vitamin D

1. 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

2. 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)

3. 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

4. If shadow TALLER than you are tall,
you CANNOT make vitamin D
(UV index = 3)

5. Chapter 1
INTRODUCTORY BACKGROUND TO
VITAMIN D

6. 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

7. 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

8. 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

9. 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

10. 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)

11. 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

12. 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

13. 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

14. 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

15. 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

16. 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

17. 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

18. FRACTURE-PREVENTION STUDIES WITH VITAMIN D3
=20 mcg/d
72
72
Bischoff-Ferrari et alJAMA. 2005;293:2257-2264

19. 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

20. 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

21. “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

22. Vitamin D Beyond Bone
Brain & Nerves
Muscle
Bone
Cardiovascular
Immune

23. Vitamin D Beyond Bone

24. 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

25. The Big New Randomized Clinical Trials

26. 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

27. 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

28. 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

29. Chapter 2
WHAT IS “NORMAL” FOR 25(OH)D ?

30. 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

31. 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

32. Maasai median 25(OH)D = 104 nmol/L = 41 ng/mL
Luxwolda and Muskiet , Brit J Nutrition 2011

33. 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

34. 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”

35. Why is vitamin D toxic? Because it works.
Paraphrasing Paraclesius:
“anything that actually
works, will be harmful if
the dose is high enough”

36. 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

37. 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…

38. Quart J Med 1948, Volume 17 : 203-228
Minimum 46000 IU/d
for weeks.

39. 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

40. 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

41. 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

42. VITAMIN D A MODERN
EXAMPLE OF THE
FORTIFICATION
VS
SUPPLEMENTATION
DILEMMA

43. 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

44. DO DOSAGE RECOMMENDATIONS FOR
VITAMIN D MAKE SENSE?

45. 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

46. VITAMIN D INTAKE
RECOMMENDATIONS:
IOM VS ENDOCRINE SOCIETY

48. RISKS/BENEFITS FOR
GOVERNMENT POLICY:
“Political Controversy”

49. 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

50. 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

51. 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

52. Evidence-Based Decision
with vitamin D:
Is it Realistic to demand
Perfect Evidence?

53. 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

54. Policy is slow to adapt because it demands the
Ultimate in Evidence: RCT + meta-analysis
Metaanalysis of RCT’s
Primary vs 2o outcomes

55. 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

56. 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

57. 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)

58. Evidence-Based Decision
with vitamin D:
An example of how IOM
has used key evidence.

60. KEY TEACHING
POINT
“Risk of vitamin D
deficiency
osteomalacia in bone
maintenance”
What does this
minimal risk actually
mean in IOM
context????

61. 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”

62. 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%

63. 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%

64. 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?

65. 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 -