Vitamin D and Calcium Therapy: how much is enough DISCLOSURE Daniel D Bikle, MD, PhD Professor of Medicine VA Medical Center and University of California San Francisco Nothing to disclose 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 1
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? Metaanalysis suggesting calcium is hazardous to your health. Random effects models of effect of calcium supplementation on cardiovascular events and death. Mark J Bolland et al. BMJ 2010;341:bmj.c3691 Mark J Bolland et al. BMJ 2010;341:bmj.c3691 2
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 The Effects of Calcium Supplementation on All Cause Mortality Lewis et al. Journal of Bone and Mineral Research 30:165-175, 2014 Lewis et al. Journal of Bone and Mineral Research 30:165-175, 2014 How much calcium do we need? Relation between calcium output (fecal calcium + urinary calcium excretion) and calcium intake What About Vitamin D? Curtiss D Hunt, and LuAnn K Johnson Am J Clin Nutr 2007;86:1054-1063 3
THE BIKLE APPROACH TO THE LITERATURE ON VITAMIN D THERAPY VITAMIN D DEFICIENCY WITH AGING 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 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 Vitamin D Production in the Skin of Elderly vs Young Adults Following Total Body UVR Declining Ability to Respond to PTH re 1,25D Production with Age Holick MF et al., Lancet 2:1104-1105 1989 Riggs et al J Cell Biochem 88: 209-215, 2002 4
Decline in Intestinal Calcium Absorption in Response to 1,25D with Age How do we judge vitamin D sufficiency? Riggs et al J Cell Biochem 88: 209-215, 2002 25(OH)D & SERUM ipth* How much vitamin D does it take to suppress PTH? Depends on basal levels of 25OHD and calcium intake 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 5
Various levels of serum 25OHD (nanograms per milliliter) at which serum PTH (picograms per milliliter) plateaus and/or is maximally suppressed. The relationship between PTH suppression and vitamin D depends on calcium intake Sai A J et al. JCEM 2011;96:E436-E446 S Adami et al Bone 42:267-270, 2008 Response of PTH to Vitamin D Depends on Basal 25OHD Levels How Much Vitamin D is Required to Stimulate Intestinal Calcium Absorption Depends on basal levels of 25OHD Malabanan A et al. Lancet 351:805-806, 1998 6
Modest increase in 12-month calcium absorption (percent absorbed) on vitamin D3 doses of 400 4800 IU daily in healthy adults. How Much Vitamin D is Required for Skeletal Health? Depends on basal vitamin D levels and calcium intake Gallagher J C et al. JCEM 2012;97:3550-3556 Serum 25(OH)D and Hip BMD Lack of increase in BMD with vitamin D supplementation in D replete subjects Baseline values Delta values (value at end of study minus baseline) NHANES-III Adults Age 20 49 yrs LOWESS plot of slope of BMD on 25(OH)D Non-Hispanic whites African-Americans 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 Hispanics 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 Bischoff-Ferrari HA. Am J Med 2004; 116: 634-9. 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 7
6/22/2015 Increased osteoid at 25OHD < 50nM FRACTURE RISK ACCORDING TO VITAMIN D DOSE AND 25OHD LEVEL METAANALYSIS OF 12 STUDIES (n=42279) Priemel M et al JBMR 25: 305, 2010 Bischoff-Ferrari HA et al Arch Int Med:169:551561, 2009 Mobility decreases with decreasing 25OHD levels Fragility and Falls Contribute to Fracture Risk Vitamin D Helps But Doses Required are Moderate 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 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. 8
Physical performance in 1234 older persons in relation to 25-OHD. Fall prevention with high dose (700-1000 IU a day) and low dose (200-600 IU a day) of supplemental vitamin D Wicherts I S et al. JCEM 2007;92:2058-2065 Bischoff-Ferrari H A et al. BMJ 2009;339:bmj.b3692 WHAT ABOUT NON CLASSIC ACTIONS OF VITAMIN D Prodifferentiation, Antiproliferation Regulation of Hormone Secretion Modulation of Immune Function 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 COLORECTAL CANCER Odds Rat io 1.0 0.8 0.6 0.4 0.2 0.0 1st 1st 1st 1st 16 16 16 16 2n 2n 2n 2nd 22d 22 d 22 d 22 3r 3r 3r 3rd 27d 27 d 27 d 27 4t 4t 4t 4th 31h 31 h 31 h 31 5t 5t 5t 5th 40h 40 h 40 h 40 25(OH)D Quintiles (with medians*) *ng/ml 9
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 Effect of calcium and vitamin D on progression to DM No clear benefit of vitamin D + calcium on BP Pittas et al Diabetes Care 30:980-86, 2007 500mg Ca + 700u D3 placebo Pittas et al. Ann Int Med 152:307-14, 2010 10
Potential benefit for preventing MI Role of Calcium and Vitamin D in Overall Mortality over Time Giovannucci et al Arch Int Med 168:1174-1180, 2008 Rejnmark L et al. JCEM 2012;97:2670-2681 Adaptive Immunity Innate Immunity Dendritic Cell - CD4 + Treg + 25OHD - Th1 + Th2 - Th17 25OHD CYP27B1 + + CYP27B1 VDR + Cathelicidin 1,25(OH) 2 D 1,25(OH) 2 D Macrophage or Keratinocyte Macrophage or Keratinocyte 11
Vitamin D Did Not Enhance TB Rx 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 Vit D 100,000IU days 0, 14, 28, 42 Martineau AR et al. Lancet 377:242-250, 2011 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 12