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Kliniske konsekvenser af D-vitamin mangel

Kliniske konsekvenser af D-vitamin mangel. Lars Rejnmark, MD. Ph.D. rejnmark@post6.tele.dk. Vitamin D and calcium supplementation reduces cancer risk: results of a randomized trial. Design: a 4-yrs, population-based, double-blind, RCT. Subjects : - 1179 women > 55 yrs

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Kliniske konsekvenser af D-vitamin mangel

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  1. Kliniske konsekvenser af D-vitamin mangel Lars Rejnmark, MD. Ph.D. rejnmark@post6.tele.dk

  2. Vitamin D and calcium supplementation reduces cancer risk: results of a randomized trial Design: a 4-yrs, population-based, double-blind, RCT. Subjects: - 1179 women > 55 yrs - Randomly selected - Absence of known cancers • Treatments: • 1400–1500 mg supplemental calcium/d alone • Calcium + 1100 IU vitamin D3/d • Placebo. Lappe et al. Am J Clin Nutr 2007, 85: 1586ff

  3. Vitamin D and calcium supplementation reduces cancer risk: results of a randomized trial Kaplan-Meier survival curves: year 0 to 4: • Cancer risk: • Ca-only group: RR 0.53 (0.27 - 1.03) • Ca + D-vit group: RR 0.40 (0.20 - 0.82) Lappe et al. Am J Clin Nutr 2007, 85: 1586ff

  4. Vitamin D and calcium supplementation reduces cancer risk: results of a randomized trial Kaplan-Meier survival curves: year 1 to 4: • Cancer risk: • Ca-only group: RR 0.58 (0.29 - 1.21) • Ca + vit-D group: RR 0.23 (0.09 - 0.60) Lappe et al. Am J Clin Nutr 2007, 85: 1586ff

  5. For every 25 nmol/L ↑ in P-25(OH)D:↓35% cancer risk Vit-D  60-80% ↓ risk of cancer Vitamin D and calcium supplementation reduces cancer risk: results of a randomized trial P-25(OH)D: Baseline: 71.8 ± 20.3 nmol/L 12 mo. 96.0 ± 21.4 nmol/L Lappe et al. Am J Clin Nutr 2007, 85: 1586ff

  6. Women’s Health Initiative: Randomised armRisk of Colorectal Cancer Design:a 7-yrs, double-blind, RCT. Subjects: 36,282 women - aged 50-79 yrs • Treatments: • 1g calcium + 400 IU vitamin D3 per day • Placebo. Wactawski-Wende et al. NEJM 2006

  7. Nested case-control study: breast cancer 1394 cases and 1365 controls – all postmenopausal women Abbas et al. Carcinogenesis 2008; 29: 93-99

  8. Lowest tertile (< 50 nmol/l) at baseline: 40% of those classified in the lowest tertile at baseline remained in the lowest tertile during all subsequent measurements A single P-25OHD measurement as a predictor for vitamin D status? DOPS-study: measurements performed at baseline and at year 1, 2, and 5 (same time of year). AIM: concordance between P-25OHD tertile at baseline and at subsequent measurement: Rejnmark et al Scand J Clin Lab Invest 2006

  9. 25OHD 25OHD 1α-hydroxylase 1,25(OH)2D Vitamin D – Biology 25OHD Vit D CYP27B1 1,25(OH)2D Ca++ VDR VDR Holick. Recent Results Cancer Res. 2003;164:3-28

  10. ↓ cellular proliferation ↑ terminal differentiation ↑ apoptosis In normal and in cancer cells T cell-mediated immunity Muscle function (skeletal / myocardial) Cardiovascular morbidity Dental health Neuro-psychiatric morbidity Vitamin D – Biology 1,25(OH)2D controls more than 200 genes which affects: Lars Rejnmark, 2008

  11. Vitamin D - an immunomodulator T cell-mediated immunity: Multiple sclerosis Type 1 diabetes mellitus Systemic lupus Inflammatory bowel disease Rheumatoid arthritis Vitamin D ↓ inflammatory responses T helper type 1 lymphocytes Lars Rejnmark, 2008

  12. A marked geographical variance: > 50° lattitude: 200 cases per 100.000 Near equator: 1-2 cases per 100.000 Multiple sclerosis An autoimmune disorder whereby an unknown agent triggers a T cell–mediated inflammatory attack, causing demyelination of CNS tissue Lars Rejnmark, 2008

  13. Nurses’ Health Study Cohort: Multiple sclerosisNested case-control study Vitamin D (IU/day) from supplements: Adjusted for age, smoking, and latitude at birth. Munger et al. Neurology 2004;62:60-65

  14. Type 1 diabetes The Finnish experiment - Vitamin D supplementation to infants Hypponen et al. Lancet 2001;358:1500-1503

  15. T1DM – in theFinnish birth-cohort study Included: All babies born in 1966 • At age 1 year (n=10,821) - data collected on: • Frequency and dose of vitamin D supplementation Primary outcome: a diagnosis of T1DM before 1998 Adjusted for sex, parity, gestational and maternal age, length of maternal education, social status, and standardised birth weight, and growth rate in infancy Hypponen et al. Lancet 2001;358:1500-1503

  16. T1DM – in Norway Cod liver oil in the first year of life vs. not: RR 0.74 (0.56, 0.99) Stene et al. Am J Clin Nutr 2003;78:1128-1134. Use of cod liver oil during pregnancy vs. not T1DM in offsprings: OR 0.30 (0.12 to 0.75) Stene et al.Diabetologia 2000;43:1093-1098

  17. - High vs. low vitamin D intake: RR 0.87 (95% CI 0.75–1.00; p< 0.05) - High vs. low calcium intake: RR 0.79 (0.70–0.90; p<0.001) ) >1,200 mg calcium and >800 IU vitamin D vs. RR 0.67 (0.49–0.90) <600 mg calcium and <400 IU vitamin D Vitamin D – and risk of T2DM Nurses’ Health Study: Risk of type 2 diabetes (T2DM) during 20 yrs of follow-up in 83,779 women who had no history of diabetes, cardiovascular disease, or cancer at baseline. - No overall association between total vitamin D intake and T2DM (Pittas et al Diabetes Care 2006; 29:650-6 )

  18. R = 0.2469*); p<0.01 Vitamin D – and insulin sensitivity Relationship of 25OHD with insulin sensitivity and b-cell function in 52 normotensive healthy subjects (normal OGTT). Hyperglycemic clamp:Continuous infusion with 30% dextrose for 180 min. to maintain p-Glc levels at 10 mmol/L Insulin sensitivity index: the average amount of glucose infused during the last hour divided by the averaged steady-state p-insulin level. *) Adjusted for age, sex, BMI, DBP, and ethnicity (Chiu et al. Am J Clin Nutr 2004;79:820-5).

  19. P-25OHD (nmol/l) * Changes (%) in BP (Mean±SD) * * UVB UVA Vitamin D and hypertension RCT: 18 patients with untreated mild essential hypertension were randomised to receive thrice-weekly full-body UVB or UVA irradiation at sub-erythematous doses over 6 weeks (during February to March). Krause et al. The Lancet 1998; 352:709-10

  20. Hearth muscle • Cardiac • insufficiency • Smooth muscle • hypertension • Skeletal muscle • Sway • Impaired strength Vitamin D and hypertension • Potential mechanisms of action: • Vit D: directly ↓ renin gene transcription by a VDR-dependent mechanism • Effects on smooth muscles: Holick. Recent Results Cancer Res. 2003;164:3-28

  21. Vitamin D and risk of fallsMetaanalysis – randomized studies Forest plot comparing the effect of vitamin D and the risk of fall Source D-vitamin OR (95% Cl) favors favors vitamin D control Pfeiffer et al. 2000 800 IU D 0.47 (0.20-1.10) Bischoff et al. 2003 800 IU D 0.68 (0.30-1.54) Gallacher et al. 2001 0.5 μg calcitriol 0.53 (0.52-0.88) Dukas et al. 2004 1.0 μg calcitriol 0.69 (0.41-1.16) Graffmans et al 1996 400 IU D 0.91 (0.61-1.40) pooled estimate 0.69 (0.53- 0.88) 0.1 0.5 5 10 Bischoff-Ferrari et al JAMA 2004; 291:1999-2006

  22. 500 400 300 200 VDR expression (# of positive nuclei) 20 30 40 50 60 70 80 90 100 age years VDR in striated muscledecrease with age Striated muscle, VDR antibodies Bischoff-Ferrari et al 2004

  23. Vitamin D and periodontal disease RCT: 3 yrs of treatment with: Placebo or 500 mg Ca + 700 IU (17.5 μg) vitamin D/day. OR 0.4 (0.2 - 0.9) Lost ≥ 1 teeth (%) 145 healthy subjects aged > 65 yrs P-25OHD: 71 → 112 nmol/l Krall et al. Am J Med 2001

  24. Vitamin D StatusOptimal serum 25OHD thresholds - -0.04 - 0.02 - -0.00 g/cm2 1.5 – 1.0 – 0.5 – 0.0 - BMD g/cm2 Fracture, RR 0.0 -0.1 -0.2 -0,3 -0.4 -0,5 S or mm RR (95% CL) Colon cancer, RR 8`Walk time, s Attachment loss, mm 30 50 70 90 110 P-25OHD, nmol/l Bischoff-Ferrari et al. Am J Clin Nutr 2006;84:18 –28.

  25. RR 0.93 (0.87 – 0.99) χ2 Test for heterogeneity: P = 0.52 Vitamin D Supplementation and Total Mortality A Meta-analysis of Randomized Controlled Trials 18 independent RCT Mean trial duration: 5.7 yrs N = 57,311 participants. Deaths, any cause: n= 4777 Daily doses of vitamin D: 300 - 2000 IU (mean 528 IU) Autier et al. Arch Intern Med 2007;167:1730ff

  26. Vitamin D – PTH axis & mortality

  27. ↓ 25OHD & ↑ PTH vs. ↓ 25OHD & ≈ PTH HR 1.35 (1.12–1.64) ≈ PTH & ↓ 25OHD vs. ≈ PTH & ≈ 25OHD HR 0.87 (0.64–1.18) Vitamin D – PTH axis & mortality DESIGN: A prospective cohort study SUBJECTS: 1280 elderly subjects living in residential care facilities AIM: whether PTH levels in the presence of hypovitaminosis D affects mortality. adjusted for age, sex, immobility, SMMSE, IISC, number of medications and weight. Chen JS et al. Clin Endocrinol 2008; 68: 290-298

  28. Secondary Hyperparathyreoidisme Functional Hypoparathyreoidisme Vitamin D – PTH axis DOPS: The Danish Osteoporosis Prevention Study R Square = 0.033, p<0.001 Rejnmark et al. Clin Endocrinol 2008. In Press

  29. Spine BMD (g/cm2) P < 0.05 P < 0.05 P < 0.05 SHPT P-25OHD (nmol/l) Bone-ALP (U/l) FHPT Parathyroid status Vitamin D – PTH axis Rejnmark et al. Clin Endocrinol 2008. In Press

  30. PHPT: P < 0.01 P < 0.05 SHPT FHPT Fat mass (kg) Bolland et al. JCEM 2005; 90; 1525-30 Vitamin D – PTH axis Body weight (Kg) Rejnmark et al. Clin Endocrinol 2008. In Press

  31. Vitamin D – PTH axis Lars Rejnmark, 2008

  32. Vitamin D – PTH axisPotential mechanisms of action Systemic: ↓ 25OHD Þ↑ PTH ↓ P-25OHD Þ↓ [1,25(OH)2D]IC ↑ P-PTH Þ ↑ [Ca+2]IC Local: CVD: ↑PTH Þ↑ [Ca+2]ICÞ↑ vascular tone and stiffness ↓1,25(OH)2D Þ ↑ renin–angiotensin system (Li et al. J Steroid Biochem Mol Biol 2004; 89-90:387-92) Adipocyte: ↑PTH Þ ↑ [Ca+2]ICÞ ↑ fatty acid synthase (FAS) Þ Antilipolytic effect (↓HSL) (Xue et al. FASEB J 2001; 15:2527-29) ↓ 1,25(OH)2D Þ↑PPRgÞ ↑ adipocyte (Hida et al. Life Sciences 1998; 62: 205-11 ) Calcium supplements may reduce CVD and risk of cancer - due to ↓ PTH levels??

  33. Vitamin D – in summary • The vitamin D receptor is expressed by most tissues • In most cells, 25OHD is activated by a local 1a-hydroxylase Several lines of evidence suggest that vitamin D has generalised biological effects Vitamin D may affect: - Risk of cancer and cancer related mortality - T cell-mediated immunity - Fat and glucose metabolism - Risk of cardiovascular diseases - Neuromuscular function - Dental health - Bone metabolism and risk of fracture Lars Rejnmark, 2008

  34. Vitamin D – in summary • A sufficient vitamin D status: P-25OHD > 80 nmol/l • Further research issues: • How to determine long-term vitamin D status? • RCT on effects of vitamin D with different diseases • as primary outcome • Vitamin D – PTH axis • Imprinting? • Living below 35 degrees latitude for the first 10 years of life reduces the risk of multiple sclerosis by approximately 50% Lars Rejnmark, 2008

  35. Kliniske konsekvenser af D-vitamin mangel Lars Rejnmark, MD. Ph.D. rejnmark@post6.tele.dk

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