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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)