Performance of Radiological and Biochemical Biomarkers in Predicting Radio-Symptomatic Knee Osteoarthritis Progression.

Imaging biomarkers permit improved approaches to identify the most at-risk patients encountering knee osteoarthritis (KOA) progression. This study aimed to investigate the utility of trabecular bone texture (TBT) extracted from plain radiographs, associated with a set of clinical, biochemical, and radiographic data, as a predictor of long-term radiographic KOA progression. We used data from the Foundation for the National Institutes of Health (FNIH) Biomarkers Consortium dataset. The reference model made use of baseline TBT parameters adjusted for clinical covariates and radiological scores. Several models based on a combination of baseline and 24-month TBT variations (TBT∆TBT) were developed using logistic regression and compared to those based on baseline-only TBT parameters. All models were adjusted for baseline clinical covariates, radiological scores, and biochemical descriptors. The best overall performances for the prediction of radio-symptomatic, radiographic, and symptomatic progression were achieved using TBT∆TBT parameters solely, with area under the ROC curve values of 0.658 (95% CI: 0.612-0.705), 0.752 (95% CI: 0.700-0.804), and 0.698 (95% CI: 0.641-0.756), respectively. Adding biochemical markers did not significantly improve the performance of the TBT∆TBT-based model. Additionally, when TBT values were taken from the entire subchondral bone rather than just the medial, lateral, or central compartments, better results were obtained.

Short-term variations in trabecular bone texture parameters associated to radio-clinical biomarkers improve the prediction of radiographic knee osteoarthritis progression.

The present study aims to examine whether the short-term variations in trabecular bone texture (TBT) parameters, combined with a targeted set of clinical and radiographic data, would improve the prediction of long-term radiographic knee osteoarthritis (KOA) progression. Longitudinal (baseline, 24 and 48-month) data, obtained from the Osteoarthritis Initiative cohort, were available for 1352 individuals, with preexisting OA (1 < Kellgren-Lawrence < 4) at baseline. KOA progression was defined as an increase in the medial joint space narrowing score from the 24-months to the 48-months control point. 16 regions of interest were automatically selected from each radiographic knee and analyzed using fractal dimension. Variations from baseline to 24 months in TBT descriptors as well as selected radiographic and clinical readings were calculated. Different logistic regression models were developed to evaluate the progression prediction performance when associating TBT variations with the selected clinical and radiographic readings. The most predictive model was mainly determined using the area under the receiver operating characteristic curve (AUC). The proposed prediction model including short-term variations in TBT parameters, associated with clinical covariates and radiographic scores, improved the capacity of predicting long-term radiographic KOA progression (AUC of 0.739), compared to models based solely on baseline values (AUC of 0.676, p-value < 0.008).

Effectiveness of Shiatsu on Fatigue in Patients with Axial Spondyloarthritis: Protocol for a Randomized Cross-Over Pilot Study.

INTRODUCTION: Spondyloarthritis (SpA) is a serious chronic inflammatory rheumatism implying different painful and crippling symptoms that require a multidisciplinary approach for the patient. Fatigue is one of the less well treated symptoms, even if its repercussion on everyday life is noticeable. Shiatsu is a Japanese preventive and well-being therapy that aims to promote better health. However, the effectiveness of shiatsu in SpA-associated fatigue has never been studied yet in a randomized study. METHODS AND ANALYSIS: We describe the design of SFASPA (Etude pilote randomisée en cross-over évaluant l'efficacité du Shiatsu sur la FAtigue des patients atteints de SPondyloarthrite Axiale), a single-center, randomized controlled cross-over trial with allocation of patients according to a ratio (1:1) evaluating the effectiveness of shiatsu in SpA-associated fatigue. The sponsor is the Regional Hospital of Orleans, France. The two groups of 60 patients each will receive three "active" shiatsu and three sham shiatsu treatments (120 patients, 720 shiatsu). The wash-out period between the active and the sham shiatsu treatments is 4 months. PLANNED OUTCOMES: The primary outcome is the percentage of patients responding to the FACIT-fatigue score. A response to fatigue is defined as an improvement, i.e., an increase of ≥ 4 points in the FACIT-fatigue score, which corresponds to the "minimum clinically important difference" (MCID). Differences in the evolution of activity and impact of the SpA will be assessed on several secondary outcomes. An important aim of this study is also to gather material for further trials with higher proof of evidence. TRIAL REGISTRATION: NCT05433168, date of registration, June 21st, 2022 (clinicaltrials.gov).

Novel insights into the anatomy and histopathology of the sacroiliac joint and correlations with imaging signs of sacroiliitis in case of axial spondyloarthritis.

For a better understanding of the pathophysiology of spondyloarthropathy (SpA), a detailed anatomical description of the sacroiliac joint is required because sacroiliitis is the earliest and most common sign of SpA and an essential feature for the diagnosis of ankylosing spondylitis. Beyond the anatomy, the histopathology of sacroiliac entheses and immunological mechanisms involved in sacroiliitis are crucial for a better understanding of disease causation. In this narrative review, we discuss the core anatomical, histological, and immunohistological observations involved in the development of sacroiliitis, focusing particularly on imaging-based information associated with sacroiliitis. Finally, we try to answer the question of whether at the sacroiliac joint, enthesitis precedes synovitis and subchondral bone changes in SpA.

Radiographic Biomarkers for Knee Osteoarthritis: A Narrative Review.

Conventional radiography remains the most widely available imaging modality in clinical practice in knee osteoarthritis. Recent research has been carried out to develop novel radiographic biomarkers to establish the diagnosis and to monitor the progression of the disease. The growing number of publications on this topic over time highlights the necessity of a renewed review. Herein, we propose a narrative review of a selection of original full-text articles describing human studies on radiographic imaging biomarkers used for the prediction of knee osteoarthritis-related outcomes. To achieve this, a PubMed database search was used. A total of 24 studies were obtained and then classified based on three outcomes: (1) prediction of radiographic knee osteoarthritis incidence, (2) knee osteoarthritis progression and (3) knee arthroplasty risk. Results showed that numerous studies have reported the relevance of joint space narrowing score, Kellgren-Lawrence score and trabecular bone texture features as potential bioimaging markers in the prediction of the three outcomes. Performance results of reviewed prediction models were presented in terms of the area under the receiver operating characteristic curves. However, fair and valid comparisons of the models' performance were not possible due to the lack of a unique definition of each of the three outcomes.

Gene Expression and Chondrogenic Potential of Cartilage Cells: Osteoarthritis Grade Differences.

Recent data suggest that cells isolated from osteoarthritic (OA) cartilage express mesenchymal progenitor cell (MPC) markers that have the capacity to form hyaline-like cartilage tissue. Whether or not these cells are influenced by the severity of OA remains unexplored. Therefore, we analyzed MPC marker expression and chondrogenetic potential of cells from mild, moderate and severe OA tissue. Human osteoarthritic tibial plateaus were obtained from 25 patients undergoing total knee replacement. Each sample was classified as mild, moderate or severe OA according to OARSI scoring. mRNA expression levels of MPC markers-CD105, CD166, Notch 1, Sox9; mature chondrocyte markers-Aggrecan (Acan), Col II A1, hypertrophic chondrocyte and osteoarthritis-related markers-Col I A1, MMP-13 and ALPL were measured at the tissue level (day 0), after 2 weeks of in vitro expansion (day 14) and following chondrogenic in vitro re-differentiation (day 35). Pellet matrix composition after in vitro chondrogenesis of different OA-derived cells was tested for proteoglycans, collagen II and I by safranin O and immunofluorescence staining. Multiple MPC markers were found in OA cartilage resident tissue within a single OA joint with no significant difference between grades except for Notch1, which was higher in severe OA tissues. Expression levels of CD105 and Notch 1 were comparable between OA cartilage-derived cells of different disease grades and bone marrow mesenchymal stem cell (BM-MSC) line (healthy control). However, the MPC marker Sox 9 was conserved after in vitro expansion and significantly higher in OA cartilage-derived cells compared to its levels in the BM-MSC. The in vitro expansion of cartilage-derived cells resulted in enrichment while re-differentiation in reduction of MPC markers for all three analyzed grades. However, only moderate OA-derived cells after the in vitro chondrogenesis resulted in the formation of hyaline cartilage-like tissue. The latter tissue samples were also highly positive for collagen II and proteoglycans with no expression of osteoarthritis-related markers (collagen I, ALPL and MMP13). MPC marker expression did not differ between OA grades at the tissue level. Interestingly after in vitro re-differentiation, only moderate OA-derived cells showed the capacity to form hyaline cartilage-like tissue. These findings may have implications for clinical practice to understand the intrinsic repair capacity of articular cartilage in OA tissues and raises the possibility of these progenitor cells as a candidate for articular cartilage repair.

Proton Pump Inhibitors and Bone Health: An Update Narrative Review.

Proton pump inhibitors (PPIs) are an antacid drug often used in acid-related disorders. They decrease acid secretion in the stomach by blocking an enzyme called H+/K+ ATPase which controls acid production. Introduced to the market in 1989, their use has increased rapidly worldwide and they are now among the top 10 most prescribed drugs in the United States. As of 2015, the FDA has already approved six drugs of this class (omeprazole, esomeprazole, lansoprazole, dexlansoprazole, pantoprazole and rabeprazole). Recently, the risks and benefits of long-term PPI use were questioned and many studies indicated that their use should be carefully considered, especially in young patients, whose treatment with these drugs could last many years. Even greater concerns have been raised about a potential positive association between PPIs and osteoporotic fracture risk including the hip, spine and wrist. Although based on observational studies, there is substantial evidence associating the long-term use of PPIs and fracture. This relationship is only partially admitted due to the lack of consistent effects of PPIs on bone mineral density loss. Therefore, this narrative review aimed to discuss the recent findings pertaining to the risk of osteoporotic fracture associated with PPIs, in particular prolonged use, and to call for further research to elucidate the mechanisms associated with this bone fragility.

Subchondral tibial bone texture of conventional X-rays predicts total knee arthroplasty.

Lacking disease-modifying osteoarthritis drugs (DMOADs) for knee osteoarthritis (KOA), Total Knee Arthroplasty (TKA) is often considered an important clinical outcome. Thus, it is important to determine the most relevant factors that are associated with the risk of TKA. The present study aims to develop a model based on a combination of X-ray trabecular bone texture (TBT) analysis, and clinical and radiological information to predict TKA risk in patients with or at risk of developing KOA. This study involved 4382 radiographs, obtained from the OsteoArthritis Initiative (OAI) cohort. Cases were defined as patients with TKA on at least one knee prior to the 108-month follow-up time point and controls were defined as patients who had never undergone TKA. The proposed TKA-risk prediction model, combining TBT parameters and Kellgren-Lawrence (KL) grades, was performed using logistic regression. The proposed model achieved an AUC of 0.92 (95% Confidence Interval [CI] 0.90, 0.93), while the KL model achieved an AUC of 0.86 (95% CI 0.84, 0.86; p < 0.001). This study presents a new TKA prediction model with a good performance permitting the identification of at risk patient with a good sensitivy and specificity, with a 60% increase in TKA case prediction as reflected by the recall values.

Prediction of knee osteoarthritis progression using radiological descriptors obtained from bone texture analysis and Siamese neural networks: data from OAI and MOST cohorts.

BACKGROUND: Trabecular bone texture (TBT) analysis has been identified as an imaging biomarker that provides information on trabecular bone changes due to knee osteoarthritis (KOA). In parallel with the improvement in medical imaging technologies, machine learning methods have received growing interest in the scientific osteoarthritis community to potentially provide clinicians with prognostic data from conventional knee X-ray datasets, in particular from the Osteoarthritis Initiative (OAI) and the Multicenter Osteoarthritis Study (MOST) cohorts. PATIENTS AND METHODS: This study included 1888 patients from OAI and 683 patients from MOST cohorts. Radiographs were automatically segmented to determine 16 regions of interest. Patients with an early stage of OA risk, with Kellgren and Lawrence (KL) grade of 1 < KL < 4, were selected. The definition of OA progression was an increase in the OARSI medial joint space narrowing (mJSN) grades over 48 months in OAI and 60 months in MOST. The performance of the TBT-CNN model was evaluated and compared to well-known prediction models using logistic regression. RESULTS: The TBT-CNN model was predictive of the JSN progression with an area under the curve (AUC) up to 0.75 in OAI and 0.81 in MOST. The predictive ability of the TBT-CNN model was invariant with respect to the acquisition modality or image quality. The prediction models performed significantly better with estimated KL (KLprob) grades than those provided by radiologists. TBT-based models significantly outperformed KLprob-based models in MOST and provided similar performances in OAI. In addition, the combined model, when trained in one cohort, was able to predict OA progression in the other cohort. CONCLUSION: The proposed combined model provides a good performance in the prediction of mJSN over 4 to 6 years in patients with relevant KOA. Furthermore, the current study presents an important contribution in showing that TBT-based OA prediction models can work with different databases.

Free-fall landing and interval running have different effects on trabecular bone mass and microarchitecture, serum osteocalcin, biomechanical properties, SOST expression and on osteocyte-related characteristics.

The effects of treadmill interval training (IT) and free-fall exercise were evaluated on bone parameters including osteocyte related characteristics. Thirty-eight 4-month-old male Wistar rats were randomly divided into a control (C) group and exercise groups: IT, 10 free-fall impacts/day with a 10-s (FF10) or 20-s interval between drops (FF20), 5 days/week, for 9 weeks. We assessed bone mineral density (BMD); microarchitecture by µCT; mechanical strength by a 3-point bending test; density and occupancy of the osteocyte lacunae by toluidine blue staining; osteocalcin and NTx systemic levels by ELISA; and bone tissue Sost messenger RNA (mRNA) expression by RT-PCR. NTx levels were significantly lower in exercise groups as compared with the C group. In exercise groups the Sost mRNA expression was significantly lower than in C. Tb.N was significantly higher for IT and FF20 compared with the C group. Tb.Sp was significantly lower in FF10 compared with the C group. Both IT and FF20 were associated with higher tibial lacunar density as compared with FF10. compared with FF10, IT fat mass was lower, while tibial osteocyte lacunae occupancy and systemic osteocalcin level were higher. All exercise modes were efficient in reducing bone resorption. Both IT and free-fall impact with appropriate recovery periods, which may be beneficial for bone health and osteocyte-related characteristics. Novelty: Interval training is beneficial for bone mineral density. Exercises decreased both bone resorption and inhibition of bone formation (Sost mRNA). Longer interval recovery time favors osteocyte lacunae density.

Trabecular bone texture analysis of conventional radiographs in the assessment of knee osteoarthritis: review and viewpoint.

BACKGROUND: Trabecular bone texture analysis (TBTA) has been identified as an imaging biomarker that provides information on trabecular bone changes due to knee osteoarthritis (KOA). Consequently, it is important to conduct a comprehensive review that would permit a better understanding of this unfamiliar image analysis technique in the area of KOA research. We examined how TBTA, conducted on knee radiographs, is associated to (i) KOA incidence and progression, (ii) total knee arthroplasty, and (iii) KOA treatment responses. The primary aims of this study are twofold: to provide (i) a narrative review of the studies conducted on radiographic KOA using TBTA, and (ii) a viewpoint on future research priorities. METHOD: Literature searches were performed in the PubMed electronic database. Studies published between June 1991 and March 2020 and related to traditional and fractal image analysis of trabecular bone texture (TBT) on knee radiographs were identified. RESULTS: The search resulted in 219 papers. After title and abstract scanning, 39 studies were found eligible and then classified in accordance to six criteria: cross-sectional evaluation of osteoarthritis and non-osteoarthritis knees, understanding of bone microarchitecture, prediction of KOA progression, KOA incidence, and total knee arthroplasty and association with treatment response. Numerous studies have reported the relevance of TBTA as a potential bioimaging marker in the prediction of KOA incidence and progression. However, only a few studies have focused on the association of TBTA with both OA treatment responses and the prediction of knee joint replacement. CONCLUSION: Clear evidence of biological plausibility for TBTA in KOA is already established. The review confirms the consistent association between TBT and important KOA endpoints such as KOA radiographic incidence and progression. TBTA could provide markers for enrichment of clinical trials enhancing the screening of KOA progressors. Major advances were made towards a fully automated assessment of KOA.

Limb Muscular Strength and Bone Mineral Density in Elderly Subjects with Low Skeletal Muscle Mass Index.

The aim of the current study was to investigate the relationships between limb muscular strength and bone mineral density (BMD) in a group of elderly subjects with low skeletal muscle mass index (SMI).55 elderly Lebanese subjects (35 women and 20 men) participated in the current study. Handgrip, one-repetition maximum (1-RM) dumbbell curl (1-RM biceps), 1-RM lying one arm triceps (1-RM triceps), 1-RM calf raise, 1-RM leg extension and 1-RM leg curl were evaluated using validated methods.In both genders, 1-RM biceps, 1-RM triceps, 1-RM leg extension and 1-RM leg curl were positively correlated to total hip BMD. The current study shows that limb muscular strength is positively correlated to hip BMD in elderly subjects with low SMI. This may have clinical implications in the field of osteoporosis prevention in elderly subjects with low SMI.

Cumulative Effects of Strontium Ranelate and Impact Exercise on Bone Mass in Ovariectomized Rats.

OBJECTIVE: To explore the effect of physical exercise (EXE), strontium ranelate (SR), or their combination on bone status in ovariectomized (OVX) rats. DESIGN: Sixty female Wistar rats were randomized to one of five groups: sham (Sh), OVX (O), OVX+EXE (OE), OVX+SR (OSR), and OVX+EXE+SR (OESR). Animals in EXE groups were subjected to 10 drops per day (45 cm in height); rats in SR groups received 625 mg/kg/day of SR, 5 days/week for 8 weeks. Bone mineral density (BMD) and bone mineral content (BMC, dual-energy X-ray absorptiometry (DXA)), mechanical strength of the left femur (three-point bending test), and femur microarchitecture of (micro-computed tomography imaging, microCT) analyses were performed to characterize biomechanical and trabecular/cortical structure. Bone remodeling, osteocyte apoptosis, and lipid content were evaluated by ELISA and immunofluorescence tests. RESULTS: In OVX rats, whole-body BMD, trabecular parameters, and osteocalcin (OCN) levels decreased, while weight, lean/fat mass, osteocyte apoptosis, and lipid content all increased. EXE after ovariectomy improved BMD and BMC, trabecular parameters, cross-sectional area (CSA), moment of inertia, and OCN levels while decreasing osteocyte apoptosis and lipid content. SR treatment increased BMD and BMC, trabecular parameters, CSA, stiffness, OCN, and alkaline phosphatase (ALP) levels. Furthermore, fat mass, N-telopeptide (NTX) level, osteocyte apoptosis, and lipid content significantly decreased. The combination of both EXE and SR improved bone parameters compared with EXE or SR alone. CONCLUSION: EXE and SR had positive and synergistic effects on bone formation and resorption.

Emerging Natural-Product-Based Treatments for the Management of Osteoarthritis.

Osteoarthritis (OA) is a complex degenerative disease in which joint homeostasis is disrupted, leading to synovial inflammation, cartilage degradation, subchondral bone remodeling, and resulting in pain and joint disability. Yet, the development of new treatment strategies to restore the equilibrium of the osteoarthritic joint remains a challenge. Numerous studies have revealed that dietary components and/or natural products have anti-inflammatory, antioxidant, anti-bone-resorption, and anabolic potential and have received much attention toward the development of new therapeutic strategies for OA treatment. In the present review, we provide an overview of current and emerging natural-product-based research treatments for OA management by drawing attention to experimental, pre-clinical, and clinical models. Herein, we review current and emerging natural-product-based research treatments for OA management.

Animal Model for Glucocorticoid Induced Osteoporosis: A Systematic Review from 2011 to 2021.

Clinical and experimental data have shown that prolonged exposure to GCs leads to bone loss and increases fracture risk. Special attention has been given to existing emerging drugs that can prevent and treat glucocorticoid-induced osteoporosis GIOP. However, there is no consensus about the most relevant animal model treatments on GIOP. In this systematic review, we aimed to examine animal models of GIOP centering on study design, drug dose, timing and size of the experimental groups, allocation concealment, and outcome measures. The present review was written according to the PRISMA 2020 statement. Literature searches were performed in the PubMed electronic database via Mesh with the publication date set between April, 2011, and February 2021. A total of 284 full-text articles were screened and 53 were analyzed. The most common animal species used to model GIOP were rats (66%) and mice (32%). In mice studies, males (58%) were preferred and genetically modified animals accounted for 28%. Our work calls for a standardization of the establishment of the GIOP animal model with better precision for model selection. A described reporting design, conduction, and selection of outcome measures are recommended.

Does the Severity of Obesity Influence Bone Mineral Density Values in Premenopausal Women?

The aim of this study was to compare bone mineral content (BMC), bone mineral density (BMD), and geometric indices of hip bone strength among 3 groups of adult obese premenopausal women (severely obese, morbidly obese, and super morbidly obese). This study included 65 young adult premenopausal women whose body mass index (BMI) > 35 kg/m2. They were divided into 3 groups using international cut-offs for BMI. Body composition and bone variables were measured by DXA. DXA measurements were completed for the whole body (WB), lumbar spine, total hip (TH), and femoral neck (FN). Geometric indices of FN strength (cross-sectional area, cross-sectional moment of inertia [CSMI], section modulus [Z], strength index [SI], and buckling ratio) were calculated by DXA. Results showed that age and height were not significantly different among the 3 groups. WB BMC values were higher in super morbidly obese women compared to severely and morbidly obese women. WB BMD, L1-L4 BMD, total hip BMD, FN BMD, cross-sectional area, CSMI, Z, and buckling ratio values were not significantly different among the 3 groups. SI values were lower in super morbidly obese compared to morbidly and severely obese women. In the whole population (n = 65), body weight, BMI, lean mass, fat mass, and trunk fat mass were positively correlated to WB BMC and negatively correlated to SI. Weight and lean mass were positively correlated to WB BMD and CSMI. Our findings suggest that the severity of obesity does not influence BMD values in premenopausal women.

Ixekizumab in the treatment of psoriatic arthritis.

Psoriatic arthritis (PsA) is a heterogeneous chronic rheumatic disorder with numerous phenotypic facets. A better in deep understanding of the pathophysiologic mechanisms leading to psoriasis and PsA has contributed to the introduction of novel therapeutic agents. IL-17 is at the heart and a critical factor in the onset of PsA. Ixekizumab, a high-affinity monoclonal antibody against IL-17 A, has been approved by the US FDA in March 2016 for baseline psoriasis and Dec 2017 for PsA; by the EMA in April 2016 and January 2018, respectively. This article reviews the published data relating to ixekizumab efficacy and safety in the PsA treatment.

Enthesopathy-An Underappreciated Role in Osteoarthritis?

Osteoarthritis (OA) continues to be a debilitating disease worldwide, to date, no therapies have been definitely proven to modify disease progression or moderate symptom relief long term other than joint replacement. A contributing factor may be the lack of attention to the potential role of the periarticular enthesis and development and progression of OA. The enthesis is the site of attachment for a tendon, ligament, or joint capsule to the bony skeleton, thereby allowing centralized transmission and dissipation of mechanical loads. Because of this design, the enthesis is a site of stress concentration subject to inflammation during sports-related activities or spondyloarthropathies, which may lead to long-term degeneration. Our hypothesis is that functional incompetence of the enthesis resulting from either degenerative or inflammatory changes could be an initiating factor for OA and may thus provide a novel basis for the development of future disease management in this phenotype of patients.

Andrographis paniculata and Its Bioactive Diterpenoids Against Inflammation and Oxidative Stress in Keratinocytes.

Andrographis paniculata was widely used in traditional herbal medicine to treat various diseases. This study explored the potential anti-aging activity of Andrographis paniculata in cutaneous cells. Human, adult, low calcium, high temperature (HaCaT) cells were treated with methanolic extract (ME), andrographolide (ANDRO), neoandrographolide (NEO), 14-deoxyandrographolide (14DAP) and 14-deoxy-11,12-didehydroandrographolide (14DAP11-12). Oxidative stress and inflammation were induced by hydrogen peroxide and lipopolysaccharide/TNF-α, respectively. Reactive oxygen species (ROS) production was measured by fluorescence using a 2',7'-dichlorofluorescein diacetate (DCFH-DA) probe and cytokines were quantified by ELISA for interleukin-8 (IL-8) or reverse transcription-quantitative polymerase chain reaction (RT-qPCR) for tumor necrosis factor-α (TNF-α). Hyaluronic acid (HA) secretion was determined by an ELISA. Our results show a decrease in ROS production and TNF-α expression by ME (5 µg/mL) in HaCaT under pro-oxidant and pro-inflammatory conditions, respectively. ME protected HaCaT against oxidative stress and inflammation. Our findings confirm that ME can be used for the development of bioactive compounds against epidermal damage.