Bleeding assessment in a large cohort of patients with Osteogenesis Imperfecta.

BACKGROUND: Osteogenesis Imperfecta (OI) is characterised by bone fragility. Among several features, easy bruising and multiple case reports on haemorrhagic events have been reported. This paper describes the diverse manifestations of bleeding and bruising in a large cohort of 328 OI patients. The aim of this study is to provide insight in the diverse aspects and therapeutic considerations of bleedings in OI. METHODS: This descriptive cohort study was conducted at the National Expert Center for adults with OI in the Netherlands. Bleeding was assessed by the validated self-bleeding assessment tool (Self-BAT) The tool was distributed among 328 adults with different clinically confirmed types of OI. RESULTS: 195 of 328 invited patients (completion rate 60%) with OI type 1 (n = 144), OI type 3 (n = 17) and OI type 4 (n = 34), aged between 18 and 82 years, completed the tool. Self-BAT scores were above the normal range in 42% of all patients. For males Self-BAT scores were increased in 37% with a mean score of 3.7, ranged between 0 and 18. For females the Self-BAT scores were increased in 44% with a mean of 5.4 and a range of 0-24. No statistical differences in OI subtypes were found. CONCLUSIONS: Bleeding tendency appears to be a relevant complication in OI patients as this study confirms the presumption of bleeding tendency. There are specific recommendations to clinicians who treat OI patients to consider an assessment of bleeding tendency and use potential interventions to reduce haemorrhagic complications and improve quality of life.

Incidence and nonunion rates of tibial fractures in adults with osteogenesis imperfecta: a retrospective cohort study of 402 patients with 42 fractures at an expert clinic.

BACKGROUND: Tibial fractures are the most common fractures seen in adults and lead to the most nonunions. Osteogenesis imperfecta (OI) is characterized by increased bone fragility and higher risk of fractures. No studies have been published on the incidence of tibial fractures and nonunions in adults with OI. This study aims to summarize the incidence of tibial fractures and nonunions in this population. METHODS: A retrospective, descriptive study. All medical charts of adult patients in the OI database of our OI expert clinic were analyzed for tibial fractures between 2008 and 2020. Tibial fracture incidence, nonunion rate, treatment modality and potential risk factors were determined. RESULTS: The database consisted of 402 patients, 34 of whom had suffered one or more tibial fractures, resulting in 42 fractures. The incidence of tibial fractures in adults with OI is 870 per 100,000 person-years. Two out of 42 fractures led to nonunion (5%). It was not possible to adjust for risk factors or type of treatment. CONCLUSION: There is a higher incidence of tibial fractures in patients with OI, but a nonunion rate comparable to the general population. With only two nonunions it is not possible to draw conclusions on the influence of risk factors or treatment of tibial fractures on OI.

Impact of digital interdisciplinary consultation on secondary care referrals by general practitioners: a protocol for a stepped-wedge cluster randomised controlled trial.

INTRODUCTION: Optimal collaboration between general practice and hospital care is crucial to maintain affordable and sustainable access to healthcare for the entire population. General practitioners (GPs) are the gatekeepers to specialist care and patients will visit hospitals mostly only after referral. However, a substantial part of these referrals may be inappropriate, as communication between GPs and medical specialists can be challenging and referring patients may be the most obvious action for a GP to perform.A new digital platform (Prisma) connects GPs and specialists in interdisciplinary groups and facilitates asynchronous, accessible and fast teleconsultation within the group. No previous research has been done to evaluate the impact of this new platform on the referral rates to the hospital. METHODS AND ANALYSIS: A stepped-wedge randomised controlled trial (RCT) will be performed in Zwolle region in the Netherlands to analyse the effect of introduction of the platform on rate of inappropriate referrals to orthopaedic surgery. In four steps, GPs in the region will be given access to the platform. GPs will be part of the control condition until randomisation to the intervention. According to our sample size calculation, we need to include 18 practices with 1008 patients presenting with hip and knee symptoms. Routine care data of hospital registrations will be analysed to calculate the rate of inappropriate referrals (primary outcome). Secondary outcome are costs, primary and secondary care workload, posted cases and user satisfaction. Alongside this quantitative analysis, we will evaluate patient experience, facilitators and barriers for use of the platform. ETHICS AND DISSEMINATION: The medical ethics review board of University Medical Center Groningen (UMCG), the Netherlands (METc-number: 2021/288) has confirmed that the Medical Research Involving Human Subjects Act (WMO) does not apply to the process evaluation because the study does not involve randomisation of patients or different medical treatments (letter number: M21.275351). TRIAL REGISTRATION NUMBER: NL9704.

A roadmap to surgery in osteogenesis imperfecta: results of an international collaboration of patient organizations and interdisciplinary care teams.

Background and purpose - Involvement of patient organizations is steadily increasing in guidelines for treatment of various diseases and conditions for better care from the patient's viewpoint and better comparability of outcomes. For this reason, the Osteogenesis Imperfecta Federation Europe and the Care4BrittleBones Foundation convened an interdisciplinary task force of 3 members from patient organizations and 12 healthcare professionals from recognized centers for interdisciplinary care for children and adults with osteogenesis imperfecta (OI) to develop guidelines for a basic roadmap to surgery in OI.Methods - All information from 9 telephone conferences, expert consultations, and face-to-face meetings during the International Conference for Quality of Life for Osteogenesis Imperfecta 2019 was used by the task force to define themes and associated recommendations.Results - Consensus on recommendations was reached within 4 themes: the interdisciplinary approach, the surgical decision-making conversation, surgical technique guidelines for OI, and the feedback loop after surgery.Interpretation - The basic guidelines of this roadmap for the interdisciplinary approach to surgical care in children and adults with OI is expected to improve standardization of clinical practice and comparability of outcomes across treatment centers.

A standard set of outcome measures for the comprehensive assessment of osteogenesis imperfecta.

BACKGROUND: Osteogenesis Imperfecta (OI) is a genetic disorder also known as 'brittle bone disease'. The clinical manifestation of OI shows a wide variation. Therefore, care for patients with OI requires an interdisciplinary approach. The effectiveness of particular interventions and treatment protocols of interdisciplinary teams is not clear due to a non-standardized and wide variation of patient outcomes thus making the comparison of outcome measures available in the literature difficult. It is only by agreeing on a common, standard set of outcome measures for the comprehensive appraisal of OI that comparisons across interdisciplinary treatment centers for OI will be possible in the future. METHODS: The Key4OI international interdisciplinary working group of 27 members used a consensus-driven modified Delphi approach to develop a set of global outcome measures for patients with OI. The International Classification of Functioning, Disability and Health (ICF), was used to define domains and organize the outcomes from the literature search. After reviewing the outcomes extracted from the literature, trials and registries, the working group agreed on a final selection of domains and their definition (ICF definition as well as a lay description). These domains were then presented to the focus groups who prioritized the outcome domains by taking into account the items important to the OI community. All content was collected and analyzed and final domains were determined. A consensus of appropriate measuring instruments for each domain was reached with Delphi rounds. The entire approach was in line with the International Consortium for Health Outcomes Measurement ICHOM methodology. RESULTS: More than 400 different outcome measures were identified in our literature search. After three Delphi rounds, 24 domains were selected. After the focus group sessions, the number of domains were reduced to 15. A consensus was reached on the measuring instruments to cover these domains for both children and adults. CONCLUSION: The Key4OI project resulted in standard set of outcome measures focused on the needs and wishes of individuals with OI and their families. This outcome set will enable healthcare teams and systems to compare and to improve their care pathways and quality of care worldwide. Further studies are needed to evaluate the implementation of this standardized outcome set.

A Baseline Measurement of Quality of Life in 322 Adults With Osteogenesis Imperfecta.

Osteogenesis imperfecta (OI) is characterized by bone fragility and secondary features such as blue sclerae, dentinogenesis imperfecta, hearing loss, ligamentous laxity, and short stature. It was thought that health-related quality of life (QoL) in patients with OI mainly depends on the severity of the skeletal deformities. However, it has become clear that additional factors can affect the QoL in all patients with OI. In this study, we compare dimensions of QoL in adults with OI with a control population. The SF-36 questionnaire was distributed among 330 adult patients with different OI types. Results were compared with two control populations from the Netherlands. Age-matched comparisons were made with one of the two control populations. The results were summarized in eight domains: general and mental health, physical and social function, bodily pain, vitality, and physical and emotional role. General health and physical function in all types of OI are low compared with controls, except patients with OI type 4 aged 55+ years. Bodily pain in patients with OI appeared significantly worse than in the control population. There was no significant difference between OI types regarding pain and vitality. Vitality was only in the OI type 1 group significantly lower compared with controls. Patients with OI type 1 had a significantly reduced mental health. Social functioning appeared most effective in type 3 around 20 years of age. QoL in adult patients with OI should be an important outcome measure in every OI clinic, but the amount of baseline data on this subject is sparse. This baseline measurement study is the largest study to date investigating QoL in adult patients with OI. The mean scores indicate that people with OI generally have a significantly lower QoL than the control population. Further qualitative evaluation of QoL and its influences is important for future management. © 2020 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.

Interaction between KDELR2 and HSP47 as a Key Determinant in Osteogenesis Imperfecta Caused by Bi-allelic Variants in KDELR2.

Osteogenesis imperfecta (OI) is characterized primarily by susceptibility to fractures with or without bone deformation. OI is genetically heterogeneous: over 20 genetic causes are recognized. We identified bi-allelic pathogenic KDELR2 variants as a cause of OI in four families. KDELR2 encodes KDEL endoplasmic reticulum protein retention receptor 2, which recycles ER-resident proteins with a KDEL-like peptide from the cis-Golgi to the ER through COPI retrograde transport. Analysis of patient primary fibroblasts showed intracellular decrease of HSP47 and FKBP65 along with reduced procollagen type I in culture media. Electron microscopy identified an abnormal quality of secreted collagen fibrils with increased amount of HSP47 bound to monomeric and multimeric collagen molecules. Mapping the identified KDELR2 variants onto the crystal structure of G. gallus KDELR2 indicated that these lead to an inactive receptor resulting in impaired KDELR2-mediated Golgi-ER transport. Therefore, in KDELR2-deficient individuals, OI most likely occurs because of the inability of HSP47 to bind KDELR2 and dissociate from collagen type I. Instead, HSP47 remains bound to collagen molecules extracellularly, disrupting fiber formation. This highlights the importance of intracellular recycling of ER-resident molecular chaperones for collagen type I and bone metabolism and a crucial role of HSP47 in the KDELR2-associated pathogenic mechanism leading to OI.

Fatigue in adults with Osteogenesis Imperfecta.

BACKGROUND: Osteogenesis Imperfecta (OI) is characterized by bone fragility, and features such as blue sclerae, dentinogenesis imperfecta, hearing loss, ligamentous laxity and short stature can be present. It has long been assumed that the functional ability and quality of life of patients with OI depends primarily on the severity of skeletal deformities. However, fatigue is often mentioned in clinic by patients with all types of OI as an important modifier of their quality of life and does not always seem to be related to their functional ability. The aim of this study is to investigate whether adults with Osteogenesis Imperfecta are significantly more fatigued than the normal population. METHODS: The Fatigue Severity Scale (FSS) was distributed by mobile phone application among 151 adult patients with different OI types. Results of the FSS in the OI group were compared with two control populations from America (n = 20) and the Netherlands (n = 113). RESULTS: Ninety-nine patients (OI type 1 (n = 72), OI type 3 (n = 13), OI type 4 (n = 14) completed the FSS questionnaire. The mean FSS score of this cohort was 4.4 and significantly higher than the control populations (2.3/2.9). 65% of our cohort reported at least moderate fatigue compared with 2 control populations from America and the Netherlands. CONCLUSION: Fatigue in patients with OI is a frequently encountered problem in our expert clinic but research into this topic is sparse. This pilot study is the largest study to date investigating fatigue in patients with OI and results have been compared with two control groups. The mean FSS score of 4.4 in the OI group indicates that people with OI are generally significantly more fatigued than the control population. Further evaluation of fatigue and its influencers in a larger group of OI patients is important for future management.

Incidence and treatment of femur fractures in adults with osteogenesis imperfecta: an analysis of an expert clinic of 216 patients.

PURPOSE: Osteogenesis imperfecta (OI) is characterized by increased bone fragility and susceptibility for fractures. A few studies described and compared treatment modalities for femur fractures in children with OI. However, no cohort studies on adults with OI have been published. This study on adult OI patients aims to give insight into the incidence of femur fractures and non-unions and its best treatment options to avert non-union. METHODS: In this retrospective, descriptive study of the OI expert clinic in The Netherlands, all medical charts of patients 16 years or older were analyzed for femur fracture incidence, non-union rate and treatment modality. RESULTS: Of 216 OI patients, 34 patients suffered a femur fracture with 12 patients having more than 1 femur fracture. For all types of femur fractures, the incidence was 651 fractures per 100,000 person-years annually. In 49 total fractures, 10 fractures resulted in a non-union, mostly shaft fractures of type 4 OI patients. Surgically treated shaft fractures had the best outcomes for non-union. CONCLUSIONS: OI adults were prone to developing femur fractures and non-unions. Especially type 4 OI adults, with conservatively treated shaft fractures, were at high risk for non-unions.

Short-term results of total shoulder arthroplasty for ochronotic arthritis.

Alkaptonuria is a rare inherited autosomal recessive disorder resulting in large joint osteoarthritis with black discoloration of the cartilage. The glenohumeral is the third most affected joint. Two cases of ochronotic shoulder arthropathy with three shoulder joint replacements are presented. Stemless shoulder arthroplasty was implanted with moderate to good results up to 2 years follow-up regarding pain and range of motion.

Bleeding and bruising in Osteogenesis Imperfecta: International Society on Thrombosis and Haemostasis bleeding assessment tool and haemostasis laboratory assessment in 22 individuals.

Osteogenesis imperfecta (OI) is characterized by susceptibility to bone fractures. Other symptoms, such as easy bruising and bleeding complications during surgery necessitating transfusions, have also been reported. The aim of the cross-sectional pilot study was to assess the bleeding and bruising tendency in OI patients and to screen for possible underlying haematological disorders. Bleeding tendency was investigated using the International Society on Thrombosis and Haemostasis bleeding assessment tool (ISTH-BAT) in 22 adult OI patients. Laboratory testing was performed to investigate for bleeding disorders or abnormal coagulation. Four patients [OI type 1(n = 3), OI type 4(n = 1)] had a bleeding score (BS) fitting with a bleeding tendency, but without test results pointing to a coagulopathy. Two patients [OI type 1(n = 1), OI type 3 (n = 1)] without a bleeding tendency according to the BS had increased fibrinolysis. This is the second largest study to date addressing bleeding tendency in OI and the first study to use ISTH-BAT and elaborate laboratory testing for coagulopathies. Four patients had an increased bleeding tendency. However, laboratory testing demonstrated no bleeding disorder or abnormal coagulation. Increased fibrinolysis was demonstrated in two patients without bleeding tendency on BS. Vascular fragility as a cause of bleeding tendency in OI has been suggested earlier. Further research on bleeding tendency in OI is important.

Adults with osteogenesis imperfecta: Clinical characteristics of 151 patients with a focus on bisphosphonate use and bone density measurements.

An expert center for adults with Osteogenesis Imperfecta (OI) has been founded at the Isala Hospital in Zwolle, the Netherlands to achieve optimal care for adults with OI. Clinical data such as patient history, Dual Energy X-ray Absorptiometry measurements and laboratory findings are collected with patient consent. This study provides an overview of clinical characteristics of the patients who visited the clinic during its first 5 years, a total of 151 patients. In this study, we focus on bisphosphonate use and bone density measurements at time of presentation at the expert center. As such, insight into the natural history of OI in adults will be increased. Analysing the data of a large group of adults with this rare disorder within a national expert center will allow detailed exploration of the course of OI over time.

[A male with limited movement in the forearm]. / Een man met beperkte rotatie van de onderarm.

A 33-year-old male with a history of over 50 fractures visited our outpatient clinic for adults with osteogenesis imperfecta. Rotation of his elbow joint was limited. An X-ray revealed ossification of the radio-ulnar interosseous membrane. These findings are highly suggestive of osteogenesis imperfecta type V.