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VITAMIN D
WHAT IT DOES &HOW MUCH WE NEED
Robert P. Heaney, M.D.
Creighton University Osteoporosis Research Center
Working definitionWorking definitionWorking definitionWorking definition::::� a deficiency is any condition in which a deficiency is any condition in which a deficiency is any condition in which a deficiency is any condition in which inadequate intake of a nutrient results in inadequate intake of a nutrient results in inadequate intake of a nutrient results in inadequate intake of a nutrient results in significant dysfunction or diseasesignificant dysfunction or diseasesignificant dysfunction or diseasesignificant dysfunction or disease
� conversely, nutrient adequacy is the conversely, nutrient adequacy is the conversely, nutrient adequacy is the conversely, nutrient adequacy is the situation in which further increases in situation in which further increases in situation in which further increases in situation in which further increases in intake produce no further reduction in intake produce no further reduction in intake produce no further reduction in intake produce no further reduction in dysfunction or diseasedysfunction or diseasedysfunction or diseasedysfunction or disease
What is the operative model What is the operative model What is the operative model What is the operative model for nutrition?for nutrition?for nutrition?for nutrition?
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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
For a package ofmacaroni & cheese
http://vm.cfsan.fda.gov/~dms/foodlab.html
Limit these nutrients
Get enough of these
nutrients
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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 leastone 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 wearingout 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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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
THEORETICAL MORTALITY CURVE
AGE (yrs)AGE (yrs)AGE (yrs)AGE (yrs)
0000 20202020 40404040 60606060 80808080 100100100100
THEORETICAL MORTALITY CURVE
AGE (yrs)AGE (yrs)AGE (yrs)AGE (yrs)
0000 10101010 20202020 30303030 40404040 50505050 60606060 70707070 80808080 90909090 100100100100
SURVIV
AL (%)
SURVIV
AL (%)
SURVIV
AL (%)
SURVIV
AL (%)
0000
20202020
40404040
60606060
80808080
100100100100
Age (yrs)Age (yrs)Age (yrs)Age (yrs)
0000 10101010 20202020 30303030 40404040 50505050 60606060 70707070 80808080 90909090 100100100100
Perc
ent alive/w
ell
Perc
ent alive/w
ell
Perc
ent alive/w
ell
Perc
ent alive/w
ell
0000
20202020
40404040
60606060
80808080
100100100100
SQUARING THE MORTALITY CURVE
Certainly, NCEP and DGA Certainly, NCEP and DGA Certainly, NCEP and DGA Certainly, NCEP and DGA take this for grantedtake this for grantedtake this for grantedtake this for granted
Optimal nutrition has the Optimal nutrition has the Optimal nutrition has the Optimal nutrition has the potential to contribute to potential to contribute to potential to contribute to potential to contribute to
this improvementthis improvementthis improvementthis improvement
The role of vitamin D in The role of vitamin D in The role of vitamin D in The role of vitamin D in this reduction is the topic this reduction is the topic this reduction is the topic this reduction is the topic of this presentationof this presentationof this presentationof this presentation
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
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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
� There has been a gradually growingThere has been a gradually growingThere has been a gradually growingThere has been a gradually growingacceptance of 75acceptance of 75acceptance of 75acceptance of 75––––80 nmol/L 80 nmol/L 80 nmol/L 80 nmol/L (30(30(30(30––––32 ng/mL ) as the lower end 32 ng/mL ) as the lower end 32 ng/mL ) as the lower end 32 ng/mL ) as the lower end of the of the of the of 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
ABSORPTION FRACTION
0.0
0.1
0.2
0.3
0.4
0.5
A VITAMIN D THRESHOLD
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SERUM 25(OH)D (nmol/L)
0 20 40 60 80 100 120 140 160
ABSORPTION FRACTION
0.0
0.1
0.2
0.3
0.4
0.5
A VITAMIN D THRESHOLD
physiological physiological physiological physiological regulation of Ca is no regulation of Ca is no regulation of Ca is no regulation of Ca is no longer limited by vit longer limited by vit longer limited by vit longer 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
ABSORPTION FRACTION
0.0
0.1
0.2
0.3
0.4
0.5
A VITAMIN D THRESHOLD
VITAMIN D STATUS
EF
FE
CT
THE RESPONSE THRESHOLD
Ca absorptionCa absorptionCa absorptionCa absorption
EF
FE
CT
THE RESPONSE THRESHOLD
Clinical rickets?Clinical rickets?Clinical rickets?Clinical rickets?
VITAMIN D STATUS
EF
FE
CT
THE RESPONSE THRESHOLD
Histological ricketsHistological ricketsHistological ricketsHistological rickets
VITAMIN D STATUS
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
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%
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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%
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
13–2
1 y
13–2
1 y
13–2
1 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
13–2
1 y
13–2
1 y
13–2
1 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
13–2
1 y
13–2
1 y
13–2
1 y
Pre
vale
nce (%)
Pre
vale
nce (%)
Pre
vale
nce (%)
Pre
vale
nce (%)
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
All studies, in virtually all All studies, in virtually all All studies, in virtually all All 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 the show that the majority of the show that the majority of the show that the majority of the worldworldworldworld’’’’s population has s population has s population has s population has inadequate vitamin D status.inadequate vitamin D status.inadequate vitamin D status.inadequate vitamin D status.
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)
FRACTURE RELATIVE RISK
(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
Fall Risk
Ca only Ca + D
*Bischoff et al. JBMR. 2003;18:343–351.
–49%
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.
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
Systo
lic B
P (m
m H
g)
Systo
lic B
P (m
m H
g)
Systo
lic B
P (m
m H
g)
Systo
lic B
P (m
m H
g)
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
Hazard
Rati
o
< 10ng/mL
< 15ng/mL
> 15ng/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
% w
ith
UR
TI
< 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
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Vitamin Vitamin
DD
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
Hazard
Ratio
< 30
30–45
45–60
60–75
> 75
69 % decrease in risk
Serum 25(OH)D (nmol/L)
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
Odds R
ati
o
1st–
162n
d–22
3rd–
274t
h–31
5th–
40
25(OH)D Quintiles (with medians*)
P = 0.02
*ng/mL
VITAMIN D & CANCER*
Time (yrs)Time (yrs)Time (yrs)Time (yrs)
0000 1111 2222 3333 4444 5555
Fra
ction C
ancer-
Fre
eFra
ction C
ancer-
Fre
eFra
ction C
ancer-
Fre
eFra
ction C
ancer-
Fre
e
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
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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
� ????
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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
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Safety
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)
Serum 25(OH)D (nmol/L)
15 studies of adultsreceiving vitamin Dsupplementation(means)
8 studies reportingtoxicity (individualvalues)
VITAMIN D INTAKE & TOXICITY*
* Hathcock JN et al. Am J Clin Nutr. 2007;85:6–18.
no toxicity below 500 no toxicity below 500 no toxicity below 500 no 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 below no toxicity below no toxicity below no toxicity below 30,000 IU/d30,000 IU/d30,000 IU/d30,000 IU/d
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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
Thank youThank youThank youThank you