Osteoarthritis Clinical Trials Research Articles

Osteoarthritis year in review 2024: Imaging

ObjectiveTo review recent literature evidence describing imaging of osteoarthritis (OA) and to identify the current trends in research on OA imaging. MethodThis is a narrative review of publications in English, published between April, 2023, and March, 2024. A Pubmed search was conducted using the following search terms: osteoarthritis/OA, radiography, ultrasound/US, computed tomography/CT, magnetic resonance imaging/MRI, DXA/DEXA, and artificial intelligence/AI/deep learning. Most publications focus on OA imaging in the knee and hip. Imaging of OA in other joints and OA imaging with artificial intelligence (AI) are also reviewed. ResultsCompared to the same period last year (April 2022 – March 2023), there has been no significant change in the number of publications utilizing CT, MRI, and artificial intelligence. A notable reduction in the number of OA research papers using radiography and ultrasound is noted. There were several observational studies focusing on imaging of knee OA, such as the Multicenter Osteoarthritis Study, Rotterdam Study, Strontium ranelate efficacy in knee OA (SEKOIA) study, and the Osteoarthritis Initiative FNIH Biomarker study. Hip OA observational studies included, but not limited to, Cohort Hip and Cohort Knee study and UK Biobank study. Studies on emerging applications of AI in OA imaging were also covered. A small number of OA clinical trials were published with a focus on imaging-based outcomes. ConclusionMRI-based OA imaging research continues to play an important role compared to other modalities. Usage of various AI tools as an adjunct to human assessment is increasingly applied in OA imaging research.

Measuring the effect of the anti-nerve growth factor antibodies bedinvetmab and frunevetmab on quality of life in dogs and cats with osteoarthritis using a validated health-related quality of life outcome measure: an observational real-world study.

Osteoarthritis causes chronic pain, impaired joint function, decreased mobility and negatively impacts quality of life (QOL). Anti-nerve growth factor antibodies bedinvetmab for dogs and frunevetmab for cats are licensed for the alleviation of osteoarthritis pain but their QOL impact is unreported. Our aim was to determine if these therapeutics improve QOL using a validated health-related QOL measure that generates scores in four domains of QOL-energetic and enthusiastic (E/E), happy and content (H/C), active and comfortable (A/C) and calm and relaxed (C/R)-in the dog and three in the cat-vitality, comfort and emotional wellbeing (EWB). Summary scores for physical wellbeing (PWB) and emotional wellbeing (EWB) for dogs and PWB for cats are calculated from the domain scores. Animals received bedinvetmab (dogs) at 0.5-1 mg/kg or frunevetmab (cats) at 1-2.8 mg/kg by subcutaneous injection on days 0, 28 and 56 and owners completed QOL assessments within 48 hours of day 0 and on days 14, 28, 56, 63 and 70 using a study-specific app. Assessments were completed by 75 dog and 56 cat owners. By day 14 there was a statistically significant improvement (p ≤ 0.001) in PWB, EWB and all domains except C/R (p = 0.005) in dogs and in all domains and PWB in the cat. Subsequently there was a continued improvement in all domains and summary scores (p ≤ 0.001) except for H/C in the dog and EWB in the cat, which were excluded from the statistical model. The overall improvement in all domain scores in the cat and E/E and A/C in the dog exceeded the previously reported minimum important difference scores for the QOL measure, indicating a clinically significant change. Treatment with bedinvetmab and frunevetmab produced a significant improvement in the QOL of dogs and cats. This latest evidence for the use of these OA pain medications could be helpful in the clinical management of osteoarthritis and post-marketing clinical trials.

ELIXCYTE®, an Allogenic Adipose-Derived Stem Cell Product, Mitigates Osteoarthritis by Reducing Inflammation and Preventing Cartilage Degradation In Vitro.

Adipose-derived stem cells (ADSCs) comprise a promising therapy for osteoarthritis (OA). The therapeutic potential of ELIXCYTE®, an allogeneic human ADSC (hADSC) product, was demonstrated in a phase I/II OA clinical trial. However, the exact mechanism underlying such effects is not clear. Moreover, studies suggest that interleukin-11 (IL-11) has anti-inflammatory, tissue-regenerative, and immune-regulatory functions. Our aim was to unravel the mechanism associated with the therapeutic effects of ELIXCYTE® on OA and its relationship with IL-11. We cocultured ELIXCYTE® with normal human articular chondrocytes (NHACs) in synovial fluid obtained from individuals with OA (OA-SF) to investigate its effect on chondrocyte matrix synthesis and degradation and inflammation by assessing gene expression and cytokine levels. NHACs exposed to OA-SF exhibited increased MMP13 expression. However, coculturing ELIXCYTE® with chondrocytes in OA-SF reduced MMP13 expression in chondrocytes and downregulated PTGS2 and FGF2 expression in ELIXCYTE®. ELIXCYTE® treatment elevated anti-inflammatory cytokine (IL-1RA, IL-10, and IL-13) levels, and the reduction in MMP13 was positively correlated with IL-11 concentrations in OA-SF. These findings indicate that IL-11 in OA-SF might serve as a predictive biomarker for the ELIXCYTE® treatment response in OA, emphasizing the therapeutic potential of ELIXCYTE® to mitigate OA progression and provide insights into its immunomodulatory effects.

The design of a sample rapid magnetic resonance imaging (MRI) acquisition protocol supporting assessment of multiple articular tissues and pathologies in knee osteoarthritis

ObjectiveThis expert opinion paper proposes a design for a state-of-the-art magnetic resonance image (MRI) acquisition protocol for knee osteoarthritis clinical trials in early and advanced disease. Semi-quantitative and quantitative imaging endpoints are supported, partly amendable to automated analysis. Several (peri-) articular tissues and pathologies are covered, including synovitis. MethodA PubMed literature search was conducted, with focus on the past 5 years. Further, osteoarthritis imaging experts provided input. Specific MRI sequences, orientations, spatial resolutions and parameter settings were identified to align with study goals. We strived for implementation on standard clinical scanner hardware, with a net acquisition time ≤30 ​min. ResultsShort- and long-term longitudinal MRIs should be obtained at ≥1.5T, if possible without hardware changes during the study. We suggest a series of gradient- and spin-echo-sequences, supporting MOAKS, quantitative analysis of cartilage morphology and T2, and non-contrast-enhanced depiction of synovitis. These sequences should be properly aligned and positioned using localizer images. One of the sequences may be repeated in each participant (re-test), optimally at baseline and follow-up, to estimate within-study precision. All images should be checked for quality and protocol-adherence as soon as possible after acquisition. Alternative approaches are suggested that expand on the structural endpoints presented. ConclusionsWe aim to bridge the gap between technical MRI acquisition guides and the wealth of imaging literature, proposing a balance between image acquisition efficiency (time), safety, and technical/methodological diversity. This approach may entertain scientific innovation on tissue structure and composition assessment in clinical trials on disease modification of knee osteoarthritis.

Cartilage Collagen Neoepitope C2C Expression in the Articular Cartilage and Its Relation to Joint Tissue Damage in Patients with Knee Osteoarthritis.

Pathological cleavage of type II collagen (Col2) and generation of Col2 neoepitopes can serve as useful molecular markers of the progression of osteoarthritis (OA). One of such potential biomarkers is type II collagen neoepitope C2C. The aim of this study was to correlate the degree of articular cartilage damage in OA patients with C2C expression in histological samples of tissues removed during total knee replacement. Cartilage samples were obtained from 27 patients ranging in age from 55 to 66 years. In each patient, medial and lateral tibia plateau samples were analyzed according to the OARSI histopathology grading system. The C2C expression was evaluated on histological slides by semi-quantitative analysis using ImageJ Fiji 2.14.0 software. Spearman's rank correlation analysis revealed a positive weak correlation (rho = 0.289, p = 0.0356) between the histological grade of tissue damage and the percentage of C2C staining. In addition, a highly significant positive correlation (rho = 0.388, p = 0.0041) was discovered between the osteoarthritis score (combining the histological grade of damage with the OA macroscopic stage) and the percentage of C2C staining in the samples. The C2C expression was detected in all the regions of the articular cartilage (i.e., the superficial zone, mid zone, deep zone and tidemark area, and the zone of calcified cartilage). Our findings imply that local expression of C2C correlates with the articular cartilage damage in OA-affected knees. This confirms that C2C can be used as a prospective marker for assessing pathological changes in the OA course and OA clinical trials.

Effect size varies based on calculation method and may affect interpretation of treatment effect: an illustration using randomised clinical trials in osteoarthritis

BackgroundTo illustrate how (standardised) effect sizes (ES) vary based on calculation method and to provide considerations for improved reporting.MethodsData from three trials of tanezumab in subjects with osteoarthritis were analyzed. ES of tanezumab versus comparator for WOMAC Pain (outcome) was defined as least squares difference between means (mixed model for repeated measures analysis) divided by a pooled standard deviation (SD) of outcome scores. Three approaches to computing the SD were evaluated: Baseline (the pooled SD of WOMAC Pain values at baseline [pooled across treatments]); Endpoint (the pooled SD of these values at the time primary endpoints were assessed); and Median (the median pooled SD of these values based on the pooled SDs across available timepoints). Bootstrap analyses were used to compute 95% confidence intervals (CI).ResultsES (95% CI) of tanezumab 2.5 mg based on Baseline, Endpoint, and Median SDs in one study were − 0.416 (− 0.796, − 0.060), − 0.195 (− 0.371, − 0.028), and − 0.196 (− 0.373, − 0.028), respectively; negative values indicate pain improvement. This pattern of ES differences (largest with Baseline SD, smallest with Endpoint SD, Median SD similar to Endpoint SD) was consistent across all studies and doses of tanezumab.ConclusionDifferences in ES affect interpretation of treatment effect. Therefore, we advocate clearly reporting individual elements of ES in addition to its overall calculation. This is particularly important when ES estimates are used to determine sample sizes for clinical trials, as larger ES will lead to smaller sample sizes and potentially underpowered studies.Trial RegistrationClinicaltrials.gov NCT02697773, NCT02709486, and NCT02528188.

MiR-29a-3p mediates phosphatase and tensin homolog and inhibits osteoarthritis progression.

Despite substantial progress in clinical trials of osteoarthritis (OA) gene therapy, the prevalence of OA is still on the rise. MiRNAs have a potential biomarker and therapeutic target for OA. OA cartilage and chondrosarcoma cells were studied to determine the role of miR-29a-3p and PTEN. OA cartilage and human chondrosarcoma cells (SW1353) were obtained. miR-29a-3p and PTEN signature expression was determined by RT-qPCR. The binding relationship between miR-29a-3p and PTEN was investigated by dual-luciferase reporter gene and western blot assay. TUNEL, immunohistochemistry, CCK-8, and flow cytometry were utilized to determine the proliferation and apoptosis of SW1353 cells. This study indicated downregulation of miR-29a-3p expression and upregulation of PTEN expression in human OA primary chondrocytes or OA tissue samples, compared with the normal cartilage cells or tissues. PTEN expression was negatively correlated with miR-29a-3p expression, and miR-29a-3p targeted PTEN mechanistically. miR-29a-3p reduced SW1353 cell activity and proliferation and promoted cell apoptosis. However, the aforementioned effects could be reversed by downregulating PTEN. miR-29a-3p can stimulate chondrocyte proliferation and inhibit apoptosis by inhibiting PTEN expression.

Unveiling MRI-based structural phenotypes in temporomandibular joint osteoarthritis: implications for clinical practice and research.

Osteoarthritis (OA) is a progressive degenerative disease characterized by the gradual degradation of cartilage, remodeling of subchondral bone, synovitis, and chronic pain. This condition impacts various large and small joints, including the temporomandibular joint (TMJ). However, addressing OA, particularly in impeding or reducing disease progression, is challenging due to its clinical and imaging heterogeneity. Authors are increasingly suggesting that this heterogeneity involves different phenotypes or subpopulations, discernible by variations in the disease's pathophysiology and structural manifestations. Even within the TMJ, these phenotypes may display distinct clinical features, laboratory parameters, biochemical markers, and imaging criteria. Recent research has proposed MRI as a reference standard for TMJ OA, highlighting its substantial agreement with histopathological changes. MRI-based phenotypes offer a promising avenue for understanding disease progression and treatment response, potentially providing valuable insights for prognosis and treatment planning. This article introduces the ROAMES-TMJ (Rapid OsteoArthritis MRI Eligibility Score for TMJ) to assess the structural eligibility of individuals for inclusion in TMJ OA clinical trials.

Placebo effects in osteoarthritis: implications for treatment and drug development.

Osteoarthritis (OA) is the most common form of arthritis worldwide, affecting ~500 million people, yet there are no effective treatments to halt its progression. Without any structure-modifying agents, management of OA focuses on ameliorating pain and improving function. Treatment approaches typically have modest efficacy, and many patients have contraindications to recommended pharmacological treatments. Drug development for OA is hindered by the gradual and progressive nature of the disease and the targeting of established disease in clinical trials. Additionally, new medications for OA cannot receive regulatory approval without demonstrating improvements in both structure (pathological features of OA) and symptoms (reduced pain and/or improved function). In clinical trials, people with OA show high 'placebo responses', which hamper the ability to identify new effective treatments. Placebo responses refer to the individual variability in response to placebos given in the context of clinical trials and other settings. Placebo effects refer specifically to short-lasting improvements in symptoms that occur because of physiological changes. To mitigate the effects of the placebo phenomenon, we must first understand what it is, how it manifests, how to identify placebo responders in OA trials and how these insights can be used to improve clinical trials in OA. Leveraging placebo responses andeffects in clinical practice might provide additional avenues to augment symptom management of OA.

Development and validation of a machine learning-supported strategy of patient selection for osteoarthritis clinical trials: the IMI-APPROACH study

ObjectivesTo efficiently assess the disease-modifying potential of new osteoarthritis treatments, clinical trials need progression-enriched patient populations. To assess whether the application of machine learning results in patient selection enrichment, we developed a machine learning recruitment strategy targeting progressive patients and validated it in the IMI-APPROACH knee osteoarthritis prospective study. DesignWe designed a two-stage recruitment process supported by machine learning models trained to rank candidates by the likelihood of progression. First stage models used data from pre-existing cohorts to select patients for a screening visit. The second stage model used screening data to inform the final inclusion. The effectiveness of this process was evaluated using the actual 24-month progression. ResultsFrom 3500 candidate patients, 433 with knee osteoarthritis were screened, 297 were enrolled, and 247 completed the 2-year follow-up visit. We observed progression related to pain (P, 30%), structure (S, 13%), and combined pain and structure (P ​+ ​S, 5%), and a proportion of non-progressors (N, 52%) ∼15% lower vs an unenriched population. Our model predicted these outcomes with AUC of 0.86 [95% CI, 0.81–0.90] for pain-related progression and AUC of 0.61 [95% CI, 0.52–0.70] for structure-related progression. Progressors were ranked higher than non-progressors for P ​+ ​S (median rank 65 vs 143, AUC = 0.75), P (median rank 77 vs 143, AUC = 0.71), and S patients (median rank 107 vs 143, AUC = 0.57). ConclusionsThe machine learning-supported recruitment resulted in enriched selection of progressive patients. Further research is needed to improve structural progression prediction and assess this strategy in an interventional trial.

A call for screening MRI as a tool for osteoarthritis clinical trials.

Conventional radiography is the most commonly used imaging modality for the evaluation of osteoarthritis (OA) in clinical trials of disease-modifying OA drugs (DMOADs). Unfortunately, radiography has many shortcomings as an imaging technique to meaningfully assess the pathological features of OA. In this perspective paper, we will describe the reasons why radiography is not an ideal tool for structural OA assessment and why magnetic resonance imaging (MRI) should be preferred for such purposes. These shortcomings include a lack of reproducibility of radiographic joint space measurements (if conducted without using a standardized positioning frame), a lack of sensitivity and specificity, an insufficient definition of disease severity, a weak association of radiographic structural damage and pain, a lack of ability to depict many faces of OA, and incapability to depict diagnoses of exclusion. MRI offers solutions to these limitations of radiography. Several different phenotypes of OA have been recognized and it is important to recruit appropriate patients for specific therapeutic approaches in DMOAD trials. Radiography does not allow such phenotypical stratification. We will explain known hurdles for widespread deployment of MRI at eligibility screening and how they can be overcome by technological advances and the use of simplified image assessment.

Mesenchymal Stromal Cells Laden in Hydrogels for Osteoarthritis Cartilage Regeneration: A Systematic Review from In Vitro Studies to Clinical Applications.

This systematic review is focused on the main characteristics of the hydrogels used for embedding the mesenchymal stromal cells (MSCs) in in vitro/ex vivo studies, in vivo OA models and clinical trials for favoring cartilage regeneration in osteoarthritis (OA). PubMED and Embase databases were used to select the papers that were submitted to a public reference manager Rayyan Systematic Review Screening Software. A total of 42 studies were considered eligible: 25 articles concerned in vitro studies, 2 in vitro and ex vivo ones, 5 in vitro and in vivo ones, 8 in vivo ones and 2 clinical trials. Some in vitro studies evidenced a rheological characterization of the hydrogels and description of the crosslinking methods. Only 37.5% of the studies considered at the same time chondrogenic, fibrotic and hypertrophic markers. Ex vivo studies focused on hydrogel adhesion properties and the modification of MSC-laden hydrogels subjected to compression tests. In vivo studies evidenced the effect of cell-laden hydrogels in OA animal models or defined the chondrogenic potentiality of the cells in subcutaneous implantation models. Clinical studies confirmed the positive impact of these treatments on patients with OA. To speed the translation to the clinical use of cell-laden hydrogels, further studies on hydrogel characteristics, injection modalities, chemo-attractant properties and adhesion strength are needed.

Placebo gait retraining for use in knee osteoarthritis clinical trials does not change surrogate knee load measures: A randomized pilot study

Introduction: Gait retraining is a novel management strategy which has shown ability to reduce pain and the peak knee adduction moment (KAM) (a surrogate measure of medial knee load) in people with medial knee osteoarthritis. However, no published study has compared gait retraining to placebo gait retraining (a gait change which does not affect KAM). Therefore, it is unknown whether pain improvement with gait retraining is due to KAM reduction. Our primary aim was to determine knee joint loading outcomes during placebo, toe-in, and toe-out gait retraining compared to baseline.

Placebo Response to Oral Administration in Osteoarthritis Clinical Trials and Its Associated Factors

In osteoarthritis (OA) clinical trials, a placebo is often used as control. Therefore, a thorough understanding of the placebo response is important for guiding drug development in OA. To develop an oral placebo response model for OA. PubMed, EMBASE, and Cochrane Library databases were searched systematically from January 1, 1991, to July 2, 2022. Randomized double-blind placebo-controlled trials of patients with primary OA were included. The interventions and placebo were administered orally. A total of 3032 trials were identified; of these, 130 (4.3%) met the inclusion criteria. Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) scores, dosage form of the placebo, sample size, proportion of patients who previously used nonsteroidal anti-inflammatory drugs, publication year, intervention categories, Kellgren-Lawrence grades, proportion of White patients, duration of pain, funding source, and risk of bias were extracted. A model-based meta-analysis was used to evaluate the time course of the placebo response in OA treatment and estimate the influencing factors. For subgroup analyses, a meta-analysis with a random-effects model was used to summarize the typical values of the model parameters and their SEs. The primary end point was the time course of the oral placebo response on the WOMAC pain, stiffness, and function subscale scores. The 130 trials selected for analysis included 12 673 participants (mean age, 59.9 years; 68.9% women). The baseline scores of WOMAC pain, stiffness, and function subscales were found to be significantly associated with the placebo response. The placebo response reached 90% of its maximum response between 5 and 7 weeks. The placebo responses on the WOMAC subscales were also associated with the sample size, proportion of patients who had previously used nonsteroidal anti-inflammatory drugs, intervention drugs, and publication year. In this study, an oral placebo response model of OA was developed that may quantitatively describe the placebo response at different baseline levels of symptoms. The findings may provide valuable references for future clinical trial design and decision-making.

Astragalin mitigates inflammatory osteolysis by negatively modulating osteoclastogenesis via ROS and MAPK signaling pathway

Inflammatory bone destruction has gradually attracted attention worldwide and has been observed in several kinds of pathological bone diseases, such as osteoarthritis, osteomyelitis, rheumatic arthritis, and other infectious clinical trials in the skeletal system. In this regard, excessive osteoclasts and bone resorption activity participate in osteolytic processes. Thus, negatively modulating osteoclast differentiation and bone erosion has been considered an effective therapeutic strategy to limit the poor progression of inflammatory osteolysis. Astragalin (AST) is a bioactive component of traditional Chinese drugs, such as Rosa agrestis, which presents anti-inflammatory and antioxidant effects. However, it is unclear how AST may play an essential role in regulating the dynamic balance of the bone matrix by affecting osteoclastogenesis. This study found that AST could inhibit osteoclastic formation and bone resorption activity in a dose‐dependent manner without cytotoxicity. Administration of AST also inhibited the expression of cathepsin K, c-Fos, NFATc1, and TRAP at different stages of mRNA and protein levels during osteoclastogenesis. Reactive oxygen species (ROS) signalling could also be modulated by treatment with AST during RANKL-induced osteoclast differentiation through the Nrf2-HO1 signalling pathway. Additionally, AST could negatively regulate mitogen-activated protein kinase (MAPK) signalling in this process. In vivo, AST significantly reduced lipopolysaccharide (LPS)-induced bone loss in an osteolytic mouse model. AST might be a promising therapeutic candidate for treating osteolytic bone diseases in the future.

Responsiveness of an activity tracker as a measurement tool in a knee osteoarthritis clinical trial (ACTIVe-OA study).

In osteoarthritis (OA) clinical trials, reliable and responsive outcome measures to document physical and functional improvements are limited. This study aimed to assess whether the use of an activity tracker in an OA clinical trial is a responsive measurement tool. Secondary objectives assessed feasibility and validity. We recruited 65 participants in a prospective cohort study nested in a placebo-controlled clinical trial of platelet-rich plasma injection in knee OA. Participants wore an activity tracker (Fitbit Flex 2), and a smartphone was preloaded with a mobile application (OApp) designed to monitor load rates as a surrogate of knee loading. Participants used the systems for 7 days at baseline and for 7 days before the 2-month follow-up assessment. Effect size (ES) and standardised response mean (SRM) were calculated for change in step count and knee loading rate and regularly used knee OA outcome measures. Correlation coefficients (r) were calculated to examine the strength of the association between outcome measures. . Step count showed a trivial ES and SRM and mean knee loading rate measurements a moderate ES and SRM. We found a weak but significant correlation between change in mean steps per day and global improvement overall (r=0.28) and Western Ontario and McMaster Universities Osteoarthritis Index function (r=-0.28). Compliance was high with the activity trackers. Despite good feasibility, this study did not show significant responsiveness or validity of the activity trackers as compared with currently recommended outcome measures in OA clinical trials. The main challenge is the lack of a gold standard outcome measure to validate against, and because of the complex interplay between pain and measured function, a lack of correlation does not necessarily represent a failed validation in this context. ACTRN12617000853347. This trial is a substudy of the "Platelet-rich plasma as a symptom-and disease-modifying treatment for knee osteoarthritis - the RESTORE trial".

The Science of Placebo, to Understand the Importance of Placebo Effects in OA:

A placebo is an inert substance that produces beneficial therapeutic effects. In the context of clinical trials, the placebo response refers to an improvement in symptoms in study participants assigned to placebo treatment. High placebo responses pose a substantial impediment to distinguishing active treatment effects and may in part account for the failure to identify effective treatments in clinical trials in osteoarthritis (OA) and other conditions. The treatment response to placebos has been to linked to an effect on opioid receptors in the brain.

NOVEL COMPOSITE ENDPOINT FOR SEVERE KNEE OSTEOARTHRITIS STATUS

Purpose: Knee osteoarthritis (OA) is a degenerative disease associated with pain, loss of function and possible need for total knee replacement (TKR). TKR is driven by disease severity and many other non-clinical factors; consequently, studying TKR endpoints for OA clinical trials has not been optimal. The recent report from Kim et al. (Kim et al., 2020) proposes the use of composite clinical endpoints based on combinations of severe pain and/or functional impairment utilizing WOMAC (Likert version) or the occurrence of TKR.

Heterogeneity of cartilage damage in Kellgren and Lawrence grade 2 and 3 knees: the MOST study

Eligibility for clinical trials in osteoarthritis (OA) is usually limited to Kellgren-Lawrence (KL) grades 2 and 3 knees. Our aim was to describe the prevalence and severity of cartilage damage in KL 2 and 3 knees by compartment and articular subregion. The Multicenter Osteoarthritis (MOST) study is a cohort study of individuals with or at risk for knee OA. All baseline MRIs with radiographic disease severity KL2 and 3 were included. Knee MRIs were read for cartilage damage in 14 subregions. We determined the frequencies of no, any and widespread full-thickness cartilage damage by knee compartment, and the prevalence of any cartilage damage in 14 articular subregions. 665 knees from 665 participants were included (mean age 63.8±7.9 years, 66.5% women). 372 knees were KL2 and 293 knees were KL3. There was no cartilage damage in 78 (21.0%) medial tibio-femoral joint (TFJ), 157 (42.2%) lateral TFJ and 62 (16.7%) patello-femoral joint (PFJ) compartments of KL2 knees, and 17 (5.8%), 115 (39.3%) and 35 (12.0%) compartments, respectively, of KL3 knees. There was widespread full-thickness damage in 94 (25.3%) medial TFJ, 36 (9.7%) lateral TFJ and 176 (47.3%) PFJ compartments of KL2 knees, and 217 (74.1%), 70 (23.9%) and 104 (35.5%) compartments, respectively, of KL3 knees. The subregions most likely to have any damage were central medial femur (80.5%), medial patella (69.8%) and central medial tibia (69.9). KL2 and KL3 knees vary greatly in cartilage morphology. Heterogeneity in the prevalence, severity and location of cartilage damage in in KL2 and 3 knees should be considered when planning disease modifying trials for knee OA.

The current state of the osteoarthritis drug development pipeline: a comprehensive narrative review of the present challenges and future opportunities.

In this narrative review article, we critically assess the current state of the osteoarthritis (OA) drug development pipeline. We discuss the current state-of-the-art in relation to the development and evaluation of candidate disease-modifying OA drugs (DMOADs) and the limitations associated with the tools and methodologies that are used to assess outcomes in OA clinical trials. We focus on the definition of DMOADs, highlight the need for an updated definition in the form of a consensus statement from all the major stakeholders, including academia, industry, regulatory agencies, and patient organizations, and provide a summary of the results of recent clinical trials of novel DMOAD candidates. We propose that DMOADs should be more appropriately targeted and investigated according to the emerging clinical phenotypes and molecular endotypes of OA. Based on the findings from recent clinical trials, we propose key topics and directions for the development of future DMOADs.