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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 -
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 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 -
Nature Reviews. Disease Primers Aug 2017Skeletal deformity and bone fragility are the hallmarks of the brittle bone dysplasia osteogenesis imperfecta. The diagnosis of osteogenesis imperfecta usually depends... (Review)
Review
Skeletal deformity and bone fragility are the hallmarks of the brittle bone dysplasia osteogenesis imperfecta. The diagnosis of osteogenesis imperfecta usually depends on family history and clinical presentation characterized by a fracture (or fractures) during the prenatal period, at birth or in early childhood; genetic tests can confirm diagnosis. Osteogenesis imperfecta is caused by dominant autosomal mutations in the type I collagen coding genes (COL1A1 and COL1A2) in about 85% of individuals, affecting collagen quantity or structure. In the past decade, (mostly) recessive, dominant and X-linked defects in a wide variety of genes encoding proteins involved in type I collagen synthesis, processing, secretion and post-translational modification, as well as in proteins that regulate the differentiation and activity of bone-forming cells have been shown to cause osteogenesis imperfecta. The large number of causative genes has complicated the classic classification of the disease, and although a new genetic classification system is widely used, it is still debated. Phenotypic manifestations in many organs, in addition to bone, are reported, such as abnormalities in the cardiovascular and pulmonary systems, skin fragility, muscle weakness, hearing loss and dentinogenesis imperfecta. Management involves surgical and medical treatment of skeletal abnormalities, and treatment of other complications. More innovative approaches based on gene and cell therapy, and signalling pathway alterations, are under investigation.
Topics: Bone and Bones; Child, Preschool; Collagen; Collagen Type I; Fractures, Bone; Genetic Predisposition to Disease; Genetic Testing; Humans; Infant; Infant, Newborn; Mutation; Osteogenesis; Osteogenesis Imperfecta; Protein Processing, Post-Translational
PubMed: 28820180
DOI: 10.1038/nrdp.2017.52 -
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 -
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 -
Delaware Medical Journal Jun 2016
Topics: Humans; Osteogenesis Imperfecta
PubMed: 27506061
DOI: No ID Found -
International Journal of Molecular... May 2023Vitamin D affects several body functions, and thus general health, due to its pleiotropic activity. It plays a key role in bone metabolism, and its deficiency impacts... (Review)
Review
Vitamin D affects several body functions, and thus general health, due to its pleiotropic activity. It plays a key role in bone metabolism, and its deficiency impacts bone development, leading to bone fragility. In osteogenesis imperfecta (OI), a group of hereditary connective tissue disorders characterized by bone fragility, additional factors, such as vitamin D deficiency, can affect the expression of the phenotype and aggravate the disorder. The aim of this scoping review was to assess the incidence of vitamin D deficit in OI patients and the association between vitamin D status and supplementation in individuals affected by OI. We searched the PubMed Central and Embase databases and included studies published between January/2000 and October/2022 evaluating vitamin D measurement and status (normal, insufficiency, deficiency) and supplementation for OI. A total of 263 articles were identified, of which 45 were screened by title and abstract, and 10 were included after a full-text review. The review showed that low levels of vitamin D was a frequent finding in OI patients. Vitamin D supplementation was mainly indicated along with drug therapy and calcium intake. Even if widely used in clinical practice, vitamin D supplementation for OI individuals still needs a better characterization and harmonized frame for its use in the clinical setting, as well as further studies focusing on its effect on bone fragility.
Topics: Humans; Vitamin D; Osteogenesis Imperfecta; Vitamins; Vitamin D Deficiency; Phenotype
PubMed: 37298368
DOI: 10.3390/ijms24119416