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Calcified Tissue International Jun 2024Osteogenesis imperfecta (OI) is a Mendelian connective tissue disorder associated with increased bone fragility and other clinical manifestations most commonly due to... (Review)
Review
Osteogenesis imperfecta (OI) is a Mendelian connective tissue disorder associated with increased bone fragility and other clinical manifestations most commonly due to abnormalities in production, structure, or post-translational modification of type I collagen. Until recently, most research in OI has focused on the pediatric population and much less attention has been directed at the effects of OI in the adult population. This is a narrative review of the literature focusing on the skeletal as well as non-skeletal manifestations in adults with OI that may affect the aging individual. We found evidence to suggest that OI is a systemic disease which involves not only the skeleton, but also the cardiopulmonary and gastrointestinal system, soft tissues, tendons, muscle, and joints, hearing, eyesight, dental health, and women's health in OI and potentially adds negative affect to health-related quality of life. We aim to guide clinicians as well as draw attention to obvious knowledge gaps and the need for further research in adult OI.
PubMed: 38836890
DOI: 10.1007/s00223-024-01236-x -
BMJ Open Jun 2024Severe osteogenesis imperfecta (OI) is a debilitating disease with no cure or sufficiently effective treatment. Mesenchymal stem cells (MSCs) have good safety profile,...
An exploratory open-label multicentre phase I/II trial evaluating the safety and efficacy of postnatal or prenatal and postnatal administration of allogeneic expanded fetal mesenchymal stem cells for the treatment of severe osteogenesis imperfecta in infants and fetuses: the BOOSTB4 trial protocol.
INTRODUCTION
Severe osteogenesis imperfecta (OI) is a debilitating disease with no cure or sufficiently effective treatment. Mesenchymal stem cells (MSCs) have good safety profile, show promising effects and can form bone. The Boost Brittle Bones Before Birth (BOOSTB4) trial evaluates administration of allogeneic expanded human first trimester fetal liver MSCs (BOOST cells) for OI type 3 or severe type 4.
METHODS AND ANALYSIS
BOOSTB4 is an exploratory, open-label, multiple dose, phase I/II clinical trial evaluating safety and efficacy of postnatal (n=15) or prenatal and postnatal (n=3, originally n=15) administration of BOOST cells for the treatment of severe OI compared with a combination of historical (1-5/subject) and untreated prospective controls (≤30). Infants<18 months of age (originally<12 months) and singleton pregnant women whose fetus has severe OI with confirmed glycine substitution in or can be included in the trial.Each subject receives four intravenous doses of 3×10/kg BOOST cells at 4 month intervals, with 48 (doses 1-2) or 24 (doses 3-4) hours in-patient follow-up, primary follow-up at 6 and 12 months after the last dose and long-term follow-up yearly until 10 years after the first dose. Prenatal subjects receive the first dose via ultrasound-guided injection into the umbilical vein within the fetal liver (16+0 to 35+6 weeks), and three doses postnatally.The primary outcome measures are safety and tolerability of repeated BOOST cell administration. The secondary outcome measures are number of fractures from baseline to primary and long-term follow-up, growth, change in bone mineral density, clinical OI status and biochemical bone turnover.
ETHICS AND DISSEMINATION
The trial is approved by Competent Authorities in Sweden, the UK and the Netherlands (postnatal only). Results from the trial will be disseminated via CTIS, ClinicalTrials.gov and in scientific open-access scientific journals.
TRIAL REGISTRATION NUMBERS
EudraCT 2015-003699-60, EUCT: 2023-504593-38-00, NCT03706482.
Topics: Humans; Osteogenesis Imperfecta; Female; Pregnancy; Mesenchymal Stem Cell Transplantation; Infant; Clinical Trials, Phase I as Topic; Multicenter Studies as Topic; Infant, Newborn; Clinical Trials, Phase II as Topic; Mesenchymal Stem Cells; Treatment Outcome; Male; Fetal Stem Cells
PubMed: 38834319
DOI: 10.1136/bmjopen-2023-079767 -
European Journal of Medical Genetics Dec 2023knowledge on the natural history of rare diseases is necessary to improve outcomes. Disease registries may play a key role in covering these unmet needs in the rare bone...
BACKGROUND
knowledge on the natural history of rare diseases is necessary to improve outcomes. Disease registries may play a key role in covering these unmet needs in the rare bone and mineral community.
OBJECTIVE
to map existing bone and mineral conditions registries in Europe and their characteristics.
METHODS
online survey about the use of registries/databases and their characteristics. This survey was disseminated among members of the European Reference Network on Rare Bone Diseases (ERN BOND) and non-ERN experts in the field of bone and mineral conditions as well as patient organisations.
RESULTS
sixty-three responses from health care providers (HCPs) and 10 responses from patient groups (PGs) were collected. The response rate for ERN BOND members was 55%. Of 63 HCPs, 37 declared using a registry. Osteogenesis imperfecta (OI) was the most registered condition. We mapped 3 international registries, all were disease-specific.
CONCLUSIONS
There is a need for developing a common high-quality platform for registering rare bone and mineral conditions.
Topics: Humans; Registries; Europe; Rare Diseases; Databases, Factual; Bone Diseases; Data Collection; Osteogenesis Imperfecta
PubMed: 38832910
DOI: 10.1016/j.ejmg.2023.104868 -
Orphanet Journal of Rare Diseases Jun 2024The IMPACT survey aimed to elucidate the humanistic, clinical and economic burden of osteogenesis imperfecta (OI) on individuals with OI, their families, caregivers and...
BACKGROUND
The IMPACT survey aimed to elucidate the humanistic, clinical and economic burden of osteogenesis imperfecta (OI) on individuals with OI, their families, caregivers and wider society. Research methodology, demographics and initial insights from the survey have been previously reported. The cost of illness (healthcare resource use, productivity loss, out-of-pocket spending) and drivers of the economic impact of OI are reported here.
METHODS
IMPACT was an international mixed-methods online survey in eight languages (fielded July-September 2021) targeting adults (aged ≥ 18 years) or adolescents (aged ≥ 12-17 years) with OI, caregivers with or without OI and other close relatives. Survey domains included demographics, socioeconomic factors, clinical characteristics, treatment patterns, quality of life and health economics. The health economic domain for adults, which included questions on healthcare resource use, productivity loss and out-of-pocket spending, was summarised. Regression and pairwise analyses were conducted to identify independent drivers and associations with respondent characteristics.
RESULTS
Overall, 1,440 adults with OI responded to the survey. Respondents were mostly female (70%) and from Europe (63%) with a median age of 43 years. Within a 12-month period, adults with OI reported visiting a wide range of healthcare professionals. Two-thirds (66%) of adults visited a hospital, and one-third (33%) visited the emergency department. The mean total number of diagnostic tests undergone by adults within these 12 months was 8.0. Adults had undergone a mean total of 11.8 surgeries up to the time point of the survey. The proportions of adults using queried consumables or services over 12 months ranged from 18-82%, depending on the type of consumable or service. Most adults (58%) were in paid employment, of which nearly one-third (29%) reported missing a workday. Of the queried expenses, the mean total out-of-pocket spending in 4 weeks was €191. Respondent characteristics such as female sex, more severe self-reported OI and the experience of fractures were often associated with increased economic burden.
CONCLUSION
IMPACT provides novel insights into the substantial cost of illness associated with OI on individuals, healthcare systems and society at large. Future analyses will provide insights into country-specific economic impact, humanistic impact and the healthcare journey of individuals with OI.
Topics: Humans; Osteogenesis Imperfecta; Adult; Female; Male; Surveys and Questionnaires; Cost of Illness; Adolescent; Middle Aged; Young Adult; Quality of Life; Child; Health Expenditures
PubMed: 38831282
DOI: 10.1186/s13023-024-03218-6 -
Journal of Clinical Research in... Jun 2024Osteogenesis imperfecta (OI) is a group of phenotypically and genetically heterogeneous connective tissue disorders that share similar skeletal anomalies causing bone...
INTRODUCTION
Osteogenesis imperfecta (OI) is a group of phenotypically and genetically heterogeneous connective tissue disorders that share similar skeletal anomalies causing bone fragility and deformation. This study aimed to investigate the molecular genetic etiology and determine the relationship between genotype and phenotype in OI patients with targeted next-generation sequencing (NGS).
METHOD
In patients with OI, a targeted NGS analysis panel (Illumina TruSight One) containing genes involved in collagen/bone synthesis was performed on the Illumina Nextseq550 platform.
RESULTS
Fifty-six patients (female/male: 25/31) from 46 different families were enrolled in the study. Consanguinity between parents was noted in 15 (32.6%) families. Clinically according to Sillence classification; 18(33.1%) patients were considered to type I, 1(1.7%) type II, 26(46.4%) type III and 11(19.6%) type IV. Median body weight was -1.1 (-6.8, - 2.5) SDS, and height was -2.3 (-7.6, - 1.2) SDS. Bone deformity was detected in 30 (53.5%) of the patients, while 31 (55.4%) were evaluated as mobile. Thirty-six (60.7%) patients had blue sclera, 13 (23.2%) had scoliosis, 12 (21.4%) had dentinogenesis imperfecta (DI), and 2 (3.6%) had hearing loss. Disease-causing variants in COL1A1 and COL1A2 genes were found in 24 (52.1%) and 6 (13%) families, respectively. In 8 (17.3%) of the remaining 16 (34.7%) families, the NGS panel revealed disease-causing variants in three different genes (FKBP10, SERPINF1, and P3H1). Nine (23.6%) of the variants detected in all investigated genes were not previously reported in the literature and were classified to be pathogenic according to ACMG guidelines pathogenity scores. In ten (21.7%) families, a disease-related variant was not found in a total of 13 OI genes included in the panel.
CONCLUSION
Genetic etiology was found in 38 (82.6%) of 46 families by targeted NGS analysis. In addition, 9 new variants were assessed in known OI genes which is a significant contribution to the literature.
PubMed: 38828893
DOI: 10.4274/jcrpe.galenos.2024.2022-12-8 -
Archives of Disease in Childhood May 2024Zoledronic acid (ZA), used for treatment of children with osteoporosis, can cause acute phase reaction (APR) following the first infusion. Many institutions have a...
INTRODUCTION
Zoledronic acid (ZA), used for treatment of children with osteoporosis, can cause acute phase reaction (APR) following the first infusion. Many institutions have a policy to admit and monitor all children for their first ZA infusion.
OBJECTIVE
To determine if the APR with the first ZA dose warrants hospital-level care and evaluate if its severity correlates with the underlying condition.
DESIGN
Retrospective cross-sectional analysis.
SETTINGS
Two tertiary centres across the UK that run paediatric metabolic bone disease services.
PATIENTS
Children who received first ZA infusion as inpatients at these centres.
INTERVENTIONS
Nil.
MAIN OUTCOME MEASURES
The Paediatric Early Warning Score (PEWS) and length of hospital stay to assess the severity of APR.
RESULTS
107 patients were included. Peak PEWS≤3 was found in 85% of children. 83% required admission for <24 hours. The various patient populations (osteogenesis imperfecta (OI), immobility-induced osteoporosis, idiopathic juvenile osteoporosis, systemic inflammatory disorders and steroid-induced osteoporosis, Duchenne muscular dystrophy (DMD)) did not differ significantly in the mean peak PEWS and the length of hospital stay. However, when compared directly, the group with DMD and that with systemic inflammatory disorders and steroid-induced osteoporosis differed significantly in the mean peak PEWS (p=0.011) and the length of hospital stay (p=0.048), respectively, as compared with the OI group.
CONCLUSION
Most patients had a mild APR not requiring overnight hospital admission, after their first ZA dose. However, certain groups seem to suffer more severe APR and may warrant consideration of inpatient monitoring with the first infusion.
PubMed: 38821713
DOI: 10.1136/archdischild-2023-326287 -
Osteogenesis imperfecta type 10 and the cellular scaffolds underlying common immunological diseases.Genes and Immunity May 2024Osteogenesis imperfecta type 10 (OI10) is caused by loss of function codon variants in the gene SERPINH1 that encodes heat shock protein 47 (HSP47), rather than in a... (Review)
Review
Osteogenesis imperfecta type 10 (OI10) is caused by loss of function codon variants in the gene SERPINH1 that encodes heat shock protein 47 (HSP47), rather than in a gene specifying bone formation. The HSP47 variants disrupt the folding of both collagen and the endonuclease IRE1α (inositol-requiring enzyme 1α) that splices X-Box Binding Protein 1 (XBP1) mRNA. Besides impairing bone development, variants likely affect osteoclast differentiation. Three distinct biochemical scaffold play key roles in the differentiation and regulated cell death of osteoclasts. These scaffolds consist of non-templated protein modifications, ordered lipid arrays, and protein filaments. The scaffold components are specified genetically, but assemble in response to extracellular perturbagens, pathogens, and left-handed Z-RNA helices encoded genomically by flipons. The outcomes depend on interactions between RIPK1, RIPK3, TRIF, and ZBP1 through short interaction motifs called RHIMs. The causal HSP47 nonsynonymous substitutions occur in a novel variant leucine repeat region (vLRR) that are distantly related to RHIMs. Other vLRR protein variants are causal for a variety of different mendelian diseases. The same scaffolds that drive mendelian pathology are associated with many other complex disease outcomes. Their assembly is triggered dynamically by flipons and other context-specific switches rather than by causal, mendelian, codon variants.
PubMed: 38811682
DOI: 10.1038/s41435-024-00277-4 -
Medical Science Monitor : International... May 2024BACKGROUND This retrospective study aimed to evaluate the presentation, diagnosis, management, and outcomes of 27 patients diagnosed with osteogenesis imperfecta at a...
BACKGROUND This retrospective study aimed to evaluate the presentation, diagnosis, management, and outcomes of 27 patients diagnosed with osteogenesis imperfecta at a single center in Türkiye between January 2011 and January 2020. MATERIAL AND METHODS We analyzed data from the medical records of 27 patients with osteogenesis imperfecta admitted to Çukurova University Faculty of Medicine, Department of Orthopedics and Traumatology, between January 2011 and January 2020. The data included the clinical examination notes of the cases classified according to the Sillence and Shapiro systems, age, sex, parental consanguinity, genetic analysis (DNA isolation) results, the number and localization of past fractures, treatment methods, complications, hypermobility, and ambulation scoring. RESULTS The mean age of the patients (n=13 male, n=14 female) was 10.4±7.4 years, ranging from 3 to 39 years. Almost half (n=15, 55.6%) had consanguineous parents. The patients had 131 fractures during the 9 years between January 2011 and January 2020, with the femur being the most commonly fractured bone; 13 patients (48.15%) received surgical and conservative treatments, while the remaining 14 underwent only conservative treatments. The results revealed a strong association between the number of fractures and the types of genetic mutations (P=0.004). CONCLUSIONS Study findings indicate that the type of genetic mutation was not significantly correlated with the risk of treatment complications in osteogenesis imperfecta cases. Nevertheless, the study reveals a noteworthy association between the type of mutation and the number of surgeries required. Specifically, patients with the COL1A1 mutation needed more surgeries.
Topics: Humans; Osteogenesis Imperfecta; Male; Female; Retrospective Studies; Child; Child, Preschool; Adult; Adolescent; Young Adult; Fractures, Bone; Collagen Type I; Collagen Type I, alpha 1 Chain; Treatment Outcome; Consanguinity; Mutation
PubMed: 38807347
DOI: 10.12659/MSM.944364 -
Cureus Apr 2024Osteogenesis imperfecta (OI) is a rare skeletal disorder that increases a patient's susceptibility to bone fracture. One complication commonly associated with fractures...
Osteogenesis imperfecta (OI) is a rare skeletal disorder that increases a patient's susceptibility to bone fracture. One complication commonly associated with fractures in this population is the occurrence of non-union leading to pseudoarthrosis. In this case series, three cases of non-union of the distal humerus leading to pseudoarthrosis in the pediatric OI population are presented. One case presents a successful attempt at treatment, one case presents a failed attempt at treatment, and the third case presents a patient's refusal to get treated. Furthermore, a literature review highlighting other institutions' attempts, successes, and failures at treating this clinical entity is presented. Combining the data retrieved from our institution and others, this review demonstrates that there is currently no standard for treating these patients. Additionally, based on the small case series and literature review presented in this article, definitive guidelines for the treatment of pseudoarthrosis of the distal humerus in pediatric OI patients cannot be outlined. However, our findings suggest that both non-surgical and surgical treatments could be viable options for patients with asymptomatic pseudoarthrosis of the distal humerus.
PubMed: 38800212
DOI: 10.7759/cureus.58991 -
Morphologie : Bulletin de L'Association... May 2024In addition to bone fragility, patients with osteogenesis imperfecta (OI) type III have typical craniofacial abnormalities, such as a triangular face and maxillary...
OBJECTIVES
In addition to bone fragility, patients with osteogenesis imperfecta (OI) type III have typical craniofacial abnormalities, such as a triangular face and maxillary micrognathism. However, in the osteogenesis imperfecta mouse (oim), a validated model of OI type III, few descriptions exist of craniofacial phenotype. Treatment of OI mostly consists of bisphosphonate administration. Cathepsin K inhibition has been tested as a promising therapeutic approach for osteoporosis and positive results were observed in long bones of cathepsin K knocked out oim (oim/CatK). This craniometry study aimed to highlight the craniofacial characteristics of oim and Cathepsin K KO mouse.
MATERIALS AND METHODS
We analyzed the craniofacial skeleton of 51 mice distributed in 4 genotype groups: Wt (control), oim, CatK, oim/CatK. The mice were euthanized at 13 weeks and their heads were analyzed using densitometric (pQCT), X-ray cephalometric, and histomorphometric methods.
RESULTS
The craniofacial skeleton of the oim mouse is frailer than the Wt one, with a reduced thickness and mineral density of the cranial vault and mandibular ramus. Different cephalometric data attest a dysmorphism similar to the one observed in humans with OI type III. Those abnormalities were not improved in the oim/CatK group.
CONCLUSION
These results suggest that oim mouse could serve as a complete model of the human OI type III, including the craniofacial skeleton. They also suggest that invalidation of cathepsin K has no impact on the craniofacial abnormalities of the oim model.
PubMed: 38788496
DOI: 10.1016/j.morpho.2024.100785