1. Fortification with Vitamin D Edward Giovannucci, MD, ScD

2. Vitamin D Sunlight (UV-B) Diet Liver 25(OH) Vitamin D  [Ca ++]   PTH  Kidney 1  -OHase Other cells 1  -OHase 1,25(OH) 2 D Calcium Phosphorus Homeostasis (Endocrine) Other Functions (Paracrine, Autocrine)

3. 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:

4. 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?

5. Suppressing maximally PTH Bone mineral density Calcium absorption Rate of bone loss Fracture risk Risk of falling Criteria for Bone Health

6. Holick MF et al., J Clin Endocrinol Metab 2005 Vitamin D and PTH

7. Heaney RP et al., J Am Coll Nutr 2003 Serum Ca AUC and Related Variables

8. Heaney RP et al., J Am Coll Nutr 2003 Time course of the mean increment in serum total calcium in two studies. In one, vitamin D status was elevated (D+), and in the other, it was not (D–).

9. Forest Plots Comparing the Risk of Falling between Vitamin D-Treated Groups and Control Groups for the Primary Analysis Bischoff-Ferrari, H. A. et al. JAMA 2004

10. 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

11. Colorectal Cancer: Serum 25(OH)D Studies Garland C. et al., 2006 0.11.010.0 Odds 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

12. NHS, HPFS Combined Cases Season of Blood Draw Multivariable RR Season-Specific 25(OH) Vitamin D Quartile Summer Winter Wu, K., Submitted. P trend = 0.26 P trend <0.001

13. Vitamin D Oral Intake Associated with 50% Reduction in Risk of Colorectal Cancer Observation Studies, 1985-2005 Gorham ED et al., J Steroid Biochem Mol Biol 2005

14. BMD (g/cm2) Median 25-OHD Fracture (RR) Colon Cancer (RR) 8’ Walk (sec) Attachment Loss (mm) 0.02 0.04 g/cm2 sec or mm RR 0

15. 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

16. Photosynthesis of precholecalciferol (previtamin D 3 ) at various times on cloudless days in Boston in October ( ) and July (  ). Holick MF. Am J Clin Nutr 1994

17. 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

18. Increase sunlight exposure Increase natural food sources Supplementation Fortification Approaches To Increase Vitamin D

19. Sun Exposure Recommendations Need 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

20. Adult Dietary Reference Intake (U.S.) Ages 19–50 y200 IU / day 51–70 y400 IU / day  70 y600 IU / day

21. 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)D 3 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 Concentration for 4 Dosage Groups Heaney RP et al., Am J Clin Nutr 2003

22. Regression of the Equilibrium Increment (  ) in Serum 25(OH)D 3 Concentration for the Means of Each Treatment Group Heaney RP et al., Am J Clin Nutr 2003

23. Increase sunlight exposure Increase natural food sources Supplementation Fortification Approaches To Increase Vitamin D

24. Supplementation Most supplements have 400 IU Many supplements have D 2 instead of D 3 Manufacturers hesitate to  vitamin D because T.U.L. is 2000 IU/day

25. Fortification

26. 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

29. 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/CP1 May 12, 2006

30. 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/CP1 May 12, 2006

31. 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

32. 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

33. Calvo MS & Whiting SJ, J Nutr, 2006

34. 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

35. Cost Stability Objections by vegetarians (D3) Toxicity Fortification: Practical Issues

36. Women’s Health Initiative Trial 400 IU Vitamin D + 1000 mg Calcium Risk of Kidney Stones: TreatmentPlacebo 449381 18,17618,106 RR = 1.17 (CI, 1.02-1.34)