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

Transkript

1 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

2 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

3 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

4 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

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6 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

7 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

8 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

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

10 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)

11 Sri Lankans Oslo (n=242) Sri Lanka (n=196) Ethnic Norwegians (n=580) (OH)D (nmol/l) H. Meyer 2009 Meyer et al. Br J Nutr 2008

12 Vitamin D deficiency in Persons with Pakistani and Norwegian Background The Oslo Health Study 40 Andel av de undersøkte (%) Fødeland: Norge 0 Pakistan < Vitamin D (25(OH)D (nmol/l)) (Meyer et al. BONE 2004)

13 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)

14 H. Meyer 2009 Osteoporotic fractures

15 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

16 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: Copyright 2007 The Endocrine Society

17 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: Copyright 2007 The Endocrine Society

18 Vitamin D deficiency in Persons with Pakistani and Norwegian Background The Oslo Health Study Andel av de undersøkte (%) Fødeland: Norge 0 <15 Pakistan Vitamin D (25(OH)D (nmol/l)) (Meyer et al. BONE 2004)

19 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, Age (Alvær K et al. Ost Int 2004)

20 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)

21 Cancer H. Meyer 2009

22 Colorectal cancer, observational studies, IARC vitamin D and cancer report,

23 Breast cancer, observational studies, IARC vitamin D and cancer report,

24 Prostate cancer, observational studies, IARC vitamin D and cancer report,

25 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 < >=80 25(OH)D (nmol/l) H. Meyer 2009 Tuohimaap et al. Int. J. Cancer 2004; 108,104 8

26 H. Meyer

27 H. Meyer 2009

28 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

29 Calcium plus Vitamin D Supplementation and the Risk of Colorectal Cancer H. Meyer ,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 ) (Wactawski-Wende et al., NEJM 2006)

30 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: Copyright 2007 The American Society for Nutrition

31 Dødelighet

32 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: Copyright restrictions may apply.

33 Hjerte-kar sykdommer

34 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: Copyright restrictions may apply.

35 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: Copyright restrictions may apply.

36 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: Copyright restrictions may apply.

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

38 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

39 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, Scragg, R. et al. Am. J. Epidemiol : ; doi: /aje/kwn163 Copyright restrictions may apply.

40 Vitamin D PTH VEKT

41 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: persone ble randomisert i 3 grupper Svært høy vitamin D ( IU (1000 ug) cholecalciferol per uke), Høy vitamin D ( 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

42 Konfunderende faktor Vitamin D PTH VEKT

43 Konfunderende faktor Vitamin D PTH Reverse causation VEKT

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

45 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

46 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

47 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: nmol/l versus nmol/l (conf BP) H. Meyer 2009

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

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

51 Vitamin D Metabolites and Calcium Absorption in Severe Vitamin D Deficiency 110 1,0 Calsium absorption 1,25(OH)2D ,8 0,6 0,4 0,2 0, (OH)D (nmol/l) (OH)D (nmol/l) 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: ) H. Meyer 2009

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

53 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

54 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 < >=80 25(OH)D (nmol/l) H. Meyer 2009 Tuohimaap et al. Int. J. Cancer 2004; 108,104 8

55 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

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

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

58 H. Meyer 2009