Continuing Education Activity

Osteogenesis imperfecta (OI) is a genetic disorder of connective tissues caused by an abnormality in the synthesis or processing of type I collagen. It is also called brittle bone disease. It is characterized by an increased susceptibility to bone fractures and decreased bone density. Other manifestations include blue sclerae, dentinogenesis imperfecta, short stature, as well as deafness in adulthood. There are also reports of valvular insufficiencies and aortic root dilation. Milder manifestations include generalized laxity, easy bruising, hernias, and excess sweating. Clinical manifestations range from mild with a nearly asymptomatic form to most severe forms (involving infants presenting with crumpled ribs, fragile cranium, and long bone fractures incompatible with life), resulting in increased perinatal mortality.[ This activity reviews the pathophysiology of osteogenesis imperfecta and highlights the role of the interprofessional team in its management.

Objectives:

• Identify the etiology of osteogenesis imperfecta.
• Review the presentation of a patient with osteogenesis imperfecta.
• Outline the management options available for osteogenesis imperfecta.
• Describe some interprofessional team strategies for improving care coordination and outcomes in patients with osteogenesis imperfecta.

Introduction

Osteogenesis imperfecta is a genetic disorder of connective tissues caused by an abnormality in the synthesis or processing of type I collagen.[1][2] It is also called brittle bone disease. It is characterized by increased susceptibility to fractures and reduced bone density. Other manifestations include blue sclerae, dentinogenesis imperfecta, short stature, and deafness in adulthood. There are also reports of valvular insufficiencies and aortic root dilation. Milder manifestations include generalized laxity, easy bruising, hernias, and excess sweating.[3] Clinical manifestations range from mild, nearly asymptomatic presentations to severe forms characterized by crumpled ribs, a fragile cranium, and long bone fractures in infancy, which are often incompatible with life and associated with increased perinatal mortality.[4]

Etiology

Overview of Osteogenesis Imperfecta Genetics

Osteogenesis imperfecta is a rare genetic disorder most commonly caused by mutations in the COL1A1 and COL1A2 genes, which encode type I collagen. Advances in molecular genetics have identified additional gene mutations associated with osteogenesis imperfecta, expanding understanding of its heterogeneous presentation and inheritance patterns.[5]

International Society of Skeletal Dysplasias Classification

The International Society of Skeletal Dysplasias classifies osteogenesis imperfecta based on inheritance pattern and the genes involved.[6] This framework supports a genotype-based approach to diagnosis and management.

Nondeforming Osteogenesis Imperfecta (Type I) This form typically follows an autosomal dominant inheritance pattern and is associated with mutations in COL1A1 and COL1A2. An X-linked variant has also been identified and is associated with mutations in the PLS3 gene.

Perinatal Osteogenesis Imperfecta (Type II) Type II may demonstrate autosomal dominant or autosomal recessive inheritance. Associated gene mutations include COL1A1, COL1A2, CRTAP, LEPRE1, PPIB, and BMP1.

Progressively Deforming Osteogenesis Imperfecta (Type III) This type can be inherited in either an autosomal dominant or autosomal recessive pattern. Identified genetic mutations include COL1A1, COL1A2, CRTAP, LEPRE1, PPIB, FKBP10, SERPINH1, SERPINF1, and WNT1.

Moderate Osteogenesis Imperfecta (Type IV) Type IV demonstrates autosomal dominant or autosomal recessive inheritance and is associated with mutations in COL1A1, COL1A2, CRTAP, FKBP10, SP7, SERPINF1, WNT1, and TMEM38B.

Calcification of the Interosseous Membrane or Hypertrophic Callus (Type V) Type V follows an autosomal dominant inheritance pattern and is caused by mutations in the IFITM5 gene.

Epidemiology

Osteogenesis imperfecta is a rare disease occurring in 1 in 15,000 to 20,000 births.[4] The population frequencies of type I osteogenesis imperfecta have been reported to range between 2.35 to 4.7 in 100,000 worldwide. Reports of the incidence of type II osteogenesis imperfecta range between 1 in 40,000 and 1.4 in 100,000 live births. The exact incidence of types III and IV osteogenesis imperfecta is unknown, although they are much less common than type I.[7][8][9] In Shapiro's study, the incidence of types A congenita, B congenita, A tarda, and B tarda was approximately 19%, 31%, 25%, and 25%, respectively.[10][11]

Pathophysiology

Two pro-alpha-1 chains and 1 pro-alpha-2 chain make up type I collagen, which forms the main protein of the extracellular membrane of skin, bones, and tendons, and creates a rigid, triple helix structure. Each alpha chain consists of an amino-terminal pro-peptide, a carboxyl-terminal pro-peptide, and a central pro-peptide consisting of 338 glycine repeats. Glycine is the smallest residue that can occupy the axial position of the triple helix.[12] The triple helix structure of type I collagen is possible because of the presence of glycine at every third amino acid residue. 

At least 90% of osteogenesis imperfecta patients have a genetic defect resulting in quantitative and qualitative (or both) abnormalities in type I collagen molecules. This disorder is inherited in an autosomal dominant, autosomal recessive, or spontaneous mutation pattern.[12][13] Direct defects in type 1 collagen cause the autosomal dominant forms, while autosomal recessive forms are caused by non-collagenous proteins, which take part in post-translational modifications or triple helix formation.[4]

Defects Involving Type 1 Collagen Molecules 

Frameshift mutations (involving a premature stop codon in the affected allele) can result in a quantitative decrease in the amount of structurally normal type 1 collagen. Patients who are heterozygous for this condition may secrete half the normal amount of type 1 collagen [haplo-insufficiency, as seen in type IA osteogenesis imperfecta in Sillence Classification].[9] Alternatively, errors in substitution or deletion involving a glycine residue along the polypeptide chain can result in the production of structurally or qualitatively abnormal collagen, or collagen that is less effective. The phenotypic expression of these defects depends on the position of substitution, whether glycine substitutes at the carboxy-terminal (severe form) or the amino-terminal (milder form) of the polypeptide chains.[14]

Substitutions at the carboxy end of the peptide are potentially more serious owing to cross-linking of the triple helix beginning at the carboxy terminus of polypeptide chains. These patients with mutations in glycine residues that affect the quality of collagen chains (commonly identified in Sillence types II, III, and IV) develop more severe skeletal manifestations than patients with haploinsufficiency.[15]

Other Mutations

In addition to type I collagen mutations, other genetic mutations that cause autosomal recessive osteogenesis imperfecta (types VI, VII, VIII, IX, X, and XI) have been described. These mutations may involve components of the collagen 3-hydroxylation complex, which facilitates triple-helix assembly. These recessive mutations account for less than 5% of cases of osteogenesis imperfecta.[15]

Histopathology

Generally, defects that reduce collagen type 1 secretion or result in abnormal collagen secretion lead to insufficient osteoid production.[16] Both enchondral and intramembranous ossification are affected. Thin, poorly organized bony trabeculae and collagen matrix, scanty spongiosa; a relative abundance of osteoblasts and osteoclasts, increased bone turnover; and broad, irregular physes with disorganized proliferative and hypertrophic zones, as well as a thinned calcified zone, are typical histological features.[17] Recent studies have identified problems with specific growth factors, particularly transforming growth factor beta (TGFβ), and are developing innovative treatments to neutralize this factor with a specific antibody.[18]

History and Physical

Classification Systems for Osteogenesis Imperfecta

Two clinically useful classification systems for osteogenesis imperfecta have been described by Sillence and colleagues and by Shapiro and colleagues.[7][10][19] In 1979, Sillence and Danks initially identified 4 types based on clinical presentation and genetic inheritance. Types I and IV were described as autosomal dominant, while types II and III were initially classified as autosomal recessive. Subsequent genetic research has demonstrated that true autosomal recessive inheritance is uncommon. As understanding of the molecular basis expanded, Cole extended the Sillence classification to include types V through XI, with type V showing autosomal dominant inheritance and types VI through XI demonstrating autosomal recessive transmission.[4][12]

Modified Sillence Classification (Phenotype and Inheritance)

Type I Type I is inherited in an autosomal dominant pattern due to COL1A1 mutations that result in reduced production of structurally normal type I collagen. Collagen quantity is approximately 50% of normal. Clinical features include generalized osteoporosis, increased bone fragility with fractures typically occurring during ambulatory childhood years, blue sclera, conductive hearing loss, and mild short stature. Subtypes include type IA, characterized by normal dentition, and types IB and IC, which are associated with dentinogenesis imperfecta.[6][9]

Type II Type II was originally classified as autosomal recessive but is now recognized as a dominant negative disorder, often caused by spontaneous mutations, with an estimated 7% recurrence risk in subsequent pregnancies. This type results in severe qualitative disruption of collagen and represents a lethal perinatal form. Clinical manifestations include extreme bone fragility with “accordion” femurs, delayed skull ossification, blue sclera, and perinatal death. Radiographic subtypes include IIA, characterized by short, wide long bones with multiple fractures and wide ribs; IIB, with short, widened long bones and rib fractures; and IIC, with thin long bones and ribs.[12][20]

Type III Type III demonstrates autosomal recessive or dominant negative inheritance and involves both qualitative and quantitative abnormalities of type I collagen. This category includes many patients with the most severe nonlethal disease. Clinical features include blue sclera in infancy that normalizes in adolescence, moderate to severe bone fragility, coxa vara, multiple fractures, and marked long-bone deformities with significant ambulation difficulties. Early-onset scoliosis, triangular facies, frontal bossing, basilar invagination, and profound short stature are common. Prophylactic intramedullary rodding is often required.[3][13][21][22][23]

Type IV Type IV represents a heterogeneous autosomal-dominant group characterized by both qualitative and quantitative collagen abnormalities. Clinical severity is greater than type I but less than type III. Patients typically have normal sclera, moderate to severe bone fragility, deformities of long bones and the spine, and moderate to severe growth restriction. Type IVA is associated with normal dentition, while type IVB includes dentinogenesis imperfecta.

Type V Type V follows an autosomal dominant inheritance pattern and results from mutations in the IFITM5 gene. Histologic evaluation shows a mesh-like pattern of lamellar bone. Disease severity is usually mild to moderate. Distinctive features include normal sclera, absence of dental involvement, calcification of the interosseous membrane—particularly in the forearm—leading to possible radial head dislocation, hypertrophic callus formation, and a radiodense metaphyseal band near the growth plate.[24][25][26]

Type VI Type VI is caused by mutations in the SERPINF1 gene and is characterized histologically by a “fish-scale” pattern of lamellar bone under polarized light microscopy, reflecting severe mineralization defects. Clinical presentation includes moderate to severe skeletal involvement, normal sclera, and absence of dental abnormalities.

Types VII, VIII, and IX

Common Features These subtypes result from defects in the prolyl 3-hydroxylation complex within the endoplasmic reticulum, which plays a critical role in proper collagen triple-helix assembly. Inheritance is autosomal recessive.[4][27][28] Specific molecular defects include cartilage-associated protein (CRTAP) in type VII, prolyl 3-hydroxylase 1 (LEPRE1) in type VIII, and peptidyl-prolyl cis–trans isomerase B (PPIB) in type IX.

General Manifestations Type VII is characterized by moderate to severe disease and is commonly associated with rhizomelia and coxa vara. Type VIII is typically severe to lethal and is also associated with rhizomelia. Type IX represents a severe autosomal recessive form with significant skeletal involvement.

Types X and XI

Common Features These types arise from defects in collagen chaperone proteins that facilitate the transport of procollagen from the endoplasmic reticulum to the Golgi apparatus. Inheritance is autosomal recessive.[28][29] Identified molecular defects include SERPINH1 in type X and FKBP10 in type XI.

General ManifestationsSevere bone dysplasia, dentinogenesis imperfecta, transient skin bullae, blue sclera, pyloric stenosis, and renal stones characterize type X. Type XI presents with bone dysplasia, ligamentous laxity, scoliosis, and platyspondyly, with normal sclera and absence of dental involvement.

Limitations of the Sillence Classification A major limitation of the Sillence classification is the substantial variability in fracture frequency and severity of skeletal deformity within each category, which limits its prognostic utility.

Historical Classifications

Looser Classification (1906) Looser and colleagues initially classified osteogenesis imperfecta into 2 forms: osteogenesis imperfecta congenita, defined by multiple fractures present at birth, and osteogenesis imperfecta tarda, in which fractures occur after the perinatal period.

Shapiro Modification of the Looser Classification Shapiro expanded this framework into 4 types, offering improved prognostic value for survival and ambulation.[10] Congenita A is incompatible with life and is characterized by fractures sustained in utero or at birth, with radiographic findings of crumpled long bones and ribs, rib cage deformity, and a fragile skull. Congenita B is compatible with survival and includes fractures sustained in utero or at birth, with more tubular long bones, metaphyseal funnelization, normally formed ribs, and no rib cage deformity. Tarda A presents with fractures before walking age, although the age of onset is not predictive of ambulation. Tarda B is defined by the first fracture occurring after walking age, with most individuals maintaining the ability to ambulate.

Evaluation

Diagnostic Considerations

In patients presenting with multiple fractures, it is essential to exclude non-accidental trauma as part of the initial evaluation.[30][31] The diagnosis of osteogenesis imperfecta is based on a combination of clinical presentation, family history, lumbar spine bone mineral density assessment, bone biochemistry, and characteristic radiographic findings.[32] Bone fragility is the most common clinical feature across most osteogenesis imperfecta types, with additional distinguishing features described by Van Dijk and Sillence.[33]

Clinical Features

Patients commonly present with 4 hallmark features: decreased bone mass with increased fracture risk, blue sclera, dentinogenesis imperfecta characterized by normal enamel with abnormal dentin, and hearing loss. Additional manifestations may include ligamentous laxity, increased joint mobility, short stature, and a tendency toward easy bruising. The timing of fracture onset is prognostically significant, as earlier fractures are associated with poorer outcomes.[34][35] Fractures generally heal at a normal rate, although hypertrophic callus formation may occur and can radiographically resemble osteosarcoma. Recurrent fractures may result in skeletal deformities, including protrusio acetabuli, coxa vara, anterolateral femoral bowing, anterior tibial bowing, cubitus varus, and other proximal forearm deformities.[36] Characteristic facial features include elfin facies and a helmet-shaped head. Clinical manifestations vary by osteogenesis imperfecta subtype.

Laboratory and Genetic Evaluation

No single commercially available diagnostic test exists due to the broad range of genetic mutations associated with osteogenesis imperfecta. Routine laboratory studies are typically within reference ranges, although alkaline phosphatase levels may be mildly elevated.

Imaging Findings

Plain Radiography Radiographic findings may include wormian bones, basilar invagination, kyphoscoliosis with reported prevalence ranging from 39% to 100%, and platyspondyly involving the head, neck, and spine. Chest imaging may reveal pectus excavatum or pectus carinatum. Pelvic abnormalities include protrusio acetabuli and coxa vara. General skeletal findings include osteoporosis, cortical thinning, absence of metaphyseal funneling of long bones, hypertrophic callus formation, popcorn calcifications of the metaphysis and epiphysis, and pseudoarthrosis at fracture sites. Prenatal ultrasonography may demonstrate decreased calvarial ossification, shortened and angulated long bones, multiple fractures, beaded ribs, and polyhydramnios.[37]

Computed Tomography Computed tomography may identify wormian bones, basilar invagination, otosclerosis, and long-bone fractures.[38]

Magnetic Resonance Imaging MRI is particularly useful for evaluating basilar invagination.

Histologic and Specialized Testing

Fibroblast culture with type I collagen analysis is positive in approximately 80% of type IV cases and may aid in confirming the diagnosis when findings are equivocal. Biopsy options include collagen analysis from a punch biopsy or iliac crest biopsy, which typically shows reduced cortical thickness, decreased cancellous bone volume, and increased bone remodeling.

Treatment / Management

Management Overview

Management of osteogenesis imperfecta varies based on patient age, disease severity, and functional status.

Disease Severity–Based Management Patients with mild disease typically experience subtle functional limitations and are advised to avoid contact sports, with treatment focused on fracture management.[39] Moderate to severe disease often requires comprehensive rehabilitation and orthopedic interventions, including management of acute fractures and scoliosis.[40] In severe disease, intramedullary rodding combined with osteotomy may be necessary to correct pronounced bowing of the long bones.[41][42]

Medical Management

Medical therapy has been explored through several approaches.[43][44][45][46][47][48][49] Historically, hormonal therapies, sodium fluoride, calcium, calcitonin, magnesium oxide, and vitamins C and D were used but demonstrated limited or inconsistent benefit. Bisphosphonates, including intravenous pamidronate and oral alendronate, have shown clinical utility by reducing osteoclastic bone resorption, decreasing fracture risk, improving bone mineral density, and enhancing ambulatory status in pediatric patients with osteogenesis imperfecta.[50][51][52][53]

Emerging and investigational therapies include gene therapy and cell transplantation targeting COL1A1 and COL1A2 mutations, which have demonstrated promising results in animal models but are not yet widely available.[54][55][56] Sclerostin antibody therapy (romosozumab) has shown beneficial skeletal effects in animal studies, though human trials are lacking.[57][58][59][60] Denosumab has improved bone quality in small studies but is not approved for routine use; ongoing research is evaluating its role.[61] Anabolic therapy with teriparatide increased bone density in a small clinical trial but remains unapproved for this population.[62] Antibodies targeting transforming growth factor beta (TGFβ) represent another investigational approach with encouraging preclinical results.[18][63][64]

Orthopedic Management

Orthopedic care aims to improve functional status, prevent deformity and disability, correct existing deformities, and monitor for complications.

Supportive interventions include orthotic devices, walking aids, and wheelchairs. Fracture management and correction of long bone deformities are central components of care. In infants and children, treatment options include closed osteoclasis with or without percutaneous intramedullary fixation, as well as open osteotomy with internal fixation, using techniques such as the Sofield–Millar procedure and devices such as Rush nails and Williams rods.[65][66][67][68] In young adults, correction of deformity may involve external fixation with circular or uniplanar constructs, combined with osteotomy.

Prophylactic intramedullary rodding is recommended for children with recurrent long bone fractures, with rod selection based on bone size and skeletal maturity. Options include telescoping rods (eg, Bailey–Dubow, Sheffield, and Fassier–Duval) and non-telescoping devices (eg, Kirschner wires, Steinmann pins, Williams rods, and other fixed-length rods). Management also includes careful monitoring and treatment of spinal deformities, including basilar invagination, kyphoscoliosis, and spinal fractures.

Differential Diagnosis

Differential diagnoses to keep in mind when suspecting osteogenesis imperfecta include: 

• Congenital hypophosphatasia [30]
• Achondroplasia
• Pyknodysostosis [31]
• Diffuse osteopenia in the early stages of leukemia [69]
• Idiopathic juvenile osteoporosis
• Child abuse or battered child syndrome [70]

Prognosis

Prognosis varies widely across the diverse spectrum of osteogenesis imperfecta.[10] As previously discussed, the Shapiro classification serves as a stronger prognostic indicator than the Sillence classification. The age at onset of long bone fractures is a critical predictor of future ambulatory ability. Survival is most strongly influenced by fracture location and severity and the overall radiographic appearance of the skeleton. Engelbert and colleagues demonstrated that children who achieved independent sitting, standing, or both by age 12 were ultimately able to ambulate. Additionally, children who attained independent sitting or standing by 12 months of age were likely to achieve walking ability later in life.[71]

Complications

Several complications may occur in patients with osteogenesis imperfecta. Hyperplastic callus formation is uncommon and is typically managed with conservative measures, palliative radiotherapy—with caution due to the risk of secondary malignancy—and bisphosphonate therapy.[72] Rarely, patients may develop tumors such as osteogenic sarcoma.[73] Basilar invagination is a serious complication that can lead to cranial nerve involvement, direct brainstem compression, and disruption of cerebrospinal fluid dynamics.[74]In addition, the potential for malignant hyperthermia should be considered during surgical procedures, requiring heightened awareness and preparedness from both the surgeon and anesthesiologist.[75]

Deterrence and Patient Education

Parent and Family Education

It is essential to educate parents about the prognosis of osteogenesis imperfecta, including expected survival, potential deformities, functional limitations, and ambulatory capacity. Genetic counseling and prenatal screening, including ultrasonography, may be indicated for future pregnancies. Parents should also be informed that, despite orthopedic impairments, children with osteogenesis imperfecta generally have normal intelligence and social abilities. Counseling should include strategies to prevent falls and minimize the risk of recurrent fragility fractures.[76]

Antenatal Diagnosis

Antenatal ultrasound can detect osteogenesis imperfecta, Sillence type II, as early as 16 weeks' gestation. Depending on the severity of disease expression, Sillence types I, III, and IV may also be identified prenatally through imaging.[3] For parents with a history of a fetus affected by type II osteogenesis imperfecta, there is a 2% to 7% recurrence risk in future pregnancies. In such cases, antenatal diagnosis can be confirmed through DNA analysis of chorionic villus samples obtained under ultrasonographic guidance.

Enhancing Healthcare Team Outcomes

The management of osteogenesis imperfecta is complex and challenging and requires an interprofessional healthcare team approach.[76] The primary reason for the complexity of management is the wide variation in phenotypic expression across the spectrum of the disease. The significant role of early diagnosis (clinical, imaging, biochemical, and genetic evaluation) and early risk stratification in the long-term management of the child should never be understated. The importance of an interprofessional intervention over the long term, involving a family physician, pediatrician, endocrinologist, radiologist, orthopedic surgeon, neurosurgeon, anesthesiologist, mid-level practitioners (NPs and PAs), orthotic expert, occupational therapist, physiotherapist, and pharmacist, across different stages of management, needs to be understood. The orthopedic surgeon is involved in the prevention and management of fractures and deformities of the extremities.

Medical management with bisphosphonates can prevent fractures in children with recurrent fractures. The pharmacist can perform medication reconciliation, verify dosing, counsel parents on potential adverse effects, and address their medication-related questions. If they note any concerns in the patient's medication regimen, they must immediately contact the prescriber or nurse to implement corrective measures. A neurosurgeon may be involved in managing compressive pathologies of the upper cervical spine/craniocervical junction or spinal deformities. The role of parent education on what to expect at different stages of disease management is also highly significant. Nurses can play a vital role in delivering holistic care to patients and providing necessary support to caregivers. Such interprofessional care can aid in achieving basic goals in the management of osteogenesis imperfecta, including improving functional status, preventing deformity and disability, correcting existing deformities, and monitoring for potential complications.

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Disclosure: Surabhi Subramanian declares no relevant financial relationships with ineligible companies.

Disclosure: Catherine Anastasopoulou declares no relevant financial relationships with ineligible companies.

Disclosure: Vibhu Krishnan Viswanathan declares no relevant financial relationships with ineligible companies.