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
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
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
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
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
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
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
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
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
How much vitamin D does it take to suppress PTH? Depends on basal levels of 25OHD and calcium intake 25(OH)D & SERUM ipth* 290 consecutive pts. on a general medical ward MGH SERUM PTH (pg/ml) 120 100 80 60 40 20 0 20 40 60 80 100 SERUM 25(OH)D (nmol/l) *after Thomas et al., 1998 NEJM;338:777 783 10
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
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
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
Serum 25(OH)D and Hip BMD NHANES-III Adults Age 20 49 yrs LOWESS plot of slope of BMD on 25(OH)D Non-Hispanic whites African-Americans 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 (g/cm 2 ) BMD total hip (g/cm 2 ) 1.270 ± 0.155 1.235 ± 0.161 1.251 ± 0.170 0.008 ± 0.036 0.008 ± 0.039 0.007 ± 0.042 1.107 ± 0.133 1.067 ± 0.128 1.092 ± 0.130 0.008 ± 0.014 0.011 ± 0.014 0.009 ± 0.017 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 (nmol/l) 61.3 ± 20.7 58.3 ± 21.2 60.1 ± 22.3 79.9 ± 31.3 41.7 ± 22.8-2.2 ± 16.8 Serum PTH (pmol/l) 5.1 ± 1.6 5.4 ± 1.8 5.7 ± 1.7-0.9 ± 1.5-0.7 ± 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
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
Fragility and Falls Contribute to Fracture Risk Vitamin D Helps But Doses Required are Moderate Mobility decreases with decreasing 25OHD levels 8-foot walk Repeated sit-to-stand 4.5 Sec 16 Sec 4 15 14 3.5 0 20 40 60 80 100 120 140 160 180 200 220 240 25-OHD nmol/l 0 20 40 60 80 100 120 140 160 180 200 220 240 25-OHD nmol/l Bischoff-Ferrari HA et al Am J Clin Nutr 2004;80:752 758. 16
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
Odds Ratio 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 ages 46 78 nested case-control study 193 incident cases 25(OH)D measured twice, prior to diagnosis Feskanich et al., Cancer Epidemiol Biomarkers Prev 2004 13:1502 08 1.0 0.8 0.6 0.4 0.2 0.0 1st 16 2nd 22 3rd 27 4th 31 5th 40 25(OH)D Quintiles (with medians*) *ng/ml 18
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) C. Prostate Gandini et al 19 11 0.99 (0.95-1.03) 250HD levels 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
Effect of calcium and vitamin D on progression to DM Pittas et al Diabetes Care 30:980-86, 2007 500mg Ca + 700u D3 placebo No clear benefit of vitamin D + calcium on BP Pittas et al. Ann Int Med 152:307-14, 2010 20
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
Adaptive Immunity Dendritic Cell - CD4 + Treg 25OHD - + - Th1 Th2 Th17 CYP27B1 1,25(OH) 2 D Macrophage or Keratinocyte Innate Immunity + 25OHD CYP27B1 + + VDR + 1,25(OH) 2 D Cathelicidin Macrophage or Keratinocyte 22
Vitamin D Did Not Enhance TB Rx Martineau AR et al. Lancet 377:242-250, 2011 Vit D 100,000IU days 0, 14, 28, 42 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
RECOMMENDATIONS 800-2000 IU vitamin D per day is safe and generally sufficient to achieve a serum level of 25OHD around 30ng/ml. Higher levels have not been proven to be better Rule of thumb: For repletion, supplement with 100IU vitamin D for each 1ng/ml increment of 25OHD desired 800-1200mg calcium per day in adults should suffice to maintain balance in most individuals without malabsorption urine calcium provides a good guide with a goal around 150mg/24hr 24