Vitamin D Requirements

1. 1
Vitamin D Requirements
and Setting
Recommendations
Elizabeth A. Yetley, Ph.D.
Sr. Nutrition Research Scientist (Retired)
Office of Dietary Supplements
National Institutes of Health, USA

2. Nature of Nutritional Risk
RISK
High
Low
Adequate and safe intakes
INTAKE 2

3. U.S. Dietary Reference Intakes
Institute of Medicine
RISK
High
Low
EAR RDA UL
AI??
INTAKE 3

4. 4
Decision-Making Steps*:
A Systematic Approach
1. Outcome Identification
(Literature Review)
2. Dose-Response
Assessment
( € Ref. Value)
3. Intake Assessment
(Prevalence of Intakes
Outside Ref. Value)
4. Risk Characterization
(Public Health Implications)
*Based on nutrient risk assessment models (WHO, 2006)

5. Step 1: Outcome (Endpoint)
Identification
Exposure:
Intakes + UVB
25(OH)D
Concentrations
Health Outcomes:
Functional, Clinical
Endpoint Identification
5

6. Health Outcome Identification --
6
Ideal
■ Evidence: Causal relationship
• Nutrient intake € outcome
■ Most protective of public health:
• Is:
■ Adequacy: Endpoint with a relatively high intake
level
■ Safety: Endpoint with a relatively low intake level
• May Not Be:
■ Severity of adverse effect
■ Endpoint with the strongest evidence
■ May differ by life stage group

7. Possible Outcomes of Adequacy
7
for Consideration 2008-2010
■ Growth
■ Cardiovascular health
■ Cancer
■ Immunological outcomes
■ Pregnancy-related outcomes
■ Bone health
■ Hypertension and blood pressure
■ Obesity

8. “Indicators” Used for 1997 DRIs –
8
Real World
■ Adequacy
• Infants:
■Human milk levels, serum 25(OH)D, linear
growth, bone mass
• Children and adults ≤ 50 y:
■ Serum 25(OH)D <27.5 nmol/L (11ng/ml)
• Adults > 50 y:
■Serum 25(OH)D <27.5 nmol/L (11ng/ml)
■Bone loss

9. Possible Endpoints of Safety for
9
Consideration 2008-2010
■ Hypercalcemia and hypercalciuria
■ Renal stones
■ ↑ risk of some cancers (e.g., pancreatic
cancer)

10. “Indicators” Used for 1997 DRIs –
10
Real World
■ Safety
• Infants:
■Retarded linear growth
• All others:
■Serum calcium >2.75 nmol/liter (11 mg/dl)

11. 11
Decision-Making Steps*:
A Systematic Approach
1. Outcome Identification
(Literature Review)
2. Dose-Response
Assessment
( € Ref. Value)
3. Intake Assessment
(Prevalence of Intakes
Outside Ref. Value)
4. Risk Characterization
(Public Health Implications)
*Based on nutrient risk assessment models (WHO, 2006)

12. Step 2: Dose-Response
Relationships
Exposure:
Intakes + UVB
25(OH)D
Concentrations
Health Outcomes:
Functional, Clinical
Dose Response
Dose Response
12

13. Challenges: Deriving Dose-
13
Response Relationships
■ Measurement challenges:
• Exposure = sun + diet
• 25(OH)D varies by assay
• Studies limited in number of doses used
• Time to detect many outcomes
■ Evidence + Scientific Judgment

14. Dose-response Relationships:
14
Unstudied Groups
■ Limited or no data for some life-stage
groups – but need DRIs
• Use scientific judgment to extrapolate from
studied groups
■ Examples of 1997 U.S. AI extrapolations:
• Children 1-8 y -- data from:
■ Slightly older children
■ Different continents
• Adult males:
■ Data from women
• Lactation:
■ Data from nonlactating women

15. Dose-response Relationships:
15
Unstudied Groups
■ Examples of 1997 ULs:
• Children 1-18 yr:
■Used adult UL
• Pregnancy and lactation:
■Used adult UL

16. 1997 DRIs
All persons ≥ 1 y
Adequate Intake*
200 IU (5 µg)
400 IU (10 µg)
600 IU (15 µg)
Upper Limit
2000 IU (50 µg)
Group
7 mon – 50 y
51-70 y
>70 y
*Used AI instead of EAR/RDA because of limited information on sun expo1s6ure

17. 17
Decision-Making Steps*:
A Systematic Approach
1. Outcome Identification
(Literature Review)
2. Dose-Response
Assessment
( € Ref. Value)
3. Intake Assessment
(Prevalence of Intakes
Outside Ref. Value)
4. Risk Characterization
(Public Health Implications)
*Based on nutrient risk assessment models (WHO, 2006)

18. 18
Step 3: Intake and Status
Assessments
■ Meets user needs – how to use the
reference intake values in policy and
other applications?
■ What is the prevalence of intakes
and 25(OH)D concentrations:
• < DRIs for adequacy?
• > ULs for safety?
• By life-stage group?

19. 0
80
60
40
20
100
1-5 y* 6-11 y 12-19 y 1-5 y* 6-11 y 12-19 y
<27.5 nmol/L <50 nmol/L <75 nmol/L
Percent
Children with serum 25OHD < selected
cutpoints (NH 2000-2004)
Males Females
**
**may be statistically unreliable; relative standard error > 30%
*Data for age 1-5 available from NHANES 2003-04 only
** **

20. 20
Decision-Making Steps*:
A Systematic Approach
1. Outcome Identification
(Literature Review)
2. Dose-Response
Assessment
( € Ref. Value)
3. Intake Assessment
(Prevalence of Intakes
Outside Ref. Value)
4. Risk Characterization
(Public Health Implications)
*Based on nutrient risk assessment models (WHO, 2006)

21. Step 4: Risk Characterization
21
■ Taking into account the:
• Prevalences for low and high intakes and
25(OH)D concentrations, and
• DRI values for adequate and safe intakes
• Across all life-stage groups
• What is the nature of the public health
concerns (if any)?
■ What other groups warrant special
concern?
• How to apply DRI values for special groups?

22. Groups Warranting Special
22
Attention in 1997 DRIs
■ Persons or conditions that may require
intakes > AI:
• Persons with ↓ skin production of Vit. D3:
■ Older
■ Limited sun exposure
■ Darker skin pigmentation
■ Use of sunscreens
• Conditions causing malabsorption
• Medications that interfere
■ Glucocorticoids
■ Seizure control medications

23. 23
DRI Applications
Planning Assessment
Groups EAR or AI EAR*
UL UL
Individuals RDA or AI EAR or AI
UL UL
*If AI is reference intake of adequacy, group status
assessments can not be made.

24. 24
Reference Intakes for Nutrients
RISK
High
Low
INTAKE
EAR RDA UL
AI??
Can’t use for group status assessments
Planning
for individuals
Group planning
& assessment

25. Next Steps: U.S. DRIs for Vitamin D
■ Current Institute of Medicine Committee
• http://www.iom.edu/en/Activities/Nutrition/DRIVit
DCalcium.aspx
■ Reviewing Vitamin D and calcium
■ Systematic reviews:
• 2007 -– Effectiveness and Safety of Vitamin D
in Relation to Bone Health
http://www.ahrq.gov/clinic/tp/vitadtp.htm
• 2009 -- Vitamin D and Calcium: Systematic
Review of Health Outcomes
http://www.ahrq.gov/clinic/tp/vitadcaltp.htm
■ Publication date: May 2010
25

26. Possible Outcomes: New DRIs
26
■ Confirmation of previous values
• ± confidence
■ Change from AI € EAR/RDA
■ Change values based on:
• New endpoints
• Better data on Dose-response relationships
• New data to replace extrapolations for
unstudied groups
■ Some combination of the above

27. EXTRA SLIDES
27

28. Characteristics of
28
Nutrient Reference Values
■ Maintenance of nutritional status
• Safe and adequate intakes
• Not: treatment
■ Apparently healthy population
• Not diseased population
■ Health promotion and disease risk
reduction
• Primary prevention for disease risk (↓ incidence)
• Not: ↓ severity without ↓ incidence
■ Dose-response relationships
• Not effect size

29. Process € Reference Intakes
29
■ Scientific Review:
• Qualified experts
• Comprehensive scientific review +
• Expert scientific judgment
■ Free of vested interests:
• Food industry
• Government policy-makers
• Consumer advocacy groups

30. Process € Reference Intakes
30
■ No reference value: not an option
• Consensus regarding “essentiality”
• Uncertainties € “optimal” intakes
• Adverse public health consequences if
no reference value
■ Decision-making process:
• Systematic and transparent
• Document, document, document

31. DRI Reference Intake Values
31
of Adequacy: U.S.
■ EAR:
• Estimated Average Requirement
• Meet requirements of half of healthy persons
■ RDA
• Recommended Daily Allowance
• Meet requirements of nearly all
• Derived from EAR
■ Adequate Intake
• Adequate Intake
• Assumed to be adequate
• Used when insufficient data for EAR/RDA

32. DRI Reference Intake Values
32
for Safety: U.S.
■ UL:
• Tolerable Upper Intake Level
• Highest intake likely to pose no risk