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.