Effecten van vitamine D: een veranderend perspectief Paul Lips Interne Geneeskunde, Sectie Endocrinologie en EMGO Instituut VU Medisch Centrum Amsterdam

25(OH)-vitamin D3 (liver) Vitamin D-metabolism Nutrition e.g. herring Sun April-sept Limiting: age, pigmentation, sunscreen, clothing Vitamin D3 25(OH)-vitamin D3 (liver) 1,25(OH)2-vitamin D3 (kidney) 24,25(OH)2vitamin D3 Calcium absorption from the gut catabolism

Vitamin D receptor (VDR) binding, formation of heterodimer with retinoid receptor (RXR) and transcription VDR distribution: gastrointestinal, liver, kidney, heart, bone, parathyroid, B and T cells, skin, breast, brain, muscle, fibroblasts

Characteristics of vitamin D metabolites 25-hydroxyvitamin D 1,25-dihydroxyvitamin D typical concentration 20-125 nmol/l 8-50 ng/ml 50-150 pmol/l 20- 60 pg/ml half life 25 days 7 hours external influence: sun, season, fish immobility, calcium intake hormonal control ----- serum PTH, calcium, phosphate, cortisol affinity to VDR very low very high action ?? gut, bone, muscle etc

* At the end of this presentation we want to thank all study nurses and investigators working for MORE that were involved in the QOL project. We are also grateful to dr Michael Minshall from Eli Lilly and Michele Ennis from UCSF for their assistance during the project. * Thank you for your attention. E V M

25-hydroxyvitamin D concentration (nmol/l) Longitudinal Aging Study Amsterdam (LASA) Vitamin D-status in 1319 participants >65 yr % participants Zwolle Oss Amsterdam Germany Belgium North Sea 25-hydroxyvitamin D concentration (nmol/l)

The Hoorn study: vitamin D status in 538 men and women 60-87 yr

Vitamin D and adiposity 25-OH-D (nmol/l) men women Total body fat percent (%) Adjusted for age, season, smoking Snijder M et al J Clin Endocrinol Metab 2005

Determinants of vitamin D status in the Hoorn Study

Consequences of vitamin D deficiency Skeletal: Low calcium absorption, secondary hyperparathyroidism, bone resorption and osteoporosis, impaired bone mineralisation and osteomalacia Non-skeletal: Muscle weakness, falls Auto-immune diseases (diabetes type1, MS) Insuline resistance (diabetes type 2) Decreased immunity (tuberculosis) Cancer (breast, colon, prostate)

decreased renal function decreased Ca absorption low sunshine exposure Vitamin D deficiency, falls and fractures low vitamin D intake low serum 25 (OH)D low serum 1,25 (OH)2D - decreased renal function + + decreased Ca absorption + higher PTH muscle weakness low serum calcium mineral deficit hyperosteoidosis high turnover bone resorption osteomalacia osteoporosis falls (hip) fractures

25(OHD and PTH in LASA

25(OH)D and bone mineral density in the hip in LASA

Serum 25-hydroxyvitamin D and physical performance score (0-12) in LASA unadjusted adjusted for age, sex, chronic diseases, BMI Wicherts et al J Clin Endocrinol Metab 2007 (in press)

Serum 25(OH)D < 25 nmol/l as predictor for falls in LASA participants < 75 vs > 75 yr < 75 yr, P<0.01 > 75 yr, N.S. RR Snijder et al JCEM 2006; 91: 2980-5

Effect on vitamin D3 800 IU/d and calcium 1200 mg/d vs placebo on fracture incidence in 3270 French nursing home residents (mean age 84 yr) MC Chapuy et al. N Engl J Med 1992; 327: 1637-42

Calcium +/- vitamin D to prevent fractures: a meta-analysis Tang et al Lancet 2007; 370: 657-66

Regulation of gene expression by VDR ligands Nagpal et al.Endocrine Rev 2005; 26: 662-87

1-hydroxylation of 25(OH)D kidney negative feedback control not substrate-dependent, only in case of vitamin D deficiency general endocrine function extrarenal no feedback control substrate-dependent linear correlation between serum 25(OH)D and 1,25(OH)2D local paracrine function

Hypovitaminosis D, insulin resistance and  cell dysfunction Study in 126 glucose-tolerant subjects using hyperglycemic clamp Chiu KC et al. Am J Clin Nutr 2004; 79: 820-5

Vitamin D receptor polymorphisms

Effect of vitamin D3 400 IU/d on BMD of femoral neck according to vitamin D receptor genotype WC Graafmans et al. J Bone Miner Res 1997; 12: 1241-5

Effect of different doses and time intervals of oral vitamin D3 in nursing home residents Chel et al Osteoporos Int 2007

Effect of different doses and time intervals of oral vitamin D3 in nursing home residents Chel et al Osteoporos Int 2007

Effect of different doses and time intervals of oral vitamin D3 in nursing home residents Chel et al Osteoporos Int 2008

Conclusie Vitamine D-gebrek veroorzaakt botverlies, lage botdichtheid, osteoporose of osteomalacie, en fracturen. Vitamine D-gebrek is ook geassocieerd met spierzwakte, een lagere “physical performance”, en vallen. Vitamine D suppletie kan het evenwicht en de spierkracht verbeteren en vallen voorkomen. Vitamine D en calcium kunnen botbreuken voorkomen.

Conclusie (2) Ongeveer 10 % van de fracturen op oudere leeftijd kan worden voorkomen met calcium en vitamine D. Drempelwaarden voor 25-hydroxyvitamine D voor vallen, fracturen en “physical performance” zijn tussen 25 en 50 nmol/l. Locale 1-hydroxylatie van 25-hydoxyvitamine D kan mede bepalend zijn voor de locale effecten van vitamin D.

Conclusion (3) Een vitamine D dosis van 600 IU/dag of 4200 IU/week verzekert een serum 25(OH)D > 50 nmol/l bij 90 % van de vepleeghuisbewoners cq ouderen met nauwelijks blootstelling aan zonlicht. Vitamine D-suppletie is mogelijk gunstig voor de insuline-gevoeligheid. Vitamine D-suppletie op jonge leeftijd kan mogelijk auto-immuunziekten zoals diabetes type 1 en multiple sclerose voorkomen.