Seminar 15-01-2009 - osteoporose, calcium en vitamine d


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  • Upon exposure to ultraviolet irradiation, 7-dehydrocholesterol or provitamin D 3 in the skin is converted to previtamin D 3 , which is subsequently isomerized to the more stable vitamin D 3 via a thermally induced transformation. 18,40 Both vitamin D 3 formed in the skin or provided in the diet and vitamin D 2 derived from dietary sources and multivitamins are hydroxylated in the liver to 25(OH)D, the major circulating form of vitamin D. 3,41 25(OH)D, which is biologically inert at physiologic concentrations, is hydroxylated in the kidneys to 1,25(OH) 2 D, the major biologically active form of vitamin D. Production of 1,25(OH) 2 D is regulated by PTH and serum phosphate levels. 41,42 When vitamin D concentrations are inadequate, 1,25(OH) 2 D increases intestinal absorption of calcium and phosphorus and, in concert with PTH, mobilizes calcium and phosphorus stores from bone to maintain serum calcium and phosphorus levels adequate for bone health and metabolic and neuromuscular functions. 12,19,42
  • Vitamin D 2 , or ergocalciferol, another inactive type of vitamin D, does not occur naturally in any mammalian species but is formed by the irradiation of the plant sterol ergosterol. Vitamin D 2 is structurally similar to vitamin D 3 , with the exception of a double bond between C 22 and C 23 and a methyl group at C 24 . However, vitamin D 2 is considerably less potent than vitamin D 3 . 19,36,37 Vitamin D 2 has been added to dairy products and multivitamin preparations, although it is now frequently being replaced by vitamin D 3 . 3,19  
  • Vitamin D 3 , or colecalciferol, is a biologically inert type of vitamin D that is synthesized in the skin upon exposure to ultraviolet radiation. Vitamin D 3 is also contained in certain nutrients, such as fatty fish and eggs. 3,19,35  
  • 1,25(OH) 2 D, or calcitriol, is the major biologically active metabolite of vitamin D. Calcitriol is 1000 times more active than any of its precursors. 1,25(OH) 2 D is formed by the metabolic conversion of the two inactive forms of vitamin D. Vitamin D 2 provided in vitamin supplements and fortified dietary products and vitamin D 3 synthesized in the skin and obtained from dietary sources are hydroxylated in the liver to 25[OH]D, which is then hydroxylated in the kidney to 1,25(OH) 2 D. 19,38 Synthetic calcitriol is also available but is given only to individuals in whom endogenous synthesis of 1,25(OH) 2 D is not possible due to conditions such as renal failure or hypoparathyroidism. Calcitriol is the most active form of vitamin D available. The optimal daily dose of calcitriol must be carefully determined for each patient. The administration of calcitriol to patients in excess of their daily requirements is dangerous and can cause hypercalcemia, leading to generalized vascular calcification, nephrocalcinosis, and other soft-tissue calcification, hypercalciuria, and hyperphosphatemia. 39
  • No consensus exists on the optimal level of 25(OH)D or the definition of vitamin D inadequacy, 3,4 but concentrations of 25(OH)D below the suggested level of 30 ng/ml (75 nmol/L) appear to be associated with suboptimal calcium absorption and increased PTH. 6
  • The findings of an international epidemiologic study indicate that vitamin D inadequacy is highly prevalent among postmenopausal women with osteoporosis throughout the world, even in regions with ample sunlight. This cross-sectional, observational, single-visit study enrolled 2589 postmenopausal women with osteoporosis between May 2004 through March 2005 who were living independently within the community in 18 countries in Europe, Latin America, the Middle East, Asia, and Australia. 7 Vitamin D inadequacy was defined by serum 25(OH)D level <30 ng/ml. 6 In 63.9% of these women, the serum 25(OH)D concentration was below 30 ng/ml, the threshold level recommended to maximize intestinal calcium absorption and prevent secondary hyperparathyroidism, and 48.7% had serum 25(OH)D levels below 25 ng/ml. 8–10
  • Patients ≥50 years old hospitalized for nontraumatic fractures Serum 25(OH)D <30 ng/ml in 97% Half had little or no vitamin D supplementation A study conducted in a single Midwest healthcare organization examined the prevalence of vitamin D inadequacy, determined by serum 25(OH)D levels, in 78 adults, 50 years of age or older, hospitalized with nontraumatic fractures between August 1, 2001, and January 31, 2002. 7 Serum levels of 25(OH)D were below 30 ng/ml in 97% of these patients, and 81% had 25(OH)D levels below 20 ng/ml. The prevalence of vitamin D inadequacy was not significantly affected by age, gender, or the use of medications for the treatment or prevention of osteoporosis. One half of the study population reported little or no vitamin D supplementation. 7 Mean serum levels of 25(OH)D were significantly higher in patients taking at least 400 IU of vitamin D daily than in those without this level of vitamin D supplementation (p=0.002). However, the prevalence of vitamin D inadequacy remained high even with moderate daily supplementation with vitamin D. 7 Ref 7, p 1070, C1, ¶5, L7-12, ¶6, L3, C2, L1-9,18-20; p 1071, C1, ¶2, L1,2,7,8, ¶3, L1,2 Ref 7, p 1071, C1, ¶4, L1-6, C2, Table 2, L1-3, ¶1, L1-5 Ref 7, p 1071, C2, L3-7, Table 3, Rows 8,9 + footnote Ref 7, p 1070, C1, ¶6, L3, C2, L1-9; p 1071, C1, ¶2, L1-4, ¶3, L1,2, ¶4, L1-6, C2, Table 2, ¶1, L1-4; p 1022, C1, Fig 1 Ref 2, p 554, C2, ¶2, L4-6 Ref 3, Source B, p 1, L1,2 Ref 7, p 1070, C1, ¶5, L7-12, ¶6, L3, C2, L1-9; p 1071, C1, ¶2, L1,2,7,8, ¶3, L1,2
  • Guidelines issued by the Food and Nutrition Board specify 2000 IU/day as an acceptable upper limit for vitamin D intake, 5 although chronic exposure to substantially higher levels will likely cause no harmful effects. 6 No statistically significant changes from baseline in serum calcium levels or urinary calcium excretion were detected in 61 volunteers given 4000 IU/day of vitamin D for up to five months. 47 Almost all cases of vitamin D toxicity have been associated with 25(OH)D concentrations >88 ng/ml (200 nmol/L), a level that would necessitate a daily intake of more than 40,000 IU of vitamin D. 48
  • Seminar 15-01-2009 - osteoporose, calcium en vitamine d

    1. 1. Osteoporose, Calcium en Vitamine D Dr. JPW van den Bergh, internist-endocrinoloog 15 april 2009
    2. 2. Vitamine D: productie en effect ProD3=provitamin D3; PreD3=previtamin D3 Holick MF Osteoporos Int 1998;8(suppl 2):S24–S29. Huid Lever Nieren Diëet Vitamine D3 Vitamine D2 Darm Bot ProD3  PreD3  Vitamine D3 25(OH)D 1,25(OH)2D PTH (+) UVBZon (+) Laag PO4 2-Toename calcium en fosfaat absorptie Mobiliseren van calcium voorrraden Reguleren serum calcium en fosfaat Metabole werking Gezond Bot Neuromusculaire functie
    3. 3. Vitamine D2 - Ergocalciferol Vitamine D2 • Wordt gevonden in planten • In sommige voedingsmiddelen en multivitaminen (vooral US) • Biologisch inert • Conversie (OH) in lever en nieren naar actieve vorm • D2 is veel minder sterk dan D Parfitt AM et al Am J Clin Nutr 1982;36:1014–1031;Lips P Endocr Rev 2001;22:477–501; Holick MF Osteoporos Int 1998;8(suppl 2): S24–S29; Holick MF et al. In: Bone and Mineral Research, Vol 7. Amsterdam: Elsevier, 1990:313–366 CH3 HO CH2 CH3 H H3C CH3 CH3 H
    4. 4. Vitamine D3 - Colecalciferol Vitamine D3 • Gevormd door activatie met ultraviolet licht op vitamine D precursors in de huid • Sommige voedingsmiddelen • Biologisch inert • Conversie (OH) in lever en nieren naar actieve vorm Parfitt AM et al Am J Clin Nutr 1982;36:1014–1031; Lips P Endocr Rev 2001;22:477–501 HO CH2 CH3 H H3C CH3 CH3 H
    5. 5. 1.25 dihydroxy-vitamine D - Calcitriol (1,25[OH]2D) • Gevormd door achtereenvolgende hydroxyleringen in lever en nieren • Biologisch actieve vorm • 1000 keer meer actief dan vitamine D3 of D2 • Teveel kan leiden tot toxiciteit: hypercalciëmie en hypercalciürie Parfitt AM et al Am J Clin Nutr 1982;36:1014–1031; Guyton AC and Hall JE. In: Textbook of Medical Physiology, 10th ed. Philadelphia, Pa: WB Saunders, 2000:899–915 HO CH2 CH3 H H3C CH3 CH3 H OH OH
    6. 6. 1,25 (OH)2 vit D maintains calcium homeostasis Thus vit D deficiency results in elevated parathyroid hormone Rickets in children Osteomalacia in adults Osteoporosis Calcium en Phosphate balance
    7. 7. 262 postmenopausal women aged 40-87 yrs Nordin et al 2004 Am J Clin Nutr Relation calcium absorption and 1,25(OH)2 vitaminD
    8. 8. Nordin et al 2004 Am J Clin Nutr Calcium absorption, effect of age
    9. 9. What this study adds Healthy older women randomised to calcium supplementation showed increased rates of myocardial infarction This effect could outweigh any benefits on bone from calcium supplements Bolland et al BMJ 2008: Conclusion Calcium supplementation in healthy postmenopausal women is associated with upward trends in cardiovascular events rates Vascular events in healthy older women receiving calcium supplementation: randomised controlled trial Substitution 1000 mg Ca +Substitution 1000 mg Ca + Dietary intake 860 mg CaDietary intake 860 mg Ca
    10. 10. Vascular events & calcium supplementation Letters to BMJ Calcium supplementation: Results may not be generalisable • Confounders (non-adjusted) • Calcium group had more smokers (RR 1.3) • Calcium group had history of ischaemic heart disease (RR 1.1) • Previous “treated” dislipideamia (RR1.2) • Calcium group had history of stroke (RR1.6) • Drop-outs • Calcium & control group had high drop out rates (46% & 40%) • Intention to treat analysis • Was not mentioned in article
    11. 11. Calcium/vitamin D supplementation and cardiovascular events (WHI) • Randomized 36,282 postmenopausal women – 50 to 79 years of age – calcium carbonate 1000 mg / vitamin D 400 IU or placebo. • 499 vs 475 women had myocardial infarction or coronary heart disease death: HR 1.04 (95% CI 0.92 - 1.18) • 362 & 377 women had a stroke: HR 0.95 (95% CI 0.82 - 1.10) • CONCLUSIONS: – Calcium/vitamin D supplementation neither increased nor decreased coronary or cerebrovascular risk in generally healthy postmenopausal women over a 7-year use period. Hsia et al Circulation 2007
    12. 12. Calcium, vitamine D en het skelet
    13. 13. •Antifractuur effect vitamine D en calcium •De rol van calcium als monotherapie •De rol van therapietrouw Tang BM, Eslick GD, Nowson C, Smith C, Bensoussan A. Use of calcium or calcium in combination with vitamin D supplementation to prevent fractures and bone loss in people aged 50 years and older: a meta- analysis. Lancet 2007; 370: 657-666 Effecten bij mensen ouder dan 50 jaar
    14. 14. Tang BM, et al. The Lancet 2007
    15. 15. Tang BM, et al. The Lancet 2007
    16. 16. Overall therapie effect Tang BM, et al. The Lancet 2007
    17. 17. Het effect van calcium t.o.v. calcium en vitamine D Tang BM, et al. The Lancet 2007
    18. 18. Het effect van therapietrouw Tang BM, et al. The Lancet 2007
    19. 19. Conclusie meta-analyse • 63.897; 29 RCTs • 52.625; 17 RCTs fractuur – 12% 0.88, 95% CI (0.83-0.95) • Hoge compliance rate 24% meer effect • < 1200mg contra 1200mg calcium (0.80 vs. 0.90; p= 0.006) • < 700-800IU contra 800IU vit. D (0.84 vs. 0.87; p= 0.03) Tang BM, Eslick GD, Nowson C, Smith C, Bensoussan A. Use of calcium or calcium in combination with vitamin D supplementation to prevent fractures and bone loss in people aged 50 years and older: a meta- analysis. Lancet 2007; 370: 657-666
    20. 20. • The treatment effect was greater in people who were institutionalised than in those living in the community (RR 0·76 vs 0·94; p=0·003) • Age was an important determinant of treatment efficacy. Risk reduction was less in people aged 50–70 years than in those who were older than 70 years Tang et al, the Lancet 2007
    21. 21. Calcium and vitamin D versus placebo for prevention of osteoporotic fractures. Analysis excludes two studies of very old, frail women living in institutions. Correspondence Calcium and vitamin D for prevention of osteoporotic fractures Bo Freyschuss, et al. The Lancet 2007;
    22. 22. •6 RCTs 45.000 Vit. D + calcium effect •4 RCTs 8083 Vit. D geen effect De rol van calcium en heupfracturen Boonen S et al. Need for additional calcium to reduce the risk of hip fracture with vitamin d supplementation: evidence from a comparative metaanalysis of randomized controlled trials.J Clin Endocrinol Metab. 2007; 92: 1415-23. 0.75 (95% CI 0.58, 0.96)
    23. 23. Bischoff-Ferrari HA, Willett WC, Wong JB, Giovannucci E, Dietrich T, Dawson- Hughes B. Fracture prevention with vitamin D supplementation: a meta-analysis of randomized controlled trials. JAMA 2005; 293: 2257-2264.
    24. 24. Vitamine D deficiëntie bij osteoporose patiënten
    25. 25. Vitamine D tekort Definitie • Geen consensus • 25(OH)D concentratie <30 ng/ml (75 nmol/L) voorgesteld als indicatie voor tekort Klinische Consequenties • Suboptimale calcium absorptie • Toegenomen PTH Adapted from Boonen S et al Osteoporos Int 2004;15:511–519; Lips P Endocr Rev 2001;22:477–501; Heaney RP Osteoporos Int 2000;11:553–555.
    26. 26. 0 10 30 40 60 80 90 30.8% 48.7% 2.8% 14.3% Cutoff points for 25(OH)D concentration (nmol/L) N=2589 63.9% 50 70 20 <50 <63<23 <38 <75 Bijna 2/3 van Postmenopauzale Vrouwen Vitamine D Insufficiëntie (<75 nmol/L) Study Design: Observational, cross-sectional study of 2589 community-dwelling women with osteoporosis from 18 countries to evaluate serum 25(OH)D distribution. Adapted from Lips P et al. Poster presented at ASBMR, Nashville, TN, USA, September 23– 27, 2005; Heaney RP Osteoporos Int 2000;11:553–555. Prevalentie(%)
    27. 27. Vitamine-D-spiegels bij fractuurpatiënten 0 20 40 60 80 100 120 <22,5 <37,5 <50 <75 Bewerkt naar Simonelli C et al Curr Med Res Opin 2005;21:1069–1074 25(OH)D3 nmol/l Prevalentie(%) 20,5% 52,5% 80,8% 97,4% - Studie Verenigde Staten 2004, n=78 > 50 jaar. - Patiënten opgenomen in ziekenhuis met laagenergetische fractuur (waarvan 97% met een heupfractuur).
    28. 28. Dumitrescu et al., BMC Musculoskeletal Disorders 2008: 109
    29. 29. Relatie vitamine D en therapie bisfosfonaten • In de meeste bisfosfonaten trials werd 250 – 500 U/d colecalciferol gesubstitueerd • Er zijn aanwijzingen dat de (BMD) respons op bisfosfonaten niet optimaal is bij inadequate vitamine D status en/of substitutie • Bij ernstige deficiëntie: substitutie van vitamine D voordat gestart wordt met een bisfosfonaat
    30. 30. Conclusie Vitamine D deficiëntie bij osteoporose patiënten • Vitamine D deficiëntie komt zeer frequent voor bij de osteoporose en fractuur patiënten • Een deel heeft niet (alleen) osteoporose maar osteomalacie! (PTH↑, Alk Fosf↑, 25 OH vit D↓) • Substitutie van vitamine D (en calcium) bij of soms voor het starten met een bisfosfonaat noodzakelijk
    31. 31. Advies gezondheidsraad voorlichting • Lichte huidskleur van 4- 50 jaar (vrouwen) of 70 (mannen) – Elke dag kwartier buitenshuis en gezonde voeding • Andere groepen in aanvulling hierop – 400 IE extra per dag • Ouderen met osteoporose of in verzorging/verpleeghuis en mensen vanaf 50 (vrouwen) of 70 (mannen) met een donkere huidskleur of onvoldoende buiten en gesluierd – 800 IE per dag
    32. 32. Toedieningsvormen Colecalciferol • Oraal – In combinatie met Calcium (500/400, 600/400, 500/440 of 1000/880) – Devaron 400U – Vit D caps 2800U – Vit D drank FNA 50.000 U/ml – In combinatie met alendronaat 2800 of 5600 U/week • Parenteraal – Injectievloeistof 600.000 IE/ml (in olie); ampul 1 ml. i.m. Calcitriol of alfa-calcidol (bij voorkeur niet)
    33. 33. Bij osteomalacie of malabsorptie • Start met 50.000 U per week 3–12 weken, daarna 800 U per dag • Bij malabsorptie overweeg i.m. substitutie / 6 of 12 maanden • Let op anti-epileptica
    34. 34. Bovengrens van Vitamine inname • Food and Nutrition Board: 2000 IU/dag • Hogere waarden waarschijnlijk niet schadelijk • Geen toxische effecten waargenomen in studie met 61 personen 4000 IU/dag vijf maanden • Vitamine D toxiciteit met hypercalciëmie bij 25(OH)D spiegel >200 nmol/L – Dagelijks vitamine D inname >40,000 IU noodzakelijk om deze spiegel te bereiken Dietary Reference Intakes for Calcium, Phosphorus, Magnesium, Vitamin D, and Fluoride. Washington, DC: Institute of Medicine, National Academy Press, 1997; Heaney RP Osteoporos Int 2000;11:553–555; Vieth R et al Am J Clin Nutr 2001;73:288–294; Vieth R Am J Clin Nutr 1999;69:842–856.
    35. 35. 10 100 1,000 10,000 100 1,000 10,000 100,000 Dose of Vitamin D (IU/day) Serum25(OH)Dng/ml Group Means Toxic Group Toxic Case Reports 1,000,000 Vitamin D Dosage and Toxicity Source: Vieth R. et al., Annals Epidemiol (in press)
    36. 36. Samenvatting • Calcium – Substitutie tot 1200 mg / dag op basis van voedingsanamnese • Vitamine D – In combinatie met bisfosfonaat: substitutie 800 U/dag – Let op bij ernstige deficiëntie met secundaire hyperparathyreoidie, malabsorptie, anti-epileptica • Hogere substitutiedosis noodzakelijk • Bij osteomalacie in eerste instantie bij voorkeur geen bisfosfonaat