Fortification with Vitamin DFortification with Vitamin D

Edward Giovannucci, MD, ScD

Vitamin D

Sunlight(UV-B) Diet

Liver

25(OH) Vitamin D

[Ca ++] PTH Kidney1-OHase

Other cells1-OHase

1,25(OH)2D 1,25(OH)2D

Calcium PhosphorusHomeostasis(Endocrine)

Other Functions(Paracrine,Autocrine)

Diseases Potentially Related to

Vitamin D Deficiency:

• Rickets • Osteomalacia• Osteoporosis / fractures• Muscle weakness / falls

Evidence Compelling:

• Some cancers • Multiple sclerosis• Other autoimmune diseases• Some infections / TB

Evidence Strong:

• CVD • Asthma• Congestive heart failure• Periodontitis• High Blood pressure• Type 2 diabetes mellitus

Some Suggestive Evidence:

• 25(OH) vitamin D is best indicator• Bone health is currently clearest endpoint• Examine intakes required to achieve

a specific 25(OH)D level

How Much Vitamin D is Required

For Optimal Health?

• Suppressing maximally PTH

• Bone mineral density

• Calcium absorption

• Rate of bone loss

• Fracture risk

• Risk of falling

Criteria for Bone Health

Holick MF et al., J Clin Endocrinol Metab 2005

Vitamin D and PTH

Heaney RP et al., J Am Coll Nutr 2003

With 25OHD Without 25OHD

P

N 24 24

Serum 25(OH)D (nmol/L) 85.5 24.0 50.2 15.7 <0.001

Baseline serum Ca (mg/dL) 9.64 0.33 9.31 0.34 <0.002

Incremental AUC9 Ca (mg ·hr/dL) 3.63 1.15 2.20 1.18 <0.001

Baseline serum PTH (pg/mL) 36.9 13.7 43.0 13.3 NS

Incremental AUC10 PTH (pg ·hr/mL) 116.0 79.5 103.1 79.9 NS

Serum Ca AUC and Related Variables

Heaney RP et al., J Am Coll Nutr 2003

Time course of the mean increment in serum total calciumin two studies. In one, vitamin D status was elevated (D+),and in the other, it was not (D–).

Forest Plots Comparing the Risk of Fallingbetween Vitamin D-Treated Groups and Control Groups

for the Primary Analysis

Bischoff-Ferrari, H. A. et al. JAMA 2004

Hip and Nonvertebral Fracture Efficacies by Achieved 25-Hydroxyvitamin D Levels

in 400 IU/d and 700-800 IU/d Vitamin D-Treated Groups

Bischoff-Ferrari, H. A. et al. JAMA 2005

Colorectal Cancer: Serum 25(OH)D Studies

Garland C. et al., 2006

0.1 1.0 10.0Odds ratio (highest vs. lowest quintile) and 95% confidence interval

Garland 1989

Braun

Tangrea 1996

Feskanich 2004

p < 0.0001

Pooled odds ratio = 0.49

Wactawski-Wende 2006

0.89

1.32

0.62

0.32

1.00

0.66

0.35

0.0

0.2

0.4

0.6

0.8

1.0

1.2

1.4

Q1 Q2 Q3 Q4

NHS, HPFS Combined CasesSeason of Blood Draw

Mul

tivar

iabl

e R

R

Season-Specific 25(OH) Vitamin D Quartile

Summer

Winter

Wu, K., Submitted.

P trend = 0.26

P trend <0.001

Author, year, references Vitamin D Intake for 50% risk reduction

(IU/Day)

p for trend

Garland et al., 1985 (50) 480 0.05

Bostick et al., 1993 (51) 1000 0.02

Kearney et al., 1996 (52) 770 0.02

Martinez et al., 1996 (53) 800 0.04

Pritchard et al., 1996 (54) 430 0.08

Marcus et al., 1998 (55) 1000 0.05

McCollough et al., 2003 (4) 600 0.02

LaVecchia et al., 1997 (56) 475 0.01

Vitamin D Oral Intake Associated with50% Reduction in Risk of Colorectal Cancer

Observation Studies, 1985-2005

Gorham ED et al., J Steroid Biochem Mol Biol 2005

BMD (g/cm2)

0

0.5

1

0

0.5

1

-0.5

-0.4

-0.3

-0.2

-0.1

0

0.1

30 50 70 90 110

-0.5

-0.4

-0.3

-0.2

-0.1

0

0.1

30 50 70 90 110

Median 25-OHD

Fracture (RR)

Colon Cancer (RR)

8’ Walk (sec)

AttachmentLoss (mm)

0.02

0.04

g/cm2

sec ormm

RR 0

• Living in the North

• Dark skin pigmentation

• Old age

• Obesity

• Avoidance of sun

• Low intake

• Various medical conditions

• Clothing practices

Risk Factors for Hypovitaminosis D

Photosynthesis of precholecalciferol (previtamin D3)at various times on cloudless days in Boston

in October () and July ().

Holick MF. Am J Clin Nutr 1994

Effect of month of year on mean 25(OH)D levels (upper panel),

and the percentage prevalence of vitamin D insufficiency.

Vieth R et al., Eur J Clin Nutr 2001

• Increase sunlight exposure

• Increase natural food sources

• Supplementation

• Fortification

Approaches To Increase Vitamin D

Sun Exposure RecommendationsNeed to Account For:

region

season

time of day

% exposed skin

length of exposure

skin pigmentation

prevention of sun burn

prevention of skin cancer

use of sun screen

Adult Dietary Reference Intake (U.S.)

Ages

19–50 y 200 IU / day

51–70 y 400 IU / day

70 y 600 IU / day

The points represent the mean values, and error bars are 1 SEM. The curves are the plot of Equation 1, fitted to the mean 25(OH)D3 values for each dosage group.

The curves, from the lowest upward, are for 0, 25, 125, and 250 µg cholecalciferol (labeled dose)/d. The horizontal dashed line reflects zero change from baseline.

Time Course of Serum 25(OH)D Concentrationfor 4 Dosage Groups

Heaney RP et al., Am J Clin Nutr 2003

Regression of the Equilibrium Increment ()in Serum 25(OH)D3 Concentration

for the Means of Each Treatment Group

Heaney RP et al., Am J Clin Nutr 2003

• Increase sunlight exposure

• Increase natural food sources

• Supplementation

• Fortification

Approaches To Increase Vitamin D

Supplementation

• Most supplements have 400 IU

• Many supplements have D2 instead of D3

• Manufacturers hesitate to vitamin D because T.U.L. is 2000 IU/day

Fortification

Calvo MS & Whiting SJ, J Nutr, 2006

Serum 25(OH)D concentration (nmol/L) by intake category for African American (dark bars) and white (gray bars) women. Intake categories: none = reference (lowest response in any reference category); milk = >3 servings/wk; cereal = >3 servings of fortified cereal/wk; supple. = daily intake of supplement containing 400 IU/d

Vitamin D has been approved by the FDA in recent years as a nutrient supplement in

calcium fortified fruit juice and fruit juice drinks under 21 CFR Part 172.380, and

these are also now being used for calcium and Vitamin D nutrient enrichment to

increase intake in the U.S. population. We applaud such increased diversity of food

enrichment. However, we strongly suggest that cereal grain products be added to

the list, as a group of very reliable nutrient carriers, little prone to permit excess

intake, safe and simple to use, low cost, very broadly consumed and well distributed

in the general population. This group of foods is widely consumed across wide

variations of ethnic, cultural and age differences in the U.S.

Docket #2006P-0205/CP1May 12, 2006

Our choice of cereal grain products for enrichment as a vehicle to increase calcium

intake in the U.S. is guided by the following:

1. Approximately one fourth of the daily calorie intake in the U.S. is from cereal

grain products, and the intake of total cereal grain products does not vary greatly

by income or geographic region in the U.S.

2. Cereal grain product enrichment has been historically credited for (essentially)

the eradication of pellagra by niacin enrichment in the U.S. . . . More recently,

addition of folic acid (I.e. folate) to cereal grain enrichment has significantly

reduced neural tube defects in newborns in the U.S.

Docket #2006P-0205/CP1May 12, 2006

Section and Para. Nos.

Title Current Statement of Vitamin D Proposal: Shall

Contain Vitamin D

136.115 Enriched bread, rolls, and buns None 90 IU / 100g

137.160 Enriched bromated flour None 90 IU / 100g

137.165 Enriched flour None 90 IU / 100g

137.185 Enriched self-rising flour None 90 IU / 100g

137.260 Enriched corn meals May contain 250-1000 IU vitamin D/lb 90 IU / 100g

137.305 Enriched farina May contain 250 IU vitamin D/lb 90 IU / 100g

137.350 Enriched rice May contain 250-1000 IU vitamin D/lb 90 IU / 100g

137.115 Enriched macaroni products May contain 250-1000 IU vitamin D/lb 90 IU / 100g

139.117 Enriched macaroni products with fortified protein

None 90 IU / 100g

139.122 Enriched nonfat milk macaroni products

None 90 IU / 100g

139.135 Enriched vegetable products May contain 250-1000 IU vitamin D/lb 90 IU / 100g

139.155 Enriched noodle products None 90 IU / 100g

139.165 Enriched vegetable noodle products

May contain 250-1000 IU vitamin D/lb 90 IU / 100g

Selected Parts of the U.S. Code of Federal Regulations (2001),Title 21, Sections 136, 137, and 139, That Relate to Calcium and Vitamin D

Year 2000 Per Capita Vitamin D Enrichment Annual Daily Amount Daily Intake Item lb lb I.U. / lb I.U.

Wheat flour & products 137 0.375 400 I.U. 150 Corn flour and meal 16.1 0.044 400 I.U. 18 Pastas (macaroni, noodles, etc: semolina and durum flour

13 0.036 400 I.U. 14

Rice 20 0.055 400 I.U. 22 Total -- 0.51 -- 204

Estimated Increased Daily Intake of Vitamin D

from Major Cereal Grain Product Foods,

If Current Optional Enrichment Regulation

Became Mandatory (USDA Data, 1997)

USDA, Economic Research Service, Food Consumption Data System 2005

Calvo MS & Whiting SJ, J Nutr, 2006

The Nutrition Facts panel from

a new type of dietary supplement

showing the highest vitamin D content

of a dietary supplement to date.

Calvo MS & Whiting SJ, J Nutr, 2006

• Cost

• Stability

• Objections by

vegetarians (D3)

• Toxicity

Fortification: Practical Issues

Women’s Health Initiative Trial

400 IU Vitamin D + 1000 mg Calcium

Risk of Kidney Stones:

Treatment Placebo449 381

18,176 18,106

RR = 1.17 (CI, 1.02-1.34)