Osteogenesis Imperfecta

Author(s): Heakyung Kim, MD, Hannah Aura Shoval, MD

Originally published:08/07/2012

Last updated:08/17/2016



Osteogenesis imperfecta (OI) is a heritable, heterogeneous group of connective tissue disorders characterized primarily by abnormal bone formation and fragility with fractures. A classification system originally proposed by Silence included four subtypes. This was expanded in 2007 to include a total of eight subtypes because of distinguishing clinical features or known genetic causative mutation.

Type of OI Mutated gene/

Mode of inheritance

Severity of

clinical syndrome

Clinical features
I COL1A1/2 AD Mild Blue sclera, normal stature, fractures, hearing loss
II COL1A1/2 AD Lethal in perinatal period Blue-grey sclera, small for age, limb deformities, respiratory distress, soft calvarium
III COL1A1/2 AD Severe Short stature, multiple fractures, progressive deformities, usually non-ambulatory, hearing loss in adolescence, may have dentinogenesis imperfecta
IV COL1A1/2 AD Moderate Blue-grey sclera, usually ambulatory, dentinogenesis imperfecta, adult onset hearing loss
V Unknown AD Moderate Calcification of the interosseous membrane, radial head dislocation, hyperplastic callous formation
VI Unknown AR Moderate to severe Similar to type III, dentinogenesis imperfecta absent, abnormal bone mineralization on histologic evaluation
VII CRTAP AR Moderate Overlaps with type II and III
VIII LEPRE1 AR Severe to lethal Overlaps with type II and III


The majority (90%) of individuals with this disorder (types I-IV) are positive for a mutation of one of the genes that encodes collagen type 1, COL1A1 or COL1A2. Most forms are autosomal dominant in transmission but over one-third of individuals with OI are born into families with no history of the disease OI is now understood as a predominantly collagen-related disorder because there are a number of autosomal recessive forms affecting genes that interact with collagen.1 Mutation types can include missense mutations, 1 in-frame deletions and substitutions.

Epidemiology including risk factors and primary prevention

The incidence has been estimated at 1-2 per 20,000 births. However, this may be an underestimate because milder forms may go unrecognized. From 25,000 to 50,000 Americans are believed to have OI.


The defects in bone formation and bone fragility result from abnormal collagen microfibril quantity and/or quality or abnormal collagen related proteins1. Collagen defects also may result in blue sclera, dentinogenesis imperfecta (early eruption of fragile, discolored teeth prone to premature wear), hyperlaxity of ligaments and skin, easy bruising and hearing impairment.

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

Type of OI Age of presentation Progression during childhood Progression during adulthood
I Fractures begin in toddlerhood Fractures persist through puberty Fractures decrease after puberty and then increase again in 5thdecade
II Prenatal/immediately postnatal Fatal within one year of birth
III Fractures begin in infancy Very high fracture frequency with progressive deformity and dramatically short stature, often not ambulatory, hearing loss occurs in adolescence Incidence of fractures remains high in adulthood
IV Variable phenotype, most severe presenting in infancy and others much later Fractures occur but typically remains ambulatory Variable, hearing loss often occurs in adulthood, typically remains ambulatory
V Variable phenotype Variable Variable
VI Clinically indistinguishable from type IV
VII Variable, severe forms lethal in perinatal period, others with multiple fractures in infancy, milder forms reported Fractures and progressive deformity in childhood Occasional survival into adulthood
VIII Similar to Type VII

Specific secondary or associated conditions and complications

Multiple fractures may result in pain, loss of function, and deformity. Ligamentous laxity and short stature are common, though the severity of height difference varies. Kyphoscoliosis, chest wall pathology contribute to pulmonary insufficiency and infections which is the major cause of morbidity and mortality.2 Mitral valve prolapse and aortic dilatation rarely cause serious morbidity. Gross motor delays are common. Conductive hearing loss most often begins in the second to fourth decades of life, secondary to otosclerosis-like pathology or ossicular discontinuity, but typically progresses to a mixed type hearing loss.4 The most emergent side effect is from skull base deformities which can cause brainstem compression, hydrocephalus and syrinx1.



Historical details required include fracture history (when, how many, under what circumstances), stature, bone deformity, scleral color, tooth eruption and development, hearing loss, ligamentous laxity, pain, motor/cognitive/speech and language developmental status, unusual facial features, and pain. Family history of perinatal demise, stature, fractures and musculoskeletal deformity is critical. The clinician should ask about success of prior treatments such as medications or surgery. Number of fractures and bone density scores may be used to track disease progression and response to bisphosphonates.

Physical examination

The newborn with OI must be handled with extreme caution, given risk of fractures. Head and neck exam may reveal large head size, triangular face shape, soft skull, and large fontanelles. Eye exam may show blue or grey sclera. Skeletal exam might be notable for deviation of the sternum, short narrow rib cage, short bowed long bones, generalized growth deficiency.1

Exam of the older child and adult should include eye exam for scleral color and oral exam for dentition. Cranial nerve exam includes assessment of hearing. Thorough musculoskeletal exam includes assessment of height, long bone deformity, acute fracture, chest and spine abnormality and joint range of motion. Careful manual muscle testing and reflex exam should be performed.

Functional assessment

Careful assessment of bed mobility, transfers and gait should be included. Early milestone achievement can be tracked using tests such as the Bayley, Peabody, or Bruininks, though acute fracture will limit ability. Self-care measures such as the PEDI and AMPS, and mobility measures such as the gross motor function measure (GMFM) and Brief Assessment of Motor Function (BAMF2) are available and considered to quantify and follow motor performance. Even patients with severe OI generally have the skills needed for independent living and occupational success.1

Laboratory studies

Genomic DNA sequencing of COL1A1 and COL1A2 or molecular analysis of collagen type 1 will be abnormal in the majority of affected individuals. However, a negative result does not rule out OI.  If negative, sequencing for other osteogenesis imperfect genes is recommended, especially if more than one family member has the condition1.  A normal serum alkaline phosphatase and phosphate rule out idiopathic autosomal-recessive hyperphosphatasia.


X-rays may reveal abnormalities such as osteopenia, long bone and rib fractures at various stages of healing, bowing or shortening (“crumpling”) of the long bones, compressed or “codfish” vertebra, “beading” of the ribs, wormian changes of the skull, “popcorn” epiphyses.

Bone densitometry results using dual-energy x-ray absorptiometry (DEXA) vary with the type of OI. DEXA may be normal in Type I but significantly decreased in other types.

Supplemental assessment tools


Available or current treatment guidelines

At present, no cure is available. Best practice rehabilitative approaches include education regarding safety measures, exercise, brace or splint fabrication and assistive aides. Medical management with bisphosphonates such as pamidronate and alendronate is widely used to increase bone density, however there is not sufficient evidence as of yet that this results in a significant decrease in fractures.3 Orthopedic surgical options include internal fixation of the long bones using rods (not plates and screws, as they may create further stress in fragile bone) to minimize the incidence of fracture, restore bone integrity and decrease bowing. Scoliosis is not responsive to bracing. Posterior spinal fusion is generally done for scoliosis over 50°.1

Coordination of care

Patient care is best with a multi-disciplinary team1. This may include a geneticist, physiatrist, physical therapist, occupational therapist, orthopedist, nurse, social worker, and family.

Transitioning from a pediatric care team to an adult provider team requires medical record transfer, educating individuals with OI to assume responsibility for their care and identifying care providers who are familiar with needs related to OI.

Patient & family education

Families and patients should receive education regarding their rights within the school system. For example, they should be aware of the Individuals with Disabilities Education Act (IDEA), a law ensuring services to children with disabilities throughout the nation. The Americans with Disabilities Act (ADA) ensures equal opportunities in employment for individuals with disabilities. Vocational rehabilitation may be helpful in identifying and facilitating safe employment.


Cutting edge concepts and practice

Other treatments under exploration include bone morphogenic protein modulators, receptor activator of nuclear factor-kappaB ligand (RANKL) inhibitors, and stem cell-based therapies. Two novel antibodies that have anabolic action on bone have been successful at decreasing fracture in animal models. Pediatric trials are anticipated. 1


Gaps in the evidence-based knowledge

A number of studies including reviews3,5,6 and a multicenter trial7 confirm that bone density improves with bisphosphonate administration. However, a recent placebo control trial8 and Cochrane review from 20143 do not show improvement in fracture incidence. Research studies related to genetic transmission and cure are ongoing.


  1. Forlino A, Marini JC. Osteogenesis imperfecta. The Lancet. 2016 April;387( 10028: 1657-1671, ISSN 0140-6736.
  2. Singer RB, Ogston SA, Paterson CR. Mortality in various types of osteogenesis imperfecta. J Insur Med. 2001;33: 216–220.
  3. Dwan K, Phillipi CA, Steiner RD, Basel D. Bisphosphonate therapy for osteogenesis imperfect. Cochrane Database Syst Rev. 2014;7 CD005088.
  4. Freya KR et al. Osteogenesis imperfecta: the audiological phenotype lacks correlation with the genotype. Orphanet Journal of Rare Diseases. 2011;6:1-8.
  5. Wekre LL, Froslie KF, Haugen L, Falch JA. A population-based study of demographical variables and ability to perform activities of daily living in adults with osteogenesis imperfecta. Dis and Rehab. 2010;32(7):579-587.
  6. Phillipi CA, Remmington T, Steiner RD. Bisphosphonate therapy for osteogenesis imperfecta. Cochrane Database of Systematic Reviews 2008;4: Art.No.: CD005088. DOI:10.1002/14651858.CD005088.pub2.
  7. Castillo H, Samson-Fang L. Effects of bisphosphonates in children with osteogenesis imperfecta: an AACPDM systematic review. Dev Med Child Neurol. 2009;51: 17-29.


Basel D, Steiner RD. Osteogenesis imperfecta: recent findings shed new light on this once well-understood condition. Genet Med. 2009;11(6):375-385.

Cintas HL, Siegel KL, Furst GP, Gerber LH. Brief assessment of motor function: reliability and concurrent validity of the Gross Motor Scale. Am J Phys Med Rehabil. 2003 Jan;82(1):33-41.

Glorieux FH. Osteogenesis imperfecta. Best Pract Res Clin Rheum. 2008;22(1):85-100.

Graf A, et al. Gait characteristics and functional assessment of children with type I osteogenesis imperfecta. J Orthop Res. 2009;27:1182-1190.

Hackley L, Merritt L. Osteogenesis imperfecta in the neonate. Adv Neonat Care. 2008;8(1):21-30.

Shapiro JR, Sponsellor PD. Osteogenesis imperfecta: questions and answers. Curr Opin Pediatr. 2009;21:709-716.

van Brussel M, van der Net J, Hulzebos E, Helders PJM, Takken T. The Utrecht approach to exercise in chronic childhood conditions: The decade in review. Pediatr Phys Ther. 2011;23:2-14.

Ward LM, Rauch F, Whyte MP, et al. Alendronate for the treatment of pediatric osteogenesis imperfecta: a randomized placebo-controlled study. Journal of Clinical Endocrinology & Metabolism. 2011 Feb; 96(2):355-364.

Original Version of the Topic:

Osteogenesis Imperfecta. Sherilyn A. Driscoll, MD. Publication Date: 2012/08/07.

Author Disclosure

Heakyung Kim, MD
Nothing to Disclose

Hannah Aura Shoval, MD
Nothing to Disclose

Related Articles