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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 -
Lancet (London, England) Apr 2016Osteogenesis imperfecta is a phenotypically and molecularly heterogeneous group of inherited connective tissue disorders that share similar skeletal abnormalities... (Review)
Review
Osteogenesis imperfecta is a phenotypically and molecularly heterogeneous group of inherited connective tissue disorders that share similar skeletal abnormalities causing bone fragility and deformity. Previously, the disorder was thought to be an autosomal dominant bone dysplasia caused by defects in type I collagen, but in the past 10 years discoveries of novel (mainly recessive) causative genes have lent support to a predominantly collagen-related pathophysiology and have contributed to an improved understanding of normal bone development. Defects in proteins with very different functions, ranging from structural to enzymatic and from intracellular transport to chaperones, have been described in patients with osteogenesis imperfecta. Knowledge of the specific molecular basis of each form of the disorder will advance clinical diagnosis and potentially stimulate targeted therapeutic approaches. In this Seminar, together with diagnosis, management, and treatment, we describe the defects causing osteogenesis imperfecta and their mechanism and interrelations, and classify them into five groups on the basis of the metabolic pathway compromised, specifically those related to collagen synthesis, structure, and processing; post-translational modification; folding and cross-linking; mineralisation; and osteoblast differentiation.
Topics: Bone Density Conservation Agents; Calcification, Physiologic; Cell Differentiation; Collagen Type I; Disease Management; Genetic Predisposition to Disease; Humans; Mutation; Osteoblasts; Osteogenesis; Osteogenesis Imperfecta; Protein Processing, Post-Translational
PubMed: 26542481
DOI: 10.1016/S0140-6736(15)00728-X -
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 -
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 -
European Journal of Human Genetics :... Jul 2019Osteogenesis imperfecta (OI) is a rare genetic disorder of the connective tissue and 90% of cases are due to dominant mutations in COL1A1 and COL1A2 genes. To increase... (Clinical Trial)
Clinical Trial
Osteogenesis imperfecta (OI) is a rare genetic disorder of the connective tissue and 90% of cases are due to dominant mutations in COL1A1 and COL1A2 genes. To increase OI disease knowledge and contribute to patient follow-up management, a homogeneous Italian cohort of 364 subjects affected by OI types I-IV was evaluated. The study population was composed of 262 OI type I, 24 type II, 39 type III, and 39 type IV patients. Three hundred and nine subjects had a type I collagen affecting function mutations (230 in α1(I) and 79 in α2(I)); no disease-causing changes were noticed in 55 patients. Compared with previous genotype-phenotype OI correlation studies, additional observations arose: a new effect for α1- and α2-serine substitutions has been pointed out and heart defects, never considered before, resulted associated to quantitative mutations (P = 0.043). Moreover, some different findings emerged if compared with previous literature; especially, focusing the attention on the lethal form, no association with specific collagen regions was found and most of variants localized in the previously reported "lethal clusters" were causative of OI types I-IV. Some discrepancies have been highlighted also considering the "50-55 nucleotides rule," as well as the relationship between specific collagen I mutated region and the presence of dentinogenesis imperfecta and/or blue sclera. Despite difficulties still present in defining clear rules to predict the clinical outcome in OI patients, this study provides new pieces for completing the puzzle, also thanks to the inclusion of clinical signs never considered before and to the large number of OI Italian patients.
Topics: Adult; Amino Acid Substitution; Child, Preschool; Collagen Type I; Collagen Type I, alpha 1 Chain; Female; Genotype; Humans; Infant; Italy; Male; Mutation, Missense; Osteogenesis Imperfecta; Phenotype; Young Adult
PubMed: 30886339
DOI: 10.1038/s41431-019-0373-x -
The Journal of Clinical Endocrinology... Jun 2023Osteogenesis imperfecta (OI) is a genetic disorder characterized by increased bone fragility largely caused by defects in structure, synthesis, or post-translational... (Review)
Review
CONTEXT
Osteogenesis imperfecta (OI) is a genetic disorder characterized by increased bone fragility largely caused by defects in structure, synthesis, or post-translational processing of type I collagen. The effectiveness of medications used for fracture reduction in adults with OI is understudied and practice recommendations are not well established. Drugs currently used to improve skeletal health in OI were initially developed to treat osteoporosis. Oral and intravenous bisphosphonates have been shown to improve bone mineral density (BMD) in adults with OI and are commonly used; however, conclusive data confirming fracture protection are lacking. Similarly, teriparatide appears to increase BMD, an effect that seems to be limited to individuals with type I OI. The role of denosumab, abaloparatide, romosozumab, and estradiol/testosterone in adult OI have not been systematically studied. Anti-sclerostin agents and transforming growth factor-beta antagonists are under investigation in clinical trials.
OBJECTIVE
This review summarizes current knowledge on pharmacologic treatment options for reducing fracture risk in adults with OI.
METHODS
A PubMed online database search of all study types published in the English language using the terms "osteogenesis imperfecta," "OI," and "brittle bone disease" was performed in June 2022. Articles screened were restricted to adults. Additional sources were identified through manual searches of reference lists.
CONCLUSION
Fracture rates are elevated in adults with OI. Although clinical trial data are limited, bisphosphonates and teriparatide may be useful in improving BMD. Further research is needed to develop medications for adults with OI that will lead to definite fracture rate reduction.
Topics: Adult; Humans; Bone Density Conservation Agents; Osteogenesis Imperfecta; Teriparatide; Fractures, Bone; Diphosphonates; Bone Density; Fracture Fixation
PubMed: 36658750
DOI: 10.1210/clinem/dgad035 -
Current Osteoporosis Reports Dec 2023This review aims to provide a review of the multidisciplinary management of infants with osteogenesis imperfecta (OI) during the first year of life, focusing on those... (Review)
Review
PURPOSE OF REVIEW
This review aims to provide a review of the multidisciplinary management of infants with osteogenesis imperfecta (OI) during the first year of life, focusing on those with severe disease. The authors draw on published literature and direct experience of working in a large paediatric centre specialising in the management of rare bone disease.
RECENT FINDINGS
Whilst understanding of the pathophysiology of OI has grown over the past decade, the evidence base for management of infants remains limited. There has been a greater recognition of certain subjects of concern including pain management, cervical spine deformity, and neurocognitive development. Both international consensus guidelines on rehabilitation and disease-specific growth charts have been welcomed by clinical teams. The early involvement of multidisciplinary specialist care is critical in ensuring optimal care for the infant with severe OI. A long-term perspective which focuses on the axial, craniofacial, and peripheral skeleton as well as on development more generally provides a framework which can guide the management of infants with severe OI.
Topics: Child; Infant; Humans; Osteogenesis Imperfecta; Diphosphonates; Bone and Bones
PubMed: 37752354
DOI: 10.1007/s11914-023-00823-5 -
Matrix Biology : Journal of the... Oct 2018Osteogenesis imperfecta, or brittle bone disease, is a congenital disease that primarily causes low bone mass and bone fractures but it can negatively affect other... (Review)
Review
Osteogenesis imperfecta, or brittle bone disease, is a congenital disease that primarily causes low bone mass and bone fractures but it can negatively affect other organs. It is usually inherited in an autosomal dominant fashion, although rarer recessive and X-chromosome-linked forms of the disease have been identified. In addition to type I collagen, mutations in a number of other genes, often involved in type I collagen synthesis or in the differentiation and function of osteoblasts, have been identified in the last several years. Seldom, the study of a rare disease has delivered such a wealth of new information that have helped our understanding of multiple processes involved in collagen synthesis and bone formation. In this short review I will describe the clinical features and the molecular genetics of the disease, but then focus on how OI dysregulates all aspects of extracellular matrix biology. I will conclude with a discussion about OI therapeutics.
Topics: Collagen Type I; Extracellular Matrix; Genetic Predisposition to Disease; Humans; Metabolic Networks and Pathways; Molecular Targeted Therapy; Mutation; Osteogenesis Imperfecta
PubMed: 29540309
DOI: 10.1016/j.matbio.2018.03.010