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Should adults take vitamin D supplements to prevent disease (No, if you ignore most of the studies) - Nov 2016

Should adults take vitamin D supplements to prevent disease?

British Medical Journal 2016; 355 doi: http://dx.doi.org/10.1136/bmj.i6201 Nov 2016
Mark J Bolland, associate professor1, Alison Avenell, professor2, Andrew Grey, associate professor1

    Note: Letters to the editor at the bottom of this page which strongly disagrees

Authors may have 2 conflicts of interests: get prize money and keep students


It is truly amazing how a case can be made for NOT taking vitamin D when you ignore a majority of the data


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Some of the references highlighted above

A few other items of interest


 Download the marked up PDF from VitaminDWiki

Their press release - which will probably be widely reposted on the web

examples from the first 12 hours include
Vitamin D doesn't prevent disease for most, study says
VITAMIN DUD Vitamin D pills branded ‘waste of time’ and could even be ‘harmful’ according to new research
British Medical Journal piece says evidence does not back vitamin D supplements
Review questions recent official vitamin D guidance
Should adults take vitamin D supplements? Journal suggests they may be waste of time
Popping vitamin D pills don't prevent disease for most, study says
Vitamin D supplements are not all they're cracked up to be, say scientists
British Medical Journal Piece Says Evidence Does Not Back Vitamin D Supplements
Are YOU taking Vitamin D? It's a waste of time and doesn't prevent disease, scientists say


Letters to the Editor = rapid response

Re: Should adults take vitamin D supplements to prevent disease?

Helga Rhein, GP, Sighthill HC, 380 Clader Rd, Edinburgh EH11 4AUm 27 November 2016
Cite this as: BMJ 2016;355:i6201
Condescending neglect of North Britain?

Although existing evidence on taking vitamin D supplements might be imperfect according to Bolland (1), it is, however, good enough for me.

If we have evidence that giving large doses of vitamin D gets you through intensive care with a much better chance of survival (2), and if we have evidence that quality of life and survival is improved after a cancer diagnosis (3-7), or that giving vitamin D reduces severe asthma attacks by half (8) and improves live in IBS (9) and IBD (10), in addition to anecdotal evidence from our patients (11) for the improvement of their lives concerning depressed mood, frequency of infections, walking capability, and if we furthermore consider that Scotland’s population has an average serum vitamin D level of 37 nmo/l (12) when at the same time even Bolland reported that sufficiency is defined as 50 to 80 nmol/l, then I ask: Why should my patients in cloudy, windy, cool Scotland be deprived of reaching sufficiency in vitamin D?

However, aiming for vitamin D sufficiency in my patients would mean prescribing a decent sized dose to all of our “healthy adult population”, which I will continue to do. In fact, shouldn’t it be called neglect if so much evidence is ignored?

Spector, in the same BMJ issue, (13) mentions “unexpected toxic effects”, strong words indeed when vitamin D supplements of much higher than 800 IU have worldwide been accepted as safe. The two studies he refers to showed increased falls and fractures after a high dosed bolus was given to elderly, when both studies only lasted for one year. As pointed out by others (14), a more likely explanation is the much faster improvement in D-deficiency myopathy, (giving people a get-up-and-go attitude), than the slower strengthening of bones. Another older UK study (15) has used similar bolus doses but after 5 years of observation, the actively treated group had significantly reduced fractures. Spector also asks to ‘save NHS resources’. Surely, reducing prescriptions for antibiotics or antidepressants, as well as reducing time spent in hospital admissions (16) is saving more NHS resources than the relatively cheap prescriptions for vitamin D.
References

  1. Bolland MJ, Avenell A, Grery A. Will vitamin D supplements for healthy adults help prevent disease? BMJ 2016;355:i6201
  2. Putzu A, Belletti A, Cassina T, et al. Vitamin D and outcomes in adult critically ill patients. A systematic review and meta-analysis of randomized trials, Journal of Critical Care 2016
  3. Keum N, Giovannucci E. Vitamin D supplements and cancer incidence and mortality: a meta-analysis. British Journal of Cancer 111, 976-980 (26 August 2014)
  4. Robsahm TE, Schwartz GG, Tretli S. The Inverse Relationship between 25-Hydroxyvitamin D and Cancer Survival: Discussion of Causation. Cancers 2013, 5, 1439-1455
  5. Rastelli AL, Taylor ME, Gao F, et al. Vitamin D and aromatase inhibitor-induced musculoskeletal symptoms (AIMSS): a phase II, double-blind, placebo-controlled, randomized trial. Breast Cancer Res Treat. 2011;129(1):107-116
  6. Pilz S, Kienreich K, Tomaschitz A,et al. Vitamin D and Cancer Mortality: Systematic Review of Prospective Epidemiological Studies. Anti-Cancer Agents in Medicinal Chemistry, 2013, 13, 107-117
  7. Kim Y, Je Y. Vitamin D intake, blood 25(OH)D levels, and breast cancer risk or mortality: a meta-analysis. British Journal of Cancer (2014) 110, 2772–2784
  8. Martineau AR, Cates CJ, Urashima M, et al. Vitamin D for the management of asthma. Cochrane Database of Systematic Reviews 2016
  9. Tazzyman S, Richards N, Trueman AR, et al. Vitamin D associates with improved quality of life in participants with irritable bowel syndrome: outcomes from a pilot trial. BMJ Open Gastro 2015;2:e000052
  10. Rafferty T, Martineau AR, Greiller CL.Effects of vitamin D supplementation on intestinal permeability, cathelicidin and disease markers in Crohn’s disease: Results from a randomised double-blind placebo-controlled study. United European Gastroenterology Journal 2015, Vol. 3(3) 294–302
  11. Rhein HM, Johnson G. Vitamin D supplementation in an Edinburgh general practice population and anecdotal evidence. Poster. Vitamin D and Human Health: from the Gamete to the Grave”: Report on a meeting held at Queen Mary University of London, 23rd–25th April 2014. Nutrients 2014, 6(7), 2759-2919
  12. Food Standards Agency in Scotland. Vitamin D status of Scottish adults: Results from the 2010 & 2011 Scottish Health Surveys . Purdon G, Comrie F, Rutherford L, Marcinkiewicz A. September 2013
  13. Spector TD, Levy L. Do healthy people need a vitamin D supplement in the winter? BMJ 2016;355:i6183
  14. personal communication with Dr. David Grimes
  15. Trivedi D, Doll R, Shaw KT. Effect of four monthly 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. Graedel L, Merker M, Felder S, et al. Vitamin D Deficiency Strongly Predicts Adverse Medical Outcome Across Different Medical Inpatient Populations. Medicine 95(19):e3533

Re: Should adults take vitamin D supplements to prevent disease? (submitted but not on-line as of Nov 28)
William B. Grant, Ph.D.1 and Barbara J. Boucher, M.D.2
1Sunlight, Nutrition, and Health Research Center , P.O. Box 641603; San Francisco, CA 94164-1603, USA, wbgrant at infionline.net; www.sunarc.org,
2The Blizard Institute, Barts & The London School of Medicine & Dentistry, Queen Mary University of London, London, UK. bboucher at doctors.org.uk.

Short summary Bolland et al. recommended that low-dose vitamin D supplementation (400-800 IU/d) and vitamin D blood levels of >25 nmol/L were adequate for good health. They also stated that randomized controlled trials with vitamin D only support its role for bone health. They dismissed observational studies of vitamin D blood levels and health outcomes as not being able to show causality. In fact, there is a large body of scientific evidence that vitamin D levels greater than 75-100 nmol/L from either oral vitamin D intake or solar UVB exposure are associated with reduced risk of many adverse health outcomes including Alzheimer's disease, 15 types of cancer, cardiovascular disease, autoimmune diseases such as multiple sclerosis, infectious diseases such as influenza, all-cause mortality rates, and adverse pregnancy and birth outcomes. For more information, go to www.GrassrootsHealth.net, www.vitaminDCouncil.org, www.VitaminDSociety.org, www.VitaminDWiki.com and/or pubmed.gov.

In their article in the series on areas of practice where management lacks convincing supporting evidence, Bolland et al. conclude that the only health outcomes with strong evidence that vitamin D prevents are skeletal diseases such as osteomalacia, that 25-hydroxyvitamin D '[25(OH)D] concentrations >25 nmol/L are sufficient to prevent it, and that high risk individuals should be offered low dose vitamin D of 400-800 IU/d '[1]. It is noted that the authors as well as the series editor, David Tovey, editor in chief of the Cochrane Library, consider randomized clinical trials (RCTs) to be the primary if not the only evidence that should be used to guide clinical practice. Unfortunately, the majority of vitamin D RCTs have not been properly designed since they were based on guidelines for pharmaceutical drugs. The two underlying assumptions of such trials are that the trial is the only source of the agent and that there is a linear dose-response relation. Of course, neither is satisfied for vitamin D, as Heaney outlined in guidelines for studying clinical effects of nutrients '[2]. One of the key points is to base the trial on low-baseline 25(OH)D concentration-health outcomes of interest. A recent review of vitamin D RCTs with biomarkers of inflammation as outcomes found that 50% of the trials with baseline 25(OH)D concentrations <49 nmol/L showed a beneficial effect, while only 26% of those with baseline 25(OH)D concentrations >49 nmol/L did so '[3].

Scientific evidence Scientific evidence relating to causality between agent and outcome can come from a variety of approaches. For pharmaceutical drugs, RCTs are generally required to show efficacy and lack of harm. However, as shown by the Vioxx debacle, RCTs do not assess all harms, especially those that may take some time to occur '[4, 5].

Ecological studies treat populations as individuals. In health studies, they look at health/disease outcomes as a function of geographical location, or time, with respect to risk-modifying factors. Single-country geographical ecological studies have been very important in studying the effect of solar UVB exposure on cancer incidence and mortality rate, and are accepted as having identified ~15 types of epithelial cancer with reduced risks with higher solar UVB exposure '[6]. Temporal ecological studies linked increased UVB exposure to reduced risk of influenza '[7]. The advantages of ecological studies is that large populations are studied, the data are generally readily available, long time periods are involved, and many risk-modifying factors can be allowed for. Ecological studies have often identified beneficial effects of UVB exposure, as a likely surrogate for vitamin D provision, years before observational studies did, and been followed by positive RCTs (e.g., for cancer '[8]) '[9].

Observational studies related to vitamin D can use data on personal UVB exposure, vitamin D intake, or serum 25(OH)D concentrations, but a problem with the last of these is that 25(OH)D concentrations vary with time, so that determination of 25(OH)D concentration from blood drawn at the time of entry into a cohort study does not necessarily relate to 25(OH)D concentration during the follow-up period. This problem is substantial for breast cancer incidence, as it is a rapidly developing cancer, so that case-control studies in which 25(OH)D concentration is measured near the time of cancer diagnosis produce results consistent with ecological studies and RCTs while prospective studies with longer than 3-yr follow up generally do not '[10].

Laboratory studies can be conducted to determine the mechanisms by which vitamin D acts to maintain optimal health and reduce risk of disease. Since vitamin D generally acts through vitamin D receptors (VDRs) to affect gene expression, epidemiological studies can also be used to examine whether VDR polymorphisms are linked to risk of cancer. For example, compared with the wild-type bb, the BB genotype of the VDR BsmI polymorphism was associated with a reduced risk of colon cancer '[11]. Since such findings are independent of 25(OH)D concentrations, they are often considered evidence for a causal link between vitamin D and disease risk. In addition, Mendelian randomization studies based on the association between single nucleotide polymorphisms (SNPs) associated with circulating 25(OH)D concentration as found in studies of ovarian cancer '[12].

Thus, rather than requiring RCTs, one should consider all of the scientific evidence. Bradford Hill, in his well-known presidential address to the Royal Medical Society, outlined the criteria for causality in a biological system '[13]. Experiment (e.g., RCT) was but one of nine criteria. Others include strength of association, a dose-response relation, identifying relevant mechanisms, and consistent findings in different populations.

Let's examine the evidence for the roles of UVB exposure and vitamin D in reducing four adverse health outcomes: cancer, influenza, all-cause mortality rates, and adverse pregnancy and birth outcomes. Since solar UVB exposure is the primary source of vitamin D, and nearly all of the health benefits related to these health outcomes are considered to be due to vitamin D production, UVB exposure can be considered a good measure, or surrogate for, the contribution of vitamin D to health outcomes.

Cancer. The mechanisms whereby vitamin D reduces risk and increases cancer survival are well known. Observational studies provide strong support that higher 25(OH)D concentrations are associated with reduced risk of cancer. A meta-analysis of 11 case-control studies from seven countries finds that incidence rates rise rapidly for 25(OH)D concentrations <60 nmol/L '[10 Grant, 2015], and an observational study in the U.S. found that 25(OH)D concentrations >100 nmol/L were associated with a 65% reduced risk of cancer compared to <60 nmol/L '[14]. A pair of vitamin D plus calcium RCTs conducted on post-menopausal women in Nebraska found significantly reduced risks of cancer by-32 to -35% when 25(OH)D concentrations were increased from ~75 nmol/L to ~100 nmol/L '[8, 15]. In the U.S. Women's Health Initiative vitamin D+calcium RCT (400 IU/d vitamin D3 plus 1000 mg/d, calcium or placebo), women who were not taking vitamin D or calcium prior to entry had significantly decreased the risks of total, breast, and invasive breast, cancers by 14-20% and non-significantly reduced risks of colorectal cancer -17% '[16]. Thus, there is support for a role of vitamin D in reducing cancer risks, while the role of vitamin D in breast cancer was shown to satisfy Hill's criteria '[17].

Influenza. Influenza is largely seasonal, with high rates in winter, and low rates in summer. Cannell proposed the UVB-vitamin D-influenza hypothesis in 2006 '[7]. which is now supported by two clinical trials, one involving African-American postmenopausal women living in New York '[18], the other involving school children in Japan '[19]. The mechanism whereby vitamin D reduces risk of influenza is thought to be through induction of the bactericidal/viricidal compound, cathelecidin, LL-37, in humans, and vitamin D also reduces the rates of death from pneumonia '[20].

All-cause mortality rates and economic burden related to disease.
Observational studies find that all-cause mortality rate rises in a nearly linear fashion as 25(OH)D concentration declines below 90 nmol/L '[21 Garland, 2014]. This value is consistent with findings for various diseases from observational studies related to incidence '[22]. A meta-analysis of vitamin D3 RCTs in community dwelling and hospital-based study groups found a relative risk with vitamin D supplementation of 0.89 (0.80-0.99) '[23]. A recent study from Sweden, in women, found that avoidance of sun was associated with 0.6-2.1 years lower life expectancy compared to the highest sun exposure group '[24]. This increase in life expectancy is similar to the 2 years found in an analysis based on observational studies '[25]. A recent analysis estimates that increasing serum 25(OH)D concentrations to >100 nmol/L in all Canadians would significantly reduce the economic burden of disease and mortality rates '[26]. Given the economic pressures to lower the budget of the National Health Service in the U.K., any simple measures that could offer significant reductions in the disease burden should be explored.

Pregnancy. Vitamin D requirements during pregnancy and lactation are high. A vitamin D RCT conducted in South Carolina showed that taking 4000 IU/d vitamin D3 was safe and that serum 1,25-dihydroxyvitamin D3 concentrations were maximally increased only when serum 25(OH)D concentrations reached ≥100 nmol/L '[27]. In a subsequent analysis of two vitamin D supplement trials during pregnancy, women with serum 25(OH)D concentrations ≥100 nmol/L (n=233) had a 57% lower risk of preterm birth compared to those with concentrations ≤50 nmol/L '[n=82; RR=0.43, 95% confidence interval (CI)=0.22,0.83] '[28], whilst a recent narrative review found that "The currently available results indicate that vitamin D supplementation during pregnancy reduces the risk of preterm birth, low birth weight, dental caries of infancy, and neonatal infectious diseases such as respiratory infections and sepsis." '[29]. clearly these benefits are additional to avoidance of rickets, hypocalcemic fits and hypovitaminosis D induced heart failure in neonates.

Recommendations by others. Various groups, organizations, and agencies have made assessments and recommendations regarding vitamin D. A Task Force of the U.S. Endocrine Society recommended >75 nmol/L for those at risk of vitamin D deficiency '[30]. The European Menopause and Andropause Society (EMAS) recommended >75 nmol/L for postmenopausal women '[31]. Vitamin D opinion leaders from the U.S., Canada, and Central and Eastern Europe meeting in Warsaw in 2012 recommended >75 nmol/L for the general population '[32] based primarily on a review of the evidence from observational studies '[33]. The simplest way to ensure that most of the population has 25(OH)D concentrations >75 nmol/L is to encourage non-burning UV exposure and vitamin D supplementation and introduce vitamin D fortification. Measurement of 25(OH) concentrations is expensive and not necessary. There is very little risk of adverse health effects with 25(OH)D concentrations up to 250 nmol/L '[34]

UVB exposure. Solar UVB exposure is the primary way to obtain vitamin D. The importance of vitamin D for optimal health is underscored by the geographical variation in human skin pigmentation, dark in the tropical planes, intermediate in forested tropical and lower mid-latitude regions, and generally pale at high northern latitudes. This distribution has led to the UVB-vitamin D-skin pigmentation hypothesis '[35]. There are some health benefits of UV exposure beyond vitamin D production. Thus, in the summer, non-burning solar UV exposure is the preferred way to obtain vitamin D '[36].

Food fortification. Perhaps the most efficient way to increase serum 25(OH)D concentrations during wintertime in populations is through food fortification, especially in winter '[37]. (A study in the UK found that mean serum 25(OH)D concentrations for 45-year olds dropped to ~37 nmol/L in winter compared to 75 nmol/L at the end of summer '[38]). Vitamin D fortification is widely accepted in the U.S. and Canada, supplying approximately 60% of the vitamin D obtainable from food '[39]. While milk is the most commonly fortified food there, good results have also been obtained from fortifying bread '[40-42].

References

  • 1. Bolland MJ, Avenell A, Grey A. Should adults take vitamin D supplements to prevent disease? BMJ. 2016;355:6201.
  • 2. Heaney RP. Guidelines for optimizing design and analysis of clinical studies of nutrient effects. Nutr Rev. 2014;72(1):48-54. VitaminDWiki
  • 3. Cannell JJ, Grant WB, Holick MF. Vitamin D and inflammation. Dermatoendocrinol. 2015;6(1):e983401.
  • 4. Krumholz HM, Ross JS, Presler AH, Egilman DS. What have we learnt from Vioxx? BMJ. 2007;334(7585):120-3.
  • 5. Sobel M, Madigan D, Wang W. Causal Inference for Meta-Analysis and Multi-Level Data Structures, with Application to Randomized Studies of Vioxx. Psychometrika. 2016 Jul 7. '[Epub ahead of print]
  • 6. Moukayed M, Grant WB. Molecular link between vitamin D and cancer prevention. Nutrients. 2013;5:3993-4023.
  • 7. Cannell JJ, Vieth R, Umhau JC, et al. Epidemic influenza and vitamin D. Epidemiol Infect. 2006;134(6):1129-40.
  • 8. 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(6):1586-91.
  • 9. Grant WB. The Role of geographical ecological studies in identifying diseases linked to UVB exposure and/or vitamin D. Dermatoendocrinol. 2016;8(1):e1137400
  • 10. Grant WB. 25-Hydroxyvitamin D and breast cancer, colorectal cancer, and colorectal adenomas: case–control versus nested case–control studies, Anticancer Res. 2015;35(2):1153-60.
  • 11. Jenab M, McKay J, Bueno-de-Mesquita HB, et al. Vitamin D receptor and calcium sensing receptor polymorphisms and the risk of colorectal cancer in European populations. Cancer Epidemiol Biomarkers Prev. 2009;18(9):2485-91
  • 12. Ong JS, Cuellar-Partida G, Lu Y, et al. Association of vitamin D levels and risk of ovarian cancer: a Mendelian randomization study. Int J Epidemiol. 2016; 45:1619-30.
  • 13. Hill AB. The environment and disease: Association or causation? Proc R Soc Med. 1965;58:295-300.
  • 14. McDonnell SL, Baggerly C, French CB, et al. Serum 25-hydroxyvitamin D concentrations ≥40 ng/ml are associated with >65% lower cancer risk: Pooled analysis of randomized trial and prospective cohort study. PLoS One. 2016;11(4):e0152441.
  • 15. Lappe J, Travers-Gustafon D, Garland C, Heaney R, Recker R, Watson P. Vitamin D3 and calcium supplementation significantly decreases cancer risk in older women. Poster 3352. 0. American Public Health Association 2016 meeting Oct 31, 2016. https://apha.confex.com/apha/144am/meetingapp.cgi/Paper/368368
  • 16. 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):1144-9.
  • 17. Mohr SB, Gorham ED, Alcaraz JE, et al. Does the evidence for an inverse relationship between serum vitamin D status and breast cancerrisk satisfy the Hill criteria? Dermatoendocrinol. 2012;4(2):152-7.
  • 18. Aloia JF, Li-Ng M. Re: epidemic influenza and vitamin D. Epidemiol Infect. 2007;135(7):1095-6; author reply 1097-8.
  • 19. 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(5):1255-60.
  • 20. Grant WB, Giovannucci E. The possible roles of solar ultraviolet-B radiation and vitamin D in reducing case-fatality rates from the 1918–1919 influenza pandemic in the United States. Dermatoendocrinol. 2009;1(4):215-9.
  • 21. Garland CF, Kim JJ, Mohr SB, et al. Meta-analysis of all-cause mortality according to serum 25-hydroxyvitamin D. Am J Pub Health. 2014;104(8):e43-50.
  • 22. Spedding S, Vanlint S, Morris H, Scragg R. Does vitamin d sufficiency equate to a single serum 25-hydroxyvitamin d level or are different levels required for non-skeletal diseases? Nutrients. 2013;5(12):5127-39.
  • 23. Chowdhury R, Kunutsor S, Vitezova A, et al. Vitamin D and risk of cause specific death: systematic review and meta-analysis of observational cohort and randomised intervention studies. BMJ. 2014;348:g1903.
  • 24. Lindqvist PG, Epstein E, Nielsen K, Landin-Olsson M, Ingvar C, Olsson H. Avoidance of sun exposure as a risk factor for major causes of death: a competing risk analysis of the Melanoma in Southern Sweden cohort. J Intern Med. 2016;280(4):375-87.
  • 25. Grant WB. An estimate of the global reduction in mortality rates through doubling vitamin D levels. Eur J Clin Nutr. 2011;65(9):1016-26.
  • 26. Grant WB, Whiting SJ, Schwalfenberg GK, Genuis SJ, Kimball SM. An Estimate of the Economic Benefit of Increasing 25-hydroxyvitamin D Concentrations of Canadians to or above 100 nmol/L. Dermatoendocrin. 2016;8(1):e1248324.
  • 27. 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(10):2341-57.
  • 28. Wagner CL, Baggerly C, McDonnell S, et al. Post-hoc analysis of vitamin D status and reduced risk of preterm birth in two vitamin D pregnancy cohorts compared with South Carolina March of Dimes 2009-2011 rates. J Steroid Biochem Mol Biol. 2016;155(Pt B-):245-51.
  • 29. Karras S, Fakhoury H, Muscogiuri G, et al Maternal Vitamin D status in pregnancy and neonatal health: evidence to date and clinical implications. Ther Adv Musculoskelet Dis. 2016 Aug;8(4):124-35.
  • 30. Holick MF, Binkley NC, Bischoff-Ferrari HA, et al, Weaver CM. Evaluation, treatment, and prevention of vitamin D deficiency: an Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab, 2011;96(7):1911-30.
  • 31. Pérez-López FR, Brincat M, Erel CT, et al. EMAS position statement: Vitamin D and postmenopausal health. Maturitas. 2012;71(1):83-8.
  • 32. Pludowski P, Karczmarewicz E, Bayer M, et al. Practical guidelines for the supplementation of vitamin D and the treatment of deficits in Central Europe - recommended vitamin D intakes in the general population and groups at risk of vitamin D deficiency. Endokrynol Pol. 2013;64(4):319-27.
  • 33. Pludowski P, Holick MF, Pilz S, et al. Vitamin D effects on musculoskeletal health, immunity, autoimmunity, cardiovascular disease, cancer, fertility, pregnancy, dementia and mortality- a review of recent evidence. Autoimmun Rev. 2013;12(10):976-89.
  • 34 Grant WB, Karras SN, Bischoff-Ferrari HA, Annweiler C, Boucher BJ, Juzeniene A, Garland CF, Holick MF. Do studies reporting ‘U’-shaped serum 25-hydroxyvitamin D–health outcome relationships reflect adverse effects? Dermato-Endocrinology, 2016;8(1):e1187349.
  • 34. Grant WB, Karras SN, Bischoff-Ferrari HA, et al. Do studies reporting ‘U’-shaped serum 25-hydroxyvitamin D–health outcome relationships reflect adverse effects? Dermato-Endocrinology, 2016;8(1): e1187349.
  • 35. Grant WB. The UVB-vitamin D3-skin pigmentation is alive and well. Am J Phys Anthro. 2016; 61(4):752-755.
  • 36. Hoel DG, Berwick M, de Gruijl FR, Holick MF. The risks and benefits of sun exposure 2016. Dermatoendocrinol. 2016;8(1):e1248325.
  • 37. Cashman KD, Kazantzidis A, Webb AR, Kiely M. An Integrated Predictive Model of Population Serum 25-Hydroxyvitamin D for Application in Strategy Development for Vitamin D Deficiency Prevention. J Nutr. 2015;145(10):2419-25.
  • 38. 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;85(3):860-8.
  • 39. Calvo MS, Whiting SJ. Survey of current vitamin D food fortification practices in the United States and Canada. J Steroid Biochem Mol Biol. 2013;136:211-3.
  • 40. Madsen KH, Rasmussen LB, Andersen R, et al. Randomized controlled trial of the effects of vitamin D–fortified milk and bread on serum 25-hydroxyvitamin D concentrations in families in Denmark during winter: the VitmaD study. Am J Clin Nutr. 2013;98(2):374-82.
  • 41. Allen RE, Dangour AD, Tedstone AE, Chalabi Z. Does fortification of staple foods improve vitamin D intakes and status of groups at risk of deficiency? A United Kingdom modeling study. Am J Clin Nutr. 2015;102(2):338-44.
  • 42. Nikooyeh B, Neyestani TR, Zahedirad M, et al. Vitamin D-Fortified Bread Is as Effective as Supplement in Improving Vitamin D Status: A Randomized Clinical Trial. J Clin Endocrinol Metab. 2016;101(6):2511-9.


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