Osteogenesis imperfecta (OI) (brittle bone disease), the most common genetic cause of osteoporosis, is a generalized disorder of connective tissue.

The spectrum of OI is extremely broad, ranging from forms that are lethal in the perinatal period to a mild form in which the diagnosis may be equivocal in an adult.

Classical OI was described with the triad of fragile bones, blue sclerae, and early deafness, although most cases do not have all of these features.

Other major clinical feature includes skeletal deformity and fragile opalescent teeth.

Less severe manifestation may include generalized ligamentous laxity, hernias, easy bruisability, and excessive sweating.

The Sillence classification divides OI into four types based on clinical and radiographic criteria.

Types V and VI were later proposed based on histologic distinctions.

Subsequent types of VII-XVIII was based on the identification of the molecular defect, followed by the clinical description.

Defects in collagen synthesis and structure:

OI type – Type I, II, III, IV

Inheritance – Autosomal dominant

Defective gene – COL1A1 or COL1A2

Defective protein – alpha1 (1) or alpha2 (1) collagen

Defects in bone mineralization:

OI type – Type V, VI

Inheritance – Type V – Autosomal dominant and Type VI –Autosomal recessive

Defective gene – Type V – IFITMS and Type VI – SERPINF1

Defective protein – Type V – BRIL and Type VI – PEDF

Defects in collagen modification:

OI type – Type VII, VIII & IX

Inheritance – Autosomal recessive

Defective gene – Type VII – CRTAP, Type VII – LEPRE1I & Type IX – PPIB

Defective protein – Type VII – CRTAP, Type VIII – P3H1 & Type IX – PPIB (CyPB)

Defects in collagen processing and crosslink:

OI type – Type X, XI, Unclassified, and XII

Inheritance – Autosomal recessive

Defective gene –  Type X – SERPINH1, Type XI – FKBP10, Unclassified – PLOD2, and Type XII – BMP1

Defective protein – Type X – HSP47, Type XI – FKBP65, Unclassified – LH2, and Type XII – BMP1

Defects in osteoblast differentiation and function:

OI type – Type XIII, XIV, XV, XVI, XVII, XVIII

Inheritance – Type XIII – Autosomal recessive, Type XIV – Autosomal recessive, Type XV – Autosomal recessive/dominant, Type XVI – Autosomal recessive, Type XVII – Autosomal recessive, Type XVIII – X linked recessive

Defective gene – Type XIII – SP7, Type XIV – TMEM38B, Type XV – WNT1, Type XVI – CREB3L1, Type XVII – SPARC, Type XVIII – MBTPS2

Defective protein – Type XIII – SP7 (OSTERIX), Type XIV – TRIC-B, Type XV – WNT1, Type XVI – OASIS, Type XVII – SPARC (Osteonectin), Type XVIII – S2P

Osteogenesis imperfecta type I (Mild):

OI type I is sufficiently mild have blue sclerae, recurrent fractures in childhood, and presenile (i.e. beginning in early adulthood) hearing loss (30–60%).

Types I are divided into A and B subtypes, depending on the absence (A) or presence (B) of dentinogenesis imperfecta, a type of dentin dysplasia resulting in discolored (often blue-gray or amber), translucent teeth that wear down rapidly or break.

Other possible connective tissue abnormalities include hyperextensible joints, easy bruising, thin skin, joint laxity, scoliosis, wormian bones, hernia, and mild short stature compared with family members.

Fractures result from mild to moderate trauma but decrease after puberty.

Osteogenesis Imperfecta Type II (Perinatal Lethal):

Infants with OI type II may be stillborn or die in the 1st yr of life.

Birth weight and length are small for gestational age.

There is extreme fragility of the skeleton and other connective tissues. There are multiple intrauterine fractures of long bones, which have a crumpled appearance on radiographs.

There are striking micromelia and bowing of extremities; the legs are held abducted at right angles to the body in the frog-leg position.

Multiple rib fractures create a beaded appearance, and the small thorax contributes to respiratory insufficiency.

The skull is large for body size, with enlarged anterior and posterior fontanels.

Sclerae are dark blue-gray.

The cerebral cortex has multiple neuronal migrations and other defects (agyria, gliosis, and periventricular leukomalacia).

Osteogenesis Imperfecta Type III (Progressive Deforming):

OI type III is the most severe nonlethal form of OI and results in significant physical disability.

Birth weight and length are often low normal.

Fractures usually occur in utero.

There are relative macrocephaly and triangular facies.

Postnatally, fractures occur from inconsequential trauma and heal with deformity.

Disorganization of the bone matrix results in a “popcorn” appearance at the metaphyses.

The rib cage has flared at the base, and pectoral deformity is frequent.

Virtually all type III patients have scoliosis and vertebral compression.

Growth falls below the curve by the 1st year; all type III patients have extreme short stature.

Scleral hue ranges from white to blue.

Dentinogenesis imperfecta, hearing loss, and kyphoscoliosis may be present or develop over time.

Osteogenesis Imperfecta Type IV (Moderately Severe):

Patients with OI type IV can present at birth with in-utero fractures or bowing of lower long bones.

They can also present with recurrent fractures after ambulation and have normal to moderate short stature.

Most children have moderate bowing even with infrequent fractures.

Children with OI type IV require orthopedic and rehabilitation intervention, but they are usually able to attain community ambulation skills.

Fracture rates decrease after puberty.

Scleral hue may be blue or white.

Radiographically, they are osteoporotic and have metaphyseal flaring and vertebral compressions.

Osteogenesis imperfecta Type V (Hyperplastic Callus) and Type VI Hyperosteoidosis (Mineralization defect):

Types V and VI OI patients clinically have OI similar in skeletal severity to types IV and III, respectively, but they have distinct findings on bone histology.

Type V patients also usually have some combination of hyperplastic callus, calcification of the interosseous membrane of the forearm, and /or a radiodense metaphyseal band.

They constitute <5% of OI cases.

Ligamentous laxity may be present; blue sclera or dentinogenesis imperfect is not present.

Patients with type VI OI have progressive deforming OI that does not manifest at birth.

They have distinctive bone histology with broad osteoid seams and fish-scale lamellation under polarized light, caused by a deficiency of pigment epithelium-derived factor, encoded by SERPINF1.

Osteogenesis Imperfecta Types VII, VIII, and IX:

Types VII and VIII patients overlap clinically with types II and III OI but have distinct features including white sclerae, rhizomelia, and small to normal head circumference.

Surviving children have severe osteochondrodysplasia with extreme short stature.

Type IX OI is very rare. The severity is quite broad, ranging from lethal to moderately severe. These children have white sclerae but do not have rhizomelia.

Osteogenesis Imperfecta Types X and XI:

Type X OI has severe to lethal OI.

Type XI OI is a more prevalent recessive form with a moderate to severe skeletal phenotype, including white sclerae and normal teeth.

Osteogenesis imperfecta Type XII:

Individuals with dominant mutations have normal stature, white sclerae and teeth, and mild to moderate OI.

Null mutations in BMP1 lead to a more severe skeletal phenotype with short stature, scoliosis, and bone deformity.

Osteogenesis imperfecta Type XIII-XVIII:

Type XIV OI – Clinically indistinguishable from type IV OI.

Type XV OI – Severe progressive deforming OI.

Type XVII OI – Moderate to severe OI

The radiologic sine qua non of osteogenesis imperfecta is generalized osteoporosis of both the axial and appendicular skeleton.

Milder forms – Thin, overtubulated (gracile) bones with thin cortices and relatively few fractures.

The short tubular bones are also affected, though they are less frequently fractured.

In addition, radiographs of the skull in milder forms of osteogenesis imperfecta may reveal normal skull development.

More severe forms (types II and III) – Thickened, shortened long bones with multiple fractures; these forms are often complicated by hyperplastic callus formation.

The skull demonstrates poor mineralization and multiple wormian, or intrasutural, bones.

The chest may be small. Multiple rib fractures are often found; these can cause the ribs to become broad and deformed.

In addition, spinal abnormalities in all subtypes of osteogenesis imperfecta include platyspondyly and scoliosis.

DNA sequencing is the first diagnostic laboratory test; several Clinical Laboratory Improvement Amendments (CLIA)-certified sequencing labs offer panels to test for dominant and recessive OI.

Mutation identification is useful to determine the type with certainty and to facilitate family screening and prenatal diagnosis.

In the neonatal period, the normal to elevated alkaline phosphatase levels present in OI distinguish it from hypophosphatasia.

During the school-age period, children with type VI OI have notably elevated serum alkaline phosphatase.

There is no cure for OI.

For severe nonlethal OI, active physical rehabilitation in the early years allows children to attain a higher functional level than orthopedic management alone.

Children with OI type I and some with type IV are spontaneous ambulators.

Children with types III, IV, V, VI, and XI OI benefit from gait aids and a program of swimming and conditioning.

Severely affected patients require a wheelchair for community mobility but can acquire transfer and self-care skills.

Teens with OI can require psychological support with body image issues.

Growth hormone improves bone histology in growth-responsive children (usually types I and IV).

Orthopedic management of OI is aimed at fracture management and correction of deformity to enable function. Fractures should be promptly splinted or cast; OI fractures heal well, and cast removal should be aimed at minimizing immobilization osteoporosis. Correction of long-bone deformity requires an osteotomy procedure and placement of an intramedullary rod.

A several-year course of treatment of children with OI with bisphosphonates (IV pamidronate or oral olpadronate or risedronate) confers some benefits.

Bisphosphonates decrease bone resorption by osteoclasts; OI patients have increased bone volume that still contains the defective collagen.

Bisphosphonates are more beneficial for vertebrae (trabecular bone) than long bones (cortical bone).

There is no effect of bisphosphonates on mobility scores, muscle strength, or bone pain.

Limiting treatment duration to 2-3 years in mid-childhood can maximize the benefits and minimize the detriment to cortical material properties.

Benefits appear to persist several years after the treatment interval, and alternation of treatment intervals and drug holidays may be beneficial.

Side effects include abnormal long-bone remodeling, increased incidence of fracture nonunion, and osteopetrosis-like brittleness to the bone.

The morbidity and mortality of OI are cardiopulmonary. Recurrent pneumonia and declining pulmonary function occur in childhood, and cor pulmonale is seen in adults.

Neurologic complications include basilar invagination, brainstem compression, hydrocephalus, and syringohydromyelia.