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Current Opinion in Pediatrics Dec 2019The purpose of this review is to outline the current understanding of the molecular mechanisms and natural history of osteogenesis imperfecta, and to describe the... (Review)
Review
PURPOSE OF REVIEW
The purpose of this review is to outline the current understanding of the molecular mechanisms and natural history of osteogenesis imperfecta, and to describe the development of new treatments for this disorder.
RECENT FINDINGS
The introduction of next-generation sequencing technology has led to better understanding of the genetic cause of osteogenesis imperfecta and enabled cost-effective and timely diagnosis via expanded gene panels and exome or genome sequencing. Clinically, despite genetic heterogeneity, different forms of osteogenesis imperfecta share similar features that include connective tissue and systemic manifestations in addition to bone fragility. Thus, the goals of treatment in osteogenesis imperfecta extend beyond decreasing the risk of fracture, to include the maximization of growth and mobility, and the management of extraskeletal complications. The standard of care in pediatric patients is bisphosphonates therapy. Ongoing preclinical studies in osteogenesis imperfecta mouse models and clinical studies in individuals with osteogenesis imperfecta have been instrumental in the development of new and targeted therapeutic approaches, such as sclerostin inhibition and transforming growth factor-β inhibition.
SUMMARY
Osteogenesis imperfecta is a skeletal dysplasia characterized by bone fragility and extraskeletal manifestations. Better understanding of the mechanisms of osteogenesis imperfecta will enable the development of much needed targeted therapies to improve the outcome in affected individuals.
Topics: Adaptor Proteins, Signal Transducing; Animals; Child; Diphosphonates; Humans; Mice; Molecular Targeted Therapy; Osteogenesis Imperfecta
PubMed: 31693577
DOI: 10.1097/MOP.0000000000000813 -
Medicina (Kaunas, Lithuania) May 2021Osteogenesis imperfecta (OI), or brittle bone disease, is a heterogeneous disorder characterised by bone fragility, multiple fractures, bone deformity, and short... (Review)
Review
Osteogenesis imperfecta (OI), or brittle bone disease, is a heterogeneous disorder characterised by bone fragility, multiple fractures, bone deformity, and short stature. OI is a heterogeneous disorder primarily caused by mutations in the genes involved in the production of type 1 collagen. Severe OI is perinatally lethal, while mild OI can sometimes not be recognised until adulthood. Severe or lethal OI can usually be diagnosed using antenatal ultrasound and confirmed by various imaging modalities and genetic testing. The combination of imaging parameters obtained by ultrasound, computed tomography (CT), and magnetic resource imaging (MRI) can not only detect OI accurately but also predict lethality before birth. Moreover, genetic testing, either noninvasive or invasive, can further confirm the diagnosis prenatally. Early and precise diagnoses provide parents with more time to decide on reproductive options. The currently available postnatal treatments for OI are not curative, and individuals with severe OI suffer multiple fractures and bone deformities throughout their lives. In utero mesenchymal stem cell transplantation has been drawing attention as a promising therapy for severe OI, and a clinical trial to assess the safety and efficacy of cell therapy is currently ongoing. In the future, early diagnosis followed by in utero stem cell transplantation should be adopted as a new therapeutic option for severe OI.
Topics: Adult; Collagen Type I; Female; Genetic Testing; Humans; Mesenchymal Stem Cell Transplantation; Mutation; Osteogenesis Imperfecta; Pregnancy
PubMed: 34068551
DOI: 10.3390/medicina57050464 -
European Journal of Endocrinology Oct 2020Osteogenesis imperfecta (OI) is an inherited skeletal dysplasia characterized by bone fragility and skeletal deformities. While the majority of cases are associated with... (Review)
Review
Osteogenesis imperfecta (OI) is an inherited skeletal dysplasia characterized by bone fragility and skeletal deformities. While the majority of cases are associated with pathogenic variants in COL1A1 and COL1A2, the genes encoding type I collagen, up to 25% of cases are associated with other genes that function within the collagen biosynthesis pathway or are involved in osteoblast differentiation and bone mineralization. Clinically, OI is heterogeneous in features and variable in severity. In addition to the skeletal findings, it can affect multiple systems including dental and craniofacial abnormalities, muscle weakness, hearing loss, respiratory and cardiovascular complications. A multi-disciplinary approach to care is recommended to address not only the fractures, reduced mobility, growth and bone pain but also other extra-skeletal manifestations. While bisphosphonates remain the mainstay of treatment in OI, new strategies are being explored, such as sclerostin inhibitory antibodies and TGF beta inhibition, to address not only the low bone mineral density but also the inherent bone fragility. Studies in animal models have expanded the understanding of pathomechanisms of OI and, along with ongoing clinical trials, will allow to develop better therapeutic approaches for these patients.
Topics: Animals; Endocrinology; Fractures, Bone; Humans; Osteogenesis; Osteogenesis Imperfecta
PubMed: 32621590
DOI: 10.1530/EJE-20-0299 -
Current Opinion in Endocrinology,... Dec 2017Here we summarize the diagnosis of osteogenesis imperfecta, discuss newly discovered genes involved in osteogenesis imperfecta, and review the management of this disease... (Review)
Review
PURPOSE OF REVIEW
Here we summarize the diagnosis of osteogenesis imperfecta, discuss newly discovered genes involved in osteogenesis imperfecta, and review the management of this disease in children and adults.
RECENT FINDINGS
Mutations in the two genes coding for collagen type I, COL1A1 and COL1A2, are the most common cause of osteogenesis imperfecta. In the past 10 years, defects in at least 17 other genes have been identified as responsible for osteogenesis imperfecta phenotypes, with either dominant or recessive transmission. Intravenous bisphosphonate infusions are the most widely used medical treatment. This has a marked effect on vertebra in growing children and can lead to vertebral reshaping after compression fractures. However, bisphosphonates are less effective for preventing long-bone fractures. At the moment, new therapies are under investigation.
SUMMARY
Despite advances in the diagnosis and treatment of osteogenesis imperfecta, more research is needed. Bisphosphonate treatment decreases long-bone fracture rates, but such fractures are still frequent. New antiresorptive and anabolic agents are being investigated but efficacy and safety of these drugs, especially in children, need to be better established before they can be used in clinical practice.
Topics: Child; Child Development; Collagen Type I; Collagen Type I, alpha 1 Chain; Diphosphonates; Fractures, Bone; Humans; Mutation; Osteogenesis Imperfecta; Phenotype
PubMed: 28863000
DOI: 10.1097/MED.0000000000000367 -
Biomolecules Oct 2021Osteogenesis Imperfecta (OI) is a group of connective tissue disorders with a broad range of phenotypes characterized primarily by bone fragility. The prevalence of OI... (Review)
Review
Osteogenesis Imperfecta (OI) is a group of connective tissue disorders with a broad range of phenotypes characterized primarily by bone fragility. The prevalence of OI ranges from about 1:15,000 to 1:20,000 births. Five types of the disease are commonly distinguished, ranging from a mild (type I) to a lethal one (type II). Types III and IV are severe forms allowing survival after the neonatal period, while type V is characterized by a mild to moderate phenotype with calcification of interosseous membranes. In most cases, there is a reduction in the production of normal type I collagen (col I) or the synthesis of abnormal collagen as a result of mutations in col I genes. Moreover, mutations in genes involved in col I synthesis and processing as well as in osteoblast differentiation have been reported. The currently available treatments try to prevent fractures, control symptoms and increase bone mass. Commonly used medications in OI treatment are bisphosphonates, Denosumab, synthetic parathyroid hormone and growth hormone for children therapy. The main disadvantages of these therapies are their relatively weak effectiveness, lack of effects in some patients or cytotoxic side effects. Experimental approaches, particularly those based on stem cell transplantation and genetic engineering, seem to be promising to improve the therapeutic effects of OI.
Topics: Cellular Reprogramming; Endoplasmic Reticulum Stress; Humans; Models, Biological; Osteogenesis Imperfecta; Phenotype; Stem Cell Transplantation
PubMed: 34680126
DOI: 10.3390/biom11101493 -
Lancet (London, England) Apr 2004Osteogenesis imperfecta is a genetic disorder of increased bone fragility, low bone mass, and other connective-tissue manifestations. The most frequently used... (Review)
Review
Osteogenesis imperfecta is a genetic disorder of increased bone fragility, low bone mass, and other connective-tissue manifestations. The most frequently used classification outlines four clinical types, which we have expanded to seven distinct types. In most patients the disorder is caused by mutations in one of the two genes encoding collagen type 1, but in some individuals no such mutations are detectable. The most important therapeutic advance is the introduction of bisphosphonate treatment for moderate to severe forms of osteogenesis imperfecta. However, at present, the best treatment regimen and the long-term outcomes of bisphosphonate therapy are unknown. Although this treatment does not constitute a cure, it is an adjunct to physiotherapy, rehabilitation, and orthopaedic care. Gene-based therapy presently remains in the early stages of preclinical research.
Topics: Bone and Bones; Diphosphonates; Humans; Osteogenesis Imperfecta
PubMed: 15110498
DOI: 10.1016/S0140-6736(04)16051-0 -
Current Osteoporosis Reports Jun 2021The purpose of this review is to precise the indications for intramedullary rodding of long bones in osteogenesis imperfecta, the classic treatment for fractures and... (Review)
Review
PURPOSE OF REVIEW
The purpose of this review is to precise the indications for intramedullary rodding of long bones in osteogenesis imperfecta, the classic treatment for fractures and deformities in this condition.
RECENT FINDINGS
The use of plates and screws alone is not recommended, but its use in conjunction with rodding is becoming more popular as demonstrated in recent literature. The different types of rods are reviewed and their advantages/disadvantages exposed. There is a clear advantage for telescopic rods in terms of incidence of revision surgery but complications are still to be expected. An interdisciplinary approach combining a medical treatment with a surgical correction of deformities as well as a rehabilitation program is the key for success in the treatment of osteogenesis imperfecta children.
Topics: Braces; Child; Child, Preschool; Diphosphonates; Fracture Fixation, Intramedullary; Fractures, Bone; Humans; Infant; Internal Fixators; Osteogenesis Imperfecta; Reoperation
PubMed: 33646506
DOI: 10.1007/s11914-021-00665-z -
American Journal of Medical Genetics.... Jun 2014Recently, the genetic heterogeneity in osteogenesis imperfecta (OI), proposed in 1979 by Sillence et al., has been confirmed with molecular genetic studies. At present,... (Review)
Review
Recently, the genetic heterogeneity in osteogenesis imperfecta (OI), proposed in 1979 by Sillence et al., has been confirmed with molecular genetic studies. At present, 17 genetic causes of OI and closely related disorders have been identified and it is expected that more will follow. Unlike most reviews that have been published in the last decade on the genetic causes and biochemical processes leading to OI, this review focuses on the clinical classification of OI and elaborates on the newly proposed OI classification from 2010, which returned to a descriptive and numerical grouping of five OI syndromic groups. The new OI nomenclature and the pre-and postnatal severity assessment introduced in this review, emphasize the importance of phenotyping in order to diagnose, classify, and assess severity of OI. This will provide patients and their families with insight into the probable course of the disorder and it will allow physicians to evaluate the effect of therapy. A careful clinical description in combination with knowledge of the specific molecular genetic cause is the starting point for development and assessment of therapy in patients with heritable disorders including OI. © 2014 The Authors. American Journal of Medical Genetics Published by Wiley Periodicals, Inc. This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.
Topics: Collagen Type I; Collagen Type I, alpha 1 Chain; Extracellular Matrix Proteins; Fractures, Bone; Humans; Molecular Chaperones; Osteogenesis Imperfecta; Osteoporosis; Phenotype
PubMed: 24715559
DOI: 10.1002/ajmg.a.36545 -
Current Opinion in Pediatrics Feb 2021Osteogenesis imperfecta is a disease with many different causes and clinical presentations. Surgery at a young age is the often required in order to improve the... (Review)
Review
PURPOSE OF REVIEW
Osteogenesis imperfecta is a disease with many different causes and clinical presentations. Surgery at a young age is the often required in order to improve the patients' growth development and quality of life. This manuscript highlights the current approach to treat children with osteogenesis imperfecta. The main purpose of this review is to compare and discuss the latest surgical techniques and procedures.
RECENT FINDINGS
Recent studies have indicated that telescoping intramedullary Faisser-Duval rods are one of the most suitable surgical devices to correct long bone deformities. The design permits elongation with growth and helps reduce the number of revision surgeries compared to previous static devices.
SUMMARY
Osteogenesis imperfecta patients require an interdisciplinary and tailored treatment that involves both medical and surgical components. On the basis of the most recent surgical and medical findings, the authors recommend treating osteogenesis imperfecta patients early with bisphosphonates prior to surgical intervention and then utilizing Faisser-Duval rods in a surgical setting to correct lower extremity deformities and fractures.
Topics: Child; Diphosphonates; Fracture Fixation, Intramedullary; Humans; Osteogenesis Imperfecta; Quality of Life; Reoperation
PubMed: 33278111
DOI: 10.1097/MOP.0000000000000968 -
Pediatric Endocrinology Reviews : PER Jun 2013Osteogenesis imperfecta (OI), an inherited skeletal disorder characterized by low bone mass, bone fragility, and often short stature. The clinical severity varies widely... (Review)
Review
Osteogenesis imperfecta (OI), an inherited skeletal disorder characterized by low bone mass, bone fragility, and often short stature. The clinical severity varies widely from being nearly asymptomatic with a mild predisposition to fractures, normal stature and normal lifespan being to profoundly disabling and even lethal. Extra skeletal manifestations may include blue-grey sclera and dental abnormalities. Initially, the classification of OI into four types was based on clinical findings, but more recently additional types OI (types V-XI) have been ascertained, based on the identification of different mutations. While this classification is somewhat controversial, it is described in this article. The treatment of patients with OI is based on the nature and severity of symptoms. The goal of therapy is to prevent fractures and disability, improve function and quality of life. A multidisciplinary approach is needed, and treatment options include medication such as bisphosphonates, surgery, and rehabilitation. Investigations continue to explore gene and cell therapies that may be developed in the future.
Topics: Fractures, Bone; Humans; Osteogenesis Imperfecta
PubMed: 23858623
DOI: No ID Found