Should adults take vitamin D supplements to prevent disease?BMJ 2016; 355 doi: https://doi.org/10.1136/bmj.i6201 (Published 23 November 2016) Cite this as: BMJ 2016;355:i6201
All rapid responses
We wonder what compelled Rhein to accuse us of “condescending neglect” of Northern Britain,1 especially when one of us lives in North-East Scotland?
She says the evidence for vitamin D supplements is good enough for her, citing meta-analyses of randomised trials for critical care patients, cancer mortality, and asthma.1 But these meta-analyses have substantial limitations that led the authors involved2,3 or authors of similar contemporaneous reviews4 to call for more trials, not that clinical practice should change. Otherwise, the evidence she cites is from observational studies or studies with surrogate endpoints which are insufficient to inform clinical practice.
Arguably, the best evidence for whether people at risk of vitamin D insufficiency in Northern Britain should take vitamin D is from the UK RECORD trial. This large trial of older adults from 21 sites around England and Scotland showed that 800 IU daily of vitamin D, while increasing 25-hydroxyvitamin D, had no effect on total or hip fractures,5 falls,5 total, cardiovascular or cancer mortality,6 infections7 or preventing diabetes or the need for more diabetic medication.8 Furthermore, there was no evidence for a differential effect of vitamin D supplementation in the RECORD trial according to latitude, with 1636/5292 participants recruited in Scotland.5
Degner, too, seems willing to accept low-quality evidence for clinical treatments.9 He cites a meta-analysis of 2 trials of 81 patients and a subgroup analysis involving 2 trials with 149 patients as evidence that vitamin D supplements can aid anti-depressive treatment or improve depression and therefore should be used clinically.10,11
As we indicated in our article, there is no high-quality evidence to suggest that vitamin D supplementation is beneficial for non-musculoskeletal outcomes.12 It is not condescending or neglectful to require high-quality evidence that treatments work before prescribing them - it is just good clinical practice.
1. Rhein H. Condescending neglect of northern Britain? BMJ 2016;355:i6740.
2. Putzu A, Belletti A, Cassina T, Clivio S, Monti G, Zangrillo A, et al. Vitamin D and outcomes in adult critically ill patients. A systematic review and meta-analysis of randomized trials. J Crit Care 2016;38:109-14.
3. Martineau AR, Cates CJ, Urashima M, Jensen M, Griffiths AP, Nurmatov U, et al. Vitamin D for the management of asthma. Cochrane Database Syst Rev 2016;9:CD011511.
4. Bjelakovic G, Gluud LL, Nikolova D, Whitfield K, Krstic G, Wetterslev J, et al. Vitamin D supplementation for prevention of cancer in adults. Cochrane Database Syst Rev 2014:CD007469.
5. Grant AM, Avenell A, Campbell MK, McDonald AM, MacLennan GS, McPherson GC, et al. Oral vitamin D3 and calcium for secondary prevention of low-trauma fractures in elderly people (Randomised Evaluation of Calcium Or vitamin D, RECORD): a randomised placebo-controlled trial. Lancet 2005;365:1621-8.
6. Avenell A, MacLennan GS, Jenkinson DJ, McPherson GC, McDonald AM, Pant PR, et al. Long-term follow-up for mortality and cancer in a randomized placebo-controlled trial of vitamin D(3) and/or calcium (RECORD trial). J Clin Endocrinol Metab 2012;97:614-22.
7. Avenell A, Cook JA, Maclennan GS, Macpherson GC. Vitamin D supplementation to prevent infections: a sub-study of a randomised placebo-controlled trial in older people (RECORD trial, ISRCTN 51647438). Age Ageing 2007;36:574-7.
8. Avenell A, Cook JA, MacLennan GS, McPherson GC. Vitamin D supplementation and type 2 diabetes: a substudy of a randomised placebo-controlled trial in older people (RECORD trial, ISRCTN 51647438). Age Ageing 2009;38:606-9.
9. Degner D. Vitamin D supplements: don't forget depression and cognitive impairment. BMJ 2016;355:i6711.
10. Sarris J, Murphy J, Mischoulon D, Papakostas GI, Fava M, Berk M, et al. Adjunctive Nutraceuticals for Depression: A Systematic Review and Meta-Analyses. Am J Psychiatry 2016;173:575-87.
11. Shaffer JA, Edmondson D, Wasson LT, Falzon L, Homma K, Ezeokoli N, et al. Vitamin D supplementation for depressive symptoms: a systematic review and meta-analysis of randomized controlled trials. Psychosom Med 2014;76:190-6.
12. Bolland MJ, Avenell A, Grey A. Should adults take vitamin D supplements to prevent disease? BMJ 2016;355:i6201.
Competing interests: No competing interests
High vitamin D levels are associated with morbidity and mortality reductions, against a broad spectrum of diseases, according to published systematic reviews and meta-analyses, level I evidence. 
Focusing only on academic evidence regarding musculoskeletal health is missing the broader benefits of vitamin D supplementation.
Competing interests: No competing interests
Bolland and coauthors  described the role of vitamin D supplementation and the high rate of different, insufficient studies in recent years. Observational studies have associated low vitamin D status with a wide variety of non-skeletal adverse clinical outcomes. The authors reported that meta-analyses of randomized controlled trials show that vitamin D supplementation alone does not improve musculoskeletal outcomes and that there is no high quality evidence to suggest that it is beneficial for non-musculoskeletal outcomes.
I think that there are high quality investigations reporting effectiveness in some psychiatric disorders. Sarris et al.  reported in a systematic review and meta-analysis about a current evidence supports adjunctive use vitamin D with antidepressants to reduce depressive symptoms. Shaffer  observed that Vitamin D supplementation had no overall effect on depressive symptoms (standardized mean difference [SMD], 0.14; 95% confidence interval [CI], -0.33 to 0.05, p = .16), but in some subgroups. They concluded that Vitamin D supplementation may be effective for reducing depressive symptoms in patients with clinically significant depression, but most trials had unclear risk of bias and varied in the amount, frequency, duration, and mode of delivery of vitamin D supplementation. A very interesting aspect of Vitamin D supplementation is the subgroup of seasonal affective disorders. Another aspect should be mentioned. There is a possible influence of Vitamin D for cognitive impairment and dementia. Karakis et al.  analyzed in a an large community-based sample (Framingham Study), that low 25(OH)D concentrations were associated with smaller hippocampal volume and poorer neuropsychological function. Of course, further high-quality research is needed in such complex problems. But I think that at the moment it is correct that many guideline groups continue to recommend vitamin D supplementation in older adults , also under the aspect of affective disorders and cognitive impairment (prevention, quality of life).
1) Bolland MJ et al. Should adults take vitamin D supplements to prevent disease? BMJ 2016;355:i620
2) Sarris J et al. Adjunctive Nutraceuticals for Depression: A Systematic Review and Meta-Analyses. Am J Psychiatry. 2016;;173(6):575-87
3) Shaffer JA et al. Vitamin D supplementation for depressive symptoms: a systematic review and meta-analysis of randomized controlled trials. Psychosom Med. 2014 ;76(3):190-6.
4) Karakis I et al. Association of Serum Vitamin D with the Risk of Incident Dementia and Subclinical Indices of Brain Aging: The Framingham Heart Study. Alzheimers Dis. 2016; 51(2):451-61.
5) Annweiler C et al. Vitamin D and cognition in older adults: international consensus guidelines. Geriatr Psychol Neuropsychiatr Vieil. 2016;14(3):265-73
Competing interests: No competing interests
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 [400-800 IU/d] . The authors consider randomized clinical trials (RCTs) as the primary, perhaps the only evidence, that should be used to guide clinical practice. Unfortunately, the majority of vitamin D RCTs have not been suitably designed since they were based on guidelines for pharmaceuticals, where the two main underlying assumptions are that the trial is the only source of the agent, and that the dose-response relation will be linear. However, neither is satisfied for vitamin D, as Robert Heaney outlined in guidelines for studying clinical effects of nutrients . One other key point is to base the trial on low-baseline 25(OH)D concentration-health outcomes of interest. A recent review of vitamin D3 RCTs with biomarkers of inflammation as outcomes found that 50% of the trials with baseline 25(OH)D concentrations <49 nmol/L showed beneficial effects, but only 26% of those with baseline 25(OH)D concentrations >49 nmol/L .
Scientific evidence relating to causality between agent and outcome can come from a variety of approaches.
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. The advantages of ecological studies are 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 D3 provision, years before observational studies did, as for rickets , and then been followed by positive RCTs (e.g., for cancer ) .
Observational studies related to vitamin D can use data on personal UVB exposure, vitamin D intake, or serum 25(OH)D concentrations determined either near the time of disease diagnosis (case-control studies) or before diagnosis (prospective studies).
Laboratory studies have also determined the mechanisms by which vitamin D acts to maintain optimal health in many different tissues, and to reduce disease risks.
Bradford Hill, in his well-known presidential address to the Royal Medical Society, outlined the criteria for causality in a biological system . Experiment (e.g., RCT) was but one of nine criteria. Others include strength of association, dose-response relationships, identification of relevant mechanisms, and consistent findings in different populations as demonstrated in the evidence on the roles of UVB exposure and vitamin D in reducing three adverse health outcomes: cancer, all-cause mortality rates, and adverse pregnancy outcomes.
Single-country geographical ecological studies have been very important in studying the effect of solar UVB exposure on cancer incidence and mortality rate, having identified ~15 types of epithelial cancer with reduced risks with higher solar UVB exposure . 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 . A pair of vitamin D3 plus calcium RCTs conducted on postmenopausal 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 [5,10]. 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 risks of total, breast, and invasive breast, cancers by 14-20% and non-significantly reduced risks of colorectal cancer -17% . The mechanisms whereby vitamin D reduces risk and increases cancer survival are well known .
All-cause mortality rates.
Observational studies find that prospective all-cause mortality rates rises rapidly as 25(OH)D concentration declines below 90 nmol/L . A meta-analysis of vitamin D3 RCTs in community dwelling and hospital-based study groups found a relative risk with vitamin D3 supplementation of 0.89 (0.80-0.99) . 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 . This increase in life expectancy is similar to the 2 years found in an analysis based on observational studies . A recent analysis estimated that increasing serum 25(OH)D concentrations to >100 nmol/L in all Canadians would significantly reduce the economic burden of disease as well as mortality rates .
Vitamin D requirements during pregnancy and lactation are high. A vitamin D3 RCT conducted in South Carolina showed that taking 4000 IU/d vitamin D3 was safe and that serum 1,25-dihydroxyvitamin D3 concentrations increased maximally, only when serum 25(OH)D3 concentrations reached ≥100 nmol/L . In a subsequent analysis of two vitamin D3 supplementation 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 = 0.22,0.83] , 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, e.g. respiratory infections and sepsis." .
Recommendations by others.
Various assessments and recommendations have been made regarding vitamin D status. A Task Force of the U.S. Endocrine Society recommended achieving >75 nmol/L for those at risk of vitamin D deficiency . The European Menopause and Andropause Society (EMAS) recommended >75 nmol/L for postmenopausal women . 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  based primarily on a review of the evidence from observational studies . The simplest way to ensure that most of the population has 25(OH)D concentrations >75 nmol/L is to encourage non-burning exposure to sunlight, vitamin D3 food fortification of food, and vitamin D3 supplementation for high-risk subjects. Measuring 25(OH)D concentrations is expensive and unnecessary, and there is little risk to adverse with 25(OH)D concentrations up to 250 nmol/L .
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.
3. Cannell JJ, Grant WB, Holick MF. Vitamin D and inflammation. Dermatoendocrinol. 2015;6(1):e983401.
4. Gibbs D, Rickets and the crippled child; an historical perspective. J Roy Soc Med. 1994;87:729-32.
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(6):1586-91.
6. Grant WB. The Role of geographical ecological studies in identifying diseases linked to UVB exposure and/or vitamin D. Dermatoendocrinol. 2016;8(1):e1137400
7. Hill AB. The environment and disease: Association or causation? Proc R Soc Med. 1965;58:295-300.
8. Moukayed M, Grant WB. Molecular link between vitamin D and cancer prevention. Nutrients. 2013;5:3993-4023.
9. 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.
10. 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
11. 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.
12. 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.
13. 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.
14. 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.
15. 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.
16. 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.
17. 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.
18. 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.
19. 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.
20. 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.
21. Pérez-López FR, Brincat M, Erel CT, et al. EMAS position statement: Vitamin D and postmenopausal health. Maturitas. 2012;71(1):83-8.
22. 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.
23. 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.
24. 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.
Competing interests: WBG receives funding from Bio-Tech Pharmacal, Inc. (Fayetteville, AR) and has received funding recently from the Vitamin D Society (Woodstock, ON, Canada) and the Vitamin D Council (San Luis Obispo, CA). BJB has no conflicts of interest to report.
Some people see real life through their own windows.
This article no surprise. A limited RCT window flows like this article. One can get more relevant clinical data from other windows. Selected articles.
What might the legendary Prof. Robert Heaney say about this?
A serious clinician must measure calcidiol levels and treat his or her patient after it with D supplementation.
Nutritionists who write recommendations seldom see patients with hypovitaminosis D.
Competing interests: No competing interests
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.
Bolland MJ, Avenell A, Grery A. Will vitamin D supplements for healthy adults help prevent disease? BMJ 2016;355:i6201
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
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)
Robsahm TE, Schwartz GG, Tretli S. The Inverse Relationship between 25-Hydroxyvitamin D and Cancer Survival: Discussion of Causation. Cancers 2013, 5, 1439-1455
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
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
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
Martineau AR, Cates CJ, Urashima M, et al. Vitamin D for the management of asthma. Cochrane Database of Systematic Reviews 2016
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
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
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
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
Spector TD, Levy L. Do healthy people need a vitamin D supplement in the winter? BMJ 2016;355:i6183
personal communication with Dr. David Grimes
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
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
Competing interests: No competing interests