VITAMIN D: MORE THAN GOOD FOR BONES Daniel D Bikle, MD, PhD Professor of Medicine and Dermatology UCSF and SFVAMC Liver P Ca 1,25(OH)2D FGF23 Kidney P Ca PTH FGF23 1
SERUM LEVELS OF MAJOR VITAMIN D METABOLITES 1,25(OH) 2 D! RXR! VDR! Coactivator! complex! Initiation! complex! RNA! Polymerase II! Translation! Start Site! mrna! Protein! Classical Actions: Bone Mineral Homeostasis Gut The Players Blood Bone Ca, P 25 OHD FGF23 PTH Kidney Parathyroid Glands Urine Ca P 1,25(OH) 2 D 2
Classical Actions: Bone Mineral Homeostasis Gut Hormonal Feedback Loops Bone 25 OHD FGF23 PTH Kidney Parathyroid Glands 1,25(OH) 2 D Classical Actions: Bone Mineral Homeostasis Mineral Feedback Loops Gut Blood Ca, P Bone 25 OHD FGF23 PTH Kidney Parathyroid Glands Ca Urine P 1,25(OH) 2 D NON CLASSIC TISSUE DISTRIBUTION OF VDR Hematolymphopoietic Activated T and B lymphocytes Lymph nodes Macrophages Monocytes Spleen Thymus Reticular cells Lymphocytes Tonsillar dendritic cells Unactivated lymphocytes Muscle Heart Atria1 myoendocrine cells Muscle cells Skeletal muscle Smooth muscle Pyloric sphincter Reproductive Amnion Chorioallantoic membrane Eggshell gland Epididymis Mammary gland Alveolar and duct cells Ovary Oviduct Placenta Prostate Testis Seminiferous tubule/sertoli cells Interstitial tissue/leydig cells Uterus (mammalian) Yolk sac From MR Walters Endocrine Reviews 13:719, 1992 Nervous Brain Hippocampus Cerebellum Purkinje cells Granule cells Bed nucleus Stria terminalis Amygdala central nucleus Sensory ganglia Spinal cord Endocrine tissues Adrenal medulla Cortex Pancreas bcells Pituitary Thyroid Follicular cells C Cells Parathyroid gland Skin Epidermis Fibroblasts Hair follicles Keratinocytes Melanocytes Sebaceous glands Other tissues: Alimentary tract epithelium Bladder Choroid plexus Endothelial cells Gills Liver Lung Parotid gland 3
TISSUE DISTRIBUTION OF CYP27B1 (1OHASE) Tissue RNA Protein Activity Proximal tubules ** ** *** Epidermis, hair follicle (keratinocytes) ** ** ** Placenta ** ** n.d. Brain (purkinje cells) ** ** n.d. Pancreas (beta cells) ** ** * Colon ** ** n.d. Breast * ** * Ovary * * * Endothelium ** ** * Dendritic cells *** *** *** Macrophages *** *** *** Adrenal medulla * * n.d. Parathyroid * * n.d. From Townsend et al J Ster Bioc Mol Biol:97: 103-109, 2005 VITAMIN D DEFICIENCY IS NOT RARE The percent of the older population reaching 80 nmol/l serum vitamin D Age 60+ in NHANES III % Bischoff-Ferrari HA et al. American Journal of Medicine 2004 4
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 5
GI DISEASE BIG CAUSE OF VITAMIN D DEFICIENCY: OFTEN UNRECOGNIZED INCIDENCE OF BONE DISEASE IN GI DISORDERS Postgastrectomy: up to 70%, increases with age Celiac Disease: up to 80% if untreated Crohns Disease: up to 30%, affects the young Bariatric surgery: up to 60%, depending on procedure THE 25(OH)D CONTINUUM rickets/osteomalacia osteoporosis normal 0 25 50 75 100 125 150 (nmol/l) 6
3/19/10 WHAT IS THE BASIS FOR CHOOSING 80nmol/l TO DEFINE VITAMIN D SUFFICIENCY? NB: the conversion factor between ng/ml and nmol/l is 2.5. 32ng/ml=80nmol/L VITAMIN D STATUS & Ca ABSORPTION What is the desirable serum 25-OHD level for optimal lower extremity function? 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. 7
Long-Term Effect of Vitamin D and Calcium on the Rate of Falling in ambulatory Older Persons 246 women, 199 men Age: 65 years+ Randomized, double-blind, controlled trial Calcium 500 mg/day + vitamin D 700 IU/day Placebo 3-year duration Mean serum 25(OH)D 67 nmol/l at baseline P < 0.05 all inactive Adapted from Bischoff-Ferrari HA et al Archives of Internal Medicine 2006 Effect was neutral in men Forest Plot Meta-analysis: Effect of vitamin D on falls 800 IU 800 u800 IU IU 700 IU 0.5 µg 1 µg 400 IU pooled corrected OR = 0.78; 95% CI [0.64, 0.92] (n= 1237) Bischoff-Ferrari HA et al.; JAMA 2004 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. 8
Fracture Efficacy by achieved 25(OH)D levels WHI RR = 0.88 Hip fracture Any non-vertebral fracture Record RR = 1.01 46 to 59 21 to 62 Meta-regression: p = 0.02 Meta-regression: p = 0.03 Bischoff-Ferrari HA et al. JAMA 2005 NON CLASSIC TARGET TISSUES AND RESPONSES PROVIDE ADDITIONAL REASONS FOR MAINTAINING ADEQUATE VITAMIN D LEVELS Prodifferentiation, Antiproliferative Actions Regulation of Specific Hormone Secretion Modulation of Immune Function CANCER EPIDERMIS 25OHD 7DHC D 3-1,25(OH) 2 D + - Differentiation Differentiation + 25OHD 3 1,25(OH) 2 D 3 - - Proliferation Proliferation Adequate 25OHD may protect against cancer and various hyperproliferative diseases of the skin 9
CALCIPOTRIENE + UVB RX OF PSORIASIS From Rogers Dermatol Nursing 18:258-61, 2006 BREAST CANCER MORTALITY US breast CA deaths (1970 1994) vs. solar UV exposure Grant, WB Cancer 2002; 94:1867 75 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 P = 0.02 25(OH)D Quintiles (with medians*) *ng/ml 10
PROSPECTIVE TRIAL WITH VITAMIN D Lappe et al AJCN 85:1586-91, 2007 CANCERS BY SITE AND TREATMENT GROUP Years 1-5 Years 2-5 Site Placebo (n = 288) Calcium only (n = 445) Vitamin D plus calcium (n = 446) Placebo (n = 266) Calcium only (n = 416) Vitamin D plus calcium (n = 403) Breast(n) 8 6 5 7 6 4 Colon (n) 2 0 1 2 0 0 Lung (n) 3 3 1 3 2 1 Lymph, leukemia, myeloma (n) 4 4 2 4 4 2 Uterus (n) 0 2 1 0 1 0 Other (n) 3 2 3 2 2 1 Total 1 20 (6.9) 17 (3.8) 13 (2.9) 18 (6.8) 15 (3.6) 8 (2.0) L Hormonal Regulation by and of 1,25(OH) 2 D Pancreas Bone 25 OHD Insulin FGF23 PTH Kidney Renin 1,25(OH) 2 D Parathyroid Glands 11
25(OH)D & SERUM ipth* 290 consecutive pts. on a general medical ward MGH PTH minimum *after Thomas et al., 1998 NEJM;338:777 783 Vitamin D/Calcium Interactions S Adami et al Bone 42:267-270, 2008 TWO FINNISH STUDIES ASSOCIATING 25OHD LEVELS AND DEVELOPMENT OF TYPE 2 DM (highest quartile 69nM vs lowest quartile 22nM) Knekt et al E;pidemiology 19:666-671, 2008 12
Effect of calcium and vitamin D on progression to DM Pittas et al Diabetes Care 30:980-86, 2007 500mg Ca + 700u D3 placebo Vitamin D in the aetiology of type 2 diabetes: published studies in humans Study parameters Study design Type of subjects studied (age at study) Study results Vitamin D intake via supplementation 2,000 IU/day (50 g) for 1 month Observat ional Vitamin D-deficient women (adulthood) Improved glucose tolerance and improved beta cell function Vitamin D intake via supplementation 2,000 IU/day for 6 months Casecontrol Vitamin D-deficient subjects (adulthood) Improved insulin secretion Vitamin D intake via single i.m. injection 100,000 IU/day Casecontrol Vitamin D-deficient subjects (adulthood) Improved insulin and C-peptide responses 1,25(OH) 2 D 3 treatment 0.5 g/day for 21 days (or +500 mg Ca 2+ ) Casecontrol Uraemic women (adulthood) Improved first-phase insulin secretion and insulin sensitivity 1,25(OH) 2 D 3 treatment 1 g/day for 4 days Casecontrol Type 2 diabetic women (adulthood) Improved insulin and C-peptide responses to Sustacal (Mead Johnson, Evansville, IN, USA) Hypovitaminosis (<5 ng/ml) Observat ional Type 2 diabetic women (adulthood) Decreased 25-hydroxyvitamin D 3 levels decreased beta cell function Vitamin D intake via supplementation 1,332 IU/day for 1 month Casecontrol Type 2 diabetic women (adulthood) Improved first-phase insulin secretion Vitamin D intake via single i.m. injection 300,000 IU/day Observat ional Type 2 diabetic men and women (adulthood) Increased insulin resistance From C Mathieu et al. Diabetologia 48:1247-57, 2005 The antihypertensive effects of vitamin D Pilz, S. et al. (2009) Vitamin D status and arterial hypertension: a systematic review Nat. Rev. Cardiol. doi:10.1038/nrcardio.2009.135 13
Findings from cross sectional studies of 25(OH)D and blood pressure Pilz, S. et al. (2009) Nat. Rev. Cardiol. 6:621 ASSOCIATION OF 25OHD LEVELS WITH DEVELOPMENT OF MI Giovannucci et al Arch Int Med 168:1174-1180, 2008 LOWEST ALL CAUSE MORTALITY ASSOCIATED WITH 25OHD BETWEEN 30-40ng/ml Melamed et al Arch Intern Med 168:1629-1637, 2008 14
VITAMIN D and IMMUNE FUNCTION DEFINITIONS Adaptive Immunity: Mediated by cells specialized in antigen presentation, eg. dendritic cells, and by cells responsible for antigen recognition, eg. T and B lymphocytes Innate immunity: Characterized by rapid responses largely based on proinflammatory mediators such as cytokines, chemokines, and reactive oxygen species triggered by recognition of stereotyped patterns in infectious microorganisms by toll-like receptors found in many cells. ADAPTIVE IMMUNITY Vitamin D suppresses 15
Adaptive Immunity Dendritic Cell 25OHD - - + - + CYP27B1 1,25(OH) 2 D Macrophage or Keratinocyte Examples of VDR agonist treatment in animal models of autoimmune diseases Experimental models Arthritis Autoimmune diabetes Experimental allergic encephalomyelitis Inflammatory bowel disease Psoriasis Systemic lupus erythematosus Main effects Decreased incidence and severity of collagen-induced or Lyme arthritis, also when given at disease onset Inhibition of insulitis and reduction of diabetes, even when given after islet infiltration Prevention and treatment of disease, inhibition of relapses Significant amelioration of symptoms, block of disease progression Inhibition of leukocyte activation and amelioration of histological and clinical signs of disease in human psoriatic skin grafts transplanted to SCID mice Inhibition of proteinuria, prevention of skin lesions From L Adorini Cell Immunol 233:115-124, 2005 INNATE IMMUNITY Vitamin D potentiates 16
Innate Immunity TLR + Macrophage or Keratinocyte TWO EXAMPLES OF INNATE IMMUNITY REGULATED BY VITAMIN D Schauber, J. et al. J. Clin. Invest. 2007;117:803-811 VITAMIN D & INNATE IMMUNITY* Mycobacterium 25OHD 1,25D Cyp27B1 VDR Cathelicidin Cyp24 Courtesy of Robert Heaney *Liu et al., Science 2006 17
CIRCULATING 25OHD LEVELS IMPORTANT serum 25(OH)D: 78 nmol/l serum 25(OH)D: 22 nmol/l Courtesy of Robert Heaney *Liu et al., Science 2006 VITAMIN D & TUBERCULOSIS* 67 pts with pulmonary TB standard treatment for all in addition, randomized to either vit D 10,000 IU/d or placebo P = 0.002 Courtesy of Robert Heaney *Nursyam et al., Acta Med Indones 2006 THE INNATE IMMUNE RESPONSE IS LACKING IN THE ANIMAL UNABLE TO PRODUCE 1,25(OH)2D Schauber, J. et al. J. Clin. Invest. 2007;117:803-811 18
HOW TO TREAT VITAMIN D DEFICIENCY VITAMIN D SOURCES 25(OH)D RESPONSE TO ORAL D 3 66 males aged 38.7 yr (± 11.2 ) dosed with vit D 3 from October through February D3 dose (IU/d) 10,000 5,000 1,000 0 Heaney et al AJCN 77:204-210, 2003 100IU D3 daily increases 25OHD3 by 1ng/ml 19
D 2 vs. D 3 * single oral dose 50,000 IU D 2 or D 3 n = 10 in each group D 3 D 2 *Armas et al., 2004 SUMMARY Vitamin D deficiency is not rare Vitamin D itself is the best treatment The levels of vitamin D required to prevent rickets or osteomalacia are inadequate to optimize BMD, intestinal calcium absorption and muscle function resulting in increased falls and fractures Newly recognized functions such as cancer prevention, insulin secretion, adaptive and innate immunity also may require higher than normal vitamin D levels The target 25OHD level is around 80nmol/l or 32ng/ml 20