Osteogenesis imperfecta (OI), also known as brittle bone disease, is a genetic disorder characterized by bones that break easily. It is caused by mutations in genes that produce type 1 collagen, which is important for bone strength. Symptoms can include bone fractures, skeletal deformities, weak bones, hearing loss, and blue sclera. Treatment focuses on surgery to repair bones, bracing to prevent deformities, and bisphosphonates to increase bone density and reduce fractures.

1. • OSTEOGENESIS
IMPERFECTA

2. Earliest known case of osteogenesis
imperfecta in a partially mummified infant’s
skeleton from ancient Egypt now housed in
the British Museum in London.
 In 1835, Lobstein coined the term
osteogenesis imperfecta
Other names for OI: Lobstein disease, brittle-
bone disease, blue-sclera syndrome, and
fragile-bone disease

3.  Manifest itself with 1 or more of
the following findings:
 Blue sclerae
 Triangular facies
 Macrocephaly
 Hearing loss
 Defective dentition
 Barrel chest
 Scoliosis
 Limb deformities
 Fractures
 Joint laxity
 Growth retardation
 Constipation and sweating

4.  Pathologic changes seen in all tissues in which type 1
collagen is an important constituent (eg, bone,
ligament, dentin, and sclera)
 Basic defect : qualitative or quantitative reduction in
type 1 collagen
 Mutations in genes encoding type 1 collagen affect the
coding of 1 of the 2 genes
 Mutations are either genetically inherited or new
 Inherited mutations : recurrence risk in subsequent
pregnancies of 50% if a parent is affected
 New mutations unpredictable recurrence risk

5.  Quantitative defects of
type 1 collagen : mutations
on COL1A gene, production
of premature stop codon or
a microsense frame
shift, which leads to mutant
messenger RNA (mRNA) in
the nucleus
 Cytoplasm contains normal
alpha1 mRNA; reduced
amounts of structurally
normal collagen produced
 Mild form of disease

6.  Qualitative defects of
type 1 collagen:
autosomal dominant
mutations on either
the COL1A or
the COL1B gene,
production of mixture of
normal and mutant
collagen chainstype 1
collagen thus formed is
functionally impaired
because of mutant chain

7.  In bone :both endochondral
and intramembranous
ossification affected
 Epiphysis and physis :broad
and irregular, with
disorganization of proliferative
and hypertrophic zones ,loss
of typical columnar
arrangement, thinning of zone
of calcified cartilage,
deficiency of primary
spongiosa of the metaphysis
and delay of the secondary
centers of ossification in the
epiphysis.

8.  Scoliosis and kyphosis
 Vertebral bodies
:wedged, translucent,
and shallow

9.  Thinning of the skull
and multiple
ossification centers
(wormian bones) are
present, particularly in
the occiput

10. Epidemiology
 Incidence : 1 case for
every 20,000 live births
 Equally common in males
and females
 Described in every human
population in which
skeletal dysplasias have
been studied
 No predilection for a
particular race

11. History
 Family history , but most cases
due to new mutations
 Commonly present with
fractures after minor trauma
 In severe cases, prenatal
screening ultrasonography
performed during the second
trimester may show bowing of
long bones, fractures, limb
shortening, and decreased
skull echogenicity. Lethal OI
cannot be diagnosed with
certainty in utero

12. Physical Examination
 Clinical presentation
depends on phenotype
 Sillence classificatiom : 4
types on basis of clinical
and radiologic features
 Dentinogenesis
imperfecta denoted as
subtype B, whereas OI
without dentinogenesis
imperfecta is denoted
as subtype A

14. Many cases of OI do not fit into the
aforementioned categories; osteoporosis-
pseudoglioma, Bruck syndrome, and Cole-
Carpenter syndrome.
Osteoporosis-pseudoglioma syndrome :
caused by mutations in gene encoding for
low-density-lipoprotein receptor-related
protein 5 (LRP5), with clinical features
including blindness and bone fragility

15. Bruck syndrome: autosomal recessive
condition caused by mutations in bone-
specific collagen type 1 telopeptide lysyl
hydroxylase enzyme, with clinical features that
include congenital joint contractures and bone
fragility
Cole-Carpenter syndrome : severe progressive
form of OI, with associated multisutural
craniosynostosis and growth failure

16. Complications
 Repeated respiratory
infections
 Basilar impression caused
by a large head, which
causes brainstem
compression
 Cerebral hemorrhage
caused by birth trauma
 High risk for
complications of
anesthesia

17. Diagnostic Considerations
Differential
diagnoses
categorized into 3
stages of life:
Prenatal/neonatal
Preschool/childhood
Adolescence/adultho
od

18. Conditions that should be
considered in
prenatal/neonatal stage
include:
 Jeune dystrophy
 Camptomelic dysplasia
 Chondrodysplasia punctata
 Chondroectodermal
dysplasia (Ellis–van Creveld
syndrome)
 Nonaccidental injury
 Hypophosphatasia

19. Preschool/childhood
stage include:
 Pyknodysostosis
 Hajdu-Cheney
syndrome
 Osteochondromatosis
 Nonaccidental injury

20. Differentiate between OI and child
abuse
 Keys to distinguishing OI from
child :
 Metaphyseal corner fractures,
which are common in child abuse,
rare in OI
 In children with OI, fractures may
continue to occur while they are
in protective custody
 Child abuse has nonskeletal
manifestations (eg, retinal
hemorrhage, visceral intramural
hematomas, intracranial bleeds
of various ages, pancreatitis, and
splenic trauma)

21. Differential Diagnoses
 Achondroplasia
 Menkes Kinky Hair Disease
 Glucocorticoid Therapy
 Cushing Syndrome
 Homocysteinemia
 McCune-Albright Syndrome
 Osteopetrosis
 Osteoporosis
 Pediatric Acute Lymphoblastic
Leukemia
 Rickets
 Scurvy
 Thanatophoric Dysplasia
 Wilson Disease

22. Laboratory Studies
 Within reference ranges,
and useful in ruling out
other metabolic bone
diseases
 An analysis of type I, III, and
V collagens synthesized by
fibroblasts helpful
 Collagen synthesis analysis :
culturing dermal fibroblasts
obtained during skin biopsy
 Results are negative in
syndromes resembling OI.

23. Tests
 Sodium dodecyl sulfate–
polyacrylamide gel
electrophoresis (SDS-
PAGE)
 2-Dimensional SDS-PAGE
 Cyanogen bromide (CNBr)
mapping
 Thermal stability studies
 An analysis of amino acid
composition of collagens

24.  DNA blood testing for gene
defects has an accuracy of 60-
94%.
 Prenatal DNA mutation
analysis can be performed in
pregnancies with risk of OI to
analyze uncultured chorionic
villus cells.
 Samples are obtained during
chorionic villus sampling
performed under
ultrasonographic guidance
when a mutation in another
member of the family is
already known

25. Prenatal ultrasonography :
 Useful in evaluating OI types II
and III
 Detects limb-length
abnormalities at 15-18 weeks
 Features include
supervisualization of
intracranial contents caused by
decreased mineralization of
calvaria (also calvarial
compressibility), bowing of the
long bones, decreased bone
length (especially of the
femur), and multiple rib
fractures

26. Radiographic skeletal survey after birth
 Plain radiographs :3 radiologic categories of
OI
A. Category I – Thin and gracile bones
B. Category II – Short and thick limbs
C. Category III – Cystic changes

27. Radiologic features
 Fractures – Commonly, transverse fractures and those
affecting the lower limbs
 Excessive callus formation and popcorn bones - Multiple
scalloped, radiolucent areas with radiodense rims
 Skull changes - Wormian bones enlargement of frontal and
mastoid sinuses, and platybasia with or without basilar
impression
 Deformities of the thoracic cage - Fractured and beaded
ribs and pectus carinatum
 Pelvic and proximal femoral changes - Narrow pelvis,
compression fractures, protrusio acetabuli, and shepherd’s-
crook deformities of the femurs

28.  Mild OI (type I) : thinning of the long bones with
thin cortices,wormian bones,no deformity of long
bones
 Extremely severe OI (type II) : beaded ribs, broad
bones, and numerous fractures with deformities
of long bones
 Moderate and severe OI (types III and IV) :cystic
metaphyses, or a popcorn appearance of growth
cartilage, deformities of long bones, old rib
fractures, vertebral fractures

30. Dual x-ray absorptiometry (DEXA)
 To assess bone mineral density in children with
milder forms
 Bone mineral density low in children and adults
regardless of severity.
 Bone mineral densities can be normal in infants
with OI, even in severe cases
 In pediatric patients, DEXA results not useful for
predicting risk of fracture
 No reliable published reference data regarding
DEXA in infants available

31.  Polarized light microscopy or microradiography
used in combination with scanning electron
microscopy to assess dentinogenesis imperfecta
 With skin biopsy, collagen can be isolated from
cultured fibroblasts and assessed for defects,
with an accuracy of 85-87%
 Bone biopsy : show changes in concentrations of
noncollagenous bone proteins, such as
osteonectin, sialoprotein, and decorin

32. Histologic Findings
• Width of biopsy cores, width of cortex, and
volume of cancellous bone decreased in all
types of OI
• Number and thickness of trabeculae reduced
• Evidence of defects in modeling of external
bone in terms of size and shape production of
secondary trabeculae by endochondral
ossification, thickening of secondary
trabeculae by remodeling

33. Treatment
No cure
Orthotics: limited role, to stabilize lax joints
(eg, ankle and subtalar joints with ankle-foot
orthoses) and to prevent progressive
deformities and fractures.
Provide walking aids, specialized wheelchairs,
and home adaptation devices to help improve
patient’s mobility and function

34. Surgery
 Pillar of treatment
Only if it is likely to improve function and
treatment goals are clear
Intramedullary rod placement, surgery to
manage basilar impression, and correction of
scoliosis
Soft tissue surgery : lower-limb
contractures, particularly those of the Achilles
tendon

35.  Painful bony deformities and recurrent fractures are
typically treated with intramedullary stabilization with or
without corrective osteotomies.
 In children with severe forms of OI (eg, type III), rodding of
lower extremities is performed to correct deformities and
provide preventive protection around the time of first
attempts at standing
 Because bone is soft in OI, rods (eg, extendable Sheffield
rods or Bailey-Dubow rods), pins (eg, Rush pins), and wires
(eg, Kirschner wires) are used rather than solid
nails, plates, and screws; the latter are associated with
increased fracture risk above and below the device and
with poor fixation

36.  Rod placement use in femur and less commonly
used in tibia, humerus, and forearm
 In the prebisphosphonate era, extendable rods
preferred to nonextendable ones in order to
prevent bone bowing and bone growth beyond
end of rod
 Bailey-Dubow rods : high incidence of
mechanical failures (eg, migration and
disconnection of T-parts)
 Sheffield rods and the Fassier-Duval
modification commonly used

37.  With decreased fragility of bone exposed to
bisphosphonate, future role of extendable rods
unclear
 In long bones (eg, tibiae and radii), nonextendable
rods such as Rush pins and Kirschner wires most often
used
 Complications of rod placement include breakage,
rotational deformities, and migration
 Extendable and nonextendable rods associated with
similar complications
 Rate of repeat surgical intervention is lower with
extendable rods than with nonextendable rods

38. Surgery for basilar impression
Basilar invagination: result in long tract signs
and respiratory depression from direct
compression of brainstem and upper cervical
and cranial nerves
 Treated with decompression and stabilization
of the craniocervical junction; reserved for
cases with neurologic deficiencies

39. Surgery for spinal deformities
 Bracing not effective in treating spinal deformities
such as scoliosis and kyphosis, because the rib cage is
fragile to transfer brace pressure to vertebral column.
 External pressure may worsen the chest deformities.
 Surgery is indicated when the following 2 conditions
are present:
 Acceptable bone quality
 Progressive scoliosis with curvature of more than 45° if
OI is mild or more than 30-35° if OI is severe

40.  Posterior spinal
arthrodesis is the
treatment of choice and is
best performed with
segmental
instrumentation. Often,
significant correction and
stable fixation are not
achieved. Pretreatment
with pamidronate
appears to improve the
surgical outcome

41.  Skilled administration of anesthetics and awareness of
the limitations of surgery are essential prerequisites.
 Anesthetic-related problems :
 Patients with relatively large heads and tongues and
in those with short necks
 Chest deformities may cause respiratory
complications
 On the operating table, fractures may arise as a result
of the application of a blood pressure cuff or
tourniquet, or they may occur during transfers
 Watch for hyperthermia and increased sweating

42. Bisphosphonates
 Synthetic analogues of
pyrophosphate that
inhibit osteoclast-
mediated bone resorption
on the endosteal surface
of bone by binding to
hydroxyapatite.
 Unopposed osteoblastic
new bone formation on
the periosteal surface
results in an increase in
cortical thickness.

43. Cyclic intravenous (IV) pamidronate :
 Dosage of 7.5 mg/kg/y at 4- to 6-month intervals
 Dosages have ranged from 4.5 to 9 mg/kg/y, depending on
the protocol used
 Cyclic administration of IV pamidronate reduces the
incidence of fracture and increases bone mineral density
 Current evidence does not support the use of oral
bisphosphonates in patients with OI.
 IV pamidronate effective in babies and can be used to
relieve pain in severe cases
 Adverse effects of pamidronate : acute febrile reaction,
mild hypocalcemia, leukopenia, a transient increase in bone
pain, and scleritis with or without anterior uveitis

44.  Risedronate, alendronate, and zoledronic acid
being assessed
 Growth hormone: act on growth plate,stimulate
osteoblast function, possibly via IGF-1 ,IGFBP-3
 Teriparatide :
Recombinant human form of parathyroid
hormone that increases number and activity of
osteoblasts
Potential use of teriparatide for the treatment of
OI remains to be defined

45. Cellular and Genetic Therapy
 Bone marrow transplantation: potential future therapeutic
modality for OI
 Because there are very few MSCs in the average human bone
marrow graft, approaches involving expansion of the number of
MSCs in ex vivo cultures with subsequent infusion into the recipient
needed
 Such cell therapies usually result in somatic mosaicism, where
normal and abnormal osteoblasts exist in the same body
 Unfortunately, higher proportion of engrafted normal cells required
to achieve the level of normal osteoblasts necessary to functionally
correct the OI phenotype.
 Use of immunosuppressive agents to prevent graft rejection and
graft versus host reaction can itself damage bone

46. • Future approaches: autografting of genetically
modified mutant osteoblasts, whereby mutant
collagen gene is inactivated
• Gene therapy: being explored in animal
models, but major obstacles remain, both
because of intrinsic difficulties and because of
dominant negative mechanism of disease

47. Diet and Activity
 Nutritional evaluation and intervention
paramount to ensure appropriate intake of
calcium, phosphorus, and vitamin D
 Caloric management important, particularly in
adolescents and adults with severe forms of OI
 Physical therapy, in form of comprehensive
rehabilitation programs, directed toward
improving joint mobility and developing muscle
strength

48.  In early infancy, gentle handling of babies by
parents to prevent fractures, with frequent
positional changes advised to prevent occipital
flattening, torticollis, and frog-leg positioning of
hips
 When infant is crawling: upper-limb mobility,
propelling a wheelchair or ambulating with
walking aids
 When child starts to stand: walking encouraged,
both as exercise and as primary or secondary
means of mobility

49.  Weightbearing promoted
in pool, on tricycles, and
with walkers
 Prone positioning to
prevent hip flexion
contractures; aided by
strengthening of hip
extensors and quadriceps.
 Bisphosphonates have
significantly improved the
walking ability of children
with severe forms of OI

50.  Care of patients with OI
multidisciplinary:
occupational therapist,
physical therapist,
nutritionist, audiologist,
orthopedic surgeon,
neurosurgeon,
pneumologist, and
nephrologist, among others
 Genetic counseling to
parents of child with OI who
plan to have more children

51. Prognosis
 Morbidity and mortality vary widely, depending
on genotype
 Variability occurs between individuals with
different mutations
 Life expectancy of subjects with nonlethal OI
appears same as that for the healthy population,
except for those with severe respiratory or
neurologic complications.
 Although patients with lethal OI may die in
perinatal period, individuals with extremely
severe OI can survive until adulthood

52. Patient Education
Patients with OI: well motivated and keen to
achieve as much as possible despite their
physical limitations
Education extremely important
Education of parents and families :to know
how to position child in crib and how to hold
child so as to minimize risk of fractures while
maintaining bonding and physical stimulation

53. Living with ostogenesis imperfecta
The tips reproduced below have been
developed by the Osteogenesis
Imperfecta Foundation for taking care
of children with osteogenesis
imperfecta.
 Do not be afraid to touch or hold an
infant with osteogenesis imperfecta,
but be careful. To lift an infant with
osteogenesis imperfecta, spread your
fingers apart and put one hand
between the legs and under the
buttocks, and place the other hand
behind the shoulders, neck, and
head.
 Never lift a child with osteogenesis
imperfecta by holding him or her
under the armpits.

54.  Do not pull on arms or legs or, in those with
severe osteogenesis imperfecta, lift the legs by
the ankles to change a diaper.
 Select an infant car seat that reclines. It should be
easy to place or remove your child in the seat.
Consider padding the seat with foam and using a
layer of foam between your child and the
harness.
 Be sure your stroller is large enough to
accommodate casts. Do not use a sling- or
umbrella-type stroller

55.  Follow your doctor's instructions carefully, especially
with regard to cast care and mobility exercises.
Swimming and walking are often recommended as safe
exercises.
 Adults with osteogenesis imperfecta should avoid
activities such as smoking, drinking, and taking steroids
because they have a negative impact on bone density.
 Increasing awareness of child abuse and a lack of
awareness about osteogenesis imperfecta may lead to
inaccurate conclusions about a family situation. Always
have a letter from your family doctor and a copy of
your child's medical records handy.