Vitamin D:Tilting the Odds in your Favor
Vitamin D:Tilting the Odds in your Favor
Iowa Dietetic AssociationAnnual Meeting
November 5, 2009
Karen Rafferty, RD, LMNTOwner, Nutrition Science Resource
D DD
Scope of presentationI. Skeletal and non-skeletal
functions of vitamin D
II. Optimal vitamin D status
III. Treatment strategies: sources and amounts of vitamin D
The function of vitamin D
In the mid 1990s, the IOM revisited the nutrient intake
recommendations for the bone-related nutrients
Vitamin D was one of the five re-evaluated – 1997 DRI (AI)
The function of vitamin D What we knew:
Vitamin D prevented rickets
The RDA for vitamin D was sufficient to afford protection
Vitamin D was important for calcium absorption
RDA = 400 IU/day
RDA = 400 IU/day
0 25 50 75 100 125 150
Functional indicator of vitamin D
Blood level of vitamin D Serum 25(OH)D 1 ng/ml (= 2.5 nmol/L) – clinical 1 nmol/L (= .4 ng/ml) – research
20ng/ml
30ng/ml
10ng/ml
(nmol/L)
The function of vitamin DWhat we didn’t know:
Was there a connection between vitamin D status and any other (non-skeletal) disease?
What is the optimal serum 25(OH)D level?
What is the dose-response?
Evidence base
Disease Status of Evidence
osteoarthritis/RAfalls/neuromuscular functionmultiple sclerosisfibromyalgiatype I diabetes insulin sensitivity cardiovascular diseaseperiodontal diseasevarious cancerstuberculosishypertension
++++++++++++++++++++++++++
0 25 50 75 100 125 150
Evidence base
Prevention of rickets/
osteomalacia
reference range “normal”
calcium absorption falls/neuromuscular
function multiple sclerosis fibromyalgia type I diabetes insulin sensitivity cardiovascular disease periodontal disease various cancers tuberculosis
??(nmol/L)
Vitamin D schemes
25(OH)D3D3
skindiet liver
1,25(OH)2D3
gut
CaAb
kidneyendocrine
periphery
1,25(OH)2D3
varioustissues
cellsignal
s
autocrine
0 25 50 75 100 125 150
Vitamin D & Ca absorptionA
BSO
RPT
ION
FRA
CT
ION
0.0
0.1
0.2
0.3
0.4
+68%
reference range “normal”
34 post- menopausal women studied twice, one yr apart (Spring) given vitamin D one year & not the other
Heaney RP et al JACN 2003; 22:142-146
(nmol/L)
Vitamin D & Ca absorption
SERUM 25(OH)D (nmol/ L)
0 20 40 60 80 100 120 140 160
ABSO
RPTIO
N F
RA
CTIO
N
0.0
0.1
0.2
0.3
0.4
0.5
Heaney RP Am J Clin Nutr 2008;88:541S-544S
Bischoff et al. (2003); JBMR 18:3243–51
Barger-Lux et al. (2002); JCEM 87:4952–56
Heaney et al. (2003); JACN 22:142–46
Vitamin D & Ca absorption
Heaney RP Am J Clin Nutr 2008;88:541S-544S
Bischoff et al. (2003); JBMR 18:3243–51
Barger-Lux et al. (2002); JCEM 87:4952–56
Heaney et al. (2003); JACN 22:142–46
SERUM 25(OH)D (nmol/ L)
0 20 40 60 80 100 120 140 160
ABSO
RPTIO
N F
RA
CTIO
N
0.0
0.1
0.2
0.3
0.4
0.5
usual laboratory reference range
calcium absorption is suboptimal
in the lower half of
the reference range
0 25 50 75 100 125 150
Vitamin D & fractures
FRA
CTU
RE R
ELA
TIV
E R
ISK
(hip
, fore
arm
, spin
e)
0.0
0.2
0.4
0.6
0.8
1.0
–33% N = 2,686 ages 65–85 5 yr RCT Vit D 800
IU/d
Trivedi DP et al BMJ 2003; 326:469
(nmol/L)
Vitamin D & falling
0.0
0.2
0.4
0.6
0.8
1.0
Fall R
isk
Ca only Ca + D
–49%
122 women age: 63–99 DB-RCT
Ca 1200 mg/d Ca + 800 IU Vit
D 12 week duration 25(OH)D 30 nmol/L
at baseline
Bischoff et al JBMR 2003; 18:343-351
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
Wicherts et al.
JBMR. 2005.
Vit D & neuromuscular function
0 25 50 75 100 125 150 (nmol/L)
1. 8–foot walk test 2. Sit–to–stand test
Assessing muscle function:
Accurately predict disability
Bischoff et al AJCN 2004; 80:752-758
Vit D & neuromuscular function
Vit D & nursing home admissions
Visser et al AJCN 2006:616-622
Visser, M. et al
ACJN 2006: 616-622
Vitamin D & mortality
Raising serum 25(OH)D
from 50 nmol/L to > 80 nmol/L :
improves calcium absorption
improves neuromuscular function
reduces fracture risk and falls
reduces nursing home admissions
0 25 50 75 100 125 150
Vit D & endocrine functions
(nmol/L)
CU ORC
25(OH)D3D3
1,25(OH)2D3
skin liver
periphery
gut
CaBP
Vit D – expanded scheme
kidney
1,25(OH)2D3
varioustissues
cellsignal
s
endocrine
autocrine
~ 5%
85+%
cell proliferation
cell differentiation
apoptosis
immune response
inflammation
Vit D & autocrine functions
Autocrine action
Transcription
~ 200 genes have VDREs
VDRE
25(OH)D
Vitamin D & Cancer
Altoona 150 mi
Vitamin D & Cancer 1179 healthy women aged 66.7 four year trial three treatment groups:
control (placebo) Ca (1400–1500 mg/d) Ca plus D3 (1100 IU/d)
baseline 25(OH)D: 72 nmol/L achieved 25(OH)D: 96 nmol/L
Lappe J et al
AJCN 2007
Vitamin D & Cancer
Time (yrs)
0 1 2 3 4 5
Frac
tion C
ance
r-Fr
ee
0.90
0.92
0.94
0.96
0.98
1.00
Ca+D
Placebo
Ca-only
72 nmol/L
96 nmol/L
Lappe J et al
AJCN 2007
UV-B & breast cancer mortality
UV-B Exposure (kJ/ m2)
3 4 5 6 7 8 9 10 11
Mort
ality
Rate
– U
S(c
ase
s/100,0
00/y
r)
14
16
18
20
22
24
26
28
30
32
34
36
US breast CA deaths (1970 – 1994) vs. solar UV exposure
Grant WB
Cancer 2002; 94:1867
Vitamin D & prostate cancer
13 yr longitudinal study
19,000 men 149 cases
prostate CA
Ahonen et al, 2000CancerCauses&Control 11:847-852
25(OH)D QUARTILES
1 2 3 4
RELA
TIVE
RIS
K
0.0
0.5
1.0
1.5
2.0
2.5
those below themedian 25(OH)D level were 70% more likely to develop prostate CA than those above
25(OH)D QUARTILES
1 2 3 4
RELA
TIVE
RIS
K
0.0
0.5
1.0
1.5
2.0
2.5
P for trend = 0.01
Ahonen et al, 2000CancerCauses&Control 11:847-852
Vitamin D & prostate cancer
Vitamin D & colon cancer
0.0
0.5
1.0
1.5
2.0
2.5
3.0
< 31 31–42 42–58 >58
Serum 25(OH)D (nmol/ L)
Odds Ratios of Colon CA
risk of incidentcolon CA, as afunction ofbaseline 25(OH)Din the Women’sHealth InitiativeStudy
P = 0.02
UV-B and cancer risk
“…relative immunity to cancer is a direct effect of sunlight…”
Apperly FLCancer Research Vol 1, No1 (1941)1934-1938 health statistics
CU ORC
40–70% 70–100% 100–130% 130–160% 160–190% 190–220%
Percent national average incidence:
Vitamin D and MS
37º N
modified from: http://mscenter.ucsf.edu/Vitamin D
Vitamin D & Influenza
0
5
10
15
20
25
30
35
Placebo Vitamin D
208 African-American postmenopausal women
3 yr DB-RCT placebo or vit D3
800 IU/d – 2 yrs 2000 IU/d – 3rd yr
BL 25(OH)D: 47 nmol/L
70%
0 25 50 75 100 125 150 (nmol/L)
Vitamin D & Blood
pressure
25(OH)D nmol/L
<50 >80
Age related change Blood press
ure
mm Hg/year
0.0
0.1
0.2
0.3
0.4
0.5
0.6
20% NHANES III
survey N=7,699 men
and women >18 years Non-
hypertensive
0 25 50 75 100 125 150 (nmol/L)
Copyright ©2008 American Society for Nutrition
Heaney RP J Nutr 2008;138:1591-1595
Vitamin D & disease risk
0 25 50 75 100 125 150
reference range “normal”
calcium absorption falls/neuromuscular
function multiple sclerosis fibromyalgia type I diabetes insulin sensitivity cardiovascular disease periodontal disease various cancers tuberculosis
??(nmol/L)
Vitamin D & disease risk
Prevention of rickets/
osteomalacia
0 25 50 75 100 125 150
Vitamin D & disease risk
Prevention of rickets/
osteomalacia
reference range “normal”
Optimal for Ca endocrine related functions
Reduced relative risk of
cancer
Lowered BP
Reduced flu
(nmol/L)
Reduced periodontal
disease
CU ORC25(OH)D (nmol/ L)
0 20 40 60 80 100 120 140
RELA
TIV
E F
REQ
UEN
CY
0.000
0.005
0.010
0.015
0.020
0.025
Prevalence of Vit. D deficiency
NHANES-III women aged 60–79 summer northern states
10%
77%
Looker et al., Bone 2002; 30:771–77
Nebraska women aged 55–79 adjusted year
round 41º N latitude
4%
68%
Vitamin D
Copyright ©2008 The American Society for Nutrition
Yetley EA AJCN 2008;88:558S-564S
Prevalence of Vit. D deficiency
0 25 50 75 100 125 150
Prevention of rickets/
osteomalacia
reference range “normal”
Life guards at end of summer
Eastern Nebraska &NHANES III white women aged 60+
Optimal for health related functions
Outdoor agricultural workers in the
tropics
NHANES III Black women
age 10+
Prevalence of Vit. D deficiency
(nmol/L)
Sources of vitamin D
?
?
?Body D3
stores 25(OH)D
Fish as a Vitamin D source
Vitamin D IU/ 3.5oz
0 200 400 600 800 1000 1200
0
1
2
3
4
5
6
Wild salmon
Farmed Salmon
Mahi
Cod
Haddock
Lu et al. JBMR 2006
Meat as a Vitamin D source
Vitamin D IU/ 3.5 oz.
0 20 40 60 80 100
0
1
2
3
4
Pork fat
Pork muscle
Beef
Armas et al. unpublished data
Milk as a Vitamin D source
Skim milk (Fat Free) 1% milk (Low Fat) 2% milk (Reduced Fat) Vitamin D (Whole milk)
Skim milk (Fat Free) 1% milk (Low Fat) 2% milk (Reduced Fat) Vitamin D (Whole milk)
HC HC–D+ UC UC–D+
200 IU/d * 68% 89% 20% 52%
400 IU/d † 16% 43% < 1% 1%
> 2000 IU/d (UL) 0 0 0 0
Cheese as a Vitamin D source ?
Percentage of 149teenage girls on High Calcium (HC) or Usual Calcium (UC) diets, who met the AI for Vit. D
* 1997 IOM Vitamin D AI† 2008 AAP Vitamin D recommendation for all children through age 18
D+ = Vitamin D content of diet if all dairy foods were fortified with vitamin D at the same level as fluid milk (100 IU vitamin D per 300 mg Ca)
Rafferty et al. unpublished data
Vitamin D Supplements
Combinations: Multi-vitaminsCa plus D Fosamax plus D (400 IU/d)
typical: 400 IU
Pure vitamin D3 (often hard to find)
1,000 IU Douglas Labs
Vitamin D Supplements
D2 vs. D3
single oral dose 50,000 IU D2 or D3
n = 10 in each group
TIME (days)
0 5 10 15 20 25 30
25(O
H)D
(nm
ol/
L)
-10
-5
0
5
10
15
20
25
Armas et al., 2004
D3
D2
Vitamin D and UV-B
sunlightAt risk for low vitamin D levels: Northern climates, winter months
Elderly
Dark skinned
Sunscreen users
House bound/nursing home
CU ORC
Vitamin D & latitude
37º N
modified from: http://mscenter.ucsf.edu/Vitamin D
41º N
No UV-B sunrays October – March
10 – 15 min/day sun exposure April – September
Vitamin D & latitude
26 male outdoor workers
41% body surface exposure for 38 hrs/wk for 14 wks
varying degrees of skin pigmentation
0
25
50
75
100
125
150
175
200
225
Late Latesummer winter
25(O
H)D
(nm
ol/
L)
Armas L. et al. 2007J Am Acad Dermatol 57:588.
Vitamin D and aging
TIME (days)
0 1 2 3 4 5 6 7
SERU
M D
3 (ng/m
L)
0
10
20
30
40Old Young
whole body exposure of 0.032J/cm2
(~1MED)
young: age 20–30old: age 62–80
Holick et alLancet 1989
Vitamin D and aging
AGE
0 20 40 60 80 100
7-D
EHYD
RO
CH
OLE
STER
OL
(g/6
.25 c
m2)
0
1
2
3
4
5
6
7
8
9
surgically obtained skin samples
Caucasian pts.
McLaughlin & HolickJCI 1985 76:1536–38
–50%
HOUV-A II UV light booth (National Biological Corp.)
72 males and females
19-49 yrs
Various skin tones
90% skin exposed to UVB 3x weekly for 4 weeks
Vitamin D and skin color
Vitamin D and skin color
Darker skinnedsubjects required twice as much UVB light to raise Vitamin D levels as lighter skinned subjects M
inut
es o
f Jul
y no
on s
un
0
10
20
30
40
50
60
70
Dark Light
Armas L. et al. 2007J Am Acad Dermatol 57:588
2 x
Vitamin D and sun-screen
Rise
in V
itam
in D
3 Co
ncen
tratio
ns
n
g/m
L
0
5
10
15
20
25
30
No SPF
SPF 8
95 %
SPF 8 reduces Vitamin D production by 95%
SPF 15 reduces Vitamin D production by 99%
Matsuoka JCEM 1987
WHO annual global disease burden due to UVR exposure
1.6 million Disability Adjusted Life Yrs due to UVR over exposure
Lucas RM
Int J Epidemiology 2008
3.3 billion Disability Adjusted Life Yrs due to UVR under exposure
x 2000
Vitamin D dose response
66 males aged 38.7 yr
( 11.2 ) dosed with
vit D3 from October – February
TIME (days)
0 20 40 60 80 100 120 140 160
25(O
H)D
(nm
ol/
L)
0
50
100
150
200
250 D3 dose (IU/d)
10,000
5,000
1,000 0
Ilahi M. et al 2008Am J Clin Nutr 87:688.
Vitamin D dose response
Time (days)
0 20 40 60 80 100 120
Seru
m 2
5(O
H)D
(nm
ol/
L)
60
70
80
90
100
110
Vitamin D3
100,000 IU by mouth one time
Ilahi M. et al 2008Am J Clin Nutr 87:688.
Vitamin D dose response
150 IU ↑ 25(OH)D levels ≈ 1 ng/ml
150 IU raises 25(OH)D ~ 2.5 nmol/L 1000 IU raises 25(OH)D ~ 17 nmol/L1500 IU raises 25(OH)D ~ 25 nmol/L2000 IU raises 25(OH)D ~ 33 nmol/L
Clinical Recommendations
Baseline values Dose62-80 nmol/L 1,000 IU/daily37-62 nmol/L 2,000 IU/daily< 37nmol/L 3,000 IU/daily
Safety at high doses
in our experiments, doses of 5,000–10,000 IU/d in healthy adults for 4–5 months have not:
elevated serum Ca elevated urine Ca
further, these doses reproduce 25(OH)D levels frequently found at end of summer in outdoor workers – at which levels no hyperabsorption of calcium occurs
Safety at high doses
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)
Seru
m 2
5(O
H)D
(nm
ol/
L)
15 studies of adultsreceiving vitamin Dsupplementation(means)
8 studies reportingtoxicity (individualvalues)
no toxicity below 500 nmol/L (200 ng/mL)
no toxicity below 30,000 IU/d
Safety at high doses
UL: 10,000 IU/d
Hathcock et al.,2007 AJCN 85:6–18
CONCLUSIONS
vitamin D sufficiency can no longer be defined as the mere absence of rickets vitamin D acts in multiple systems serum 25(OH)D levels below 80 nmol/L are not adequate for optimal health outcomes inputs from all sources combined (needed to sustain 80 nmol/L) are in the range of ~ 2,000 – 4,000 IU/dayAsk physician to include serum vitamin D with scheduled blood work
Thank You