5/22/2015 Vitamin D and Calcium Therapy: how much is enough Daniel D Bikle, MD, PhD Professor of Medicine VA Medical Center and University of California San Francisco DISCLOSURE Nothing to disclose 1
5/22/2015 RECOMMENDATIONS FROM THE INSTITUTE OF MEDICINE 25OHD level of 20ng/ml is enough (UL 50ng/ml) 600 IU/qd is enough (800 IU qd for >71yo) (UL 4000IU qd) Calcium intake during puberty: 1300 mg qd (UL 3000 mg qd) Calcium intake ages 19-50: 1000mg qd (UL 2500 mg qd) Calcium intake ages 51-70 males: 1000mg qd (UL 2000 mg qd) Calcium intake ages 51-70 females: 1200mg qd (UL 2000 mg qd) Calcium intake ages >70: 1200mg qd (UL 2000 mg qd) But Controversy Reigns The Endocrine Society Guidelines 25OHD level of 30ng/ml 1500-2000IU Vitamin D qd Calcium recommendations comparable to IOM 2
5/22/2015 Much of our data comes from epidemiologic studies • Associations do not prove causality • We do not know the optimal dose of vitamin D and calcium or the optimal level of 25OHD for most diseases for which it is used • Too much of a good thing may be a bad thing • We need RCTs of sufficient power and duration to answer these questions The Calcium Controversy Is Calcium Supplementation associated with cardiovascular events and myocardial infarction? 3
5/22/2015 Metaanalysis suggesting calcium is hazardous to your health . Mark J Bolland et al. BMJ 2010;341:bmj.c3691 Random effects models of effect of calcium supplementation on cardiovascular events and death. Mark J Bolland et al. BMJ 2010;341:bmj.c3691 4
5/22/2015 But Maybe Not The Effects of Calcium Supplementation on Verified Coronary Heart Disease Hospitalization and Death in Postmenopausal Women: A Collaborative Meta‐Analysis of Randomized Controlled Trials Lewis et al. Journal of Bone and Mineral Research 30:165-175, 2014 The Effects of Calcium Supplementation on All Cause Mortality Lewis et al. Journal of Bone and Mineral Research 30:165-175, 2014 5
5/22/2015 How much calcium do we need? Relation between calcium output (fecal calcium + urinary calcium excretion) and calcium intake Curtiss D Hunt, and LuAnn K Johnson Am J Clin Nutr 2007;86:1054-1063 What About Vitamin D? 6
5/22/2015 THE BIKLE APPROACH TO THE LITERATURE ON VITAMIN D THERAPY • Rule 1: Someone somewhere has found an association between low vitamin D levels and every disease: clinical potential may be limitless • Rule 2: If someone finds a disease with no association to low vitamin D levels, see rule 1 VITAMIN D DEFICIENCY WITH AGING • Decreased vitamin D production in the skin • Decreased vitamin D intake in the diet • Decreased vitamin D absorption by intestine • Decreased 1,25D production by the kidney • Decreased intestinal response to 1,25D 7
5/22/2015 Vitamin D Production in the Skin of Elderly vs Young Adults Following Total Body UVR Holick MF et al., Lancet 2:1104-1105 1989 Declining Ability to Respond to PTH re 1,25D Production with Age Riggs et al J Cell Biochem 88: 209-215, 2002 8
5/22/2015 Decline in Intestinal Calcium Absorption in Response to 1,25D with Age Riggs et al J Cell Biochem 88: 209-215, 2002 How do we judge vitamin D sufficiency? 9
5/22/2015 How much vitamin D does it take to suppress PTH? Depends on basal levels of 25OHD and calcium intake 25(OH)D & SERUM iPTH* 120 120 290 consecutive pts. on a mL) g/mL 100 100 general medical ward – MGH SERUM PTH (pg/ 80 80 60 60 40 40 20 20 0 20 20 40 40 60 60 80 80 100 100 SERUM 25(OH OH)D (nmo mol/L /L) *after Thomas et al., 1998 NEJM;338:777 – 783 10
5/22/2015 Various levels of serum 25OHD (nanograms per milliliter) at which serum PTH (picograms per milliliter) plateaus and/or is maximally suppressed. Sai A J et al. JCEM 2011;96:E436-E446 The relationship between PTH suppression and vitamin D depends on calcium intake S Adami et al Bone 42:267-270, 2008 11
5/22/2015 Response of PTH to Vitamin D Depends on Basal 25OHD Levels Malabanan A et al. Lancet 351:805-806, 1998 How Much Vitamin D is Required to Stimulate Intestinal Calcium Absorption Depends on basal levels of 25OHD 12
5/22/2015 Modest increase in 12-month calcium absorption (percent absorbed) on vitamin D3 doses of 400 – 4800 IU daily in healthy adults. Gallagher J C et al. JCEM 2012;97:3550-3556 How Much Vitamin D is Required for Skeletal Health? Depends on basal vitamin D levels and calcium intake 13
5/22/2015 Serum 25(OH)D and Hip BMD • NHANES-III Non-Hispanic whites • Adults Age 20 – 49 yrs • LOWESS plot of African-Americans slope of BMD on 25(OH)D Hispanics Bischoff-Ferrari HA. Am J Med 2004; 116: 634-9. Lack of increase in BMD with vitamin D supplementation in D replete subjects Baseline values Delta values (value at end of study minus baseline) DD group DP group PP group DD group DP group PP group N 110 97 105 Males (%) 40.0 40.2 39.0 Age (years) 47.3 ± 11.1 47.7 ± 11.6 50.8 ± 10.7 BMI (kg/m 2 ) 34.4 ± 3.9 33.7 ± 3.5* 35.2 ± 3.9 0.01 ± 1.33 0.13 ± 1.10 0.09 ± 1.35 Smokers (%) 20.9 20.6 17.1 BMD L2-L4 1.270 ± 0.155 1.235 ± 0.161 1.251 ± 0.170 0.008 ± 0.036 0.008 ± 0.039 0.007 ± 0.042 (g/cm 2 ) BMD total hip 1.107 ± 0.133 1.067 ± 0.128 1.092 ± 0.130 0.008 ± 0.014 0.011 ± 0.014 0.009 ± 0.017 (g/cm 2 ) OPG (pg/ml) 1875 ± 509 1961 ± 600 2092 ± 650 56 ± 306 1 - 34 ± 472 2 RANKL (pg/ml) 0.09 ± 0.15 0.10 ± 0.27 0.05 ± 0.10 - 0.01 ± 0.10 1 0.00 ± 0.06 2 Serum 25(OH)D 79.9 ± 31.3 † 41.7 ± 22.8 † 61.3 ± 20.7 58.3 ± 21.2 60.1 ± 22.3 - 2.2 ± 16.8 (nmol/L) - 0.9 ± 1.5 † Serum PTH (pmol/L) 5.1 ± 1.6 5.4 ± 1.8 5.7 ± 1.7 - 0.7 ± 1.4* - 0.2 ± 1.6 Serum calcium (mmol/L) 2.30 ± 0.11 2.32 ± 0.11 2.31 ± 0.10 - 0.01 ± 0.12 - 0.02 ± 0.12 - 0.01 ± 0.11 DD 40,000IU D per wk, DP 20,000IU D per wk, PP placebo; all on 500mg Ca/day Jorde et al. Nutrition J 9:1, 2010 14
5/22/2015 Increased osteoid at 25OHD < 50nM Priemel M et al JBMR 25: 305, 2010 FRACTURE RISK ACCORDING TO VITAMIN D DOSE AND 25OHD LEVEL METAANALYSIS OF 12 STUDIES (n=42279) Bischoff-Ferrari HA et al Arch Int Med:169:551- 561, 2009 15
5/22/2015 Fragility and Falls Contribute to Fracture Risk Vitamin D Helps But Doses Required are Moderate Mobility decreases with decreasing 25OHD levels Repeated sit-to-stand 8-foot walk 4.5 16 Sec Sec 15 4 14 3.5 0 20 40 60 80 100 120 140 160 180 200 220 240 0 20 40 60 80 100 120 140 160 180 200 220 240 25-OHD nmol/l 25-OHD nmol/l Bischoff-Ferrari HA et al Am J Clin Nutr 2004;80:752 – 758 . 16
5/22/2015 Physical performance in 1234 older persons in relation to 25-OHD . Wicherts I S et al. JCEM 2007;92:2058-2065 Fall prevention with high dose (700-1000 IU a day) and low dose (200-600 IU a day) of supplemental vitamin D Bischoff-Ferrari H A et al. BMJ 2009;339:bmj.b3692 17
5/22/2015 WHAT ABOUT NON CLASSIC ACTIONS OF VITAMIN D • Prodifferentiation, Antiproliferation • Regulation of Hormone Secretion • Modulation of Immune Function COLORECTAL CANCER • Nurses’ Health Study 1.0 • ages 46 – 78 0.8 • nested case-control Odds Ratio 0.6 study • 193 incident cases 0.4 • 25(OH)D measured 0.2 twice, prior to diagnosis • Feskanich et al., Cancer 0.0 Epidemiol Biomarkers Prev 2004 1st–16 2nd–22 3rd–27 4th–31 5th–40 13:1502 – 08 25(OH)D Quintiles (with medians*) * ng/mL 18
5/22/2015 Epidemiologic Studies are Mixed Table 1: Meta-analyses of human epidemiologic studies Cancer Author n Studies/Analysis Pooled Relative Risks (RR) Ma et al. ⁴ 9 0.88 (0.8-0.96) Vit D Intake A. Colorectal 0.67 (0.54-0.80) 250HD levels Yin et al. ⁵ 10 0.82 (0.69-0.97) 250HD levels Chen et al 12 11 0.91 (0.85-0.97) Vit D intake 8 0.55 (0.38-0.80) 250HD levels B. Breast Gandini et al 19 0.83 (0.79-0.87) a case control (5) 10 250HD levels 0.97 (0.92-1.03) b prospective (5) Gandini et al 19 11 0.99 (0.95-1.03) 250HD levels C. Prostate Gilbert et al 21 13 1.14 (0.99-1.31) Vit D Intake 14 1.04 (0.99-1.10) 250HD levels Bikle, Endocrine 46: 29-38, 2014 19
5/22/2015 Effect of calcium and vitamin D on progression to DM 500mg Ca + 700u D3 Pittas et al Diabetes Care 30:980-86, 2007 placebo No clear benefit of vitamin D + calcium on BP Pittas et al. Ann Int Med 152:307-14, 2010 20
5/22/2015 Potential benefit for preventing MI Giovannucci et al Arch Int Med 168:1174-1180, 2008 Role of Calcium and Vitamin D in Overall Mortality over Time Rejnmark L et al. JCEM 2012;97:2670-2681 21
5/22/2015 Adaptive Immunity Treg Dendritic Cell CD4 - + 25OHD - + - Th17 Th1 Th2 CYP27B1 1,25(OH) 2 D Macrophage or Keratinocyte Innate Immunity + 25OHD + CYP27B1 + Cathelicidin VDR + 1,25(OH) 2 D Macrophage or Keratinocyte 22
5/22/2015 Vitamin D Did Not Enhance TB Rx Vit D 100,000IU days 0, 14, 28, 42 Martineau AR et al. Lancet 377:242-250, 2011 SUMMARY • Vitamin D and calcium deficiency is detrimental to health • The optimal levels of vitamin D intake and 25OHD levels in blood are not established with certainty and may vary with calcium intake and disease process. • Megadoses of vitamin D are NOT indicated and may be detrimental • Calcium has an important synergistic role with vitamin D in maintaining health — calcium does not increase the risk of CVD or death 23
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