Statistical modeling in pharmaceutical research and development.
Osteogenesis imperfecta
1.
2. OI is one of the most common skeletal dysplasias. It is
a generalized disease of connective tissue
In 1835, Lobstein coined the term osteogenesis
imperfecta and was one of the first to correctly
understand the etiology of the condition.
Other names for OI are Lobstein disease, brittle-bone
disease, blue-sclera syndrome, and fragile-bone
disease.
3. Pathophysiology
In OI, pathologic changes are seen in all tissues with
type 1 collagen. The basic defect is one of a qualitative
or quantitative reduction in type 1 collagen.
Most cases of OI, are now known to arise from
autosomal dominant mutations.
The disease affects both endochondral and
intramembranous ossification.
4.
Quantitative defects : a mild form . The numbers of
osteoclasts and osteocytes are normal. Bone trabeculae
are thin and disorganized. Lamellar bone is seen in the
diaphysis and metaphysis
Qualitative defects: a severe form of the disease occurs.
There is reduced cortical bone thickness, lack of
normal cortical bone formation, and disorganization
of the growth plate. Woven bone is seen, with minimal
osteoid bone and no lamellar bone
5. Etiology
In OI due to quantitative defects of type 1 collagen,
mutations are usually found on the COL1A gene.
In OI due to qualitative defects of type 1 collagen,
autosomal dominant mutations are found on either
the COL1A or the COL1B gene
The mutations result in the production of a mixture of
normal and mutant collagen chains
The type 1 collagen thus formed is functionally
impaired because of the mutant chain
6. Epidemiology
The overall incidence of OI is approximately 1 case for
every 20,000 live births
OI can present at any age, although the age when
symptoms (ie, fractures) begin varies widely
OI is equally common in males and females. The
disease appears to have no predilection for a particular
race.
11. OI classification & Characteristics
Most widely used classification is that of Sillence
which defines four clinical types
Type I-IV
Recently added 3 more classifications (V-VIII)
Causes unknown
12. Type 1 OI
Most common & mildest form
Collagen is of normal quality but is produced in
insufficient quantities
Bone fractures are common during childhood &
adolescence from minor trauma (fractures less frequent
during adulthood)
Normal or near-normal stature
Loose joints and muscle weakness
13. Sclera usually have a blue, purple, or gray tint
Tendency toward spinal curvature
Bone deformity absent or minimal
Brittle teeth possible
Hearing loss possible (early 20s or 30s)
Normal life expectancy
14. Type 2 OI
Most severe form
Collagen is not of a sufficient quality or quantity
Frequently lethal at or shortly after birth, often due to
respiratory problems.
Numerous fractures and severe bone deformity.
Small stature with underdeveloped lungs.
Usually still-birth or dies shortly after birth
15. Type 3 OI (progressive)
Collagen quantity is sufficient but is not of a high
enough quality
Bones fracture easily, sometimes even before birth
Bone deformity, often severe
Respiratory problems possible
Short stature, spinal curvature and barrel-shaped rib cage
Loose joints
Poor muscle tone in arms and legs
Discoloration of the sclera
Early loss of hearing
Life expectancy shorter than normal
16. Type 4 OI
Collagen quantity is sufficient but is not of a high
enough quality
Between Type I and Type III in severity
Bones fracture easily, especially before puberty
Short stature, spinal curvature and barrel-shaped rib
cage
Bone deformity is mild to moderate
Discoloration of the sclera (whites of the eyes)
Early loss of hearing
Normal life expectancy
17. Type 5 OI
Type V OI is an autosomal dominant condition with a
severity similar to that of type IV disease but a
predisposition to hyperplastic callus formation.
Characteristic features include ossification of the
interosseous membrane of the forearms and legs,
leading to limited pronation and supination and a
radiopaque metaphyseal band in growing patients.
18. Type VI
OI type VI is clinically similar to types II and IV, but it
has distinctive histology, including hyperosteoid bone
due to a mineralization defect, and does not have a
disturbance of bone mineral metabolism.
Type VII
OI type VII has been described in an isolated First
Nations community in northern Quebec.It is clinically
similar to OI types II and IV but has rhizomelia as a
distinctive feature.
20. Investigations
Plain Radiography
Obtain a radiographic skeletal survey after birth. Plain
radiographs may depict the following 3 radiologic
categories of OI:
Category I – Thin and gracile bones
Category II – Short and thick limbs
Category III – Cystic changes
21. Fractures – Commonly, transverse fractures and those
affecting the lower limbs
Excessive callus formation and popcorn bones -
Multiple scalloped, radiolucent areas with radiodense
rims
22. Skull changes - Wormian bones, enlargement of
frontal and mastoid sinuses, and platybasia with or
without basilar impression
23. 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
24. Densitometry
Dual x-ray absorptiometry (DEXA) may be used to
assess bone mineral density in children with milder
forms of OI. Bone mineral density, as measured with
DEXA, is low in children and adults with OI regardless
of severity.
CT densitometric bone scanning may be helpful in
atypical cases of OI, though normal bone density does
not exclude mild forms of the disease.
25. Polarized light microscopy or microradiography
may be used in combination with scanning electron
microscopy to assess dentinogenesis imperfecta.
Skin biopsy, collagen can be isolated from cultured
fibroblasts and assessed for defects, with an accuracy
of 85-87%.
Bone biopsy may show changes in the concentrations
of noncollagenous bone proteins, such as osteonectin,
sialoprotein, and decorin.
26. Collagen synthesis analysis
Sodium dodecyl sulfate–polyacrylamide gel
electrophoresis (SDS-PAGE)
2-Dimensional SDS-PAGE
Cyanogen bromide (CNBr) mapping
Thermal stability studies
An analysis of the amino acid composition of collagens
may be useful.
27. Prenatal testing
Prenatal DNA mutation analysis can be performed in
pregnancies with risk of OI to analyze uncultured
chorionic villus cells.
Prenatal ultrasonography is most useful in evaluating
OI types II and III. It is capable of detecting limb-
length abnormalities at 15-18 weeks’ gestation. In its
most severe form, the disease may be evident as early
as 16 weeks’ gestation.
28. Treatment-General
NO CURE
Care for broken bones & brittle teeth
Pain medication
Physical therapy
Use of orthotics, wheelchairs, braces, and other aids
Surgery remains a pillar of treatment for patients with
OI
29. Treatment-Specific
Bisphosphonates (BPs)
Analogues of inorganic pyrophosphate and act by
binding to hydroxyapatite in bone matrix, thereby
inhibiting the dissolution of crystals. They prevent
osteoclast attachment to the bone matrix and osteoclast
recruitment and viability.
Increase bone mass and reduce the incidence of fracture
Administered orally or by IV
Pamidronate, risedronate, alendronate,
30. Surgery
Insert metal rods (rodding) in long bones to improve
strength
Because the 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
Osteotomies should be simple, preferably single, and
performed under direct vision with maximum care and
gentle handling of tissues.
31. Surgery for basilar impression
Best treated with decompression and stabilization of
the craniocervical junction. This procedure is reserved
for cases with neurologic deficiencies.
Surgery for spinal 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
Posterior spinal arthrodesis is the treatment of choice
and is best performed with segmental
instrumentation.
32. Physiotherapy (or hydrotherapy)
strengthen muscles and improve mobility in a gentle
manner
Physiotherapy has become more effective in the
postbisphosphonate era because of the decrease in bone
fragility and the improved prognosis for standing or
walking
Weightbearing is promoted in the pool, on tricycles, and
with walkers. Prone positioning is used to prevent hip
flexion contractures
