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Osteoporosis in Children Dr Raja Padidela Consultant Paediatric Endocrinologist.

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Presentation on theme: "Osteoporosis in Children Dr Raja Padidela Consultant Paediatric Endocrinologist."— Presentation transcript:

1 Osteoporosis in Children Dr Raja Padidela Consultant Paediatric Endocrinologist

2  Forms of osteoporosis in children  Pathophysiology and genetics of Osteogenesis Imperfecta  Types of Osteogenesis Imperfecta  Investigations  Supportive Care  Bisphosphonate therapy  Cases OUTLINE

3 Osteoporosis l Osteoporosis in childhood is defined as reduced bone mass for body size and the presence of significant fracture

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6 l OI is a condition of extreme fragility of the bones. l OI is the most common cause of primary osteoporosis l Osteoporosis is defined as reduced bone mass for body size and presence of significant fractures What is Osteogenesis Imperfecta (OI)?

7 Collagen Fibres Structure of a Long Bone Structure of a Long Bone

8 Type 1 Collagen is the predominant collagen in bones Type 1 Collagen is the predominant collagen in bones Type 1 collagen is formed by two α 1 chains and one α 2 chain α 1 chain is coded by COL1A1 gene α 2 chains are coded by COL1A2 gene Mutations in the gene leads to OI

9 OI - Sillence Classification Type I - mild with blue/grey sclera Type II – usually lethal Type III – multiple fractures with deformities of limbs & spine deformities of limbs & spine Type IV - intermediate between types I & III IVa – : Normal teeth IVa – : Normal teeth IVb – : Dentinogenesis Imperfecta Loose joints, Thin & smooth skin, Blue/grey sclera, Wormian bones, Dentinogenesis imperfecta, Presenile deafness. Inheritance AD

10 OI – Types V  Type V - Similar to Type IV but form hypertrophic callus - Calcification of the interosseous membrane - Dense metaphyseal band on x-ray - No mutations in type 1 collagen - No mutations in type 1 collagen Inheritance AD

11 Family Tree of J Affected Unaffected

12 Recessive forms of OI Type VI – More severe than OI Type IV Type VI – More severe than OI Type IV Vertebral compression fractures, no mutations in type 1 collagen Type VII- Type VII- Moderately severe. Rhizomelic in both arms and legs; femurs and humeri are very bowed. White sclerae (CRTAP mutation) Type VIII- Type VIII- Very severe/lethal. Round face, white sclerae, thin ribs. Common in Pakistan, W Africa and Ireland (LEPRE1 mutation)

13 Incidence and prevalence of OI l A Danish study of a geographically defined population observed population prevalence 10.6 per 100,000. l Overall OI has an incidence of between 1 in 10,000 to 1 in 20,000. l Approximately two thirds of those surviving infancy are at the mild end of the spectrum.

14 Teeth in OI Type IV

15 OI - Investigations No definitive biochemical or imaging marker for OI X-ray Generalised osteoporosis of axial and appendicular skeleton Milder forms- Thin, slender bones with thin cortices Severe forms- Broad, shortened long bones with multiple fractures complicated by hyperplastic callous formation Skull X-ray for Wormian bones Vertebral X-ray for crush fractures Bone Mineral Density Scans MUTATIONS IN GENES CODING FOR TYPE I COLLAGEN Molecular biology tests to look for mutations in COL1A1 and COL1A2 genes responsible for production of Type 1 collagen

16 Radiological changes in OI

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18 OI-AR

19 OI-AR

20 Management Multidisciplinary Approach!!

21 Supportive Care  Occupational therapy  Physiotherapy Assessment: posture, hypermobility, joint contractures, posture & gait  Liaison with school + local services  Advice about handling and day-to-day care  Medical specialists- Orthopaedics, Dentist, Spinal, Neurologist

22 Treatment with Bisphosphonates

23  Bisphosphonates are taken up by osteoclasts and cause apoptosis  Net effect: Reduced bone resorption and an increase in bone mineral density Effects of Bisphosphonates on Bone

24 Copyright ©2005 BMJ Publishing Group Ltd. Shaw, N J et al. Arch Dis Child 2005;90: Figure 2 Cascade of events triggered by administration of a bisphosphonate. Apoptosis of Osteoclasts

25 Bisphosphonates in OI  30 children with severe to moderately severe OI  I.V. Pamidronate every 4 to 5 monthly for 1.3 to 5 years  Fracture incidence ↓ by 1.7 per year  Mobility & ambulation improved in 16 children  4 wheelchair bound children → independent walking  No evidence of an adverse effect on longitudinal growth  Metacarpal cortical width ↑ by 27% per year  Mean Spinal areal BMD ↑ by 42 ± 29% per year  ↓  ↓ in urinary N-linked Telopeptide Glorieux, Bishop, Plotkin et al N. Eng. J. Med. 1998; 339 (14),

26 Bisphosphonates in OI Glorieux, Bishop, Plotkin et al N. Eng. J. Med. 1998; 339 (14),

27 Bisphosphonates in OI Before Rx After Rx  Iliac Crest biopsies in OI patients before & 2.4 years after cyclical IV Pamidronate Rx  Cortical width ↑ by 88%  Trabecular volume ↑ by 44%, due to ↑in trabecular number & not thickness Rauch, Travers, Plotkin et al J. Clin. Invest. 2002; 110 (9),

28 Bisphosphonates in OI Before Rx After Rx

29 SIDE EFFECTS  Acute phase reaction at the first IV infusion (influenza-like symptoms); Rx with paracetamol or ibuprofen  Hypocalcemia (uncommon problem) after ~ 72 hrs from infusion ↓  Bone pain: ↓ with subsequent use  Transient iritis and/or uveitis (uncommon)

30 Bisphosphonates in Children: Unanswered Questions  Minimum effective dose?  Ideal I.V. treatment frequency?  The role of newer oral agents?  How long to continue treatment?  What are the potential long term effects of inhibition of bone turnover?  Teratogenicity?  Fracture healing?

31 CURRENT EVIDENCE After more than 18 years of clinical, radiological and histological evaluation:  Satisfactory growth  No interference with pubertal spurt  No mineralisation defects (Vitamin D)  Sclerotic lines - no apparent clinical significance  Normal fracture repair

32 Prolonged use of Bisphosphonates l Prolonged half life of 8 yr can pose skeletal and reproductive risks l Defective remodeling and accumulation of microdamage l Atypical fractures in adults l Delayed osteotomy healing

33 March 2008

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35 Oct 2010

36 Feb 2012

37 Sept 2012

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40 Differential diagnosis between IJO & OI type 1

41 Clinical History  8 yr old male  Low trauma fractures of R 15 & 22 months  ? NAI but severe osteopenia on radiographs  Spinal compression fractures of T10, T12 & L1  No family history fragility fractures, premature hearing loss or dental problems  O/E normal growth (75 th Centile), white sclerae & no dentinogenesis imperfecta  Working diagnosis - ? OI Type IV  No mutation of COL1A1 or COL1A2  ? LRP5 or other candidate gene  Rx: I.V. Pamidronate 1mg/kg on 3 consecutive days, 3 monthly, for 4 years

42 Conclusion l OI is the most common cause for primary osteoporosis in children l OI presents with extra skeletal manifestations l OI and IJO are important DD for NAI l Bisphosphonate therapy are widely used for preventing risks of fractures and correcting bone deformities in OI l Long term risk of bisphosphonate therapy is still not clear.


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