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Objective: Attempts to utilise growth factors (GF) such as bone morphogenic proteins (BMPs) to treat osteoarthritis (OA) in the clinic have not secured widespread adoption. However, the novel crystalline GF formulation called PODS offers new perspectives. This study investigated the hypothesis that Polyhedrin Delivery System (PODS) BMP-2 and PODS BMP-7, compared with conventional BMP-2 and BMP-7 increase capacity for cartilage repair. Design: Sustained release from PODS BMP-2 and PODS BMP-7 and their effects on OA patient-derived cells as well as a chondrocyte cell line were first assessed in vitro. Here, extra cellular matrix (ECM) protein gene expression and actual ECM deposition were measured and compared to the effect achieved with conventional, soluble BMPs. Subsequently, in an established murine model of cartilage regeneration of the knee joint, changes were traced over 8 weeks and scored with two metrics, modified Pineda and Mankin. Results: Both crystalline PODS BMP formulations strongly induced proliferation in primary as well as immortal cell line chondrocytes, outperforming conventional soluble BMP-2 and BMP-7. Furthermore, ECM-producing genes were upregulated and the production of ECM could be demonstrated. In the murine cartilage regeneration model, both PODS BMP-2 and PODS-BMP-7 improved cartilage repair assessed with both histological scoring methods. Conclusions: This study showed that the sustained release of GF from PODS BMPs is effective in promoting chondrogenesis in vitro. The small animal data suggests that this novel approach of delivering therapeutic proteins sustainably and locally to the knee has promise for developing future disease-modifying therapies of OA.

A novel apatite-wollastonite/poly(lactic acid) (AW/PLA) composite structure, which matches cortical and cancellous bone properties has been produced and evaluated in vitro and in vivo. The composites structure has been produced using an innovative combination of 3D printed polymer and ceramic macrostructures, thermally bonded to create a hybrid composite structure. In vitro cell assays demonstrated that the AW structure alone, PLA structure alone, and AW/PLA composite were all biocompatible, with the AW structure supporting the proliferation and osteogenic differentiation of rat bone marrow stromal cells. Within a rat calvarial defect model the AW material showed excellent osseointegration with the formation of new bone, and vascularisation of the porous AW structure, both when the AW was implanted alone and when it was part of the AW/PLA composite structure. However, the AW/PLA structure showed the largest amount of the newly formed bone in vivo, an effect which is considered to be a result of the presence of the osteoinductive AW structure stimulating bone growth in the larger pores of the adjacent PLA structure. The layered AW/PLA structure showed no signs of delamination in any of the in vitro or in vivo studies, a result which is attributed to good initial bonding between polymer and ceramic, slow resorption rates of the two materials, and excellent osseointegration. It is concluded that macro-scale composites offer an alternative route to the fabrication of bioactive bone implants which can provide a match to both cortical and cancellous bone properties over millimetre length scales.

OBJECTIVE: To assess reliability and discriminative validity of cartilage compositional magnetic resonance imaging (MRI) in knee osteoarthritis (OA). DESIGN: The study was carried out per PRISMA recommendations. We searched MEDLINE and EMBASE (1974 - present) for eligible studies. We performed qualitative synthesis of reliability data. Where data from at least two discrimination studies were available, we estimated pooled standardized mean difference (SMD) between subjects with and without OA. Discrimination analyses compared controls and subjects with mild OA (Kellgren-Lawrence (KL) grade 1-2), severe OA (KL grade 3-4) and OA not otherwise specified (NOS) where not possible to stratify. We assessed quality of the evidence using Quality Appraisal of Diagnostic Reliability (QAREL) and Quality Assessment of Diagnostic Accuracy (QUADAS-2) tools. RESULTS: Fifty-eight studies were included in the reliability analysis and 26 studies were included in the discrimination analysis, with data from a total of 2,007 knees. Intra-observer, inter-observer and test-retest reliability of compositional techniques were excellent with most intraclass correlation coefficients >0.8 and coefficients of variation

PURPOSE The utility of magnetic resonance imaging (MRI) quantitative imaging biomarkers (QIBs) of cartilage in experimental medicine studies of potential disease modifying osteoarthritis treatments (DMOATs) is uncertain due to the small sample sizes and short follow-up involved. To be relevant to such studies, candidate QIBs must demonstrate acceptable repeatability, discriminative ability and responsiveness. The purpose of this study was to evaluate test-retest repeatability and discriminative ability of 4 cartilage QIBs at the knee (thickness, T1rho, T2 and delayed gadolinium enhanced MRI of cartilage [dGEMRIC]) to assess their utility in experimental medicine studies. METHODS We imaged 9 participants with mild-moderate knee osteoarthritis (OA), characterised by radiographs with medial tibiofemoral predominant disease and Kellgren-Lawrence grades 2-3, and 4 healthy volunteers (HVs) matched for age, sex and body mass index. Participants were imaged at baseline and 1 month. MR studies were performed on a 3T system (MR 750, GE Healthcare) and were split into 2 sessions. The first MR session included a 3-dimensional spoiled gradient echo (3D SPGR) sequence and T1rho and T2 mapping sequences. At the end of this session, we administered an intravenous gadolinium based contrast agent (Dotarem, Guerbet LLC) at double dose (0.2 mmol/kg). Participants then performed 10 minutes of exercise on a stationary cycle to facilitate contrast penetration into the joint for dGEMRIC. The second MR session began 90 minutes following injection of contrast agent and consisted of T1 mapping using a variable flip angle technique. MR pulse sequence details are provided in table 1. We performed surface based analysis of cartilage parameters using Stradwin software (http://mi.eng.cam.ac.uk/~rwp/stradwin). In brief, this consists of semi-automated thickness measurement on 3D SPGR images, with generation of accurate inner and outer cartilage surfaces. Following rigid registration of the compositional (T1rho, T2, dGEMRIC) data to the 3D SPGR images, the same surfaces were used to sample the compositional data. This analysis pipeline allows each parameter to be measured at ~5,000 surface vertices per participant. We assessed overall (pooled OA and HV data) test-retest repeatability by calculating the root-mean-square coefficient of variation (RMS-CV) and the smallest detectable change (SDC) for each parameter. We assessed overall discriminative validity by estimating effect sizes for the difference in the mean value of each parameter in OA participants and HVs. We also mapped the test-retest errors and mean difference in each parameter between groups onto a representative surface for each cartilage region. RESULTS Participant characteristics are provided in table 2. RMS-CVs, SDCs and effect size estimates are provided in table 3. Overall test-retest RMS-CV values ranged from 2.5% (T1rho) to 10.3% (dGEMRIC). The largest overall effect size was demonstrated for dGEMRIC (-1.3, 90% confidence interval [CI] -2.3 to -0.2), followed by thickness (-0.67, 90% CI -1.5 to 0.3), T1rho and T2 (both 0.61, 90% CI -0.4 to 1.5). Mapping of test-retest errors and between-group differences to a representative surface revealed substantial spatial heterogeneity in these metrics for all parameters (figure 1). This suggests that surface based approaches may offer improved sensitivity over traditional region of interest based measurements. CONCLUSION This study demonstrates that cartilage QIBs may be useful in experimental medicine studies of knee osteoarthritis. Statistical approaches reflecting the spatial heterogeneity of changes in cartilage should be used to provide an indication of where significant results are located, not just whether an average value is significantly different. Future work will evaluate responsiveness of these cartilage QIBs.

BACKGROUND: Osteoarthritis is the most common form of arthritis worldwide and is a major cause of pain and disability in elderly people. The health economic burden of osteoarthritis is increasing commensurate with obesity prevalence and longevity. Osteoarthritis has a strong genetic component but the success of previous genetic studies has been restricted due to insufficient sample sizes and phenotype heterogeneity. METHODS: We undertook a large genome-wide association study (GWAS) in 7410 unrelated and retrospectively and prospectively selected patients with severe osteoarthritis in the arcOGEN study, 80% of whom had undergone total joint replacement, and 11,009 unrelated controls from the UK. We replicated the most promising signals in an independent set of up to 7473 cases and 42,938 controls, from studies in Iceland, Estonia, the Netherlands, and the UK. All patients and controls were of European descent. FINDINGS: We identified five genome-wide significant loci (binomial test p≤5·0×10(-8)) for association with osteoarthritis and three loci just below this threshold. The strongest association was on chromosome 3 with rs6976 (odds ratio 1·12 [95% CI 1·08-1·16]; p=7·24×10(-11)), which is in perfect linkage disequilibrium with rs11177. This SNP encodes a missense polymorphism within the nucleostemin-encoding gene GNL3. Levels of nucleostemin were raised in chondrocytes from patients with osteoarthritis in functional studies. Other significant loci were on chromosome 9 close to ASTN2, chromosome 6 between FILIP1 and SENP6, chromosome 12 close to KLHDC5 and PTHLH, and in another region of chromosome 12 close to CHST11. One of the signals close to genome-wide significance was within the FTO gene, which is involved in regulation of bodyweight-a strong risk factor for osteoarthritis. All risk variants were common in frequency and exerted small effects. INTERPRETATION: Our findings provide insight into the genetics of arthritis and identify new pathways that might be amenable to future therapeutic intervention. FUNDING: arcOGEN was funded by a special purpose grant from Arthritis Research UK.

Malalignment may contribute to early prosthesis failure through point loading and premature polyethylene wear. Femoral resection requires for distal planar resection contingent upon correct rotation and coronal alignment. Using a standard model, we have examined the influence of differing femoral entry points and rotations upon final femoral component positioning. A graphical method and navigation system independently quantified the individual and combined impact of these variables, in 3 planes. Nine permutations were assessed with reference to neutral rotation and a central entry point. The graphical results were corroborated by the navigation analyses. We found that external rotation and a superolateral entry point introduced the greatest error in final component positioning. We have identified a safe envelope for femoral rod positioning and recommend that the rotational alignment is determined before distal bone resection.

Summary Osteoporosis causes an increased risk of fracture through decreased bone mineral density, disruption of bone microarchitecture and reduction in non-collagenous proteins. The effect of osteoporosis on the complex process of fracture healing in humans is not well understood, however there is laboratory evidence for reduced healing in the elderly. First line anti-resorptive therapies such as calcium, vitamin D and bisphosphonates appear, from laboratory studies, to have a neutral or positive effect on fracture healing. Newer anabolic therapies offer the possibility of positive effects on callus formation.

Summary Falls are a major concern in the elderly consuming considerable healthcare resources. This study evaluates the incidence of falls in patients suffering osteoarthritis (OA) and their impact on health status. 199 patients awaiting primary hip or knee replacement surgery for OA were recruited (84 hips, 115 knees). Patients completed a questionnaire including the Western Ontario and McMaster University OA Index (WOMAC), Short Form 36 (SF-36), and history of falls. Function was measured using the Timed Up and Go (TUG) test. Seventy-five patients (39%) reported falling within a 4-week period with 50 (25%) having fallen more than once. Fallers had significantly lower WOMAC pain and function scores, slower TUG, and worse SF-36 scores excluding social functioning and mental health. This study demonstrates that patients with hip or knee OA frequently fall. Considering the increasing numbers of patients undergoing total knee and hip replacement for OA, and the catastrophic consequences of peri-prosthetic fractures, the need to incorporate a falls prevention programme within arthroplasty management requires evaluation.

Surgery for osteoarthritis (OA) is generally reserved for patients who find non-surgical options ineffective. Surgery aims to reduce or eliminate pain and restore function and there are many ways to achieve this. The choice should be tailored to the needs of the patient with particular reference to the specific joint affected and the degree of pathological change. Surgical treatments for OA covered in this article include arthroscopic debridement, osteotomy, arthrodesis and arthroplasty. Whilst arthroplasty or joint replacement has been a great success and has revolutionized the outcome for patients severely disabled by OA, there remains a role for other modalities. The future will see further enhancement of surgical solutions both by technique and by technological improvements. Particularly, solutions will emerge combining implants, biomolecules and cells further enhancing indication and performance.

Cement mantle voids remain controversial with respect to survival of total hip arthroplasty. Void evolution is poorly understood, and attempts at void manipulation can only be empirical. We induced voids in a cement model simulating the constraints of the proximal femur. Intravoid pressure and temperature were recorded throughout polymerization, and the initial and final void volumes were measured. Temperature-dependent peak intravoid pressures and void volume increases were observed. After solidification, subatmospheric intravoid pressures were observed. The magnitude of these observations could not be explained by the ideal gas law. Partial pressures of the void gas at peak pressures demonstrated a dominant effect of gaseous monomer, thereby suggesting that void growth is a pressure-driven phenomenon resulting from temperature-dependent evaporation of monomer into existing trapped air voids.

Despite the fact that 50% of postmenopausal women with Colles' fracture have evidence of osteoporosis, the vast majority of women with forearm fractures are neither investigated nor treated for osteoporosis. Digital X-ray radiogrammetry (DXR) provides an attractive option in patients with distal forearm fracture, as it requires no additional X-rays over and above those performed as part of clinical management. We have compared DXR analysis of nonstandardised plain films taken routinely in accident and emergency with peripheral dual energy X-ray absorptiometry (pDXA) in a group presenting with distal forearm fracture. Women presenting with a fracture of the distal forearm underwent pDXA measurements of the calcaneus. Plain X-rays performed at the time of presentation were taken to allow adequate fracture treatment. No additional radiographer training or standardisation of films was performed. The DXR technique relies upon visualisation of the metacarpal shafts and this was not visualised on 123 of 201 (61%) films. The AP plain film was thus assessed using DXR for BMD in the remaining 78 patients with a mean age of 70.6 years (SE = 1.3). Mean BMD for DXR was 0.46 g/cm2 (SE = 0.01) and for pDXA was 0.40 g/cm2 (SE = 0.01). The correlation between BMD measured using the two techniques was 0.55 (P < 0.001). Although DXR measurements could not be performed in all patients, this proportion could easily be increased by routinely including the metacarpal shaft region in X-rays obtained after suspected distal forearm fracture. The correlation between the pDXA and DXR results is comparable with those reported between DXA measurements at the forearm, spine and hip. Our study suggests that DXR may provide a feasible method for the assessment of future fracture risk. The potential advantage of DXR over calcaneal pDXA measurements is that standard forearm X-ray obtained as part of fracture management could be used.

Modern cementing techniques aim to improve microinterlock and to reduce aseptic loosening. The Norwegian and Swedish Arthroplasty Registers have shown an increased risk of revision using reduced-viscosity cement. We have compared 2 modern cementing techniques using retrograde insertion of normal-viscosity and reduced-viscosity cements. Laboratory-simulated arthroplasty was performed in paired human femora. Performance was evaluated by measuring pressures generated during cementation, cement penetration, and shear strength of the prosthesis-cement and bone-cement interfaces. Large differences exist between these 2 modern techniques. Despite no statistical differences between the pressure measurements with the 2 techniques, greater penetration of reduced-viscosity cement was found proximally, with a trend toward increased penetration of the more viscous cement distally. Areas of greater cement penetration with reduced-viscosity cement proximally produced higher values of ultimate shear strength. Both techniques showed a progressive increase in the shear strength as the level of the section progressed toward the tip of the prosthesis. There is a trend with both techniques for the distal fixation to be stronger.

In atable trays for the prevention of contamination in surgery J.R.W. Hardy*, A.W. McCaskie, S.J. Calder, G.T.R. Pattison Department of Orthopaedic Surgery, University of Bristol, Avon Orthopaedic Centre, Southmead Hospital, Bristol, BS10 5NB, UK Department of Trauma and Orthopaedic Surgery, Medical School, University of Newcastle, Newcastle upon Tyne, NET 4HH, UK Department of Trauma and Orthopaedic Surgery, St James's University Hospital, Beckett Street, Leeds LS9 7TF, UK

Anterior knee pain is a common clinical problem. Patient assessment is difficult. Recently, it has been suggested that the so-called ‘skyline' views of the patellofemoral joint have no role to play in screening for maltracking and some would suggest that computerized tomography (CT) offers a more accurate method of investigation. The aim of this study was to evaluate the performance of CT in the assessment of three populations: patients suffering form anterior knee pain, patients treated for this condition by tibial tubercle transfer and a control group. The patellofemoral joint was assessed by measuring the trochlear angle, the congruence angle and the patella tilt from the CT images. In summary, the preoperative group had significantly different values of each parameter when compared with other groups but the group that had undergone surgical correction did not demonstrate a significant alteration toward the values of the control group. This study suggests that CT was not useful as either a diagnostic tool or as a indicator of successful surgical outcome.

The relevance of Henry's pelvic deltoid and its contribution to hip abductor strength is often not considered in hip arthroplasty. This small cadaveric study (n = 11) aimed to quantify the relative contributions of the pelvic deltoid muscles to abductor strength and to assess how different surgical approaches(anterolateral, direct lateral and posterior) impact on each of these muscle groups. We inspected the path of each approach and measured the cross-sectional area of the hip abductors, from which the contribution of each muscle to abductor moment was derived. We concluded that the posterior approach has the least impact on the pelvic deltoid and overall abductor moment.