When does prolonged vitamin D intake confer a risk for health?

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1 When does prolonged vitamin D intake confer a risk for health? Glenville Jones, Ph.D Craine Professor of Biochemistry, Dept Biomedical & Molecular Sciences Professor, Department of Medicine Queen's University, Kingston, ON, Canada gj1@queensu.ca

2 RECOMMENDED DIETARY ALLOWANCE (RDA): Daily requirement which meets the needs of >97.5% of population TOLERABLE UPPER LIMIT (TUL or UL) Highest average daily intake that is likely to pose NO risk

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5 Prevention of vitamin D toxicity IOM-2011 SUGGESTED UPPER LIMIT = 50 ng/ml or 125 nmol/l ENDO. SOC SUGGESTED UPPER LIMIT = 100 ng/ml or 250 nmol/l 50 ng/ml 4000 IU/DAY 100 ng/ml Insufficiency Deficiency Sufficiency? Toxicity Acute Toxicity >200 ng/ml Adapted from Hollis Plasma 25-OH-D ng/ml

6 From: Dose Response to Vitamin D Supplementation in Postmenopausal Women: A Randomized Trial Gallagher JC, Sai A, Templin T, Smith L Ann Intern Med. 2012;156(6): doi: / nmol/l Figure Legend: 4000 IU/d Appendix Figure 1. Serum 25-(OH)D levels according to vitamin D dosage. Levels are shown with a fitted line by using the mixed-effects model, with 95% bootstrapped limits at 12 mo. 25-(OH)D = 25- hydroxyvitamin D. Date of download: 9/19/2012 Copyright The American College of Physicians. All rights reserved.

7 THE VITAMIN D ENDOCRINE SYSTEM Schlingmann et al (2011) N Engl J Med 365:

8 WHAT IS THE MECHANISM OF VITAMIN D TOXICITY? INVOLVES HYPERCALCIURIA AND HYPERCALCEMIA INVOLVES HYPERPHOSPHATEMIA IS IT CAUSED BY EXCESS VDR-MEDIATED ACTIONS OF 1,25-(OH) 2 D 3? IF SO, THEN: IS SERUM OR CELLULAR 1,25-(OH) 2 D 3 ELEVATED? BUT IS IT THE SAME IN HYPERVITAMINOSIS D (EXCESSIVE D INTAKE)? PROBABLY NOT!

9 IOM 2011

10 IOM-2011

11 Serum 25-OH-D considered toxic in acute studies nmol/l or ng/ml Prior to IOM 2011 Clinical labs set normal range at ng/ml

12 Reviewed Pre-2008 literature on vitamin D toxicity Many animal studies report that serum 1,25-(OH) 2 D 3 not elevated, indeed it is suppressed in most cases Most notable was the study of Shepard & DeLuca in rats given graded doses of VITAMIN D 3 OR 25-OH-D 3 showing elevated serum 25-OH-D 3 & other metabolites but not 1,25-(OH) 2 D 3 Few definitive reports of human vitamin D intoxication Based on available data, two THEORIES PROPOSED:- 25-OH-D 3 IS THE TOXIC METABOLITE because of high levels FREE 1,25-(OH) 2 D 3 IS THE TOXIC METABOLITE released from transport protein DBP by the high concentration of 25-OH-D 3 and other metabolites

13 Postscript to vitamin D toxicity story DeLuca and colleagues (2011) repeated the Shepard & Deluca experiment in CYP27B1-knockout mice (lack 1α-hydroxylase & thus 1,25-(OH) 2 D 3 ) Found vitamin D toxicity/hypercalcemia in CYP27B1-XO and normal mice at similar doses of vitamin D 3 Concluded that toxic metabolite in hypervitaminosis D is NOT 1,25-(OH) 2 D 3 Speculated that toxic metabolite in hypervitaminosis D IS 25-OH-D 3 but mechanism for toxicity still unknown

14 CHRONIC MODERATE VITAMIN D DOSING ACUTE TOXICITY DUE TO DOSES WHICH RAISE SERUM 25-OH-D >100 ng/ml ANY RISK TO MODERATE DOSING >4000 IU/DAY FOR MONTHS OR YEARS? SOME EPIDEMIOLOGICAL DATA SUGGESTS U-SHAPED or REVERSE-J CURVE HIGH SERUM 25-OH-D IS ASSOCIATED WITH INCREASED RISK eg. Increased Mortality eg. Increased Pancreatic Cancer MECHANISM OF TOXICITY OF CHRONIC DOSES IS UNKNOWN IOM COMMITTEE SUGGESTS CAUTION AT HIGH DOSES >4000 IU/DAY

15 REVERSE J-SHAPED CURVE SHOWN IN MORTALITY DATA FIGURE 6-2 Risk of death in elderly people according to baseline serum 25OHD level in the Longitudinal Aging Study (subjects with serum 25OHD levels of nmol/l are the referent category). NOTE: Model 1 is adjusted for gender, age, and education; model 2 is adjusted for as in model 1 and for chronic disease, serum creatinine concentration, cognitive status, and depressive symptoms; model 3 is adjusted for as in model 2 and for lifestyle variables including body mass index, smoking status, alcohol consumption, and physical activity; model 4 is adjusted for as in model 3 and for frailty indicators: mobility performance, low serum albumin concentration, and low serum total cholesterol concentration. SOURCE: Visser et al. (2006).

16 American Journal of Epidemiology 185, No. 8 DOI: /aje/kww244 Advance Access publication: March 15, 2017 The Reverse J-Shaped Association Between Serum Total 25-Hydroxyvitamin D Concentration and All-Cause Mortality: The Impact of Assay Standardization Ramo n A. Durazo-Arvizu*, Bess Dawson-Hughes, Holly Kramer, Guichan Cao, Joyce Merkel, Paul M. Coates, and Christopher T. Sempos We evaluated the impact of standardizing the originally measured serum total 25-hydroxyvitamin D (25(OH)D) values from Third National Health and Nutrition Examination Survey (NHANES III, ) on the association between 25(OH)D and rate of all-cause mortality. Values were standardized to the gold-standard laboratory method. Follow-up from consisted of 15,099 participants aged at least 20 years at baseline, among whom there were 3,784 deaths. Relative risk of death was adjusted for age, sex, race/ethnicity, and season using Poisson re- gression. Results were obtained for eight 25(OH)D (nmol/l) categories: <20 nmol/l, nmol/l, nmol/l, nmol/l, nmol/l, nmol/l, nmol/l (reference), and 100 nmol/l. Assay standardization dramatically shifted original 25(OH)D values toward zero. Accordingly, risk 120 nmol/l could not be evaluated (i.e., n = 7 and ndeaths = 2). Relative risk (95% confidence interval (CI)) <40 nmol/l remained significant (30 39 nmol/l: relative risk (RR) = 1.4 (95% CI: 1.1, 1.6); nmol/l: RR = 1.6 (95% CI: 1.3, 1.9), and <20 nmol/l: RR = 2.1 (95% CI: 1.6, 2.7). However, adjusted relative risk estimates for 25(OH)D levels 40 nmol/l were no longer significant (40 49 nmol/l: RR = 1.2 (95% CI: 0.99, 1.4); nmol/l: RR = 1.2 (95% CI: 1.04, 1.4); nmol/l: RR = 1.1 (95% CI: 0.94, 1.2); nmol/l: RR = 1.0 (referent), and 100 nmol/l: RR = 1.1 (95% CI: 0.6, 2.1). In summary, after standardization, risk of death from all causes increased with decreasing 25(OH)D <40 nmol/l, while there was no association with values in categories between 40 nmol/l & 120 nmol/l

17 Growing body of research indicating high levels of serum 25(OH)D predict increased risk of various outcomes: e.g., Pooling project of serum vitamin D and cancer risk:

18 WHAT HAS CHANGED SINCE IOM-2011? Evidence Report/Technology Assessment-- Number 217 Vitamin D and Calcium: A Systematic Review of Health Outcomes (Update) Prepared for: Agency for Healthcare Research and Quality U.S. Department of Health and Human Services 540 Gaither Road Rockville, MD Contract No I Prepared by: Southern California Evidence-based Practice Center Santa Monica, CA (RAND) Investigators: Sydne J. Newberry, Ph.D. Mei Chung, Ph.D., M.P.H Paul G. Shekelle, M.D., Ph.D. Marika Suttorp Booth, M.S. Jodi L. Liu, M.S. Alicia Ruelaz Maher, M.D. Aneesa Motala, B.A. Mike Cui, M.P.H.Tanja Perry, B.H.M. Roberta Shanman, M.L.S. Ethan M. Balk, M.D., M.P.H AHRQ Publication No. 14-E004-EF September 2014

19 WHAT HAS CHANGED SINCE IOM-2011? 2014-AHRQ (Rand) evidence-based report Technical Expert Panel Glenville Jones, Ph.D. Dept. Biomedical & Molecular Sciences, Queen s University. Kingston, Canada Susan T. Mayne, Ph.D., F.A.C.E. Chronic Disease Epidemiology Yale School of Public Health, Yale Cancer Center, New Haven, CT Clifford Rosen, M.D., Maine Medical Center Research Institute Scarborough, ME Peer Reviewers Michael F. Holick, Ph.D., M.D. Boston University School of Medicine Boston, MA Anne C. Looker, Ph.D. National Center for Health Statistics Centers for Disease Control and Prevention Hyattsville, MD Patsy Brannon, Ph.D. Division of Nutritional Sciences Cornell University, Ithaca, NY Kevin D. Cashman, School of Food & Nutritional Sciences University College Cork Cork, Ireland J. Christopher Gallagher, M.D. Bone Metabolism Unit, Creighton University, Omaha, NE

20 WHAT HAS CHANGED SINCE IOM-2011? 2014-AHRQ (Rand) evidence-based report No major change in published data to support changes in IOM-2011 recommendations Conclusions. In solid agreement with the findings of the original report, the majority of the findings concerning vitamin D, alone or in combination with calcium, on the health outcomes of interest were inconsistent. Associations observed in prospective cohort and nested case-control studies were inconsistent, or when consistent, were rarely supported by the results of randomized controlled trials. Clear dose-response relationships between intakes of vitamin D and health outcomes were rarely observed. Although a large number of new studies (and longer followups to older studies) were identified, particularly for cardiovascular outcomes, all-cause mortality, several types of cancer, and intermediate outcomes for bone health, no firm conclusions can be drawn. Studies identified for the current report suggest a possible U-shaped association between serum 25(OH)D concentrations and both all-cause mortality and hypertension and also suggest that the level of supplemental vitamin D and calcium administered in the Women s Health Initiative Calcium-Vitamin D Trial are not associated with an increased risk for cardiovascular disease or cancer among postmenopausal women who are not taking additional supplemental vitamin D and calcium. Studies suggest the method used to assay 25(OH)D may influence the outcomes of dose-response assessments. Beyond these observations, it is difficult to make any substantive statements on the basis of the available evidence concerning the association of either serum 25(OH)D concentration, vitamin D supplementation, calcium intake, or the combination of both nutrients, with the various health outcomes because most of the findings were inconsistent.

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22 CHRONIC MODERATE VITAMIN D DOSING ACUTE TOXICITY DUE TO DOSES WHICH RAISE SERUM 25-OH-D >100 ng/ml ANY RISK TO MODERATE DOSING >4000 IU/DAY FOR MONTHS OR YEARS? SOME EPIDEMIOLOGICAL DATA SUGGESTS U-SHAPED or REVERSE-J CURVE HIGH SERUM 25-OH-D IS ASSOCIATED WITH INCREASED RISK e.g. Increased Mortality e.g. Increased Pancreatic Cancer e.g. Increased Risk of Falls in Elderly MECHANISM OF TOXICITY OF CHRONIC DOSES IS UNKNOWN Difficult to rationalize in terms of physiological effects of vitamin D IOM COMMITTEE SUGGESTS CAUTION AT HIGH DOSES >4000 IU/DAY

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24 THE VITAMIN D ENDOCRINE SYSTEM Schlingmann et al (2011) N Engl J Med 365:

25 Molin A, et al (2015) CYP24A1 Mutations in a Cohort of Hypercalcemic Patients: evidence for a recessive trait. J Clin Endocrinol Metab. 100 (10):E Ca WHAT HAS CHANGED SINCE IOM-2011? PTH 25OHD 3 24,25(OH) 2 D 3 Ratio 25OHD 3 : 24,25(OH) 2 D 3

26 Shah AD, Hsiao EC, O'Donnell B, Salmeen K, Nussbaum R, Krebs M, Baumgartner-Parzer S, Kaufmann M, Jones G, Bikle DD, Wang Y, Mathew AS, Shoback D, Block-Kurbisch I. (2015) Maternal Hypercalcemia Due to Failure of 1,25-Dihydroxyvitamin-D3 Catabolism in a Patient With CYP24A1 Mutations. J Clin Endocrinol Metab.100(8): History: Hypercalcemia during all 4 pregnancies & frequent renal stones Elevated 25-OH-D 3 :24,25-(OH) 2 D 3 ratio; CYP24A1 with E143del & R396W mutations Conclusion: Pregnancy is crucial in IIH as placenta increases 1,25-(OH) 2 D 3 burden

27 CONCLUSIONS IOM advice for UPPER LIMITS remain appropriate as they reflect the safest guidelines for NORMAL populations in terms of ACUTE and CHRONIC dosing with vitamin D (UPPER LIMIT=4,000 IU D 3 /day serum 25-OH-D= 50 ng/ml) Based upon Mortality and Falls data, certain bodies (e.g. Bone Specialists) skeptical that 25-OH-D 50 ng/ml is too high In pediatric and obstetric settings, we should be on the look out for hypercalcemic individuals who might be hypersensitive to vitamin D