1/31/2011. Dietary Reference Intakes. for Vitamin D: the Evidence, Challenges and Implications

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1 Dietary Reference Intakes (DRI) for Vitamin D: the Evidence, Challenges and Implications IOM Committee to Review Dietary Reference Intakes for Vitamin D & Calcium Patsy M. Brannon Graduate Field of Nutrition Seminar January 24, 2011 A Brief History of Today s DRI s Recommended Dietary Allowances (RDA s_ first issued by National Academies of Science in 1941 o in response to request from Roosevelt Administration to recommend levels of intake of essential nutrients to maintain health of the U.S. population. Issued regularly through 1989 as National Research Council reports from Food and Nutrition Board. Food & Nutrition Board moved to the Institute of Medicine and in 1990 s the DRI s replace RDA s First issued DRI s in 1997 Adapted & used with permission from L. Meyers, IOM-FNB IOM-FNB Institute of Medicine Dietary Reference Intakes Institute of Medicine Dietary Reference Intakes High High RISK of Adverse Outcome AI?? EAR RDA UL RISK of Adverse Outcome AI?? EAR RDA UL Adequate and safe intakes for healthy population Low Low INTAKE INTAKE 3 Used with permission from E. Yetley, NIH-ODS 4 Used with permission from E. Yetley, NIH-ODS High RISK of Adverse Outcome Low Institute of Medicine Dietary Reference Intakes Likely Inadequate for healthy population AI?? EAR RDA UL Adequate and safe intakes for healthy population INTAKE 5 Used with permission from E. Yetley, NIH-ODS DRI s: Impact & Use Part of science standard for federal nutrition guidance HHS/USDA Dietary Guidelines for Americans USDA MyPyramid Health Canada Canadian Food Guide Statutory or De Facto standard for virtually all food programs 4 official USDA food plans Food stamp allotments/wic food packages DOD service members Standard of comparison for USDA review of food distribution programs on Indian Reservation Assessing risk for food fortification levels by Health Canada and fortification goals by FAO/WHO Fortification Guidelines Adapted & used with permission from L. Meyers, IOM-FNB IOM-FNB 1

2 Why Revisit DRI for Vitamin D Now? DRI s established 1997 AI & UL Policy Decision-making Process Vitamin D New Evidence since 1996 Conflicting Experts Disagree Science Feasibility Scientific Evidence after 1996 until % of current evidence relating 25(OH)D to health outcomes Some health outcomes (falls and performance measures in older adults and non-bone health) not considered by the 1997 DRI Committee Policy Decision-Making Process Food and Nutrition Board IOM Stakeholders: Legal Framework: Industry Consumers Costs Politicians Academics Sister agencies Policy Yetley EA et al. Am J Clin Nutr 2009;89: Policy Decision-making Process Vitamin D New Evidence since 1996 Conflicting Experts Disagree Science Feasibility Policy Decision-making Process Vitamin D New Evidence since 1996 Conflicting Experts Disagree Science Feasibility Stakeholders: Industry Consumers Politicians Academics Sister agencies Policy Decision-Making Process Food and Nutrition Board IOM Costs Legal Framework: Policy Policy Decision-Making Process Food and Nutrition Board IOM Stakeholders: Legal Framework: Industry Consumers Costs US & Politicians Canadian Academics Federal Sister agencies Agencies Policy Policy Decision-making Process Vitamin D New Evidence since 1996 Conflicting Experts Disagree Science Feasibility Policy Decision-making Process Vitamin D New Evidence since 1996 Conflicting Experts Disagree Science Feasibility Policy Decision-Making Process Food and Nutrition Board IOM Stakeholders: Industry Consumers Politicians Academics Sister agencies Costs US & Canadian Federal Agencies Legal Framework: Risk Assessment Framework Policy Policy Decision-Making Process Food and Nutrition Board IOM Stakeholders: Industry Consumers Politicians Academics Sister agencies Costs US & Canadian Federal Agencies Legal Framework: Risk Assessment Framework Policy DRI 2010 Federal Policymakers 2

3 How and By Whom Were the DRI s Developed IOM Convened Expert Committee 14 scientists across broad array of disciplines Committee Worked during Public Workshop and Open Sessions 8 committee meetings (closed) Website for information submission External review Backdrop: Considerable Public Awareness Interest in enhanced roles, especially for vitamin D Theme that sunlight is not a factor Many doctors ordering blood tests for vitamin D Theme of widespread deficiency Committee Membership A. CATHARINE ROSS (Chair), The Pennsylvania State University STEVEN A. ABRAMS, Baylor College of Medicine JOHN F. ALOIA, Winthrop-University Hospital PATSY M. BRANNON, Cornell University STEVEN K. CLINTON, The Ohio State University RAMON A. DURAZO-ARVIZU, Loyola University J. CHRISTOPHER GALLAGHER, Creighton University Medical Center RICHARD L. GALLO, University of California San Diego GLENVILLE JONES, Queens University, Ontario CHRISTOPHER S. KOVACS, Memorial University of Newfoundland JOANN E. MANSON, Harvard Medical School SUSAN T. MAYNE, Yale School of Public Health CLIFFORD J. ROSEN, Maine Medical Center Research Institute SUE A. SHAPSES, Rutgers University 10 What Was Done: Scope of Work Review evidence regarding health outcomes relevant to developing DRIs for vitamin D and Ca Update DRIs for vitamin D and Ca, as appropriate ospecify the requirement -> Distribution of requirements oindicate how much is too much Incorporate risk assessment approach Incorporate systematic evidence-based reviews (SEBR s) Consider SEBR conducted by Agency for Health Quality Research Evidence Based Practice Centers at Tufts and by Ottawa Enhance transparency of decision-making Identify research needs Decision-Making Steps*: A Systematic Approach 1. Hazard (Outcome) Identification (Literature Review) 2. Hazard Characterization (Dose-Response Assessment Ref. Value) 3. Intake Assessment (Prevalence of Intakes Outside Ref. Value) 4. Risk Characterization (Public Health Implications) *Based on nutrient risk assessment models (WHO, 2006) Decision-Making Steps*: A Systematic Approach 1. Hazard (Outcome) Identification (Literature Review) 2. Hazard Characterization (Dose-Response Assessment Ref. Value) 3. Intake Assessment (Prevalence of Intakes Outside Ref. Value) 4. Risk Characterization (Public Health Implications) 1. Hazard (Outcome) Identification (Literature Review) Based on probability, prevalence, risk & distribution Risk Analysis Foundation Supports: transparency, objective independent review & scientific judgment re: limited data Specified roles & tasks Specifies Problem Formulation *Based on nutrient risk assessment models (WHO, 2006) 3

4 SEBRs for Calcium and Vitamin D Report Key questions were appropriate (Questions formulated did not cover all relevant issue) Useful Efficient Outside IOM/committee reduced bias and increased transparency Committee examined EBRs carefully Additional literature identified and reviewed Committee worked to integrate all data Committee used expert opinion and made scientific judgments SEBR functioned as a tool, not a driver SEBRS were a valuable adjunct SEBR in DRI Development: Additional Challenges Identified by Tufts Evidence Based Practice Center Selection of critical health outcomes for establishing nutrient reference values How to choose outcomes of most value How to decide which outcomes, designs, populations, p etc. of limited value SEBR technical expert panel critical, but outcomes might differ with different panel Establishment of instructions on how to weigh outcome might eliminate variability Use of evidence map might facilitate decisions Use of existing SEBR s Chung M et al. Systematic review to support the development of nutrient reference intake values: challenges and solutions. Am J Clin Nutr 2010; 92(2): Data Evaluation Process Full review of health outcomes critical Included as many as reasonable, 25+ Outlined approach to be used Totality of evidence Evidence maps Summary tables Forest plots Quality of studies and strength of the evidence Consistency of effect Confounding factors Randomized clinical trials (RCT) provide greatest level of confidence Preliminary evidence is not always complete or substantiated / Observational data are mixed Functions of Vitamin D Sun-UVB Skin Vitamin D Intestine 25OHase Ca-P homeostasis Target cells 25OHD Bone 1αOHase Intestine Kidney 1,25(OH) 2 D 25OHD 1αOHase Parathyroids 1,25(OH) 2 D D = D2+D3 VDR Gene expression Endocrine functions VDR Gene expression Intra/Para/autocrine Functions (?) Diet Other functions Target cells Immune system Cardiovascular system Muscle (?) Cartilage Adipose tissue Liver Pancreas Brain Lung Skin Breast Placenta Uterus/decidua Ovary, testes & others Vitamin D: Challenges Vitamin D Hormone Sun exposure Known factor based on seasonal changes in serum Cannot incorporate readily in DRI considerations Not well quantified Risk of skin cancer Serum 25OHD: Biomarker of exposure Most data relate to serum values, not to intake Measurement issues regarding standardization and harmonization Not validated as biomarker of effect Studies that combined vitamin D and calcium and administered only relatively high doses Health Outcomes Evaluated Health Outcomes Evaluated Cancer/Neoplasms All Cancers, Breast Cancer, Colorectal Cancer/Colon Polyps, Prostate Cancer Cardiovascular Diseases and Hypertension Diabetes (Type 2) and Metabolic Syndrome (Obesity) Falls Immune Functioning Asthma Autoimmune Disease Type 1 Diabetes, Inflammatory Bowel and Crohn s Disease, Multiple Sclerosis, Rheumatoid Arthritis, Systemic Lupus Erythematosus Infectious Diseases Tuberculosis, Influenza/Upper Respiratory Infections Neuropsychological Functioning Autism, Cognitive Function, Depression Physical Performance Preeclampsia of Pregnancy Skeletal Health (commonly Bone Health) Calcium Absorption, Calcium Balance, BMC/BMD, Fracture Risk, Rickets/Osteomalacia, 24OHD (intermediate), PTH (intermediate) 4

5 CANCER - RCT (placebo-conrolled) conrolled) secondary analysis Cancer Randomized clinical trials Observational studies Case control studies Lappe : women, age 67yrs, 4 years vitamin D 1,000 IU 2.9% vitamin D + calcium1gm 3.8% no difference 2 treatments placebo 6.9% significantly higher p<0.03 n 1179 cancer incidence Trivedi : men + women, age 75 yrs, 5 years quarterly 100,000IU tabs Vitamin D 833IU/d 13.90% placebo 12.86% no significant difference n 2686 cancer incidence WHI women, age 62 yrsv,6 years vitamin D 400 IU+ Ca1gm 0.27% OR 0.89 [ ] placebo 0.30% n 36,282 annualized cancer mortality 2 5 Used with permission C. Gallagher 2 6 Cancer and serum 25OHD - Observational studies Study Freedman 2007 NHANES 12 years Giovannuci 2006 HPS 14 years Pilz years Jenab 2010 (EPIC) Nested case control Serum 25OHD nmol/l Each 25 nmol/l increase Cancer mortality No interaction with cancer Decrease of 29% < 25 Increased mortality < >90 Cancer incidence Decrease of 17% 1.32 ( ) 1.28 ( ) 1.0 ref 0.88 ( ) 0.77 ( ) Evidence Summary: Vitamin D Data on Cancer, Cardiovascular Disease, Diabetes, Neuropsychological, Immune Disorders, Pre-eclampsia, Physical Performance, Falls, PTH, do not support their use as indicators for DRI development (contradictory, lack causality, inconclusive) Bone Health: Accretion (BMC, rickets, Ca absorption) Maintenance (BMD, osteomalacia, Ca absorption) Loss (BMD, fractures, Ca absorption) Used with permission C. Gallagher Adapted & used with permission C. Gallagher Vitamin D and BMD Relationship serum 25OHD with BMD discordant across 6 RCT s, 7 prospective cohort studies, and 6 case-control studies, Evidence is fair that support an association between serum 25OHD and BMD or change in BMD. 21 RCT - vitamin D usually combined with calcium mg/day. Meta analysis (AHRQ Ottawa/Tufts) -small positive effect on BMD at spine, femoral neck and total body sites on Vitamin D3 800 IU + calcium ~500mg/d *None of the 21 studies had a dose response design Vitamin D and Fractures Inconsistent relation between serum 25OHD and fractures. No dose response studies A) 14 RCT s of vitamin D2 or D3 ± calcium versus calcium or placebo Outcome total fractures OR 0.90 ( ) 1.20) B) 8 studies of vitamin D3 + calcium versus placebo Outcome total fractures OR 0.87 ( ) C) 8 studies of vitamin D3 + calcium versus placebo Outcome hip fractures OR 0.83 ( ) Doses of vitamin D : (3), (7), (3) AHRQ - Ottawa and Adapted & used with permission C. Gallagher 2 Tufts 9 Adapted & used with permission C. Gallagher 3 0 5

6 Evidence Summary: Vitamin D & Bone Health Serum 25OHD Ca absorption < 12.5 nmol/l Supportive for BMC in children Only fair for BMD in adults Good for low 25OHD ( < 50 nmol/ ) and fractures < 1% osteomalacia with serum 25OHD > 50 nmol/l No threshold for rickets, but risk <30 nmol/l 2. Hazard Characterization (Dose-Response Assessment Ref. Value) BMD -. small with Vitamin D 800IU (& 500mg Ca) in older Fractures - with vitamin D ( IU/d) & Ca ~1000mg Adapted & used with permission C. Gallagher What level of serum 25OHD affects bone health? Association between Serum 25OHD and Osteomalacia Calcium absorption Rickets Fracture risk: RCTs Fracture risk: Observational a Osteomalacia OV/BV >2 - osteomalacia Priemel et al. BMR 2010; 25: Association between Serum 25OHD and Osteomalacia Association between Serum 25OHD and Osteomalacia 97.5 th % at nmol/l (17/675 people) th % at nmol/l (17/675 people)0 OV/BV >2 - osteomalacia OV/BV >2 - osteomalacia Priemel et al. BMR 2010; 25: Priemel et al. BMR 2010; 25:

7 Association between Serum 25OHD and Osteomalacia Evidence for a threshold of serum 25OHD between nmol/l related to prevention of fractures 97.5 th % at nmol/l (17/675 people)0 Study Serum 25OHD(nmol /L) OR/HR 95% CL) Outcome N Age (yrs) Gender Melhus 2010 < ( ) Hip fracture men 99 th % at 50 nmol/l (7/675 people) OV/BV >2 - osteomalacia Cauley ( (1.05- <25 (WHI) 2.79) Cauley 2010 (Mr. OS) Looker 2008 (NHANES 3) < ( ) Hip fracture women Hip fracture men < Hip fracture both Gerdhem 2005 < ( ) Hip fracture women Priemel et al. BMR 2010; 25: Used with permission C. Gallagher Gallagher JC, Sai AJ Vitamin D Insufficiency, Deficiency and Bone Health 2010 JCEM 95,2630 What level of serum 25OHD affects bone health? Vitamin D: Development of Requirement Distribution Step 1 Link serum levels to distribution requirement 40 nmol/l (16 ng/ml) roughly equivalent to EAR 50 nmol/l (20 ng/ml) roughly equivalent to RDA Note: Some studies (bone) suggest 50 nmol/l TOO HIGH for RDA; others suggest 50 nmol/l TOO LOW for RDA; Decision was made by the COMMITTEE based on the totality of the evidence. Why not 75 nmol/l (30 ng/ml)? Other lines of evidence also did not support: Calcium Absorption Falls PTH Suppression 19 Process of Evaluation: Reanalysis Calcium Absorption Process of Evaluation: Reanalysis Calcium Absorption Single Isotope Heaney, R. P The Vitamin D requirement in health and disease. Journal of Steroid Biochemistry and Molecular Biology 97(1-2): Heaney, R. P The Vitamin D requirement in health and disease. Journal of Steroid Biochemistry and Molecular Biology 97(1-2):

8 Process of Evaluation: Reanalysis Calcium Absorption Process of Evaluation: Reanalysis Calcium Absorption Single Isotope Single Isotope AUC + Ca load AUC + Ca load from urinary Ca excretion Heaney, R. P The Vitamin D requirement in health and disease. Journal of Steroid Biochemistry and Molecular Biology 97(1-2): Heaney, R. P The Vitamin D requirement in health and disease. Journal of Steroid Biochemistry and Molecular Biology 97(1-2): Effect of vitamin D Dose on Falls: Relation to serum 25OHD Process of Evaluation : Reanalysis Falls Falls Conclusions Vitamin D IU daily significantly reduced falls by 19% FIGURE 4-2 Relative risk of falls and vitamin D supplementation doses: correct meta-regressions with continuous predictors showing non-significance. NOTE: RR=0.95 ([CI] 0.89 to 1.02; p = 0.13) per 100 IU/day To prevent falls serum 25OHD should exceed 60 nmol/l Bischoff Ferrari et al. BMJ 2009 FIGURE 4-3 Relative risk of falls and mean achieved serum 25OHD concentrations: correct metaregressions with continuous predictors showing nonsignificance. NOTE: RR=0.92 (CI] 0.80 to 1.05; p = 0.17) per 10 nmol/l. Used with permission C. Gallagher Vitamin D : Parathyroid hormone ( PTH ) Inverse correlation serum PTH and 25OHD No consistent threshold serum 25OHD and suppression of serum PTH* Vitamin D: Development of Requirement Distribution Step 2 Determine how much intake to achieve designated serum level 75 nmol/l Assumption of minimal sun exposure Integration of studies conducted in winter in northern latitudes (many recent studies) Simulation of dose-response appreciation to Francoise Vermeylen and Shamil Sadigov (Sai AJ et al. JCEM 2010 December - online) * Used Sai AJ with et al. permission JCEM Dec C Gallagher online 8

9 Figure 5-3. Age Does Not Affect Response of Serum 25OHD to Total Dietary Vitamin D Intake at Latitudes >50⁰ During Winter Figure 5-4. Response of 25OHD Level to Total Dietary Vitamin D Intake in All Age Groups at Latitudes >50⁰ During Winter Age: main effect, p=0.162 interaction Age Xl n Intake, p=0.142 Vitamin D DRI EAR (IU/day) RDA (IU/day) 1-70 years >70 years Preg/lac years Infants 0 to 12 mos: AI = 400 Vitamin D Potential Indicators for Excess Intake Hypercalcemia; hypercalciuria 10,000 IU/d (Infants) retarded growth Emerging evidence for all-cause mortality, cancer, CVD, falls and fractures at high exposures Committee determined serum 25(OH)D levels > nmol/l associated with risk Confounding possible: Risk at low status- lack physical activity, obesity, race, and SES (poorer diet/no supplement use) Risk at high status - recent weight loss, supplementtaking in individuals with chronic illness Used with permission S. Mayne Committee Analysis of NHANES Data: Confirmed published U-Shaped Relationship (Melamed, Arch Int Med 2008) Derivation of UL: Adults 5000 IU/d for 160 days, did not surpass 150 nmol/l Additional adjustment for uncertainty leads to 4,000 IU/d IU D/d 10,000 5,000 1,000 0 Heaney et al., AJCN

10 Caution! Cannot infer definitive harm at higher exposures in observational studies and in trials, but caution is warranted as extremely limited data showing safety of long-term high serum concentrations achieved through supplementation Tolerable Upper Intake Levels (ULs) Vitamin D (IU/day) Infants 0 to 6 mos 1000 Infants 6 to 12 mos years years years years years 4000 Preg/Lac Preg/Lac Used with permission S. Mayne 3. Intake Assessment (Prevalence of Intakes Outside Ref. Value) Where from? Achieved 25OHD Is Higher at Latitudes 40-48⁰ N Than At Latitudes >50⁰ During Winter In Simulated Dose- Response of Total Dietary Vitamin D Intake 4. Risk Characterization (Public Health Implications) Latitude main effect, p=0.000; Intxn Latitude X ln Intake, p=

11 Cumulative Distribution of Serum 25OHD (QC Adjusted) for 31 to 50 year-olds in the US for 2003 to 2006 (NHANES) Cumulative Distribution of Serum 25OHD (QC Adjusted) for 31 to 50 year-olds in the US for 2003 to 2006 (NHANES) Research Needs Note: Confidence Intervals were not provided. Health Outcomes Explore causal role for vitamin D in non-bone health Elucidate effect genetic variation including that among racial/ethnic groups epigenetic regulation of vitamin D and developmental outcomes Elucidate inter-relationship between vitamin D and Ca and their independent effects Basic Physiology and Molecular Pathways Evaluate nature and significance of extra-renal activation of vitamin D for health outcomes Clarify 25OHD distribution in body pools including storage and mobilization from adipose tissue Examine influence of Ca and P, through PTH and FGF23, on activation and catabolism of vitamin D Research and Consensus Guidelines Needs Dose-Response Relationship Identify specific health outcomes in relation to graded and fully measured intake of vitamin D Clarify influence of age, body weight and body composition on 25OHD levels in response to intake/exposure Sun Exposure Investigate whether minimal risk sun exposure relative to skin cancer exists that enables vitamin D production Clarify how physiological and environmental factors influence vitamin D synthesis Intake Assessment Clarify differences if any between D2 and D3 Consensus Guideline Development Evidence-based consensus guidelines for interpretation of serum 25OHD levels relative to deficiency, insufficiency and sufficiency 11