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Osteogenesis imperfecta (OI) is a heritable, heterogeneous group of connective tissue disorders characterized primarily by abnormal bone formation leading to bone fragility and fractures. A classification system originally proposed in 1979 by Sillence et al. included four OI subtypes.1  Given advancements in our genetic understanding of the disorder, a genetic-functional classification has been largely adopted, linking genes to numerical types.2,3  There has also been a method of classification of clinical phenotypes of mild, moderate or severe.  There are now over 19 types of OI, classified by primary gene mutation.2

Table 1: Common OI Types, genetic classification, phenotype severity, clinical features

OI TypeGeneInheritanceSeverityClinical features
ICOL1A1ADmildblue sclera, normal stature, fractures, hearing loss
IICOL1A1 COL1A2ADlethal in perinatal periodblue-grey sclera, small for age, limb deformities, respiratory distress / pulmonary hypoplasia, soft calvarium
IIICOL1A1 COL1A2ADsevereshort stature, multiple fractures, progressive deformities, usually non-ambulatory, hearing loss in adolescence, may have dentinogenesis imperfecta
IVCOL1A1 COL1A2ADmoderateblue-grey sclera, usually ambulatory, dentinogenesis imperfecta, adult onset hearing loss
VIFITM5ADmild to severe, variesinterosseous membrane calcifications of forearms, radial head dislocation, hyperplastic callous formation
VISERPINF1ARmoderate to severesimilar to type III, dentinogenesis imperfecta absent, abnormal bone mineralization on histologic evaluation
VIICRTAPARsevere to lethalsevere rhizomelia, white sclera
VIIIP3H1ARsevere to lethalrhizomelia, coxa vara, popcorn metaphyses, short stature
AD, autosomal-dominant; AR, autosomal recessive; OI, osteogenesis imperfecta. 2,3


The majority (90%) of individuals with this disorder (types I-IV) are positive for a mutation of the genes COL1A1 or COL1A2 that encode the a chains of Type 1 collagen. Type 1 collagen makes up the structural framework of bone but also other connective tissues in the body.  Most forms of OI are autosomal dominant in transmission but over one-third of individuals have de novo mutations with no history of the disease.  OI is now understood as a predominantly collagen-related disorder because there are a number of autosomal recessive forms affecting genes that interact with collagen, such as in bone mineralization, collagen post-translational modification, collagen processing and crosslinking and even osteoblast function.2,3

Epidemiology including risk factors and primary prevention

The incidence has been estimated at 1:10,000 births.3  However, this may be an underestimate because mild forms may go unrecognized.


The defects in bone formation and bone fragility result from abnormal collagen microfibril quantity and/or quality or abnormal collagen related proteins.3,4 Collagen defects also may result in extraskeletal manifestations due to presence of collagen in non-bone structures.  This can result in the presence of blue-grey sclera, dental anomalies termed dentinogenesis imperfecta (early eruption of fragile, discolored teeth prone to premature wear), hearing loss, hyperlaxity of ligaments and skin and leading to joint hypermobility, easy bruising, and sometimes muscle weakness and cardiopulmonary complications. 

Disease progression including natural history, disease phases or stages, disease trajectory (clinical features and presentation over time)

Table 2: Common OI Types, age of clinical presentation, phenotype progression2,3

OI TypeAge of presentationProgression during childhoodProgression during adulthood
IFractures begin in toddlerhoodFractures persist through pubertyFractures decrease after puberty and then increase again in 5thdecade
IIPrenatal/immediately postnatalFatal within one year of birth
IIIFractures begin in infancyVery high fracture frequency with progressive limb deformity and dramatically short stature, often not ambulatory, hearing loss occurs in adolescenceIncidence of fractures remains high in adulthood
IVVariable phenotype, most severe presenting in infancy and others much laterFractures occur but typically remains ambulatoryVariable, hearing loss often occurs in adulthood, typically remains ambulatory
VVariable phenotypeVariableVariable
VISimilar to Type IV
VIIVariable, severe forms are lethal in perinatal period, others with multiple fractures in infancy, milder forms reportedFractures and progressive deformity in childhoodOccasional survival into adulthood
VIIISimilar to Type VII

Specific secondary or associated conditions and complications

Multiple fractures may result in pain, loss of function, and bony limb and chest deformity. Ligamentous laxity and short stature are common, though the severity of height difference varies.5  Kyphoscoliosis, chest wall pathology contribute to pulmonary insufficiency and infections which is the major cause of morbidity and mortality.6-9  Mitral valve prolapse and aortic dilatation rarely cause serious morbidity. Gross motor delays are common. Conductive hearing loss most often begins in the second to fourth decades of life, especially in Type I OI, secondary to otosclerosis-like pathology or ossicular discontinuity, but typically progresses to a mixed type hearing loss.10-13  CNS complications can be life-threatening and described as pathology of the craniocervical junction (CVJ).  Basilar invagination is the protrusion of the upper cervical vertebrae into the foramen magnum.  Basilar impression is caused by lowering of the skull base on the spine and platybasia is flattening of the cranial base.  These CVJ abnormalities can lead to compression of the medulla and cervical spinal cord which can result in hydrocephalus and syrinx.14



Historical details required include prenatal history and present of in-utero fractures and shortening of long bones on prenatal ultrasound.3  Post-birth history should include fracture history (when, how many, what body part, under what circumstances), stature, bone deformity, scleral color, tooth eruption and development, hearing function, ligamentous laxity, pain, motor/cognitive/speech and language developmental status, unusual facial features, and pain. Family history of perinatal demise, stature, fractures and musculoskeletal deformity is critical.  If diagnosis of OI has not been made in a child with multiple fracture, risk of abuse should be considered.15-17  Treatment history will describe historic and current medications (bisphosphonates, calcium, vitamin D, pain medications) as well as past surgical history including orthopedic surgical procedures.  Number of fractures and bone density scores may be used to track disease progression, response to medical treatment with bisphosphonates and the need for additional interventions such as surgery to limbs or spine.

Physical examination

The newborn with OI must be handled with extreme caution, given risk of fractures.  Exam should include using wide hand support and slow and gentle movements to prevent limb fractures.18  Infants with OI should not be picked up under the axilla.  Head and neck exam may reveal large head size or relative macrocephaly, triangular face shape, soft skull, and large open fontanelles. Eye exam may show blue or grey sclera. Skeletal exam might be notable for deviation of the sternum such as pectus excavatum, short narrow rib cage, short bowed long bones, rhizomelia (shortening of the proximal long bones), joint hypermobility, low tone and possibly generalized growth deficiency. Infants with acute fracture may be irritable, have pain on palpation or demonstrate fewer spontaneous movements of the affected body part.

Exam of the older child and adult should include accurate height and weight and avoid using of blood pressure cuffs that can lead to limb fractures.  Exam should include eye exam for scleral color and oral exam to evaluate dentition.  Dentition in more severe types of OI can show dentinogenesis imperfecta, darkening and weakness of the teeth, malocclusion or missing teeth.  Cranial nerve exam includes assessment of hearing but thorough audiology evaluation should be done.  Complete musculoskeletal exam includes assessment of height (which can be modified to body segments for seated children5), long bone deformity, acute fracture, chest and spine abnormality, joint range of motion and limb length difference.  Careful manual muscle testing to avoid fractures and reflex exam should be performed.  If the child is ambulatory, gait should be observed, noting presence of antalgic gait, common with limb length differences, decreased push-off, crouch gait and difficulty with activities like running or jumping.19,20

Functional assessment

Careful assessment of bed mobility, transfers and gait should be included. Early milestone achievement can be tracked using tests such as the Bayley, Peabody, or Bruininks, though acute fracture will limit observable motor ability. Self-care measures such as the Pediatric Evaluation of Disability Inventory (PEDI) and mobility measures such as the gross motor function measure (GMFM 88) and Brief Assessment of Motor Function (BAMF) can be considered to quantify and follow motor performance.18,21  People with severe OI generally have the skills needed for independent living and normal cognition that can lead to greater occupational success, though may require adaptations and equipment to be as independent as possible.25-27

Laboratory studies

If suspecting OI, then diagnostic work-up would start with DNA sequencing of the three most common genes COL1A1, COL1A2, and IFITM5 and duplication/deletion testing.15 If preliminary DNA testing is negative, sequencing for other osteogenesis imperfect genes is recommended, especially if more than one family member has the condition.2-4,15  A normal serum alkaline phosphatase and phosphate rule out idiopathic autosomal-recessive hyperphosphatasia.  Vitamin D 25-OH levels should be followed.  Pregnant parents can be offered prenatal genetic testing using chorionic villus samples if prenatal ultrasound shows severe limb shortening or in-utero fractures.3 


X-rays may reveal abnormalities such as osteopenia, long bone and rib fractures at various stages of healing, bowing or shortening (“crumpling”) of the long bones, vertebral fractures with compressed or “codfish” vertebra, “beading” of the ribs, wormian changes of the skull, “popcorn” epiphyses.  For people who have undergone prior orthopedic surgery such as rodding, X-rays of the limbs should be obtained to follow the intramedullary rod positioning over time and growth and subsequent limb length differences.20

Bone densitometry results using dual-energy x-ray absorptiometry (DEXA) vary with the type of OI. DEXA may be normal in Type I but significantly decreased in other types of OI.

Supplemental assessment tools

Mobility measures in OI studies often involved the Bleck score of motor ability (non-ambulator or ambulator in various areas — therapeutic area, household or community — with or without assistive device) and the PEDI.22-24  Quality of life measurements are being developed to reflect OI-specific measures of functioning, pain, fear of fracture, independence, isolation and remaining safe by avoiding activities with risk of injury.3,28

Early predictors of outcomes

Type of OI and total muscle strength are significant predictors of level of ambulation and ADL support needs.   Children with higher body weight have a greater decline in ambulation.29

Social role and social support system

A systematic review looking into the psychosocial experience of people with OI noted that given the normal cognitive potential, intellectual challenges and competences were highly valued.  Additionally, children can feel negative feelings from feeling different and can be socially isolating due to being left out, not well understood by peers or not being able to participate in some common activities.  Social support system is very important in making children with disabilities feel connected and understood.  This can be found through connection with peers in the community or through organizations such as the Osteogenesis Imperfecta Foundation (OIF).25

Professional issues

Genetic counseling support can be important for individuals with OI as they pursue family planning.  Prenatal screening can help with early diagnosis, however there are limitations in the genotype phenotype correlation in OI limiting the ability to accurately predict long-term functional outcome of a fetus.   Physicians must balance the the risk of fracture with advising a child with OI about the benefit of mobility and strengthening when discussing the goals of treatment, physical activity and participation.  Cell and gene therapy is still considered experimental and continues to have ethical and safety concerns around the treatments given off-label internationally.2


Available or current treatment guidelines

At present, there is no cure for OI.  Best practice rehabilitative approaches include education regarding safety measures, exercise, brace or splint fabrication and assistive devices for ADLs and mobility.  Medical management with bisphosphonates such as pamidronate and alendronate is widely used to increase bone density, and there has been some varying evidence for effect on fracture frequency.30  In a study evaluating the difference between IV and oral bisphosphonates, IV bisphosphonate zoledronic acid was shown to be better than oral bisphosphonate alendronate in decreasing fracture rate.31  Orthopedic surgical options include internal fixation of the long bones using intramedullary rods (not plates and screws, as they may create further stress in fragile bone) to minimize the incidence of fracture, restore bone integrity, decrease bowing, and improve function.20,32,33  Scoliosis is progressive over time and not responsive to spine bracing, but bracing can be considered to help sitting balance and independence. Posterior spinal fusion is considered a treatment option for scoliosis over 50°.34,35

Coordination of care

Patient care in OI is best delivered with a multi-disciplinary team.3,36  The care team for the person with OI can include specialists in genetics, physiatry, physical therapy, occupational therapy, orthopedic surgery, endocrinology, audiology, dentistry, nursing, social work, PCP and family.  Children should undergo pulmonary function screening testing and some children may need to be followed by a pulmonologist and a cardiologist if cardiac involvement is suspected.8

Transitioning from a pediatric care team to an adult provider team requires adequate expertise in OI for both pediatric and adult specialists, medical record transfer, educating individuals with OI to assume responsibility for their care and identifying care providers who are familiar with needs related to OI.37

Patient & family education

Families and patients should receive education regarding safe handling of the child, balancing safety with mobility and strengthening and adaptations in the community and school settings. Educationally, they should know their rights within the school system. For example, they should be aware of the Individuals with Disabilities Education Act (IDEA), a law ensuring services to children with disabilities throughout the nation. The Americans with Disabilities Act (ADA) ensures equal opportunities in employment for individuals with disabilities. School adaptations can include adaptive physical education to avoid concerning contact or collision activities, assistance with toileting or transfers if needed, use of an elevator if a child has difficulty with stairs, adaptive transportation for wheelchair uses.  School therapies can support a child’s development as well and school adaptive skills for challenges in fine motor areas. Voice dictation software can help with challenges with prolonged typing or handwriting. Vocational rehabilitation may be helpful in identifying and facilitating safe employment.


Other treatments under exploration include bone morphogenic protein modulators, receptor activator of nuclear factor kappa-B ligand (RANKL) inhibitors, and cell and gene based therapies.2,3 Antibodies found with possible treatment potential include the sclerostin-inhibitory antibody that can recruit osteoblasts and TGF-b neutralizing antibodies that can lead to increase bone mass, cortical thickness and strength.2,3  These treatments can have anabolic action on bone have been successful at decreasing fracture in animal models with adult studies ongoing.2 Pediatric trials are not complete but on-going at this time.2


Bisphosphonate therapy has been shown to increase bone density, but scientific studies have shown they are less convincing in improving fracture rate.30,38 Research needs to continue in the pediatric population for some of the adult OI treatment studies.2,3  The is limited research evidence regarding the recommendations for limb orthotics and their affect on fractures or function. 18,39


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31. Lv F, Liu Y, Xu X, et al. Zoledronic acid versus alendronate in the treatment of children with osteogenesis imperfecta: a 2-year clinical study. Endocr Pract. 2018;24(2):179-188.

32. Enright WJ, Noonan KJ. Bone plating in patients with type III osteogenesis imperfecta: results and complications. Iowa Orthop J. 2006;26:37-40.

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38. Rijks EB, Bongers BC, Vlemmix MJ, et al. Efficacy and Safety of Bisphosphonate Therapy in Children with Osteogenesis Imperfecta: A Systematic Review. Horm Res Paediatr. 2015;84(1):26-42.

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Original Version of the Topic:

Osteogenesis Imperfecta. Sherilyn A. Driscoll, MD. 8/07/2012.

Previous Revision(s) of the Topic

Heakyung Kim, MD, Hannah Aura Shoval, MD. Osteogenesis Imperfecta. 8/17/2016

Author Disclosure

Amy Kanallakan, MD
Nothing to Disclose