Bone Study Day, 28th September 2012 Vitamin D Zulf Mughal Consultant in Paediatric Bone Disorders Department of Paediatric Endocriology Royal Manchester Children's Hospital Manchester M13 0JH Bone Study Day, 28th September 2012

Overview Sources & Metabolism of Vitamin D Musculoskeletal consequences of Vitamin D deficiency Non-musculoskeletal associations of Vitamin D deficiency The Criteria or Definition of Vitamin D deficiency Prevention of Vitamin D deficiency

Vitamin D: Sources & Metabolism

Sources & Metabolism of Vitamin D (7-dehydoxycholesterol) Solar UVB (280-310nm) Endogenous Vitamin D3 Dietary source Vitamin D2 & D3 Oily fish, eggs, fortified foods e.g: Infant formulas Cereals Liver 25-Hydroxyvitamin D (major circulating metabolite) 1,25-Dihydroxyvitamin D DBP 25-hydroxylase (CYP2R1) (7-dehydoxycholesterol) DBP Kidney 24,25-hydroxyvitamin D PTH (+) ↓ P (+) FGF23 (-) 1α hydroxylase (CYP27B1) 24-hydroxylase (CYP24A1) Calcitroic acid

Roles of 1,25-Dihydroxyvitamin D in Bone Mineral Homeostasis Stimulates GI calcium absorption Promotes renal calcium re-absorption Stimulates GI phosphorous absorption Calcium homeostasis: together with PTH it mobilises calcium from skeletal stores Mineralisation of the growth plate & osteoid Low Calcium or Low Phosphorous Radiograph showing Rachitic Changes Normal Growth Plate Rachitic Growth Plate

Factors which contribute to development of Vitamin D deficiency Residence in Northern or Southern Latitudes Pigmented skin Sun blocking creams – Factor 8 ↓ Vit D synthesis by >95% Sunshine avoidance for religious or cultural reasons Cloud Cover & Atmospheric Pollution Obesity Genetic propensity An independent protective effect of meat consumption Low dietary Calcium & High Fibre diets

Maternal & Cord 25-Hydroxyvitamin D Concentrations R=0.98 (p<0.001) N = 22 Lau 2001 (Unpublished) Vitamin D stores acquired during fetal life last ~ 8 weeks

Cutaneous Vitamin D Synthesis

Serum 25(OH) Levels after Simulated Summer Sunlight Exposures in Whites & South Asians South Asians need 4 times longer Exposure 2 Hours of Summer Sunlight Exposure 3 x Week 109 Whites 15 South Asians Farrar et al Am J Clin Nutr. 2011;94(5):1219-24.

Criteria or Definition of Vitamin D Deficiency

Vitamin D Deficiency & Insufficiency Definition of vitamin D deficiency & sufficiency based on serum 25(OH)D concentrations Davies JH & Shaw NJ. Arch Dis Child. 2010 Jul 23. [Epub ahead of print]

Low Calcium Diet & Vitamin D Deficiency

Low Calcium Diet & Vitamin D Deficiency Pune (18.340N) N = 50 Manchester (54.40N) N=51 Age (years) 14.7 ± 0.7 15.3 ± 0.4 Serum 25OHD concentrations < 12 ng/ml 70% 73% PTH > upper end of the reference range 48% 6% Serum calcium concentration < 2.2 mmol/l (%) 74% 0% Non-specific aches and pains (%) 76% 26% Genu Varum or Genu Valgum (%) 44% Dietary vitamin D intake (µg/day) 0.17 1.3 % Ca intake (mg/day) - dairy products 65 (31-76) 401 (195 - 594) Total Ca intake (mg/day) 449 (356 - 538) Data not available Khadilkar, Das, Sayyad, Sanwalka, Bhandari, Khadilkar, Mughal. Low Calcium intake & Hypovitaminosis D in Adolescent Girls. Archives of Disease in Childhood. 2007 ;92(11):1045

Low Calcium & High Fibre Diet and Vitamin D Status High fibre & phytic acid reduce dietary Ca intake Low Ca intake leads to secondary hyperparathyroidism & raised serum 1,25(OH)2D concentration Raised serum 1,25(OH)2D concentration degrades 25OHD to inactive 24,25-dihydroxyvitamin D, thereby depleting body stores of vitamin D Clements et al. Nature 1987;325:62–5 Vitamin D Dietary Ca

DIETARY CALCIUM INTAKE 1 ml ~ 1mg RNI (mg/day) in the UK Infants up to 1 yr 525 Children 1- 3 yrs 350 Children 2-6 yrs 450 Children 7-10 yrs 550 Adolescent boys 11-18 yrs 1000 Adolescent girls 11-18 yrs 800 1 oz ~ 200 mg 1 pot ~ 150 mg ~ 35 mg/slice 1 Bowl ~ 80 mg

Vitamin D Deficiency & Muscle

Vitamin D Deficiency & Myopathy 8th April 09 5th May 09 Pre Rx Post Rx 25(OH)D (ng/ml) <2 27.1 PTH (ng/ml) (10-60) 593 90 Calcium (mmol/l) (2.15 – 2.65) 1.38 2.23 Phosphate (mmol/l) (1.0 – 1.8) 1.68 1.43 Alk Phos (I/U) 1020 592 14 year old female Limb pains Difficulty walking & Climbing stairs Life long intolerance of dairy products (Ca intake <300 mg/day) Arrived from Saudi Arabia 8 months ago DIAGNOSIS: Severe vitamin D deficiency & low calcium intake Rx: Single orally dose 180, 000 IU Vitamin D3 + 500mg/day Ca supplement

Life threatening Cardiomyopathy in Early Infancy 16 infants (6 South Asian, 10 Black ethnicity) admitted to GOS with Heart Failure Median age 5.3 months (3 weeks - 8 months);12 exclusively breast-fed 12 needed inotropic support 8 ventilated & 2 needed ECMO 2 referred for cardiac transplantation 6 suffered a cardiac arrest & 3 died! Median (range) Reference range Calcium (mmol/L) 1.50 (1.07 – 1.74) 2.17 – 2.44 PTH (pmol/L) 34.3 (8.9 – 102) 0.7 – 5.6 25OHD (nmol/L) 18.5 (0.00 – 46) >50 Fractional shortening (%) 10 (5-18) 28 – 45 Left ventricular end diastolic dimension Z score 4.1 (3.1-7) -2 < +2 Maiya S et al .Hypocalcaemia and Vitamin D deficiency: an important, but preventable cause of life threatening infant heart failure.Heart. 2007 Aug 9; [Epub]

Non-Musculoskeletal Consequences of Vitamin D Deficiency

Possible Consequences of Vitamin D Deficiency Holick BMJ June 2008;336:1318-1319

Vitamin D & Innate Immunity Toll like receptors recognise pathogens   expression of VDR & CYP27B1 enzyme 25(OH)D  1,25(OH)2D 1,25(HO)2D leads to production of antimicrobial proteins (AMPs) AMPs (e.g. Cathelcidin) important role in defence against bacterial & viral infections Adequate serum 25(OH)D

Vitamin D Deficiency & Pneumonia New RMCH July 2009

Tropical Medicine & International Health 2010;15 (10), 1148–1155 Effects of Vitamin D supplementation in children diagnosed with pneumonia in Kabul: A randomised controlled trial Proportion of children free of a repeat episode of pneumonia up to 90 days post-treatment Rx of 1-36 month olds with 100,000 i.u. Vitamin D3/Placebo + antibiotics DID NOT reduce the duration of illness (p=0.17) DID reduce readmission to hospital with pneumonia (p=0.01) Manaseki-Holland S, Qader G, Masher M I, Bruce J. Mughal M Z, Chandramohan D, Walraven G, Effects of Vitamin D supplementation to children diagnosed with pneumonia in Kabul:  A randomised controlled trial. Tropical Medicine & International Health 2010;15 (10), 1148–1155

Vitamin D Supplementation to Infants in Kabul had NO effect on the incidence of Pneumonia: A randomised controlled trial Proportion of Children without First or Only Episode of X-Ray Confirmed Severe & Non-Severe Pneumonia 3,406 infants randomised to 100,000 i.u. Vitamin D3 or Placebo every 3-monthly, for 18 months Subjects visited fortnightly to assess their health status Subjects with signs of pneumonia had a chest radiograph to confirm the diagnosis of pneumonia. No difference in the incidence of pneumonia between the vitamin D and the placebo group Manaseki-Holland, Maroof, Bruce, Mughal, Masher, Bhutta, Walraven, Chandramohan Effect on the incidence of pneumonia of vitamin D supplementation by quarterly bolus dose to infants in Kabul: a randomised controlled superiority trial LANCET .2012;14;379(9824):1419-27

Summary Subclinical vitamin D deficiency is very common in the UK Severe vitamin D deficiency is associated skeletal muscle weakness & cardiomyopathy. No clear definition of vitamin D deficiency based on serum 25(OH)D levels in children. Pragmatic lower limit of vitamin D sufficiency – 20 ng/ml or 50 nmol/l. Adequate dietary calcium intake is important in order to prevent vitamin D breakdown. Musculoskeletal symptoms of vitamin D deficiency are less likely to occur when dietary calcium intake is adequate & serum PTH is normal. Vitamin D deficiency may be associated with increased risk of infections, autoimmune disorders, respiratory diseases & certain cancers. RCTs needed to confirm these associations!

Thank You zulf.mughal@cmft.nhs.uk