1. Metabolic Bone Disease Dr Neil Hopper

2. Metabolic Bone Disease in Children Rickets Osteogenesis Imperfecta Other –Renal osteodystrophy –Non-OI osteoporosis e.g. Cerebral Palsy –Rarities

3. Rickets Wricken (OE) ‘to bend’ Fully described by Glisson 1650 Deficient mineralisation of growth plate Adult equivalent is Osteomalacia

4. Pathogenesis Defective growth plate mineralisation Inhibition of chondrocyte apoptosis, so transformation to bone inhibited. Disordered cartilaginous growth plate extends laterally Osteomalacia of bone Bone strength compromised leading to bowing

5. Skeletal Clinical Findings Widened wrist and long bone bowing Costochondral enlargement ‘rachetic rosary’ Craniotabes Frontal bossing Harrison’s sulcus Delayed closure of fontanelles

7. Rickets Radiology

8. Extraskeletal features Hypocalcaemia and seizures –At times of rapid bone turnover i.e. Infancy and puberty Muscle hypotonia and delayed milestones Infections Cardiomyopathy

9. Does this child have rickets? Clinical suspicion ALP usually elevated –note age specific reference ranges X-Ray of wrist or knee should be abnormal

10. Causes Majority of cases are due to Vitamin D deficiency Major differential is X-linked hypophosphataemic rickets Rarer causes due to enzyme defects, receptor mutations and calcium deficiency

11. Biochemical workup Bone profile, LFTs PTH 25(OH) Vitamin D3 Save serum Urine Phosphate, Creatinine –to work out Tubular Resorption of Phosphate

12. Expected findings (in Vitamin D Deficiency) High ALP Low 25(OH) Vitamin D3 Calcium may be low or normal Phosphate may be low

13. When to suspect phosphopenic rickets (or rarities) ALP high (may be subtle) PTH normal or marginal Phosphate low and TRP low Lack of response to Vitamin D therapy Family history!

14. Treatment of Vitamin D deficient rickets Pharmacological doses of Vitamin D (Ergo or Cholecalciferol) for 3 months –Under 6m age 3000 IU OD –Over 6m age 6000 IU OD Stoss therapy Then repeat biochemistry and Vit D level Vit D 400 IU per day (Abidec 0.6ml OD) long term Screen sibs and mother

15. Prevention Vitamin D deficiency common in northern England, especially in dark skinned people No effective production from October to March at this lattitude Can be prevented by –Education –Vitamin D supplementation in adult women –Especially during pregnancy and lactation Screening for Vitamin D deficiency in at-risk populations Screening in chronic disease

16. Osteogenesis Imperfecta Group of inherited connective tissue disorders leading to increased bone fragility 1 in 20,000 Mostly an AD mutation in COL1A1 or COL1A2 affecting type 1 collagen

17. Sillence classification TypeDescriptionGene Imild[Null COL1A1 allele] II severe and usually lethal in the perinatal period COL1A1, COL1A2, III considered progressive and deforming COL1A1, COL1A2 IV deforming, but with normal sclerae COL1A1, COL1A2 Types V-IX identified based on histological variants and new gene mutations Type II and severe type III are lethal, type I is common and mild and others share features between

18. Clinical features Family history in 65% Excessive fractures Short stature Scoliosis Basilar skull invagination Blue sclerae Dentinogenesis Imperfecta Hearing Loss Wormian Bones Ligamentous and Cutaneous Laxity

19. Radiology Lethal forms are often detected antenatally on USS Slender, gracile long bones More than 10 Wormian bones Multiple deformities

24. Diagnosis Can be difficult in early days DD involves child abuse but OI much rarer –5000 UK kids PA with unexplained #, 100 OI X ray long bones, skull AP and lateral Blue sclera can be normal in neonates Biochemistry unhelpful COL1A1 and COL1A2 genes can be sequenced Skin biopsy allows collagen analysis in difficult cases

25. OI - treatment Physio Orthopaedic care is difficult and specialised Scoliosis surgery Pain relief Look for signs of basilar invagination –Headache, pseudoulnar palsy, paraesthesia below waist, CN palsy, nystagmus

26. OI - Bisphosphonates Widely used in all types except type VI and mild type 1 Most experience with IV pamidronate Oral agents e.g. Risedronate Osteonecrosis of jaw never seen in paeds Makes bone strong, but brittle, like chalk. Long term effects unknown

27. Questions