Osteogenesis Imperfecta (OI) is a heritable bone disorder characterized by bone fragility and often caused by mutations in the Type I collagen-encoding genes COL1A1 and COL1A2. The pathophysiology of OI, particularly at the cellular level, is still not well understood. This contributes to the lack of a cure for this disorder as well as an effective preventive or management options of its complications. In the bone environment, mesenchymal stem cells (MSCs) and osteoblasts (Ob) exert their function, at least partially, through the secretion of extracellular vesicles (EV). EV is a heterogeneous group of nanosized membrane-enclosed vesicles that carry/transfer a cargo of proteins, lipid and nucleic acids from the secreting cell to its target cells. Our objective is to characterize EVs secreted by human control (HC)- and OI-MSCs and their derived Obs, with focus on their protein content. We hypothesize that there will be differences in the protein content of EVs secreted by OI-Obs compared to HC-Ob, which may indicate a deviation from healthy Ob behavior and, thus, a role in OI pathophysiology. MSCs were harvested from the adipose tissue of four COL1A1-OI and two HC patients. They were proliferated in an EV-depleted media, then induced to differentiate to extracellular matrix (ECM)-producing osteoblasts, which then gets mineralized. EVs secreted by MSCs (MSC-EV) and Obs (Ob-EV) were then purified and concentrated. Using liquid chromatography- tandem mass spectrometry, proteomic analysis of the EV groups was done. A total of 384 unique proteins were identified in all EVs, 373 were found in Vesiclepedia indicating a good enrichment of our samples with EV proteins. 67 proteins of the total 384 were exclusively or significantly upregulated (p-value < 0 .05) in OI-Ob-EV and 28 proteins in the HC-Ob-EVs, relative to each other. These two groups of differentially expressed proteins were compared by Gene Ontology (GO) analysis of their cellular compartment, molecular functions and biological processes. We observed that there were differences in the cellular origin of EV-proteins, which may indicate heterogeneity of the isolated EVs. Molecular function and biological process analyses of the HC-Ob-EV proteins showed, as expected, predominantly calcium-related activities such as extracellular matrix (ECM) mineralization. OI-Ob-EV proteins were still predominantly exhibiting ECM organization and formation functions. Annexins A1,2,4,5 and 6 were differentially and significantly upregulated by the HC-Ob-EVs. Fibronectin (FN), Fibulin-1 and −2, and Laminins (α4 & γ1), which are amongst the early non-collagenous proteins to form the ECM, were differentially and significantly upregulated in the OI-Ob-EVs. We concluded that the persistent expression of Fibronectin (FN), Fibulin-1 and −2, and Laminins in OI-Ob-EVs might indicate the presence of an immature ECM that the OI-Obs are trying to organize. ECM mineralization is largely dependent on the presence of an organized mature ECM, and this being compromised in OI bone environment, may be a contributor to the bone fragility seen in these patients. Annexins, which are calcium-binders that are vital for ECM mineralization, were significantly downregulated in the OI-Ob-EVs and this may be a further contributor to ECM mineralization impairment and bone fragility

Bones are thought to become fragile with advancing age due to a loss of mass and structure. However, there are important aspects of bone fragility and fracture that cannot be explained simply by a loss of bone: 30% of all patients told they have healthy bone based on bone mineral density (BMD) measurements go on to fracture. It has been suggested that increased fracture risk might also be due to ageing at the nanoscale, which might deteriorate the overall mechanical properties of a bone. However, it is not clear how mechanics at the level of the collagen-mineral matrix relate to mechanical properties of the whole bone, or whether nano-mechanics contribute to fracture risk. In order to answer these questions our group is developing state of the art methods for analysing the structure and function of the collagen mineral matrix under loading. To image the collagen mineral matrix we obtained beam time on a synchrotron particle accelerator at the Diamond Light Source (Didcot, UK). Electrons are accelerated to near light speed by powerful electromagnets, then slowed to create high energy monochromatic X-Ray beams. Through a combination of X-Ray computed tomography and X-Ray diffraction we have been able to image the collagen/mineral matrix. Furthermore, using in situ loading experiments it has been possible to visualise collagen fibrillar sliding and mineral crystal structure. Our group is analysing how age related changes in nano-structure affect bone mechanical behaviour. As well as comparing fragility fracture patients with ‘healthy’ age matched controls to investigate whether ageing at the nano-scale could increase fracture risk. We are also assessing the effect of common treatments for bone fragility (e.g. bisphosphonate) on nano-mechanics. Unfortunately the expense and high radiation dose associated with synchrotron imaging prevents the technology from being adapted for patients. Therefore the next step will be to identify and test tools that can be used to indirectly assess bone chemistry and mechanical properties at point of care (e.g. laser spectroscopy and indentation). The data could be used to improve the diagnosis, monitoring and treatment of bone fragility

Purpose. To describe the implication of Family Physicians (FPs) in the management of osteoporosis revealed by a fragility fracture. Method. The impact and costs of fractures is straining the health system. A better collaboration between specialists and FPs should improve the evaluation and treatment of affected patients. Since January 2007, the OPTIMUS initiative is an attempt to reach that objective in the Estrie area of the Province of Quc. With OPTIMUS, rates of appropriate treatment of osteoporosis at one year in previously untreated patients more than double (53% vs 20%). In OPTIMUS, FPs remain responsible for investigation and treatment of their patients after identification of a bone fragility fracture. A coordinator based in orthopaedists outpatient clinics identifies fragility fractures in patients older than 50 y.o., informs them about bone fragility and its link to osteoporosis, and spurs them to contact their FPs to get treated; the importance of persistence on treatment is reinforced during phone follow ups. Initially and when patients remain untreated upon follow up, the coordinator sends a letter to the patients FP about the occurrence of the fracture, its predictive value for future fractures, and the need for investigation and treatment. This represents a personalized form of continuous medical education for FPs, in the hope that FPs become leaders in the prevention of fragility fractures. To evaluate the perception of FPs about OPTIMUS, we performed a mail survey targeting FPs reached at least once by OPTIMUS. Results. The survey was sent to a total of 212 FPs. One hundred and nine (51.4%) answered. Of these, 97 (89%) agreed that a fragility fracture is an indication for treatment of osteoporosis; 56 (51%) agreed that OPTIMUS had helped them take charge of osteoporosis; and 105 (96.3%) were Satisfied or Very Satisfied of the OPTIMUS initiative. Conclusion. Because of this high level of acceptance, we propose to put into place a more elaborate intervention including a fall prevention program that will be managed by nurse coordinators in 16 FP Groups (GMF); these 16 Groups include 178 of the 360 FPs of the area. The FPs practicing in GMF are also involved in teaching to colleagues, residents and medical students; we expect an exponential effect on the practice of FPs over the years. We believe this enhanced intervention will improve the quality of life and autonomy of the patients while decreasing their rate of fractures

Periprosthetic fractures after total hip arthroplasty lead to considerable morbidity in terms of loss of component fixation, bone loss and subsequent functional compromise. The prevention, early recognition and appropriate management of such fractures are therefore critical. The pathogenesis of periprosthetic factors is multi-factorial. There are a number of intrinsic patient influences such as poor bone stock, biomechanics and compliance. There are also a host of extrinsic factors over which the surgeon has more control. The key tenets for fracture avoidance include careful planning, identifying the risk, choosing the correct implant, understanding the anatomy, and using appropriate surgical technique. There are a number of recognised risk factors for periprosthetic hip fractures The prevalence of intraoperative fractures during total hip arthroplasty is higher in the patient with osteopenia / osteoporosis. Other conditions causing increased bone fragility, such as osteomalacia, Paget's disease, osteopetrosis, and osteogenesis imperfecta are also at a higher risk of intraoperative fracture. The use of more and more press fit cementless components has also increased the number of periprosthetic femoral fractures because of the force required to obtain such a fit. Complex deformities of the proximal femur, particularly when associated with a narrow medullary canal, may also increase the risk of intraoperative fractures. Revision surgery is associated with a higher risk of intraoperative fracture than primary hip replacement surgery. These fractures typically occur during hip dislocation, cement extraction, or reaming through old cement. Other risk factors for postoperative femoral fractures following total hip replacement include loosening of the prosthesis with cortical bone loss, local osteolysis, stress risers within the cortex, such as old screw holes, the ends of plates, or impingement of a loose stem against the lateral femoral cortex. The management of periprosthetic fractures requires appropriate preoperative imaging, planning and templating, the availability of the necessary expertise and equipment, and knowledge of the potential pitfalls so that these can be avoided both intraoperatively and in follow-up. There is a danger that these cases fall between the expertise of the trauma surgeon and that of the revision arthroplasty surgeon. The past two decades have afforded us clear treatment algorithms based on fracture location, component fixation and the available bone stock. We still nevertheless face the enduring challenge of an elderly population with a high level of comorbidity who struggle to rehabilitate after such injuries. Perioperative optimization is critical as we have seen prolonged hospital stays, high rates of systemic complications and a significant short term mortality in this cohort. We have also been presented with new difficult fracture patterns around anatomic cementless stems and in relation to tapered cemented and cementless stems, as well as biologically challenging transverse or oblique fractures at the tip of a stem. In many cases, fixation techniques are biomechanically and biologically doomed to fail and intramedullary stability, achieved through complex revision is required. The sequelae of periprosthetic fractures include the financial cost of fixation or revision surgery, the associated morbidity and mortality in an elderly frail population, the difficulty with mobilization if the patient cannot fully weight bear, and a poor functional outcome in a proportion of cases. The battle over which patients or fractures require fixation and which require revision surgery continues

Introduction. Osteoporosis is a common skeletal disorder characterised by a reduced bone mass and a progressive micro-architectural deterioration in bone tissue leading to bone fragility and susceptibility to fracture. With a progressively aging population, osteoporosis is becoming an increasingly important public health issue. The Wnt/β-catenin pathway is a major signalling cascade in bone biology, playing a key role in regulating bone development and remodelling, with aberrations in signalling resulting in disturbances in bone mass. Objectives. To assess the effects of silencing the expression of the Wnt antagonist Dickkopf-1 (Dkk1) on the bone profile of primary human osteoblasts exposed in vitro to 10-8M dexamethasone. Methods. Primary human osteoblasts (HOBs) were cultured in vitro and exposed to 10-8M dexamethasone over a time course of 4hr, 12hr and 24hr. Dkk1 expression was silenced using small interfering RNA (siRNA). Quantitative RT-PCR was performed to confirm gene knockdown. Control and Dex-treated phObs (silenced & non-silenced) were compared with respect to bone turnover. Markers of bone turnover analyzed included alkaline phosphatase activity, calcium deposition and osteocalcin expression as determined by pNPP assay, quantitative alizarine red staining and ELISA respectively. Results. Dkk1 expression in HOBs was increased in response to dexamethasone exposure with an associated reduction in alkaline phosphatase activity, calcium deposition and osteocalcin expression. Silencing of Dkk1 expression, as confirmed by quantitative RT-PCR, was associated with a rescue effect in dexamethasone-induced bone loss in vitro. Conclusions. Dkk1 is an antagonist of Wnt/β-catenin signalling and plays a key role in regulating bone development and remodelling. Silencing the expression of Dkk1 in primary human osteoblasts has been shown to rescue the effects of dexamethasone-induced bone loss in vitro. The pharmacological targeting of the Wnt/β-catenin signalling pathway offers an exciting opportunity for the development of novel anabolic bone agents to treat osteoporosis and disorders of bone mass

The objective of this study was to consider whether an impaction bone graft (IBG) with their own bone tips surrounded with an X-changed rim mesh was useful when en bloc bone inplantation was not possible for a total knee replacement with large bone defect. Materials and Method. 4 cases and 5 knees (OA: 2 cases 3 knees, RA: 2 cases 2 knees) more than 2 years after the IBG procedure was done using X-changed rim mesh for the large medial tibial defect. All 4 cases were ladies, with the average age being 66.2 years old at that point of the procedure. A medial and posterior release for the connective tissues of knee was performed. The post and pre radiographic evaluations were done by knee society score and JOA score. All the defect or abrasion of the weighted surface was more than 5 mm from the last stage of osteoarthritis. We used a posterior-stabilized type of TKA (Zimmer nexgen), then took radiographs at pre and post operation periods and evaluated the knee scores, FTA, radiolucent line, range of motion and more than 2 years after the operation. Result. The graft bones were not depressed after more than 2 years and all the patients were satisfied the condition of their knees and made no mention of any knee pain. The average range of motion of their knee joint was: Pre-operation, passive flexion 133°, passive extension -21°; Post-operation, passive flexion 149°, passive extension -3°. All of the patients did not complain during movement and their walking ability including going up and down stairs was not reduced more than 2 years later. The component placement angle was not changed. The radiolucent line of the femur and tibiae did not appear. The average femoro-tibial angle improved from 197° to 173° over the course of two years. The femoral/tibial component setting angle was not changed more than 2 years after the TKA operation procedure. Radiolucent zone and component sinking was not seen on both side of femur and tibiae. Conclusion. After this survey we've found that an IBG procedure with an X-changed rim mesh is a good treatment for large bone defect of the tibiae. We can use this technique if we are not able to take out en bloc bone from their own tibiae or if their en bloc bone is crushed into pieces when trying to fix the bone to their tibiae because of bone fragility

Periprosthetic fractures in total hip arthroplasty lead to considerable morbidity in terms of loss of component fixation, bone loss and subsequent function. The prevention, early recognition and appropriate management of such fractures are therefore critical. The pathogenesis of periprosthetic factors is multi-factorial. There are a number of intrinsic patient influences such as bone stock, biomechanics and compliance. There are also a host of extrinsic factors over which the surgeon has more control. The prevention of periprosthetic fractures requires careful pre-operative planning and templating, the availability of the necessary expertise and equipment, and knowledge of the potential pitfalls so that these can be avoided both intra-operatively and in follow-up. The key issues here are around identifying the risk, choosing the correct implant, understanding the anatomy, understanding the possible risks and avoiding them and using appropriate technique. There are a number of recognized risk factors for periprosthetic hip fractures. The prevalence of intra-operative fractures during total hip arthroplasty is higher in the patient with osteopenia/osteoporosis. Other conditions causing increased bone fragility, such as osteomalacia, Paget's disease, osteopetrosis, and osteogenesis imperfecta are also at a higher risk of intra-operative fracture. The use of more and more press fit cementless components has also increased the number of periprosthetic femoral fractures because of the force required to obtain such a fit. Complex deformities of the proximal femur, particularly when associated with a narrow medullary canal, as seen in secondary degenerative joint disease following developmental dysplasia of the hip may also increase the risk of intra-operative fractures. Revision surgery is associated with a higher risk of intra-operative fracture than primary hip replacement surgery. These fractures typically occur during hip dislocation, cement extraction, or reaming through old cement. Other risk factors for post-operative femoral fractures include loosening of the prosthesis with cortical bone loss, local osteolysis, stress risers within the cortex, such as old screw holes, the ends of plates, or impingement of a loose stem against the lateral femoral cortex. Periprosthetic acetabular fractures are increasingly recognized. This is in part due to the popularity of press fit components, which increase fracture risk both at the time of insertion and later due to medial wall stress shielding and pelvic osteolysis, and partly due to the increasing frequency of severe defects encountered at the time of revision surgery. Both over- and under-reaming are significant risk factors for acetabular fractures during total hip replacement. It is imperative to deal with the osteopenic patient gently and appropriately, being aware of the rim on the acetabular side and having the capacity for screw fixation where needed, having an understanding of where you wish to place your components and creating the appropriate runways for them, thinking about the stability of an implant as it is inserted and understanding that an implant that is less stable than expected probably is associated with either a size mismatch, a fracture or an implant that will not sit properly probably requires more or a different direction of reaming rather than harder blows with a hammer. A typical example where extra care is required is the scenario of a fractured neck of femur that requires total hip arthroplasty. The virgin native acetabulum in a patient likely to have some bony deficiency may be more difficult to deal with as it has a higher fracture risk. Pre-operative templating helps to identify the correct entry point for preparation of the lateral runway for linear insertion of a femoral stem. If resistance is met during insertion, the situation should be re-appraised to ensure that the direction and level of the rasp and prosthesis are the same. This reduces the risk of varus/valgus positioning which increases the risk of intra- and post-operative fractures. It is also important to avoid a change of version during insertion of the prosthesis as this can lead to high stresses