Author(s): Jeremy Roberts, MD, Denesh Ratnasingam, MD, Cara Vernacchia, DO, Erin Mundy, MD, Amy Kanallakan, MD
Originally published: August 7, 2012 Last updated: April 3, 2024
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Disease/Disorder

Definition

Osteogenesis imperfecta (OI), (brittle bone disease) is a heritable, heterogeneous group of connective tissue disorders characterized primarily by abnormal bone formation leading to bone fragility and fractures.1,2 In 1979, Sillence et al. proposed a classification system that included four OI subtypes.3 Given advancements in our genetic understanding of the disorder, a genetic functional classification has been adopted, linking genes to numerical types.4,5 There is also a method of classification of clinical phenotypes of mild, moderate, severe, or perinatal lethality.1 There are now over 19 types of OI, classified by primary gene mutation.4

AD, autosomal-dominant; AR, autosomal recessive; OI, osteogenesis imperfecta4,5

Table 1: OI Type, Inheritance, Genes, Severity, and Clinical Features

OI TypeInheritanceGeneSeverityClinical Features
IADCOL1A1MildNormal or short stature, little or no deformity; may have blue sclera, fractures, and hearing loss
IIAD
AR (rare)		COL1A1 COL1A2
AR genes below		Lethal in perinatal periodMinimal calvarial mineralization, beaded ribs, long bone deformities, blue-grey sclera, respiratory distress/pulmonary hypoplasia
IIIAD
AR		COL1A1 COL1A2
AR genes below		SevereProgressively deforming bones, short stature, usually non-ambulatory, hearing loss in adolescence, may have dentinogenesis imperfecta
IVADCOL1A1 COL1A2ModerateShort stature, blue-grey sclera, usually ambulatory, dentinogenesis imperfecta, adult-onset hearing loss
VADIFITM5Variable – Mild to SevereInterosseous membrane calcifications of forearm, radial head dislocation, hyperplastic callus formation
VIARSERPINF1Moderate to SevereDentinogenesis imperfecta absent, accumulation of un-mineralized osteoidl fish-scale pattern of lamellae on biopsy
VIIARCRTAPSevere to LethalSevere rhizomelia, white sclera
VIIIARLEPRE1Severe to LethalRhizomelia, coxa vara, popcorn metaphyses, short stature
IXARPPIBSevereAnterior bowing of tibia and short bowed femur
XARSERPINH1Severe 
XIARFKBP10Moderate to SevereJoint contractures; fish scale-like pattern of lamellae on biopsy distorted
XIIARSP7Moderate 
XIIIARBMP1Severe 
XIVARTMEM38BModerate to Severe 
XVAR
AD (causing osteoporosis)		WNT1Moderate to SevereBrain malformations
XVIARCREB2L1SeverePerinatal fractures, tubular bone with accordion-like broadened appearance fractures
XVIIARSPARCProgressively Severe 
XVIIIARFAM64AModerate to SevereDysmorphic features, developmental delays
XIXX-linkedMBTPS2Moderate to SeverePectus deformity
UnclassifiedARPLOD2Moderate to SevereJoint contractures
UnclassifiedX-linkedPLS3 Osteoporosis with fractures, clinical overlap with OI

Though in the past, it was thought that AD forms were less severe than AR ones, it is now clear that different mutations in the same gene can be associated with a large variation in severity.    For example, there are some de novo AD forms and cases where recessive disease tends toward the milder of the two mutations in a compound heterozygous situation.4

Etiology 

The majority (90%) of individuals with this disorder (types I-IV) are positive for a
mutation of the genes COL1A1 or COL1A2: the triple helix molecule of type 1 collagen is
composed of two alpha 1 chains for COL1A1 and one alpha 2 chain for COL1A2.4,6 Type 1
collagen makes up the structural framework of bone and other connective tissues in the body. It
is the major component of the extracellular matrix in bone, skin, and tendon, and is secreted by
osteoblasts, dermal fibroblasts, and tenocytes.5 Most forms of OI are autosomal dominant in
transmission, but over one-third of individuals have de novo mutations with no family history of
the disease. OI is now understood as a predominantly collagen-related disorder because there are
several 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.4,5

Epidemiology including risk factors and primary prevention 

Incidence ranges from 1:10,000 births to 0.3-0.7 per 10,000 births.5 However, this may be an underestimate because mild forms may go unrecognized.

Patho-anatomy/physiology 

The defects in bone formation and bone fragility result from abnormal collagen microfibril quantity and/or quality (structural defect) or abnormal collagen related proteins.4,7 Typically, a quality issue results in moderate or severe deformity and a quantity issue results in a mild phenotype.8 Both quality and quantity issues can result in osteopenia.1 Typically, the long bones are affected, but axial bones can also be affected as well.1 Abnormal collagen in non-bone structures cause extra-skeletal manifestations including blue-grey sclera, dental anomalies termed dentinogenesis imperfecta (early eruption of fragile, discolored teeth prone to premature wear), hearing loss, aortic dilatation, gastrointestinal issues, hyperlaxity of ligaments and skin and leading to joint hypermobility, easy bruising, and occasional muscle weakness and cardiopulmonary complications.1,5,9,10

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

There are many historical schemes that have changed over time and vary based on phenotype, genetic mutation, and clinical and radiologic findings.4,5 Depending on the phenotype, patients may develop repeated fractures, reduced function, wheelchair dependence, and even contractures.1 Of note, scoliosis typically starts around six years of age and is progressive.6 Patients with Type I are typically community ambulators but may have limitations in sports and physical function. Patients with type III are typically exercise ambulators.11

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.12 Kyphoscoliosis and chest wall pathology may contribute to pulmonary insufficiency and infections, which are the major causes of morbidity and mortality.13 However, pulmonary insufficiency can occur regardless of presence of scoliosis.14 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.15 Patients are at high risk of scoliosis, kyphosis, craniocervical junction abnormalities, and lumbosacral pathology.6 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. Platybasia is flattening of the cranial base, and more severe phenotypes result in more abnormalities of the skull base.6 Sillence has recommended independent upright posture be delayed until age 18 months to prevent basilar impression.16 CVJ abnormalities can lead to compression of the cranial nerves, medulla, and cervical spinal cord, the latter two of which can result in hydrocephalus and syrinx.6,17,18 Fusion may ultimately be required.6

Essentials of Assessment 

History

Important elements of obtaining a history include a prenatal history and presence of in-utero Important elements of obtaining a history include a prenatal history and presence of in utero fractures and shortening of long bones on prenatal ultrasound.5,19 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, 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 fractures, risk of abuse should be considered. Treatment history will describe historic and current medications (bisphosphonates, calcium, vitamin D, pain medications) as well as past surgical history including orthopedic surgical procedures. The 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.20-23

Physical examination

The newborn with OI must be handled with extreme caution, given the risk of fractures. The exam should include using wide hand support and slow and gentle movements to prevent limb fractures.24 Infants with OI should not be picked up under the axilla. The head and neck exam may reveal large head size or relative macrocephaly, a triangular face shape, soft skull, and large open fontanelles.7 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.7 Regular surveillance for fractures is recommended.25 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 use of blood pressure cuffs that can lead to limb fractures.25 Dentition should be evaluated as well. Dentition in more severe types of OI can show dentinogenesis imperfecta, darkening and weakness of the teeth, malocclusion or missing teeth. The 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 children), long bone deformity, acute fracture, chest and spine abnormality, joint range of motion, and limb length difference. Careful manual muscle testing and reflex exam to avoid fractures 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.25,26

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.24,27 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.28,29

Laboratory studies

Pregnant parents can be offered prenatal genetic testing using chorionic villus samples if prenatal ultrasound shows severe limb shortening or in-utero fractures.5 Bone biopsy can be considered as well.2 When OI is suspected, an OI and bone fragility panel should be considered. Since COL1a and 1b account for most cases, initial genetic sequencing for those mutations can be considered if trying to reduce costs; however, OI and other bone fragility genetic testing should be done to be comprehensive.4,5,7,21 Both hyperphosphatasia including Mabry syndrome and hypophosphatasia can contribute to symptomatology as well.30,31 Alkaline phosphatase is low in hypophosphatasia and can be normal to high in OI.31 Panels should be reviewed to be sure genes of interest in a specific case are covered.4 When women are considering pregnancy and there is a concern for OI, they can speak to a genetic counselor for possible collagen testing or prenatal diagnosis. In vitro fertilization and embryo analysis can be considered. Ultrasound can examine the fetal skeleton, and chorionic villus sampling and amniocentesis can be done to help diagnose OI as a fetus. This may affect delivery recommendations of obstetricians.32

Imaging

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, or “popcorn” epiphyses.5,25 Acetabular protrusion and shoulder socket abnormalities and radial head dislocation can be assessed as well.25,33,34 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.25 Ultrasound may be able to detect OI prenatally, by assessing for limb shortening or fractures.5

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(7,20). Lateral cervical radiographs should be assessed before the age of 6.6 MRI and CT are gaining traction for assessment.2,19 MRA can be considered for intracranial aneurysm screening.35

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.36–38 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.5,39

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.40 A smaller height during infancy has poorer outcomes. A Lower age at initial fracture can be a predictor for becoming a non-ambulator. Surgical intervention, such as osteotomy, performed at a lower age was associated with walking.41 Engelbert demonstrated that those who were independently sitting or standing by 12 months old were more likely to walk, though the type of OI was the biggest predictor of ambulation.42

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.29 Additionally, children can feel socially isolated due to not being understood by peers or able to participate in common activities. A strong 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).

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 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.4

Rehabilitation Management and Treatments

Available or current treatment guidelines

For most specific protocols, please see the current consensus statement by Mueller et Al.24 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.1,24 Aquatic therapies can also be considered.25 Exercise and core strengthening has been shown to be helpful for muscle and bone strengthening, positioning, and walking.43 Consider weight-bearing activities, isometric exercises, and muscular strengthening with the goal to avoid methods entailing fracture risk and avoidance of deconditioning.24 Consider compensatory strategies, home modifications, and assistive devices.24 A standing frame can be considered, though is typically not well tolerated and may not be used routinely.24 Therapies can improve bone mineral density.1

Range of motion is extremely important to prevent contractures, but it must be done gently to prevent fractures.1 Safety and modification of range of motion and manual muscle testing should be stated clearly. In many, if not most, cases only active range of motion should be performed, and active assistive range of motion or any passive technique must avoid endpoint stretching, use hand placement very close to the joint to avoid torque through long bones, and avoid ballistic techniques. Patients should take vitamin D and calcium supplementation.25 Medical management with bisphosphonates (which can be considered before age 6) such as pamidronate and alendronate is widely used to increase bone density, and there has been some varying evidence for effect on fracture frequency.38,44-47 It may also improve gross motor function, muscle force, level of ambulation, though not self-care.38 However, there is discrepancy on when to start (such as after one vertebral body fracture or more than three long bones per year for two years or by monitoring DEXA scans).25,44,48 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.49 Denosumab and anabolic agents are also gaining traction as treatment options.1,25

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 . Gait analyses should be considered beforehand.25 Upper extremity surgery has been shown to improve ADLs, transfers, and self-care, especially if patients are already using a wheelchair for mobility.25 Surgical interventions may also be used to assist with contractures.1

Scoliosis is progressive over time and not responsive to spine bracing, though bracing can be considered to support sitting balance and independence. Fusion can be helpful to prevent pulmonary decline, especially if done before a 45-degree curve develops.52 However, it should definitely be considered at 45-50°.1,6,25,53 A thoraco-lumbar-sacral orthosis can be considered post-operatively for supported sitting,6,25 but it has not been shown to be efficacious.24 Scoliosis may also be refractory to surgery.1 Post-operatively, it is very important that patient resume mobilizing as soon as possible, to prevent muscle atrophy and a loss in bone density.1

Respiratory function, bowel and bladder function, cardiac function, audiologic function, bleeding, dental evaluation, and bone densitometry should be monitored closely1,54 as should neurologic examination and imaging of the cervical spine. Orthoses such as AFOs may help prevent equinus and support muscle weakness.5 Echocardiograms, hearing aids, and spirometry can also be considered.5 Pes planovalgus may develop, but it does not require orthoses; however, orthoses may be helpful to facilitate activity and decrease pain. Other rehabilitation considerations include target joint stretching, muscle strengthening, weightbearing, ambulation aides, mobility devices, adaptive equipment.5 For pain management, psychosocial support, bisphosphonate therapies, surgical interventions, and physical therapies are all considered.55 In the infant, fracture mitigation, fracture management, and family support are all important as well.56 Patients should also be assessed, or guidance should be provided on hyperplastic callus formation, osteogenic sarcoma, basilar invagination, and malignant hyperthermia.2

Coordination of care

Patient care in OI is best delivered with a multi-disciplinary team.5,48 The care team for the person with OI can include specialists in genetics, physiatry, physical therapy, occupational therapy, orthopedic surgery, neurosurgery, endocrinology, audiology, dentistry, nursing, social work, PCP, and family.2 Children should undergo pulmonary function testing, and some children may need to be followed by a pulmonologist and a cardiologist if cardiac involvement is suspected.57

Though in the general population, patients younger than three years old are significantly more likely to have fractures secondary to child abuse and non-accidental trauma than OI, it should always be a consideration. Wormian bones (supernumerary bones found at the lambdoid or coronal sutures of the skull) and blue sclera should be looked for and may differentiate the two.58 Posterior rib and metaphyseal fractures especially under age 1 are associated strongly with physical abuse but have been reported rarely in some forms of OI as well.

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.59 Adults should be assessed for headaches, joint osteoarthritis, glaucoma, renal changes, and menopausal effects on bones.5,60,61 During surgery, surgeons must be cognizant of risk for fractures, airway compromise, reduced pulmonary function, and blood loss.6,25

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. Families should be educated on assistance with position, bonding, handling, and transportation with their baby. They should be placed in prone position when possible and encouraged to have frequent head turns. As they grow, it is important to promote activities and developmental milestones. Maximizing mobility will be important for adolescents as they navigate their classrooms and should be monitored for overprotection.25,62 Families must be educated on home setting and splinting of fractures and when to pursue orthopedic care for certain fractures. They should encourage mobilization to reduce disuse osteopenia, atrophy, and fracture risk.25 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, and adaptive transportation for wheelchair use. School therapies can support a child’s development 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.

Cutting Edge/Emerging and Unique Concepts and Practice

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.4,5 Antibodies found with possible treatment potential include the sclerostin inhibitory antibody that can recruit osteoblasts and TGF-b neutralizing antibodies that can increase bone mass, cortical thickness, and strength.4,5,63 These treatments can have anabolic action on bone and have been successful at decreasing fracture in animal models with adult studies ongoing.4 Denosumab is gaining traction, but it is not yet approved for wide use.64 Teriparatide (an anabolic) has been trialed with good effect on bone density, but it has not been fully approved for use.65 Synthetic parathyroid hormone, cell and gene targeting therapies, estradiol, testosterone, abaloparatide, romosozumab, DKK1 inhibitors, bortezomib, strontium, NBPs, are being investigated as well.66-68

Gaps in the Evidence-Based Knowledge 

Bisphosphonate therapy has been shown to increase bone density, and potentially selfcare skills, but scientific studies have shown they are less convincing in improving fracture rate, pain, growth, or functional mobility. More research on outcomes in adults with OI is needed, and treatment continuation is generally recommended with options similar to pediatric options.1,4,5,44,69 There is limited evidence regarding the recommendations for limb orthotics and their effect on fractures or function.24,70

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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

Amy Kanallakan, MD. Osteogenesis Imperfecta. 4/20/2020

Author Disclosure

Jeremy Roberts, MD
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Denesh Ratnasingam, MD
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Cara Vernacchia, DO
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Amy Kanallakan, MD
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