Vitamin D and Calcium in Childhood A/Prof Craig Munns The Children’s Hospital at Westmead University of Sydney Australia Conflicts of Interest • Consultant for Pfizer and Sanofi • Research grants from – Novartis – BioCeuticals Outline • Vitamin D physiology – Bone and Mineral – Non-calcaemic • Simple Vitamin D deficiency rickets • Calcium and bone health • Cases • Recommendations Vitamin D Metabolism 7-dehydrocholesterol Solar UVB Skin Previtamin D3 Heat Vitamin D3 Vitamin D-25 hydroxylase Liver 25-hydroxyvitamin D3 25(OH)-1α-hydroxylase CYP27B1 Dietary Vitamin D2 (Ergocalciferol) or Vitamin D3 (Cholecalciferol) CYP24 24,25-dihydroxyvitamin D3 Kidney 1,25-dihydroxyvitamin D3 Vitamin D Receptor (VDR) Function of Vitamin D Hormone and a Cytokine • Hormone – Endoskeleton – 1,25(OH)2D3 produced by the kidney – Circulating regulator of mineral and skeletal homeostasis • Cytokine – Primitive function – 1,25(OH)2D3 produced by macrophage CYP27B1 – Intracrine modulator of the innate immune system – Interacts with VDR-expressing T- and B-lymphocytes Adams et al JCEM 2009;95(2) Maintenance of 1,25(OH)2D3 • Hormone – When 25OHD supply inadequate rely on renal CYP27B1-hydroxylase to maintain or increase production of 1,25(OH)2D3 via secondary hyperparathyroidism • Cytokine – Deficiency of 25OHD to extrarenal CYP27B1hydroxylase leads to deficient 1,25(OH)2D3 Adams et al JCEM 2009;95(2) What Happens When the Hormone Vitamin D is not Maintained – PTH and FGF23? Hypocalcaemia ↑Calcium Calcium sensing receptor Parathyroid gland (PTH) PTH/PTHrP receptor (Kidney) 24,25(OH)2D3 CYP24 25OHD CYP27B1 1,25(OH)2D3 Bone and Gut FGF23 Calcium and phosphate from bone VDR Intestinal calcium and phosphate absorption What Happens When Vitamin D the Hormone is not Maintained? Hypocalcaemia Hyperparathyroidism ↑Alkaline phosphatase Hypophosphataemia Osteomalacia and Rickets Vitamin D Deficiency “Nutritional Rickets” Countries with Reports on Vitamin D Deficiency North America Canada U.S South America Argentina Chile Columbia Europe Asia Africa/M.East Algeria Denmark Finland France Netherlands Norway Spain Sweden U.K Australia Bangladesh China India Israel Japan Kuwait Lebanon Mongolia New Zealand Vietnam Ethiopia Kenya Nigeria Sudan S Africa Saudi Arabia Yemen Case • y/o female • 14 months of age referred to orthopaedics for lower extremity bowing • “This isn't physiological bowing” Case • Only child of non-consanguineous Bangladeshi parents – recent immigrants to Australia • LSCS at 40 weeks gestation • Breast fed until 10 months of age • Cow’s milk • Developmentally normal • Lower extremity bowing from 12 months of age Case • • • • • Good growth Clinical rickets Normal teeth Closed fontanelle Frontal bossing 10th centile Further Investigations • Calcium 2.46 mmol/L (2.10-2.65) • Phosphorus 1.10 mmol/L (1.20-1.65) • Magnesium 0.81 mmol/L (0.71-0.96) • Alk-phos 768 U/L (140-360) • 25-(OH)vit D 32 nmol/L (>50) • PTH 14.7 pmol/L (1.0-7.0) Case • Only child of non-consanguineous Bangladeshi parents – recent immigrants to Australia • Mother 27 y/o – – – – y/o diagnosed with rickets No medical treatment – surgery ages 13 years Continues to have leg pains Height 145 cm (50) • PTH 17.4 pmol/L (1.0-7.0) Treatment of Child • Cholecalciferol 5000 IU daily for months • Calcium 250 mg twice daily for months Months Baseline mon Calcium (2.1-2.6 mmol/L) Phosphoru s 2.46 2.40 1.18 1.21 768 640 mon mon (1.2-2.1 mmol/l) Alk Phos (140-360 IU/L) PTH (1-7 pmol/l) 25-OHD (>50 nmol/L) 14.7 8.0 32 >250 Baseline months Continue Vit D 400 IU daily Calcium 250 mg twice daily Question • Why minimal improvement in rickets? a Poor compliance (daily therapy) b Vitamin D deficiency was only part of the story Months Baseline months months mon Calcium (2.1-2.6 mmol/L) 2.46 2.40 2.36 Phosphorus (1.2-2.1 mmol/L) 1.18 1.21 0.96 Alk Phos (140-360 IU/L) 768 640 756 PTH (1-7 pmol/L) 14.7 8.0 6.8 25-OHD (>50 nmol/L) 32 >250 69 Phosphate 750mg daily Calcitriol 0.2 mcg bd TmPO4 / GFR = 0.80 mmol/L (1.2-2.1) Months Baseline months months months Calcium (2.1-2.6 mmol/L) 2.46 2.40 2.36 2.43 Phosphorus (1.2-2.1 mmol/L) 1.18 1.21 0.96 1.19 Alk Phos (140-360 IU/L) 768 640 756 652 PTH (1-7 pmol/L) 14.7 8.0 6.8 2.8 25-OHD (>50 nmol/L) 32 >250 69 71 PHEX mutation testing positive Good Growth and Resolution of Rickets Recommendations • Always consider vitamin D deficiency • Check vitamin D levels annually* • High dose therapy to establish sufficiency – Recheck 25OHD at months • Lower dose maintenance – compliance • Consider secondary causes of vitamin D deficiency and other causes of rickets • When treating rickets always include Calcium • serves of calcium daily (600mg) adequate Treatment Thank you [...]... Hypertension Vitamin D and Cardio-metabolic Risk • Study of 3577 adolescents in NHANES survey • 25 OH Vitamin D levels inversely related to systolic blood pressure and fasting glucose • Odds ratio of 3.9 for metabolic syndrome in those with low vitamin D (65nmol/L) • Data adjusted for age, gender, race, physical activity and BMI Reis JP et al, Pediatrics...Features of Vitamin D Deficiency • • • • • • • • • • Hypocalcaemic seizure Rickets Osteomalacia Limb deformity Developmental delay and myopathy Fracture Bone pain Delayed tooth eruption and enamel hypoplasia Raised intracranial pressure Cardiomyopathy Osteomalacia Normal Osteomalacia Bone Marrow Osteoid Bone Marrow Mineralised Bone Mineralised Bone Pediatric Bone; 2003 Typical Radiology and Biochemistry... 2009;124:e371-379 Vitamin D supplementation in infancy and development of type 1 diabetes Zipitis C S , Akobeng A K Arch Dis Child 2008;93:512-517 ©2008 by BMJ Publishing Group Ltd and Royal College of Paediatrics and Child Health Vitamin D and Tuberculosis (Innate Immunity) • RCT of high dose Vitamin D in adults with pulmonary tuberculosis • Primary outcome: Time to sputum culture conversion • Randomised to placebo... of vitamin D – – – – Maternal vitamin D deficiency Prolonged breast feeding Darker skin colour – Recent Migrants Limited sun exposure • Disability • Clothing • Sunscreen – Limited intake of food / supplements with vitamin D • Abnormal gut function / malabsorption – Small bowel: Coeliac disease – Pancreatic insufficiency: Cystic fibrosis – Biliary obstruction • Reduced synthesis / increased degradation... CYP27B1-hydroxylase and/ or vitamin D receptor (VDR) – Monocytes – Activated T and B cells – Pancreas (β cells) – Prostate – Breast – Colon – Heart – Gonads – Brain Bikle et al ASBMR Primer 2009 Vitamin D Deficiency and Adverse Health Outcomes • Epidemiological studies and RCT’s Hip fractures and risk of falls in the elderly Periodontal disease Colorectal Cancer • Weaker evidence Multiple Sclerosis Tuberculosis... pmol/L (1.0-7.0) Diagnosis • Simple vitamin D deficiency rickets with dietary calcium deficiency Treatment • Standard daily Cholecalciferol for 3 months: – >12 months: 5000 IU (125mcg) • Calcium 600gm daily • Maintenance therapy – 400 IU daily Munns et al MJA 2006; 185(5) Follow-up of Case 1 6 months 18 months 30 months Case 2 Case 2 • • • • 3 month old female Irritable Painful leg and bruise No history... (100,000 iu) of Vitamin D3 at baseline, 14, 28 and 42 days • 126 subjects – 60% had Vitamin D levels less than 20 nmol/l at baseline • Mean Vitamin D level of 101.4 nmol/l in intervention group Martineau AR et al Lancet 2011;377:242-250 Martineau AR et al Lancet 2011;377:242-250 What level of Vitamin D is Deficient? • Depends on whether you think vitamin D is important just for bone or not • If bone then... nmol/L = mild deficiency (↑Alkaline phosphatase and PTH) – 12.5-25 nmol/L = moderate deficiency (↑Rickets and hypocalcaemia) – ... 25(OH)-1α-hydroxylase CYP27B1 Dietary Vitamin D2 (Ergocalciferol) or Vitamin D3 (Cholecalciferol) CYP24 24,25-dihydroxyvitamin D3 Kidney 1,25-dihydroxyvitamin D3 Vitamin D Receptor (VDR) Function of Vitamin. .. • Calcium and bone health • Cases • Recommendations Vitamin D Metabolism 7-dehydrocholesterol Solar UVB Skin Previtamin D3 Heat Vitamin D3 Vitamin D- 25 hydroxylase Liver 25-hydroxyvitamin D3 ... for Vitamin D Deficiency • Reduced intake or synthesis of vitamin D – – – – Maternal vitamin D deficiency Prolonged breast feeding Darker skin colour – Recent Migrants Limited sun exposure • Disability