INTRODUCTION — Osteogenesis imperfecta (OI) is an inherited connective tissue disorder with many phenotypic presentations. It is often called "brittle bone disease." Severely affected patients suffer multiple fractures with minimal or no trauma, and infants with the worst form of OI die in the perinatal period. Mild forms of OI may manifest with only premature osteoporosis or severe postmenopausal bone mineral loss.

An overview of the pathogenesis, clinical features, diagnosis, differential diagnosis, and management of OI are presented in this topic.

EPIDEMIOLOGY — The estimated incidence of OI is approximately 1 per 20,000 births [1]. The estimated prevalence of OI in the US is between 20,000 and 50,000. This qualifies it as an orphan disease, which is defined in the United States as a disease affecting 200,000 patients or less.

PATHOGENESIS — The cause of OI is established in most cases. In patients with identified molecular defects, OI is most commonly caused by mutations in genes encoding the alpha 1 and alpha 2 chains of type I collagen [2] or proteins involved in posttranslational modification of type I collagen [3]. Type I collagen fibers are polymers of tropocollagen (collagen molecule), each of which is a triple helix that contains portions of one alpha 2 and two alpha 1 polypeptide chains. The composition of tropocollagen is shown in the figure (figure 1). Type I collagen is an important structural protein for bone, tendon, ligament, skin, and sclerae. Defective bone quality explains many clinical aspects of OI. (See "Bone physiology and biochemical markers of bone turnover", section on 'Bone formation'.)

Type I collagen (Col1A) defects — Most patients with OI have an autosomal dominant mutation in collagen type I alpha 1 chain (COL1A1; located at 17q21.31-q22) or collagen type I alpha 2 chain (COL1A2; located at 7q22.1) that affects the structure of one of the two alpha chains of type I collagen. The severity of the clinical presentation depends upon the effect of the mutation (table 1 and table 2) [4-8]. As an example, mutations in COL1A1 or COL1A2 that lead to decreased amounts of normal collagen cause the mild phenotype seen in OI type I. In contrast, mutations that disrupt the formation of the normal type I collagen triple helix cause the lethal phenotype seen in OI type IIA. Other COL1A1 and COL1A2 mutations that result in structural protein defects cause moderate (OI type IV) and severe, but not lethal (OI type III), forms of OI.

COL1A1 and COL1A2 genes are normal in approximately 10 percent of cases. Many of these patients have autosomal recessive genetic defects.

Posttranslational defects

●IFITM5 defects – A recurrent mutation (c.-14C>T) in the 5’ untranslated region (UTR) of the interferon-induced transmembrane protein 5 (IFITM5) gene located at 11p15.5 is the cause of OI type V in several families and also in simplex cases [9,10]. Expression of this protein, which is thought to be involved in bone formation and osteoblast maturation, is highly restricted to skeletal tissue.

●FKBP10 defects – Mutations in the FK506-binding protein 10 (FKBP10 or FKBP65) gene, located at 17q21, were identified in a cohort of five consanguineous Turkish families and in a Mexican-American family with recessively inherited, moderately severe OI [11]. FKBP10 encodes a molecular chaperone that interacts with type I collagen and tropoelastin and is involved in the folding of type I procollagen. Mutations in FKBP10 affect type I procollagen secretion. The OI phenotype associated with FKBP10 mutations (designated OI type VI) most closely resembles OI type III because of its severity and progressive nature. However, histologic findings of distorted lamellar structure and elevated alkaline phosphatase in some of the affected children are consistent with OI type VI. Mutations in FKBP10 can cause a related disorder, Bruck syndrome. (See 'Other skeletal syndromes' below.)

●3-prolyl-hydroxylation complex defects – Mutations in any of the three components of the 3-prolyl-hydroxylation complex that modifies type I collagen posttranslation can cause lethal/severe, recessive forms of OI with normal collagen folding. These components include:

•Cartilage-associated protein (CRTAP, gene located at 3p22) [12,13]. CRTAP deficiency was detected in 3 of 10 children with recessively inherited lethal or severe OI who had type I collagen with normal primary structure but excess posttranslational modification of the alpha chain helical regions [14]. Mutations in CRTAP cause OI type IIB (a perinatal lethal form) and OI type VII (a severe, nonlethal form) [14-16].

•Prolyl-3-hydroxylase-1 (P3H1; encoded by leprecan-like 1 [LEPRE1], located at 1q34) [17,18]. Mutations in LEPRE1 cause OI type VIII [13,18-20].

•Peptidyl-prolyl isomerase B (also called cyclophilin B; PPIB gene located at 15q21-q22). Mutations in PPIB cause OI type IX [21-23].

Other defects — Mutations causing severe, recessive OI resembling OI type III have also been identified in other genes encoding proteins involved in bone formation and homeostasis:

●OI type X is caused by pathogenic variants in SERPINH1 (located at 11q13.5), which encodes a collagen chaperone-like protein (serpin peptidase inhibitor, clade, H, member 1; also called collagen-binding protein 2 [CBP2]; and heat-shock protein 47 [HSP47]) [24].

●OI type XI is caused by pathogenic variants in SERPINF1 (located at 17p13.3), which encodes a multifunctional glycoprotein that is a strong inhibitor of angiogenesis (serpin peptidase inhibitor, clade F, member 1; also called pigment epithelium-derived factor [PEDF]) [25].

●OI type XII is caused by pathogenic variants in SP7/OSX (located at 12q13.13), which encodes specificity protein 7 or osterix, a zinc finger transcription factor that is an essential regulator of bone cell differentiation [26].

●OI type XV is caused by homozygous or compound heterozygous mutations in WNT1, the gene encoding wingless-type mouse mammary tumor virus integration site family member 1 [27-30]. WNT1 plays a role in osteoblast function, bone development, and fetal brain development. Single heterozygous mutations in WNT1 cause early-onset osteoporosis. (See "Normal skeletal development and regulation of bone formation and resorption", section on 'Wnt signaling pathway'.)

●OI type XVI is caused by a homozygous mutation in the cAMP-responsive element binding protein 3-like 1 (CREB3L1), located on chromosome 11p11.2, that encodes an endoplasmic reticulum stress transducer [31]. The variant disrupts a DNA-binding site, preventing it from acting on its transcriptional sites.

DISEASE CLASSIFICATION — OI is classified into a number of major subtypes based on genetic, radiographic, and clinical characteristics (table 1 and table 2) [4,15,32,33]. A more useful clinical classification, based upon the typical problems that manifest in infants, children, and adults with mild, moderate to severe, and lethal disease [34], is presented below.

CLINICAL MANIFESTATIONS — The clinical manifestations vary substantially within families [35]. For milder types of OI, one member may be significantly affected clinically, whereas another member with the same mutation may have normal function. This emphasizes that identifying a mutation in a particular gene does not necessarily result in a clear clinical diagnosis and suggests that it may take defects in other connective tissue components to fully express the genetic syndrome of clinically observable OI. (See 'Diagnosis' below.)

Clinical manifestations of OI include (table 1 and table 2) [35-39]:

●Excess or atypical fractures (brittle bones) [40]; fractures most commonly associated with OI were transverse humerus, olecranon, and diaphyseal humerus fractures, whereas physeal and supracondylar humerus fractures were least likely to indicate OI in one study [41].

●Short stature.

●Scoliosis.

●Basilar skull deformities, which may cause nerve compression or other neurologic symptoms.

●Blue sclerae (picture 1).

●Hearing loss (usually detected in later childhood to early adulthood).

●Opalescent teeth that wear quickly (dentinogenesis imperfecta) (picture 2). (See "Developmental defects of the teeth", section on 'Dentinogenesis imperfecta'.)

●Increased laxity of the ligaments and skin.

●Wormian bones (small, irregular bones along the cranial sutures) [42].

●Easy bruisability.

Mild (type I) — Bone fragility is the least severe in OI type I [36]. The fracture rate is variable. Individuals with OI type I may have few or no fractures before puberty or numerous fractures throughout their lives [35,43]. Deformity is minimal, and stature is usually normal [44]. Individuals with OI type I occasionally present in the perinatal period with intrauterine femoral bowing or fractures [35,45], but they usually do not begin to have fractures until they begin toddling or walking [46]. The most frequently involved bones are the long bones of the arms and legs, ribs, and the small bones of the hands and feet. The frequency of fractures declines after puberty [35].

Adults with OI type I may have premature or accelerated osteoporosis following menopause. They may also have premature hearing loss. In one study of 133 adults with OI type I, 58 percent had hearing loss confirmed by audiometric evaluation, predominantly mixed conductive and sensorineural that began in the second to fourth decade of life and was generally progressive, and 17 percent had subjective hearing impairment with normal audiometry [47].

Moderate to severe (types III to IX, XV, and XVI) — Bone fragility is moderate to severe in patients with OI types III to IX, XV, and XVI [36]. Those with OI type III are usually the most severely affected. However, children with OI type VII and VIII occasionally develop a severe, lethal type of OI resembling OI type II as described below.

Children with OI of these types have an increased number and frequency of fractures, mild to moderate bone deformities, kyphoscoliosis, and variable short stature [18,36]. Some children are immobile and require motorized wheelchairs. In addition, children may develop ossicular dislocation, stapes fixation, or fracture of the ossicles, resulting in conductive hearing loss. (See "Hearing loss in children: Screening and evaluation" and "Hearing loss in children: Treatment".)

Patients with moderate OI develop hearing loss and osteoporosis as adults, similar to patients with mild OI. However, the onset may be earlier and the expression more intense. Mothers are prone to accelerated bone loss following pregnancy and breastfeeding. Aging and physical inactivity also accelerate OI-related osteoporosis. Hypermobility of the joints of the hands, wrists, and feet can cause pain and decreased function requiring orthopedic intervention. Cardiovascular abnormalities are more common in patients with OI, particularly type III, compared with the general population [48]. Some patients with OI type XV have brain abnormalities, learning and/or developmental delay, and blue sclera, but tooth development and hearing are normal [27-30].

The practical aspect of identifying moderate to severe OI is that bisphosphonate therapy is helpful in these patients.

Lethal perinatal form (type II) — Patients with lethal perinatal OI (type II) usually die in utero or in early infancy. Severe fractures and pulmonary failure are typical problems that accelerate death in this group. Genetic counseling is indicated for affected families. Treatment of OI type II is supportive. (See "Approach to prenatal diagnosis of the lethal (life-limiting) skeletal dysplasias", section on 'Osteogenesis imperfecta type 2'.)

LABORATORY FINDINGS — Although biochemical parameters of bone and mineral metabolism are usually normal in OI, some abnormalities may be noted, including:

●Elevated levels of serum alkaline phosphatase have been reported in OI type VI, reflecting impaired bone mineralization [32].

●Hypercalciuria is common in OI children, and its magnitude appears to reflect the severity of the skeletal disease. One study found increased urinary excretion of calcium in 36 percent of children with OI [49]. The children with hypercalciuria were of shorter stature and had a greater lifelong fracture rate compared with OI children with normal urinary calcium excretion. However, their renal function was not compromised [50].

●Markers of bone formation (C-terminal propeptide of type I procollagen) may be lower, and markers of bone resorption (C-telopeptide of type I collagen) can be higher in OI, particularly in severely affected subjects [51].

These tests are useful in assessing bone metabolism and excluding other conditions (see 'Differential diagnosis' below) and are typically repeated yearly for ongoing monitoring (frequency varies depending upon the type/severity of OI).

PATHOLOGY — Bone histology may show disorganized (woven) bone, especially in more severely affected children. A bone biopsy study in 70 children with OI types I, III, and IV demonstrated normal mineralization with significant reductions in cortical width, cancellous bone volume, trabecular number, and trabecular width [52]. This study also found significantly increased bone remodeling (turnover) in all types of OI studied (ie, approximately a 70 percent increase compared with age-matched controls). The latter observation provides a rationale for the use of bisphosphonates in children with OI. Bone remodeling, however, is normal in OI type VI, which is characterized by defective mineralization [32], and, thus, bisphosphonates should not be prescribed to these children.

DIAGNOSIS — The clinical diagnosis of OI is based on the signs and symptoms described above. The diagnosis is usually straightforward in individuals with bone fragility and a positive family history or several extraskeletal manifestations [36]. However, in the absence of these features, diagnosis may be difficult. Extraskeletal manifestations can be subclinical (eg, hearing loss [47,53-55]), nonspecific (eg, dark or bluish sclerae are commonly present in infants, limiting the usefulness of this sign in this age group), or more obvious at certain ages (eg, dentinogenesis imperfecta may be more noticeable in the primary than the permanent dentition [56]). (See 'Clinical manifestations' above.)

There is no definitive, readily available lab test for OI. However, research labs have made advances in molecular genetic testing that will eventually be more accessible. The types of tests available for the various genetic defects and laboratories that perform them can be found on the Genetic Testing Registry (GTR) website. Sequence analysis of cDNA (which requires skin biopsy for fibroblast culture) or genomic DNA testing of white blood cells for mutations in COL1A1 and COL1A2 can detect 90 percent or more of all collagen type I mutations [36,57,58]. Negative studies do not exclude the diagnosis, because there is a false-negative rate of approximately 10 percent and there are OI types that are not associated with COL1A1 and COL1A2 mutations (types II B and types V through IX).

The structure and quantity of type I collagen can be determined in vitro from fibroblast culture using a small skin biopsy. This test is used when the clinical diagnosis is not clear. Abnormalities either in quantity or quality of type I collagen are present in approximately 90 percent of OI cases.

Prenatal diagnosis of OI is discussed in detail separately. (See "Approach to prenatal diagnosis of the lethal (life-limiting) skeletal dysplasias".)

DIFFERENTIAL DIAGNOSIS — The differential diagnosis of OI includes inflicted injury (child abuse) and a variety of skeletal conditions associated with bone fragility, including rickets and osteomalacia.

Child abuse — Children with inflicted trauma have multiple fractures in various stages of healing, similar to children with moderate to severe types of OI. In addition, they also may have metaphyseal, rib, and skull fractures. OI is a well-recognized cause of fractures that occur with minimal or no witnessed trauma, but it is a rare disorder and consequently is seldom the cause of such fractures. The differentiation between OI and child abuse is discussed in detail elsewhere. (See "Differential diagnosis of the orthopedic manifestations of child abuse", section on 'Osteogenesis imperfecta'.)

Rickets — Rickets can cause slow growth, bone deformities, elevation of alkaline phosphatase, defective bone mineralization, and, in some forms, abnormal tooth formation. However, scleral abnormalities and hearing loss typically do not occur. Radiographic findings in rickets are characteristic and include an increased width of the epiphyseal plate, irregular hazy margins of the distal metaphysis, and marginal metaphyseal overgrowth that results in a ball-in-cup-like appearance. (See "Overview of rickets in children".)

Hereditary resistance to vitamin D in children, or osteomalacia in adults, may be associated with hypophosphatemia. (See "Etiology and treatment of calcipenic rickets in children" and "Hereditary hypophosphatemic rickets and tumor-induced osteomalacia".)

Osteomalacia — Osteomalacia in adults can cause bone pain, insufficiency fractures, and alkaline phosphatase elevation but neither hearing loss nor blue sclerae. The most common radiologic finding in osteomalacia is reduced bone density; other abnormalities include Looser's zones or pseudofractures (image 1), narrow lines of radiolucency at the cortical margins of bones, and the loss of distinctiveness of trabeculae in vertebral bodies. (See "Epidemiology and etiology of osteomalacia" and "Clinical manifestations, diagnosis, and treatment of osteomalacia".)

Other skeletal syndromes — Other skeletal syndromes with moderate to severe bone fragility and/or deformity include [36]:

●Bruck syndrome – Bruck syndrome (MIM #312750 and %259450), previously called OI with congenital joint contractures, is an autosomal recessive disorder [36]. Clinical features that distinguish it from OI include congenital contractures of the knees, ankles, and feet; webbing (pterygia) of the elbow and knee; and clubfoot (talipes equinovarus) [59].

●Osteoporosis-pseudoglioma syndrome – Osteoporosis-pseudoglioma syndrome (MIM #259770) is an autosomal recessive disorder that was previously called the ocular form of OI [36,60-62]. It is caused by deletion of the gene for low-density-lipoprotein (LDL) receptor-related protein 5 (LRP-5). Other characteristic findings include microcephaly; pseudoglioma (inflammatory changes of the vitreous body, secondary to iridochoroiditis, that mimic retinal glioma); blindness (with onset in infancy); vitreoretinal abnormalities; cataract; absent anterior chamber; iris atrophy; intraocular calcification; and hypotonia [63,64].

●Panostotic fibrous dysplasia – Panostotic fibrous dysplasia, the extreme form of polyostotic fibrous dysplasia (McCune-Albright syndrome, MIM #174800), is caused by a somatic mutation in the guanine nucleotide stimulatory protein (GNAS1) gene [36,65]. It is characterized by cystic or ground glass lesions in all bones. (See "Nonmalignant bone lesions in children and adolescents", section on 'Fibrous dysplasia'.)

●Juvenile Paget disease – Juvenile Paget disease (MIM #239000), also known as idiopathic hyperphosphatasia, is an autosomal recessive disorder [36,66]. Patients with idiopathic hyperphosphatasia have increased serum alkaline phosphatase, which distinguishes it from OI, in which alkaline phosphatase is usually normal. However, elevated levels of serum alkaline phosphatase have been reported in some patients with OI type VI [32]. (See "Transient hyperphosphatasemia of infancy and early childhood" and "Clinical manifestations and diagnosis of Paget disease of bone".)

●Hypophosphatasia – Hypophosphatasia (MIM #241500) is a rare, autosomal disease caused by a deficiency of tissue nonspecific alkaline phosphatase and characterized by abnormal mineralization of bone and dental tissues [36,67]. Patients with hypophosphatasia have decreased serum concentrations of alkaline phosphatase, which distinguishes it from OI. (See "Periodontal disease in children: Associated systemic conditions", section on 'Hypophosphatasia'.)

●Cole-Carpenter syndrome – The inheritance pattern of Cole-Carpenter syndrome (MIM 112240) is unknown. It is characterized by osteoporosis, short stature, craniosynostosis, hydrocephalus, and proptosis [68].

●Idiopathic juvenile osteoporosis – Idiopathic juvenile osteoporosis is a nonhereditary form of transient, isolated childhood osteoporosis that occurs in prepubertal, previously healthy children [69].

MANAGEMENT — Treatment requires a coordinated multidisciplinary team approach and consists of physical therapy (PT), surgical interventions, and medications [70-72]. Bisphosphonates may be prescribed for patients at high risk of fracture, except for patients with type VI OI. These and other treatment decisions are most appropriately made by specialists at medical centers with significant experience in treating OI.

In addition, patients with OI require regular surveillance for potential complications including hearing loss, worsening of osteoporosis, growth retardation, and bone deformities (table 1) such that appropriate intervention is initiated as soon as possible. Pneumococcal and influenza vaccination are provided if there are no contraindications.

SUMMARY

●Osteogenesis imperfecta (OI) is a rare, inherited connective tissue disorder with many phenotypic presentations. Severely affected patients suffer multiple fractures with minimal or no trauma, and infants with the worst form of OI die in the perinatal period. Mild forms of OI may be manifested by only premature osteoporosis or severe postmenopausal bone mineral loss. (See 'Introduction' above and 'Clinical manifestations' above.)

●OI is most commonly caused by autosomal dominant mutations in genes encoding the alpha 1 and alpha 2 chains of type I collagen (COL1A1 and COL1A2). The autosomal recessive forms are caused by mutations in genes encoding proteins involved in posttranslational modification of type I collagen (table 1). (See 'Pathogenesis' above.)

●OI is classified into a number of major subtypes based on genetic, radiographic, and clinical characteristics (table 1). It can also be classified by clinical severity. (See 'Disease classification' above and 'Clinical manifestations' above.)

●The diagnosis should be considered in patients who have bone fragility and any of the following clinical manifestations (table 1 and table 2) (see 'Clinical manifestations' above):

•Short stature

•Scoliosis

•Basilar skull deformities

•Blue sclerae (picture 1)

•Hearing loss

•Opalescent teeth that wear quickly (dentinogenesis imperfecta) (picture 2)

•Increased laxity of the ligaments and skin

•Wormian bones (small, irregular bones along the cranial sutures)

•Easy bruisability

●The differential diagnosis includes child abuse, rickets, osteomalacia, and other rare skeletal syndromes. The diagnosis usually can be made clinically in patients with a positive history and/or several extraskeletal manifestations. However, the diagnosis can be difficult in the absence of these features. Skin biopsy for analysis of type I collagen genes and/or testing of genomic DNA for mutations in COL1A1 and COL1A2 may be helpful. However, normal results of these tests do not exclude the diagnosis. (See 'Diagnosis' above and 'Differential diagnosis' above.)

●The management of OI includes physical therapy (PT), surgical interventions, and medications and is best implemented by a coordinated multidisciplinary team at a medical centers with significant experience in treating OI. In addition, patients with OI require regular surveillance for potential complications including hearing loss and worsening of osteoporosis. (See 'Management' above.)

ACKNOWLEDGMENT — The editorial staff at UpToDate would like to acknowledge Arkadi A Chines, MD, who contributed to earlier versions of this topic review.