Forms of osteoporosis in children Pathophysiology and genetics of Osteogenesis Imperfecta Types of Osteogenesis Imperfecta Investigations Supportive Care Bisphosphonate therapy Cases OUTLINE
Osteoporosis l Osteoporosis in childhood is defined as reduced bone mass for body size and the presence of significant fracture
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)?
Collagen Fibres Structure of a Long Bone Structure of a Long Bone
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
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
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
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)
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.
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
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)
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?
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
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
Clinical History 8 yr old male Low trauma fractures of R femur @ 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
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.