Study Guide

Osteogenesis Imperfecta

Key Points:

  • Characterized by bone fragility, ligamentous laxity and joint hypermobility
  • 87% of cases are caused by a defect in type I collagen 
  • High variability in the severity of the disorder
  • Must be differentiated from non-accidental trauma
  • Bisphosphonates are utilized for medical management
  • Intramedullary fixation is favored for operative treatment of fractures 

Description:

Osteogenesis Imperfecta (OI) encompasses a group of disorders characterized by a varying degree of bone fragility and frequent fractures often leading to limb bowing or other deformities.  The most widely used clinical classification is the Sillence classification, which originally included four groups (Sillence, 1979).  (Table 1)
 
Table 1: Original Silence Classification
Type I Dominantly Inherited OI with blue sclerae
Type II Lethal perinatal OI with radiographically crumpled femora and beaded ribs
Type III Progressively deforming OI
Type IV Dominantly inherited OI with normal sclerae


  A subsequent expansion of the classification added an additional 3 groups (Rauch,
2004).  As additional genetic causes were identified, the number of subtypes gradually increased up to OI type XIV (Forlino, 2011). 

  In 2009, the International Nomenclature group for Constitutional Disorders ICHG of the Skeleton decided to use a phenotypic basis to group the existing OI syndromes into 5 types, utilizing the original 4 types with a type 5 representing OI with calcification in the interosseous membranes (Warman, 2011). (Table 2) The new nomenclature transitioned to Arabic numerals from Roman numerals which had implied a distinct genetic locus.
 
Table 2: New Phenotypic OI Nomenclature
Mild to Moderate Severity
Type 1 Non-deforming OI with blue sclerae
Type 4 Common variable OI with normal sclerae
Type 5 OI with calcification in interosseous membranes
Progressively Deforming and Perinatally Lethal
Type 3 Progressively deforming OI
Type 2 Perinatally lethal OI

Epidemiology:

OI affects approximately one in 10,000 births. There is no racial or ethnic predisposition (Roughley, 2003). In type I, the annual fracture rate appears to be less than or equal to 1, while the pre-pubertal rates of fracture in more severe types are likely to be greater than 3 annually (Van Dijk, 2014). Type I accounts for 50% of cases in Europe and the US (Steiner, 2017).

Clinical Findings:

Children with type I are on the milder end of the spectrum. The dominant clinical features are blue sclerae with or without involvement of the teeth, known as dentinogenesis imperfecta. Often this is referred to as “non-deforming OI” as bowing and deformity is less common. 

The most severe cases of the condition are found in type II where children experience multiple prenatal fractures. This type is often lethal in the perinatal period.

Type III is the most severe form that is routinely compatible with life. Children affected often have severe growth retardation and depend on a wheelchair for mobility. Osteopenia leads to multiple fractures and progressive bowing. (Figure X) Teeth and sclerae appear to be unaffected.  Osteopenia, ligamentous laxity and compression deformity of the vertebral bodies may lead to thoracolumbar scoliosis.  Basilar invagination may also be present.

In Type IV, there is bone fragility of a more severe degree then in type I but less severe than type III, most often with normal sclerae.  Involvement of the teeth may be present. 

A severity grading scale has been proposed which utilizes clinical data, frequency of fractures, bone densitometry, and mobility (Van Dijk, 2014).  (Table 3)

OI is a disorder of connective tissue and those children affected may also exhibit associated hearing loss (up to 40% in type I), decreased pulmonary function, skin fragility, valvular regurgitation, and joint hyperlaxity (Bonita, 2010; LoMauro, 2012).        

Children who present with isolated olecranon apophyseal fractures should be evaluated for OI given its incidence in this group. 

Imaging Studies:

OI may be identified by prenatal ultrasonography. (Table 3) In severe forms of the disease, characteristic radiographic findings include generalized osteopenia, with bowing deformities of the limbs.  There may be multiple fractures at different stages of healing. Joints are not involved. Children with less severe OI often present a greater diagnostic challenge as plain radiographs will not reveal the diagnosis.

Children with OI do not require imaging for every presumed fracture. In the absence of instability or deformity, empiric treatment without imaging is reasonable. Additionally, follow-up radiographs for inherently stable injuries again is not required.  Dual-energy x-ray absorptiometry (DEXA) bone density can provide diagnostic information and guide treatment (Huang, 2007).

Etiology:

Type I collagen is the dominant collagen type in bone, tendons, skin, teeth, fibrocartilage, cornea, and endomysium. Type I collagen is made up of two alpha-1 chains and one alpha-2 chain encoded by COL1A1 and COL1A2. The mechanism by which the chains are translated, processed and ultimately cross-linked is subject to genetic alterations leading to the OI phenotype.

Of those children with the osteogenesis phenotype, 87% have an alteration in the COL1A1 or COL1A2 gene consistent leading to an abnormality of type I collagen (Lindahl, 2015). Gene alterations that lead to a decrease in the quantity of type I alpha chains produced are commonly associated with milder phenotypes. Those alterations that lead to abnormality in the formation of the triple helix and therefore the quality of the of the collagen produced are more commonly associated the more severe phenotypes (type 3, 4, or 5).  Though much less common, there are a number of other genes which may lead to a similar phenotype (Forlino, 2016).

Treatment:

A multidisciplinary approach to OI is preferred. This should include physical therapy, medical management, and orthopedic considerations. The goal in treatment is for improvement of independent mobility, pain control and fracture prevention and management. Therapy can help to mobilize joints, improve strength and aerobic conditioning and allow for greater independence in ambulation as well as guide treatment with bracing or ambulatory aids (Brussel, 2008; Montpetit, 2015).

Bisphosphonates act as specific inhibitors to osteoclast-mediated bone resorption and have been widely utilized in these children. In a recent Cochrane review of fourteen studies, bisphosphonates were shown to improve bone density after treatment (Dwan, 2016). This increase in bone density has decreased the number of clinical fractures (Gatti, 2004).
 
Most fractures in OI children may be treated nonoperatively.  Fracture healing is unaffected in patients with OI and therefore the duration of immobilization should not be extended.  General treatment guidelines are similar to those of other children, although intramedullary fixation is used whenever possible instead of plate fixation (Fassier, 2014). Operative treatment of limb deformity as well as prophylactic treatment should be done with intramedullary fixation. Growing, telescoping implants are most commonly used to allow for longer-term prophylaxis. Scoliosis should be treated early to help prevent respiratory complications from progressive, severe deformity. Growing rod instrumentation is a consideration for progressive early onset scoliosis. 

Complications:

Side effects of bisphosphonate use include atypical femur fractures, delayed healing of osteotomies as well as hypocalcemia, vomiting, fever or even respiratory depression during the first dose of the intravenous forms (Kumar, 2016; Munns, 2004; Vasanwala, 2016)

Surgical complications arise from poor implant choice or can arise from the implants themselves. Plates leave stress risers in weak bone leading to repeat fractures. Migration, extrusion, and implant failure are common for telescoping and traditional intramedullary implants (Zionts, 2014). 

Figures and Tables:

Table 3: Pre-and Postnatal Severity Grading Scale of Osteogenesis Imperfecta (from Van Dijk, 2014). Postnatal characteristics are not modified by bisphosphonate therapy.
Mild OI
Prenatal No intra-uterine long bone fractures or bowing
Postnatal Rarely congenital fractures
Normal or near normal growth velocity and height
Straight long bones i.e. no intrinsic long bone deformity
Fully ambulant other than at times of acute fracture
Minimal vertebral crush fractures
Lumbar spine bone mineral density Z-score usually >−1.5 (−1.5 to +1.5)
Annualized fracture rate of less than or equal to 1.
Absence of chronic bone pain or minimal pain controlled by simple analgesics.
Regular school attendance, i.e., does not miss school due to pain, lethargy, or fatigue
Moderate OI
Prenatal Rarely fetal long bone fractures or bowing (but may increase in the last trimester)
Postnatal Occasionally congenital fractures
Decreased growth velocity and height
Anterior bowing of legs and thighs
Bowing of long bones related to immobilization for recurrent fractures
Vertebral crush fractures
Lumbar spine bone mineral density Z-score usually > −2.5 to <−1.5) but a wide range
Annualized prepubertal fracture rate greater than 1 (average 3 with a wide range)
Absent from school due to pain more than 5 days per year.
Severe OI
Prenatal Shortening of long bones
Fractures and/or bowing of long bones with some under-modeling
Slender ribs with absent or discontinuous rib fractures (cases intermediate between severe and extremely severe have few rib fractures but crumpled long bones)
Decreased mineralization
Postnatal Marked impairment of linear growth
Wheel-chair dependent
Progressive deformity of long bones and spine (unrelated to fractures)
Multiple vertebral crush fractures
Lumbar spine bone mineral density Z-score usually <−3.0 (wide range with age comparison as measurement is size/height dependent)
Annualized prepubertal fracture rate greater than 3 fractures per annum (age dependent)
Chronic bone pain unless treated with bisphosphonates
School attendance characterized by absences for fracture care and fatigue or pain
Extremely Severe OI
Prenatal Shortening of long bones
Fractures and/or bowing of long bones with severe under-modeling leading to crumpled (concertina-like) long bones
Thick continuously beaded ribs due to multiple sites of fracture or thin ribs (previously described as OI type 2-A and 2-B, respectively)
Decreased mineralization
Postnatal Thighs held in fixed abduction and external rotation with limitation of movement of most joints
Clinical indicators of severe chronic pain (pallor, sweatiness, whimpering or grimacing on passive movement)
Decreased ossification of skull, multiple fractures of long bones and ribs. Small thorax.
Shortened compacted femurs with a concertina-like appearance
All vertebrae hypoplastic/crushed
Respiratory distress leading to perinatal death
Perinatally lethal course

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References:

  1. Bonita RE et al. Valvular Heart Disease in Osteogenesis Imperfecta: Presentation of a Case and Review of the Literature. Echocardiography. 2010; 27: 69-73. 
  2. Brussel MV. Physical Training in Children with Osteogenesis Imperfecta. The Journal of Pediatrics 2008; 152: 111-116.e1 
  3. Dwan K. Bisphosphonate Therapy for Osteogenesis Imperfecta. Cochrane Database of Systematic Reviews. 2016. 
  4. Fassier et al. Chapter 45: Implant considerations in Long Bones In: Shapiro et al. ed. Osteogenesis Imperfecta. A Translational Approach to Brittle Bone Disease. London: Academic Press: 2014: 427–442. 
  5. Forlino A. Osteogenesis Imperfecta. The Lancet. 2016; 387: 1657-671. 
  6. Forlino A, Cabral WA, Barnes AM, Marini JC. New perspectives on osteogenesis imperfecta. Nat Rev Endocrinol. 2011; 7: 540–557.
  7. Kumar C. Zoledronate for Osteogenesis Imperfecta: Evaluation of Safety Profile in Children. Journal of Pediatric Endocrinology and Metabolism. 2016: 29: 947-52.
  8. Gatti D. Intravenous Neridronate in Children With Osteogenesis Imperfecta: A Randomized Controlled Study. Journal of Bone and Mineral Research. 2004: 20: 758-63. 
  9. Huang RP et al. Functional Significance of Bone Density Measurements in Children with Osteogenesis Imperfecta. The Journal of Bone and Joint Surgery (American). 2006: 88: 1324.  
  10. Lindahl, K et al. Genetic Epidemiology, Prevalence, and Genotype–phenotype Correlations in the Swedish Population with Osteogenesis Imperfecta. European Journal of Human Genetics. 2015: 23: 1042–1050. 
  11. LoMauro, A et al. Rib Cage Deformities Alter Respiratory Muscle Action and Chest Wall Function in Patients with Severe Osteogenesis Imperfecta. Ed. West et al.. PLoS ONE .2012: 7: e35965
  12. Montpetit K. Multidisciplinary Treatment of Severe Osteogenesis Imperfecta: Functional Outcomes at Skeletal Maturity. Archives of Physical Medicine and Rehabilitation. 2015: 96: 1834-1839.
  13. Munns CF. Delayed Osteotomy but Not Fracture Healing in Pediatric Osteogenesis Imperfecta Patients Receiving Pamidronate. Journal of Bone and Mineral Research. 2004: 19: 1779-1786. 
  14. Munns CF. Respiratory Distress with Pamidronate Treatment in Infants with Severe Osteogenesis Imperfecta. Bone. 2004: 35: 231-234. 
  15. Rauch F, Glorieux FH. Osteogenesis imperfecta. Lancet. 2004; 363: 1377–1385.
  16. Roughley PJ et al. Osteogenesis imperfecta-clinical and molecular diversity. European cells & materials. 2003: 5: 41-47: discussion 47.
  17. Sillence DO et al. Genetic Heterogeneity in Osteogenesis Imperfecta. Journal of Medical Genetics. 1979: 16: 101–116. 
  18. Steiner RD et al. COL1A1/2-Related Osteogenesis Imperfecta. GeneReviews. University of Washington, Seattle; 1993-2017.
  19. Van Dijk FS et al. Osteogenesis Imperfecta: Clinical Diagnosis, Nomenclature and Severity Assessment. American Journal of Medical Genetics Part a. 2014: 164: 1470–1481. 
  20. Vasanwala RF. Recurrent Proximal Femur Fractures in a Teenager with Osteogenesis Imperfecta on Continuous Bisphosphonate Therapy: Are We Overtreating. Journal of Bone and Mineral Research. 2016: 31: 1449-454.
  21. Warman ML, Cormier-Daire V, Hall C, Krakow D, Lachman R, LeMerrer M, Mortier G, Mundlos S, Nishimura G, Rimoin DL, Robertson S, Savarirayan R, Sillence D, Spranger J, Unger S, Zabel B, Superti-Furga A. Nosology and classification of genetic skeletal disorders: 2010 revision. Am J Med Genet Part A. 2011; 155A: 943–968.
  22. Zionts et al. Chapter 46: Treatment of Fractures and Non- Unions in Children with Osteogenesis Imperfecta. In: Shapiro et al. ed A Translational Approach to Brittle Bone Disease. London: Academic Press: 2014: 427–442.

Top Contributors:

Holly Leshikar MD
Jeff Martus MD