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1 서울대학교의과대학 가정의학과조희경

2 Contents Introduction Biological Mechanisms Epidemiologic Studies Randomized Controlled Trials Guidelines on vitamin D intake

4 Known and Unknowns WE KNOW Vitamin D is important < 20 ng/ml : deficient or insufficient Potentially harmful level: 150 ng/ml hypercalcemia, vascular soft tissue calcification, hyperphosphatemia UNKNOWNS? Optimal intake? Optimal blood 25(OH)D level?

5 Biological Mechanisms

7 Non-Skeletal Functions of Vitamin D N Engl J Med 2007; 357;3

8 Effects of Vitamin D Receptor(VDR) Activation on Tumorigenesis VDR: Vitamin D Receptor VDRE: Vitamin D Response Elements Vuolo L. Front Endocrinol 2012;3:58

9 Vuolo L. Front Endocrinol 2012;3:58

10 Manson JE. Contemporary Clinical Trials 2012;33:

11 Epidemiologic studies

12 GRANT WB. Anticancer Research 2006; 26: Colon cancer Breast cancer Prostate cancer NHL (Non-Hodgkin lymphoma) Pancreatic cancer Bladder cancer Kidney cancer Lung cancer Ovarian cancer Endometrial cancer Esophageal cancer Gastric cancer

13 Colorectal Cancer

14 Vitamin D Intake

15 Blood 25(OH)D Levels Ma Y. J Clin Oncol 2011;29:

Meta-regression Dose-Response Relationship Ptrend < 0.001 Per 10 ng/ml increment in blood 25(OH)D, RR = 0.74 (95% CI, 0.63-0.

16 Meta-regression Dose-Response Relationship Ptrend < Per 10 ng/ml increment in blood 25(OH)D, RR = 0.74 (95% CI, ) 50% projected reduction in CRC incidence with 33 ng/ml, compared to 12 ng/ml Ma Y. J Clin Oncol 2011;29: Gorham ED. Am J Prev Med 2007;32(3):

17 Colorectal CancerMortality Adjusted cumulative incidence curve of CRC-specific mortality by prediagnostic 25(OH)D levels in the EPIC cohort Fedirko. Cancer EpidemiolBiomarkers Prev 2012; 21(4)

18 CRC and Overall Mortality CRC: Colorectal Cancer Fedirko. Cancer EpidemiolBiomarkers Prev 2012; 21(4)

19 Summary of Colorectal Cancer in epidemiologic studies Consistently inverse relationship Between vitamin D levels and CRC risk or mortality

20 Breast Cancer

21 Relative Risks of Breast Cancer per 1 ng/ml Increase in Serum 25(OH)D CC: Case-Control study Co: Cohort study NCC: Nested Case Control study within a prospective cohort study Gandini S. Int. J. Cancer 2011; 128:

22 prospective nested case-control study within the Nurses Health Study II 613 cases vs. 1,218 matched controls Relative Risks (95% CI) of Breast Cancer by Quartile of Pre-diagnostic Plasma 25(OH)D Eliassen AH. Breast Cancer Research 2011;13:R50

23 Summary of Breast Cancer in epidemiologic studies Inconsistent relationship

24 Other Cancers

25 Relative Risks of Prostate Cancer per 1 ng/ml Increase in Serum 25(OH)D Gandini S. Int. J. Cancer 2011; 128:

26 A pooled nested case-control study (the Cohort Consortium Vitamin D Pooling Project of Rarer Cancers) Kidney cancer non-hodgkin lymphoma Upper GI cancers pancreatic cancer Endometrial cancer ovarian cancer Am J Epidemiol 2010;172:4 9

27 Limitations in Observational Studies Single serum 25(OH)D measurement at atime of enrollment CANNOT representlong-term vitamin D levels In large-scale epidemiological studies For whole population multiple measurement of blood 25(OH)D for a long-term period might be UNFEASIBLE Predicted 25(OH)D scores Combined influences of major determinants of circulating 25(OH)D Can be used in a large population without blood samples Can be updated multiple times during follow-up

28 Derivatives of predicted plasma 25(OH)D score Race UV-B radiation flux at residence Leisure-time physical activity Body mass index Dietary and supplemental vitamin D intakes Alcohol intake Post-menopausal hormone use (in women) NatlCancer Inst2013; Apr 8 [Epub]

29 METHODS STUDY POPULATION - Two independent prospective cohorts in the US 72,051 women (Nurses Health Study) 46,380 men (Health Professionals Follow-Up Study) Follow-up : (22 years) Predicted 25(OH)D score & all covariables: updated every 2 years No. of incident RCC cases 201 cases in women 207 cases in men

30 Predicted Plasma 25(OH)D and Risk of Renal Cell Cancer per 10 ng/ml increment in 25(OH)D HR = 0.66 ( ) Joh HK. J NatlCancer Inst 2013; Apr 8 [Epub]

31 Vitamin D Intake and Risk of Renal Cell Cancer Joh HK. J NatlCancer Inst 2013; Apr 8 [Epub]

32 RCTs NoRCT in vitamin D has been completed with canceras the pre-specified primary outcome. - All evidence are from secondary analyses

33 Am J Clin Nutr 2007;85: Population & Follow-up 1179 postmenopausal women aged >55 y followed 4 years Intervention Ca-only : mg/d Calcium Ca+ D : mg/d Calcium IU/d cholecalciferol Placebo Outcome variables Primary outcome: fracture incidence Secondary outcome: total cancer incidence

34 P = 0.01 P < P = 0.06 P = 0.06 Lappe JM. Am J Clin Nutr 2007;85:

Women s Health Initiative (WHI) Study 1994-1999 (average 7 years) in the US postmenopausal women (50-79y) HT: Hormone Therapy DM: Dietary Modification CaD: Calcium + Vitamin D supplementation CT:

35 Women s Health Initiative (WHI) Study (average 7 years) in the US postmenopausal women (50-79y) HT: Hormone Therapy DM: Dietary Modification CaD: Calcium + Vitamin D supplementation CT: Clinical Trial OS: Observational Study CaDsupplementation: in 36,282 women -18,176 received 1000 mgof elemental calcium and 400 IU of vitamin D3 daily - 18,106 received placebo - Primary outcome: hip fracture - Secondary outcome: total fracture and colorectal cancer

36 Critics of WHI study - LOW dosage of vitamin D supplementation (400 IU/d) - More than half (57%) of the participants were taking personal calcium or vitamin D supplements at randomization - Poor adherence : - 1/3 of the intervention group did not take supplements. - Off-study use of additional vitamin D and calcium supplements during the trial in placebo group minimize the difference between placebo and supplement - Lack of blood 25-(OH)D measurement - No regular or end-of-study colonoscopy - 15% had no bowel assessment - Short length of follow-up

37 Colorectal Cancer WHI study

38 RCT Effect of CaD supplementation? Colorectal cancer: secondary outcome A Cox proportional hazards model Nested Case-Control Study Effect of Baseline serum 25(OH)D levels? 306 cases 306 controls logistic regression model

39 HR 1.08 (95% CI, ) P=0.51

Odds Ratios for Invasive Colorectal Cancer by the Quartile of

baseline serum 25(OH)D levels However, findings from the nested case

40 Odds Ratios for Invasive Colorectal Cancer by the Quartile of Baseline Serum 25(OH)D Level in a Nested Case Control Study P for trend = 0.02 P for interaction = 0.54 Significantly increased risk of colorectal cancer in the lower baseline serum 25(OH)D levels However, findings from the nested case control study revealed no significant interaction between serum 25(OH)D levels at baseline and treatment assignment.

41 Breast cancer WHI ChleboswskiRT. J NatlCancer Inst 2007; 100: RCT Effect of CaD supplementation? Nested Case-Control Study Effect of Baseline serum 25(OH)D levels? 1067 cases 1067 controls

42 Cumulative Hazard Ratio for Invasive Breast Cancer with Supplemental Calcium + Vitamin D HR, 0.96 (95% CI, )

43 Subgroup Analysis P interaction = Chleboswski RT. J Natl Cancer Inst 2007; 100:

44 Baseline Serum 25(OH)D Levels Baseline 25(OH)D levels were not associated with subsequent breast cancer risk Chleboswski RT. J Natl Cancer Inst 2007; 100:

45 Invasive Cancer WHI Study Invasive cancer incidence HR (95% CI) Total cancer 0.98 ( ) Breast 0.96 ( ) Colon 0.98 ( ) Cancer mortality HR (95% CI) Total cancer 0.90 ( ) Brunner RL. Nutrition and Cancer 2011; 63(6):

46 Calcium and Vitamin D Supplements and Health Outcomes: a Reanalysis of the WHI limited-access data set Among 15,646 women who were NOTtaking personal calcium or vitamin D supplements at baseline. Bolland, MJ. Am J Clin Nutr 2011;94:

47 Prentice, R. L. Osteoporos Int 2013;24:

48 Hazard ratios (95% confidence intervals) for Invasive Cancer in the WHI CaD trial and Observational Study Prentice, R. L. Osteoporos Int 2013;24:

49 Hazard ratios (95% confidence intervals) in the WHI CaD trial among Adherent Women Prentice, R. L. Osteoporos Int 2013;24:

50 1 st RCT for the primary prevention of cancer & CVD 20,000 healthy men ( 50yrs) and women ( 55yrs) in the US 2,000 IU/day of vitamin D3 1 g/day of marine omega-3 fatty acids For 5 years Contemporary Clinical Trials 33 (2012)

52 Limitations in RCTs 1. Generalizability 2. Low power 3. Single dose or a limited set of doses 4. Contamination between intervention and placebo group

53 Guidelines

54 Optimal serum 25OHD level: 30 ng/ml Efficacy of doses Fractures : 800 IU/day Falls : 1,000 IU/day Recommended dose for older adults: 800-1,000 IU/d

20 3,000 9 70 yrs 600 20 4,000 >70 yrs 800 20 4,000 RDA:

55 Vitamin D DRIs (Dietary Reference Intakes) Age RDA (IU/day) Serum 25(OH)D level (ng/ml)* UL (IU/day) 1 3 yrs , yrs , yrs ,000 >70 yrs ,000 RDA: Recommended Dietary Allowance UL: Upper Level Intake *Corresponding to the RDA

Optimal 25(OH)D : 40 60 ng/ml 600 IU/d will raise and maintain blood concentrations of 25(OH)D > 20 ng/ml, but <30

57 Optimal 25(OH)D : ng/ml 600 IU/d will raise and maintain blood concentrations of 25(OH)D > 20 ng/ml, but <30 ng/ml Recommended doses Children: 400 1,000 IU/d Adults: 1,500 2,000 IU/d J Clin Endocrinol Metab 2011;96:

58 Summary Most evidence for vitamin D and cancer is derived from laboratory studies, ecologic correlations, observational associations, and secondary analysis of RCTs. New trials assessing moderate-to-high dose vitamin D supplementation for cancer prevention are in progress.

한국성인에서초기황반변성질환과 연관된위험요인연구

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