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Vitamin D: some perspective please – July 2012

This web page has the first portion of the article, followed by 5 letters to the editor

See also VitaminDWiki

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BMJ 2012; 345 doi: 10.1136/bmj.e4695 (Published 19 July 2012)

Nicholas C Harvey, senior lecturer and honorary consultant rheumatologist, Cyrus Cooper, director and professor of rheumatology
Author Affiliations

nch at mrc.soton.ac.uk
Health claims are ahead of the evidence

Vitamin D deficiency has been associated with an ever expanding list of diseases, and with this has come almost tonic-like claims for vitamin D supplementation. In observational studies, low vitamin D status has been associated with increased risk of multiple sclerosis, type 1 and type 2 diabetes, cardiovascular disease, colon cancer, breast cancer, autoimmunity, and allergy.1 The UK government has advised that all pregnant women, and children under 5 years, should take 400 IU vitamin D daily; a recent news story, however, reported a survey conducted by a charity which suggested that only 26% of pregnant women and 46% of healthcare professionals are aware of these guidelines.2 The most recent musculoskeletal trend seems to be the attribution of childhood problems such as Blount’s disease and slipped femoral epiphyses to vitamin D deficiency and the incorrect conflation of rickets with low serum calcidiol (25-hydroxyvitamin D3) concentrations.3 So are health professionals causing ill health through their lack of awareness and advocacy of vitamin D supplementation?

The high profile news coverage and the enthusiastic promotion of the results of observational studies as though they proved … end of free text
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Letter to editor about this item Re: Vitamin D: some perspective please – 6 August 2012


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).
William B. Grant, Independent Researcher
Sunlight, Nutrition and Health Research Center, PO Box 641603, San Francisco, CA 941641603 USA
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Response by original author – 31 July 2012

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: None declared

Nicholas C Harvey, Senior Lecturer and Honorary Consultant Rheumatologist
Cyrus Cooper, Director and Professor of Rheumatology
MRC Lifecourse Epidemiology Unit, University of Southampton, Southampton General Hospital, Southampton, SO16 6YD
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Vitamin D: don’t forget mental health – 30 July 2012

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: None declared

David B Menkes, Associate Professor
Waikato Clinical School, Private Bag 3200, Hamilton 3240, New Zealand
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The health benefits of vitamin D are well supported

23 July 2012
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 cancer 7 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. VitaminDWiki
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 VitaminDWiki
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. VitaminDWiki
19. Rejnmark L, Avenell A, Masud T, Anderson F, Meyer HE, Sanders KM, 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 May 17. VitaminDWiki
20. Lappe JM, Heaney RP. Why randomized controlled trials of calcium and vitamin D sometimes fail. Dermatoendocrin 2012;4(2) epub VitaminDWiki
21. Armstrong B, Doll R. Environmental factors and cancer incidence and mortality in different countries, with special reference to dietary practices. Int J Cancer 1975;15:617-31.
22. Cho E, Chen WY, Hunter DJ, Stampfer MJ, Colditz GA, Hankinson SE, et al. Red meat intake and risk of breast cancer among premenopausal women. Arch Intern Med 2006;166:2253-9.
23. Hathcock JN, Shao A, Vieth R, Heaney R. Risk assessment for vitamin D. Am J Clin Nutr 2007;85:6-18.
24. Ross AC, Manson JE, Abrams SA, Aloia JF, Brannon PM, Clinton SK, 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.
25. Grant WB. An estimate of the global reduction in mortality rates through doubling vitamin D levels. Eur J Clin Nutr 2011 September;65:1016-26. VitaminDWiki

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).

William B. Grant, Independent Researcher
Sunlight, Nutrition and Health Research Center, PO Box 641603, San Francisco, CA 94164-1603, USA
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Re: Vitamin D: some perspective please 23 July 2012

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
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