7/11/2019 Vitamin D and the Skeleton: Conflict of Interest Statement- What’s New is Old Corporate • NO STOCKS or EQUITY • Editor- UpToDate, New England Journal of Medicine, and Endocrine Reviews Clifford J Rosen MD • Speakers bureaus Maine Medical Center – None Research Institute – no consulting fees rosenc@mmc.org Sun Physiology of Vitamin D Outline Skin • Physiology of vitamin D ProD 3 PreD 3 Vitamin D 3 • The Vitamin D paradox- Liver DIET – Little strong positive RCT solar 25(OH)D 40-70% evidence, widespread usage 20-40% PTH (+) (+) low PO 4 – Evidence for or against Vitamin D Kidney FGF-23 and Musculoskeletal health 1,25(OH) 2 D Bone Intestines • Is There Anything new? Increase Calcium & Mobilize • Take homes Phosphorus Absorption Calcium Stores 1
7/11/2019 Vitamin D works through the VDR which is expressed Hollis et al 2013 in many tissues Revised Does DBP concentration vary by ethnicity ? Hormones circulating bound to albumin or circulating in a free form (collectively known as Bioavailable Vitamin D) are more readily available to enter cells than hormones bound to their traditional binding proteins Study Study Study Black Black Black White White White Assay Assay Assay Vitamin D Binding Protein- Re-emerging Schwartz et al, 2014 Schwartz et al, 2014 152 ± 152 ± 107 (SD) mg/L 107 (SD) mg/L 301 ± 301 ± 210 (SD)* mg/L 210 (SD)* mg/L R&D R&D 168 ± 168 ± 168 ± 3 (SE) 3 (SE) 3 (SE) 337 ± 337 ± 337 ± 5 (SE)* 5 (SE)* 5 (SE)* Powe et al, 2013 Powe et al, 2013 Powe et al, 2013 R&D R&D R&D Denburg et al, 2013 Denburg et al, 2013 100 100 240* 240* R&D R&D African Americans Bhan et al, 2012 Bhan et al, 2012 75 75 189* 189* R&D R&D R&D R&D Powe et al, 2011 Powe et al, 2011 144 ± 144 ± 102 (SE) 102 (SE) 248 ± 248 ± 122 (SE)* 122 (SE)* White Americans 491 ± 128 (SD) 529 ± 202 (SD)** Winters et al, 2009 ALPCO Albumin Bouillon et al, 1977 329 ± 54 (Zaire/Congo) 329 ± 43 (Belgium)** RID * Ethnic difference P<0.05 Powe et al, 2013 NEJM 1. ‘ Bioavailable ’ D is consistent with other hormones ** No ethnic difference Bouillon NEJM 2015 2
7/11/2019 What Supports the Widespread Use Summary-Part I • Vitamin D circulates in the 25OHD form of Vitamin D Supplementation? although 1,25OHD is present in smaller concentrations and is the active compound • Evidence from clinical trials • 25OHD is bound to D binding protein (DBP) • Observational data and albumin • Expert opinion • Dissociation of 25OHD from DBP may be a determinant of cellular action • Case Reports • D binding protein assays are still being • Magical Thinking validated, but it is likely that there are no differences in DBP by race • serum 25OHD is really low in AA So What is the evidence for Vitamin D and Fractures ? There are now more than 2 meta-analyses published for every 1 RPCT of calcium/vitamin D and fracture risk STEENBOCK 1920s 3
7/11/2019 Vitamin D and Calcium Reduces Fracture Risk (800IU+1200 2018 Met Analysis Ca/VitD for hip mg/d) Tang Lancet 2007 fractures JCEM, March 2019 USPSTF: No Risk Reduction for Calcium/ Vitamin D and Hip Fracture- 2014 Why the Difference? A Closer Look at the Randomized Controlled Trials Total Fractures 0.90-1.04 4
7/11/2019 Ca 1000mg+400 IU D Placebo Risk of Hip Fracture by Age Group in WHI: Age and Fall Interaction JAMA Int Med 2015 Target to > 30 ng/ml serum 25OHD- 21 ng/ml at baseline: 100,000/mo 800 IU/d Placebo Calcium and Vitamin D with hormone therapy reduces hip fractures by nearly 50%! But Calcium and Vitamin D alone do not reduce hip fracture risk 5
7/11/2019 Bone Mineral Density Unchanged But, is there a place for targeted vitamin D therapy? Chapuy et al NEJM 1992 800 IU per day Vitamin D • 1200 mg Ca + 800 IU Vitamin D • Nursing home patients (n=1600) • RPCT- • 33% reduction in hip fractures 6
7/11/2019 Micro Archictectural Changes in the Skeleton with Low Vitamin D Why Might Vitamin D Supplementation Protect Against Fractures in the Elderly? SciTransl 2013 Osteomalacia in some subjects with low Vit D Primel Study of 1200 Subjects 7
7/11/2019 Cortical Porosity is increased in D Deficiency as is Osteomalacia and Cortical Porosity Are Haversian Canal Diameter and Osteocyte Lacunae Volume Associated with Micro Cracks and Propagation in Severe Vit D Deficiency Secondary Hyperparathyroidism: Summary-Part II A Case for Vit D prevention of fractures? • Vitamin D promotes calcium absorption in the gut • Vitamin D binding protein is important in carrying 25OHD and is genetically determined • Vitamin D supplementation with calcium may reduce hip fracture risk but only in a subgroup of individuals, likely those who are deficient • Vitamin D is important for prevention of rickets in susceptible populations 8
7/11/2019 JAMA 2010 303 1815-25 So what ’ s wrong with taking more vitamin D? Dose was single annual dose of 500,000 IU (daily equivalent IF/365 = 1370 IU; High Dose Vitamin D increases serum levels of 25OHD levels in 75-125 nmol range Sanders et al , 2010 90 nmol/l 9
7/11/2019 Is there truly a vitamin D epidemic? Prevalence of Vitamin D Levels from Commerical Lab Mayo ’ s Experience 90 25-80 Patients (%) 60 10-24 30 <10 >80 0 6 6 6 7 7 7 7 7 7 8 8 8 8 8 8 9 9 9 9 9 9 0 0 0 0 0 0 1 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 1 1 1 1 1 1 1 u l p v n r y u l p v n r y u l p v n r y u l p v n r y u l p v n a a a a J e o a a J e o a a J e o a a J e o a a J e o a M M M M M M M M S N J S N J S N J S N J S N J Month 5 year pattern has changed very little Oral Dosing of Vitamin D Depends on Baseline Levels of 25OHD How should we use vitamin D 10,000 IU D/d supplementation in management 5,000 IU D/d of osteoporosis? 1,000 IU/d 0 IU/d *Heaney et al., AJCN 2003 10
7/11/2019 DR. MICHAEL HOLICK The Leading Authority on Vitamin D His new book, The Vitamin D Solution is now available! Vitamin D upcoming trials 11
7/11/2019 Cumulative survival rates free of D2D Flow of participants diabetes 2423 randomized 1211 Assigned to 4,000 IU of vitamin D daily 1212 Assigned to placebo daily 1211 Received vitamin D as 1211 Received placebo as randomized randomized 3 Had no contact after randomization 5 Had no contact after randomization 5 Died 5 Died 34 Withdrew 28 Withdrew 1 Withdrawn administratively 0 Withdrawn administratively 1199 Completed at least one follow-up Hazard ratio 0.88 (95%CI 0.75 to 1201 Completed at least one follow-up encounter (98.9%) encounter (99.2%) 1.04); p = 0.12 1131 Met primary outcome, died or 1130 Met primary outcome, died or completed last follow-up completed last follow-up encounter (93.3%) encounter (93.2%) No. at risk 0 6m 12 18 24 30 36 42 48 54 1211 Included in the intention-to-treat 1212 Included in the intention-to-treat m m m m m m m m analysis analysis Vitamin D 4000 121 117 108 100 812 625 466 283 141 21 IU/d 1 1 9 1 45 Placebo 121 117 109 975 779 577 419 258 121 13 2 1 1 Take Home Messages Hazard Ratio Subgroup Vitamin D n/N Placebo n/N Subgroup analysis • Vitamin D is a hormone that promotes calcium Serum 25-hydroxyvitamin D < 20 ng/mL 73/276 66/249 >= 20 ng/mL 220/935 256/962 absorption in the gut Race White 207/810 227/806 Black / African American 64/301 69/315 Other 22/100 27/91 • Impaired calcium absorption due to low Glycemic risk by pre-diabetes criteria Met all three criteria 143/427 163/429 Met two criteria 150/784 160/783 vitamin D reduces mineralization and leads to Body Mass Index, kg/m2 D< 12 ng/ml all subjects < 30 82/435 105/429 >= 30 211/776 218/783 changes in bone microstructure Glycemic risk Met 2hPG criterion 191/604 215/635 Met FPG/A1c only 102/607 108/577 • There is minimal RPCT data to support Ethnicity Hispanic 36/120 27/105 Non-Hispanic 257/1091 296/1107 Sex calcium/ vitamin D supplementation to Women 131/541 127/545 Men 162/670 196/667 Waist circumference prevent most chronic disease-except in the < median of 104.2 cm 127/620 135/585 >= median of 104.2 cm 166/591 188/627 0.38 (0.18, 0.80) Age, years frail with OM, high risk of falls, or low 25OHD 0.92 (0.78, 1.08) < median of 60.9 158/622 153/587 >= median of 60.9 135/589 170/625 Geographic location • Basic studies of vitamin D are essential to fully Above 37o N latitude 205/892 235/898 Below 37o N latitude 88/319 88/314 Calcium intake from supplements, mg/day understand its actions < median of no intake 198/826 216/793 >= median of any intake 95/385 107/419 0.5 0.75 1 1.25 1.5 12
7/11/2019 Conclusions • Vitamin D supplementation for the general population is not warranted • Vitamin D + calcium probably does not prevent fractures, except in a subgroup of elderly institutionalized individuals • Vitamin D supplemetation does not prevent cardiovascular disease nor Type 2 diabetes 13
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