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 (OI) 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 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.[3] 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.[4]

Etiology

Osteogenesis imperfecta is a rare genetic disease. In the majority of cases, it occurs secondary to mutations in the COL1A1 and COL1A2 genes. More recently, diverse mutations related to OI have been identified.[5]

The following is the OI classification according to the International Society of Skeletal Dysplasias based on the mode of inheritance and genes involved.[6] 

Osteogenesis Imperfecta / Type / Inheritance / Genes

• Nondeforming OI (Type I) / AD / COL1A1, COL1A2 / X-linked / PLS3
• Perinatal (type II) / AD, AR / COL1A1, COL1A2, CRTAP, LEPRE1, PPIB, BMP1   
• Progressively deforming (type III) / AD, AR / COL1A1, COL1A2, CRTAP, LEPRE1, PPIB, FKBP10, SERPINH1, SERINF1, WNT1
• Moderate (type IV) / AD, AR / COL1A1, COL1A2, CRTAP, FKBP10, SP7, SERPINF1, WNT1, TMEM38B
• Calcification of interosseous membrane or hypertrophic callus (type V) / AD / IFITM5

Epidemiology

Osteogenesis imperfecta is a rare disease occurring in 1 in 15,000 to 20,000 births.[4] The population frequencies of type I OI have been reported to range between 2.35 to 4.7 in 100,000 worldwide. Reports of the incidence of type II OI range between 1 in 40,000 to 1.4 in 100,000 live births. The exact incidence of types III and IV OI is not known, although their incidence is much less common than type I.[7][8][9]

In Shapiro's study, the incidence of types congenita A, congenita B, tarda A, and tarda B was approximately 19%, 31%, 25%, and 25%, respectively.[10][11]

Pathophysiology

Two pro-alpha-1 chains and one pro-alpha-2 chain make up type I collagen, which forms the main protein of the extracellular membrane of skin, bones, tendons, etc., and create a rigid, triple helix structure. Each alpha chain consists of an amino-terminal pro-peptide, 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 OI 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] The autosomal dominant forms are caused by direct defects in type 1 collagen, 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 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 OI in Sillence Classification].[9] Alternatively, errors in substitution or deletion involving a glycine peptide residue along the polypeptide chain can result in the production of structurally or qualitatively abnormal or less effectual collagen. 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 of glycine residues affecting the quality of collagen chains (commonly identified defects in Sillence types II, III, and IV types) develop more severe skeletal manifestations than patients with haploinsufficiency defects.[15]

Other Mutations

Apart from type I collagen mutations, other genetic mutations producing autosomal recessive types of OI (types VI, VII, VIII, IX, X, and XI) have also been described. These mutations may involve components that encode collagen 3-hydroxylation complex, which helps assemble the triple helix. These recessive mutational types account for less than 5% of the cases of OI collectively.[15]

Histopathology

Generally, the defects involving decreased collagen type 1 secretion or secretion of abnormal collagen result in 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 thinned calcified zone, are typical histological features.[17] Newer studies have proposed problems with specific growth factors, particularly transforming growth factor beta (TGFb), so completely innovative treatments are being developed to neutralize this factor with a specialized antibody.[18]

History and Physical

Two clinically useful classification systems of osteogenesis imperfecta have been described by Sillence et al. and Shapiro et al.[7][19][10] In 1979, Sillence and Danks initially described four types of OI based on the clinical and genetic basis. They originally identified types I and IV as autosomal dominant and types II and III as autosomal recessive inheritance. More recent literature has shown that true autosomal recessive inheritance is quite rare. Based on further research on the genetic defects involved, Cole further added types V to XI to the original Sillence Classification (type V with autosomal dominant and types VI to XI with autosomal recessive transmissions).[12][4]

Osteogenesis imperfecta classification based on phenotypic characteristics and mode of inheritance modified from Sillence et al.:

• Type I: Autosomal dominant (COL1A1 gene does not produce viable mRNA for procollagen); collagen amount is 50% reduced; however, the molecule is structurally normal. General manifestation shows generalized osteoporosis, abnormal bone fragility (fractures typically during the ambulatory years of child development and reduced bone maturity), blue sclera, conductive deafness, and mild stunting. IA (Normal Teeth), IB/IC (dentinogenesis imperfecta).[9][6]

• Type II: Originally classified as autosomal recessive; however, recent work indicates that it follows a dominant negative inheritance (7% risk of disease in subsequent pregnancies), often due to spontaneous mutation. This form results in severe disruption in the qualitative function of the collagen molecule: lethal perinatal form. General manifestation demonstrates extreme bone fragility (accordion femur), delayed skull ossification, blue sclera, and perinatal death. Type IIA  has short and wide long bones with fractures and wide ribs with sparse fractures. II-B manifests with short and widened long bones with fractures and ribs with sparse fractures. II-C presents with thin, long bones with fractures and thin ribs.[20][12]

• Type III: Autosomal recessive or dominant negative inheritance; type I collagen alteration is both qualitative and quantitative. Most children with severe clinical manifestations belong to this category. General manifestation presents with blue sclera in infancy and returns to normal hue in adolescence. Moderate to severe bone fragility, coxa vara, multiple fractures, and marked long bone deformities (more severe than type I with greater ambulation difficulties). These patients require intramedullary nailing prophylactically. Other specific features: Early onset scoliosis, triangular facies, frontal bossing, basilar invagination, and extremely short stature.[3][21][13][22][23]

• Type IV: Heterogenous group; autosomal dominant that also has qualitative and quantitative changes in type I collagen—more severe clinical manifestations than type I OI. General manifestation shows normal sclera, moderate to severe bone fragility and deformity of the long bones and spinal column, and moderate to severe growth stunting. Type IV A presents with normal teeth, while Type IV B shows dentinogenesis imperfect.

• Type V: Autosomal dominant; mutation in the gene encoding interferon-induced transmembrane protein-5 (IFITM5); histologically demonstrates a mesh-like appearance of the lamellar bone. It presents with mild to moderate degrees of severity. Specific features include normal sclera, the absence of dental involvement, calcification of interosseous membrane, especially the forearm that can lead to secondary dislocation of the radius, hypertrophic callus, and a radiodense band near long bone physis are specific characteristics of this type.[24][25][26]

• Type VI: Mutation involving SERPINF1 gene; characteristic histological presentation includes lamellar bone with fish scale pattern under a polarized light microscope and severe mineralization defects. This type presents with moderate to severe skeletal manifestations, normal sclera, and an absence of dental involvement.

Types VII, VIII, and IX

Common Features

1. A defect in the prolyl 3-hydroxylation complex in the endoplasmic reticulum (ER) (which helps in the assembly of the triple helix)
2. Autosomal recessive[4][27][28]

Specific defects include cartilage-associated protein defects (CRTAP) - type VII, prolyl 3-hydroxylase (LEPRE1) - type VIII, and peptidyl-prolyl cis-trans isomerase B (PPIB) - type IX.

General Manifestation

• Type VII: Moderate to severe. It is associated with rhizomelia and coxa vara.

• Type VIII: Severe to lethal. It is associated with rhizomelia.

• Type IX:  Severe autosomal recessive form.

Types X and XI

Common Features

1. A defect in collagen chaperones that accompany procollagen molecules from ER to Golgi apparatus
2. 2.Autosomal recessive[28][29]

Specific defects: SERPINH1 - type X, FKBP10 - type XI.

General Manifestation 

• Type X: Severe bone dysplasia, dentinogenesis imperfecta, transient skin bullae, blue sclera, pyloric stenosis, and renal stones.

• Type XI: Bone dysplasia, ligamentous laxity, scoliosis, and platyspondyly. Normal sclera and absence of dental involvement.

The pitfall of Sillence Classification: Significant variability in the severity of deformities and fractures within different classification categories. Less prognostic relevance.

Looser et al. (1906):

Classified OI into two types - OI congenita (presence of numerous fractures at birth) and OI tarda (fractures occur after the perinatal period).

Shapiro's modification of Looser classification (4 types): Excellent practical application regarding prognostication for survival and ambulation.[10]

• Congenita A (Incompatible with life) - Sustain fractures in utero or at birth; Radiographically, present with crumpled long bones, crumpled ribs, rib cage deformity, and fragile skull.

• Congenita B (Compatible with survival) - Sustain fractures in utero or at birth; Radiographically, present with more tubular long bones with funnelization in the metaphysis, normally formed ribs, and no rib cage deformity.

Tarda A - Fractures before walking; Age of onset of fractures - not prognostic for ambulation.

Tarda B - First fracture after walking age; All patients usually ambulate.

Evaluation

It is important to rule out non-accidental trauma in these patients presenting with multiple fractures.[30][31]

Diagnosis: is based on clinical and family history, bone mineral density (lumbar vertebra), bone biochemistry, and radiographic features.[32]

The most common clinical finding is bone fragility in most OI types. Most of them have specific features, as described by Van Dijk and Sillence.[33]

Patients usually present with four Major Clinical Features:

• Decreased bone mass, increased bone fragility
• Blue sclera
• Dentinogenesis imperfecta (Normal enamel with dentin abnormality)
• Hearing loss
• Other features include ligament laxity, increased joint mobility, short stature, and easy bruising.

Fractures in OI: the earlier the onset of fractures, the poorer the prognosis is.[34][35] There is a possibility of hypertrophic callus during fracture healing (which may resemble osteosarcoma); however, the fractures, on most occasions, heal at the usual rate. Bony deformities may occur secondary to fractures; protrusio acetabuli, proximal varus or anterolateral bowing (femur), anterior bow (tibia), cubitus varus, and other proximal forearm deformities are known to occur.[36] 

Facies in OI: Elfin facies, helmet head appearance.

Manifestations depend on the type of OI.

Laboratory: no commercially available diagnostic test is available due to a wide variety of genetic mutations. Laboratory values are typically within the normal range with potentially mildly elevated alkaline phosphatase (ALP).

Plain Radiograph

• Head, neck, and Spine: wormian bones, basilar invagination, kyphoscoliosis (39 to 100%), platyspondyly
• Chest: pectus excavatum or carinatum
• Pelvis: protusio acetabuli, coxa vara
• General: osteoporosis, lack of funneling of long bones, cortical thinning, hypertrophic callus formation, popcorn calcifications involving metaphysis and epiphysis, pseudoarthrosis at the site of fractures

Prenatal ultrasound: decreased calvarial ossification, shortened and angulated long bones, multiple bone fractures, a beaded appearance of ribs, polyhydramnios.[37]

Computed Tomography (CT)

• Wormian bone
• Basilar invagination
• Otosclerosis
• Long bone fractures[38]

Magnetic Resonance Imaging (MRI) (to evaluate basilar invagination)

Fibroblast culturing to analyze type I collagen (positive in 80% of type IV): used for confirmation of the diagnosis in equivocal cases

Biopsy

• Collagen analysis of a punch biopsy
• Iliac crest biopsy which demonstrates a decrease in cortical widths and the volume of cancellous bone, with increased bone remodeling

Treatment / Management

Management varies with the age, severity, and functional status of patients:

• Mild disease: subtle restriction, avoid contact sports, treated for any fractures[39]
• Moderate to Severe disease: rehabilitation and orthopedic interventions, management of acute fractures and scoliosis[40]
• Severe disease: an intramedullary rod with osteotomy used to correct severe bowing of long bones[41][42]

Medical Management 

Medical management can take a number of forms, as listed below.[43][44][45][46][47][48][49]

• Sex hormones, sodium fluoride, calcium, calcitonin, magnesium oxide, and vitamins C and D - attempted in the past with no or mixed results. 
• Bisphosphonates (intravenous pamidronate, oral alendronate) have been demonstrated to be useful (decrease fracture risk, improve bone mineral density as well as ambulatory status) through their ability to reduce the osteoclastic resorption of bone in children with OI[50][51][52][53][52]
• Gene therapy and cell transplantation (to correct defective COL1A1 and COL1A2 genes) are still not widely available, but experimental studies in animals showed promising results[54][55][56]
• Sclerostin antibody medication (romosozumab) has been used in animal models with beneficial effects on the skeleton, but there are no human studies reported yet[57][58][59][60][57]
• Denosumab has been proven to help with bone quality in small-scale studies, but it is not yet approved for wide use in OI patients; ongoing studies are looking into more details of this treatment[61]
• Anabolic bone therapy with teriparatide was also tried in a small study and showed an increase in the bone density of the OI-treated patients compared to the placebo group, but this medication is also not officially approved for use in this population[62]
• An antibody to transforming growth factor beta (TGFb) is one of the latest medical treatments studied in animal models with OI, and it has also offered some promising results[18][63][64]

Orthopedic Management

The goals focus on ways to ameliorate patient functional status, prevent deformity and disability, correct deformities, and monitor for complications.

1. Orthotic treatment: orthosis, walking aids, wheelchairs

2. Management of long bone fractures

3. Management of long bone deformities includes: 

• In infants and children:  

  • Closed osteoclasis without intramedullary fixation
  • Closed osteoclasis with percutaneous intramedullary fixation
  • Open osteotomy with internal fixation (Sofield and Millar procedure) - Rush nail, Williams rod[65][66][67][68]
• In young adult patients:

  • External fixation with circular or uniplanar constructs with osteotomy.

4. Prophylactic intramedullary rod for children who repeatedly fracture their long bones. Different types of rods according to bone size and skeletal maturity are used:

• Osteotomy and fixation with telescoping rod (Bailey-Dubow rod, Sheffield rod, Fassier-Duval rod)
• Osteotomy and fixation with a non-telescoping rod (Kirschner wire, Steinmann pin, Williams rod, push rod, other fixed-length rods)

5. Management of spinal deformities: basilar invagination, kyphoscoliosis, spinal fractures

Differential Diagnosis

Major differentials 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

Varied across the diverse spectrum of the disease.[10]

As previously discussed, the Shapiro classification (more than the Sillence classification) is a good prognostic indicator. 

The age of onset of long bone fractures has been demonstrated as an important prognostic indicator for ambulatory ability.

Survival: The most significant indicators include the location and severity of fractures and the general radiographic appearance of the skeleton.

Engelbert et al. demonstrated that children who achieved independent sitting or standing, or both, by 12 years of age were finally able to ambulate. 

The authors also found that children who could achieve independent sitting or standing, or both, at 12 months old were likely to be able to walk.[71]

Complications

The following complications may present with osteogenesis imperfecta:

1. Hyperplastic callus formation is rare and managed by conservative, palliative radiotherapy (caution: secondary malignancy) and bisphosphonates[72]
2. Tumors: Osteogenic sarcoma[73]
3. Basilar invagination: Cranial nerve involvement, direct brain stem compression, altered cerebrospinal fluid (CSF) dynamics[74]
4. Malignant hyperthermia: both the surgeon and anesthesiologist should keep in mind the possibility of malignant hyperthermia during anesthesia[75]

Deterrence and Patient Education

It is vital to educate the parent regarding the likelihood of survival and what to expect regarding deformity, disability, and ambulatory capacity. Genetic counseling and prenatal screening (including ultrasonography) may be necessary during future pregnancies. The parents should also receive counseling that their children, despite their orthopedic impairments, have normal intelligence and social abilities. They should also receive information regarding the need for caution against falls to obviate recurrent fragility fractures.[76]

Antenatal diagnosis:

Antenatal ultrasound can demonstrate OI Sillence type II by 16 weeks of fetal age. Based on the severity of disease expression, Sillence types I, III, and IV can also be diagnosable on imaging.[3]

Parents with a history of a fetus affected by OI type II carry a 2% to 7% risk of a similarly affected fetus in future pregnancies. Antenatal diagnosis can be made in such scenarios by DNA analysis of chorionic villus samples obtained by ultrasonographic imaging.

Enhancing Healthcare Team Outcomes

The management of osteogenesis imperfecta is challenging and complex and requires an interprofessional healthcare team approach to management.[76] The primary reason underlying the complexity of management is the wide variation in the phenotypic expression across the different spectra 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 over different stages of management needs to be understood. The orthopedic surgeon is involved in preventing and managing fractures and deformities of extremities.

Medical management with bisphosphonates can prevent fractures in children with recurrent fractures. The pharmacist can perform medication reconciliation, verify dosing, counsel parents on the potential adverse effects, and answer their medication 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 upper cervical spine/craniocervical junction compressive pathologies 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 imparting holistic care to the patient and providing the needed support to the caregivers. Such interprofessional care can aid in meeting basic goals in the management of OI, including ameliorating the patient's functional status, preventing deformity and disability, correcting existing deformities, and monitoring for possible complications.

Most of the current knowledge on the subject of OI has its basis in available level 3 to 5 evidence.

Review Questions

• Access free multiple choice questions on this topic.
• Comment on this article.

References

1.

Uttarilli A, Shah H, Bhavani GS, Upadhyai P, Shukla A, Girisha KM. Phenotyping and genotyping of skeletal dysplasias: Evolution of a center and a decade of experience in India. Bone. 2019 Mar;120:204-211. [PubMed: 30408610]

2.

Nicol L, Morar P, Wang Y, Henriksen K, Sun S, Karsdal M, Smith R, Nagamani SCS, Shapiro J, Lee B, Orwoll E. Alterations in non-type I collagen biomarkers in osteogenesis imperfecta. Bone. 2019 Mar;120:70-74. [PubMed: 30290234]

3.

Ablin DS. Osteogenesis imperfecta: a review. Can Assoc Radiol J. 1998 Apr;49(2):110-23. [PubMed: 9561014]

4.

Forlino A, Cabral WA, Barnes AM, Marini JC. New perspectives on osteogenesis imperfecta. Nat Rev Endocrinol. 2011 Jun 14;7(9):540-57. [PMC free article: PMC3443407] [PubMed: 21670757]

5.

Valadares ER, Carneiro TB, Santos PM, Oliveira AC, Zabel B. What is new in genetics and osteogenesis imperfecta classification? J Pediatr (Rio J). 2014 Nov-Dec;90(6):536-41. [PubMed: 25046257]

6.

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 A. 2011 May;155A(5):943-68. [PMC free article: PMC3166781] [PubMed: 21438135]

7.

Sillence D. Osteogenesis imperfecta: an expanding panorama of variants. Clin Orthop Relat Res. 1981 Sep;(159):11-25. [PubMed: 7285446]

8.

Stoltz MR, Dietrich SL, Marshall GJ. Osteogenesis imperfecta. Perspectives. Clin Orthop Relat Res. 1989 May;(242):120-36. [PubMed: 2650946]

9.

Sillence DO, Senn A, Danks DM. Genetic heterogeneity in osteogenesis imperfecta. J Med Genet. 1979 Apr;16(2):101-16. [PMC free article: PMC1012733] [PubMed: 458828]

10.

Shapiro F. Consequences of an osteogenesis imperfecta diagnosis for survival and ambulation. J Pediatr Orthop. 1985 Jul-Aug;5(4):456-62. [PubMed: 4019761]

11.

Jain M, Tam A, Shapiro JR, Steiner RD, Smith PA, Bober MB, Hart T, Cuthbertson D, Krischer J, Mullins M, Bellur S, Byers PH, Pepin M, Durigova M, Glorieux FH, Rauch F, Lee B, Sutton VR, Members of the Brittle Bone Disorders Consortium*, Nagamani SCS. Growth characteristics in individuals with osteogenesis imperfecta in North America: results from a multicenter study. Genet Med. 2019 Feb;21(2):275-283. [PMC free article: PMC6320321] [PubMed: 29970925]

12.

Cole WG. The Nicholas Andry Award-1996. The molecular pathology of osteogenesis imperfecta. Clin Orthop Relat Res. 1997 Oct;(343):235-48. [PubMed: 9345229]

13.

Minch CM, Kruse RW. Osteogenesis imperfecta: a review of basic science and diagnosis. Orthopedics. 1998 May;21(5):558-67; quiz 568-9. [PubMed: 9606696]

14.

Makareeva E, Mertz EL, Kuznetsova NV, Sutter MB, DeRidder AM, Cabral WA, Barnes AM, McBride DJ, Marini JC, Leikin S. Structural heterogeneity of type I collagen triple helix and its role in osteogenesis imperfecta. J Biol Chem. 2008 Feb 22;283(8):4787-98. [PubMed: 18073209]

15.

Rauch F, Lalic L, Roughley P, Glorieux FH. Relationship between genotype and skeletal phenotype in children and adolescents with osteogenesis imperfecta. J Bone Miner Res. 2010 Jun;25(6):1367-74. [PubMed: 19929435]

16.

Hoyer-Kuhn H, Netzer C, Semler O. Osteogenesis imperfecta: pathophysiology and treatment. Wien Med Wochenschr. 2015 Jul;165(13-14):278-84. [PubMed: 26055811]

17.

Doty SB, Mathews RS. Electron microscopic and histochemical investigation of osteogenesis imperfecta tarda. Clin Orthop Relat Res. 1971 Oct;80:191-201. [PubMed: 5133325]

18.

Grafe I, Yang T, Alexander S, Homan EP, Lietman C, Jiang MM, Bertin T, Munivez E, Chen Y, Dawson B, Ishikawa Y, Weis MA, Sampath TK, Ambrose C, Eyre D, Bächinger HP, Lee B. Excessive transforming growth factor-β signaling is a common mechanism in osteogenesis imperfecta. Nat Med. 2014 Jun;20(6):670-5. [PMC free article: PMC4048326] [PubMed: 24793237]

19.

Sillence DO, Rimoin DL, Danks DM. Clinical variability in osteogenesis imperfecta-variable expressivity or genetic heterogeneity. Birth Defects Orig Artic Ser. 1979;15(5B):113-29. [PubMed: 393318]

20.

Sanguinetti C, Greco F, De Palma L, Specchia N, Falciglia F. Morphological changes in growth-plate cartilage in osteogenesis imperfecta. J Bone Joint Surg Br. 1990 May;72(3):475-9. [PubMed: 2187879]

21.

Cole WG, Jaenisch R, Bateman JF. New insights into the molecular pathology of osteogenesis imperfecta. Q J Med. 1989 Jan;70(261):1-4. [PubMed: 2687927]

22.

Nicholls AC, Oliver J, Renouf DV, Keston M, Pope FM. Substitution of cysteine for glycine at residue 415 of one allele of the alpha 1(I) chain of type I procollagen in type III/IV osteogenesis imperfecta. J Med Genet. 1991 Nov;28(11):757-64. [PMC free article: PMC1017111] [PubMed: 1770532]

23.

Aarabi M, Rauch F, Hamdy RC, Fassier F. High prevalence of coxa vara in patients with severe osteogenesis imperfecta. J Pediatr Orthop. 2006 Jan-Feb;26(1):24-8. [PubMed: 16439896]

24.

Cho TJ, Lee KE, Lee SK, Song SJ, Kim KJ, Jeon D, Lee G, Kim HN, Lee HR, Eom HH, Lee ZH, Kim OH, Park WY, Park SS, Ikegawa S, Yoo WJ, Choi IH, Kim JW. A single recurrent mutation in the 5'-UTR of IFITM5 causes osteogenesis imperfecta type V. Am J Hum Genet. 2012 Aug 10;91(2):343-8. [PMC free article: PMC3415533] [PubMed: 22863190]

25.

Glorieux FH, Rauch F, Plotkin H, Ward L, Travers R, Roughley P, Lalic L, Glorieux DF, Fassier F, Bishop NJ. Type V osteogenesis imperfecta: a new form of brittle bone disease. J Bone Miner Res. 2000 Sep;15(9):1650-8. [PubMed: 10976985]

26.

Semler O, Garbes L, Keupp K, Swan D, Zimmermann K, Becker J, Iden S, Wirth B, Eysel P, Koerber F, Schoenau E, Bohlander SK, Wollnik B, Netzer C. A mutation in the 5'-UTR of IFITM5 creates an in-frame start codon and causes autosomal-dominant osteogenesis imperfecta type V with hyperplastic callus. Am J Hum Genet. 2012 Aug 10;91(2):349-57. [PMC free article: PMC3415541] [PubMed: 22863195]

27.

Morello R, Bertin TK, Chen Y, Hicks J, Tonachini L, Monticone M, Castagnola P, Rauch F, Glorieux FH, Vranka J, Bächinger HP, Pace JM, Schwarze U, Byers PH, Weis M, Fernandes RJ, Eyre DR, Yao Z, Boyce BF, Lee B. CRTAP is required for prolyl 3- hydroxylation and mutations cause recessive osteogenesis imperfecta. Cell. 2006 Oct 20;127(2):291-304. [PubMed: 17055431]

28.

van Dijk FS, Nesbitt IM, Zwikstra EH, Nikkels PG, Piersma SR, Fratantoni SA, Jimenez CR, Huizer M, Morsman AC, Cobben JM, van Roij MH, Elting MW, Verbeke JI, Wijnaendts LC, Shaw NJ, Högler W, McKeown C, Sistermans EA, Dalton A, Meijers-Heijboer H, Pals G. PPIB mutations cause severe osteogenesis imperfecta. Am J Hum Genet. 2009 Oct;85(4):521-7. [PMC free article: PMC2756556] [PubMed: 19781681]

29.

Christiansen HE, Schwarze U, Pyott SM, AlSwaid A, Al Balwi M, Alrasheed S, Pepin MG, Weis MA, Eyre DR, Byers PH. Homozygosity for a missense mutation in SERPINH1, which encodes the collagen chaperone protein HSP47, results in severe recessive osteogenesis imperfecta. Am J Hum Genet. 2010 Mar 12;86(3):389-98. [PMC free article: PMC2833387] [PubMed: 20188343]

30.

Augarten A, Laufer J, Szeinberg A, Passwell J. Child abuse, osteogenesis imperfecta and the grey zone between them. J Med. 1993;24(2-3):171-5. [PubMed: 8409779]

31.

Knight DJ, Bennet GC. Nonaccidental injury in osteogenesis imperfecta: a case report. J Pediatr Orthop. 1990 Jul-Aug;10(4):542-4. [PubMed: 2358497]

32.

Trejo P, Rauch F. Osteogenesis imperfecta in children and adolescents-new developments in diagnosis and treatment. Osteoporos Int. 2016 Dec;27(12):3427-3437. [PubMed: 27492436]

33.

Van Dijk FS, Sillence DO. Osteogenesis imperfecta: clinical diagnosis, nomenclature and severity assessment. Am J Med Genet A. 2014 Jun;164A(6):1470-81. [PMC free article: PMC4314691] [PubMed: 24715559]

34.

Gamble JG, Rinsky LA, Strudwick J, Bleck EE. Non-union of fractures in children who have osteogenesis imperfecta. J Bone Joint Surg Am. 1988 Mar;70(3):439-43. [PubMed: 3346270]

35.

Moorefield WG, Miller GR. Aftermath of osteogenesis imperfecta: the disease in adulthood. J Bone Joint Surg Am. 1980 Jan;62(1):113-9. [PubMed: 7351402]

36.

Wenger DR, Abrams RA, Yaru N, Leach J. Obstruction of the colon due to protrusio acetabuli in osteogenesis imperfecta: treatment by pelvic osteotomy. Report of a case. J Bone Joint Surg Am. 1988 Aug;70(7):1103-7. [PubMed: 3403582]

37.

Renaud A, Aucourt J, Weill J, Bigot J, Dieux A, Devisme L, Moraux A, Boutry N. Radiographic features of osteogenesis imperfecta. Insights Imaging. 2013 Aug;4(4):417-29. [PMC free article: PMC3731461] [PubMed: 23686748]

38.

Heimert TL, Lin DD, Yousem DM. Case 48: osteogenesis imperfecta of the temporal bone. Radiology. 2002 Jul;224(1):166-70. [PubMed: 12091678]

39.

Montpetit K, Palomo T, Glorieux FH, Fassier F, Rauch F. Multidisciplinary Treatment of Severe Osteogenesis Imperfecta: Functional Outcomes at Skeletal Maturity. Arch Phys Med Rehabil. 2015 Oct;96(10):1834-9. [PubMed: 26140741]

40.

Lin TY, Yang CY, Liu SC. Corrective osteotomy with retrograde Fassier-Duval nail in an osteogenesis imperfecta patient with bilateral genu valgum: A case report. Medicine (Baltimore). 2017 Nov;96(47):e8459. [PMC free article: PMC5708919] [PubMed: 29381920]

41.

Marom R, Rabenhorst BM, Morello R. Osteogenesis imperfecta: an update on clinical features and therapies. Eur J Endocrinol. 2020 Oct;183(4):R95-R106. [PMC free article: PMC7694877] [PubMed: 32621590]

42.

Rossi V, Lee B, Marom R. Osteogenesis imperfecta: advancements in genetics and treatment. Curr Opin Pediatr. 2019 Dec;31(6):708-715. [PMC free article: PMC7017716] [PubMed: 31693577]

43.

Aeschlimann MI, Grunt JA, Crigler JF. Effects of sodium fluoride on the clinical course and metabolic balance of an infant with osteogenesis imperfecta congenita. Metabolism. 1966 Oct;15(10):905-14. [PubMed: 5923526]

44.

Castells S, Inamdar S, Baker RK, Wallach S. Effects of porcine calcitonin in osteogenesis imperfecta tarda. J Pediatr. 1972 May;80(5):757-62. [PubMed: 5062955]

45.

Nishi Y, Hamamoto K, Kajiyama M, Ono H, Kihara M, Jinno K. Effect of long-term calcitonin therapy by injection and nasal spray on the incidence of fractures in osteogenesis imperfecta. J Pediatr. 1992 Sep;121(3):477-80. [PubMed: 1517930]

46.

Lee YS, Low SL, Lim LA, Loke KY. Cyclic pamidronate infusion improves bone mineralisation and reduces fracture incidence in osteogenesis imperfecta. Eur J Pediatr. 2001 Nov;160(11):641-4. [PubMed: 11760017]

47.

Fujiwara I, Ogawa E, Igarashi Y, Ohba M, Asanuma A. Intravenous pamidronate treatment in osteogenesis imperfecta. Eur J Pediatr. 1998 Mar;157(3):261-2. [PubMed: 9537501]

48.

Gerber LH, Binder H, Berry R, Siegel KL, Kim H, Weintrob J, Lee YJ, Mizell S, Marini J. Effects of withdrawal of bracing in matched pairs of children with osteogenesis imperfecta. Arch Phys Med Rehabil. 1998 Jan;79(1):46-51. [PubMed: 9440417]

49.

Gerber LH, Binder H, Weintrob J, Grange DK, Shapiro J, Fromherz W, Berry R, Conway A, Nason S, Marini J. Rehabilitation of children and infants with osteogenesis imperfecta. A program for ambulation. Clin Orthop Relat Res. 1990 Feb;(251):254-62. [PubMed: 2295183]

50.

Bains JS, Carter EM, Citron KP, Boskey AL, Shapiro JR, Steiner RD, Smith PA, Bober MB, Hart T, Cuthbertson D, Krischer J, Byers PH, Pepin M, Durigova M, Glorieux FH, Rauch F, Sliepka JM, Sutton VR, Lee B, Members of the BBD Consortium. Nagamani SC, Raggio CL. A Multicenter Observational Cohort Study to Evaluate the Effects of Bisphosphonate Exposure on Bone Mineral Density and Other Health Outcomes in Osteogenesis Imperfecta. JBMR Plus. 2019 May;3(5):e10118. [PMC free article: PMC6524673] [PubMed: 31131341]

51.

Hald JD, Evangelou E, Langdahl BL, Ralston SH. Bisphosphonates for the prevention of fractures in osteogenesis imperfecta: meta-analysis of placebo-controlled trials. J Bone Miner Res. 2015 May;30(5):929-33. [PubMed: 25407702]

52.

Dwan K, Phillipi CA, Steiner RD, Basel D. Bisphosphonate therapy for osteogenesis imperfecta. Cochrane Database Syst Rev. 2016 Oct 19;10(10):CD005088. [PMC free article: PMC6611487] [PubMed: 27760454]

53.

Jovanovic M, Guterman-Ram G, Marini JC. Osteogenesis Imperfecta: Mechanisms and Signaling Pathways Connecting Classical and Rare OI Types. Endocr Rev. 2022 Jan 12;43(1):61-90. [PMC free article: PMC8755987] [PubMed: 34007986]

54.

Guillot PV, Abass O, Bassett JH, Shefelbine SJ, Bou-Gharios G, Chan J, Kurata H, Williams GR, Polak J, Fisk NM. Intrauterine transplantation of human fetal mesenchymal stem cells from first-trimester blood repairs bone and reduces fractures in osteogenesis imperfecta mice. Blood. 2008 Feb 01;111(3):1717-25. [PubMed: 17967940]

55.

Panaroni C, Gioia R, Lupi A, Besio R, Goldstein SA, Kreider J, Leikin S, Vera JC, Mertz EL, Perilli E, Baruffaldi F, Villa I, Farina A, Casasco M, Cetta G, Rossi A, Frattini A, Marini JC, Vezzoni P, Forlino A. In utero transplantation of adult bone marrow decreases perinatal lethality and rescues the bone phenotype in the knockin murine model for classical, dominant osteogenesis imperfecta. Blood. 2009 Jul 09;114(2):459-68. [PMC free article: PMC2714216] [PubMed: 19414862]

56.

Sinder BP, Novak S, Wee NKY, Basile M, Maye P, Matthews BG, Kalajzic I. Engraftment of skeletal progenitor cells by bone-directed transplantation improves osteogenesis imperfecta murine bone phenotype. Stem Cells. 2020 Apr;38(4):530-541. [PMC free article: PMC7755312] [PubMed: 31859429]

57.

Sinder BP, Eddy MM, Ominsky MS, Caird MS, Marini JC, Kozloff KM. Sclerostin antibody improves skeletal parameters in a Brtl/+ mouse model of osteogenesis imperfecta. J Bone Miner Res. 2013 Jan;28(1):73-80. [PMC free article: PMC3524379] [PubMed: 22836659]

58.

Grafe I, Alexander S, Yang T, Lietman C, Homan EP, Munivez E, Chen Y, Jiang MM, Bertin T, Dawson B, Asuncion F, Ke HZ, Ominsky MS, Lee B. Sclerostin Antibody Treatment Improves the Bone Phenotype of Crtap(-/-) Mice, a Model of Recessive Osteogenesis Imperfecta. J Bone Miner Res. 2016 May;31(5):1030-40. [PMC free article: PMC4862916] [PubMed: 26716893]

59.

Perosky JE, Khoury BM, Jenks TN, Ward FS, Cortright K, Meyer B, Barton DK, Sinder BP, Marini JC, Caird MS, Kozloff KM. Single dose of bisphosphonate preserves gains in bone mass following cessation of sclerostin antibody in Brtl/+ osteogenesis imperfecta model. Bone. 2016 Dec;93:79-85. [PMC free article: PMC5077648] [PubMed: 27641475]

60.

Little DG, Peacock L, Mikulec K, Kneissel M, Kramer I, Cheng TL, Schindeler A, Munns C. Combination sclerostin antibody and zoledronic acid treatment outperforms either treatment alone in a mouse model of osteogenesis imperfecta. Bone. 2017 Aug;101:96-103. [PubMed: 28461254]

61.

Hoyer-Kuhn H, Netzer C, Koerber F, Schoenau E, Semler O. Two years' experience with denosumab for children with osteogenesis imperfecta type VI. Orphanet J Rare Dis. 2014 Sep 26;9:145. [PMC free article: PMC4180531] [PubMed: 25257953]

62.

Orwoll ES, Shapiro J, Veith S, Wang Y, Lapidus J, Vanek C, Reeder JL, Keaveny TM, Lee DC, Mullins MA, Nagamani SC, Lee B. Evaluation of teriparatide treatment in adults with osteogenesis imperfecta. J Clin Invest. 2014 Feb;124(2):491-8. [PMC free article: PMC3904621] [PubMed: 24463451]

63.

Tauer JT, Abdullah S, Rauch F. Effect of Anti-TGF-β Treatment in a Mouse Model of Severe Osteogenesis Imperfecta. J Bone Miner Res. 2019 Feb;34(2):207-214. [PubMed: 30357929]

64.

Tauer JT, Robinson ME, Rauch F. Osteogenesis Imperfecta: New Perspectives From Clinical and Translational Research. JBMR Plus. 2019 Aug;3(8):e10174. [PMC free article: PMC6715783] [PubMed: 31485550]

65.

Morel G, Houghton GR. Pneumatic trouser splints in the treatment of severe osteogenesis imperfecta. Acta Orthop Scand. 1982 Aug;53(4):547-52. [PubMed: 7102270]

66.

Frost RB, Middleton RW, Hillier LG. A stereotaxic device for the closed exchange of intramedullary rods, using image-intensified X-rays, in children with osteogenesis imperfecta. Eng Med. 1986 Jul;15(3):131-5. [PubMed: 3527804]

67.

Ryöppy S, Alberty A, Kaitila I. Early semiclosed intramedullary stabilization in osteogenesis imperfecta. J Pediatr Orthop. 1987 Mar-Apr;7(2):139-44. [PubMed: 3558793]

68.

Sijbrandij S. Percutaneous nailing in the management of osteogenesis imperfecta. Int Orthop. 1990;14(2):195-7. [PubMed: 2373568]

69.

Swischuk LE, Hayden CK. Rickets: a roentgenographic scheme for diagnosis. Pediatr Radiol. 1979 Oct;8(4):203-8. [PubMed: 514674]

70.

Marlowe A, Pepin MG, Byers PH. Testing for osteogenesis imperfecta in cases of suspected non-accidental injury. J Med Genet. 2002 Jun;39(6):382-6. [PMC free article: PMC1735162] [PubMed: 12070242]

71.

Engelbert RH, Uiterwaal CS, Gulmans VA, Pruijs H, Helders PJ. Osteogenesis imperfecta in childhood: prognosis for walking. J Pediatr. 2000 Sep;137(3):397-402. [PubMed: 10969267]

72.

Mrosk J, Bhavani GS, Shah H, Hecht J, Krüger U, Shukla A, Kornak U, Girisha KM. Diagnostic strategies and genotype-phenotype correlation in a large Indian cohort of osteogenesis imperfecta. Bone. 2018 May;110:368-377. [PubMed: 29499418]

73.

Cheung MS, Glorieux FH, Rauch F. Natural history of hyperplastic callus formation in osteogenesis imperfecta type V. J Bone Miner Res. 2007 Aug;22(8):1181-6. [PubMed: 17451374]

74.

Takahashi S, Okada K, Nagasawa H, Shimada Y, Sakamoto H, Itoi E. Osteosarcoma occurring in osteogenesis imperfecta. Virchows Arch. 2004 May;444(5):454-8. [PubMed: 15214333]

75.

Engelbert RH, Gerver WJ, Breslau-Siderius LJ, van der Graaf Y, Pruijs HE, van Doorne JM, Beemer FA, Helders PJ. Spinal complications in osteogenesis imperfecta: 47 patients 1-16 years of age. Acta Orthop Scand. 1998 Jun;69(3):283-6. [PubMed: 9703404]

76.

Paterson CR, Ogston SA, Henry RM. Life expectancy in osteogenesis imperfecta. BMJ. 1996 Feb 10;312(7027):351. [PMC free article: PMC2350292] [PubMed: 8611834]

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.