Transcript Document
Osteoporosis in Children
Dr Raja Padidela
Consultant Paediatric Endocrinologist
OUTLINE
Forms of osteoporosis in children
Pathophysiology and genetics of Osteogenesis
Imperfecta
Types of Osteogenesis Imperfecta
Investigations
Supportive Care
Bisphosphonate therapy
Cases
Osteoporosis
Osteoporosis in childhood is defined as
reduced bone mass for body size and the
presence of significant fracture
What is Osteogenesis Imperfecta (OI)?
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
Structure of a Long Bone
Collagen Fibres
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
Inheritance
Type I - mild with blue/grey sclera
AD
Type II – usually lethal
AD
Type III – multiple fractures with
deformities of limbs & spine
AD
Type IV - intermediate between types I & III
AD
IVa – : Normal teeth
IVb – : Dentinogenesis Imperfecta
Loose joints, Thin & smooth skin, Blue/grey sclera, Wormian bones,
Dentinogenesis imperfecta, Presenile deafness.
OI – Types V
Type V
Inheritance
- 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
AD
Affected
Unaffected
Family Tree of J
Recessive forms of OI
Type VI – More severe than OI Type IV
Vertebral compression fractures, no mutations in
type 1 collagen
Type VII- Moderately severe. Rhizomelic in both
arms and legs; femurs and humeri are very bowed.
White sclerae (CRTAP mutation)
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
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 IV
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
Radiological changes in OI
Radiological changes in OI
OI-AR
OI-AR
Management
Multidisciplinary Approach!!
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
Treatment with Bisphosphonates
Effects of Bisphosphonates on Bone
Bisphosphonates are taken up by osteoclasts and
cause apoptosis
Net effect: Reduced bone resorption and an increase
in bone mineral density
Figure 2 Cascade of events triggered by administration of
a bisphosphonate.
Apoptosis of
Osteoclasts
Shaw, N J et al. Arch Dis Child 2005;90:494-499
Copyright ©2005 BMJ Publishing Group Ltd.
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), 947 - 364
Bisphosphonates in OI
Glorieux, Bishop, Plotkin et al N. Eng. J. Med. 1998; 339 (14), 947 - 364
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), 1293 - 1299
Bisphosphonates in OI
Before Rx
After Rx
Before Rx
After Rx
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
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
& OI type 1
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 (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
Conclusion
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.