Osteogenesis Imperfecta (OI)

Updated: Mar 03, 2022
Author: Manoj Ramachandran, MBBS, MRCS, FRCS; Chief Editor: Harris Gellman, MD 


Practice Essentials

Osteogenesis imperfecta (OI) is a disorder of bone fragility chiefly caused by mutations in the COL1A1 and COL1A2 genes that encode type I procollagen. Four types of OI were originally described by Sillence in 1979 and are now used broadly as the Sillence criteria.[1]  The Nosology and Classification of Genetic Skeletal Disorders provided similar categorization in the 2019 revision, while also listing various additional types grouped under the four major types.[2]  Precise typing is often difficult and depends in large degree on the experience of the clinician. Severity ranges from mild forms to lethal forms in the perinatal period.

Additional genes have been discovered in which mutations can also cause brittle bones. These typically are clinically indistinguishable and are considered by most to be subtypes of OI.

The earliest known case of OI is 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 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.

OI is one of the most common skeletal dysplasias. It is a generalized disease of connective tissue that may manifest itself with one 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

Additional features, such as constipation and sweating, may also occur.

Because OI is a genetic condition, it has no cure. A multidisciplinary approach is required to manage the disease.[3, 4, 5, 6, 7]  Medical treatments aimed at increasing bone mass and strength have gained popularity.[8, 9]  Orthotics play a limited role in management of OI and are used to stabilize lax joints and to prevent progressive deformities and fractures. It is more important to provide walking aids, specialized wheelchairs, and home adaptation devices to help improve the patient’s mobility and function. Surgery remains a pillar of treatment,[10, 7] but it should be performed only if it is likely to improve function and only if the treatment goals are clear.


In OI, pathologic changes are seen in all tissues of which type 1 collagen is an important constituent (eg, bone, ligament, dentin, and sclera). The basic defect is one of a qualitative or quantitative reduction in type 1 collagen. Mutations in genes encoding type 1 collagen affect the coding of one of the two genes, accounting for approximately 80% of OI cases.[11, 12, 13, 14]

Most cases of OI, previously thought to be either autosomal dominant or autosomal recessive, are now known to arise from autosomal dominant mutations. These mutations are either genetically inherited or new. The inherited mutations have a recurrence risk in subsequent pregnancies of 50% if a parent is affected, whereas the new mutations have an unpredictable recurrence risk.

A small number of cases previously thought to be autosomal recessive have now been proved by molecular and linkage analysis to be secondary to gonadal mosaicism. The recurrence risk for these cases is also unpredictable.

In bone, the degree of histologic change correlates well with the clinical severity of the disease. The disease affects both endochondral and intramembranous ossification.

In OI due to quantitative defects of type 1 collagen, a mild form of the disease occurs. On light microscopy, osteoporotic bone is present, with thick osteoid seams and reduced intercellular matrix. The numbers of osteoclasts and osteocytes are normal. Bone trabeculae are thin and disorganized. Lamellar bone is seen in the diaphysis and metaphysis. On electron microscopy, osteoblasts show distended rough endoplasmic reticulum (possibly because of accumulation of incomplete procollagen molecules), and collagen fibers are of reduced diameter.

In OI due to qualitative defects of type 1 collagen, a severe form of the disease occurs. Light microscopy reveals hyperosteocytosis and increased vascular channels. Other findings are 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. Electron microscopy shows poorly preserved osteoblasts and collagen bundles of variable diameter, particularly in the more lethal forms of OI.

The epiphysis and physis tend to be broad and irregular, with disorganization of the proliferative and hypertrophic zones and loss of the typical columnar arrangement. Thinning of the zone of calcified cartilage is evident, along with deficiency of the primary spongiosa of the metaphysis and delay of the secondary centers of ossification in the epiphysis.

With respect to the axial skeleton, scoliosis and kyphosis are common. Vertebral bodies tend to be wedged, translucent, and shallow. Thinning of the skull and multiple ossification centers (wormian bones) are present, particularly in the occiput.


Type 1 collagen is a triple helix formed by two copies of the alpha1 chain and one copy of the alpha2 chain. The COL1A gene on chromosome 17 encodes the pro-alpha1 chain, and the COL2A gene on chromosome 2 encodes the pro-alpha2 chain.[15]

The gene sequence coding for the triple-helix domain has a repeating motif of (Gly-X-Y)(n), where X is commonly hydroxyproline and Y is commonly hydroxylysine. Glycine, being the smallest of all amino acids, fits into the core of the superhelix when the chains wind around each other; therefore, glycine plays an important role in the superhelix formation.

In 85-90% of cases, the gene mutation occurs in the region where the exon and intron splice sites are sequenced. All current mutations for type 1 collagen and their associated phenotypes can be found in the Human Type 1 Collagen Mutation Database.

In OI due to quantitative defects of type 1 collagen, mutations are usually found on the COL1A gene. The mutations result in the production of a premature stop codon or a microsense frame shift, which leads to mutant messenger RNA (mRNA) in the nucleus. However, the cytoplasm contains normal alpha1 mRNA; therefore, reduced amounts of structurally normal collagen are produced.

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. Substitution of a larger amino acid (eg, cysteine or alanine) for glycine results in abnormal helix formation, but these chains can combine with normal chains to produce type 1 collagen. The type 1 collagen thus formed is functionally impaired because of the mutant chain; this is the so-called dominant negative mechanism.

Wallace et al, in a report on three patients who had type I OI and primary open angle glaucoma (POAG), identified two novel mutations in COL1A1 in these individuals.[16] They suggested that some mutations in COL1A1 may be causative for OI and POAG. Alternatively, susceptibility genes may interact with mutations in COL1A1 to cause POAG.


The overall incidence of OI is approximately 1 case for every 20,000 live births; however, the mild form is underdiagnosed, and the actual prevalence may be higher. Prevalence appears to be similar worldwide, though an increased rate has been observed in two major tribal groups in Zimbabwe.

OI can present at any age, though the age when symptoms (ie, fractures) begin varies widely. Patients with mild forms may not have fractures until adulthood, or they may present with fractures in infancy. Patients with severe cases present with fractures in utero.

OI is equally common in males and females. It has been described in every human population in which skeletal dysplasias have been studied. The disease appears to have no predilection for a particular race.


Morbidity and mortality associated with OI vary widely, depending on the genotype. (See also the adapted Sillence classification in Presentation.) In addition, variability occurs between individuals with different mutations, and variability has also been observed between unrelated individuals with the same mutations, between members of the same family, and even between identical twins on occasion.

At one extreme, early stillbirths occur, and virtually every bone in the body has multiple fractures. The severe perinatal form (type II) is usually fatal within hours after birth, though some babies survive for several months. At the other extreme is OI in its mildest form. In this setting, adults who have never sustained a fracture come to medical attention only because their family members are affected. Between these extremes is a smooth continuum of severity.

The life expectancy of subjects with nonlethal OI appears to be the same as that for the healthy population, except for those with severe OI with respiratory or neurologic complications. Although patients with lethal OI may die in the perinatal period, individuals with extremely severe OI can survive until adulthood.

Patient Education

Patients with OI are generally well motivated and keen to achieve as much as possible despite their physical limitations.[17] Education is extremely important, particularly for those patients who may respond to their condition in a more negative way and therefore be prone to low self-esteem and depression.

Education of parents and families of OI patients is also important for helping them deal with the day-to-day implications and ongoing management of the disorder. For example, parents need special instructions in handling affected children. They need to know how to position the child in the crib and how to hold the child so as to minimize the risk of fractures while maintaining bonding and physical stimulation.

Living with ostogenesis imperfecta

A number of useful tips have been developed by the Osteogenesis Imperfecta Foundation for taking care of children with OI, including the following:

  • Never pull or push on a limb, or bend it into an awkward position, not even to take an x-ray
  • Use caution when inserting IVs, taking blood pressure, or performing other medical procedures to avoid causing injury
  • Always dose medicines to the size, not the age, of short statured adults
  • When a fracture is suspected, minimize handling of the affected limb
  • Respect the opinions, advice, or instructions provided by parents, children, and adults with OI, who have experience with the condition
  • Handle babies with extra care - Lift a baby with OI by placing one hand under the buttocks and legs, and the other hand under the shoulders, neck, and head, and do not lift the baby from under the armpits; do not lift by the ankles to change a diaper but,  rather, slide a hand under the buttocks; babies need not be kept on a pillow or soft surface and should be encourage babies to explore independent movement; supporting infants in a variety of positions develops muscles that will help with sitting and standing later on

A crucial point to stress is that parents should not automatically feel guilty if their child breaks a bone. Children must grow and develop, and fractures can occur despite excellent care. Because increasing awareness of child abuse and a lack of awareness about OI may lead to inaccurate conclusions about a family situation, it is worthwhile always to have a letter from the family doctor and a copy of the child's medical records handy.




Patients often have a family history of osteogenesis imperfecta (OI), but most cases are due to new mutations.

Patients most commonly present with fractures after minor trauma. In severe cases, antenatal screening ultrasonography (US) 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.

Patients may bruise easily. They may have repeated fractures after mild trauma. However, these fractures heal readily. Deafness is another feature. About 50% of patients with type I OI (see Physical Examination) have deafness by age 40 years.

Physical Examination

The clinical presentation of OI is dependent on the phenotype. The most widely used classification has been that of Sillence,[18, 1] which classified OI into four types on the basis of clinical and radiologic features (see Table 1 below). In addition, dentinogenesis imperfecta was denoted as subtype B, whereas OI without dentinogenesis imperfecta was denoted as subtype A.

Table 1. Adapted Sillence Classification of Osteogenesis Imperfecta (OI) (Open Table in a new window)

Type of OI 



Bone Fragility

Bone Deformity








Variable but less severe than other types



20% scoliosis and kyphosis

Wormian bones




Dentinogenesis imperfecta










Very severe

Multiple fractures



Wormian bones with absence of ossification

Perinatal death



Dentinogenesis imperfecta


Progressive bowing of long bones and spine

Bluish at birth but white in adults


Hypoplastic wormian bones

Wheelchair-bound, not ambulatory








Hypoplastic wormian bones




Dentinogenesis imperfecta







AD = autosomal dominant; NA = not applicable.

More than 10 additional types of OI have since been described,[19]  including types V, VI, VII, and VIII. The Nosology Committee of the International Skeletal Dysplasia Society has cited 18 different OMIM (Online Mendelian Inheritance in Man) types of OI, grouped under the four major types.[2] The International Classification of the Osteochondrodysplasias (INCO) has continued to use the Sillence classification. Types I-VIII are described further below.

Type I

Type I OI is the mildest and most common form. Patients present with blue sclerae (often described as dark blue with a gray tinge), variable degrees of bone fragility, moderate bone deformity, and premature deafness. Height is usually normal. Exercise tolerance and muscle strength are significantly reduced, even with mild OI. Birth weight tends to be normal, though one or more bones may be fractured.

Fractures may occur for the first time at a later age (eg, when the child starts to walk). These fractures tend to heal well, though sometimes a hypertrophic callus response is seen. Fractures tend to decrease in frequency after puberty, but their frequency may increase later in life when age- and sex-related osteoporosis is superimposed. Over a lifetime, numbers of fractures can range from one to 60 or more.

People with OI have a high tolerance for pain. Old fractures can be discovered in infants only after radiographs are obtained for other reasons other than an assessment of OI, and they can occur without any signs of pain.

Involvement of the axial skeleton, in the form of scoliosis and kyphosis, is seen in 20% of cases. Dentinogenesis imperfecta is characteristic of OI type IB.

Type II

Severely affected babies with type II OI are born with dwarfism, blue sclerae, and short, bowed limbs. Patients may have a small nose, micrognathia, or both. The disease is usually fatal at birth, but some babies survive for several months. All patients have in-utero fractures, which may involve the skull, long bones, or vertebrae. The ribs are beaded, and the long bones are severely deformed. Causes of death include extreme fragility of the ribs, pulmonary hypoplasia, and malformations or hemorrhages of the central nervous system (CNS).

Type III

Of all types of OI, type III is the one that orthopedic surgeons see most often. Babies with type III OI are born with severe bone fragility and suffer multiple fractures at birth, though birth weight tends to be normal. The bone fragility may lead to joint hyperlaxity, muscle weakness, chronic unremitting bone pain, and skull deformities (eg, posterior flattening). In utero fractures are common.

The sclerae are bluish at birth but fade over the years, becoming white in adulthood. Dentinogenesis imperfecta is frequently seen. The presence of dentinogenesis imperfecta is independent of the severity of the OI. Patients may have a triangular face with frontal bossing. Malocclusion is common.

The chest and rib cage are usually spared, with few or no fractures of the ribs. Bowing of the limbs is common with growth, and multiple fractures may be seen later in life. The result is a short skeleton and a relatively less affected barrel-shaped chest, with a pectus carinatum deformity. Deformities of upper limbs may compromise function and mobility. Affected children tend to become wheelchair-bound and nonambulatory.

The classic radiographic appearance is that of popcorn bones, in which fractures of the physes in several locations result in several islands of endochondral ossification. With age, these ossifications tend to disappear, leaving an enlarged radiolucent epiphysis. The axial skeletal is also involved, with progressive platyspondyly and kyphoscoliosis. Eventually, the wide rib cage overlaps the narrow pelvis.

Basilar invagination is an uncommon but potentially fatal occurrence in OI. Vertigo is common in patients with severe OI. The incidence of congenital malformations of the heart in children with OI is probably similar to that in the healthy population. Hypercalciuria may be present in about 36% of patients with OI but does not appear to affect renal function. Constipation and hernias are also common in people with OI.

Type IV

Children with type IV OI have white sclerae with moderate bone fragility and deformity. Fractures usually begin in infancy, but some may occur in utero. The long bones are usually bowed. The clinical picture may be similar to that of type I disease, except for the presence of white sclerae. Axial skeletal involvement, in the form of kyphoscoliosis, is also common. Dentinogenesis imperfecta is seen in type IVB disease.

Type V

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.

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.[20, 21] It is clinically similar to OI types II and IV but has rhizomelia as a distinctive feature. The gene mutation has been mapped to region 3p22-24.1.


OI type VIII is a recessive form of lethal or severe OI. It is caused by null mutations in P3H1, which encodes prolyl 3-hydroxylase 1.[22]  With respect to appearance and symptoms, type VIII resembles types II and III, except for white sclerae. Severe growth deficiency and extreme under-mineralization of the skeleton are noted.

Other types of osteogenesis imperfecta

Many cases of OI do not fit into the aforementioned categories; such variants include the following:

  • Osteoporosis-pseudoglioma syndrome - This is caused by mutations in the gene encoding for the low-density-lipoprotein receptor-related protein 5 (LRP5), with clinical features including blindness and bone fragility; LRP5 is thought to mediate the proliferation and differentiation of osteoblasts
  • Bruck syndrome - This is an autosomal recessive condition caused by mutations in the bone-specific collagen type 1 telopeptide lysyl hydroxylase enzyme, with clinical features that include congenital joint contractures and bone fragility [23]
  • Cole-Carpenter syndrome - This is a severe progressive form of OI, with associated multisutural craniosynostosis and growth failure


Repeated respiratory infections are complications of severe OI. Basilar impression caused by a large head, which causes brainstem compression, is the major neurologic complication in a child with OI. This is most commonly observed in children with very severe OI. Cerebral hemorrhage caused by birth trauma is another possible complication.

Patients with OI should be considered to be at high risk for complications of anesthesia, though they are not particularly prone to malignant hyperthermia. Patients with OI have a high basal metabolism that may cause hyperthermia during anesthesia, but the hyperthermia is almost never malignant. In fact, only one case of malignant hyperthermia in a child with OI has been described in the literature, and that particular patient had a family history of malignant hyperthermia.

Pregnant women with OI are at increased risk for complications. Births to women with OI have been associated with a higher likelihood of antepartum hemorrhage, abruptio placentae, intrauterine growth restriction and small-for-gestational-age infants, congenital malformation, and preterm birth.[24]



Diagnostic Considerations

Because osteogenesis imperfecta (OI) can manifest itself in a wide variety of ways, differential diagnoses are best categorized into the following three stages of life:

  • Antenatal/neonatal
  • Preschool/childhood
  • Adolescence/adulthood

In addition to the conditions listed in the differential diagnosis, other conditions that should be considered in the antenatal/neonatal stage include the following:

  • Jeune dystrophy
  • Camptomelic dysplasia
  • Chondrodysplasia punctata
  • Chondroectodermal dysplasia ( Ellis–van Creveld syndrome)
  • Nonaccidental injury

Hypophosphatasia may also be present. Patients may have blue sclerae, fractures, and wide fontanelles. This condition is characterized by low serum alkaline phosphatase levels and, in the severe recessive form, skin dimples overlying Bowdler spurs located symmetrically on the midshaft of the fibula, ulna, and radius.

Other conditions that should be considered in the preschool/childhood stage include the following:

Other conditions that should be considered in the adolescence/adulthood stage include the following:

For genetic conditions, patients present with fractures. For idiopathic juvenile osteoporosis, patients aged 8-13 years present with skeletal pain, atraumatic fracture, and reduced bone density. The condition remits by early adulthood.

It is of particular importance to differentiate between OI and child abuse (though it must be kept in mind that the two can also coexist). Mild OI is most likely to be confused with child abuse.[25] The sclera and teeth are normal in many patients with OI. A family history is often not present. Keys to distinguishing OI from child abuse if no other stigmata of OI are present include the following points:

  • The type of fracture is of diagnostic significance; although any type of long bone fracture can occur in OI, certain types are rare; metaphyseal corner fractures, which are common in child abuse, are rare in OI
  • In children with OI, fractures may continue to occur while they are in protective custody; however, this scenario is hard to evaluate
  • Child abuse can also be differentiated from OI on the basis of nonskeletal manifestations (eg, retinal hemorrhage, visceral intramural hematomas, intracranial bleeds of various ages, pancreatitis, and splenic trauma)

Collagen analysis is useful in difficult cases, but a negative result does not rule out OI.

Differential Diagnoses



Laboratory Studies

Results from routine laboratory studies in patients with osteogenesis imperfecta (OI) are usually within reference ranges, and they are useful in ruling out other metabolic bone diseases.

An analysis of type I, III, and V collagens synthesized by fibroblasts may be helpful. Collagen synthesis analysis is performed by culturing dermal fibroblasts obtained during skin biopsy. The occurrence of false-negative results is not clear, though the rate may be about 15%. Results are negative in syndromes resembling OI.

Tests include the following:

  • Sodium dodecyl sulfate–polyacrylamide gel electrophoresis (SDS-PAGE)
  • Two-dimensional SDS-PAGE
  • Cyanogen bromide (CNBr) mapping
  • Thermal stability studies

An analysis of the amino acid composition of collagens may be useful.

DNA blood testing for gene defects has an accuracy of 60-94%. Antenatal 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 (US) guidance when a mutation in another member of the family is already known.


Antenatal US 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.

Mild forms of OI may result in normal findings on US. 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.

Plain Radiography

A radiographic skeletal survey should be obtained after birth. Plain radiographs may depict the following three radiologic categories of OI:

  • Category I – Thin and gracile bones
  • Category II – Short and thick limbs
  • Category III – Cystic changes

Radiologic features commonly seen include the following:

  • Fractures – Commonly, transverse fractures and those affecting the lower limbs (see the first image below)
  • Excessive callus formation and popcorn bones - Multiple scalloped, radiolucent areas with radiodense rims
  • Skull changes - Wormian bones (see the second image below), enlargement of frontal and mastoid sinuses, and platybasia with or without basilar impression
  • Deformities of the thoracic cage - Fractured and beaded ribs (see the third and fourth images below) and pectus carinatum
  • Pelvic and proximal femoral changes - Narrow pelvis, compression fractures, protrusio acetabuli, [26] and shepherd’s-crook deformities of the femurs
Osteogenesis imperfecta. Newborn has bilateral fem Osteogenesis imperfecta. Newborn has bilateral femoral fractures.
Osteogenesis imperfecta. Wormian bones are present Osteogenesis imperfecta. Wormian bones are present in skull.
Osteogenesis imperfecta. Acute fractures are obser Osteogenesis imperfecta. Acute fractures are observed in radius and ulna. Multiple fractures can be seen in ribs. Old healing humeral fracture with callus formation is observed.
Osteogenesis imperfecta. Beaded ribs. Multiple fra Osteogenesis imperfecta. Beaded ribs. Multiple fractures are seen in long bones of upper extremities.

In mild OI (type I), images may reveal thinning of the long bones with thin cortices. Several wormian bones may be present. No deformity of long bones is observed.

In extremely severe OI (type II), the survey may reveal beaded ribs, broad bones, and numerous fractures with deformities of the long bones. Platyspondylia may also be revealed.

In moderate and severe OI (types III and IV), imaging may reveal cystic metaphyses, or a popcorn appearance of the growth cartilage. Normal or broad bones are revealed early, with thin bones revealed later. Fractures may cause deformities of the long bones. Old rib fractures may be present. Vertebral fractures are common.


Dual x-ray absorptiometry (DEXA) may be used to assess bone mineral density (BMD) in children with milder forms of OI. BMD, as measured with DEXA, is low in children and adults with OI regardless of severity. BMD can be normal in infants with OI, even in severe cases. In pediatric patients, DEXA results are not useful for predicting the risk of fracture. No reliable published reference data regarding DEXA in infants are available.

Densitometric bone scanning with computed tomography (CT) may be helpful in atypical cases of OI, though normal bone density does not exclude mild forms of the disease.

Other Tests

Polarized light microscopy or microradiography may be 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%.[27]

Bone biopsy may show changes in the concentrations of noncollagenous bone proteins, such as osteonectin, sialoprotein, and decorin.

Histologic Findings

The width of biopsy cores, the width of the cortex, and the volume of cancellous bone are decreased in all types of OI. The number and thickness of trabeculae are reduced.

Samples may show evidence of defects in modeling of external bone in terms of the size and shape, the production of secondary trabeculae by endochondral ossification, and the thickening of secondary trabeculae by remodeling. Therefore, OI might be regarded as a disease of the osteoblast.[28]

Bone formation is quantitatively decreased, but the quality of the bone material is probably most important in the pathogenesis of the disease.



Approach Considerations

Because osteogenesis imperfecta (OI) is a genetic condition, it has no cure. For many years, surgical correction of deformities, physiotherapy, and the use of orthotic support and devices to assist mobility (eg, wheelchairs) were the primary means of treatment.[29] Subsequently, as a consequence of improved understanding of the molecular mechanisms of OI, medical treatments aimed at increasing bone mass and strength gained popularity, with surgery increasingly reserved for functional improvement.[8, 9]

Orthotics play a limited role in management of OI and are used to stabilize lax joints (eg, ankle and subtalar joints with ankle-foot orthoses [AFOs]) and to prevent progressive deformities and fractures. It is more important to provide walking aids, specialized wheelchairs, and home adaptation devices to help improve the patient’s mobility and function.

Surgery remains a pillar of treatment for patients with OI,[10, 7] but it should be performed only if it is likely to improve function and only if the treatment goals are clear. Surgical interventions include intramedullary rod placement, surgery to manage basilar impression, and correction of scoliosis. Soft-tissue surgery is used in specific circumstances (eg, lower-limb contractures, particularly those of the Achilles tendon).

Skilled administration of anesthetics and awareness of the limitations of surgery are essential prerequisites.[30] Anesthetic-related problems may arise from in 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. It is important to watch for hyperthermia and increased sweating.

Home visits and regular clinic assessments are necessary, particularly in the first few years of life. Postoperatively, close follow-up is vital to ensure fracture healing and restoration of function.

Pharmacologic Therapy


Bisphosphonates (eg, pamidronate) are synthetic analogues of pyrophosphate that inhibit osteoclast-mediated bone resorption on the endosteal surface of bone by binding to hydroxyapatite. As a result, unopposed osteoblastic new bone formation on the periosteal surface results in an increase in cortical thickness. Their use in the treatment of OI is on off-label application.

Cyclic intravenous (IV) pamidronate is commonly given in a dosage of 7.5 mg/kg/y at 4- to 6-month intervals.[31, 32] 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 (BMD), while reducing pain and increasing energy levels.[33] Current evidence does not support the use of oral bisphosphonates in patients with OI.

IV pamidronate is effective in babies and can be used to relieve pain in severe cases. Good evidence suggests that bisphosphonate therapy may significantly improve the natural history of type III and type IV disease, particularly by decreasing the rate of fracture, increasing BMD, decreasing bone pain, and significantly increasing height (especially with prolonged cyclic therapy up to 4 years).[34, 35] In some cases, crumpled femurs and flattened vertebrae may assume more normal shapes and cortical thickness.

Adverse effects of pamidronate include an acute febrile reaction, mild hypocalcemia, leukopenia, a transient increase in bone pain, and scleritis with or without anterior uveitis. With milder forms of OI, the indications for bisphosphonate therapy have yet to be evaluated.

Other bisphosphonates (eg, risedronate, alendronate,[36] and zoledronic acid) have been studied. Alendronate was found to decrease predicted material properties and to have detrimental effects on osteoblasts and bone formation in mice with OI. A study from China found that long-term (3 years) alendronate therapy significantly lowered the incidence of fractures, increased BMD in the lumbar spine and femoral neck, and reduced bone turnover biomarkers in children and adolescents with OI.[37]  Risedronate may have some effect in reducing fractures in patients with OI.[38]

In a retrospective chart review and analysis aimed at determining the safety and efficacy of pamidronate therapy in 18 children younger than 24 months who had OI (mean age at treatment, 12 months), Kusumi et al found that mean lumbar z score improved from –3.63 at baseline to –1.53 at 1 year and to 0.79 by study end, whereas fracture rate improved from 0.32 fractures/patient-month before treatment to 0.03 fractures/patient-month after treatment.[39] Height standard deviation score was conserved from baseline to study end.

Hald et al conducted a metanalysis of six placebo-controlled trials, involving 424 patients with 751 patient-years of follow-up, to determine the effects of bisphosphonate therapy on fracture risk for patients with OI.[40] They found that the proportion of patients who experienced a fracture was not significantly reduced by bisphosphonate therapy and concluded that the effects of bisphosphonates on fracture prevention in OI are inconclusive.

A Cochrane review concluded that whereas oral or IV bisphosphonates increase BMD in children and adults with OI, these agents do not differ significantly from each other in this respect, and they have not been clearly shown to decrease fractures consistently.[41]  The review did not demonstrate that bisphosphonates conclusively improve clinical status (eg, by reducing pain or improving growth and functional mobility) in people with OI.

A study by Garganta et al involving 22 children with OI found that cyclic IV bisphosphonate therapy transiently reduced pain and improved functional abilities, with pain relief occurring immediately after infusion and functional improvements seen 4 weeks later.[42] Both pain and physical functioning returned to pretreatment levels by time of the next infusion.

Other agents

Growth hormone is known to act on the growth plate and also stimulate osteoblast function, possibly via insulinlike growth factor (IGF)-1 and IGF-binding protein (IGFBP)-3. Growth hormone may be beneficial in patients with a quantitative collagen defect, but its role in the management of OI has not been clearly defined.

Teriparatide is a recombinant human form of parathyroid hormone that increases the number and activity of osteoblasts. It has been approved by the US Food and Drug Administration (FDA) for use in osteoporosis, but because of the potential risk of osteosarcoma induction (as seen in preclinical studies in rats), it has not been approved by the FDA for use in children and adolescents. The potential use of teriparatide for the treatment of OI remains to be defined.

A preclinical study demonstrated that inhibition of receptor activator of nuclear factor-kappaB ligand (RANKL) improves density and some geometric and biomechanical properties of the oim/oim mouse bone but does not decrease fracture incidence when compared with placebo.[43]

Cellular and Genetic Therapy

Bone marrow transplantation (BMT) has been advocated as a potential future therapeutic modality for OI. Transplantation of adult bone marrow in utero has been shown to decrease perinatal lethality in a murine model of OI.

Bone marrow contains both hematopoietic stem cells and mesenchymal stem cells (MSCs), the latter being the precursors of osteoblasts. 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 have been advocated.

Such cell therapies usually result in somatic mosaicism, where normal and abnormal osteoblasts exist in the same body. Unfortunately, a higher proportion of engrafted normal cells is required to achieve the level of normal osteoblasts necessary for functional correction of the OI phenotype. Furthermore, the use of immunosuppressive agents to prevent graft rejection and graft-versus-host reaction can itself damage bone.

Future approaches include the autografting of genetically modified mutant osteoblasts, whereby the mutant collagen gene is inactivated. These therapies are several years away from clinical reality.

Gene therapy is being explored in animal models, but major obstacles remain, both because of intrinsic difficulties (as illustrated by attempts to treat conditions such as cystic fibrosis) and because of the dominant negative mechanism of the disease. The success achieved in treating X-linked severe combined immunodeficiency disease (X-SCID) by means of gene therapy provides some hope that this approach may eventually be successful in conditions such as OI.

Intramedullary Rod Placement

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. Osteotomies should be simple, preferably single, and performed under direct vision with maximum care and gentle handling of tissues.

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 [K-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.

Rod placement is of particular use in the femur and is less commonly used in the tibia, humerus, and forearm. An experienced team can perform as many as four rod procedures in the long bones of the lower extremities in a single surgical session. Fractures heal normally in about 85% of patients with OI.

In the prebisphosphonate era, extendable rods were preferred to nonextendable ones in order to prevent bone bowing and bone growth beyond the end of the rod. Bailey-Dubow rods were complicated by a high incidence of mechanical failures (eg, migration and disconnection of T-parts); accordingly, Sheffield rods and the Fassier-Duval modification[44] are now more commonly used. The latter also has the advantage of being inserted through the greater trochanter (as in adult fixations), thus avoiding the need for a knee arthrotomy in femoral surgery.

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

The use of a dual interlocking telescopic rod, in which both the sleeve and the obturator are anchored with interlocking pins, has been described for tibial stabilization in children with OI,[45]  with results comparable to or better than those seen with a single interlocking telescopic rod. Anchoring the sleeve at the proximal epiphysis appear to provide better anchorage and allow easier removal.

Other Surgical Treatments

Surgery for basilar impression

Basilar invagination may result in long tract signs and respiratory depression from direct compression of the brainstem and the upper cervical and cranial nerves. It is best treated with decompression and stabilization of the craniocervical junction. A team of orthopedic surgeons and neurosurgeons is required. This procedure is reserved for cases with neurologic deficiencies.

Surgery for spinal deformities

Bracing is not effective in treating spinal deformities such as scoliosis and kyphosis, because the rib cage is too fragile to transfer the brace pressure to the vertebral column. Moreover, the external pressure may worsen the chest deformities. Surgery is indicated when the following two 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. Often, significant correction and stable fixation are not achieved. Pretreatment with pamidronate appears to improve the surgical outcome.


Nutritional evaluation and intervention are paramount to ensure appropriate intake of calcium, phosphorus, and vitamin D. Caloric management is important, particularly in adolescents and adults with severe forms of OI.


Physical therapy, in the form of comprehensive rehabilitation programs, should be directed toward improving joint mobility and developing muscle strength.[46] Physiotherapy has become more effective in the postbisphosphonate era because of the decrease in bone fragility and the improved prognosis for standing or walking. Strategies are age-dependent and are aimed at promoting gross motor development and maximizing functional independence.[17]

In early infancy, gentle handling of babies by parents is encouraged to prevent fractures, with frequent positional changes advised to prevent occipital flattening, torticollis, and frog-leg positioning of the hips.

When the infant is crawling, upper-limb mobility is promoted; this is vital for future transfers. Exercises can include propelling a wheelchair or ambulating with walking aids.

When the child starts to stand, walking is encouraged, both as exercise and as a primary or secondary means of mobility. Weightbearing is promoted in the pool, on tricycles, and with walkers. Prone positioning is used to prevent hip flexion contractures; this is aided by strengthening of hip extensors and quadriceps. Bisphosphonates have significantly improved the walking ability of children with severe forms of OI.


Care of patients with OI is multidisciplinary. Team members may include an occupational therapist (OT), a physical therapist (PT), a nutritionist, an audiologist, an orthopedic surgeon, a neurosurgeon, a pneumologist, and a nephrologist, among others. Periodic evaluation and intervention by an OT, a PT, or both is warranted.

Genetic counseling should be offered to the parents of a child with OI who plan to have more children. During genetic counseling, the possibility of germline mosaicism must be discussed.



Medication Summary

The goals of pharmacotherapy are to reduce morbidity and prevent complications.[31]


Class Summary

Bisphosphonates are drugs that have been used off label for the treatment of osteogenesis imperfecta (OI). Drugs in this class may slow the loss of existing bones and may reduce long bone fractures and vertebral compressions. The most commonly used drug in this class is pamidronate.[34, 36, 32]

Bisphosphonates are 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.

For maximum gut absorption, all oral bisphosphonates should be taken at least 2 hours before or after meals. The newer bisphosphonates are not completely free of the risk of causing a mineralization defect, but their safe therapeutic window is much wider. They clearly are more potent than etidronate in reducing disease activity and normalizing alkaline phosphatase levels

Pamidronate (Aredia, APD)

Pamidronate is a potent second-generation bisphosphonate that acts principally by inhibiting osteoclastic bone resorption. Cyclic intravenous (IV) pamidronate is given in a dose of 7.5 mg/kg/y at 4- to 6-month intervals.

Alendronate (Fosamax)

Alendronate is a potent third-generation bisphosphonate that principally acts by inhibiting osteoclastic bone resorption.

Risedronate (Actonel, Atelvia)

Risedronate is a potent aminobisphosphonate that principally acts by inhibiting osteoclastic bone resorption.

Tiludronate (Skelid)

Tiludronate is a sulfur-containing bisphosphonate of intermediate potency between etidronate and newer nitrogen-containing bisphosphonates. No food, indomethacin, or calcium should be ingested within 2 hours before and 2 hours after administration. A 3-month posttreatment evaluation follows.

Zoledronate (Reclast, Zometa)

Zoledronate inhibits bone resorption. It inhibits osteoclastic activity and induces osteoclastic apoptosis.


Questions & Answers


What is osteogenesis imperfecta (OI)?

What is the pathophysiology of osteogenesis imperfecta (OI)?

What causes osteogenesis imperfecta (OI)?

What is the prevalence of osteogenesis imperfecta (OI)?

Which patient groups have the highest prevalence of osteogenesis imperfecta (OI)?

What is the prognosis of osteogenesis imperfecta (OI)?

What is included in the patient education about osteogenesis imperfecta (OI)?

What are the Osteogenesis Imperfecta Foundation recommendations on caring for children with osteogenesis imperfecta (OI)?


Which clinical history findings are characteristic of osteogenesis imperfecta (OI)?

How is osteogenesis imperfecta (OI) classified?

Which physical findings are characteristic of osteogenesis imperfecta (OI) type I?

Which physical findings are characteristic of osteogenesis imperfecta (OI) type II?

Which physical findings are characteristic of osteogenesis imperfecta (OI) type III?

Which physical findings are characteristic of osteogenesis imperfecta (OI) type IV?

Which physical findings are characteristic of osteogenesis imperfecta (OI) type V?

Which physical findings are characteristic of osteogenesis imperfecta (OI) type VI?

Which physical findings are characteristic of osteogenesis imperfecta (OI) type VII?

Which physical findings are characteristic of osteogenesis imperfecta (OI) type VIII?

Which physical findings are characteristic of osteogenesis imperfecta (OI) variants?

What are the possible complications of osteogenesis imperfecta (OI)?


Which conditions are included in the differential diagnoses of osteogenesis imperfecta (OI)?

Which conditions are included in the differential diagnoses of osteogenesis imperfecta (OI) during the antenatal/neonatal period?

Which conditions are included in the differential diagnoses of osteogenesis imperfecta (OI) during preschool and childhood?

Which conditions are included in the differential diagnoses of osteogenesis imperfecta (OI) during adolescence and adulthood?

How is osteogenesis imperfecta (OI) differentiated from child abuse?

What are the differential diagnoses for Osteogenesis Imperfecta (OI)?


What is the role of lab tests in the workup of osteogenesis imperfecta (OI)?

What is the role of ultrasonography in the workup of osteogenesis imperfecta (OI)?

What is the role of radiography in the workup of osteogenesis imperfecta (OI)?

What is the role of dual x-ray absorptiometry (DEXA) in the workup of osteogenesis imperfecta (OI)?

What is the role of scanning electron microscopy in the workup of osteogenesis imperfecta (OI)?

What is the role of biopsy in the workup of osteogenesis imperfecta (OI)?

Which histologic findings are characteristic of osteogenesis imperfecta (OI)?


How is osteogenesis imperfecta (OI) treated?

What is the role of surgery in the treatment of osteogenesis imperfecta (OI)?

When is neurosurgery indicated in the treatment of osteogenesis imperfecta (OI)?

How are spinal deformities treated in osteogenesis imperfecta (OI)?

Which dietary modifications are used in the treatment of osteogenesis imperfecta (OI)?

Which activity modifications are used in the treatment of osteogenesis imperfecta (OI)?

Which specialist consultations are beneficial to patients with osteogenesis imperfecta (OI)?

What is the role of bisphosphonates in the treatment of osteogenesis imperfecta (OI)?

What is the role of growth hormone in the treatment of osteogenesis imperfecta (OI)?

What is the role of teriparatide in the treatment of osteogenesis imperfecta (OI)?

What is the role of receptor activator of nuclear factor-kappaB ligand (RANKL) in the treatment of osteogenesis imperfecta (OI)?

What is the role of bone marrow transplantation (BMT) in the treatment of osteogenesis imperfecta (OI)?

What is the role of gene therapy in the treatment of osteogenesis imperfecta (OI)?


What is the role of medications in the treatment of osteogenesis imperfecta (OI)?

Which medications in the drug class Bisphosphonates are used in the treatment of Osteogenesis Imperfecta (OI)?