Calcitonin treatment for osteoarthritis and rheumatoid arthritis - a systematic review and meta-analysis of preclinical data.

Purpose: The aim of this study was to investigate the efficacy of calcitonin (CT) in animal models of experimental osteoarthritis (OA) and rheumatoid arthritis (RA), as new stabilized CT formulations are currently being introduced. Methods: A comprehensive and systemic literature search was conducted in PubMed/MEDLINE and Embase databases to identify articles with original data on CT treatment of preclinical OA and RA. Methodological quality was assessed using the Systematic Review Centre for Laboratory Animal Experimentation's risk of bias tool for animal intervention studies. To provide summary estimates of efficacy, a meta-analysis was conducted for outcomes reported in four or more studies, using a random-effects model. Subgroup analyses were employed to correct for study specifics. Results: Twenty-six studies were ultimately evaluated and data from 16 studies could be analyzed in the meta-analysis, which included the following outcomes: bone mineral density, bone volume, levels of cross-linked C-telopeptide of type I collagen, histopathological arthritis score, and mechanical allodynia. For all considered outcome parameters, CT-treated groups were significantly superior to control groups (P = 0.002; P = 0.01; P < 0.00001; P < 0.00001; P = 0.04). For most outcomes, effect sizes were significantly greater in OA than in RA (P ≤ 0.025). High in-between study heterogeneity was detected. Conclusion: There is preclinical evidence for an antioxidant, anti-inflammatory, antinociceptive, cartilage- and bone-protective effect of CT in RA and OA. Given these effects, CT presents a promising agent for the treatment of both diseases, although the potential seems to be greater in OA.

Autologous bone grafting in combination with autologous chondrocyte implantation yields favourable outcomes in the treatment of osteochondral defects of the knee: A systematic literature review.

PURPOSE: This study addresses the gap in the current literature by evaluating the combined treatment of autologous bone grafting and autologous chondrocyte implantation (ABCI) for osteochondral defects of the knee. It aims to evaluate clinical outcomes against methodological quality and to summarize histological results and surgical techniques. METHODS: A thorough search was conducted across Pubmed, Cochrane and Embase databases. Studies reporting clinical outcomes of ABCI for osteochondral defects of the knee were included. Patient-reported outcome measures (PROMs), failure rates, methodological quality and potential conflicts of interest were evaluated. Histological results and surgical techniques were summarized. RESULTS: Eighteen studies with 344 analyzed patients met the eligibility criteria for inclusion. All studies showed a significant improvement (p < 0.05) across different PROMs (subjective International Knee Documentation Committee score, Cincinnati Knee Rating System, Visual Analogue Scale, Lysholm Score, Tegner Activity Scale, Knee injury and Osteoarthritis Outcome Score and Knee Society Score) compared to the preoperative status. Failure rates ranged from 0% to 17.6%, with a mean follow-up of 73.2 months (range: 9.0-143.6 months). Methodological quality was low to medium, including only one comparative study. Six studies reviewed reported a potential conflict of interest. The histological assessment showed effective bonding between autologous chondrocytes and bone graft. A large degree of variability was observed in the operative technique used. CONCLUSION: The current literature suggests that ABCI yields good clinical outcomes at mid- to long-term follow-up with favourable histological results for osteochondral defects of the knee. However, future research should focus on high-quality comparative studies to better guide treatment choices. Introducing ABCI as the standard abbreviation may enhance clarity in future research. LEVEL OF EVIDENCE: Level IV.

An interpretable data-driven prediction model to anticipate scoliosis in spinal muscular atrophy in the era of (gene-) therapies.

5q-spinal muscular atrophy (SMA) is a neuromuscular disorder (NMD) that has become one of the first 5% treatable rare diseases. The efficacy of new SMA therapies is creating a dynamic SMA patient landscape, where disease progression and scoliosis development play a central role, however, remain difficult to anticipate. New approaches to anticipate disease progression and associated sequelae will be needed to continuously provide these patients the best standard of care. Here we developed an interpretable machine learning (ML) model that can function as an assistive tool in the anticipation of SMA-associated scoliosis based on disease progression markers. We collected longitudinal data from 86 genetically confirmed SMA patients. We selected six features routinely assessed over time to train a random forest classifier. The model achieved a mean accuracy of 0.77 (SD 0.2) and an average ROC AUC of 0.85 (SD 0.17). For class 1 'scoliosis' the average precision was 0.84 (SD 0.11), recall 0.89 (SD 0.22), F1-score of 0.85 (SD 0.17), respectively. Our trained model could predict scoliosis using selected disease progression markers and was consistent with the radiological measurements. During post validation, the model could predict scoliosis in patients who were unseen during training. We also demonstrate that rare disease data sets can be wrangled to build predictive ML models. Interpretable ML models can function as assistive tools in a changing disease landscape and have the potential to democratize expertise that is otherwise clustered at specialized centers.

Assessment of the Quality and Readability of Information Provided by ChatGPT in Relation to the Use of Platelet-Rich Plasma Therapy for Osteoarthritis.

Objective: This study aimed to evaluate the quality and readability of information generated by ChatGPT versions 3.5 and 4 concerning platelet-rich plasma (PRP) therapy in the management of knee osteoarthritis (OA), exploring whether large language models (LLMs) could play a significant role in patient education. Design: A total of 23 common patient queries regarding the role of PRP therapy in knee OA management were presented to ChatGPT versions 3.5 and 4. The quality of the responses was assessed using the DISCERN criteria, and readability was evaluated using six established assessment tools. Results: Both ChatGPT versions 3.5 and 4 produced moderate quality information. The quality of information provided by ChatGPT version 4 was significantly better than version 3.5, with mean DISCERN scores of 48.74 and 44.59, respectively. Both models scored highly with respect to response relevance and had a consistent emphasis on the importance of shared decision making. However, both versions produced content significantly above the recommended 8th grade reading level for patient education materials (PEMs), with mean reading grade levels (RGLs) of 17.18 for ChatGPT version 3.5 and 16.36 for ChatGPT version 4, indicating a potential barrier to their utility in patient education. Conclusions: While ChatGPT versions 3.5 and 4 both demonstrated the capability to generate information of moderate quality regarding the role of PRP therapy for knee OA, the readability of the content remains a significant barrier to widespread usage, exceeding the recommended reading levels for PEMs. Although ChatGPT version 4 showed improvements in quality and source citation, future iterations must focus on producing more accessible content to serve as a viable resource in patient education. Collaboration between healthcare providers, patient organizations, and AI developers is crucial to ensure the generation of high quality, peer reviewed, and easily understandable information that supports informed healthcare decisions.

Loading of the Hip and Knee During Swimming: An in Vivo Load Study.

BACKGROUND: Swimming is commonly recommended as postoperative rehabilitation following total hip arthroplasty (THA) and total knee arthroplasty (TKA). So far, in vivo hip and knee joint loads during swimming remain undescribed. METHODS: In vivo hip and knee joint loads were measured in 6 patients who underwent THA and 5 patients who underwent TKA with instrumented joint implants. Joint loads, including the resultant joint contact force (F Res ), torsional moment around the femoral shaft axis or the tibial axis (M Tors ), bending moment at the middle of the femoral neck (M Bend ), torsional moment around the femoral neck axis (M Tne ), and medial force ratio (MFR) in the knee, were measured during breaststroke swimming at 0.5, 0.6, and 0.7 m/s and the breaststroke and crawl kicks at 0.5 and 1.0 m/s. RESULTS: The ranges of the median maximal F Res were 157% to 193% of body weight for the hip and 93% to 145% of body weight for the knee during breaststroke swimming. Greater maxima of F Res (hip and knee), M Tors (hip and knee), M Bend (hip), and M Tne (hip) were observed with higher breaststroke swimming velocities, but significance was only identified between 0.5 and 0.6 m/s in F Res (p = 0.028), M Tors (p = 0.028), and M Bend (p = 0.028) and between 0.5 and 0.7 m/s in F Res (p = 0.045) in hips. No difference was found in maximal MFR between different breaststroke swimming velocities. The maximal F Res was significantly positively correlated with the breaststroke swimming velocity (hip: r = 0.541; p < 0.05; and knee: r = 0.414; p < 0.001). The maximal F Res (hip and knee) and moments (hip) were higher in the crawl kick than in the breaststroke kick, and a significant difference was recognized in F Res Max for the hip: median, 179% versus 118% of body weight (p = 0.028) for 0.5 m/s and 166% versus 133% of body weight (p = 0.028) for 1.0 m/s. CONCLUSIONS: Swimming is a safe and low-impact activity, particularly recommended for patients who undergo THA or TKA. Hip and knee joint loads are greater with higher swimming velocities and can be influenced by swimming styles. Nevertheless, concrete suggestions to patients who undergo arthroplasty on swimming should involve individual considerations. LEVEL OF EVIDENCE: Therapeutic Level IV . See Instructions for Authors for a complete description of levels of evidence.

The dual pro-inflammatory and bone-protective role of calcitonin gene-related peptide alpha in age-related osteoarthritis.

BACKGROUND: The vasoactive neuropeptide calcitonin gene-related peptide alpha (αCGRP) enhances nociception in primary knee osteoarthritis (OA) and has been shown to disrupt cartilage and joint integrity in experimental rheumatoid arthritis (RA). Little is known about how αCGRP may alter articular structures in primary OA. We investigated whether αCGRP modulates local inflammation and concomitant cartilage and bone changes in a murine model of age-dependent OA. METHODS: Sixteen- to 18-month-old αCGRP-deficient mice (αCGRP-/-aged) were compared to, first, age-matched wild type (WTaged) and, second, young 4- to 5-month-old non-OA αCGRP-deficient (αCGRP-/-CTRL) and non-OA WT animals (WTCTRL). αCGRP levels were measured in serum. Knee and hip joint inflammation, cartilage degradation, and bone alterations were assessed by histology (OARSI histopathological grading score), gene expression analysis, and µ-computed tomography. RESULTS: WTaged mice exhibited elevated αCGRP serum levels compared to young WTCTRL animals. Marked signs of OA-induced cartilage destruction were seen in WTaged animals, while αCGRP-/-aged mice were mostly protected from this effect. Age-dependent OA was accompanied by an increased gene expression of pro-inflammatory Tnfa, Il1b, and Il6 and catabolic Mmp13, Adamts5, Ctsk, Tnfs11 (Rankl), and Cxcl12/Cxcr4 in WTaged but not in αCGRP-/-aged mice. αCGRP-deficiency however further aggravated subchondral bone sclerosis of the medial tibial plateau and accelerated bone loss in the epi- and metaphyseal trabecular tibial bone in age-dependent OA. CONCLUSIONS: Similar to its function in experimental RA, αCGRP exerts a dual pro-inflammatory and bone-protective function in murine primary OA. Although anti-CGRP treatment was previously not successful in reducing pain in OA clinically, these data underline a crucial pathophysiological role of αCGRP in age-related OA.

A microprocessor stance and swing control orthosis improves balance, risk of falling, mobility, function, and quality of life of individuals dependent on a knee-ankle-foot orthosis for ambulation.

INTRODUCTION: The C-Brace microprocessor stance and swing control orthosis was designed to overcome safety and functional limitations of traditional knee-ankle-foot orthoses (KAFOs) for individuals with lower limb paresis. However, a systematic comparison to established KAFO types has not been performed in a bigger sample. METHODS: International multicenter, randomized, controlled, cross-over clinical trial. Legacy KAFO users at risk of falling were randomized to KAFO/C-Brace or C-Brace/KAFO use for three months with each orthosis. Primary outcome was balance assessed with the Berg Balance Scale (BBS). Secondary outcomes were falls, mobility, function, and quality of life. RESULTS: Intention-to-treat analysis with 102 participants. With the C-Brace, the BBS improved by 3.3 ± 6.3 points (p < 0.0001). Significantly fewer participants presented BBS scores <40 indicative of increased fall risk (16 vs. 36, p = 0.018). Mean falls reduced from 4.0 ± 16.8 to 1.1 ± 3.3 (p = 0.002). Outcomes for function, mobility, and quality of life showed significant improvements with the C-Brace. DISCUSSION: The improvements in fall risk and mobility can be attributed to the stumble recovery and controlled knee flexion during weight bearing of the C-Brace and have a positive impact on the quality of life of users. CONCLUSION: The C-Brace represents an option for KAFO users with increased fall risk and reduced mobility.

When prescribing traditional knee-ankle-foot orthoses (KAFOs), their known limitations, such as limited function and mobility, and the requirement to walk with compensatory mechanisms, especially on non-level terrains, should be considered.For patients with compromised balance and increased risk of falling when using a traditional KAFO, a microprocessor stance and swing control orthosis (MP-SSCO) may be considered as an orthotic option to reduce their fall risk.For patients with mobility restrictions using a traditional KAFO, a MP-SSCO may be considered to improve function, mobility, reintegration into normal living, and quality of life.

Biomarkers for osteoarthritis: Current status and future prospects.

Osteoarthritis (OA) is the most common form of arthritis globally and a major cause of pain, physical disability, and loss of economic productivity, with currently no causal treatment available. This review article focuses on current research on OA biomarkers and the potential for using biomarkers in future clinical practice and clinical trials of investigational drugs. We discuss how biomarkers, specifically soluble ones, have a long path to go before reaching clinical standards of care. We also discuss how biomarkers can help in phenotyping and subtyping to achieve enhanced stratification and move toward better-designed clinical trials. We also describe how biomarkers can be used for molecular endotyping and for determining the clinical outcomes of investigational cell-based therapies. Biomarkers have the potential to be developed as surrogate end points in clinical trials and help private-public consortia and the biotechnology and pharmaceutical industries develop more effective and targeted personalized treatments and enhance clinical care for patients with OA.

Case report: Anti septin-5-encephalitis as a treatable cause of cerebellar ataxia and psychiatric symptoms.

Objectives: Anti-septin-5 encephalitis is a rare disease with only few published cases, mainly based on retrospective CSF and serum analyses. Predominant symptoms are cerebellar ataxia and oculomotor abnormalities. Due to the rareness of the disease, treatment recommendations are scarce. Herein, we prospectively describe the clinical course of a female patient with anti-septin-5 encephalitis. Methods: We describe diagnostic workup, treatment and follow-up of a 54-year-old patient presenting with vertigo, unsteady gait, lack of drive and behavioral changes. Results: Clinical examination revealed severe cerebellar ataxia, saccadic smooth pursuit, upbeat-nystagmus, and dysarthria. Additionally, the patient presented with a depressive syndrome. MRI of the brain and spinal cord were normal. CSF analysis showed lymphocytic pleocytosis (11 cells/µl). Extensive antibody testing revealed anti septin-5 IgG in both CSF and serum without coexisting anti-neuronal antibodies. PET/CT detected no signs of malignancy. Corticosteroids, plasma exchange, and rituximab led to transient clinical improvement followed by relapse. Re-applied treatment with plasma exchange followed by bortezomib resulted in moderate but sustained clinical improvement. Discussion: Anti septin-5 encephalitis represents a rare but treatable and therefore relevant differential diagnosis in patients with cerebellar ataxia. Psychiatric symptoms can be observed in anti septin-5 encephalitis. Immunosuppressive treatment including bortezomib is moderately effective.

NOS inhibition reverses TLR2-induced chondrocyte dysfunction and attenuates age-related osteoarthritis.

Osteoarthritis (OA) is a joint disease featuring cartilage breakdown and chronic pain. Although age and joint trauma are prominently associated with OA occurrence, the trigger and signaling pathways propagating their pathogenic aspects are ill defined. Following long-term catabolic activity and traumatic cartilage breakdown, debris accumulates and can trigger Toll-like receptors (TLRs). Here we show that TLR2 stimulation suppressed the expression of matrix proteins and induced an inflammatory phenotype in human chondrocytes. Further, TLR2 stimulation impaired chondrocyte mitochondrial function, resulting in severely reduced adenosine triphosphate (ATP) production. RNA-sequencing analysis revealed that TLR2 stimulation upregulated nitric oxide synthase 2 (NOS2) expression and downregulated mitochondria function-associated genes. NOS inhibition partially restored the expression of these genes, and rescued mitochondrial function and ATP production. Correspondingly, Nos2-/- mice were protected from age-related OA development. Taken together, the TLR2-NOS axis promotes human chondrocyte dysfunction and murine OA development, and targeted interventions may provide therapeutic and preventive approaches in OA.

Periarticular muscle status affects in vivo tibio-femoral joint loads after total knee arthroplasty.

Background: Total knee arthroplasty (TKA) is a highly effective treatment for severe knee osteoarthritis that is increasingly performed in younger, more active patients. As postoperative muscular impairments may negatively affect surgical outcomes and implant longevity, functional muscle recovery gains increasing importance in meeting future patient demands. This study aimed to assess the status of periarticular muscles in the long-term follow-up after TKA and to evaluate its impact on in vivo tibio-femoral joint loads. Methods: A case series was created, with eight patients with knee osteoarthritis. All subjects received an instrumented knee implant in unilateral TKA. Native computed tomography scans, acquired pre and postoperatively, were used to evaluate distal muscle volumes and fatty infiltration. In vivo tibio-femoral joint loads were measured telemetrically during standing, walking, stair climbing and chair rising and were correlated to muscle status. Results: Postoperatively a reduction in fatty infiltration across all periarticular muscles was pronounced. High average peak loads acted in the tibio-femoral joint ranging from 264% during stand-to-sit activities up to 341% body weight (BW) during stair descent. Fatty infiltration of the m. quadriceps femoris and hamstrings were associated with increased tibio-femoral joint contact forces during walking (r = 0.542; 0.412 and 0.766). Conclusion: The findings suggest that a fatty infiltration of periarticular muscles may lead to increased tibio-femoral joint contact forces. However, we only observed weak correlations between these parameters. Improvements in functional mobility and the restoration of a pain-free joint likely explain the observed postoperative reductions in fatty infiltration. Perioperative rehabilitation approaches targeting residual impairments in muscle quality could, contribute to reduced tibio-femoral joint loads and improved long-term outcomes of TKA. However, it has to be pointed out that the study included a small number of patients, which may limit its validity.

Individual immune cell and cytokine profiles determine platelet-rich plasma composition.

OBJECTIVE: Platelet-rich plasma (PRP) therapy is increasingly popular to treat musculoskeletal diseases, including tendinopathies and osteoarthritis (OA). To date, it remains unclear to which extent PRP compositions are determined by the immune cell and cytokine profile of individuals or by the preparation method. To investigate this, we compared leukocyte and cytokine distributions of different PRP products to donor blood samples and assessed the effect of pro-inflammatory cytokines on chondrocytes. DESIGN: For each of three PRP preparations (ACP®, Angel™, and nSTRIDE® APS), products were derived using whole blood samples from twelve healthy donors. The cellular composition of PRP products was analyzed by flow cytometry using DURAClone antibody panels (DURAClone IM Phenotyping Basic and DURAClone IM T Cell Subsets). The MESO QuickPlex SQ 120 system was used to assess cytokine profiles (V-PLEX Proinflammatory Panel 1 Human Kit, Meso Scale Discovery). Primary human chondrocyte 2D and 3D in vitro cultures were exposed to recombinant IFN-γ and TNF-α. Proliferation and chondrogenic differentiation were quantitatively assessed. RESULTS: All three PRP products showed elevated portions of leukocytes compared to baseline levels in donor blood. Furthermore, the pro-inflammatory cytokines IFN-γ and TNF-α were significantly increased in nSTRIDE® APS samples compared to donor blood and other PRP products. The characteristics of all other cytokines and immune cells from the donor blood, including pro-inflammatory T cell subsets, were maintained in all PRP products. Chondrocyte proliferation was impaired by IFN-γ and enhanced by TNF-α treatment. Differentiation and cartilage formation were compromised upon treatment with both cytokines, resulting in altered messenger ribonucleic acid (mRNA) expression of collagen type 1A1 (COL1A1), COL2A1, and aggrecan (ACAN) as well as reduced proteoglycan content. CONCLUSIONS: Individuals with elevated levels of cells with pro-inflammatory properties maintain these in the final PRP products. The concentration of pro-inflammatory cytokines strongly varies between PRP products. These observations may help to unravel the previously described heterogeneous response to PRP in OA therapy, especially as IFN-γ and TNF-α impacted primary chondrocyte proliferation and their characteristic gene expression profile. Both the individual's immune profile and the concentration method appear to impact the final PRP product. TRIAL REGISTRATION: This study was prospectively registered in the Deutsches Register Klinischer Studien (DRKS) on 4 November 2021 (registration number DRKS00026175).

Optimization of chondrocyte isolation from human articular cartilage to preserve the chondrocyte transcriptome.

The isolation of chondrocytes from human articular cartilage for single-cell RNA sequencing requires extensive and prolonged tissue digestion at 37 C. Modulations of the transcriptional activity likely take place during this period such that the transcriptomes of isolated human chondrocytes no longer match their original status in vivo. Here, we optimized the human chondrocyte isolation procedure to maximally preserve the in vivo transcriptome. Cartilage tissues were transferred into a hypoxia chamber (4% O2) immediately after being removed from OA patients and minced finely. Collagenase II at concentrations of 0.02%, 0.1%, 0.25%, 0.5%, 1%, and 2% was applied for 0.5, 1, 2, 4, and 18 h to digest the minced tissue. Actinomycin D (ActD) was added to test its capacity in stabilizing the transcriptome. Cell yield, viability, cell size, and transcriptome were determined using counter chamber, flow cytometry, and RNA sequencing (RNA-seq). Collagenase II at 2% concentration released small chondrocytes from cartilage matrix during the first digestion hour and started to release large cells thereafter, reaching a complete release at 4 h. During 4-h digestions, collagenase II at 2% and 1% but not at lower concentrations yielded maximal release also of the large chondrocyte population. RNA-seq analysis revealed that a 4-h digestion period with 1% or 2% collagenase II plus Actinomycin D optimally preserved the transcriptome. Thus, this study provides an isolation protocol for single chondrocytes from human articular cartilage optimized for transcriptome preservation and RNA-seq analysis.

Scientific Productivity of University Orthopaedics and Trauma Surgery in Germany, Austria, and Switzerland. / Wissenschaftliche Produktivität der universitären Orthopädie und Unfallchirurgie in der DACH-Region.

BACKGROUND: Despite major achievements, such as the development of hip prostheses, scientific productivity in orthopaedics and trauma surgery has hardly been investigated. Our study's aim therefore was to analyse the correlation between the leading physicians' h-index and their academic rang, in order to determine whether this objective measure of scientific accomplishments correlates with clinical position. METHODS: All physicians in leading positions at university hospitals' orthopaedics or trauma surgery departments in Germany, Austria, and Switzerland were included. Year of habilitation, number of publications and citations as well as h-index were collected from September to November 2020. RESULTS: A total of 844 leading physicians at 46 university hospitals were included. Professors had the highest number of total publications (117.4 ± 124.8, p < 0.001) and highest h-index (20.1 ± 10.1, p < 0.001). We found significant differences in the total number of publications (p = 0.001), publications in the last three years (p < 0.001), and h-index (p < 0.001) between the three investigated nations, with all parameters being highest in Switzerland. CONCLUSION: Our study shows that increasing scientific productivity is correlated with academic success. The country-specific differences indicate significant differences in the value of scientific activity in daily clinical routine.

The Impact of Hip Dysplasia on CAM Impingement.

Predisposing factors for CAM-type femoroacetabular impingement (FAI) include acetabular protrusion and retroversion; however, nothing is known regarding development in dysplastic hips. The purpose of this study was to determine the correlation between CAM-type FAI and developmental dysplastic hips diagnosed using X-ray and rotational computed tomography. In this retrospective study, 52 symptomatic hips were included, with a mean age of 28.8 ± 7.6 years. The inclusion criteria consisted of consecutive patients who suffered from symptomatic dysplastic or borderline dysplastic hips and underwent a clinical examination, conventional radiographs and rotational computed tomography. Demographics, standard measurements and the rotational alignments were recorded and analyzed between the CAM and nonCAM groups. Among the 52 patients, 19 presented with CAM impingement, whereas, in 33 patients, no signs of CAM impingement were noticed. For demographics, no significant differences between the two groups were identified. On conventional radiography, the acetabular hip index as well as the CE angle for the development of CAM impingement were significantly different compared to the nonCAM group with a CE angle of 21.0° ± 5.4° vs. 23.7° ± 5.8° (p = 0.050) and an acetabular hip index of 25.6 ± 5.7 vs. 21.9 ± 7.3 (p = 0.031), respectively. Furthermore, a crossing over sign was observed to be more common in the nonCAM group, which is contradictory to the current literature. For rotational alignment, no significant differences were observed. In dysplastic hips, the CAM-type FAI correlated to a lower CE angle and a higher acetabular hip index. In contrast to the current literature, no significant correlations to the torsional alignment or to crossing over signs were observed.

Source and hub of inflammation: The infrapatellar fat pad and its interactions with articular tissues during knee osteoarthritis.

Knee osteoarthritis, the most prevalent degenerative joint disorder worldwide, is driven by chronic low-grade inflammation and subsequent cartilage degradation. Clinical data on the role of the Hoffa or infrapatellar fat pad in knee osteoarthritis are, however, scarce. The infrapatellar fat pad is a richly innervated intracapsular, extrasynovial adipose tissue, and an abundant source of adipokines and proinflammatory and catabolic cytokines, which may contribute to chronic synovial inflammation, cartilage destruction, and subchondral bone remodeling during knee osteoarthritis. How the infrapatellar fat pad interacts with neighboring tissues is poorly understood. Here, we review available literature with regard to the infrapatellar fat pad's interactions with cartilage, synovium, bone, menisci, ligaments, and nervous tissue during the development and progression of knee osteoarthritis. Signaling cascades are described with a focus on immune cell populations, pro- and anti-inflammatory cytokines, adipokines, mesenchymal stromal cells, and molecules derived from conditioned media from the infrapatellar fat pad. Understanding the complex interplay between the infrapatellar fat pad and its neighboring articular tissues may help to better understand and treat the multifactorial pathogenesis of osteoarthritis.

HIPGEN: a randomized, multicentre phase III study using intramuscular PLacenta-eXpanded stromal cells therapy for recovery following hip fracture arthroplasty : a study design.

AIMS: The aim of the HIPGEN consortium is to develop the first cell therapy product for hip fracture patients using PLacental-eXpanded (PLX-PAD) stromal cells. METHODS: HIPGEN is a multicentre, multinational, randomized, double-blind, placebo-controlled trial. A total of 240 patients aged 60 to 90 years with low-energy femoral neck fractures (FNF) will be allocated to two arms and receive an intramuscular injection of either 150 × 106 PLX-PAD cells or placebo into the medial gluteal muscle after direct lateral implantation of total or hemi hip arthroplasty. Patients will be followed for two years. The primary endpoint is the Short Physical Performance Battery (SPPB) at week 26. Secondary and exploratory endpoints include morphological parameters (lean body mass), functional parameters (abduction and handgrip strength, symmetry in gait, weightbearing), all-cause mortality rate and patient-reported outcome measures (Lower Limb Measure, EuroQol five-dimension questionnaire). Immunological biomarker and in vitro studies will be performed to analyze the PLX-PAD mechanism of action. A sample size of 240 subjects was calculated providing 88% power for the detection of a 1 SPPB point treatment effect for a two-sided test with an α level of 5%. CONCLUSION: The HIPGEN study assesses the efficacy, safety, and tolerability of intramuscular PLX-PAD administration for the treatment of muscle injury following arthroplasty for hip fracture. It is the first phase III study to investigate the effect of an allogeneic cell therapy on improved mobilization after hip fracture, an aspect which is in sore need of addressing for the improvement in standard of care treatment for patients with FNF. Cite this article: Bone Jt Open 2022;3(4):340-347.

Is Training With Gym Machines Safe After Hip Arthroplasty?-An In Vivo Load Investigation.

Background: Training with gym machines is one of the most popular physical activities after total hip arthroplasty (THA). However, to date, there are no evidence-based recommendations for physical activity after THA, worldwide. The aim of the study is to evaluate the in vivo hip joint loads during exercises on four widely used gym machines in order to provide a source for an evidence-based patient counselling for arthroplasty surgeons. Methods: The in vivo hip joint loads in seven patients (59.6 ± 6.4 years, 28.6 ± 2.1 kg/m2) with instrumented hip implants were assessed. The resulting force (Fres), bending moment (Mbend), and torsional moment (Mtors) were evaluated during the training on leg curl/leg extension machines (loads: 20, 30, and 40 kg), leg press machine [backrest: 10°, 30°, and 60°; load: 50, 75, and 100%BW (bodyweight)], and a rope pull machine (abduction/adduction/flexion/extension; each ipsi- and contralateral; load 10 kg). These loads were compared with the loads during walking on treadmill at 4 km/h (median peak values: Fres 303%BW, Mbend 4.25%BWm, and Mtors 2.70%BWm). Results: In each of the four performed exercises with a total of 23 different load conditions or exercise modes analyzed, a significantly lower or not different load was detected with respect to Fres, Mbend, and Mtors measured while walking with 4 km/h. Nevertheless, Fres and Mbend demonstrated a trend to increased loading during the ipsilateral monopod standing rope pull exercises hip flexion, extension, and abduction. Conclusion: Based on our investigation, we assume that the investigated gym machines and external loads can be considered mainly as low-impact sports (with some exceptions) and thus as safe physical activity after THA. Due to the fact that the examinations were conducted in the mean 17.4 months after THA, the applicability of the results to the immediate postoperative period is limited.