Should we be giving enhanced vitamin D intakes to all?

Current controversies
J R Coll Physicians Edinb 2011; 41:324-9 doi:l0.4997/JRCPE.20ll.409 © 20ll Royal College of Physicians of Edinburgh
XBJ Boucher, 2MD Witham
1 Honorary Professor of Medicine, Centre for Diabetes, Barts & The London School of Medicine & Dentistry, London, UK;
2 Clinical Senior Lecturer and Clinician Scientist in Ageing and Health, University of Dundee, Ninewells Hospital, Dundee, UK
- - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - -
PDF is attached at bottom of this page

Comments and bolding by Vitamin D Life//www.vitad.org/tiki-index.php?page_id=28|Overview Seniors and Vitamin D]

• Overview Obesity and Vitamin D
• No longer debating vitamin D supplementation, now debating need for testing first – April 2013
• 29+ reasons for vitamin D deficiency some of the recent reasons not mentioned in the debate include:
  Air conditioning - to avoid the hot sun
  Increased use of multi-media indoors - TV, DVD, video games, and internet access
  4X more suburban UV than urban UV – Nov 2010
  Want whiter skin - especially women
  Cholesterol reduced - which the skin need to produce vitamin D
  More Obesity
  Soft drink cola - uses up Calcium which uses up vitamin D
  Meat from factory farms - has far less vitamin D than from free-range farms
  Some drugs consume vitamin D
  Increased use of polyunsaturated fats decreased bio-availablity of vitamin D

- - - - - - - - - - - - - - - - - - - - - - -

It is widely established that vitamin D is critical for bone health. There is also an increasing body of evidence from observational studies that low levels of vitamin D are associated with a range of other disorders, including cancer and cardiovascular disease. People in temperate climates are often deficient in vitamin D, particularly in wintertime. The key question is whether there is sufficient evidence to justify supplementing vitamin D intakes for all. In this 'Controversy in Medicine', two international experts argue the case 'for' and 'against' universal vitamin D supplementation.

DECLARATION OF INTERESTS MD Witham has received grant funding from the Chief Scientist Office, Scottish Government, Diabetes UK, Heart Research UK, Chest Heart and Stroke Scotland, ME Research UK and Tenovus Scotland, to support research into vitamin D.
Correspondence to BJ Boucher, Centre for Diabetes, Barts & The London School of Medicine & Dentistry, Blizard Institute, 2 Newark Street, London E1 2AT, UK; e-mail bboucher at doctors.org.uk
Correspondence to MD Witham, University of Dundee Ninewells Hospital, Dundee DDI 9SY, UK tel. +44 (0)1382 632436 e-mail m.witham at dundee.ac.uk

Enhanced vitamin D intakes for all? Why we should say 'yes'

BJ Boucher

Those who do not learn from history are doomed to repeat it.l

Rickets, one of several 'English diseases', appeared during the Industrial Revolution when people moved into towns, summer sunshine was blocked by air pollution and many people worked indoors rather than outdoors, often from early childhood.2 Rickets was virtually abolished in the UK in World War II when cod liver oil supplements were offered to all pregnant and nursing mothers and children under five years of age3, and when parents 'aired' their babies outdoors. It took almost a century for the old wives tale (that cod liver oil cured rickets) to be confirmed, and the two forms of vitamin D (cholecalciferol and ergocalciferol), to be discovered.4 So how is it that increasing numbers of people have developed vitamin D deficiency-related rickets and osteomalacia, osteoporosis has worsened and falls and fragility fractures have become more common over recent decades? This is mainly because most of us spend less time outdoors as we work, play, socialise, travel and exercise indoors, behind glass windows that block transmission of ultraviolet light (UVB). At the same time, we are advised to avoid midday sunshine in order to reduce skin cancer risks (and skin ageing) by seeking shade, covering up and using powerful sunscreens, especially for children. For the growing proportion of the UK population who are black or Asian, increased skin pigmentation reduces skin synthesis of vitamin D by UVB, and, the further north we live, the less available UVB there is. Thus, instead of making enough vitamin D ourselves, under tightly regulated feedback systems avoiding toxicity in normal people5, we are dependent on dietary or supplemental vitamin D, as a 'vitamin', to avoid overt manifestations of vitamin D deficiency both in the UK and globally as the problem of deficiency becomes increasingly common in both sunny and temperate climates.6

Those reading this debate in Scotland are even more likely to be vitamin D insufficient than readers in southern parts of the UK.7 The problem gets worse with age as skin synthesis and gut absorption of vitamin D become less efficient.8,9 This situation is also exacerbated in those with reduced mobility, loss of independence, and especially in those in residential care.l0 There is a large body of evidence associating hypovitaminosis D with increased risks for many diseases, in virtually all systems of the body and not just in the musculoskeletal system. Serum 25-hydroxyvitamin D (25[OH]D) is generally accepted as a measure of vitamin D repletion (status). The significance of this measurement in the investigation of disease relates to the fact that 25(OH)D is activated locally in target tissues, free of feed-back regulation. This local activation is directly dependent on serum 25(OH)D concentration, explaining the physiological significance of serum 25(OH) D concentration for human health.lM3

These data cover associations and mechanisms for cardiovascular disease, innate and acquired immunity, infections, autoimmune disease (especially multiple sclerosis), inflammatory disorders and psoriasis. Higher vitamin D status is associated with reduced risks, cross-sectionally and often prospectively, for these disorders, including melanoma, the most aggressive skin cancer and itself triggered by sunburn.l4-:!l However, randomised controlled trial (RCT) data indicating adequate supplementation with vitamin D for non-bony conditions is still insufficient to prove causality. For bone mineral density, muscle strength, falls and fragility fractures, intakes of at least 800 IU/day of vitamin D reduces risk, though massive doses may increase these risks temporarily.22-26 Thus, our evidence base supports the need to return to the situation achieved during World War II, when the reduction in vitamin D deficiency lowered the risks of rickets and osteomalacia; it does not however support the use of supplemental intakes (above 800 to l000 IU/day) in the long-term in healthy people for reducing non-bony health risks. Indeed, history teaches us that other potential 'magic bullets' thought to reduce several major health risks can prove ineffective and may even increase those risks (e.g. RCTs using beta-carotene with vitamin A for prevention of lung cancer and heart disease).27 The problems with the use of beta-carotene probably resulted from confounding by other dietary factors; similar confounding by unidentified factors affecting vitamin D status cannot as yet be excluded.

These considerations contributed to the recent Institute of Medicine (IOM) recommendations from the US that dietary intakes in the population as a whole should reach 400 IU/day in infants and children, 600 IU/day in adults and pregnant and nursing mothers, and 800 IU/day in older people (and by implication, others at increased risk of D deficiency, e.g. dark skinned, vegetarians and vegans28). Vitamin D deficiency is increasingly common worldwide and is known to increase infant mortality (from acute heart failure or hypocalcaemic fits),3 and is also associated with increased adult mortality.29 Disagreement on defining 'deficiency' based on serum 25(OH)D assays is common. Genetic variation in the vitamin D axis has a small independent effect on serum 25(OH)D concentration, but the literature demonstrates a reasonable consensus that values of <50 nmol/l by any assay reflect a deficiency severe enough to lead to clinically obvious bone problems.30,l2 Thus, in countries where this value is not reached by the majority of residents across all seasons of the year, the population should benefit, in bone health at least, from increasing vitamin D intakes to achieve 25(OH)D values of at least 50 nmol/l. In the young, 25(OH)D concentrations above 50 nmol/l increase bone density 'dose-wise', reducing bone risks in later life.32 Thus, 50 nmol/l is a serum 25(OH)D target level likely to be raised as new evidence accrues. In Scotland, a recent report on post-menopausal women showed that they never reach a mean 25(OH)D concentration of 50 nmol/l at any season of the year.33 In winter, 40% of post-menopausal women in Surrey were deficient (l0% of Caucasian and 65% of Asian women). In summer, l6% were deficient (0% of White and >50% of Asian women). Higher values, e.g. 75-ll0 nmol/l, are associated with health benefits in observational studies. At higher, but non-toxic, concentrations, however, there are suggestions of possible adverse effects that need further investigation.34,35 Better maternal vitamin D status improves bone health in children aged 9 years old,36 and other possible transgenerational effects require study.

Vitamin D deficiency (25(OH)D <25 nmol/l) is found at all ages in the UK in 5-l5% of Caucasian people. It rises to >20% in those aged between l9-24 years, increasing again after the age 60 and reaching >40% in people in their 80s. A lesser degree of deficiency (25(OH)D <50nmol/l) is never found in less than 20% of the Caucasian population at any age and is found in >40% of people over the age of ll years old; in >60% of those aged between l9-24 years, and increases in over 65-year-olds, peaking at >80% among those living in an institutional setting.37 This nationwide problem requires urgent attention. Preventative public health measures would be more cost-effective than medical management: provision of 400-800 IU/day using Healthy Start supplements costs less than £4/year (20l0 prices) but one 25(OH)D assay costs £l0.50-£25.3 The costs of modest food fortification would, as for other foods, be passed on to consumers. In Finland, voluntary food fortification with vitamin D has reduced the prevalence of vitamin D deficiency (25(OH) D <50 nmol/l) significantly in most population groups.38,39 This approach, already widely used in the USA and enforced by statute in the UK since l942 (but only for margarine [at 280-350 IU/l00G40]), requires care to avoid excessive intakes in infants.3 Ultraviolet B (UVB) irradiation of certain vegetables, notably mushrooms and yeast, increases vitamin D content and is used in some countries,3 and may prove more useful than trying to ensure controlled UVB irradiation of the skin. Surveys of representative population groups and checks on food content would be needed to audit the adequacy of provision and its safety at the population level. Such audits and safety checks would be expected to lead to adjustment of fortification levels where necessary.

The many studies of vitamin D status in the UK over recent years have clearly not been acted upon, and this must change.4 Even modest risk reductions in musculoskeletal vitamin D deficiency disorders, acute neonatal heart failure, rickets, the severity and costs of osteoporosis and its painful complications, and in fragility fractures (in the 25,000 overt vertebral fractures and the 70,000 annual hip fractures in England and Wales which have a falling in-patient mortality but a continuing mortality of 20% after six months and 30% by one year, with a 50% loss of independence42-45) would, clearly, be welcome to sufferers and their families and would also reduce NHS costs. At present, the NHS has no recommendations for vitamin D intake levels for those aged between 19 and 64 years old.3,37 Compliance with oral supplementation is well known to be poor (reducing to 50% after six months in those being treated for osteoporosis). In the UK supplements on prescription usually contain either calcium (which can cause constipation, reducing compliance and, in supplements, may increase cardiovascular risks47) or vitamin A which antagonises vitamin D.3,48 It would be helpful, therefore, if the British National Formulary (BNF) included preparations of vitamin D alone, at a range of doses, to facilitate treatment of people presenting clinically with deficiency related disorders. While many pregnant and nursing women might take supplements, as they do folic acid, others might not use them regularly, even if they could afford them, or even if they were free of charge for all.

Thus, food fortification, adjusted to achieve serum 25(OH)D concentrations across the healthy adult population of at least 50 nmol/l (but ideally < l50 nmol/l) #00F:(60 ng) Santayana G. Reason in common sense. l905.

• 2 Gibbs DD. Rickets and the crippled child: an historical perspective. J R Soc Med l994; 87:729-32.
• 3 Hypponen E, Boucher BJ. Avoidance of vitamin D in pregnancy in the United Kingdom: the case for a unified approach in national policy. Br J Nutr 20l0; l04:309-l4. http://dx.doi.org/l0.l0l7/S0007ll45l0002436
• 4 Hirsch AL. Industrial aspects of vitamin D. In: Feldman D, Pike JW Adams JS, editors. Vitamin D. International: Academic Press; 20ll. p. 73-93. http://dx.doi.org/l0.l0l6/B978-0-l2-38l978-9.l0006-X
• 5 Holick MF. Vitamin D: evolutionary, physiological and health perspectives. Curr Drug Targets 20ll; l2:4-l8. http://dx.doi.org/l0.2l74/l389450ll79359l635
• 6 Prentice A. Vitamin D deficiency: a global perspective. Nutr Rev 2008;66:Sl53-64. http://dx.doi.org/l0.llll/j.l753-4887.2008.00l00.x
• 7 Hypponen 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; 85:860-68.
• 8 Lund B, Sorensen OH. Measurement of 25-hydroxyvitamin D in serum and its relationship to sunshine, age and vitamin D intake in the Danish population. Scand J Lab Invest l979; 39:23-30. http://dx.doi.org/l0.3l09/003655l7909l04935
• 9 Barragry JM, France MW, Corless D et al. Intestinal cholecalciferol absorption in the elderly and younger adults. Clin Sci Mol Med l978; 55:2l3-20.
• 10 Corless D, Gupta SP, Switala S et al. Response of plasma-25-hydroxyvitamin D to ultraviolet irradiation in long-stay geriatric patients. Lancet l978; 2:649-5l. http://dx.doi.org/l0.l0l6/S0l40-6736(78)92760-5
• 11 Adams JS, Hewison M. Update in vitamin D. J Clin Endocrinol Metab 20l0; 95:47l-78. http://dx.doi.org/l0.l2l0/jc.2009-l773
• 12 Holick MF. Vitamin D deficiency. N Engl J Med 2007; 357:266-8l. http://dx.doi.org/l0.l056/NEJMra070553
• 13 Feldman D, Pike JW, Adams JS, editors. Vitamin D. International: Academic Press; 20ll.
• l 4 Grant WB, Boucher BJ. Requirements for vitamin D across the lifespan. Biol Res Nurs 20ll; l3:l20-33.http://dx.doi.org/l0.ll77/l0998004l039l243
• 15 Handunnetthi L, Ramagopalan SV, Ebers GC. Multiple sclerosis, vitamin D and HLA-DRBl*l5. Neurology 20l0; 74:l905-l0. http://dx.doi.org/l0.l2l2/WNL.0b0l3e3l8le24l24
• 16 Forouhi NG,Luan J,CooperA et al.Baseline serum 25-hydroxyvitamin D is predictive of future glycemic status and insulin resistance: The Medical Research Council Ely Prospective Study l990-2000. Diabetes 2008; 57:26l9-25. http://dx.doi.org/l0.2337/db08-0593
• 17 Mitri J, Muraru MD, Pittas AG et al. Vitamin D and type 2 diabetes: a systematic review. Eur J Clin Nutr 20ll; 65:l605-l5. http://dx.doi.org/l0.l038/ejcn.20ll.ll8
• 18 Boucher BJ. Vitamin D insufficiency and diabetes risks. Curr Drug Targets 20ll;l2:6l-87. http://dx.doi.org/l0.2l74/l389450ll79359l653
• 19 Grandi NC, Breitling LP, Brenner H. Vitamin D and cardiovascular disease: systematic review and meta-analysis of prospective studies. Prev Med 20l0; 5l:228-33. http://dx.doi.org/l0.l0l6/j.ypmed.20l0.06.0l3
• 20 Newton-Bishop JA, Chang YM, Eliott F et al. Relationship between sun exposure and melanoma risk for tumours in different body sites in a large case-control study in a temperate climate. Eur J Cancer 20ll; 47:732-4l. http://dx.doi.org/l0.l0l6/j.ejca.20l0.l0.008
• 21 Field S, Newton-Bishop JA. Melanoma and vitamin D. Mol Oncol 20ll; 5:l97-2l4. http://dx.doi.org/l0.l0l6/j.molonc.20ll.0l.007
• 22 Karalus J, Chlebna-Sokol D. The clinical efficacy of vitamin D in children with primary low bone mass. Pediat Endocrinol Diabetes Metab 20ll; l7:35-40.
• 23 Bischoff-Ferrari HA, Willett WC, Wong JB et al. Prevention of non-vertebral fractures with oral vitamin D and dose dependency: a meta-analysis of randomized controlled trials. Arch Int Med 2009; l69:55l-6l. http://dx.doi.org/l0.l00l/archinternmed.2008.600
• 24 Bischoff-Ferrari HA, Dawson-Hughes B, Staehelin HB et al. Fall prevention with supplemental and active forms of vitamin D: a meta-analysis of randomized controlled trials. BMJ 2009; 339:b3692. http://dx.doi.org/l0.ll36/bmj.b3692
• 25 Zhu K, Devine A, Dick IM et al. Effects of calcium and vitamin D supplementation on hip bone mineral density and calcium-related analytes in elderly ambulatory Australian women: a five year randomized controlled trial. J Clin Endocrinol Metab 2008; 93:74349. http://dx.doi.org/l0.l2l0/jc.2007-l466
• 26 Sanders KM, Stuart AL, Williamson EJ et al. Annual high-dose oral vitamin D and falls and fractures in older women: a randomized controlled trial. JAMA 20l0; 303:l8l5-22. http://dx.doi.org/l0.l00l/ jama.20l0.594
• 27 Fritz H, Kennedy D, Fergusson D et al. Vitamin A and retinoid derivatives for lung cancer: a systematic review and meta-analysis. PloS One 20ll; 6:e2ll07. http://dx.doi.org/l0.l37l/journal. pone.002ll07
• 28 Ross AC, Manson JE, Abrams SA et al. The 20ll report on dietary reference intakes for calcium and vitamin D from the Institute of Medicine: what clinicians need to know. J Clin Endocrinol Metab 20ll; 96:53-58. http://dx.doi.org/l0.l2l0/jc.20l0-2704
• 29 Bjelakovic G,Gluud LL,Nikolova D et al.Vitamin D supplementation for prevention of mortality in adults. Cochrane Database Syst Rev 20ll; 7:CD007470.
• 30 Berry DM Hypponen E. Determinants of vitamin D status: focus on genetic variations. Curr Opin Nephrol Hypertens 20ll; 20:33l-36. http://dx.doi.org/l0.l097/MNH.0b0l3e328346d6ba
• 31 Malabanan A, Veronikis IE, Holick MF. Redefining vitamin D insufficiency. Lancet l998; 35l:805-6. http://dx.doi.org/l0.l0l6/ S0l40-6736(05)78933-9
• 32 Bischoff-Ferrari HA, Dietrich T, Orav EJ et al. Positive association between 25-hydroxyvitamin D levels and bone mineral density: a population-based study of younger and older adults. Am J Med 2004; ll6:634-39. http://dx.doi.org/l0.l0l6/j.amjmed.2003.l2.029
• 33 Macdonald HM, Mavroeidi A, Fraser WD et al. Sunlight and dietary contributions to the seasonal vitamin D status of cohorts of healthy postmenopausal women living in northerly latitudes: a major cause for concern? Osteoporos Int 20ll; 22:246l-72. http://dx.doi.org/l0.l007/s00l98-0l0-l467-z
• 34 Bodnar LM, Catov JM, Zmuda JM et al. Maternal serum 25-hydroxyvitamin D concentrations are associated with small-for-gestational age births in white women. J Nutr 20l0; l40:999-l006. http://dx.doi.org/l0.3945/jn.l09.ll9636
• 35 Michaelsson K, Baron JA, Sneliman G et al. Plasma vitamin D and mortality in older men: a community-based prospective cohort study. Am J Clin Nutr 20l0; 92:84l-48. http://dx.doi.org/l0.3945/ ajcn.20l0.29749
• 36 Javaid MK, Crozier SR, Harvey NC et al. Maternal vitamin D status during pregnancy and childhood bone mass at age 9 years: a longitudinal study. Lancet 2006; 367:36-43. http://dx.doi.org/l0.l0l6/S0l40-6736(06)67922-l
• 37 Henderson LB, Prentice A, Perks J et al. The National Diet and Nutrition Survey: Adults aged 19-64 years - vitamin and mineral intake and urinary analytes [Internet]. London: The Stationery Office; 2003 [cited 20ll Nov 8]. Available from: http://www.food.gov.uk/multimedia/pdfs/ ndnsv3.pdf
• 38 O'Donnell S, Cranney A, Horsley T et al. Efficacy of food fortification on serum 25-hydroxyvitamin D concentrations: a systematic review. Am J Clin Nutr 2008; 88:l528-34. http://dx.doi.org/l0.3945/ajcn.2008.264l5
• 39 Lanham-New S, Buttriss JL, Miles LM et al. Proceedings of the Rank Forum on Vitamin D. Br J Nutr 20ll; l05:l44-56. http://dx.doi. org/l0.l0l7/S0007ll45l0002576
• 40 HM Government. The Spreadable Fats (Marketing Standards) Regulations 1995. London: The National Archives; l995.
• 41 Gillie O. Sunlight robbery: a critique of public health policy on vitamin D in the UK. Mol Nutr Food Res 20l0; 54:ll48-63.
• 42 Wu TY, Jen MH, Bottle A et al. Admission rates and in-patient hospital mortality for hip fractures in England l998-2009: time trends study.J Public Health (Oxf) 20ll; 33:284-9l. http://dx.doi.org/l0.l093/pubmed/fdq074
• 43 Scottish Intercollegiate Guidelines Network. Management of osteoporosis. A national clinical guideline (June 2003) [Internet]. Edinburgh: SIGN; 2003 [cited 20ll Nov 8]. Available from: http:// www.sign.ac.uk/pdf/sign7l.pdf
• 44 Trivedi DP, Doll R, Khaw KT. Effect of four monthly oral vitamin D3 (cholecalciferol) supplementation on fractures and mortality in men and women living in the community: randomised double blind controlled trial. BMJ 2003; 326:469. http://dx.doi.org/l0.ll36/bmj.326.7387.469
• 45 National Institute for Health and Clinical Excellence. Osteoporosis - secondary prevention including strontium ranelate: Final appraisal determination (July 2008) [Internet]. London: NICE; 2008 [cited 20ll Nov 8]. Available from: http://www.nice.org.uk/nicemedia/ pdf/OsteoporosisSecondaryPreventionFADJul08.pdf
• 46 Sanders KM, Stuart AL, Merrimen EN et al. Trials and tribulations of recruiting 2,000 older women onto a clinical trail investigating falls and fractures: Vital D study. BMC Med Res Methodol 2009; 9:78. http://dx.doi.org/l0.ll86/l47l-2288-9-78
• 47 Boucher BJ. Calcium supplements may increase the risk of cardiovascular events in postmenopausal women [commentary]. Evid Based Med 20ll; Epub 20ll Oct 25. http://dx.doi.org/l0.ll36/ebm.20ll.l00ll3
• 48 Johansson S, Melhus H. Vitamin A antagonises calcium response to vitamin D in man. J Bone Miner Res 200l; l6:l899-l905. http:// dx.doi.org/l0.l359/jbmr.200l.l6.l0.l899
• 49 DIPART (Vitamin D Individual Patient Analysis of Randomized Trials) Group. Patient level pooled analysis of 68,000 patients from seven major vitamin D fracture trials in US and Europe. BMJ 20ll; 343:d5246. http://dx.doi.org/l0.ll36/bmj.d5245. Corrected and republished from: BMJ 20l0; 340:b5463. http://dx.doi.org/l0.ll36/bmj.b5463
• 50 Current controlled trials.com [Internet]. Biomed Central. [cited 20ll Nov 8]. metaRegister of controlled trials - active registers. Available from: http://www.controlledtrials.com/mrct/search.html
• 51 Hollis BW, Johnson D, Hulsey TC et al. Vitamin D supplementation during pregnancy: double blind randomized clinical trial of safety and effectiveness. J Bone Miner Res 20ll; 26:234l-57. http://dx.doi.org/l0.l002/jbmr.463
• 52 The Goldilocks principle, based on The Story of the Three Bears, an update of an old folk tale by Robert Southey.

Enhanced vitamin D intakes for all? Why we should say 'no'

MD Witham

It would be easy to assume, given the excited media coverage that vitamin D generates, that the case for universal supplementation was already proven. Vocal lobbying is however no substitute for scientific evidence, and for vitamin D, we do not have the understanding of its biological effects or the required evidence for the efficacy or safety of universal supplementation.

There are several major disease targets that vitamin D supplementation might potentially ameliorate - bone health, cancer, cardiovascular disease, autoimmune disease (including multiple sclerosis and type l diabetes) and metabolic disease including type 2 diabetes. What evidence do we have that supplementation at the population level would improve outcomes in these conditions?

Evidence for bone health is probably the strongest. Observational studies suggest that supplementation with low doses of vitamin D reduces the risk of rickets, l and in selected older people (particularly those in institutional care), calcium and vitamin D supplements reduce the risk of falls and osteoporotic fracture. 2 However, these benefits do not appear to extend to community-dwelling older people, even if they have had a previous fracture3, and the Women's Health Initiative (WHI) trial 4 did not show a significant reduction in hip fracture when supplementing a large, population-based cohort with low-dose vitamin D and calcium.
   (Reference #1 was from 2005 - many good studies of seniors since then.)
   (#4 was for 2006 - many studies have shown great reduction in fractures when an adequate amount of vitamin D was used.)
   (Example: 7,000 community-dwelling older people will be getting 20,000 IU weekly to reduce hip fractures in 2012)

Although prospective observational data links low 25-hydroxyvitamin D (25[OH]D) levels with an increased risk of cardiovascular events, supplementation trials devised to specifically reduce the risk of cardiovascular events have not been performed. Meta-analysis of existing osteoporosis trials (which are clearly not representative of the general population) show no reduction in myocardial infarction or stroke,5 (Note: only 800 IU was used) and the effect of supplementation on cardiovascular risk factors has been variable; some but not all studies show improvement in endothelial function (a powerful marker of cardiovascular risk),6-8 but there appears to be little effect on lipid levels, and blood pressure is modestly reduced only in those with elevated blood pressure at baseline. 9
   (Hypertension is reduced with vitamin D intervention)

Data on cancer outcomes in supplementation trials is even scantier. The WHI trial showed no reduction in colorectal cancer, l0 (Reference is from 2006: Updated Overview) and the one trial frequently quoted to show an effect of vitamin D on cancer rates (again as a secondary analysis of an osteoporosis trial) actually showed a reduction in new cancers with calcium supplements, but no additional reduction when vitamin D was combined with calcium.ll Observational data are not easy to interpret; although there appears to be a lower cancer incidence with increasing 25(OH)D levels in most studies, a few studies show the opposite, albeit with better cancer survival with higher vitamin D levels.

Both type l and type 2 diabetes mellitus have been linked with lower 25(OH)D levels, but evidence that vitamin D supplementation can prevent the occurrence of type l diabetes is lacking, and the available evidence from randomised controlled trials does not suggest any effect on rates of type 2 diabetes to date. l2 Even in patients with pre-existing diabetes or impaired fasting glucose, vitamin D supplements appear to produce only a small improvement in insulin resistance and fasting glucose - and no improvement in long-term glycaemic control. Once again, robust data from large, long-term trials are lacking.
   (There have been decades long experiments in Finland showing extra vitamin D reduced Diabetes)

The evidence base for other health conditions, for example multiple sclerosis, is even flimsier, with no intervention studies to guide practice. Several trials across a variety of populations at risk from a number of infections have now been performed to assess whether vitamin D supplementation can reduce infection rates, especially rates of respiratory tract infection and tuberculosis; results have been mixed at best, as confirmed by a recent systematic review.l3
   (MS intervention study of June 2011; 14,000 IU of vitamin D daily)
   ( 300,000 IU monthly)

No large randomised controlled trials have been conducted to examine the effect of vitamin D supplementation on overall mortality in a general population; meta-analysis of existing trials (mostly for osteoporosis and fracture prevention) suggest either a small effect on mortality (absolute risk reduction of 0.5%) l4 or no effect.5 It cannot be assumed that any benefit in a group at such high risk of death as those with osteoporosis will apply to a general population.
   (2011 update: Mortality reduced by Vitamin D Ref1 Ref2 Ref3 Meta-analysis of Mortality RCT - 2008)
  (Will be a long time

What about potential harms? These are of particular importance in any population-level intervention, as large numbers of healthy people (i.e. with little scope for accruing benefits) will receive exposure to the potential harm. It is unlikely that universal supplementation will cause overt toxicity; the doses required for this appear to be very large indeed. l5 However, the WHI trial 4 showed a l6% higher risk of renal and ureteric stones in the treatment group (who received only 400U of vitamin D3). Observational data point to higher immunoglobulin E (IgE) levels in people with 25(OH)D levels above l35 nmol/l,l6 higher rates of atopic disorders in the offspring of women with 25(OH)D levels >75 nmol/l during pregnancyl7 and two observational studies suggest a slightly higher risk of cardiovascular events in those with the highest 25(OH)D levels,l8,l9 compared with people with moderate 25(OH)D levels. Finally, there is the concern that patients with primary hyperparathyroidism (often undiagnosed until a routine serum calcium level is checked) could suffer from elevated, and therefore potentially symptomatic, hypercalcaemia. Are these potential risks borne out in practice? Do they outweigh potential benefits at a population level? The truth is, we simply don't know, and until we conduct the appropriate large-scale intervention trials, we will not know.
   (Yes, there is a risk of stones if >3,000 IU of vitamin D if not take co-factors - see IoM mistake)
   (cardiovascular problems were due to high levels of vitamin D coupled with low levels of Magnesium which is known to result in artial fibrillation)
   (Overview of Hyperparathyroidism vitamin D)

In conclusion, the benefits of universal supplementation are unproved, the risks are unknown, and we require further evidence before committing to such a public health intervention. Observational and in vitro studies are a poor guide here; let us not forget how vitamins C, E and beta-carotene moved from early promise to useless (and indeed potentially harmful) interventions;20 witness the failure of B group vitamins to improve vascular outcomes, and compare the current controversy surrounding folate supplementation and cancer risk. What is good for one group may also not be good for all; we need to evaluate and tailor the balance of benefit and risk for each group of people that we care for. To supplement the entire population with vitamin D in the absence of good data that the benefits outweigh the risks for each individual would be poor medicine and an abrogation of our duty of care to individuals.
   (Seems like there is, however, a strong case for the portion of the population which is at high risk)

REFERENCES

• 1 Wagner CL, Greer FR. Prevention of rickets and vitamin D deficiency in infants, children, and adolescents. Pediatrics 2008; l22:ll42-52. http://dx.doi.org/l0.l542/peds.2008-l862
• 2 Avenell A, Gillespie WJ, Gillespie LD et al. Vitamin D and vitamin D analogues for preventing fractures associated with involutional and post-menopausal osteoporosis. Cochrane Database Syst Rev 2009; CD000227.
• 3 Grant AM, Avenell A, Campbell MK 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:l62l-28. http://dx.doi.org/l0.l0l6/S0l40-6736(05)630l3-9
• 4 Jackson RD, LaCroix AZ, Gass M et al. Calcium plus vitamin D supplementation and the risk of fractures. N Engl J Med 2006; 354:669-83. http://dx.doi.org/l0.l056/NEJMoa0552l8
• 5 Elamin MB, Abu Elnour NO, Elamin KB et al. Vitamin D and cardiovascular outcomes: a systematic review and meta-analysis. J Clin Endocrinol Metab 20ll; 96:l93l-42. http://dx.doi.org/l0.l2l0/ jc.20ll-0398 Vitamin D Life page for the 800 IU study
• 6 Tarcin O, Yavuz DG, Ozben B et al. Effect of vitamin D deficiency and replacement on endothelial function in asymptomatic subjects. J Clin Endocrinol Metab 2009; 94:4023-30. http://dx.doi.org/l0.l2l0/jc.2008-l2l2
• 7 Sugden JA, Davies JI, Witham MD et al. Vitamin D improves endothelial function in patients with type 2 diabetes mellitus and low vitamin D levels. Diabet Med 2008; 25:320-25. http://dx.doi. org/l0.llll/j.l464-549l.2007.02360.x
• 8 Witham MD, Dove FJ, Dryburgh M et al. The effect of different doses of vitamin D3 on markers of vascular health in patients with type 2 diabetes: a randomised controlled trial. Diabetologia 20l0; 53:2ll2-l9. http://dx.doi.org/l0.l007/s00l25-0l0-l838-l
• 9 Witham MD, Nadir MA, Struthers AD. Effect of vitamin D on blood pressure: a systematic review and meta-analysis. J Hypertens 2009; 27:l948-54. http://dx.doi.org/l0.l097/HJH.0b0l3e32832f075b
• 10 Wactawski-Wende J, Kotchen JM, Anderson GL et al. Calcium plus vitamin D supplementation and the risk of colorectal cancer. N Engl J Med 2006; 354:684-96. http://dx.doi.org/l0.l056/NEJMoa055222
• 11 Lappe JM, Travers-Gustafson D, Davies KM et al. Vitamin D and calcium supplementation reduces cancer risk: results of a randomized trial. Am J Clin Nutr 2007; 85:l586-9l.
• 12 Pittas AG, Chung M, Trikalinos T et al. Systematic review: vitamin D and cardiometabolic outcomes. Ann Intern Med 20l0; l52:307-l4.
• 13 Yamshchikov AV, Desai NS, Blumberg HM et al. Vitamin D for treatment and prevention of infectious diseases: a systematic review of randomized controlled trials. Endocr Pract 2009; l5:438-49. http://dx.doi.org/l0.4l58/EP09l0l.ORR
• 14 Autier P, Gandini S.Vitamin D supplementation and total mortality: a meta-analysis of randomized controlled trials. Arch Intern Med 2007; l67:l730-37.http://dx.doi.org/l0. l00l/archinte.l67.l6.l730
• 15 Vieth R. Vitamin D supplementation, 25-hydroxyvitamin D concentrations, and safety. Am J Clin Nutr l999; 69:842-56.
• 16 Hypponen E, Berry DJ, Wjst M et al. Serum 25-hydroxyvitamin D and IgE - a significant but nonlinear relationship. Allergy 2009; 64:6l3-20. http://dx.doi.org/l0.llll/j.l398-9995.2008.0l865.x
• 17 Gale CR, Robinson SM, Harvey NC et al. Maternal vitamin D status during pregnancy and child outcomes. Eur J Clin Nutr 2008;62:68-77. p://dx.doi.org/l0.l038/sj.ejcn.l602680
• 18 Wang TJ, Pencina MJ, Booth SL et al.Vitamin D deficiency and risk of cardiovascular disease. Circulation 2008; ll7:503-ll. http://dx.doi.org/l0.ll6l/CIRCULATIONAHA.l07.706l27
• 19 Rajasree S, Rajpal K, Kartha CC et al. Serum 25-hydroxyvitamin D3 levels are elevated in South Indian patients with ischemic heart disease. Eur J Epidemiol 200l; l7:567-7l. http://dx.doi.org/l0.l023/A:l0l4559600042
• 20 Druesne-Pecollo N, Latino-Martel P, Norat T et al. Beta-carotene supplementation and cancer risk: A systematic review and meta-analysis of randomized controlled trials. Int J Cancer 20l0; l27:l72-84. http://dx.doi.org/l0.l002/ijc.25008