Er det noe ved D, eller er D bare tull? (om nye roller til vitamin D)

Er det noe ved D, eller er D bare tull? (om nye roller til vitamin D) Haakon E. Meyer Professor, dr.med. Universitetet i Oslo & Nasjonalt folkehelseinstitutt 2009

Vitamin D er nødvendig for normal beinmetabolisme. Alvorlig vitamin D-mangel kan føre til rakitt hos barn og osteomalasi hos voksne. Vitamin D-mangel er en risikofaktor for osteoporose og brudd. I tillegg er dårlig vitamin D-status foreslått som en medvirkende årsak til utvikling av en rekke andre tilstander som blant annet kreft, multippel sklerose og Diabetes Tiltak for å sikre en god vitamin D-status i befolkningen, Nasjonalt råd for ernæring, 2006

FIGURE 3. A schematic representation of the major causes of vitamin D deficiency and potential health consequences Holick, M. F et al. Am J Clin Nutr 2008;87:1080S-1086S Copyright 2008 The American Society for Nutrition

Holick MF. Vitamin D: a D-lightful health perspective. Nutrition Rev 2008; Rickets Osteomalacia Osteoporosis Muscle weakness/pain Osteoarthritis Cancer (colon, breast, prostate, pancreas, etc.) Autoimmune diseases (Type 1 DM, MS, Crohn, RA) Syndrome X Type 2 DM HBP, CHD FEV1 (Asthma) Infections Schizophrenia Depression

Kalsiumstoffskiftet (deler av) Vitamin D i kosten Ca 2+ Kalsium i blod (ionisert kalsium) SVÆRT STRENGT REGULERT ± Tarm ± + 1,25(OH) 2 D Nyre 1 -hydroxylase + 25(OH)D PTH Lever + Knokler BMD Benmarkører Vitamin D dannet i hud Hud Sollys

Vitamin D lever nyre Vitamin D 25(OH)D 1,25(OH)2D 1,25(OH) 2 D binder seg til vitamin D-reseptoren (VDR) Nyere forskning har vist at en rekke vev har VDR 1α-hydroxylase (som omdanner 25(OH)D til 1,25(OH) 2 D). Det foregår altså en lokal produksjon av aktivt vitamin D Vitamin D kan påvirke celleproliferasjon og differensiering samt immunsystemet

FIGURE 6. Relative risks (RRs) of fracture (for more detail, see Figure 2) and colon cancer (for more detail, see Figure 4) Bischoff-Ferrari, H. A et al. Am J Clin Nutr 2006;84:18-28 Copyright 2006 The American Society for Nutrition

Serum vitamin D among elderly in Europe Euronut SENECA study (70-75 yrs) 60 Mean 25(OH)D (nmol/l) 50 40 30 20 10 0 0 30 60 90 Latitude (degrees North) (van der Wielen et al. Lancet 1995)

Vitamin D status among postmenopausal women The MORE study, n 7564 Prevalence of 25(OH)D < 25 nmol/l 0 % 5 % 10 % 15 % 20 % Singapore Australia/N Zealand Northern Europe North America Latin America Central Europe Southern Europe (Lips et al. J Clin Endocrinol Metab 2001)

Sri Lankans Oslo (n=242) Sri Lanka (n=196) Ethnic Norwegians (n=580) 0 29 50 73 100 150 200 25(OH)D (nmol/l) H. Meyer 2009 Meyer et al. Br J Nutr 2008

Vitamin D deficiency in Persons with Pakistani and Norwegian Background The Oslo Health Study 40 Andel av de undersøkte (%) 30 20 10 Fødeland: Norge 0 Pakistan <15 30 50 70 90 110 130 Vitamin D (25(OH)D (nmol/l)) (Meyer et al. BONE 2004)

Distribution of 25-hydroxyvitamin D in Oslo, Norway < 12.5 nmol/l Women Pakistani 21% Norwegian 0 Obs rakitt og osteomalaci Men Pakistani 9% Norwegian 0 (Meyer et al. BONE 2004)

H. Meyer 2009 Osteoporotic fractures

FIGURE 6. Relative risks (RRs) of fracture (for more detail, see Figure 2) and colon cancer (for more detail, see Figure 4) Bischoff-Ferrari, H. A et al. Am J Clin Nutr 2006;84:18-28 Copyright 2006 The American Society for Nutrition

FIG. 2. Forest plot of the risk of hip fracture between vitamin D and placebo/no-treatment groups Boonen, S. et al. J Clin Endocrinol Metab 2007;92:1415-1423 Copyright 2007 The Endocrine Society

FIG. 3. A, Forest plot comparing the risk of hip fracture between vitamin D and calcium and placebo/no-treatment groups Boonen, S. et al. J Clin Endocrinol Metab 2007;92:1415-1423 Copyright 2007 The Endocrine Society

Vitamin D deficiency in Persons with Pakistani and Norwegian Background The Oslo Health Study Andel av de undersøkte (%) 40 30 20 10 Fødeland: Norge 0 <15 Pakistan 30 50 70 90 110 130 Vitamin D (25(OH)D (nmol/l)) (Meyer et al. BONE 2004)

Mean distal BMD, by age, sex and ethnicity 0,580 0,560 BMD (g/cm2) 0,540 Pakistani men Norwegian men 0,520 0,500 0,480 0,460 0,440 0,420 Pakistani women Norwegian women 0,400 30 35 40 45 50 55 60 Age (Alvær K et al. Ost Int 2004)

Effekt av vitamin D på fall Meta-analyse: 5 RCT med 1237 deltakere Vitamin D suppl. versus placebo: 22% redusert risiko for fall NB!!! I flere av studien fikk alle deltakerne også 1,2 g kalsium I majoriteten av studiene ble det gitt 20 µg vit D eller aktiv vit D. (Bischoff-Ferrari et al, JAMA 2004)

Cancer H. Meyer 2009

Colorectal cancer, observational studies, IARC vitamin D and cancer report, 2008 http://www.iarc.fr/en/publications/pdfs-online/wrk/wrk5/index.php

Breast cancer, observational studies, IARC vitamin D and cancer report, 2008 http://www.iarc.fr/en/publications/pdfs-online/wrk/wrk5/index.php

Prostate cancer, observational studies, IARC vitamin D and cancer report, 2008 http://www.iarc.fr/en/publications/pdfs-online/wrk/wrk5/index.php

BOTH HIGH AND LOW LEVELS OF BLOOD VITAMIN D ARE ASSOCIATED WITH A HIGHER PROSTATE CANCER RISK: A LONGITUDINAL, NESTED CASE-CONTROL STUDY IN THE NORDIC COUNTRIES RR of prostate cancer 2,0 1,5 1,0 0,5 0,0 <19 20-39 40-59 60-79 >=80 25(OH)D (nmol/l) H. Meyer 2009 Tuohimaap et al. Int. J. Cancer 2004; 108,104 8

H. Meyer 2009 http://www.dietandcancerreport.org/downloads/chapters/chapter_12.pdf

H. Meyer 2009

WHO/IARC 2008: The epidemiological evidence from observational studies for an inverse association between serum 25-hydroxyvitamin D levels and the incidence of colorectal cancer and sporadic colorectal adenoma was consistent and persuasive. There is however only limited evidence of a causal link due to possible confounding by other dietary or lifestyle factors. H. Meyer 2009

Calcium plus Vitamin D Supplementation and the Risk of Colorectal Cancer H. Meyer 2009 36,282 postmenopausal women (WHI study) 10 µg vit D + 1 g calcium per day in 7 years Double-blinded RR for colorectal cancer in the intervention vrs. placebo group: 1.08 (95% CI 0.86-1.34) (Wactawski-Wende et al., NEJM 2006)

FIGURE 1. Kaplan-Meier survival curves (ie, free of cancer) for the 3 treatment groups randomly assigned in the entire cohort of 1179 women Lappe, J. M et al. Am J Clin Nutr 2007;85:1586-1591 Copyright 2007 The American Society for Nutrition

Dødelighet

Meta-analysis of data on all-cause mortality in 18 randomized controlled trials with vitamin D Autier, P. et al. Arch Intern Med 2007;167:1730-1737. Copyright restrictions may apply.

Hjerte-kar sykdommer

Kaplan-Meier plots of all-cause and cardiovascular mortality in the 25-hydroxyvitamin D quartiles (Q) Dobnig, H. et al. Arch Intern Med 2008;168:1340-1349. Copyright restrictions may apply.

Hazard Ratios (HR) for All-Cause Mortality According to 25-Hydroxyvitamin D and 1,25-Dihydroxyvitamin D Quartiles Dobnig, H. et al. Arch Intern Med 2008;168:1340-1349. Copyright restrictions may apply.

Cox proportional hazards regression model ratios (including 95% confidence intervals [CI]) for cardiovascular mortality are shown for 25hydroxyvitamin D (A) and 1,25-dihydroxyvitamin D (B) quartiles (Q) for the following 3 different statistical models (M): (1) M1 (unadjusted), (2) M2 (adjusted for age, sex, body mass index, and physical activity level), and (3) M3 (variables of M2 plus active smokers, diabetes mellitus, albumin level, cystatin C level, triglyceride level, N-terminal pro-bnp level, systolic and diastolic blood pressure, low-density lipoprotein and high-density lipoprotein cholesterol levels, and the use of statins, aspirin, -blockers, bronchodilators, and angiotensin-converting enzyme inhibitors) Dobnig, H. et al. Arch Intern Med 2008;168:1340-1349. http://archinte.ama-assn.org/cgi/content/full/168/12/1340 Copyright restrictions may apply.

Vitamin D-deficiency A cause of disease? A Confounder/indicator? Risk marker hypothesis H. Meyer 2009

Risk marker Confounding: A confounding variable is a risk factor for the disease under study and correlates simultaneously with the exposure variable Physical activity Vitamin D Disease Wang TJ et al. Vitamin D Deficiency and Risk of Cardiovascular Disease. Circulation. 2008;117:503-11: Although we attempted to adjust for all relevant covariates in the multivariable models, it is important to acknowledge the possibility of residual confounding. Unmeasured characteristics associated with vitamin D deficiency, rather than vitamin D deficiency itself, could account for the increased cardiovascular risk. H. Meyer 2009

Mean (95% confidence interval) difference in serum 25-hydroxyvitamin D concentration associated with frequency of outdoor activity in the past month, compared with no outdoor activity, by ethnic group, adjusted for sex, age, body mass index, month, milk, cereal, and vitamin D supplements, Third National Health and Nutrition Examination Survey, 1988-1994 Scragg, R. et al. Am. J. Epidemiol. 2008 168:577-586; doi:10.1093/aje/kwn163 Copyright restrictions may apply.

Vitamin D PTH VEKT

Supplementation with cholecalciferol does not result in weight reduction in overweight and obese subjects M. Snesve, Y. Figenschau and R. Jorde. Eur J Endocrinol. 2008;159:675-84. 445 persone ble randomisert i 3 grupper Svært høy vitamin D (40 000 IU (1000 ug) cholecalciferol per uke), Høy vitamin D (20 000 IU (500 ug) cholecalciferol per uke) Placebo. Tilskudd med høye doser vitamin D (verifisert med betydelig endringer i nivåene av 25(OH)D og PTH) gav ingen vekttap over ett år sammenlignet med placebo. Vitamin D Ja PTH VEKT NEI

Konfunderende faktor Vitamin D PTH VEKT

Konfunderende faktor Vitamin D PTH Reverse causation VEKT

Vitamin D: Hvor mye trenger vi? Hva er optimalt? Kan vi få for mye?

Nordic Nutrition Recommendations 2004 Vitamin D Children (< 24 mo) Children (2-9 yrs) Adults 60 yrs or less Adults 61 yrs+ pregnant and lactating 10 µg 7.5 µg 7.5 µg 10 µg 10 µg Remember: Sun exposure Remarks: Infants from 4 weeks of age: 10 µg vitamin D/day as supplement Elderly people with little or no sun exposure: Supplement of 10 µg vitamin D3 per day in addition to the dietary intake

En del forskere mener at grensen for optimalt nivå av 25(OH)D bør ligge høyere enn 50 nmol/l, og et av forslagene er 75 nmol/l (7). En del av bakgrunnen for dette er nyoppdagede mulige effekter av vitamin D. Imidlertid er evidensen for dette mangelfull. I praksis vil mange ligge på så høye nivå dersom de fleste i befolkningen har et 25(OH)D-nivå på minst 50 nmol/l. Tiltak for å sikre en god vitamin D-status i befolkningen, Nasjonalt råd for ernæring, 2006

Vitamin D - the dose debate: How much do we need/what is the optimal level? Meta-analysis on mortality: ordinary doses (mean 528 IU (~13 µg )) Given a causal effect of vitamin D: The effect is expected be greatest in those with the lowest baseline levels: 20 40 nmol/l versus 70 90 nmol/l (conf BP) H. Meyer 2009

Siden vitamin D syntetiseres (i store mengder) i huden er man mindre bekymret for bivirkninger av store doser tilskudd enn for andre vitaminer

The dose question Vitamin D 25(OH)D 1,25(OH)2D H. Meyer 2009

Vitamin D Metabolites and Calcium Absorption in Severe Vitamin D Deficiency 110 1,0 Calsium absorption 1,25(OH)2D 100 90 80 70 60 50 0,8 0,6 0,4 0,2 0,0 0-10 11-20 21-30 25(OH)D (nmol/l) 31-40 0-10 11-20 21-30 25(OH)D (nmol/l) 31-40 Vitamin D deficiency does not reduce serum 1,25(OH)2D, and therefore calcium absorption, until the serum 25(OH)D falls to ~10 nm. At this level, the substrate concentration seems to be insufficient to maintain the level of the dihydroxy metabolite (Need AG et al. J Bone Miner Res 2008:23:1859-63) H. Meyer 2009

Adverse effects of high levels of vitamin D? H. Meyer 2009

WHO/IARC 2008: The J or U-shaped curve between serum concentrations of several anti-oxidants and mortality or adverse events seems therefore to also exist for vitamin D Therefore, before changing existing recommendations on vitamin D requirements, we should wait for the results of new randomized trials H. Meyer 2009

BOTH HIGH AND LOW LEVELS OF BLOOD VITAMIN D ARE ASSOCIATED WITH A HIGHER PROSTATE CANCER RISK: A LONGITUDINAL, NESTED CASE-CONTROL STUDY IN THE NORDIC COUNTRIES RR of prostate cancer 2,0 1,5 1,0 0,5 0,0 <19 20-39 40-59 60-79 >=80 25(OH)D (nmol/l) H. Meyer 2009 Tuohimaap et al. Int. J. Cancer 2004; 108,104 8

Conclusion A normal dose of vitamin D combined with calcium reduce fracture risk A normal dose of vitamin D probably reduce mortality Vitamin D might be beneficial for a number of other health outcomes However, currently the evidence for most of these are weak High doses of vitamin D should not be recommended to the general population before randomized controlled trial have show The benefits That it is safe H. Meyer 2009

Sun (UV-B) is the best vitamin D-source, HOWEVER: H. Meyer 2009

A Prospective Study of Pigmentation, Sun Exposure, and Risk of Cutaneous Malignant Melanoma in Women Cohort-study, 106000 women from Norway and Sweden Self reported Sunburn episodes per year: Age 10-19 years: None RR = 0 (reference) <= 1/year RR = 1.64 (95% CI 1.03-2.62) >= 2/year RR = 2.42 (95% CI 1.46-4.02) H. Meyer 2009 2002 (Veierød et al., J Natl Cancer Inst 2003)

H. Meyer 2009