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