Vitamin D Replacement ROCKY MOUNTAIN MEETING NOV 2013 BANFF W.COKE UNIVERSITY OF TORONTO

Vitamin D Replacement ROCKY MOUNTAIN MEETING NOV 2013 BANFF W.COKE UNIVERSITY OF TORONTO

Disclosures: (Academic Mea Culpa) No financial conflicts I have no expertise re: Vitamin D.

OBJECTIVES: 1) Review basic metabolism and actions Vitamin D. 2) Examine the challenges interpreting Vit D literature. 1) Replacement recommendations using best available evidence.

Synthesis and Metabolism Vitamin D (ADULTS)

Sources Vitamin D: Sunlight (UV-B) Skin 7-Dehydro Cholesterol Pre vitamin D 3 Diet Foods Natural Vit D 2, D 3 + Fortified Foods Oral Supplement Cholecalciferol (D 3 ) and/or Ergocalciferol (D 2 ) Lumisterol Tachysterol 7-DHC Vitamin D 3 Vit D 3 Vit D 2 Liver 25 OH Vit D (25 OHD) Kidney 1α- hydroxylation 1, 25 Dihydroxy Vit D Inactive Metabolites

Importance Vitamin D: A) CALCIUM and BONE METABOLISM Vit D 3 Vit D 2 (CHOLECALCIFEROL) (ERGOCALCIFEROL) LIVER 25 HYDROXYLATION 25-HYDROXY VIT D (25 OHD) KIDNEY 1, 25 DIHYDROXY 1α- HYDROXYLATION VIT D PARATHYROIDS KIDNEYS SMALL INTESTINE BONE PTH PROX TUBULE ABSORPTION CA ABSORPTION PO 4 REABSORPTION CA and PO 4 OSTEOBLASTS OSTEOCLASTS

Mechanism Action Vitamin D: B) Other 25 OH Vit D 1, 25 Di OH Vit D TARGET ORGANS VDRS Multiple Tissues with 1-α-Hydroxylase MUSCLE CELLS FALLS? COLON RECTUM CANCER RISK IMMUNE SYSTEM : -DENDRITIC CELLS -MACROPHAGES -MONOCYTES -T+B LYMPHS CV SYSTEM BP Control RAS THROMBOGENESIS FIBRINOLYSIS -Autoimmune Disease -DM1 -MS -IBD -Allergies -TB / COPD / Viruses

Problems Associated with Vit D Deficiency: Bone Disease Rickets Osteomalacia Osteoporosis Low trauma fractures Muscle Increased falls

Problems Associated with Vit D Deficiency: Non-MSK Cancer Immune System Type 1 DM MS IBD Allergy Viral Infections Cardiovascular Disease

Potential Causes Vitamin D Deficiency: Sunlight Exposure (UVB) Northern Latitudes Barriers / Blocks Darker Skin?/ Obesity Dietary Intake Cod Liver Oil / Fish / Fish Oils/ Egg yolks Fortified foods Milk / Cereals / Orange Juice Malabsorption IBD Cystic Fibrosis Medications Abnormal Vit D Metabolism

Diagnosis Vit D Deficiency Lab Tests Ca PO 4 PTH levels Vit D assays Bone Density Outcomes Fractures/Falls Other

Diagnosis Vit D Deficiency Ca, PO 4 Vit D Assays 25(OH)D -Lower Limit 50 nmol/l -Upper Limit 80-100 nmol/l -Target Limit > 50 nmol/l I0M > 75 nmol/l US Endo Soc Suppression PTH 67.5 to 75mml/L

Vit D Deficiency and Bone Disease A) Observational Studies: Most show higher risk fractures (hip, vertebrae, wrist, humerus) lower level 25 (0H) D Particularly 25(OH) D < 50 nmol/l NHANES (2005) n=13, 432 46% all adults at risk Vit D Levels falling over time Specific popn s risk

Vit D Deficiency and Bone Disease A) HIGHER RISK POPULATIONS PRIMARY - Elderly - Post Menopausal Women - Decreased Sun Exposure - Obese - Dark Skin - Poor Nutrition - Lower Education SECONDARY - Evidence of Bone Disease OTHER - Malabsorption - Medications

Vit D Deficiency and Bone Disease: B) INTERVENTION TRIALS / RTCS Multiple RCTS/Meta-analyses Mixed results re: fractures Optimal dose Vit D not clear Combination Vit D and Calcium works better Very high dose Vit D (300, 000 to 500, 000 units once yearly) may fractures and falls Meta-analysis 23 RCTS no benefit bone density

B. Interventional Trials / RTCs: Women Health Initiative (WHI) n > 36, 000 F/U > 7 years Vit D 400 Placebo Calcium 1000mg Could take - own supplements - Bisphosphonates - Estrogen (over 50%)

WHI Results: Higher 25 (OH)D in Treatment Group Fracture risk < treatment vs. placebo but minimal Statistically significant only compliant (>80% meds) subset Increased risk renal stones

Vit D and Falls: Animal models Observational studies Interventional studies Most no significant impact balance/gait Meta-analysis Benefits higher doses Vit D 800-1000 units Exercise more effective

Vitamin D and Non MSK Disease: Cancer Immune System disorders Cardiovascular Disease Depression

RECOMMENDATIONS: Primary Prevention Public Health Issues Dietary recommendations Food supplements Exercise No evidence supporting routine Vit D, Calcium Assess 25(OH)D high risk groups Nutrition Canada 400 unit Vit D (over age 50)

RECOMMENDATIONS: A) Severe 25 (OH)D Deficiency 50 nmol/l Start 50, 000 units Vit D 3 (Cholecalciferol) Weekly x 6-8 weeks 1000 mg Calcium daily Maintain 600-800 units Cit D 3 daily 1000 mg Calcium daily (Ca carbonate 1, 250 mg BID) Repeat 25(OH) D level after 3-4 months maintenance dose

B) Secondary Prevention (Osteoporosis) Age group Nutrition IOM Osteoporosis Canada Canada EAR RDA 51-70 Vit D Calcium 70+ 400 400 600 800-1000 800 1000 1, 200 Vit D 400 400 800 800-1000 Calcium 1000 1, 200 1, 200

Vitamin D Supplements Falls Vit D Calcium 800-1000 units 1000 mg Cancer - - Immune System - - CV Disease - - Depression - -

Vit D Supplements: Public Health Approach Dietary intake Sunlight Food supplements Exercise Medications?

Bibliography: General Reviews Up To Date: www.uptodate.com@3013. Update August 2013 Institute of Medicine. Dietary Reference Intakes for Calcium and Vitamin D. Brief Report November 2010 Vanchinathan et al. A Dermatologist s perspective on Vitamin D. Mayo Clin Proc; 2012; 87 (4) 372 Hossein-Nezhad. Vitamin D for health: a global perspective. Mayo Clin Proc. 2013; 88 (7); 720 Papaioannou et al. 2010 clinical practice guidelines for the diagnosis and management of osteporosis in Canada: summary CMAJ 2010. DOI:10.1503/cmaj.100771

Observational studies Bischoff-Ferrari et al. Positive association between 25 (OH)D levels and bone mineral density. Am J Med. 2004; 116:634 Cawley et all. Serum 25-hydroxy vitamin D concentrations and risk for hip fractures. Ann Intern Med 2008; 149: 242 Kochuk et al. Vit D status, parathyroid function, bone turn over and BMD in post menopausal women with osteoporosis. J Bone Min Res 2009; 24:693 Cauley et al. Serum 25-hydroxy vitamin D and the risk of hep and other non spine fractures in older men. J Bone Mine Res. 2010; 25; 545

Questions?

Interventional Trials Grant et al. Oral Vitamin D3 and calcium for secondary prevention of low trauma fractures in elderly people (RECORD) Lancet 2005; 345:1621 Jackson et al. Calcium plus Vitamin D supplementation and the risk of fractures. N Engl J Med. 2006; 354: 669 Tang el al. Use of calcium or calcium in combination with Vitamin D supplementation to prevent fractures and bone loss in people aged 50 years and older; a meta-analysis. Lancet 2007; 370: 657 Salovara et al. Effect of Vitamin D and Calcium on Fracture risk in 65 to 71 year old women. J Bone Miner Res 2010, 25: 1487 Sanders et al. Annual high-dose oral Vitamin D and falls and fractures in older women; JAMA 2010; 303:1815

Chung et al. Vitamin D with or without calcium supplementation for prevention of cancer and fractures; an updated meta-analysis for the US Preventative Services task Force. Ann Intern Med 2011; 155:827 Bischoff-Ferrari et al. A pool analysis of Vitamin D dose requirements for fracture prevention. N Engl of Med 2012; 376:40 Reid et al. Effects of vitamin D supplements on bone mineral density; systematic review and meta-analysis. www.thelancet.com. Oct 2013