A Retrospective Study of the Presentation, Diagnosis, Management, and Outcomes of 27 Patients with Osteogenesis Imperfecta at a Single Center in Türkiye.

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.

Project SATURN- a real-world evidence data collaboration with existing European datasets in Osteogenesis Imperfecta to support future therapies.

Regulatory marketing authorisation is not enough to ensure patient access to new medicinal products. Health Technology Assessment bodies may require data on effectiveness, relative effectiveness, and cost-effectiveness. Healthcare systems may require data on clinical utility, savings, and budget impact. Furthermore, the exact requirements of these bodies vary country by country and sometimes even region to region, resulting in a patchwork of different data requirements to achieve effective, reimbursed patient access to new therapies. In addition, clinicians require data to make informed clinical management decisions. This requirement is of key importance in rare diseases where there is often limited data and clinical experience at the time of regulatory approval.This paper describes an innovative initiative that is called Project SATURN: Systematic Accumulation of Treatment practices and Utilization, Real world evidence, and Natural history data for the rare disease Osteogenesis Imperfecta. The objective of this project is to generate a common core dataset by utilising existing data sources to meet the needs of the various stakeholders and avoiding fragmentation through multiple approaches (e.g., a series of individual national requests/approaches, and unconnected with the regulators' potential requirements). It is expected that such an approach will reduce the time for patient access to life-changing medications. Whilst Project SATURN applies to Osteogenesis Imperfecta, it is anticipated that the principles could also be applied to other rare diseases and reduce the time for patient access to new medications.

A recurrent de novo missense mutation in COL1A1 causes osteogenesis imperfecta type II and preterm delivery in Normande cattle.

BACKGROUND: Nine male and eight female calves born to a Normande artificial insemination bull named "Ly" were referred to the French National Observatory of Bovine Abnormalities for multiple fractures, shortened gestation, and stillbirth or perinatal mortality. RESULTS: Using Illumina BovineSNP50 array genotypes from affected calves and 84 half-sib controls, the associated locus was mapped to a 6.5-Mb interval on chromosome 19, assuming autosomal inheritance with germline mosaicism. Subsequent comparison of the whole-genome sequences of one case and 5116 control genomes, followed by genotyping in the affected pedigree, identified a de novo missense substitution within the NC1 domain of the COL1A1 gene (Chr19 g.36,473,965G > A; p.D1412N) as unique candidate variant. Interestingly, the affected residue was completely conserved among 243 vertebrate orthologs, and the same substitution in humans has been reported to cause type II osteogenesis imperfecta (OI), a connective tissue disorder that is characterized primarily by bone deformity and fragility. Moreover, three COL1A1 mutations have been described to cause the same syndrome in cattle. Necropsy, computed tomography, radiology, and histology confirmed the diagnosis of type II OI, further supporting the causality of this variant. In addition, a detailed analysis of gestation length and perinatal mortality in 1387 offspring of Ly and more than 160,000 progeny of 63 control bulls allowed us to statistically confirm in a large pedigree the association between type II OI and preterm delivery, which is probably due to premature rupture of fetal membranes and has been reported in several isolated cases of type II OI in humans and cattle. Finally, analysis of perinatal mortality rates and segregation distortion supported a low level of germ cell mosaicism in Ly, with an estimate of 4.5% to 7.7% of mutant sperm and thus 63 to 107 affected calves born. These numbers contrast with the 17 cases reported and raise concerns about the underreporting of congenital defects to heredo-surveillance platforms, even for textbook genetic syndromes. CONCLUSIONS: In conclusion, we describe a large animal model for a recurrent substitution in COL1A1 that is responsible for type II OI in humans. More generally, this study highlights the utility of such datasets and large half-sib families available in livestock species to characterize sporadic genetic defects.

Dickkopf-1 (DKK1) blockade mitigates osteogenesis imperfecta (OI) related bone disease.

BACKGROUND: The current treatment of osteogenesis imperfecta (OI) is imperfect. Our study thus delves into the potential of using Dickkopf-1 antisense (DKK1-AS) to treat OI. METHODS: We analysed serum DKK1 levels and their correlation with lumbar spine and hip T-scores in OI patients. Comparative analyses were conducted involving bone marrow stromal cells (BMSCs) and bone tissues from wild-type mice, untreated OI mice, and OI mice treated with DKK1-ASor DKK1-sense (DKK1-S). RESULTS: Significant inverse correlations were noted between serum DKK1 levels and lumbar spine (correlation coefficient = - 0.679, p = 0.043) as well as hip T-scores (correlation coefficient = - 0.689, p = 0.042) in OI patients. DKK1-AS improved bone mineral density (p = 0.002), trabecular bone volume/total volume fraction (p < 0.001), trabecular separation (p = 0.010), trabecular thickness (p = 0.001), trabecular number (p < 0.001), and cortical thickness (p < 0.001) in OI mice. DKK1-AS enhanced the transcription of collagen 1α1, osteocalcin, runx2, and osterix in BMSC from OI mice (all p < 0.001), resulting in a higher von Kossa-stained matrix area (p < 0.001) in ex vivo osteogenesis assays. DKK1-AS also reduced osteoclast numbers (p < 0.001), increased ß-catenin and T-cell factor 4 immunostaining reactivity (both p < 0.001), enhanced mineral apposition rate and bone formation rate per bone surface (both p < 0.001), and decreased osteoclast area (p < 0.001) in OI mice. DKK1-AS upregulated osteoprotegerin and downregulated nuclear factor-kappa B ligand transcription (both p < 0.001). Bone tissues from OI mice treated with DKK1-AS exhibited significantly higher breaking force compared to untreated OI mice (p < 0.001). CONCLUSIONS: Our study elucidates that DKK1-AS has the capability to enhance bone mechanical properties, restore the transcription of osteogenic genes, promote osteogenesis, and inhibit osteoclastogenesis in OI mice.

'BLUES' procedure for assessing the blue level of the sclera in Osteogenesis Imperfecta.

PURPOSE: Blue sclera is a characteristic and common clinical sign of Osteogenesis Imperfecta (OI). However, there is currently no widely accepted, objective method for assessing and grading blue sclera in individuals with OI. To address this medical need, this study is aimed to design and validate a new method called 'BLUES' (BLUe Eye Sclera) to objectively identify and quantify the blue color in the sclera of patients affected by OI. METHODS: Sixty-two patients affected by OI and 35 healthy controls were enrolled in the present prospective study, for a total of 194 eyes analyzed. In the 'BLUES' procedure, eye images from patients with OI and control subjects were analyzed to assess and grade the blue level of the sclera using Adobe Photoshop Software. The validation process then involved comparing the results obtained with the 'BLUES' procedure to the judgement of experienced ophthalmologists (JEO). A receiver-operating characteristic (ROC) curve analysis was used to examine the overall discriminatory power. The sensitivity and specificity levels and the Cohen's Kappa (K) indexes of 'BLUES' and 'JEO' were estimated versus the standard OI diagnosis. The K indexes of 'BLUES' versus 'JEO' were also evaluated. RESULTS: The optimal cut-off point of the scleral blue peak was calculated at 17%. Our findings demonstrated a sensitivity of 89% (CI95%: 0.835-0.945) and specificity of 87% (CI95%: 0.791-0.949) for the 'BLUES' procedure with an agreement versus the diagnosis of OI of 0.747. In comparison, the sensitivity and specificity of 'JEO' ranged from 89 to 94% and 77% to 100%, respectively, with an agreement ranging from 0.663 to 0.871 with the diagnosis of OI. The agreement between 'BLUES 'and 'JEO' evaluations ranged from 0.613 to 0.734. CONCLUSIONS: Our findings demonstrated an 89% sensitivity and an impressive 87% specificity of our method to analyze the blue sclera in OI. The results indicated high agreement with disease diagnosis and were consistent with evaluations by experienced ophthalmologists. The 'BLUES' procedure appears to be a simple, reliable and objective method for effectively identify and quantify the blue color of the sclera in OI.

Unraveling the genetic collagen connection: clinical and therapeutic insights on genetic connective tissue disorders.

Hereditary connective tissue disorders include more than 200 conditions affecting different organs and tissues, compromising the biological role of the extracellular matrix through interference in the synthesis, development, or secretion of collagen and/or its associated proteins. The clinical phenotype includes multiple signs and symptoms, usually nonspecific but of interest to rheumatologists because of musculoskeletal involvement. The patient´s journey to diagnosis is long, and physicians should include these disorders in their differential diagnoses of diseases with systemic involvement. In this review, insights for the diagnosis and treatment of osteogenesis imperfecta, hypermobility spectrum disorder/Ehlers-Danlos syndrome, Marfan, Loeys-Dietz, and Stickler syndromes are presented.

Combining anabolic loading and raloxifene improves bone quantity and some quality measures in a mouse model of osteogenesis imperfecta.

Osteogenesis imperfecta (OI) increases fracture risk due to changes in bone quantity and quality caused by mutations in collagen and its processing proteins. Current therapeutics improve bone quantity, but do not treat the underlying quality deficiencies. Male and female G610C+/- mice, a murine model of OI, were treated with a combination of raloxifene and in vivo axial tibial compressive loading starting at 10 weeks of age and continuing for 6 weeks to improve bone quantity and quality. Bone geometry and mechanical properties were measured to determine whole bone and tissue-level material properties. A colocalized Raman/nanoindentation system was used to measure chemical composition and nanomechanical properties in newly formed bone compared to old bone to determine if bone formed during the treatment regimen differed in quality compared to bone formed prior to treatment. Lastly, lacunar geometry and osteocyte apoptosis were assessed. OI mice were able to build bone in response to the loading, but this response was less robust than in control mice. Raloxifene improved some bone material properties in female but not male OI mice. Raloxifene did not alter nanomechanical properties, but loading did. Lacunar geometry was largely unchanged with raloxifene and loading. However, osteocyte apoptosis was increased with loading in raloxifene treated female mice. Overall, combination treatment with raloxifene and loading resulted in positive but subtle changes to bone quality.

Home care needs assessment among caregivers of children and adolescents with osteogenesis imperfecta: a cross-sectional study.

BACKGROUND: Children and adolescents with complex medical issues need home care services; however, few studies have provided insight into the unmet home care needs of the families of patients with osteogenesis imperfecta (OI). In this study, we aimed to assess the home care needs of caregivers of children and adolescents with OI and the associated factors. METHODS: A self-administered questionnaire was administered online to 142 caregivers of patients with OI aged 3-17 years between May and October 2022 from 25 provinces in China. The questionnaire comprised 15 questions on demographic variables and 14 questions on home care needs. Chi-square analysis was used to compare group differences for categorical variables. Multivariate binary logistic regression analysis was conducted to examine predictors of caregivers' home care needs. RESULTS: The study findings indicated that 81.5% of caregivers had high home care needs. The three leading types of home care needs were helping the child carry out physical fitness recovery exercises at home (72.5%), understanding precautions regarding treatment drugs (72.5%), and relieving the child's pain (70.4%). OI patients' poor self-care ability (adjusted odds ratio = 5.9, 95% confidence interval = 1.8-19.0) was related to caregivers' high level of home care needs. CONCLUSIONS: The findings of this study suggest that future scientific research and nursing guidance should focus on OI patients' physical training, medication management, pain relief, fracture prevention, and treatment. In addition, caregivers of patients with poor self-care ability should receive special attention in the development of interventions. This study can help with addressing the unmet home care needs of caregivers of children and adolescents with OI. It is vital to develop a personalized intervention plan based on patients' self-care ability.

Otic Capsule Demineralization and Hearing Outcome of Stapes Surgery for Osteogenesis Imperfecta in Comparison With Otosclerosis.

OBJECTIVE: To assess the location/number of otic capsule demineralization and hearing outcomes of stapes surgery (SS) for osteogenesis imperfecta (OI) compared with otosclerosis (OS). PATIENTS: This study included 11 and 181 consecutive ears from 6 and 152 patients with OI and OS, respectively. INTERVENTIONS: Demineralization loci observed as hypodense area of the otic capsule were examined using high-resolution computed tomography. All patients underwent SS. MAIN OUTCOME MEASURES: Locations of the hypodense areas were classified into the anterior oval window, anterior internal auditory canal, and pericochlear area. The location/number of hypodense areas and preoperative/postoperative hearing parameters were correlated. Postoperative hearing outcome was evaluated 12 months after surgery. RESULTS: Hypodense area was more frequently observed in OI (9 of 11 ears [81.8%]) than in OS (96 of 181 ears [53.0%]), with significant differences. Multiple sites were involved in 81.8% OI and 18.8% OS patients, showing significant differences. Preoperative air conduction (AC), bone conduction, and air-bone gap (ABG) were 48.9 ± 17.8, 28.0 ± 11.3, and 20.7 ± 8.4 dB, respectively, in OI and 56.2 ± 13.5, 30.5 ± 9.9, and 26.4 ± 9.7 dB, respectively, in OS, demonstrating greater AC and ABG in OS than in OI. Postoperative AC (31.3 ± 20.5 dB), ABG (10.6 ± 10.0 dB), and closure of ABG (12.1 ± 4.7 dB), that is, preoperative ABG minus postoperative ABG of OI, were comparable to those of OS (AC, 30.9 ± 13.3 dB; ABG, 7.0 ± 7.4 dB; closure of ABG, 20.1 ± 11.6 dB). CONCLUSION: OI ears showed more severe demineralization of otic capsule than OS ears. However, favorable hearing outcomes could be obtained through SS for OI and OS ears.

Echocardiographic abnormalities and joint hypermobility in Chinese patients with Osteogenesis imperfecta.

BACKGROUND: Very little is known about the characteristics of echocardiographic abnormalities and joint hypermobility in Chinese patients with osteogenesis imperfecta (OI). The aim of our study was to investigate the characteristics, prevalence and correlation of echocardiographic abnormalities and joint hypermobility in Chinese patients with OI. METHODS: A cross-sectional comparative study was conducted in pediatric and adult OI patients who were matched in age and sex with healthy controls. Transthoracic echocardiography was performed in all patients and controls, and parameters were indexed for body surface area (BSA). The Beighton score was used to evaluate the degree of joint hypermobility. RESULTS: A total of 48 patients with OI (25 juveniles and 23 adults) and 129 age- and sex-matched healthy controls (79 juveniles and 50 adults) were studied. Four genes (COL1A1, COL1A2, IFITM5, and WNT1) and 39 different mutation loci were identified in our study. Mild valvular regurgitation was the most common cardiac abnormality: mild mitral and tricuspid regurgitation was found in 12% and 36% of pediatric OI patients, respectively; among 23 OI adults, 13% and 17% of patients had mild mitral and tricuspid regurgitation, respectively, and 4% had mild aortic regurgitation. In multiple regression analysis, OI was the key predictor of left atrium diameter (LAD) (ß=-3.670, P < 0.001) and fractional shortening (FS) (ß = 3.005, P = 0.037) in juveniles, whereas for adults, OI was a significant predictor of LAD (ß=-3.621, P < 0.001) and left ventricular mass (LVM) (ß = 58.928, P < 0.001). The percentages of generalized joint hypermobility in OI juveniles and adults were 56% and 20%, respectively. Additionally, only in the OI juvenile group did the results of the Mann‒Whitney U test show that the degree of joint hypermobility was significantly different between the echocardiographic normal and abnormal groups (P = 0.004). CONCLUSIONS: Mild valvular regurgitation was the most common cardiac abnormality in both OI juveniles and adults. Compared with OI adults, OI juveniles had more prevalent and wider joint hypermobility. Echocardiographic abnormalities may imply that the impairment of type I collagen is more serious in OI. Baseline echocardiography should be performed in OI patients as early as possible.

In Vitro Modelling of Osteogenesis Imperfecta with Patient-Derived Induced Mesenchymal Stem Cells.

(1) Mesenchymal stem cells (MSCs) are a valuable cell model to study the bone pathology of Osteogenesis Imperfecta (OI), a rare genetic collagen-related disorder characterized by bone fragility and skeletal dysplasia. We aimed to generate a novel OI induced mesenchymal stem cell (iMSC) model from induced pluripotent stem cells (iPSCs) derived from human dermal fibroblasts. For the first time, OI iMSCs generation was based on an intermediate neural crest cell (iNCC) stage. (2) Skin fibroblasts from healthy individuals and OI patients were reprogrammed into iPSCs and subsequently differentiated into iMSCs via iNCCs. (3) Successful generation of iPSCs from acquired fibroblasts was confirmed with changes in cell morphology, expression of iPSC markers SOX2, NANOG, and OCT4 and three germ-layer tests. Following differentiation into iNCCs, cells presented increased iNCC markers including P75NTR, TFAP2A, and HNK-1 and decreased iPSC markers, shown to reach the iNCC stage. Induction into iMSCs was confirmed by the presence of CD73, CD105, and CD90 markers, low expression of the hematopoietic, and reduced expression of the iNCC markers. iMSCs were trilineage differentiation-competent, confirmed using molecular analyses and staining for cell-type-specific osteoblast, adipocyte, and chondrocyte markers. (4) In the current study, we have developed a multipotent in vitro iMSC model of OI patients and healthy controls able to differentiate into osteoblast-like cells.

Influence of zoledronic acid and pamidronate on tooth eruption in children with osteogenesis imperfecta.

INTRODUCTION: Osteogenesis imperfecta (OI) is a congenital disease comprising a heterogeneous group of inherited connective tissue disorders. The main treatment in children is bisphosphonate therapy. Previous animal studies have shown that bisphosphonates delay tooth eruption. The aim of this study is to determine whether patients with OI treated with pamidronate and/or zoledronic acid have a delayed eruption age compared to a control group of healthy children. METHODS: An ambispective longitudinal cohort study evaluating the age of eruption of the first stage mixed dentition in a group of children with OI (n = 37) all treated with intravenous bisphosphonates compared with a group of healthy children (n = 89). Within the study group, the correlation (Pearson correlation test) between the type of medication administered (pamidronate and/or zoledronic acid) and the chronology of tooth eruption is established, as well as the relationship between the amount of cumulative dose received and tooth eruption. RESULTS: The age of eruption of the study group was significantly delayed compared to the age of eruption of the control group for molars and lateral incisors (p < 0.05). Patients who received higher cumulative doses had a delayed eruption age compared to those with lower cumulative doses (p < 0.05). There is a high positive correlation between age of delayed tooth eruption and Zoledronic acid administration. CONCLUSION: Patients with OI have a delayed eruption of the 1st stage mixed dentition compared to a control group of healthy children. This delayed eruption is directly related to the cumulative dose of bisphosphonates and the administration of zoledronic ac.

Short-term effects of Mediterranean diet on nutritional status in adults affected by Osteogenesis Imperfecta: a pilot study.

BACKGROUND: Osteogenesis Imperfecta (OI) is a heterogeneous group of connective tissue disorders, characterized by varying degrees of skeletal fragility. Patients experience a range of comorbidities, such as obesity, cardiovascular, and gastrointestinal complications, especially in adulthood. All aspects that could benefit from dietary intervention. The aim of this study was to evaluate the effects of a 6-months restricted Mediterranean Diet (rMD) on nutritional status in adult patients affected by OI. We carried out a 6-months longitudinal pilot study. 14 adults (median age: 35 years; 7 women; 7 OI type III) where recruited in 2019 among the members of As.It.O.I., the Italian Association of Osteogenesis Imperfecta. As.It.O.I. All the evaluations were performed at the University of Milan, Italy. The rMD provided a reduction of 30% from daily total energy expenditure. 45% of calories derived from carbohydrates, 35% from fat and 0.7-1.0 g/kg of body weight from proteins. Comparisons of continuous variables after 6 months of intervention were performed by the paired t-test. All P-values were two-tailed, and p < 0.05 was considered significant. RESULTS: Patients showed significant improvement in anthropometric measurements (BMI = 30.5 vs 28.1 kg/cm2, p < 0.001; Body Fat % = 32.9 vs 29.9, p = 0.006; Waist circumferences = 83.6 vs 79.6 cm; p < 0.001; Arm Fat Area = 29.8 vs 23.07 cm2; p < 0.011) and energy expenditure (REE/kg = 27.2 vs 29.2 kcal/kg, p < 0.001). Glucose and lipid profiles improved (Δglycemia = - 8.6 ± 7.3 mg/dL, p = 0.003; ΔTC = - 14.6 ± 20.1 mg/dL, p = 0.036; ΔLDL = - 12.0 ± 12.1 mg/dL, p = 0.009). Adherence to the MD significantly increased, moving from a moderate to a strong adherence and reporting an increased consumption of white meat, legumes, fish, nuts, fruits and vegetables. CONCLUSION: A rMD was effective in improving nutritional status and dietary quality in adults with OI. These results underscores the need to raise awareness of nutrition as part of the multidisciplinary treatment of this disease.

RNA-based bone histomorphometry: method and its application to explaining postpubertal bone gain in a G610C mouse model of osteogenesis imperfecta.

Bone histomorphometry is a well-established approach to assessing skeletal pathology, providing a standard evaluation of the cellular components, architecture, mineralization, and growth of bone tissue. However, it depends in part on the subjective interpretation of cellular morphology by an expert, which introduces bias. In addition, diseases like osteogenesis imperfecta (OI) and fibrous dysplasia are accompanied by changes in the morphology and function of skeletal tissue and cells, hindering consistent evaluation of some morphometric parameters and interpretation of the results. For instance, traditional histomorphometry combined with collagen turnover markers suggested that reduced bone formation in classical OI is accompanied by increased bone resorption. In contrast, the well-documented postpubertal reduction in fractures would be easier to explain by reduced bone resorption after puberty, highlighting the need for less ambiguous measurements. Here we propose an approach to histomorphometry based on in situ mRNA hybridization, which uses Col1a1 as osteoblast and Ctsk as osteoclast markers. This approach can be fully automated and eliminates subjective identification of bone surface cells. We validate these markers based on the expression of Bglap, Ibsp, and Acp5. Comparison with traditional histological and tartrate-resistant acid phosphatase staining of the same sections suggests that mRNA-based analysis is more reliable. Unlike inconclusive traditional histomorphometry of mice with α2(I)-Gly610 to Cys substitution in the collagen triple helix, mRNA-based measurements reveal reduced osteoclastogenesis in 11-wk-old animals consistent with the postpubertal catch-up osteogenesis observed by microCT. We optimize the technique for cryosections of mineralized bone and sections of paraffin-embedded decalcified tissue, simplifying and broadening its applications. We illustrate the application of the mRNA-based approach to human samples using the example of a McCune-Albright syndrome patient. By eliminating confounding effects of altered cellular morphology and the need for subjective morphological evaluation, this approach may provide a more reproducible and accessible evaluation of bone pathology.

Bone microarchitecture and strength assessment in adults with osteogenesis imperfecta using HR-pQCT: normative comparison and challenges.

Data on bone microarchitecture in osteogenesis imperfecta (OI) are scarce. The aim of this cross-sectional study was to assess bone microarchitecture and strength in a large cohort of adults with OI using high-resolution peripheral quantitative computed tomography (HR-pQCT) and to evaluate challenges of using HR-pQCT in this cohort. Second-generation HR-pQCT scans were obtained at the distal radius and tibia in 118 men and women with Sillence OI type I, III, or IV using an extremity-length-dependent scan protocol. In total, 102 radius and 105 tibia scans of sufficient quality could be obtained, of which 11 radius scans (11%) and 14 tibia scans (13%) had a deviated axial scan angle as compared with axial angle data of 13 young women. In the scans without a deviated axial angle and compared with normative HR-pQCT data, Z-scores at the radius for trabecular bone mineral density (BMD), number, and separation were -1.6 ± 1.3, -2.5 ± 1.4, and -2.7 (IQR: 2.7), respectively. They were -1.4 ± 1.5 and -1.1 ± 1.2 for stiffness and failure load and between ±1 for trabecular thickness and cortical bone parameters. Z-scores were significantly lower for total and trabecular BMD, stiffness, failure load, and cortical area and thickness at the tibia. Additionally, local microarchitectural inhomogeneities were observed, most pronounced being trabecular void volumes. In the scans with a deviated axial angle, the proportion of Z-scores <-4 or >4 was significantly higher for trabecular BMD and separation (radius) or most total and trabecular bone parameters (tibia). To conclude, especially trabecular bone microarchitecture and bone strength were impaired in adults with OI. HR-pQCT may be used without challenges in most adults with OI, but approximately 12% of the scans may have a deviated axial angle in OI due to bone deformities or scan positioning limitations. Furthermore, standard HR-pQCT parameters may not always be reliable due to microarchitectural inhomogeneities nor fully reflect all inhomogeneities.

OI is a rare condition with large clinical heterogeneity. One of the major characteristics associated with OI is the increased fracture risk due to defects in bone structure and material. Data on the defects in bone structure at the micrometer level (i.e. bone microarchitecture) are scarce. Bone microarchitecture can be assessed noninvasively using HR-pQCT, but its use in OI has not extensively been described. Yet, potential challenges may arise related to among others the occurrence of short extremities and skeletal deformities in OI. We assessed bone microarchitecture and strength in 118 adults with OI types I, III, or IV using HR-pQCT with an extremity-length-dependent scan protocol. Additionally, we evaluated potential challenges of using HR-pQCT in this cohort. Our results demonstrated that predominantly trabecular microarchitecture­especially trabecular number and separation­and overall bone strength were impaired in adults with OI as compared with normative data. Furthermore, we observed various microarchitectural inhomogeneities, most pronounced being trabecular void volumes. Regarding applicability, HR-pQCT could be used without challenges in most adults with OI. However, deviations in scan region may potentially influence HR-pQCT parameters, and standard HR-pQCT analyses may not always give accurate results due to microarchitectural inhomogeneities nor fully reflect all microarchitectural inhomogeneities.

Impaired muscle parameters in adults with mild to severe types of osteogenesis imperfecta: a cross-sectional study.

Impaired muscle parameters may further compromise the already compromised skeleton in individuals with OI. This cross-sectional study aimed to compare muscle function and body composition in adults with various OI types and healthy controls. Sixty-eight adults with OI (mean age 42.2 yr; 27 men) and 68 healthy age- and sex-matched controls were recruited. Maximal isometric muscle force was assessed by handheld dynamometry (hand grip, hip flexors, shoulder abductors, and ankle dorsiflexors), muscle endurance by posture maintenance tests (shoulder abduction, hip flexion, and wall sit), and functional lower limb strength by 30-s chair rise test. In a sub cohort, dynamic muscle function (peak power and force) was assessed by a ground reaction force plate, and lean and fat mass, muscle and fat cross-sectional area (CSA), and muscle density by dual-energy X-ray absorptiometry and peripheral quantitative computed tomography. Multiple linear regression models were fitted with group (OI type I, III, IV/V, or controls), country, sex, and age in the fixed effects part. Overall, adults with various types of OI had lower isometric, endurance, and functional muscle strength (mean difference [MD] = OI type I: 19-43%, OI type IV/V: 25-68%, OI type III: 20-72%) compared to controls. Furthermore, adults with OI type I had lower dynamic muscle function (peak force [MD = 25-29%] and power [MD = 18-60%]), lean mass (MD = 10-17%), muscle CSA (MD = 9-21%), and muscle density (MD = 2-3%) but higher adiposity indices (MD = 24-42%) compared to controls. Functional lower limb strength and maximal muscle force were significantly different between OI types, whereas muscle endurance was not. To conclude, adults with OI present with markedly impaired muscle function which may partially be explained by their altered body composition. Our findings emphasize the need for proper assessment of various muscle parameters and (research into) appropriate and safe muscle strengthening approaches in this population.

Exome sequencing identified mutations in the WNT1 and COL1A2 genes in osteogenesis imperfecta cases.

BACKGROUND: Osteogenesis imperfecta (OI) is a heritable connective tissue disorder characterized by bone deformities, fractures and reduced bone mass. OI can be inherited as a dominant, recessive, or X-linked disorder. The mutational spectrum has shown that autosomal dominant mutations in the type I collagen-encoding genes are responsible for OI in 85% of the cases. Apart from collagen genes, mutations in more than 20 other genes, such as CRTAP, CREB3L1, MBTPS2, P4HB, SEC24D, SPARC, FKBP10, LEPRE1, PLOD2, PPIB, SERPINF1, SERPINH1, SP7, WNT1, BMP1, TMEM38B, and IFITM5 have been reported in OI. METHODS AND RESULTS: To understand the genetic cause of OI in four cases, we conducted whole exome sequencing, followed by Sanger sequencing. In case #1, we identified a novel c.506delG homozygous mutation in the WNT1 gene, resulting in a frameshift and early truncation of the protein at the 197th amino acid. In cases #2, 3 and 4, we identified a heterozygous c.838G > A mutation in the COL1A2 gene, resulting in a p.Gly280Ser substitution. The clinvar frequency of this mutation is 0.000008 (GnomAD-exomes). This mutation has been identified by other studies as well and appears to be a mutational hot spot. These pathogenic mutations were found to be absent in 96 control samples analyzed for these sites. The presence of these mutations in the cases, their absence in controls, their absence or very low frequency in general population, and their evaluation using various in silico prediction tools suggested their pathogenic nature. CONCLUSIONS: Mutations in the WNT1 and COL1A2 genes explain these cases of osteogenesis imperfecta.

The impact of osteogenesis imperfecta severity on oral health-related quality of life in Spain: a cross-sectional study.

BACKGROUND: Osteogenesis imperfecta (OI) affects dental and craniofacial development; therefore, it can influence oral health-related quality of life (OHRQoL). The objective of this study was to explore the influence of the severity of OI on OHRQoL in adults older than eighteen years residing in Spain. METHOD: Adults with OI were recruited from the Spanish Association of Crystal Bone (AHUCE) foundation. OHRQoL was evaluated using the Spanish version of the Oral Health Impact Profile questionnaire (OHIP-14sp), oral hygiene habits, and a dental care survey. Clinical and radiological dental examinations were performed to evaluate the patients' oral conditions. RESULTS: A total of 65 adults (n = 46 females) aged between nineteen and sixty-two years who were diagnosed with OI and classified as type I, III, and IV (n = 20, 14, and 31, respectively) participated in this research. The total OHIP-14sp scores were significantly greater (worse) for type III (23 [SD = 10]) and type IV (21.4 [SD = 12]) than for type I (13.8 [SD = 6]) (P < 0.05). The negative impact of OHRQoL was due to the association of type III OI with all domains except for the handicap domain, while type IV OI was associated with the physical disability, social disability, and handicap domains (P < 0.05 for all). CONCLUSION: The severity of OI negatively impacted OHRQoL in adults. This association was statistically significant.