Update on vitamin D. J Chris Gallagher Professor of Medicine and Endocrinology Creighton University Omaha,Nebraska USA

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1 Update on vitamin D J Chris Gallagher Professor of Medicine and Endocrinology Creighton University Omaha,Nebraska USA Cali, Colombia 2016

2 definitions DRIs are the recommended dietary reference intakes for the healthy population for long-term intake They are not meant to be therapeutic guidelines. Estimated Average Requirement (EAR) -- specifies the median requirement for the nutrient for each age-sex group Recommended Dietary Allowance (RDA) -- intake that covers needs of 97.5% of the population, for each age-sex group Upper Level (UL) -- intake above which risk begins to increase (highest level of intake from food and supplements that does not to pose risk)

3 Report from Agency for Healthcare Research and Quality AHRQ-Tufts for Institute of Medicine (IOM) 2010 Conclusions The majority of the findings concerning vitamin D, calcium, or a combination of both nutrients on the different health outcomes were inconsistent. Synthesizing a dose-response relation between intake of either vitamin D, calcium or both nutrients and health outcomes in this heterogeneous body of literature proved challenging.

4 Vitamin D : Issues Vitamin D is a nutrient that is converted to a hormone( calcitriol) in the body in the kidney and in extra renal tissues Nutritional supply depends on two major factors: - Sun exposure - Dietary intake of vitamin D in food that is on average ~100 IU/d together with and supplements Although sun exposure is difficult to quantify measurement of serum 25OHD increases serum 25OHD by percent from winter to summer in North America Serum 25OHD is a biomarker of total vitamin D exposure

5 Vitamin D Metabolism -genes sun Thermal activation DIET 7-Dehydro- Cholesterol GENE DHCR7 Previtamin D 3 Vitamin D 3 GENE Cyp2R1 SKIN 25-hydroxylase GENE DBP Gc 25-Hydroxyvitamin D LIVER Gene CYP27B1 1 -hydroxylase 24-hydroxylase GENE 1,25-Dihydroxyvitamin D Calcium metabolism & Bone 24,25-Dihydroxy vitamin D KIDNEY

6 Definition of vitamin status according to the WHO, IOM (2010) EFSA 2016 and Endocrine Society (2011) deficiency insufficiency normal WHO IOM EFSA ES ng/ml nmol/l

7 Is there a threshold for disease or treatment linked to serum 25OHD levels? Are diseases associated with a threshold level of serum 25OHD or is a continuum? If there is a threshold is it the same for all diseases and conditions Does treatment with vitamin D alter the disease condition?

8 Bone fractures are related to a threshold serum 25OHD value ~ 20ng/ml (50nmol/L)

9 Bone markers Serum Osteocalcin and Urinary NTx/Cr Threshold 18ng/ml ( 45nmol/) n 489 Osteocalcin NTx/Cr 17ng/ml 19ng/ml Sai AJ,Walters RW, Fang X,Gallagher JC et al. J Clin Endocr Metab 2011(3) E436-46

10 Literature Evidence for a threshold of serum 25OHD between 16-20ng/ml related to prevention of hip fractures Study Serum 25OHD(ng/ml) OR/HR 95% CL) Outcome N Age (yrs) Gender Melhus 2010 < ( ) Hip fracture men Cauley 2008 (WHI) Cauley 2010 (Mr. OS) < ( ) Hip fracture women < ( ) Hip fracture men Looker 2008 (NHANES 3) < Hip fracture both Gerdhem 2005 < ( ) Hip fracture women Gallagher JC, Sai AJ Vitamin D Insufficiency, Deficiency and Bone Health 2010 JCEM 95,2630

11 All non vertebral fractures and serum 25OHD in WHI study ( nested case-control, multivariate model : weight, height, physical activity, calcium intake, fracture history) Serum 25OHD < 20 ng/ml reference 20 < 30 ng/ml 30 ng/ml p trend white black hispanics asians Cauley J et al.j Bone and Min Res 26(10), adapted

12 Another meta analysis of vitamin Ca D on total Fractures Bolland et al.lancet (4),307

13 Meta analysis of vitamin D on Hip Fractures Bolland et al.lancet (4),307

14 Summary of recommendations of IOM Vitamin D ( IU) + calcium reduces fractures The only threshold level of serum 25OHD that has an established scientific basis is 20 ng/ml This threshold can be reached with vitamin D IU day

15 Total 25D (ng/ml) Diasorin LC-MS/MS Total 25D by dose 95% bootstrap prediction interval 95% prediction interval Vitamin D dose (IU/day) Endocrine Soc 2017

16 Falls - 3 meta analysis Murad et al RR 0.84 sig Bolland et al.2014 RR 0.95 ns To understand the different results, Bolland et al 2014 used common criteria for both papers vitamin D vs placebo(12) vit D + calcium vs placebo (8) vit D + calcium vs calcium (6) RR 0.97 ns RR 0.92 ns RR 0.72 sig Murad, M. H. et al. Clinical review: the effect of vitamin D on falls. J. Clin. Endocrinol. Metab. 96, (2011) Bolland, M. J.,et al. Vitamin D supplementation and falls: Lancet Diabetes Endocrinol. 2, (2014). Bolland, M. J., et al Differences in overlapping meta-analyses of vitamin D supplements and falls JCEM 99,4265,2014

17 Intention-to-treat data from 4 randomized controlled trials of calcium vs placebo. Hip fractures are increased on calcium supplements by 64% 1.64 (95% CI: 1.02, 2.64). Bischoff-Ferrari et al. Am J Clin Nutr 2007;86:

18 Calcium may increase fractures and falls and therefore and should not be used as a control group \

19 FALLS second meta-analysis Vitamin D Ca D Bolland m et al Lancet Diabetes and endocrinology 2014

20 Is there any safety issue with vitamin D and Falls? Bolus doses - means that vitamin D is not given daily but, weekly quarterly monthly annual oral annual injection

21 Annual oral dose vitamin D 500,000 IU or placebo Sanders K et al. JAMA. 2010;303(18):

22 They found a time related increase in fractures after an annual oral dose of vitamin D Fractures IRR Falls IRR Overall effect over 3 yrs 1.26 ( ) 1.16 ( )** within 3 months of dose 1.53 ( ) 1.31 ( )** after 3 months 1.18 ( ) 1.13 ( ) Sanders K et al. JAMA. 2010;303(18):

23 Annual injection of 300,000 IU vitamin D3 for 3 years (equivalent 820 IU/d or placebo) was associated with an increase in fractures (n 4713 placebo versus 4727 vitamin D) Hip fractures Women RR 1.80 ( ) Men RR 1.02 ( ) FALL data : collected annually and retrospectively, not accurate way to collect falls data Smith, H. et al.rheumatology (Oxford) 46, (2007).

24 Monthly plain vitamin D3 increase fall rates at 12 months 24,000 IU equivalent to 800 IU/d 60,000 IU equivalent to 2,000 IU/d Serum 25OHD ng/ml lowest quartile Serum 25OHD ng/ml highest quartile ng/ml ng/ml x 5.5 increase in falls Bischoff-Ferrari H et al. JAMA Intern Med.2016;176(2)

25 What is the threshold for serum 25(OH)D and calcium / bone endpoints Serum 25(OH)D 30 ng/ml Serum 25(OH)D 20 ng/ml Bone markers - < 20 ng/ml Bone biopsy? 20 ng/ml Falls?? Bone density BMD?? vitamin D dose Hip fractures Prospective fracture trials Other diseasesdiabetes,cancer,heart 20 ng/ml?? IU + calcium??

26 SUMMARY Lack of adequate clinical trial design for evaluation of an effect of vitamin D on Fractures and Falls,almost all were single dose No dose ranging design,several studies had no placebo, some used calcium as placebo and also combine it with D Not statistically powered. Often secondary analyses Only 4/26 studies were independently significant, and 2 of these 4 were post stroke and post hip fracture patients No evidence yet that plain vitamin D reduces falls Bolus dosing of vitamin D increases falls and fracture and results suggest that serum 25OHD levels should not exceed 40 ng/ml.

27 Concept: Risk - Benefit IOM 2010 High RISK of Adverse Outcome EAR RDA TU L Low INTAKE