Osteogenesis Imperfecta

Osteogenesis Imperfecta (OI) is a rare genetic disease characterised mainly by bone fragility, decreased bone mass and a susceptibility to fractures of varying severity. Different forms have been described according to the severity of the bone manifestations. Although it is a genetically heterogeneous disease, approximately 90% of OI patients have a mutation in the gene encoding gene encoding type 1 collagen, a major component of the extracellular matrix. Chronic fatigue and decreased physical endurance are almost constant complaints of patients with OI (more than 95% according to some studies), which impacts the activities of daily living and quality of life of these patients. The causes of this decrease in endurance are multifactorial involving prolonged immobilisation secondary to fractures, chronic osteoarticular pain, but also primary muscle damage. Mechanography studies carried out in children with OI have shown a significant deficit in muscle function in terms of both strength and power. In healthy adults, physical inactivity is an important predictor of feeling of tired. In addition, in some chronic diseases (such as multiple sclerosis, rheumatoid arthritis or systemic lupus erythematosus), physical activity and training have been shown to be effective in improving muscle strength and functional capacity as well as fatigue and quality of life. In OI, it has been reported that physical activity improves muscle function and bone mass. Patients with OI should therefore benefit from a regular exercise programme taking into account their risk of fracture. This study aims to evaluate the effect of a life-skills physical activity (LSPA) programme on the endurance capacities and quality of life of children and adolescents with OI. The VO2 peak evolution will be evaluated after 6 months of program. This is a recognized parameter for the evaluation of endurance and has been validated in children. The hypothesis of this study is that the implementation of a physical activity program adapted to the daily life and interests of the child with OI will efficiently improve endurance, prevent deconditioning and promote long term benefits.

Osteoarthritis (OA) of the knee, known as gonarthrosis, causes significant movement restrictions and pain in daily life activities. Total Knee Arthroplasty (TKA) is the preferred treatment method for advanced-stage OA of the knee. While various alignment techniques such as kinematic, constrained kinematic, and anatomical alignment are used, the most commonly used and preferred method by researchers is TKA performed with a technique that conforms to mechanical alignment. Two main factors that affect patient outcomes after mechanically aligned TKA are achieving a parallel joint line and appropriate positioning of the distal femoral rotation that corresponds to the patellofemoral joint kinematics, ensuring optimal soft tissue tension. If these two aspects are not adequately addressed, patients may experience chronic pain, functional impairment, early wear at the implant interface, and ultimately, loosening. Studies have reported that 8% to 19% of patients are dissatisfied with TKA due to various reasons, including pain and unmet expectations. Problems that may arise from malrotation and/or incorrect soft tissue tension include patellofemoral instability, anterior knee pain, arthrofibrosis, and flexion gap instability. In general, the natural joint line is not orthogonal to the tibial mechanical axis; it is varus, ranging from 87 ± 3°. When the mechanical alignment technique is applied in TKA, the proximal tibia and femur are typically cut perpendicular (90°) to the tibial and femoral mechanical axes. However, in the case of symmetric implants, the classical resection technique, especially in varus knees, results in more resection than the component thickness in the medial femoral compartment and the lateral tibial compartment. This creates an average 3° valgus joint line with respect to the tibial mechanical axis. As a result, the joint line is preserved medially, but the lateral compartment becomes more distalized. Another issue regarding the joint line is its restoration, which involves achieving its anatomical height. Changes in the joint line can lead to instability, increased incidence of anterior knee pain, and decreased range of motion. The most commonly used bone markers for the restoration of the joint line are the epicondyles, fibular head (FH), and tibial tubercle (TT). Due to significant individual variations, some authors have suggested using the ratio of the distance between the epicondyles and the tangent to the joint line to the trans-epicondylar width (TEW) of the femur as a means of determining the appropriate value. This ratio based on femoral width allows for the calculation of an appropriate value for each individual regardless of size. However, it is not always easy to radiographically identify the epicondyles, especially in varus knees with severe metaphyseal damage. On the femoral side, the width of the distal femoral resection should be equal to the thickness of the metal implant to restore the normal femoral joint line level, regardless of surgical techniques such as "measured resection technique" or modified "gap balancing technique." During surgery, the distal surface of the medial femoral condyle usually serves as the anatomical reference point for the distal femoral cut because in most cases, thicker bone is cut and removed from the medial femoral condyle compared to the lateral condyle. However, in patients with severely degenerated knees, significant bone and cartilage defects occur in the distal femoral condyle, and the deformed medial condyle is no longer a suitable reference point for distal femoral resection. During total knee arthroplasty (TKA), bone defects are sometimes encountered. If there is insufficient contact between the implant surface and the bone, augmentation is performed on the bone defect to maintain implant stability. Researchers have investigated the use of metal blocks in tibial bone defects during primary TKA and reported positive results, emphasizing that the use of metal blocks is a simple and applicable method for tibial bone defects. In primary TKA, tibial or femoral defects, or both, are classified into three types by the Anderson Orthopedic Research Institute: Type 1, small defects that do not compromise component stability; Type 2, sponge-like bone loss requiring reconstruction, categorized as A: involving one condyle or B: involving both condyles; Type 3, significant bone loss jeopardizing a large portion of the condyle. Typically, in varus knee deformity, bone defects in the knee appear first in the posteromedial region. In valgus gonarthrosis, the tibial bone defect is central, while the femoral condyles have defects in the distal and posterior lateral regions. Therefore, the primary classification of bone defects includes distinguishing between central forms (defects confined within the peripheral bone cortex) and peripheral forms (characterized by involvement of the peripheral cortex). Additionally, in patients with varus alignment and gonarthrosis, differentiating between intra-articular and metaphyseal sources of alignment defects is crucial as it can lead to differences in postoperative clinical and radiological outcomes, requiring different total knee arthroplasty procedures for patients. Medial and lateral epicondylar axis (EA) has been used to determine the appropriate location of the joint line (JL) during complex primary total knee arthroplasty (TKA) or most revision TKAs. However, some studies have shown that selecting the epicondyles as a reference can yield significantly different results. In these studies, the maximum errors in intraoperative selection of the medial femoral epicondyle and lateral femoral epicondyle were found to be 7.6 mm and 4.2 mm, respectively. Furthermore, the selection of the medial epicondyle reported more varied results with errors up to 22.3 mm, while the selection of the lateral epicondyle reported errors up to 13.8 mm. Additionally, variations in the distance from the femoral epicondyle to the joint line can be up to 11 mm, and significant differences have been observed between male and female patients. In a study conducted in the researcher's country, a correlation between the adductor tubercle (AT) and the distance between the fibular head (FH) and the JL was investigated to eliminate this handicap and determine the JL instead of using a mathematical ratio between the epicondylar axis and the TEW. The study, conducted on a Turkish population consisting of healthy volunteers, found the average TEW to be 87.2 ± 10.8 mm, the average distance between AT and JL to be 47.9 ± 6.2 mm, and the average distance between FH and JL to be 20.5 ± 4.0 mm. A strong positive correlation (0.55) was found between AT-JL and TEW (adductor ratio - AR). Measurements related to AR calculation were performed on radiographs of young patient knees without osteoarthritis. Based on this, another study questioned the validity of AR by determining the differences between AR in knees with severe osteoarthritis and those without osteoarthritis, considering the significant bone and cartilage loss or osteophyte formation. In revision total knee arthroplasty cases, intraoperative measurement of TEW and calculation of AT-JL may provide more accuracy in determining the articular level compared to measurements taken on radiographs of knees with severe osteoarthritis. They claimed that it could be more logical to measure TEW intraoperatively instead of measuring it on primary or contralateral radiographs of arthritic patients. According to these two studies, the adductor tubercle can be used as a reliable marker to determine the JL level in complex primary TKA or revision knee arthroplasty surgeries. However, this new method has not been scientifically proven. In fact, there is no generally accepted standard anatomical measurement system to accurately determine the JL level on direct radiographs, especially in severely deformed knees with advanced varus. There is also no consensus on the radiographic appearance to be used and the evaluation of these images. A study found no significant difference (0.01 ± 0.03) between the calculated AR (AT-EA/TEW) ratios obtained from radiographic and intraoperative measurements. This method can be particularly beneficial in revision TKAs where the anatomical EA is not clearly visible and provides a new tool for precise positioning of prosthetic components and JL restoration even in such complex cases. Literature lacks studies on determining the epicondylar axis using these methods for advanced-stage gonarthrosis cases (Type M-F) characterized by severe bone-cartilage defects, subchondral cysts, and extensive osteophytes in the medial femoral compartment, which would render the determination of both the epicondylar axis and the AT location impossible radiologically. Advanced imaging techniques such as computed tomography (CT) or magnetic resonance imaging (MRI) can be used for these patients, but they are not practically useful and add additional time and cost. Therefore, for patients with Type M-F deformity who are candidates for total knee arthroplasty (TKA), a study will be conducted to determine the JL location observationally without interfering with the surgical technique, using both preoperative radiological measurements and intraoperative caliper measurements. The measurements will be repeated in postoperative X-rays, and the functional short-term outcomes will be evaluated over a period of two years.

Virtual Surgical Planning (VSP), Computer-Aided Surgical Simulation (CASS) for bone corrections, and the customization of implants and devices through 3D printing, known as Patient-Specific Instruments (PSI) and Graft-Specific Instruments (GSI), are assuming increasingly central roles in orthopedic clinical and surgical practice. One area witnessing notable advancement is the treatment of musculoskeletal disorders (MMS) in children, adolescents, and young adults. These disorders involve severe and rare abnormalities in skeletal formation and development across three-dimensional planes, often affecting multiple limbs. Managing such deformities is complex, challenging to standardize, and prone to unpredictable clinical, radiographic, and functional outcomes. The application of 3D modeling and printing technologies offers a deeper understanding of deformities and facilitates improved prediction, precision, reproducibility, and safety in surgical interventions. The Musculoskeletal Apparatus Network (RAMS Network) centers are equipped with advanced 3D laboratories for surgical simulation and planning, aligned with the overarching goal of improving surgery quality through "in-silico" medicine (ISM) principles. At present, numerous complex surgeries involving Virtual Surgical Planning (VSP) and sterilizable 3D-printed Patient-Specific Instruments (PSI) and/or Graft-Specific Instruments (GSI) are being simulated and performed at the Rizzoli Institute. Preliminary data from previous protocols indicate a significant reduction in surgical time with the implementation of VSP and the utilization of PSI and GSI. The aim of this study is to enhance the current process of simulating, planning, and designing surgical support tools within 3D Printing Point-of-Care (3D POC) facilities. To achieve this, it is imperative to expand case volumes and systematically organize, categorize, and standardize simulation and planning procedures.

The overriding objectives of this study are: 1. Primary outcomes: 1. To confirm that administration of oral acetate increases the proportion of A. muciniphilia in the stool samples of patients with metastatic, castration-sensitive prostate cancer compared to a standard of care arm. 2. To confirm tolerability and assess for side effects of oral acetate supplementation. 2. Secondary outcomes: 1. To determine if increased counts of A. muciniphilia correlate with improved metabolic parameters and improved bone health.

Osteogenesis Imperfecta (OI), or Lobstein's disease, is a form of congenital osteoporosis, with a prevalence between 1/10,000 and 1/20,000 in France. As of 1979, four phenotypes have been described according to severity: moderate (type I), lethal (type II), severe (type III), and moderate-to-severe (type IV). OI exhibits phenotypic and genotypic variability, however, to date no correlations have been established between specific mutations and clinical presentation. There is a well-established association between OI and hearing loss, however, the reported prevalence of hearing loss varies between 2% to 94.1%. In patients with OI, Computed Tomography (CT) has revealed bone demineralization that progresses with age. The extent of the hypodense areas on the CT corresponds to the type of hearing loss: conductive hearing loss is associated with lesions of the fissula ante fenestram and round and oval windows while mixed hearing loss is associated with additional retrofenestral lesions. Severity of hearing loss is positively correlated with OI-related bone damage in the petrous bone. Magnetic Resonance Imaging (MRI) has also revealed in the pericochlear lesions with soft tissue hypersignal and enhancement on contrast medium injection in the otic capsule. Bone demineralization has also been linked to vestibular deficits, and some studies have reported correlations between Osteogenesis Imperfecta and vestibular deficits in adult patients, however, this relationship is less clear. The aim of the study is to determine whether vestibular deficits are also present in OI. Furthermore, the study will aim to establish whether a correlation exists between genetic type, severity of OI and audiovestibular phenotype. OI patients aged 12 to 20 years will be recruited and an audiometric, immittance, and vestibular assessment (videonystagmography, video Head Impulse Test (vHIT), vestibular evoked muscular potentials (cVEMP)) will be performed during their annual visit to the Centre de Référence des Maladies Rares des maladies osseuses constitutionnelles (henceforth CRMR OI) of Hôpital Necker-Enfants malades, Paris, France. When hearing loss is conductive, or mixed or in cases where vestibular deficits are identified, a CT scan without injection will be performed for the care. In case of sensorineural hearing loss, or abnormal CT results, an MRI will be proposed for the care. The investigation team will try to establish if there is a significant association between OI and vestibular deficit, and if so, whether the degree of vestibular impairment is correlated to radiological findings with respect to bone abnormalities, as well as the type and severity of the deafness.

The purpose of this natural history study is to perform a long-term follow-up of a large group of people with osteogenesis imperfecta (OI). The research aims are: 1. To collect natural history data on all individuals enrolled in this longitudinal study. The cause of the brittle bone disease will be compared with things like severity, various features and response to treatments. 2. To determine how often people with type I OI have vertebral compression fractures of the spine. 3. To determine how often people with OI develop scoliosis (curvature of the spine). 4. To determine how often people with OI have problems with teeth alignment and how dental health impacts a person's quality of life. 5. To determine the effect of pregnancy in women with OI. There will be a total of 1000 people with OI in this study. Participants will be asked to come in every year if 17Y and younger or every other year if 18Y and older for a total of five years. The following information will be collected at the study visits: Birth History and past surgical history, Current medical history, Scoliosis evaluation, Walking ability Questionnaire, Dental Quality of Life Questionnaire, Scoliosis and fractures Quality of Life Questionnaires, Physical development evaluation, Medications Use The following tests will be performed: Physical exam, dental exam, lung function test, hearing test, mobility test. The following X-rays will be taken: DEXA scan, X-ray of the spine, X-ray of the jaw. Biospecimen (urine and blood) samples will be collected.

The objective of this observational study is to gain insight into a new approach to rehabilitation in Austria, with a particular focus on work-specific exercises that are dependent on the specific work-related needs of the patients. Two groups are being observed: one was referred to a three-week work-specific rehabilitation programme immediately upon arrival at the rehabilitation centre, while the other group underwent a three-week medical-focused rehabilitation programme before starting a four-week work-specific rehabilitation programme. Researchers will monitor for indications of improvement following completion of the rehabilitation program. As the two forms of rehabilitation are not directly comparable, they will be observed and analysed as two distinct entities. As part of their regular inpatient rehabilitation, participants will complete questionnaires at designated intervals (beginning and end of stay), with follow-up assessments scheduled at six and 12 months post-rehabilitation.

Diffuse Optical Spectroscopy, the technique is fast and painless and was developed at the University of California, Irvine. The Diffuse Optical Spectroscopy instrument is actively involved in research studies, but is not yet a part of routine clinical practice. The result of this study will aid similar research projects that seek to improve our understanding of how tissues work and how alterations in metabolism affect long-term health. TheDiffuse Optical Spectroscopy measurement consists of placing a probe onto the surface of your body (calf, bicep, or head). This probe will be secured by either gentle hand pressure or fastened to your skin using clinically-approved wraps such as Coban/wrap bandages or medical adhesive tape and medical glues. Several dots will be made on your skin outlining the probe with a surgical felt tip marker. This is so we would be able to put the probe again on the same spot in case we needed to interrupt the measurement. The probe looks like a bar code scanner in a supermarket and it shines infrared light on your skin. There is no radiation involved with this light. In some cases where light signals are low, the optical detector will be placed directly onto your skin (but contained within an electronically shielded casing, and placed inside another plastic casing). (not offered during pregnancy).

Patients will be informed about the study and potential risks. All patients giving written informed consent will undergo a screening visit to assess the eligibility criteria. Patients who meet the eligibility requirements will perform a pre-treatment visit in order to assess their healthy state. Also, patients will undergo to the radiographic visit (RX and TX) as request by clinical practice. All the patients will be treated with arthrotomy mini-open technique with bone allograft at the site of the shoulder lesion. After surgery all the patients will be followed up to 24 months through clinical and radiographic visits.

Rationale: BoneMRI is a quantitative 3D MRI technique that has been developed recently by MRIGuidance BV©, which is based on a multiple gradient-echo sequence and a machine learning processing pipeline. The BoneMRI technology is capable of generating CT-like, quantitative radiodensity bone MRI images to visualize cortical and trabecular bone, allowing to assess bone structure and morphology, in addition to regular clinical MRI images. The use of BoneMRI has been investigated and clinically validated in multiple musculoskeletal studies involving the cervical spine, hip and sacro-iliac joint. In order to clinically use BoneMRI in the entire spine, the BoneMRI technology needs to be validated in that area as well, focussing on geometrical and voxelwise accuracy of the radiodensity contrast to assure accurate visualization of the osseous structures. As robustness against expected data variability between hospitals is crucial for successful machine learning algorithms, multiple MR field strengths and scanner types from different manufacturers will be included in this study. If successful, BoneMRI will facilitate a better, easier and cheaper workflow by enabling diagnosis, treatment planning and surgical navigation using a single radiological examination, without the potential hazards of ionizing radiation. Primary objective: The primary objective of this study is to investigate the performance of BoneMRI in terms of geometrical accurate visualization of the spinal osseous structures by radiodensity reconstruction when exposed to clinically relevant data variability. Study design: This study is a prospective multi-center clinical validation study, following a comparative design. Study population: Subjects referred to the radiology department for an MRI and CT scan of the spine having symptoms related to a spine disorder with suspected underlying involvement of osseous structures, will be asked to participate in this study. Duration of the study: Expectation is that it will take approximately 36-48 months to include 50 patients per center. Main study parameters/endpoints: Geometric accuracy in terms of visualization of the 3D osseous morphology of the spinal column. Nature and extent of the burden and risk associated with participation, benefit and group relatedness: The patient does not benefit from participating in this study and will receive routine care, which includes undergoing an MRI and CT scan. For research purposes an additional MRI sequence will be obtained for each patient. The CT scan is part of routine clinical care, so patients do not receive additional ionizing radiation compared to standard care. The subjects will in no way be exposed to BoneMRI as BoneMRI will not be installed at the investigation site and will not be part of the clinical workflow, nor the BoneMRI reconstructions will be part of the patient's file or decision making process of the healthcare professional. Therefore, there are no additional risks for the patients when participating in this study. This study may contribute to lower radiation doses in future patients when concluded that BoneMRI accurately visualizes the 3D morphology of the spinal osseous structures. This would render an additional conventional CT scan redundant.