Dr. Heaney vit D issues

1. VITAMIN D
WHAT IT DOES &
HOW MUCH WE NEED
Robert P. Heaney, M.D.
Creighton University Osteoporosis Research Center

2. Working definitionWorking definitionWorking definitionWorking definition::::
a deficiency is any condition in whicha deficiency is any condition in whicha deficiency is any condition in whicha deficiency is any condition in which
inadequate intake of a nutrient results ininadequate intake of a nutrient results ininadequate intake of a nutrient results ininadequate intake of a nutrient results in
significant dysfunction or diseasesignificant dysfunction or diseasesignificant dysfunction or diseasesignificant dysfunction or disease
conversely, nutrient adequacy is theconversely, nutrient adequacy is theconversely, nutrient adequacy is theconversely, nutrient adequacy is the
situation in which further increases insituation in which further increases insituation in which further increases insituation in which further increases in
intake produce no further reduction inintake produce no further reduction inintake produce no further reduction inintake produce no further reduction in
dysfunction or diseasedysfunction or diseasedysfunction or diseasedysfunction or disease

3. What is the operative modelWhat is the operative modelWhat is the operative modelWhat is the operative model
for nutrition?for nutrition?for nutrition?for nutrition?

4. CU ORC
4
WHAT IS THE OPERATIVE MODEL?
for the media?
for regulators?
for nutritional policy makers?
for nutritional physiologists?

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WHAT IS THE OPERATIVE MODEL?
for the media and for regulators
nutrition is about killing yourself
with a fork
it’s about avoiding risks
it’s about warnings & cautions

6. For a package of
macaroni & cheese
http://vm.cfsan.fda.gov/~dms/foodlab.html

7. Limit these
nutrients
Get enough of
these
nutrients

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8
MEDIA REPORTING
most media reports about nutrition
emphasize harm and risk
while the explanation is partly that
harm is more newsworthy than benefit
(and the media battens on controversy)
still the impression unwittingly
conveyed to the general public is one
of concern and danger

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WHAT IS THE OPERATIVE MODEL?
for nutritional policy makers
nutrition is about determining the least
one can get by on without suffering
overt disease of a specific type
(once called MDRs)

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WHAT IS THE OPERATIVE MODEL?
for nutritional physiologists
adult nutrition is about preventive
maintenance of tissues and organs
it’s about keeping them from wearing
out or breaking down prematurely
its referent is the intake that prevailed
when human physiology evolved

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CHRONIC DISEASE PERSPECTIVE
chronic disease is the breakdown of structure
and/or function of a body system
its origin is usually multifactorial
genes
environment
nutrition
infection
toxins
injury
11
the body has
mechanisms to repair
this damage or to fight
it at its origin
vitamin D is an essential
component of many of
these mechanisms
low vitamin D status
impairs this protective/
reparative activity

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THE PREVENTIVE MAINTENANCE MODEL
foundational premises:
all tissues need all nutrients
shortages impair the functioning of all
body systems
premature organ/system “wearing out”,
as a consequence of nutrient deficiency,
will vary from person to person,
depending on variable genetic
composition

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13
THE PREVENTIVE MAINTENANCE MODEL
also recognizes that:
the organism will work perfectly well
without maintenance – for a while . . .
it thus reconciles the seeming paradox
that an organism can be “deficient”
without being clinically “sick”
– for a while . . .
it’s also about squaring the morbidity/
mortality curve

14. THEORETICAL MORTALITY CURVE
AGE (yrs)AGE (yrs)AGE (yrs)AGE (yrs)
0000 20202020 40404040 60606060 80808080 100100100100

15. THEORETICAL MORTALITY CURVE
AGE (yrs)AGE (yrs)AGE (yrs)AGE (yrs)
0000 10101010 20202020 30303030 40404040 50505050 60606060 70707070 80808080 90909090 100100100100
SURVIVAL(%)SURVIVAL(%)SURVIVAL(%)SURVIVAL(%)
0000
20202020
40404040
60606060
80808080
100100100100

16. Age (yrs)Age (yrs)Age (yrs)Age (yrs)
0000 10101010 20202020 30303030 40404040 50505050 60606060 70707070 80808080 90909090 100100100100
Percentalive/wellPercentalive/wellPercentalive/wellPercentalive/well
0000
20202020
40404040
60606060
80808080
100100100100
SQUARING THE MORTALITY CURVE
Certainly, NCEP and DGACertainly, NCEP and DGACertainly, NCEP and DGACertainly, NCEP and DGA
take this for grantedtake this for grantedtake this for grantedtake this for granted
Optimal nutrition has theOptimal nutrition has theOptimal nutrition has theOptimal nutrition has the
potential to contribute topotential to contribute topotential to contribute topotential to contribute to
this improvementthis improvementthis improvementthis improvement
The role of vitamin D inThe role of vitamin D inThe role of vitamin D inThe role of vitamin D in
this reduction is the topicthis reduction is the topicthis reduction is the topicthis reduction is the topic
of this presentationof this presentationof this presentationof this presentation

17. ALL-CAUSE MORTALITY*
714 community
dwelling women
aged 70–79
Baltimore Women’s
Health & Aging
Studies I & II
median follow-up:
72 months
risk adjusted for
age, race, BMI, &
other factors
associated with
mortality
< 15 ng/mL< 15 ng/mL< 15 ng/mL< 15 ng/mL
> 27 ng/mL> 27 ng/mL> 27 ng/mL> 27 ng/mL
* Semba et al. (2009) Nutr Res 29:525–530

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VITAMIN D IN NATURE
vitamin D exists in two chemically distinct
forms:
vitamin D2 – ergocalciferol
vitamin D3 – cholecalciferol
D3 is the natural form in animals; it is what
we make in our skins on exposure to UV-B
light
D2, once thought equivalent to D3, is only
~50–60% as potent as D3
18

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VITAMIN D IN NATURE
serum 25(OH)D is the way vitamin D
status is evaluated
lower end of acceptable range for
serum 25(OH)D:
75–80 nmol/L
(30–32 ng/mL)
19

20. There has been a gradually growingThere has been a gradually growingThere has been a gradually growingThere has been a gradually growing
acceptance of 75acceptance of 75acceptance of 75acceptance of 75––––80 nmol/L80 nmol/L80 nmol/L80 nmol/L
(30(30(30(30––––32 ng/mL ) as the lower end32 ng/mL ) as the lower end32 ng/mL ) as the lower end32 ng/mL ) as the lower end
of theof theof theof the ““““normalnormalnormalnormal”””” range.range.range.range.
What is the basis for this figure?What is the basis for this figure?What is the basis for this figure?What is the basis for this figure?
Will it hold?Will it hold?Will it hold?Will it hold?

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SERUM 25(OH)D (nmol/L)
0 20 40 60 80 100 120 140 160
ABSORPTIONFRACTION
0.0
0.1
0.2
0.3
0.4
0.5
A VITAMIN D THRESHOLD

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22
SERUM 25(OH)D (nmol/L)
0 20 40 60 80 100 120 140 160
ABSORPTIONFRACTION
0.0
0.1
0.2
0.3
0.4
0.5
A VITAMIN D THRESHOLD
physiologicalphysiologicalphysiologicalphysiological
regulation of Ca is noregulation of Ca is noregulation of Ca is noregulation of Ca is no
longer limited by vitlonger limited by vitlonger limited by vitlonger limited by vit
D availabilityD availabilityD availabilityD availability

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SERUM 25(OH)D (nmol/L)
0 20 40 60 80 100 120 140 160
ABSORPTIONFRACTION
0.0
0.1
0.2
0.3
0.4
0.5
A VITAMIN D THRESHOLD

24. VITAMIN D STATUS
EFFECT
THE RESPONSE THRESHOLD
Ca absorptionCa absorptionCa absorptionCa absorption

25. EFFECT
THE RESPONSE THRESHOLD
Clinical rickets?Clinical rickets?Clinical rickets?Clinical rickets?
VITAMIN D STATUS

26. EFFECT
THE RESPONSE THRESHOLD
Histological ricketsHistological ricketsHistological ricketsHistological rickets
VITAMIN D STATUS

27. 27
25(OH)D IN OLDER WOMEN*
1168 women
aged 55 &
older
latitude 41º N
25(OH)D
values
adjusted for
season
median vit D
supplement
dose = 200 IU
25(OH)D (nmol/L)
0 40 80 120 160
Frequency
0
20
40
60
80
100
*Lappe et al., JACN 2006

28. 28
25(OH)D IN OLDER WOMEN*
1168 women
aged 55 &
older
latitude 41º N
25(OH)D
values
adjusted for
season
median vit D
supplement
dose = 200 IU
25(OH)D (nmol/L)
0 40 80 120 160
Frequency
0
20
40
60
80
100
*Lappe et al., JACN 2006
~65%

29. 29
25(OH)D IN OLDER WOMEN*
1168 women
aged 55 &
older
latitude 41º N
25(OH)D
values
adjusted for
season
median vit D
supplement
dose = 200 IU
25(OH)D (nmol/L)
0 40 80 120 160
Frequency
0
20
40
60
80
100
*Lappe et al., JACN 2006
~84%

30. VIT D DEFICIENCY IN CHILDREN
NHANES
2001–2004
girls
n=3012
Kumar et al.
Pediatrics 2009 1–6
y
1–6
y
1–6
y
1–6
y7–12
y
7–12
y
7–12
y
7–12
y13–21
y
13–21
y
13–21
y
13–21
y
1–6
y
1–6
y
1–6
y
1–6
y7–12
y
7–12
y
7–12
y
7–12
y13–21
y
13–21
y
13–21
y
13–21
y
1–6
y
1–6
y
1–6
y
1–6
y7–12
y
7–12
y
7–12
y
7–12
y13–21
y
13–21
y
13–21
y
13–21
y
Prevalence(%)Prevalence(%)Prevalence(%)Prevalence(%)
0000
20202020
40404040
60606060
80808080
100100100100
<15 ng/mL<15 ng/mL<15 ng/mL<15 ng/mL
15-30 ng/mL15-30 ng/mL15-30 ng/mL15-30 ng/mL
NH White NH Black MexAmer

31. All studies, in virtually allAll studies, in virtually allAll studies, in virtually allAll studies, in virtually all
nations, irrespective of latitude,nations, irrespective of latitude,nations, irrespective of latitude,nations, irrespective of latitude,
show that the majority of theshow that the majority of theshow that the majority of theshow that the majority of the
worldworldworldworld’’’’s population hass population hass population hass population has
inadequate vitamin D status.inadequate vitamin D status.inadequate vitamin D status.inadequate vitamin D status.

32. WHAT ARE THE CONSEQUENCES?
bone diseases, falls, & fractures
hypertension
risk of cardiac disease & death
prematurity, low birth weight, &
Caesareans
diabetes & metabolic syndrome
periodontal disease
decreased resistance to infection
various cancers
risk of multiple sclerosis

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THE 25(OH)D CONTINUUM
0 25 50 75 100 125 150
(nmol/L)
FRACTURERELATIVERISK
(hip,forearm,spine)
0.0
0.2
0.4
0.6
0.8
1.0
N = 2,686
ages 65–85
5 yr RCT
Vit D ≅≅≅≅ 800 IU/d
Trivedi et al. BMJ
2003; 326:469
–33%

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VITAMIN D & RISK OF FALLING*
122 women
Age: 63–99
DB-RCT
Ca 1,200 mg/d
Ca + 800 IU Vit D
12 week duration
25(OH)D 12 ng/mL
at baseline 0.0
0.2
0.4
0.6
0.8
1.0
FallRisk
Ca only Ca + D
*Bischoff et al. JBMR. 2003;18:343–351.
–49%

35. VIT D & NEUROMUSCULAR FUNCTION*
1359 men & women;
mean age 75.5
Amsterdam longitud.
aging study
neuromuscular
performance
measured on a scale
of 0 to 12 (higher is
better)
0
1
2
3
4
5
6
7
8
9
<25 25–50 50–75 >75
SERUM 25(OH)D
Performance Score
each step statistically
significant
*Wicherts et al. JBMR. 2005.

36. VIT D & BLOOD PRESSURE*
148 women, aged
74 ± 1
DB–RCT
baseline 25(OH)D <
50 nmol/L
treated for 8 wks
with:
Ca 1200 mg/d or
Ca + 800 IU vit D/d
*Pfeifer et al., JCEM 2001; 86:1633–37
INTERVENTION
Ca onlyCa onlyCa onlyCa only Ca+DCa+DCa+DCa+D
SystolicBP(mmHg)SystolicBP(mmHg)SystolicBP(mmHg)SystolicBP(mmHg)
0000
125125125125
150150150150
P < 0.01
P < 0.01
P < 0.02
–5.7 –13.1

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VIT D & CARDIOVASCULAR DISEASE
1739 Framingham
Offspring members
age: 59 yrs
follow-up: 5.4 yrs
120 individuals developed
a CV event
HR calculated against
25(OH)D values > 15
ng/mL
Wang et al. Circulation
2008 0.0
0.5
1.0
1.5
2.0
2.5
3.0
3.5
HazardRatio
< 10
ng/mL
< 15
ng/mL
> 15
ng/mL
80 % increase
in risk
53 % increase
in risk

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VITAMIN D & INFLUENZA*
208 African-American,
postmenopausal women
3 yr DB-RCT
placebo or vit D3
800 IU/d – 2 yrs
2000 IU/d – 3rd yr
basal 25(OH)D: 18.8 ± 7.5
0
5
10
15
20
25
30
35
Placebo Vitamin D
*Aloia & U-Ng (2007) Epidemiol & Infect
P < 0.002

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VITAMIN D & INFLUENZA*
DB–RCT
winter 2008–2009
334 Japanese
school children,
aged 6–15
mean wt: 35.5 kg
1200 IU D3/d in
addition to self-
supplementation
39
*Urashima et al., AJCN 2010
P =
0.04
P =
0.006

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VITAMIN D & THE COMMON COLD*
18,883 individuals
in NHANES-III
tested association
between serum
25(OH)D & recent
URTI
0
5
10
15
20
25
%withURTI
< 10 10–29.9 30+
Serum 25(OH)D (ng/mL)
P < 0.001
association stronger
for those with
asthma & COPD
Ginde et al., Arch Int Med 2009 169:
29 % reduction

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VITAMIN D & TUBERCULOSIS*
67 pts with pulmonary
TB
standard treatment
for all
in addition,
randomized to either
vit D 10,000 IU/d or
placebo
50
60
70
80
90
100
Placebo Vit D
Sputum Conversion (%)
*Nursyam et al., Acta Med Indones 2006
P = 0.002

42. 42
VitaminVitamin
DD

43. BREAST CANCER RISK
Case-control
study
1394 cases
1365 controls
Odds ratio for CA
inversely
associated with vit
D status [25(OH)D]
Abbas et al.,
Carcinogenesis (2008)
29:93–99
0.0
0.2
0.4
0.6
0.8
1.0
1.2
HazardRatio
< 30
30–45
45–60
60–75
> 75
69 % decrease
in risk
Serum 25(OH)D (nmol/L)

44. COLORECTAL CANCER
Nurses’ Health Study
ages 46–78
nested case-control
study
193 incident cases
25(OH)D measured
twice, prior to
diagnosis
Feskanich et al., Cancer
Epidemiol Biomarkers Prev
2004 13:1502–08
0.0
0.2
0.4
0.6
0.8
1.0
OddsRatio
1st–16
2nd–22
3rd–27
4th–31
5th–40
25(OH)D Quintiles (with medians*)
P
=
0.02
*ng/mL

45. VITAMIN D & CANCER*
Time (yrs)Time (yrs)Time (yrs)Time (yrs)
0000 1111 2222 3333 4444 5555
FractionCancer-FreeFractionCancer-FreeFractionCancer-FreeFractionCancer-Free
0.900.900.900.90
0.920.920.920.92
0.940.940.940.94
0.960.960.960.96
0.980.980.980.98
1.001.001.001.00
Ca+D
Placebo
Ca-only
*Lappe et al. AJCN 2007
96 nmol/L96 nmol/L96 nmol/L96 nmol/L
70 nmol/L70 nmol/L70 nmol/L70 nmol/L

46. CU ORC
HOW MUCH IS ENOUGH?
rickets & osteomalacia
Ca absorption
pregnancy outcomes
some cancers
other
75 nmol/L
80 nmol/L
120 nmol/L
100 nmol/L
????
46

47. CU ORC
MANAGEMENT
all-input requirement ≅≅≅≅75 IU/kg/d
most adults will need 1000–3000 IU/d in
addition to all other inputs
25(OH)D response varies widely
it is the serum 25(OH)D concentration
that must be optimized, not the oral dose
the correct oral dose is the one that
produces and maintains the desired
25(OH)D level
47

48. Safety

49. 0
200
400
600
800
1,000
1,200
1,400
1,600
1,800
1,000 10,000 100,000 1,000,000 10,000,000
Vitamin D Intake (IU/day)
Serum25(OH)D(nmol/L)
15 studies of adults
receiving vitamin D
supplementation
(means)
8 studies reporting
toxicity (individual
values)
VITAMIN D INTAKE & TOXICITY*
* Hathcock JN et al. Am J Clin Nutr. 2007;85:6–18.
no toxicity below 500no toxicity below 500no toxicity below 500no toxicity below 500
nmol/L (200 ng/mL)nmol/L (200 ng/mL)nmol/L (200 ng/mL)nmol/L (200 ng/mL)
no toxicity belowno toxicity belowno toxicity belowno toxicity below
30,000 IU/d30,000 IU/d30,000 IU/d30,000 IU/d

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50
CONCLUSIONS
serum 25(OH)D levels below 80 nmol/L
are not adequate for any body system
levels of as high as 125 nmol/L may be
closer to optimal
inputs from all sources combined are in
the range of:
~4,000 IU/d to sustain 80 nmol/L, and
~5,000 IU/d to sustain 100 nmol/L

51. Thank youThank youThank youThank you