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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
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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)
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Vieth 2001. Nutritional Aspects of Osteoporosis, Chapter 17, ed P Burckhardt, RP Heaney, B Dawson-Hughes; Academic Press
Contracted pelvis, in a case of osteomalacia (adult rickets). Normal childbirth would be impossible.
Childhood lack of vitamin D causes rickets
Normal shape of female pelvis
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If shadow TALLER than you are tall, you CANNOT make vitamin D
(UV index = 3)
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INTRODUCTORY BACKGROUND TO VITAMIN D
Chapter 1
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METABOLITE “COMPARTMENT”
Vitamin D3 Normally
Plasma=0-15 nmol/L(Context: 400 IU/quart
milk = 40 nmol/L)
Muscle and
Adipose
Unlimited Storage Capacity in
PLASMA
To Bile
LIVER
25-OHase
KIDNEY
1-α-OHase
7-dehydrocholesterol
UVB light
SKIN
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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
Muscle and
Adipose
Unlimited Storage Capacity in
PLASMA
To Bile
PLASMA LIVER
25-OHase
KIDNEY
1-α-OHase
7-dehydrocholesterol
UVB light
SKIN
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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
1,25(OH)2D 40-180 pmol/L
24,25(OH)2D Catabolism Excretion
Muscle and
Adipose
Paracrine signaling within tissues
Within Tissues
Possessing 1-OHase
PLASMA
Unlimited Storage Capacity in
PLASMA
To Bile
PLASMA LIVER
25-OHase
KIDNEY
1-α-OHase
7-dehydrocholesterol
UVB light
SKIN
Intestinal Calcium
Absorption
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METABOLITE “COMPARTMENT” Vitamin D3
25(OH)D
CALCITRIOL (Vitamin D hormone)
Within Tissues
Possessing 1-OHase
BLOOD PLASMA
Blood PLASMA
BLOOD PLASMA
Gallagher, 1979; J Clin Invest 64:729
200 1800
Bloo
d Ca
lcitr
iol L
evel
Diet Calcium mg/day
PARACRINE (WITHIN-TISSUE) ACTIONS
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25(OH)D
Vitamin D3
1,25(OH)2D Hormone control to increase calcium absorption and bone development (via Calcium)
Pharmacokinetic Features of Vitamin D Metabolites Serum vitamin D rises and falls sharply after a dose.
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
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.
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“it appears sound to offer preventive measures (vitamin D or calcium) to groups of high risk, like infants and toddlers”
Dietary Calcium
Cir
cula
tin
g 25
(OH
)D
Zone of Healthy Bone
Zone of UnhealthyBone
Calcium Supplementaton
Vita
min
D S
uppl
emen
tato
n or
Sun
shin
e “vitamin D or calcium”
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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
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25(OH)D Cholecalciferol (Vitamin D3)
7-dehydro- cholesterol
calcitriol
Cell
mito
Nucleus
Renal secretion of circulating calcitriol services endocrine
requirements of calcium homeostasis Local
Autocrine/Paracrine Effects:
Cell differentiation Reduce replication Immune function
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Record Information Issue: Current | All Restrict to: Reviews | Protocols Sort by: Record Title | Match %
Vitamin D supplementation for prevention 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, July 2010
Interventions for the prevention of nutritional rickets in term born children Christian Lerch, Thomas Meissner January 2009
Interventions for preventing falls in older people living in the community Lesley D Gillespie, October 2010
Interventions for preventing falls in older people in nursing care facilities and hospitals Ian D Cameron February 2010
THE TOP REVIEW SYSTEM OF EVIDENCE BASED MEDICINE CONCLUDES MULTIPLE BENEFITS OF VITAMIN D
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Vitamin D deficiency CAUSES DISEASE PREVENTED IF
25(OH)D Rickets / osteomalacia >25 nmol/L
Proximal-muscle weakness and back pain >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
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The „Waddling Gait“ of Osteomalacia
HD11
S.creatinine 2.13 mg/dL (-1.3) S.calcium (corr) 1.50 mmol/L (2.2-2.6) S.phosphate 1.81 mmol/L (0.84-1.45) S.magnesium 0.65 mmol/L (0.7-1.1) 1,25(OH)2D 163 pg/ml (30-70)
25(OH)D 15 nmol/L (>50 or >75 nmol/L) PTH 1082 pg/ml (<65)
62 yr old patient
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
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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
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FRACTURE-PREVENTION STUDIES WITH VITAMIN D3
Bischoff-Ferrari et alJAMA. 2005;293:2257-2264
72 72
=20 mcg/d
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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
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The actual data summarized by Bischoff-Ferrari et al AJCN2006
IOM claims that this graph represents the relationship between Serum 25(OH)D and
Bone Mineral Density NB: SAME SCALE as above
50 nmol/L
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| NATURE | 7 JULY 2011 | VOL 475: 23
“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.”
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Vitamin D Beyond Bone Muscle Bone Cardiovascular
Brain & Nerves Immune
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Vitamin D Beyond Bone
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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
MS ADS
Disease OUTCOME
150
120
90
60
30
0
INIT
IAL
PRES
ENTA
TIO
N
Seru
m 2
5-hy
drox
yvia
tmin
D (n
mol
/L)
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The Big New Randomized Clinical Trials
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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 VITAL STUDY: Cancer and Heart Disease
Cost = $30,000,000
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PLACEBO
VITAMIN D 3000 IU/day
as 100,000 IU once Monthly
2525 people
2525 people
THE VIDA STUDY: Heart Disease, Respiratory Disease, Fractures
Cost = $6,000,000
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Vitamin D deficiency is a nutritional inadequacy that :
CAUSES DISEASE PREVENTED IF 25(OH)D
Rickets / osteomalacia >25 nmol/L
Proximal-muscle weakness and back pain >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
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WHAT IS “NORMAL” FOR 25(OH)D ?
Chapter 2
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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
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Old-World Primates
Humans exposing full skin surface
to Sunshine’s
UVB
Winter 43o N
Latitude
“Normal” 0
40
120
160
Vitamin D Status in Primates and Early Humans
Sources, include Cosman, Osteoporosis Int 2000; Fuleihan NEJM 1999; Scharla Osteoporosis Int 1998; Vieth AJCN 1999, 2000
80 80
Physiological adult intake
Blood Levels when taking 1000 IU/day
Northern People Taking
4000 IU/day
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Maasai median 25(OH)D = 104 nmol/L = 41 ng/mL
Luxwolda and Muskiet , Brit J Nutrition 2011
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Ancestry Other South Asian European East Asian African
Seru
m 2
5(O
H)D
(nm
ol/l)
120
100
80
60
40
20
0
1. Traditional culture
2. Modern Africans
Are “Normal” serum 25(OH)D levels healthy?
100 nmol/L = 40 ng/mL
50 nmol/L
Rickets/osteomalacia range
Gozdzik et al, BMC Public Health 2008, 8:336
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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”
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Why is vitamin D toxic? Because it works.
Paraphrasing Paraclesius:
“anything that actually works, will be harmful if the dose is high enough”
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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
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TERAD3 Ag BLOX Rodenticide…with the low hazard benefits of Vitamin D3. TERAD3 Ag kills anticoagulant-resistant rats and mice…
Might the Fear of similar Problems Underlie Vitamin D Health Policy?
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Quart J Med 1948, Volume 17 : 203-228 Minimum 46000 IU/d for weeks.
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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
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Vitamin D3 Poisoning by Table Sugar. DOSE: 1.7 MILLION UNITS/DAY FOR 7 MONTHS!
Lancet 2002 359: 672
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.
Vit D
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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
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VITAMIN D A MODERN EXAMPLE OF THE
FORTIFICATION VS SUPPLEMENTATION
DILEMMA
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Canada Total Vitamin D intakes from food (fortification) and supplements (non-prescription):
VERY VERY FEW CANADIANS CONSUME THE VIT D RDA.
0
200
400
600
800
1000
1200
95%ile`
5%ile Median
15
30
10
0
20
Vita
min
D C
onsu
mpt
ion
(mcg
/day
)
5
Vita
min
D C
onsu
mpt
ion
(IU/d
ay)
25
Estimated average
requirment
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DO DOSAGE RECOMMENDATIONS FOR VITAMIN D MAKE SENSE?
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NEW 2011 USA/Canada IOM POLICY FOR VITAMIN D
Vitamin D mcg/day (10 mcg = 400 IU)
Risk
of
harm
(ex
cess
)
Risk
of
harm
(in
adeq
uacy
)
RDA NOAEL
15-20 100 250 1250
UL
EAR
LOAEL
UF
Traditionally
CALCIUM
Related
Purpose, to deliver >50 nmol/L 25(OH)D
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VITAMIN D INTAKE RECOMMENDATIONS:
IOM VS ENDOCRINE SOCIETY
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RISKS/BENEFITS FOR GOVERNMENT POLICY: “Political Controversy”
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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
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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
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Cost Comparison: Supplementation vs Fortification
Source: World Bank, 1994
0
1
2
3
4
Iron
Suppl Fort
Iodine Vit A
US
Dol
lars
Annual Per Capita US$ Cost of Interventions
Suppl Fort Suppl Fort
TH Tulchinsky MD MPH Braun School of Public Health
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Evidence-Based Decision with vitamin D:
Is it Realistic to demand Perfect Evidence?
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1. Personal care decisions (flexible and possibly only during sickness).
2. Physician care of patient (flexible and possibly only during sickness).
3. Government Health policy: for all society and for years to come.
1
2
Zero Evidence
The shades of grey of health/medical decisions
3 Certainty = “Causality” = RCT only
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Metaanalysis of RCT’s
Policy is slow to adapt because it demands the Ultimate in Evidence: RCT + meta-analysis
Primary vs 2o outcomes
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Potential
Effect for
DRUG
RCT
“Evidence
Based
Medicine”
Relative Dose Difference
PLACEBO TREATMENT
CLASSIC DRUG CLINICAL TRIAL •Recruit persons currently at high risk of a disease event
•Treat existing condition
•High likelihood to show effect in an individual.
Res
pons
e O
utco
me
X
Blumberg et al 2010 Nutrition Reviews Vol. 68(8):478–484
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•Recruit Healthy persons at low risk
•Prevent a currently- non-existing future condition
•Low likelihood to show effect in an individual
Potential For Non-
Index Nutrition
RCT
RDA TREATMENT
CLASSIC NUTRIENT CLINICAL TRIAL
Relative Dose Difference R
espo
nse
Out
com
e
Relative Dose Difference
X
Y
White response curve is
the “index”, classic
effect of the
nutrient.
Green represents a new, putative
effect.
Blumberg et al 2010 Nutrition Reviews Vol. 68(8):478–484
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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 SUPPLEMENT
•Health is a responsibility of:
1 THE INDIVIDUAL take a supplement
2 HEALTH PROFESSIONALS advise a supplement or PRESCRIPTION
3 GOVERNMENT POLICY Fortification (mandatory/optional)
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Evidence-Based Decision with vitamin D:
An example of how IOM has used key evidence.
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“Risk of vitamin D deficiency osteomalacia in bone maintenance”
KEY TEACHING POINT
What does this minimal risk actually mean in IOM context????
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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”
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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%
5 o’malacia 23 OK Risk = 5/28=18%
11 o’malacia 17 OK Risk = 6/28=39%
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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.
7 o’malacia 22 OK
Risk = 7/28 =25%
5 o’malacia 23 OK Risk = 5/28=18%
11 o’malacia 17 OK Risk = 6/28=39%
Does the use of the evidence by the IOM make sense to you?
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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?
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Decision Theory: Pain of a unit of loss =
2 X the Pleasure of a unit of win
-1 0 +1 +2
degree of wrong or correct
1 -
-2 -