AUTHOR AND EDITOR INFORMATION

Section 1 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

INTRODUCTION

Section 2 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Background

The earliest known case of osteogenesis imperfecta is in a partially mummified infant's skeleton from ancient Egypt now housed in the British Museum in London. In 1835, Lobstein coined the term osteogenesis imperfecta and was one of the first to correctly understand the etiology of the condition. Other names for osteogenesis imperfecta are Lobstein disease, brittle-bone disease, blue-sclera syndrome, and fragile-bone disease.

Osteogenesis imperfecta is one of the most common skeletal dysplasias. It is a generalized disease of connective tissue that may manifest itself with one or more of the following findings: blue sclerae, triangular facies, macrocephaly, hearing loss, defective dentition, barrel chest, scoliosis, limb deformities, fractures, joint laxity, and growth retardation. Additional features, such as constipation and sweating, may also occur. A multidisciplinary approach is required to manage the disease.

Pathophysiology

Pathologic changes are seen in all tissues in which type 1 collagen is an important constituent; examples include bone, ligament, dentin, and sclera. The basic defect is one of a qualitative or quantitative reduction in type 1 collagen. Mutations in genes encoding type 1 collagen affect 1 of the 2 genes coding, accounting for about 80% of cases of osteogenesis imperfecta.

Most cases of osteogenesis imperfecta, previously thought to be either autosomal dominant or autosomal recessive, are now known to arise from autosomal dominant mutations. These mutations are either genetically inherited or new. The inherited mutations have a recurrence risk in subsequent pregnancies of 50% if a parent is affected, whereas the new mutations have an unpredictable recurrence risk. A small number of cases previously thought to be autosomal recessive have now been proven by molecular and linkage analysis to be secondary to gonadal mosaicism; the recurrence risk for these cases is also unpredictable.

In bone, the degree of histologic change is well correlated with the clinical severity of the disease. The disease affects both endochondral and intramembranous ossification. In osteogenesis imperfecta due to quantitative defects of type 1 collagen, a mild form of the disease occurs. On light microscopy, osteoporotic bone is present, with thick osteoid seams and reduced intercellular matrix. The numbers of osteoclasts and osteocytes are normal. Bone trabeculae are thin and disorganized. Lamellar bone is seen in the diaphysis and metaphysis. On electron microscopy, osteoblasts show distended rough endoplasmic reticulum (possibly due to accumulation of incomplete procollagen molecules), and collagen fibers are of reduced diameter.

In osteogenesis imperfecta due to qualitative defects of type 1 collagen, a severe form of the disease occurs. Light microscopy reveals hyperosteocytosis and increased vascular channels. Other findings are a reduction in cortical bone thickness, lack of normal cortical bone formation, and disorganization of the growth plate. Woven bone is seen, with minimal osteoid bone and no lamellar bone. Electron microscopy shows poorly preserved osteoblasts and collagen bundles of variable diameter, particularly in the more lethal forms of osteogenesis imperfecta.

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

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

Frequency

International

The birth incidence is approximately 1 case in 20,000 births.

Mortality/Morbidity

Morbidity and mortality associated with osteogenesis imperfecta vary widely depending on the genotype. In addition, variability occurs between individuals with different mutations, and variability has also been observed between unrelated individuals with the same mutations, between members of the same family, and even between identical twins on occasion.

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

Race

Osteogenesis imperfecta has been described in every human population in which skeletal dysplasias have been studied. The disease appears to have no predilection for a particular race.

Sex

Osteogenesis imperfecta is equally common in males and females.

Age

Osteogenesis imperfecta can present at any age, although the more severe forms tend to become evident at a younger age.

CLINICAL

Section 3 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

History

The clinical presentation of osteogenesis imperfecta is dependent on the phenotype.

The most widely used classification is that of Sillence (1979, 1981), which classifies osteogenesis imperfecta into 4 types on the basis of clinical and radiologic features. In addition, dentinogenesis imperfecta is denoted as subtype B, whereas osteogenesis imperfecta without dentinogenesis imperfecta is denoted as subtype A.

Adapted Sillence Classification of Osteogenesis Imperfecta

^*AD indicates autosomal dominant.

^† NA indicates not applicable.

Three more types of osteogenesis imperfecta (types V, VI, and VII) have been described, though they have not been incorporated as of yet into the International Classification of the Osteochondrodysplasias (INCO), which uses the Sillence classification. The 7 forms are described in more detail below.

• Type I
• • Type I osteogenesis imperfecta is the mildest and most common form. Patients present with blue sclerae (often described as dark blue with a gray tinge), variable degrees of bone fragility, moderate bone deformity, and premature deafness. Birth weights tend to be normal, though one or more bones may be fractured.
  • Fractures may occur for the first time at a later age, such as when the child starts to walk. These fractures tend to heal well, though sometimes a hypertrophic callus response is seen. Fractures tend to decrease in frequency after puberty, but their occurrence may increase later in life when age- and sex-related osteoporosis is superimposed.
  • Involvement of the axial skeleton, in the form of scoliosis and kyphosis, is seen in 20% of cases. Dentinogenesis imperfecta is characteristic of osteogenesis imperfecta type IB.
• Type II
• • Severely affected babies with type II disease are born with dwarfism with blue sclerae and short, bowed limbs.
  • The disease is usually fatal at birth, but some babies survive for several months.
  • Multiple fractures are evident, and the long bones are short and crumpled.
• Type III
• • Babies with type III disease are born with severe bone fragility and suffer multiple fractures at birth, although their birth weight tends to be normal. The sclerae are bluish at birth but fade over the years, becoming white in adulthood. Dentinogenesis imperfecta is frequently seen.
  • The chest and rib cage are usually spared, with few or no fractures of the ribs. Bowing of the limbs is common with growth, and multiple fractures may be seen later in life. The result is a short skeleton and a relatively less affected barrel shaped chest, with a pectus carinatum deformity.
  • The classic radiographic appearance is that of popcorn bones, in which fractures of the physes in several locations result in several islands of endochondral ossification. With age, these ossifications tend to disappear, leaving an enlarged radiolucent epiphysis. The axial skeletal is also involved, with progressive platyspondyly and kyphoscoliosis. Eventually, the wide rib cage overlaps the narrow pelvis.
  • Affected children tend to become wheelchair bound and nonambulatory. Of all types of osteogenesis imperfecta, type III is the one that orthopedic surgeons see most often.
• Type IV
• • Children with type IV disease have white sclerae with moderate bone fragility and deformity. The clinical picture may be similar to that of type I osteogenesis imperfecta, except for the presence of white sclerae.
  • Axial skeletal involvement, in the form of kyphoscoliosis, is also common.
  • Dentinogenesis imperfecta is seen in type IVB osteogenesis imperfecta.
• Type V
• • Type V is an autosomal dominant condition with severity similar to that of type IV disease but with a predisposition to hyperplastic callus formation.
  • Characteristic features include ossification of the interosseous membrane of the forearms and legs, leading to limited pronation and supination and a radiopaque metaphyseal band in growing patients.
• Type VI
• • Type VI is clinically similar to types II and IV, but it has distinctive histology, including hyperosteoid bone due to a mineralization defect; however, it does not have a disturbance of bone mineral metabolism.
• Type VII
• • Type VII disease has been described in an isolated First Nations community in northern Quebec (Labuda, 2002; Ward, 2002) and is clinically similar to osteogenesis imperfecta types II and IV but with rhizomelia as a distinctive feature.
  • The gene mutation has been mapped to chromosome region 3p22-24.1.
• Other types of osteogenesis imperfecta
• • Many cases of osteogenesis imperfecta do not fit into the aforementioned categories, with variants such as osteoporosis-pseudoglioma, Bruck syndrome, and Cole-Carpenter syndrome.
  • Osteoporosis-pseudoglioma syndrome is caused by mutations in the gene encoding for the low-density-lipoprotein receptor-related protein 5 (LRP5), with clinical features including blindness and bone fragility. LRP5 is thought to mediate the proliferation and differentiation of osteoblasts.
  • Bruck syndrome is an autosomal recessive condition caused by mutations in the bone-specific collagen type 1 telopeptide lysyl hydroxylase enzyme, with clinical features that include congenital joint contractures and bone fragility.
  • Cole-Carpenter syndrome is a severe progressive form of osteogenesis imperfecta, with associated multisutural craniosynostosis and growth failure.

Physical

See Clinical, History, above, for findings with the different subtypes.

Causes

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

The gene sequence coding for the triple-helix domain has a repeating motif of (Gly-X-Y)(n), where X is commonly hydroxyproline and Y is commonly hydroxylysine. Glycine, being the smallest of all amino acids, fits into the core of the superhelix when the chains wind around each other; therefore, glycine plays an important role in the superhelix formation. In 85-90% of cases, the gene mutation occurs in the region where the exon and intron splice sites are sequenced. All current mutations for type 1 collagen and their associated phenotypes can be found in the Human Type 1 Collagen Mutation Database.

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

In osteogenesis imperfecta due to qualitative defects of type 1 collagen, autosomal dominant mutations are found on either the COL1A or the COL1B gene. The mutations result in the production of a mixture of normal and mutant collagen chains. Substitution of glycine by a larger amino acid (eg, cysteine, alanine) results in abnormal helix formation, but these chains can combine with normal chains to produce type 1 collagen. The type 1 collagen thus formed is functionally impaired because of the mutant chain; this is the so-called dominant negative mechanism.

DIFFERENTIALS

Section 4 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Other Problems to be Considered

Because osteogenesis imperfecta can manifest itself in a wide variety of ways, differential diagnoses are best categorized into 3 stages of life: prenatal/neonatal, preschool/childhood, and adolescence/adulthood.

Prenatal/neonatal

The following skeletal dysplasias should be considered:

Thanatophoric dysplasia
Jeune dystrophy
Achondroplasia
Camptomelic dysplasia
Chondrodysplasia punctata
Chondroectodermal dysplasia (Ellis–van Creveld syndrome)
Nonaccidental injury
Menkes kinky-hair syndrome

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

Preschool/childhood

Genetic conditions to consider include the following:

Pyknodysostosis
Hajdu-Cheney syndrome
Osteopetrosis
Vitamin D–resistant rickets
Osteochondromatosis

Acquired conditions to consider include the following:

Secondary osteoporosis (immobilization)
Rickets
Scurvy
Leukemia
Cushing syndrome
Nonaccidental injury

Adolescence/adulthood

Conditions to consider in the adolescent and adult populations include the following:

Mafucci syndrome
Homocystinuria
Albright hereditary osteodystrophy
Wilson disease

For genetic conditions, patients present with fractures.

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

WORKUP

Section 5 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Lab Studies

• An analysis of type I, III, and V collagens synthesized by fibroblasts may be helpful. Tests include sodium dodecyl sulfate–polyacrylamide gel electrophoresis (SDS-PAGE), 2-dimensional SDS-PAGE, cyanogen bromide (CNBr) mapping, and thermal stability studies.
• An analysis of the amino acid composition of collagens may be useful.
• DNA blood testing for gene defects has an accuracy of 60-94%.

Imaging Studies

• Prenatal sonography is most useful in evaluating osteogenesis imperfecta types II and III. In its most severe form, the disease may be evident as early as 16 weeks' gestation.
• Plain radiographs may depict 3 radiologic categories of osteogenesis imperfecta: category I, thin and gracile bones; category II, short and thick limbs; and category III, cystic changes. Radiologic features commonly seen include the following:
• • Fractures - Commonly transverse fractures and those affecting the lower limbs
  • Excessive callus formation and popcorn bones - Multiple scalloped, radiolucent areas with radiodense rims
  • Skull changes - Wormian bones, enlargement of frontal and mastoid sinuses, and platybasia with or without basilar impression
  • Deformities of the thoracic cage - Fractured and beaded ribs, pectus carinatum
  • Pelvic and proximal femoral changes - Narrow pelvis, compression fractures, protrusio acetabuli, and shepherd's crook deformities of the femurs
• Dual x-ray absorptiometry (DEXA) may be used to assess low bone mineral density in children with milder forms of osteogenesis imperfecta.
• CT densitometric bone scanning may be helpful in atypical cases of osteogenesis imperfecta, though normal bone density does not exclude mild forms of the disease.

Other Tests

• Polarized light microscopy or microradiography may be used in combination with scanning electron microscopy to assess dentinogenesis imperfecta.
• With skin biopsy, collagen can be isolated from cultured fibroblasts and assessed for defects, with an accuracy of 85-87%.
• Bone biopsy may show changes in the concentrations of noncollagenous bone proteins, such as osteonectin, sialoprotein, and decorin.

Procedures

• See Treatment, Surgical Care, below.

Histologic Findings

See Pathophysiology, above.

Staging

No staging system is used for osteogenesis imperfecta.

TREATMENT

Section 6 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical Care

Until recently, surgical correction of deformities, physiotherapy, and the use of orthotic support and devices to assist mobility (eg, wheelchairs) were the primary means of treatment for osteogenesis imperfecta. With the more recent understanding of the molecular mechanisms of the disease, medical treatment to increase bone mass and strength are gaining popularity, and surgery is reserved for functional improvement.

Bisphosphonates, particularly pamidronate, are synthetic analogues of pyrophosphate that inhibit osteoclast-mediated bone resorption on the endosteal surface of bone by binding to hydroxyapatite. As a result, unopposed osteoblastic new bone formation on the periosteal surface results in an increase in cortical thickness. Cyclic intravenous pamidronate is given in a dose of 7.5 mg/kg/y at 4- to 6-month intervals.

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

Adverse effects of pamidronate include an acute febrile reaction, mild hypocalcemia, leukopenia, a transient increase in bone pain, and scleritis with or without anterior uveitis. With milder forms of osteogenesis imperfecta, the indications for bisphosphonate therapy have yet to be evaluated. Other bisphosphonates, such as risedronate, alendronate, and zoledronic acid, are also being assessed.

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

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

Bone marrow transplantation (BMT) has been advocated as a potential future therapeutic modality in osteogenesis imperfecta. Bone marrow contains both hematopoietic and mesenchymal stem cells (MSCs), the latter being the precursors of osteoblasts. Because there are very few MSCs in the average human bone marrow graft, approaches involving expansion of the number of MSCs in ex vivo cultures with subsequent infusion into the recipient have been advocated.

Such cell therapies usually result in somatic mosaicism, where normal and abnormal osteoblasts exist in the same body. Unfortunately, a higher proportion of engrafted normal cells is required to achieve the level of normal osteoblasts necessary to functionally correct the osteogenesis imperfecta phenotype. Furthermore, the use of immunosuppressive agents to prevent graft rejection and graft versus host reaction can itself damage bone. Future approaches include the autografting of genetically modified mutant osteoblasts, whereby the mutant collagen gene is inactivated. These therapies are several years away from clinical reality.

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

Surgical Care

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

Surgery should be performed only if it is likely to improve function and only if the treatment goals are clear. Skilled administration of anesthetics and awareness of the limitations of surgery are essential prerequisites.

Soft tissue surgery is used in specific circumstances (eg, lower-limb contractures, particularly those of the Achilles tendon).

Painful bony deformity and recurrent fractures are typically treated with intramedullary stabilization with or without corrective osteotomies. In children with severe forms of osteogenesis imperfecta (eg, type III), rodding of lower extremities is performed to correct deformities and provide preventive protection around the time of first attempts at standing. Osteotomies should be simple, preferably single, and performed under direct vision with maximum care and gentle handling of tissues.

Because the bone is soft in osteogenesis imperfecta, rods (eg, extendable Sheffield rods, Bailey-Dubow rods), pins (eg, Rush pins), and wires (eg, Kirschner wires) are used rather than solid nails, plates, and screws (the latter being prone to increased fracture risk above and below the device and poor fixation). Rod placement is of particular use in the femur and is less commonly used in the tibia, humerus, and forearm.

Extendable rods were preferred over nonextendable rods in the prebisphosphonate era to prevent the bowing of bone and growth of bone beyond the end of the rod. Bailey-Dubow rods were complicated by a high incidence of mechanical failures, such as migration and disconnection of T-parts; therefore, Sheffield rods and the Fassier-Duval modification are now in use instead. The latter modification also has the advantage of being inserted through the greater trochanter (as in adult fixations), thus avoiding the need for a knee arthrotomy in femoral surgery. With the decreased fragility of bone exposed to bisphosphonate, the future role of extendable rods is unclear. In long bones, such as tibiae and radii, nonextendable rods such as Rush pins and Kirschner wires are most often used. Complications of rod placement include breakage, rotational deformities, and migration; and extendable to nonextendable rods are associated with similar complications. However, the rate of reintervention is lower with extendablerodsthan with nonextendable rods.

Bracing is ineffective in treating spinal deformities such as scoliosis and kyphosis, given that the rib cage is too fragile to transfer the brace pressure to the vertebral column. Moreover, the external pressure may worsen the chest deformities. Surgery is indicated if the bone quality is acceptable and progressive scoliosis with more than 45° curvature is present in mild forms of osteogenesis imperfecta or more than 30-35° curvature is present in severe forms of osteogenesis imperfecta. Posterior spinal arthrodesis is the treatment of choice and is best performed with segmental instrumentation. Often, significant correction and stable fixation is not achieved.

Basilar invagination may result in long tract signs and respiratory depression from direct compression of the brainstem and the upper cervical and cranial nerves. It is best treated with decompression and stabilization of the craniocervical junction.

Activity

Physiotherapy, in the form of comprehensive rehabilitation programs, has become more effective in the postbisphosphonate era because of the decrease in bone fragility and better prognosis for standing or walking. Strategies are age-dependent and are aimed at promoting gross motor development and maximizing functional independence.

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

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

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

MEDICATION

Section 7 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

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

Drug Category: Bisphosphonates

These medications are the only drugs licensed specifically for the treatment of osteogenesis imperfecta. The most commonly used drug in this class is pamidronate.

FOLLOW-UP

Section 8 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Further Outpatient Care

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

In/Out Patient Meds

• See Treatment, Medical Care, above.

Complications

• See Treatment, Medical Care and Surgical Care, above.

Prognosis

• See the table with the adapted Sillence classification in the Clinical, History section, above.

Patient Education

• Patients with osteogenesis imperfecta are generally well motivated and keen to achieve as much as possible despite their physical limitations.
• Education is extremely important, particularly for those who may respond to their condition in a more negative way and therefore be prone to low self-esteem and depression.
• Education is also important for parents and families to help them deal with the day-to-day implications and management of the patient's condition.

MISCELLANEOUS

Section 9 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical/Legal Pitfalls

• Anesthetic-related problems may arise from in patients with relatively large heads and tongues and in those with short necks.
• Chest deformities may cause respiratory complications.
• On the operating table, fractures may arise as a result of the application of a blood pressure cuff or tourniquet, or they may occur during transfers.
• Watch for hyperthermia and increased sweating.

REFERENCES

Section 10 of 10

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

• Bullough PG, Davidson DD, Lorenzo JC. The morbid anatomy of the skeleton in osteogenesis imperfecta. Clin Orthop. Sep 1981;42-57. [Medline].
• Cole WG. The Nicholas Andry Award-1996. The molecular pathology of osteogenesis imperfecta. Clin Orthop. Oct 1997;235-48. [Medline].
• Cole WG. Advances in osteogenesis imperfecta. Clin Orthop. Aug 2002;6-16. [Medline].
• Cole WG. Bone, cartilage and fibrous tissue disorders. In: Benson MKD, Fixsen JA, MacNicol MF, Parch K, eds. Children's Orthopaedics. 2002: 67-92.
• Francis MJ, Smith R, Bauze RJ. Instability of polymeric skin collagen in osteogenesis imperfecta. Br Med J. Mar 9 1974;1(905):421-4. [Medline].
• Glorieux FH, Bishop NJ, Plotkin H, et al. Cyclic administration of pamidronate in children with severe osteogenesis imperfecta. N Engl J Med. Oct 1 1998;339(14):947-52. [Medline].
• Jones D, Hosalkar H, Jones S. The orthopaedic management of osteogenesis imperfecta. Clin Orthop. 2002;16:374-88.
• Labuda M, Morissette J, Ward LM. Osteogenesis imperfecta type VII maps to the short arm of chromosome 3. Bone. Jul 2002;31(1):19-25. [Medline].
• Sillence D. Osteogenesis imperfecta: an expanding panorama of variants. Clin Orthop. Sep 1981;11-25. [Medline].
• Sillence DO, Senn A, Danks DM. Genetic heterogeneity in osteogenesis imperfecta. J Med Genet. Apr 1979;16(2):101-16. [Medline].
• Smith R, Francis MJ, Houghton GR. The brittle bone syndrome. In: Osteogenesis Imperfecta. London: Butterworth. 1983.
• Sofield HA, Page MA, Mead NC. Multiple osteotomies and metal-rod fixation for osteogenesis imperfecta. J Bone Joint Surg. 1952;34A:500-2.
• Ward LM, Rauch F, Travers R. Osteogenesis imperfecta type VII: an autosomal recessive form of brittle bone disease. Bone. Jul 2002;31(1):12-8. [Medline].
• Zeitlin L, Fassier F, Glorieux FH. Modern approach to children with osteogenesis imperfecta. J Pediatr Orthop B. Mar 2003;12(2):77-87. [Medline].

Article Last Updated: Jul 6, 2006