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Hazard Ratio
follow-up: 5.4 yrs in risk
120 individuals developed 2.0
a CV event 1.5
HR calculated against
25(OH)D values > 15 ng/mL 1.0
CU ORC
2
BREAST CANCER RISK
Case-control study 1.2
1394 cases
1.0
1365 controls
69 % decrease
Hazard Ratio
Odds ratio for CA 0.8
in risk
inversely
0.6
associated with vit
D status [25(OH)D]
0.4
Abbas et al.,
Carcinogenesis (2008)
0.2
29:93–99
0.0
30 –4
5
–6
0
–7
5 75
< 3 0 4 5 6 0 >
3 yr DB-RCT 25
placebo or vit D3
20
800 IU/d – 2 yrs
2000 IU/d – 3rd yr 15
P < 0.002 5
0
Placebo Vitamin D
CU ORC
*Aloia & U-Ng (2007) Epidemiol & Infect
4
VITAMIN D & THE COMMON COLD*
25
18,883 individuals
in NHANES-III
20
tested association
% with URTI
between serum 15
25(OH)D & recent
URTI 10 29 % reduction
P < 0.001
5
association stronger
for those with 0
< 10 10–29.9 30+
asthma & COPD
Serum 25(OH)D (ng/mL)
CU ORC
Ginde et al., Arch Int Med 2009 169:
5
DIABETES & 25(OH)D
1.0
White
Scragg et al., 2004 0.9 Hispanic
Diabetes Care 0.8
27:2813–18
Relative Risk
0.7
NHANES-III
0.6
6,228 adults
0.5
plasma glucose
0.4
independently
predicted by BMI 0.3
& serum 25OHD 0.2
(fasting and 2 hr 0.1
post load) 0.0
1st 2nd 3rd 4th
25(OH)D Quartiles
CU ORC
6
NEONATAL VIT D & DIABETES*
10,366 northern 3-fold higher risk
10
Finnish children
2000 IU Vit D/d 1st
year of life 1
Relative Risk
prevalence of
type I diabetes
assessed at age 31 0.1
RR calculated vs. no
supplementation
0.01
88% lower risk u l ar u l ar k e ts
R eg re g ri c
Ir ?
Ca economy
endocrine
autocrine
VIT D – CANONICAL SCHEME
CU ORC
13
VIT D – EXPANDED SCHEME
CU ORC
14
Autocrine functions
AUTOCRINE ACTION
25(OH)D
1,25D
VDR
1,25D
VDR VDRE
RXR
Transcription
CU ORC
16
AUTOCRINE ACTION
25(OH)D
cell proliferation
cell differentiation
apoptosis
immune response VDRE
24-hydroxylase
Transcription
CU ORC
17
AUTOCRINE ACTION
25(OH)D
~ 800 genes
have VDREs
VDRE
Transcription
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18
AUTOCRINE ACTION
25(OH)D
25OHD 25OHD
1,25D 1,25D
VDR
VDRE
1,25D
VDR
RXR
Transcription
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19
AUTOCRINE ACTION
25(OH)D
25OHD 25OHD
1,25D 1,25D
VDR
VDRE
1,25D
VDR
RXR
Transcription
CU ORC
20
This scheme means that each tissue
has the amount of 1,25(OH)2D it needs
when it needs it
and is not dependent upon a “one-size-
fits all” systemic level of circulating
1,25(OH)2D
VITAMIN D & INNATE IMMUNITY*
activated
Toll-like
receptor
CU ORC
*Liu et al., Science 2006
22
VITAMIN D & INNATE IMMUNITY*
25(OH)D
bactericidal Cathelicidin
peptide
CU ORC
*Liu et al., Science 2006
23
VITAMIN D & INNATE IMMUNITY*
25(OH)D
human
monocytes
in fetal calf
serum
the Vit D
1-a hydroxylase
Cyp27B1
VDR
the Vit D
receptor
CU ORC
*Liu et al., Science 2006
24
VITAMIN D & INNATE IMMUNITY*
25(OH)D
human
monocytes
in fetal calf
serum
fetal calf
serum is low
in both
Cyp27B1
25(OH)D & VDR
1,25(OH)2D
…………
CU ORC
*Liu et al., Science 2006
25
VITAMIN D & INNATE IMMUNITY*
25(OH)D
human
monocytes
in fetal calf
serum
add
1,25(OH)2D
to the Cyp27B1
system 1,25D VDR
Cathelicidin
Cyp24
CU ORC
*Liu et al., Science 2006
26
VITAMIN D & INNATE IMMUNITY*
25(OH)D
human
monocytes
in fetal calf
serum
add
25(OH) D to 25OHD
Cathelicidin
Cyp24
CU ORC
*Liu et al., Science 2006
27
VITAMIN D & TUBERCULOSIS
human monocytes Cathelicidin mRNA
activated with M.
4
Tuberculosis and
incubated in human
3
serum serum 25(OH)D:
78 nmol/L
African-American
2
White serum 25(OH)D:
22 nmol/L
African-American 1
with added
25(OH)D 0
A- A W A- A
+ 25D
CU ORC
*Liu et al., Science 2006
28
VITAMIN D & TUBERCULOSIS
these experiments show that:
vit D is an essential mediator in the innate
immune response
serum 25(OH)D is the critical variable
at least some of the increased sensitivity to
infection in vit D-deficiency is due to reduction
in response to infectious agents because
25(OH)D is rate-limiting
the greater tuberculosis susceptibility of blacks
is due in part to their low vit D status
CU ORC
29
If this new understanding is correct,
do we see evidence of impaired function in
patients with low vitamin D status?
VITAMIN D & TUBERCULOSIS*
67 pts with pulmonary Sputum Conversion (%)
TB 100
standard treatment 90
for all
in addition, 80
randomized to either
vit D 10,000 IU/d or 70
placebo 60
P = 0.002
50
Placebo Vit D
CU ORC
*Nursyam et al., Acta Med Indones 2006
31
CELL MODELS
newly synthesized
Response cellular equipment
CU ORC
33
HOW A CELL RESPONDS
25(OH)D
Signal/
Demand
newly synthesized
Response cellular equipment
CU ORC
34
PERSPECTIVE
vitamin D is an integral component of the
mechanism whereby cells control gene
transcription in response to a variety of
extracellular stimuli
adequate vitamin D status enables optimal
response to a broad variety of signals
deficiency will manifest itself differently,
depending upon the tissue being stressed,
thus explaining the diversity of responses
CU ORC
35
Two questions: –
How can a single nutrient have
such diverse effects in so many
different tissues ?
If these effects are real, why
haven’t they been apparent
previously ?
VITAMIN D & INFLUENZA*
35
208 African-American,
postmenopausal women 30
3 yr DB-RCT 25
placebo or vit D3
20
800 IU/d – 2 yrs
2000 IU/d – 3rd yr 15
P < 0.002 5
0
Placebo Vitamin D
CU ORC
*Aloia & U-Ng (2007) Epidemiol & Infect
37
Such differences would not be apparent in
ordinary medical practice because people
who don’t get sick do not see the doctor –
are not tracked and would not be recognized
as having been protected.
ABSORPTION FRACTION
0.4
0.3
0.2
0.1
0.0
0 20 40 60 80 100 120 140 160
CU ORC
42
A VITAMIN D THRESHOLD
0.5
physiological
ABSORPTION FRACTION
0.4
regulation no longer
limited by vit D
0.3
availability
0.2
0.1
0.0
0 20 40 60 80 100 120 140 160
CU ORC
43
A VITAMIN D THRESHOLD
0.5
ABSORPTION FRACTION
0.4
0.3
0.2
0.1
0.0
0 20 40 60 80 100 120 140 160
CU ORC
44
VITAMIN D – Sources
Body D3
? stores 25(OH)D
VITAMIN D – Sources
Body D3
? stores 25(OH)D
VITAMIN D – Sources
Body D3
150 stores 25(OH)D
VITAMIN D – Sources
Body D3
150 stores 25(OH)D
typical input,
all sources:
~2350 iu
VITAMIN D – Sources
Body D3
150 stores 25(OH)D
needed input,
all sources:
~4000 iu
VIT D – EXPANDED SCHEME
CU ORC
50
VIT D – EXPANDED SCHEME
NO!
VIT D – CANONICAL SCHEME
CU ORC
53
Bone strength
Serum 25(OH)D and Hip BMD
NHANES-III
Non-Hispanic whites
Adults Age
20 – 49 yrs
LOWESS plot
of difference Hispanics
from lowest
quantile
African-Americans
5 yr RCT
0.6
Vit D 800
0.4
IU/d
Trivedi et al.
0.2 BMJ 2003;
326:469
0.0
CU ORC
56
VITAMIN D & FRACTURES
Relative Risk
meta-analysis 1.0
9 RCTs
0.8
Vit D doses
> 400 IU (but 0.6
CU ORC
57
VITAMIN D & RISK OF FALLING*
1.0
122 women
Age: 63–99 0.8
–49%
DB-RCT
Fall Risk
0.6
Ca 1,200 mg/d
Ca + 800 IU Vit D 0.4
12 week duration
0.2
25(OH)D 12 ng/mL
at baseline 0.0
Ca only Ca + D
CU ORC
*Bischoff et al. JBMR. 2003;18:343–351.
58
VIT D & NEUROMUSCULAR FUNCTION*
Performance Score
1359 men & women; 9
mean age 75.5 8
Amsterdam longitud. 7
aging study
6
neuromuscular
5
performance
measured on a scale 4
of 0 to 12 (higher is 3
better) 2
each step statistically 1
significant
0
<25 25–50 50–75 >75
*Wicherts et al. JBMR. 2005.
SERUM 25(OH)D
In brief, raising serum 25(OH)D
from 50 to ~80 nmol/L
improves Ca absorption, raises
BMD, and reduces falls and
osteoporotic fracture risk
OTHER CHRONIC DISEASES?
Disease Status of Evidence
osteoporosis ++++
osteoarthritis +
falls/neuromusc. fcn ++++
multiple sclerosis ++
fibromyalgia-like syndrome ++
type I diabetes ++
insulin sensitivity ++
cardiovascular disease +++
periodontal disease ++++
various cancers ++++
tuberculosis ++++
hypertension ++++
CU ORC
61
Cardiovascular effects
VIT D & BLOOD PRESSURE*
P < 0.02
148 women, aged 150
P < 0.01
74 ± 1 P < 0.01
DB–RCT
0
Ca only Ca+D
*Pfeifer et al., JCEM 2001; 86:1633–37
INTERVENTION
VIT D & BLOOD PRESSURE*
1811 men & women
10
with measured
25(OH)D levels**
4 yrs’ observation
Relative Risk
97 cases of incident 3.18
hypertension 1
RR computed for
25(OH)D <15ng/mL
vs. >30 ng/mL
0.1
>30 <15
*Forman at al., 2007;Hypertension 49:1063
** Health Profs Follow-up Study & Nurses Health Study
Anti-promotion for cancer
VITAMIN D & PROSTATE CA*
2.5
13 yr
longitudinal 2.0
RELATIVE RISK
study
1.5
19,000 men
149 cases 1.0
prostate CA
0.5
0.0
1 2 3 4
*Ahonen et al., CancerCauses&Control 11:847-852 (2000) 25(OH)D QUARTILES
VITAMIN D & PROSTATE CA*
2.5
those below
the median 2.0
25(OH)D level
RELATIVE RISK
were 70% 1.5
more likely to
develop 1.0
prostate CA
than those 0.5
above
0.0
1 2 3 4
*Ahonen et al., CancerCauses&Control 11:847-852 (2000) 25(OH)D QUARTILES
COLORECTAL CANCER
1.0
Nurses’ Health Study
ages 46–78
0.8
nested case-control
Odds Ratio
study 0.6
193 incident cases
25(OH)D measured 0.4
twice, prior to
diagnosis 0.2
Feskanich et al., Cancer
Epidemiol Biomarkers Prev
0.0
2004 13:1502–08 16
0
7
2
4
2
2
t–
h–
h–
d–
d–
1s
4t
5t
3r
2n
individuals
Odds Ratio
0.6
430 cases
ORs computed 0.4
for 25(OH)D
quantiles 0.2
69
MAMMOGRAPHIC DENSITIES
1.0
543 women aged 40–60
Vit D
1989–90 Ca
0.8
dietary intakes assessed
Odds Ratio
with FFQ 0.6
odds ratios developed
for <30% vs. >70% of 0.4
film with densities
[Berube et al., 2004; Cancer 0.2
Epidemiol Biomarkers Prev
13:1466–72]
0.0
1st 2nd 3rd 4th
Quartiles
CU ORC
70
VITAMIN D & CANCER*
1179 healthy women
aged 66.7 ± 7.3
four year trial
1032 finished (87.5%)
baseline 25(OH)D: 71.8 nmol/L ± 20.3
three treatment groups:
control
Ca (1400–1500 mg/d)
Ca plus D3 (1100 IU/d)
achieved 25(OH)D: 96 nmol/L ± 21.4
CU ORC
*Lappe et al. AJCN 2007
71
VITAMIN D & CANCER*
1.00
Fraction Cancer-Free
0.98
Ca+D
0.96
Ca-only
0.94
RR
P<= 0.01
0.402
0.92
Placebo
0.90
0 1 2 3 4
0.98 Ca+D
0.96
Ca-only RR = 0.232
0.94
Placebo
0.92
0.90
0 1 2 3 4 5
96 nmol/L
Fraction Cancer-Free
0.98 Ca+D
0.96
Ca-only
0.92
0.90
0 1 2 3 4 5
1,800
Serum 25(OH)D (nmol/L)
1,600 below
no toxicity 15 studies of adults
30,000
1,400 IU/d receiving vitamin D
1,200 supplementation
(means)
1,000
800 8 studies reporting
toxicity (individual
600 values)
400
200 no toxicity below 500
nmol/L (200 ng/mL)
0
1,000 10,000 100,000 1,000,000 10,000,000
CU ORC
79
25(OH)D IN OLDER WOMEN*
*Lappe et al., JACN 2006
1168 women 100
aged 55 &
older 80
latitude 41º N
25(OH)D Frequency 60
values
adjusted for 40
season
median vit D 20
supplement
dose = 200 IU 0
0 40 80 120 160
25(OH)D (nmol/L)
CU ORC
80
SHIFTING THE DISTRIBUTION
0.025
improving
RELATIVE FREQUENCY
vitamin D 0.020
status at a
population 0.015
level means
raising
0.010
everybody’s
value, i.e.,
moving the 0.005
distribution
to the right 0.000
0 20 40 60 80 100 120 140 160 180
25(OH)D (nmol/L)
CU ORC
81
SHIFTING THE DISTRIBUTION
using an effect 0.025
size of
1 nmol/L/mg/d
RELATIVE FREQUENCY
0.020
it would require
~2000 IU of 0.015
additional D each
day to shift the
distribution 0.010
sufficiently to
ensure that no 0.005
more than 2.5 %
fell below 80
0.000
nmol/L 0 50 100 150 200
25(OH)D (nmol/L)
CU ORC
82
SHIFTING THE DISTRIBUTION
taking an effect 0.025
size of
1 nmol/L/mg/d
RELATIVE FREQUENCY
0.020
it would require
~2000 IU of 0.015
additional D each
day to shift the
distribution 0.010
sufficiently to
ensure that no 0.005
more than 2.5 %
fell below 80
0.000
nmol/L 0 50 100 150 200
25(OH)D (nmol/L)
CU ORC
83
SHIFTING THE DISTRIBUTION
0.025
what about those
already 2 SD above
RELATIVE FREQUENCY
the mean? 0.020
them to no more
than 170–180 0.005
nmol/L – well
below the toxic 0.000
range 0 50 100 150 200
25(OH)D (nmol/L)
CU ORC
84
CONCLUSIONS
vitamin D acts in multiple systems
serum 25(OH)D levels below 80 nmol/L
are not adequate for any body system
levels of as high as 120 nmol/L may be
closer to optimal
inputs from all sources combined
(needed to sustain 80 nmol/L) are in
the range of ~4,000 IU/d and higher
CU ORC
86
WHAT IS THE OPERATIVE MODEL?
CU ORC
87
WHAT IS THE OPERATIVE MODEL?
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For a package of
macaroni & cheese
http://vm.cfsan.fda.gov/~dms/foodlab.html
Limit these
nutrients
Get enough of
these
nutrients
MEDIA REPORTING
the overwhelming majority of media
reports about nutrition emphasizes 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
CU ORC
91
WHAT IS THE OPERATIVE MODEL?
for nutritional policy makers
CU ORC
92
WHAT IS THE OPERATIVE MODEL?
for nutritional physiologists
CU ORC
93
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; and
therefore, expression of nutrient deficiency
will usually be pluriform – both between
and within individuals
CU ORC
94
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
CU ORC
95
THEORETICAL MORTALITY CURVE
0 20 40 60 80 100
AGE (yrs)
CU ORC
96
THEORETICAL MORTALITY CURVE
100
80
SURVIVAL (%)
60
40
20
0
0 10 20 30 40 50 60 70 80 90 100
AGE (yrs)
CU ORC
97
SQUARING THE MORTALITY CURVE
100
80
Percent alive/well
this improvement
40
0
0 10 20 30 40 50 60 70 80 90 100
Age (yrs)
CU ORC
98
WHAT WOULD IT BE LIKE?
fewer cancers
less diabetes
fewer osteoporotic fractures
less hypertension & CV disease
less periodontal disease
less multiple sclerosis
less severe infectious disease
CU ORC
99
We don’t really know the true
burden of chronic disease.
And we won’t, until everyone
has enough vitamin D.
Thank you . . .