1. Vitamin D: Tilting the Odds in your Favor Vitamin D: Tilting the Odds in your Favor Iowa Dietetic Association Annual Meeting November 5, 2009 Karen Rafferty, RD, LMNT Owner, Nutrition Science Resource DDD

2. Scope of presentation I.Skeletal and non-skeletal functions of vitamin D II.Optimal vitamin D status III.Treatment strategies: sources and amounts of vitamin D

3. 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)

4. 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

5. 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 20 ng/ml 30 ng/ml 10 ng/ml (nmol/L)

6. The function of vitamin D What 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?

7. Evidence base DiseaseStatus of Evidence osteoarthritis/RA falls/neuromuscular function multiple sclerosis fibromyalgia type I diabetes insulin sensitivity cardiovascular disease periodontal disease various cancers tuberculosis hypertension + ++++ ++ ++++ +++ ++

8. 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)

9. Vitamin D schemes 25(OH)D 3 D3D3 skin diet liver 1,25(OH) 2 D 3 gut CaAb kidney endocrine periphery 1,25(OH) 2 D 3 various tissues cell signals autocrine

11. 0 25 50 75 100 125 150 Vitamin D & Ca absorption +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)

12. 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

13. 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 usual laboratory reference range calcium absorption is suboptimal in the lower half of the reference range

14. 0 25 50 75 100 125 150 Vitamin D & fractures –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)

15. Vitamin D & falling –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

17.  1359 men & women; mean age 75.5  Amsterdam longitud. aging study  neuromuscular performance measured on a scale of 0 to 12 (higher is better) Wicherts et al. JBMR. 2005. Vit D & neuromuscular function 0 25 50 75 100 125 150 (nmol/L)

18. 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

19. Vit D & nursing home admissions Visser et al AJCN 2006:616-622

20. Visser, M. et al ACJN 2006: 616-622 Vitamin D & mortality

21. 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)

22. CU ORC 25(OH)D 3 D3D3 1,25(OH) 2 D 3 skinliver periphery gut CaBP Vit D – expanded scheme kidney 1,25(OH) 2 D 3 various tissues cell signals endocrine autocrine ~ 5% 85+%

23.  cell proliferation  cell differentiation  apoptosis  immune response  inflammation Vit D & autocrine functions

24. Autocrine action Transcription ~ 200 genes have VDREs VDRE 25(OH)D

25. Vitamin D & Cancer Altoona 150 mi

26. Vitamin D & Cancer  1179 healthy women  aged 66.7  four year trial  three treatment groups:  control (placebo)  Ca (1400–1500 mg/d)  Ca plus D 3 (1100 IU/d)  baseline 25(OH)D: 72 nmol/L  achieved 25(OH)D: 96 nmol/L Lappe J et al AJCN 2007

27. Vitamin D & Cancer 72 nmol/L 96 nmol/L Lappe J et al AJCN 2007

28. UV-B & breast cancer mortality US breast CA deaths (1970 – 1994) vs. solar UV exposure Grant WB Cancer 2002; 94:1867

29. Vitamin D & prostate cancer  13 yr longitudinal study  19,000 men  149 cases prostate CA Ahonen et al, 2000 CancerCauses&Control 11:847-852

30. those below the median 25(OH)D level were 70% more likely to develop prostate CA than those above P for trend = 0.01 Ahonen et al, 2000 CancerCauses&Control 11:847-852 Vitamin D & prostate cancer

31. Vitamin D & colon cancer risk of incident colon CA, as a function of baseline 25(OH)D in the Women’s Health Initiative Study P = 0.02

32. UV-B and cancer risk “…relative immunity to cancer is a direct effect of sunlight…” Apperly FL Cancer Research Vol 1, No1 (1941) 1934-1938 health statistics

33. 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

34. Vitamin D & Influenza  208 African-American postmenopausal women  3 yr DB-RCT  placebo or vit D 3  800 IU/d – 2 yrs  2000 IU/d – 3 rd yr  BL 25(OH)D: 47 nmol/L 70% 0 25 50 75 100 125 150 (nmol/L)

35. Vitamin D & Blood pressure 20%  NHANES III survey  N=7,699 men and women  >18 years  Non-hypertensive 0 25 50 75 100 125 150 (nmol/L)

36. Copyright ©2008 American Society for Nutrition Heaney RP J Nutr 2008;138:1591-1595 Vitamin D & disease risk

37. 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

38. 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

39. CU ORC 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

40. Copyright ©2008 The American Society for Nutrition Yetley EA AJCN 2008;88:558S-564S Prevalence of Vit. D deficiency

41. 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)

42. Sources of vitamin D ? ? ? Body D 3 stores 25(OH)D

43. Fish as a Vitamin D source Wild salmon Farmed Salmon Mahi Cod Haddock Lu et al. JBMR 2006

44. Meat as a Vitamin D source Pork fat Pork muscle Beef Armas et al. unpublished data

45. 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)

46. HCHC–D+UCUC–D+ 200 IU/d *68%89%20%52% 400 IU/d † 16%43%< 1% 1% > 2000 IU/d (UL)0000 Cheese as a Vitamin D source ? Percentage of 149 teenage 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

47. Vitamin D Supplements Combinations: Multi-vitamins Ca plus D Fosamax plus D (400 IU/d) typical: 400 IU Pure vitamin D 3 (often hard to find) 1,000 IU Douglas Labs

48. Vitamin D Supplements D 2 vs. D 3  single oral dose  50,000 IU  D 2 or D 3  n = 10 in each group Armas et al., 2004 D3D3 D2D2

49. Vitamin D and UV-B sunlight At risk for low vitamin D levels:  Northern climates, winter months  Elderly  Dark skinned  Sunscreen users  House bound/nursing home

50. 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

51. Vitamin D & latitude  26 male outdoor workers  41% body surface exposure for 38 hrs/wk for 14 wks  varying degrees of skin pigmentation Armas L. et al. 2007 J Am Acad Dermatol 57:588.

52. Vitamin D and aging  whole body exposure of 0.032J/cm 2 (~1MED)  young: age 20–30 old: age 62–80 Holick et al Lancet 1989

53. Vitamin D and aging  surgically obtained skin samples  Caucasian pts. McLaughlin & Holick JCI 1985 76:1536–38 –50%

54. 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

55. Darker skinned subjects required twice as much UVB light to raise Vitamin D levels as lighter skinned subjects DarkLight Armas L. et al. 2007 J Am Acad Dermatol 57:588 2 x

56. Vitamin D and sun-screen No SPFSPF 8 95 %  SPF 8 reduces Vitamin D production by 95%  SPF 15 reduces Vitamin D production by 99% Matsuoka JCEM 1987

57. 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

58. Vitamin D dose response  66 males  aged 38.7 yr (  11.2 )  dosed with vit D 3 from October – February D3 dose (IU/d) 10,000 5,000 1,000 0 Ilahi M. et al 2008 Am J Clin Nutr 87:688.

59. Vitamin D dose response  Vitamin D 3  100,000 IU  by mouth  one time Ilahi M. et al 2008 Am J Clin Nutr 87:688.

60. 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/L 1500 IU raises 25(OH)D ~ 25 nmol/L 2000 IU raises 25(OH)D ~ 33 nmol/L

61. Clinical Recommendations Baseline values Dose 62-80 nmol/L 1,000 IU/daily 37-62 nmol/L 2,000 IU/daily < 37nmol/L 3,000 IU/daily

62. 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

63. Safety at high doses no toxicity below 500 nmol/L (200 ng/mL) no toxicity below 30,000 IU/d

64. Safety at high doses UL: 10,000 IU/d Hathcock et al.,2007 AJCN 85:6–18

65. 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/day Ask physician to include serum vitamin D with scheduled blood work

66. Thank You