Competing interests: No competing interests