osteoporosis in children dr raja padidela consultant paediatric endocrinologist
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Osteoporosis in ChildrenOsteoporosis in Children
Dr Raja Padidela
Consultant Paediatric Endocrinologist
Forms of osteoporosis in children Pathophysiology and genetics of Osteogenesis
Imperfecta Types of Osteogenesis Imperfecta Investigations Supportive Care Bisphosphonate therapy Cases
OUTLINEOUTLINE
OsteoporosisOsteoporosis
Osteoporosis in childhood is defined as reduced bone mass for body size and the
presence of significant fracture
OI is a condition of extreme fragility of the bones. OI is the most common cause of primary
osteoporosis 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 BoneStructure of a Long Bone
Type 1 Collagen is the predominant collagen in bonesType 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 ClassificationOI - Sillence Classification Type I Type I - mild with blue/grey sclera- mild with blue/grey sclera
Type II Type II – usually lethal– usually lethal
Type III Type III – multiple fractures with – multiple fractures with deformities of limbs & spinedeformities of limbs & spine
Type IV Type IV - intermediate between types I & III- intermediate between types I & III
IVa IVa – – : Normal teeth: Normal teeth
IVb IVb – : – : Dentinogenesis ImperfectaDentinogenesis Imperfecta
Loose joints, Thin & smooth skin, Blue/grey sclera, Wormian bones, Dentinogenesis imperfecta, Presenile deafness.
Inheritance
AD
AD
AD
AD
OI – Types V OI – Types V Type V Type V - - Similar to Type IV but form Similar to Type IV but form
hypertrophic callus hypertrophic callus
- - CalcificationCalcification of the interosseous of the interosseous membrane membrane
- - Dense metaphyseal band on x-rayDense metaphyseal band on x-ray
- - No mutations in type 1 collagen No mutations in type 1 collagen
Inheritance
AD
Family Tree of J
Affected
Unaffected
Recessive forms of OI
Type VI Type VI –– More severe than OI Type IVMore severe than OI Type IVVertebralVertebral compression fracturescompression fractures, n, no mutations in o mutations in type 1 collagen 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 OIIncidence and prevalence of OI
A Danish study of a geographically defined
population observed population prevalence 10.6 per 100,000.
Overall OI has an incidence of between 1 in
10,000 to 1 in 20,000. Approximately two thirds of those surviving
infancy are at the mild end of the spectrum.
Teeth in OI Type IVTeeth in OI Type IV
OI - InvestigationsOI - Investigations
No definitive biochemical or imaging marker for OINo definitive biochemical or imaging marker for OI
X-ray X-ray Generalised osteoporosis of axial and appendicular skeleton Generalised osteoporosis of axial and appendicular skeleton Milder forms- Thin, slender bones with thin cortices Milder forms- Thin, slender bones with thin cortices Severe forms- Broad, shortened long bones with multiple fractures Severe forms- Broad, shortened long bones with multiple fractures complicated by hyperplastic callous formation complicated by hyperplastic callous formation Skull X-ray for Wormian bones Skull X-ray for Wormian bones Vertebral X-ray for crush fracturesVertebral X-ray for crush fractures
Bone Mineral Density ScansBone Mineral Density Scans
MUTATIONS IN GENES CODING FOR TYPE I COLLAGEN MUTATIONS IN GENES CODING FOR TYPE I COLLAGEN
Molecular biology tests to look for Molecular biology tests to look for mutations in COL1A1 and mutations in COL1A1 and COL1A2 genesCOL1A2 genes responsible for production of Type 1 collagenresponsible for production of Type 1 collagen
Radiological changes in OI Radiological changes in OI
Radiological changes in OI Radiological changes in OI
OI-AROI-AR
OI-AROI-AR
Management Management
Multidisciplinary Approach!!
Supportive CareSupportive 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
Treatment with Treatment with BisphosphonatesBisphosphonates
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 BoneEffects of Bisphosphonates on Bone
Copyright ©2005 BMJ Publishing Group Ltd.
Shaw, N J et al. Arch Dis Child 2005;90:494-499
Figure 2 Cascade of events triggered by administration of a bisphosphonate.
Apoptosis of Osteoclasts
BisphosphonatesBisphosphonates in OI in OI 30 children with severe to moderately severe OI
I.V. Pamidronate every 4 to 5 monthly for 1.3 to 5 yearsI.V. Pamidronate every 4 to 5 monthly for 1.3 to 5 years
Fracture incidence Fracture incidence ↓ by 1.7 per year↓ by 1.7 per year
Mobility & ambulation improved in 16 childrenMobility & ambulation improved in 16 children
4 wheelchair bound children 4 wheelchair bound children → independent walking→ independent walking
No evidence of an adverse effect on longitudinal growthNo 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), 947 - 364Glorieux, Bishop, Plotkin et al N. Eng. J. Med. 1998; 339 (14), 947 - 364
BisphosphonatesBisphosphonates in OI in OI
Glorieux, Bishop, Plotkin et al N. Eng. J. Med. 1998; 339 (14), 947 - 364Glorieux, Bishop, Plotkin et al N. Eng. J. Med. 1998; 339 (14), 947 - 364
BisphosphonatesBisphosphonates in OI in OI
Before RxBefore Rx After RxAfter Rx
Iliac Crest biopsies in OI patients before & 2.4 years after cyclical IV Pamidronate Rx Cortical width Cortical width ↑ by 88%↑ by 88% Trabecular volume ↑ by 44%, due to ↑in trabecular number & not thicknessTrabecular volume ↑ by 44%, due to ↑in trabecular number & not thickness
Rauch, Travers, Plotkin et al J. Clin. Invest. 2002; 110 (9), 1293 - 1299Rauch, Travers, Plotkin et al J. Clin. Invest. 2002; 110 (9), 1293 - 1299
BisphosphonatesBisphosphonates in OI in OI
Before RxBefore Rx Before RxBefore RxAfter RxAfter Rx After RxAfter Rx
SIDE EFFECTSSIDE 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 Bisphosphonates in Children: Unanswered QuestionsQuestions
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 EVIDENCECURRENT 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 BisphosphonatesProlonged use of Bisphosphonates
Prolonged half life of 8 yr can pose skeletal and reproductive risks
Defective remodeling and accumulation of microdamage
Atypical fractures in adults Delayed osteotomy healing
March 2008
Oct 2010
Feb 2012
Sept 2012
Differential diagnosis between IJO Differential diagnosis between IJO & OI type 1& OI type 1
Clinical HistoryClinical 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 (75th 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
ConclusionConclusion OI is the most common cause for primary
osteoporosis in children OI presents with extra skeletal manifestations OI and IJO are important DD for NAI Bisphosphonate therapy are widely used for
preventing risks of fractures and correcting bone deformities in OI
Long term risk of bisphosphonate therapy is still not clear.