Published on March 3, 2014
Evidence-based medicine and how that relates to official policies about the tolerable upper level (safety) and approved health effects of vitamin D. Reinhold Vieth Professor, Departments of Nutritional Sciences and Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Canada GRASSROOTS HEALTH Sept 20 , 2013
The Childrens’s story HEIDI Her friend Clara who lived in the city probably suffered from • • • Rickets (bone) Weak muscles Infection-prone Probable serum 25(OH)D < 25 nmol/L (<10 ng/mL) Probable serum 25(OH)D > 75 nmol/L (>30 ng/mL)
Childhood lack of vitamin D causes rickets Normal shape of female pelvis Contracted pelvis, in a case of osteomalacia (adult rickets). Normal childbirth would be impossible. Vieth 2001. Nutritional Aspects of Osteoporosis, Chapter 17, ed P Burckhardt, RP Heaney, B Dawson-Hughes; Academic Press
If shadow TALLER than you are tall, you CANNOT make vitamin D (UV index = 3)
Chapter 1 INTRODUCTORY BACKGROUND TO VITAMIN D
UVB light SKIN 7-dehydrocholesterol LIVER METABOLITE “COMPARTMENT” Vitamin D3 Normally Plasma=0-15 nmol/L(Context: 400 IU/quart milk = 40 nmol/L) 25-OHase KIDNEY 1-α-OHase Unlimited Storage Capacity in Muscle and Adipose PLASMA To Bile
UVB light SKIN 7-dehydrocholesterol LIVER METABOLITE “COMPARTMENT” Vitamin D3 Normally Plasma=0-15 nmol/L(Context: 400 IU/quart milk = 40 nmol/L) 25(OH)D 2-225 nmol/L 25-OHase KIDNEY 1-α-OHase Unlimited Storage Capacity in Muscle and Adipose PLASMA To Bile PLASMA
UVB light SKIN 7-dehydrocholesterol LIVER METABOLITE “COMPARTMENT” Vitamin D3 Normally Plasma=0-15 nmol/L(Context: 400 IU/quart Unlimited Storage Capacity in Muscle and Adipose milk = 40 nmol/L) PLASMA To Bile PLASMA 25(OH)D 2-225 nmol/L 25-OHase Paracrine signaling within tissues KIDNEY 1-α-OHase 1,25(OH)2D 40-180 pmol/L 24,25(OH)2D Catabolism Excretion Within Tissues Possessing 1-OHase PLASMA Intestinal Calcium Absorption
METABOLITE “COMPARTMENT” Vitamin D3 BLOOD PLASMA P AR ACR I NE (W I THI NTI SSUE) ACTI ONS CALCITRIOL (Vitamin D hormone) Within Tissues Possessing 1-OHase BLOOD PLASMA Blood Calcitriol Level 25(OH)D Blood PLASMA 200 1800 Diet Calcium mg/day Gallagher, 1979; J Clin Invest 64:729
Pharmacokinetic Features of Vitamin D Metabolites Serum vitamin D rises and falls sharply after a dose. Vitamin D3 Within 2-3 days, all of a given dose of vitamin D3 is either stored in tissues, or converted to 25(OH)D. Serum 25(OH)D rises gradually over time, and if supplies of vitamin D are removed 25(OH)D Half-life = about 2 months. OR 2 weeks* Serum 1,25(OH)2D is not affected by a vitamin D dose, since its production is stimulated by PTH, and the need for Calcium. Half-life = 12 hrs. 1,25(OH)2D Hormone control to increase calcium absorption and bone development (via Calcium)
Vitamin D Supplementaton or Sunshine Circulating 25(OH)D “it appears sound to offer preventive measures (vitamin D or calcium) to groups of high risk, like infants and toddlers” “vitamin D or calcium” Zone of Healthy Bone Zone of UnhealthyBone Calcium Supplementaton Dietary Calcium
25(OH)D 1,25(OH)2D Made in Multiple Tissues •BONE •BREAST CELLS •PROSTATE CELLS •COLON CELLS •SKIN •LYMPH NODES •BRAIN (CEREBELLUM AND CORTEX) •THYROID TISSUE •PARATHYROID TISSUE •DENDRITIC CELLS •VASCULAR ENDOTHELIUM •MACROPHAGES •PLACENTA Made in multiple departments for multiple purposes
7-dehydrocholesterol Cholecalciferol (Vitamin D3) 25(OH)D Cell mito calcitriol Local Autocrine/Paracrine Nucleus Effects: Cell differentiation Reduce replication Immune function Renal secretion of circulating calcitriol services endocrine requirements of calcium homeostasis
Record Information Issue: Current | All Restrict to: Reviews | Vitamin D supplementation for prevention THE TOP REVIEW SYSTEM OF EVIDENCE BASED MEDICINE CONCLUDES MULTIPLE BENEFITS OF VITAMIN |DMatch % Protocols Sort by: Record Title of mortality in adults Goran Bjelakovic August 2011 Vitamin D supplementation for improving bone mineral density in children Tania M Winzenberg, October 2010 Vitamin D compounds for people with chronic kidney disease requiring dialysis Suetonia C Palmer, October 2009 Vitamin D compounds for people with chronic kidney disease not requiring dialysis Suetonia C Palmer October 2009 Vitamin D for the treatment of chronic painful conditions in adults Sebastian Straube, November 2010 Vitamin D and vitamin D analogues for preventing fractures D for associated with involutional and post-menopausal osteoporosis Alison Avenell, April 2009 Vitamin D for the management of multiple sclerosis Vanitha A Jagannath, December 2010 Calcium and vitamin corticosteroid-induced osteoporosis Joanne Homik, Interventions for the prevention Meissner January 2009 July 2010 of nutritional rickets in term born children Christian Lerch, Thomas Interventions for preventing falls in older people living in the community Lesley D Gillespie, October 2010 Interventions for preventing 2010 falls in older people in nursing care facilities and hospitals Ian D Cameron February
Vitamin D deficiency CAUSES DISEASE Rickets / osteomalacia Proximal-muscle weakness and back pain PREVENTED IF 25(OH)D >25 nmol/L >25 nmol/L ? Osteoporosis and fractures >50 nmol/L (Contentious) Increases risk of: multiple sclerosis, colorectal cancer, breast cancer, diabetes, depression/poor mental status >75 nmol/L
The „Waddling Gait“ of Osteomalacia 62 yr old patient S.creatinine S.calcium (corr) S.phosphate S.magnesium 1,25(OH)2D 2.13 mg/dL (-1.3) 1.50 mmol/L (2.2-2.6) 1.81 mmol/L (0.84-1.45) 0.65 mmol/L (0.7-1.1) 163 pg/ml (30-70) 25(OH)D 15 nmol/L (>50 or >75 nmol/L) PTH 1082 pg/ml (<65) CKD stage III PAOD stage II arterial hypertension chronic pancreatitis (MRI diagnosis) Case Presentation Courtesy Prof.Dr.Harald.Dobnig Klinische Abteilung für Endokrinologie und Stoffwechsel Medizinische Universität Graz, Austria HD11
Low 25(OH)D Myopathy Hypovitaminosis D Myopathy Without Biochemical Signs of Osteomalacic Bone Involvement H. Glerup et al Calcif Tissue Int (2000) 66:419–424
FRACTURE-PREVENTION STUDIES WITH VITAMIN D3 =20 mcg/d 72 72 Bischoff-Ferrari et alJAMA. 2005;293:2257-2264
All By Itself, Vitamin D Prevents Fractures Cumulative probability of any first fracture One Dose or Placebo pill sent by mail, 100,000 every 4 months vitamin D (n=1345) placebo (n=1341) based on Cox regression; difference between two groups, P=0.04 Trivedi, Doll, and Khaw 2003 BMJ 326:469
The actual data summarized by Bischoff-Ferrari et al AJCN2006 50 nmol/L IOM claims that this graph represents the relationship between Serum 25(OH)D and Bone Mineral Density NB: SAME SCALE as above
“Guyatt says that much of the current fracas could have been avoided if the IOM panel had been a bit more equivocal in its reporting.” | NATURE | 7 JULY 2011 | VOL 475: 23
Vitamin D Beyond Bone Brain & Nerves Muscle Bone Cardiovascular Immune
Vitamin D Beyond Bone
Serum 25-hydroxyvitamin D status as a determinant of MULTIPLE SCLEROSIS outcome following acute demyelination in children Banwell et al 2011 www.thelancet.com/neurology Vol 10 May 2011 INITIAL PRESENTATION Serum 25-hydroxyviatmin D (nmol/L) 150 120 90 60 30 0 ADS MS Disease OUTCOME
The Big New Randomized Clinical Trials
THE VITAL STUDY: Cancer and Heart Disease Cost = $30,000,000 VITAMIN D ZERO (Placebo) VITAMIN D 2000 IU/day Fish Oil ZERO (Placebo) 5000 people 5000 people Fish Oil 1000 mg/day 5000 people 5000 people
THE VIDA STUDY: Heart Disease, Respiratory Disease, Fractures Cost = $6,000,000 PLACEBO VITAMIN D 3000 IU/day as 100,000 IU once Monthly 2525 people 2525 people
Vitamin D deficiency is a nutritional inadequacy that : CAUSES DISEASE Rickets / osteomalacia Proximal-muscle weakness and back pain PREVENTED IF 25(OH)D >25 nmol/L >25 nmol/L ? Osteoporosis and fractures >50 nmol/L (Contentious) Increases risk of: multiple sclerosis, colorectal cancer, breast cancer, diabetes, depression/poor mental status >75 nmol/L
Chapter 2 WHAT IS “NORMAL” FOR 25(OH)D ?
World Distribution of Nonhuman Primates Regions shaded white are the natural habitat of non-human primates from; Primate Behavior: Field studies of monkeys and apes. I DeVore 1965
Vitamin D Status in Primates and Early Humans Winter 43o N Latitude 160 120 80 40 0 Old-World Primates Humans exposing full skin surface to Sunshine’s UVB “Normal” 80 Blood Levels when taking 1000 IU/day Northern People Taking 4000 IU/day Physiological adult intake Sources, include Cosman, Osteoporosis Int 2000; Fuleihan NEJM 1999; Scharla Osteoporosis Int 1998; Vieth AJCN 1999, 2000
Maasai median 25(OH)D = 104 nmol/L = 41 ng/mL Luxwolda and Muskiet , Brit J Nutrition 2011
1. Traditional culture Are “Normal” serum 25(OH)D levels healthy? 120 100 nmol/L = 40 ng/mL 2. Modern Africans Serum 25(OH)D (nmol/l) 100 80 60 50 nmol/L 40 20 Rickets/osteomalacia range 0 African East Asian European South Asian Ancestry Other Gozdzik et al, BMC Public Health 2008, 8:336
WHY NOT GET ON WITH GIVING MORE VITAMIN D? BECAUSE THERE IS RISK OF TOO MUCH Paraphrasing Paraclesius: “anything that actually works, will be harmful if the dose is high enough”
Why is vitamin D toxic? Because it works. Paraphrasing Paraclesius: “anything that actually works, will be harmful if the dose is high enough”
Difficulties in Establishing Policy • Perception that Government is Paternalistic • Resistance to “mandatory medication” • Risk of Overriding Individual choice • Clinical vs. population approaches • Professionals in nutrition focus on the clinical (supplementation) approach • WHO ambivalence/opposition • Desire for Natural, “Green” foods. TH Tulchinsky 2004 European Journal of Public Health, Vol. 14 : 226-228
Might the Fear of similar Problems Underlie Vitamin D Health Policy? TERAD3 Ag BLOX Rodenticide…with the low hazard benefits of Vitamin D3. TERAD3 Ag kills anticoagulant-resistant rats and mice…
Quart J Med 1948, Volume 17 : 203-228 Minimum 46000 IU/d for weeks.
Vitamin D3 Poisoning by Table Sugar. DOSE: 1.7 MILLION UNITS/DAY FOR 7 MONTHS! Reinhold Vieth PhDb, Tanya R Pinto BScb, Bajinder S Reen MDa, and Min M Wong MDa Lancet 2002 359: 672 June 1999, a 29-year-old man admitted to emergency with symptoms of: extreme right-sided flank pain conjunctivitis (a sign of dehydration) increased thirst vomiting in acute renal failure anorexia fever, chills Initially treated with steroids and discharged: presumed gastroenteritis
Vitamin D3 Poisoning by Table Sugar. Vit D DOSE: 1.7 MILLION UNITS/DAY FOR 7 MONTHS! October 1999, his 63-year-old father was admitted to emergency with similar complaints. He was also in acute renal failure, and no history of stones. Calcium VERY HIGH 3.82 mmol/L (normal, 2.20-2.65 mmol/L), 25(OH)D HIGH 1555 nmol/L (normal 20-80 nmol/L) 1,25(OH)2D NEAR NORMAL 151 pmol/L (normal, 30-140 pmol/L). Elevated “free” 1,25(OH)2D causing toxicity. Lancet 2002 359: 672
For Vitamin D. POTENTIAL “MECHANISMS OF TOXICITY”: Traditional: 1. Amplification or mimicking of the 1,25(OH)2D signal to intestine and bone: initially raises urine calcium, later raises serum calcium New? Phenomena 2. “High” bolus (annual) doses increase number of falls and fractures 3. “U-shaped risk curves” evident in some epidemiological studies
VITAMIN D A MODERN EXAMPLE OF THE FORTIFICATION VS SUPPLEMENTATION DILEMMA
Canada Total Vitamin D intakes from food (fortification) and supplements (non-prescription): VERY VERY FEW CANADIANS CONSUME THE VIT D RDA. 30 1000 25 800 20 600 15 400 10 200 5 0 0 Vitamin D Consumption (mcg/day) Vitamin D Consumption (IU/day) 1200 95%ile` Median 5%ile Estimated average requirment
DO DOSAGE RECOMMENDATIONS FOR VITAMIN D MAKE SENSE?
EAR Purpose, to deliver >50 nmol/L 25(OH)D RDA UL UF NOAEL Risk of harm (excess) Risk of harm (inadequacy) NEW 2011 USA/Canada IOM POLICY FOR VITAMIN D LOAEL 15-20 100 250 1250 Vitamin D mcg/day (10 mcg = 400 IU) Traditionally CALCIUM Related
VITAMIN D INTAKE RECOMMENDATIONS: IOM VS ENDOCRINE SOCIETY
RISKS/BENEFITS FOR GOVERNMENT POLICY: “Political Controversy”
18-19th Century Breakthroughs • Lind and scurvy 1747 • Lemon juice (vit C) in Royal Navy, 1796 • Davy isolates sodium, potassium, calcium, magnesium, sulphur, boron, 1807 • Chatin shows iodine prevents goiter, 1850 • Eijkman publishes Thiamine deficiency cause of beriberi, 1897 TH Tulchinsky MD MPH Braun School of Public Health
Preventing Goiter and Iodine Deficiency Disorders • 1917, high % US draftees rejected goiter • 1922-27, goiter rates fall from 39% to 9% by statewide prevention programs • 1924, Morton’s Iodized Salt (N America) • 1979, Iodization mandatory in Canada • 1980s, WHO - universal iodization of salt • Many countries achieved iodization TH Tulchinsky MD MPH Braun School of Public Health
Cost Comparison: Supplementation vs Fortification 4 US Dollars 3 2 Annual Per Capita US$ Cost of Interventions Iron 1 Iodine 0 Suppl Fort Suppl Fort Vit A Suppl Fort Source: World Bank, 1994 TH Tulchinsky MD MPH Braun School of Public Health
Evidence-Based Decision with vitamin D: Is it Realistic to demand Perfect Evidence?
The shades of grey of health/medical decisions Zero Evidence 1. Personal care decisions (flexible and possibly only during sickness). 1 2. Physician care of patient 2 (flexible and possibly only during sickness). 3. Government Health policy: 3 for all society and for years to come. Certainty = “Causality” = RCT only
Policy is slow to adapt because it demands the Ultimate in Evidence: RCT + meta-analysis Metaanalysis of RCT’s Primary vs 2o outcomes
CLASSIC DRUG CLINICAL TRIAL •Recruit persons Response Outcome currently at high risk of a disease event •Treat existing condition Potential •High likelihood to Effect for show effect in an individual. DRUG RCT “Evidence Based Medicine” X PLACEBO TREATMENT Relative Dose Difference Blumberg et al 2010 Nutrition Reviews Vol. 68(8):478–484
CLASSIC NUTRIENT CLINICAL TRIAL •Recruit Healthy persons at low risk Response Outcome •Prevent a currently- nonexisting future condition Potential For NonIndex Nutrition RCT •Low likelihood to show effect in an individual Relative Dose Difference Y X RDA White response curve is the “index”, classic effect of the nutrient. Green represents a new, putative effect. TREATMENT Relative Dose Difference Blumberg et al 2010 Nutrition Reviews Vol. 68(8):478–484
For Vitamin D. THINK ABOUT THE OPTIONS: •Change the BEHAVIOR of society to consume an ideal diet •Change diets through FORTIFICATION •Advise all of society to take a •Health SUPPLEMENT is a responsibility of: 1 THE INDIVIDUAL take a supplement 2 HEALTH PROFESSIONALS advise a supplement or PRESCRIPTION 3 GOVERNMENT POLICY Fortification (mandatory/optional)
Evidence-Based Decision with vitamin D: An example of how IOM has used key evidence.
KEY TEACHING POINT “Risk of vitamin D deficiency osteomalacia in bone maintenance” What does this minimal risk actually mean in IOM context????
IOM report states on pg 15-7 “Data from the work of Priemel et al. (2010) have been used by the committee to support a serum 25OHD level of 50 nmol/L as providing coverage for at least 97.5 percent of the population.” “Our data … strongly argue that in conjunction with a sufficient calcium intake, the dose of vitamin D supplementation should ensure that circulating levels of 25(OH)D reach this minimum threshold (75 nmol/L or 30 ng/mL) to maintain skeletal health”
The key Figure from Priemel et al 2010: The IOM Report claims that based on the figures below, 25(OH)D > 50 nmol/L prevents osteomalacia in 97.5% of people (i.e. claim is Risk< 2.5%). Below is the evidence they specify for that. 7 o’malacia 22 OK Risk = 7/28=25% 11 o’malacia 17 OK Risk = 6/28=39% 5 o’malacia 23 OK Risk = 5/28=18%
THE IOM JUSTIFIES 50 nmol/L because if 25(OH)D> 50 nM (20 ng/mL) then only about 1% of the population had evidence of Osteomalacia bone disease. Does the use of the evidence by the IOM make sense to you? 11 o’malacia 17 OK Risk = 6/28=39% 7 o’malacia 22 OK Risk = 7/28 =25% 5 o’malacia 23 OK Risk = 5/28=18%
QUESTIONS COMMONLY ASKED AFTER GIVING A TALK LIKE THIS: 1. So tell me, how much vitamin D I should be taking. 2. Should I be worried about taking vitamin D? 3. How can the IOM justify its way of making recommendations? 4. How much vitamin D do you (RV) take? 5. Why are policy makers so conservative?
Decision Theory: Pain of a unit of loss = 2 X the Pleasure of a unit of win 1- -1 0 +1 +2 degree of wrong or correct -2 -
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