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The aim of the study was to determine whether tibiofemoral contact stress predicts risk for worsening knee pain over 84 ms in adults aged 50-79 yrs with or at elevated risk for knee osteoarthritis.Baseline tibiofemoral contact stress was estimated using discrete element analysis. Other baseline measures included weight, height, hip-knee-ankle alignment, Kellgren-Lawrence grade, and Western Ontario and McMaster Universities Osteoarthritis Index pain subscale. Logistic regression models assessed the association between baseline contact stress and 84-mo worsening of Western Ontario and McMaster Universities Osteoarthritis Index pain subscale.Data from the dominant knee (72.6% Kellgren-Lawrence grade 0/1 and 27.4% Kellgren-Lawrence grade ≥ 2) of 208 participants (64.4% female, mean ± SD body mass index = 29.6 ± 5.1 kg/m 2 ) were analyzed. Baseline mean and peak contact stress were 3.3 ± 0.9 and 9.4 ± 4.3 MPa, respectively. Forty-seven knees met the criterion for worsening pain. The highest tertiles in comparison with the lowest tertiles of mean (odds ratio [95% confidence interval] = 2.47 [1.03-5.95], P = 0.04) and peak (2.49 [1.03-5.98], P = 0.04) contact stress were associated with worsening pain at 84 mos, after adjustment for age, sex, race, clinic site, and baseline pain. Post hoc sensitivity analyses including adjustment for body mass index and hip-knee-ankle alignment attenuated the effect.These findings suggest that elevated tibiofemoral contact stress can predict the development of worsening of knee pain.

Objective: \ud To identify prognostic factors for health outcomes following an eight-week supervised exercise therapy and education program for individuals with knee and hip osteoarthritis (OA) alone or with concomitant hypertension, heart or respiratory disease, diabetes, or depression.\ud \ud Methods: \ud We included individuals with knee and/or hip OA from the Good Life with osteoArthritis in Denmark (GLA:D®). GLA:D® consists of two patient education sessions and 12 supervised exercise therapy sessions. Before GLA:D®, participants self-reported any comorbidities and were categorized in eight comorbidity groups. 21 potential prognostic factors (demographics, clinical data, and performance-based physical function) gathered from participants and clinicians before the program were included. Outcomes were physical function using the 40-m Fast-Paced Walk Test (FPWT), health-related quality of life using the EQ-5D-5L index score, and pain intensity using a visual analogue scale (0-100, VAS) assessed before and immediately after the GLA:D® program. Within each comorbidity group, associations of prognostic factors with outcomes were estimated using multivariable linear regression.\ud \ud Results: \ud Data from 35,496 (40-m FPWT) and 37,576 (EQ-5D-5L and VAS) participants were included in the analyses. Clinically relevant associations were demonstrated between age, self-efficacy, self-rated health, and pain intensity with change in 40-m FPWT, EQ-5D-5L or VAS across comorbidity groups. Furthermore, anxiety, education, physical function, and smoking were associated with outcomes among subgroups having depression or diabetes in addition to OA.\ud \ud Conclusion: \ud Age, self-efficacy, self-rated health, and pain intensity may be prognostic of change in health outcomes following an eight-week exercise therapy and patient education program for individuals with OA, irrespective of comorbidities.

Objective To determine whether an apparent association between hand osteoarthritis (OA) and adiposity is explained by the presence of OA at other joint sites. Methods Data from the Canadian Longitudinal Study on Aging, first cycle, Comprehensive Cohort. Respondents aged 45-85 years (n=18,279) were asked separate questions about doctor-diagnosed OA in the hand, hip, or knee. Multinomial logistic regression was used to investigate the relationship between all combinations of hand, hip, and knee OA and body mass index (BMI) and waist to height ratio (WHtR). Results OA was reported by 34.6% of respondents, 28.0% with OA at >1 joint site. Hand OA was not significantly associated with BMI after accounting for OA at other joint sites, with similar findings for WHtR. All joint site combinations containing the knee were strongly associated with BMI, with odds ratios (ORs) ranging from OR 2.92 (95% CI: 2.53,3.37) for knee OA only with obesity class I to OR 9.98 (95% CI: 7.12,13.88) for multi-joint knee, hip, hand OA with obesity class II/III. BMI distributions including knee OA were broader and shifted to higher BMI levels than those for hand or hip OA. Conclusions Apparent associations between hand OA and BMI may be explained by concurrent OA at other joint sites. Recognizing that OA is a multi-joint disease is crucial for studies of the associations of adiposity with OA in a particular joint, especially the hand. The association between knee OA and BMI appears to be distinct from those for OA at other joint sites.

OBJECTIVE: The Cohort Hip and Cohort Knee (CHECK) is a cohort of middle-aged individuals with hip or knee pain. Radiographs were assigned Kellgren & Lawrence (KL) scores under different conditions at each follow-up visit for 10 years. We aimed to describe and consolidate each scoring approach, then illustrate implications of their use by comparing baseline KL scores assigned using two of these approaches, and evaluating their respective associations with joint replacement and incident radiographic osteoarthritis (ROA).METHODS: We compared baseline KL scores assigned to hips and knees using two scoring approaches: (i) assigned by senior researchers to baseline images alone, and (ii) assigned by trained readers, read paired and in known sequence with up to 10 years of follow-up radiographs (Poisson regression). We evaluated the associations of baseline ROA (any ≥ KL1, established ≥ KL2) with joint replacement, and of KL1 joints with incident established ROA (survival analysis).RESULTS: Of 1002 participants (79% women, mean (SD) age 55.9 (5.2) years, BMI 26.2 (4.0) kg/m2 ), the second scoring approach had 2.4 (95% CI 1.8-3.1, knees) and 2.9 (2.3-3.7, hips) times higher prevalence of established ROA than the first approach. Established hip ROA had higher risk of joint replacement using the first approach (Hazard Ratio, HR 24.2 (95%CI 15.0-39.8) vs. 7.7 (4.9-12.1), second approach), as did knees (19.3 (10.3-36.1) vs. 4.8 (2.4-9.6)). Risk of incident ROA did not differ by approach.CONCLUSIONS: This study demonstrates that evaluating ROA prevalence and predicting outcomes depends on scoring approach.

To examine the association of low back pain (LBP) and lumbar kyphosis with functional disabilities and knee symptoms in patients with knee osteoarthritis (OA).We analyzed 586 participants (80.1% female; mean ± SD age 68.8 ± 5.2 years) from the Nagahama Study who were age ≥60 years and had radiographically confirmed knee OA. The Knee Society Knee Scoring System (KSS) was used to assess functional disabilities and knee symptoms. LBP was defined as the presence of any persistent back pain for more than 3 months. Lumbar kyphosis was determined by skin-surface methods using a computer-aided electronic device called the Spinal Mouse. Multiple linear regression analysis was used for assessing the association of LBP and lumbar kyphosis with the KSS scores. Subgroup analyses based on sex were also performed.LBP and lumbar kyphosis were independently associated with a lower KSS function score after adjustment for covariates (mean difference -4.96 [95% confidence interval (95% CI) -7.56, -2.36] points for LBP alone, mean difference -4.47 [95% CI -8.51, -0.43] points for lumbar kyphosis alone, and mean difference -13.86 [95% CI -18.86, -8.86] points for the coexistence of LBP and lumbar kyphosis, respectively). The coexistence of LBP and lumbar kyphosis in women was associated with a lower KSS symptom score (mean difference -4.49 [95% CI -6.42, -2.55] points).These findings suggest that both LBP and lumbar kyphosis are useful clinical signals indicating functional disability and knee symptoms in patients with knee OA.

Evaluating outcome in osteoarthritis (OA) clinical research and practice requires reliable, valid and responsive patient-reported outcome measures (PROMs) and functional tests that reflect important problems experienced by people with OA. The goal of this work is to provide information to start to guide the reader in selecting measures for people with OA. In this narrative review, we begin by providing an overview of measurement properties that can help clinicians and researchers in making decisions about whether a measure might be appropriate for use in their research or clinical context. We then report evidence supporting the use of measures of pain (e.g., Pain Visual Analogue (VAS), Numeric Pain Rating Scale (NPRS), Intermittent and Constant Osteoarthritis Pain, PROMIS Pain Interference, and, for screening in research, the painDETECT and the Self-report Leeds Assessment of Neuropathic Symptoms and Signs) and fatigue (e.g., PROMIS-Fatigue) at a group level in clinical research. Several multi-dimensional joint-specific measures (e.g., Western Ontario McMaster Universities' Osteoarthritis Outcomes Scale, Knee/Hip Injury and Osteoarthritis Outcome Score, Oxford Hip/Knee Scale) also have evidence for group-level use. Functional tests (e.g., timed walk tests, 30 Second Chair Stand, Timed Up and Go, etc.) have measurement properties supporting their use at the group level in clinical research and at the individual patient level as do the pain VAS and NPRS. Other generic and disease-specific PROMs have been used in or could be used in OA studies but their measurement properties require further evaluation in people with OA.

BACKGROUND: Knee osteoarthritis (OA) impairs postural control and may affect how the lower limb joints are used for postural control. OBJECTIVE: To investigate how individuals with knee OA use lower limb joints for static postural control. METHODS: Ten patients with knee OA and thirteen healthy controls performed quiet standing for 30 s. The standard deviation of the center of mass (COM) and lower limb joint motions in the anterior-posterior (AP) and medial-lateral (ML) planes were calculated from three-dimensional marker trajectories. Pearson’s correlation analysis and independent t-tests were conducted to investigate the relationship between COM and lower limb joint motion and to compare group difference, respectively. RESULTS: The AP hip angular velocity alone in the knee OA group and the AP hip and knee angular velocity in the control group were significantly correlated with the AP COM velocity. The ML hip angular velocity was significantly correlated with the ML COM velocity in both groups. The knee OA group exhibited a significantly larger standard deviation of AP COM velocity than the control group. CONCLUSIONS: Individuals with knee OA depended solely on the contribution of the hip to the AP COM velocity, which could not be successfully controlled by the knee.

Objective: To compare the sensitivity of alternative case finding approaches for the identification of foot osteoarthritis (OA) based on the La Trobe radiographic atlas. Methods: This was a cross-sectional study of 533 adults age ≥50 years with foot pain in the past year. Weightbearing dorsoplantar (DP) and lateral radiographs were taken of both feet. The La Trobe radiographic atlas was used to document the presence of osteophytes (OPs) and joint space narrowing (JSN). The prevalence of OA in each joint was documented using both views and features in combination (as recommended in the original atlas), and by using a single view (DP or lateral only) and a single feature (OP or JSN only). Results: Compared to the recommended case definition based on OPs and JSN using both views, a DP-only view identified between 15% and 77% of OA cases, while a lateral-only view identified between 28% and 97% of OA cases. Compared to the recommended case definition of using both features, using only OPs identified between 46% and 94% of OA cases, while using only JSN identified between 19% and 76% of OA cases. Conclusion: Applying the La Trobe radiographic atlas but using only 1 radiograph view (DP or lateral) or 1 feature (OP or JSN) in isolation misses a substantial number of OA cases, and the sensitivity of these approaches varies considerably between different foot joints. These findings indicate that, where possible, the atlas should be administered according to the original description to avoid under-ascertainment of radiographic foot OA.

To determine the optimal combination of imaging and biochemical biomarkers for use in the prediction of knee osteoarthritis (OA) progression.The present study was a nested case-control trial from the Foundation of the National Institutes of Health OA Biomarkers Consortium that assessed study participants with a Kellgren/Lawrence grade of 1-3 who had complete biomarker data available (n = 539 to 550). Cases were participants' knees that had radiographic and pain progression between 24 and 48 months compared to baseline. Radiographic progression only was assessed in secondary analyses. Biomarkers (baseline and 24-month changes) that had a P value of0.10 in univariate analysis were selected, including quantitative cartilage thickness and volume on magnetic resonance imaging (MRI), semiquantitative MRI markers, bone shape and area, quantitative meniscal volume, radiographic progression (trabecular bone texture [TBT]), and serum and/or urine biochemical markers. Multivariable logistic regression models were built using 3 different stepwise selection methods (complex models versus parsimonious models).Among baseline biomarkers, the number of locations affected by osteophytes (semiquantitative), quantitative central medial femoral and central lateral femoral cartilage thickness, patellar bone shape, and semiquantitative Hoffa-synovitis predicted OA progression in most models (C statistic 0.641-0.671). In most models, 24-month changes in semiquantitative MRI markers (effusion-synovitis, meniscal morphologic changes, and cartilage damage), quantitative central medial femoral cartilage thickness, quantitative medial tibial cartilage volume, quantitative lateral patellofemoral bone area, horizontal TBT (intercept term), and urine N-telopeptide of type I collagen predicted OA progression (C statistic 0.680-0.724). A different combination of imaging and biochemical biomarkers (baseline and 24-month change) predicted radiographic progression only, which had a higher C statistic of 0.716-0.832.The present study highlights the combination of biomarkers with potential prognostic utility in OA disease-modifying trials. Properly qualified, these biomarkers could be used to enrich future trials with participants likely to experience progression of knee OA.

Background Pain in knee osteoarthritis is considered to be nociceptive. Recently, involvement of neuropathic pain and psychosocial factors in knee osteoarthritis has been reported. However, the following details are unclear: 1) How often are neuropathic pain and psychosocial factors involved? And 2) Which patients are associated with neuropathic pain and psychosocial factors? Methods In 104 patients with knee osteoarthritis, we evaluated neuropathic pain factor with a painDETECT questionnaire and catastrophic thinking using the pain catastrophizing scale. Pain intensity was assessed using the visual analog scale; patients with scores below the median were defined as low-pain group and others as high-pain group. Radiographic severity was categorized according to the Kellgren–Lawrence classification, with grades I–II and III–IV defined as low- and high-grades, respectively. We compared the painDETECT and pain catastrophizing scale scores between the low- and high-pain groups and low- and high-grade groups. Furthermore, the painDETECT and pain catastrophizing scale scores were compared among the following four groups: low-grade/low-pain, low-grade/high-pain, high-grade/low-pain, and high-grade/high-pain. Results Neuropathic pain factor and catastrophic thinking were found in 16% and 34% of patients, respectively. There were no significant differences in both painDETECT and pain catastrophizing scale scores between the two pain intensity groups. Between the two groups of radiographic severity, there was no significant difference in the painDETECT scores; however, the pain catastrophizing scale score was significantly high in the low-grade group. In addition, there was no significant difference in the painDETECT scores among the four groups; however, the pain catastrophizing scale scores were significantly higher in low-grade/high-pain than in high-grade/low-pain patients. Conclusions Therefore, 64% had only nociceptive pain factor. Catastrophic thinking was strong in patients with low radiographic severity, especially in those with high pain intensity. Patients with neuropathic pain factor could not be identified from radiographic severity and pain intensity.

Two previous phase 3, double-blind, randomized, placebo-controlled trials showed that duloxetine 60 mg/day for 14 weeks significantly improved pain and quality of life in Japanese patients with knee osteoarthritis or chronic low back pain. In their open-label extension studies, these improvements were maintained for ≥48 weeks. This post-hoc analysis assessed the relationship between initial response to duloxetine and long-term pain reduction and quality of life in patients with knee osteoarthritis or chronic low back pain.Patients (knee osteoarthritis: N = 43; chronic low back pain: N = 41) were subdivided based on extent of pain reduction from baseline to Week 4 of duloxetine (≥30%, 10-30%, or10% reduction in Brief Pain Inventory-Severity average pain score). Outcome measures were changes from baseline for Brief Pain Inventory-Severity and Brief Pain Inventory-Interference at regular intervals up to Week 65.Mean change from baseline in Brief Pain Inventory-Severity was greater in patients with ≥30% early pain reduction than in patients with10% early pain reduction through Week 27 for both conditions, and also Weeks 47-65 for back pain. Compared with the10% early pain reduction group, mean change from baseline in the average of seven Brief Pain Inventory-Interference domain scores was greater in the ≥30% or 10-30% early pain reduction groups for knee osteoarthritis (except Weeks 63-65), and in the ≥30% early pain reduction group for chronic low back pain through Week 19.These results suggest that patients with knee osteoarthritis who respond well to duloxetine in the first month might experience sustained, long-term pain relief with generally greater quality-of-life improvement than patients with poor initial response. Patients with chronic low back pain who had strong initial response may experience a greater long-term pain relief, but not greater quality-of-life improvement, than patients with poor initial response.

Summary Objective Early and non-invasive detection of osteoarthritis (OA) is required to enable early treatment and monitoring of interventions. Some of the earliest signs of OA are the change in proteoglycan and collagen composition. The aim of this study is to establish the relations between quantitative magnetic resonance imaging (MRI) and biochemical concentration and organization in knee articular cartilage. Methods A preregistered systematic literature review was performed using the databases PubMed and Embase. Papers were included if quantitative MRI and a biochemical assay or polarized light microscopy (PLM) was performed on knee articular cartilage, and a quantified correlation was described. The extracted correlations were pooled using a random effects model. Results 21 papers were identified. The strongest pooled correlation was found for delayed gadolinium-enhanced MRI of cartilage (dGEMRIC) vs. proteoglycan concentration (r=0.59). T1ρ relaxation times are inversely correlated to proteoglycan concentration (r=-0.54). A weak correlation between T2 relaxation times and proteoglycans was found (r=-0.38). No correlation between T2 relaxation time and collagen concentration was found (r=-0.02). A heterogeneous set of correlations between T2 relaxation times and PLM were identified, including strong correlations to anisotropy. Conclusion DGEMRIC measures are significantly correlated to proteoglycan concentration. The needed contrast agent is however a disadvantage; the T1ρ sequence was found as a non-invasive alternative. Remarkably, no correlation was found between T2 relaxation times and collagen concentration. T2 relaxation times is related to organization, rather than concentration of collagen fibers. Prospero ID CRD42020168337.

Objectives To assess the immediate and three days postintervention effect of one dry needling session compared to one sham needling session on pain, central pain processing, muscle co-contraction and spatiotemporal parameters during gait in knee osteoarthritis patients. Methods A double-blind randomized controlled trial was conducted. Sixty-one knee osteoarthritis patients were randomly assigned to the dry needling or sham needling group. Primary outcomes were pain and central pain processing. Secondary outcomes included muscle co-contraction and spatiotemporal parameters during gait. Patients were assessed at baseline and 15 min after the intervention, and pain also three days after the intervention. Linear mixed models were used to examine between- and within-group differences. Results No significant between-group differences for pain were found, but within-group scores showed a significant decrease 15 min after sham needling and three days after dry needling. The mean conditioned pain modulation effect measured at the m. Trapezius worsened significantly 15 min after sham needling compared to after dry needling (between-group difference). However, individual conditioned pain modulation percentage scores remained stable over time. Various significant within-group differences were found 15 min after sham needling: a decrease of conditioned pain modulation measured at m. Quadriceps and m. Trapezius and stride- and step-time scores, and an increase in step length and widespread pain pressure threshold. A significant decrease in muscle co-contraction index of the m. Vastus Medialis and Semitendinosus was found as within-group difference 15 min after dry needling. Conclusions Dry needling has no larger effect on pain, central pain processing, muscle co-contraction and gait pattern 15 min and three days postintervention compared to sham needling. Mean conditioned pain modulation scores worsened after sham needling compared to after dry needling. Further research remains necessary.

Objective There is an unmet need for therapies that target the underlying pathophysiology of osteoarthritis (OA). However, defining appropriate measures for clinical trials of such therapies is challenging. Our objective is to propose concept clinical endpoints that directly capture clinical benefit in this setting and evaluate the feasibility of their use. Methods This analysis used the multi-center, longitudinal, observational Osteoarthritis Initiative (OAI) database. OAI participants primarily had knee OA, with follow-up of up to nine years and assessments of joints, surgical interventions, performance outcomes, and patient-reported outcomes (PROs). We examined this dataset to identify existing outcome measures of direct clinical benefit. We evaluated the feasibility of conducting trials using these candidate endpoints by estimating incidence rates and resulting required sample sizes and study durations in time-to-event analyses. Results We identified candidate endpoints based on total knee replacement (TKR) and composite endpoints defined by TKR and conservative thresholds of PROs of pain and function. Using time to TKR as an endpoint, a study with an average follow-up time of three years requires approximately 3,000 to 18,000 subjects depending on effect size. Alternatively, a composite endpoint such as 'time to TKR or severe pain or severely impaired functioning', the required sample sizes ranged from approximately 2,000 to 11,000 for a three-year study. Conclusion The proposed concept endpoints can reliably and feasibly evaluate effectiveness of therapies for this unmet need. In particular, the composite endpoint approach can substantially reduce sample sizes (up to approximately 40%) compared to the use of TKR alone.

Objectives This study aimed to evaluate the cost-effectiveness of the randomized clinical trial STEP-KOA (STepped Exercise Program for patients with Knee OsteoArthritis). Methods The trial included 230 intervention and 115 control participants from 2 Veterans Affairs (VA) medical centers. A decision tree simulated outcomes for cohorts of patients receiving arthritis education (control) or STEP-KOA (intervention), which consisted of an internet-based exercise training program (step 1), phone counseling (step 2), and physical therapy (step 3) according to patient’s response. Intervention costs were assessed from the VA perspective. Quality of life (QOL) was measured using 5-level EQ-5D US utility weights. Incremental cost-effectiveness ratios (ICERs) were calculated as the difference in costs divided by the difference in quality-adjusted life-years (QALYs) between arms at 9 months. A Monte Carlo probabilistic sensitivity analysis was used to generate a cost-effectiveness acceptability curve. Results The adjusted model found differential improvement in QOL utility weights of 0.042 (95% confidence interval 0.003-0.080; P=.03) for STEP-KOA versus control at 9 months. In the base case, STEP-KOA resulted in an incremental gain of 0.028 QALYs and an incremental cost of $279 per patient for an ICER of $10 076. One-way sensitivity analyses found the largest sources of variation in the ICER were the impact on QOL and the need for a VA-owned tablet. The probabilistic sensitivity analysis found a 98% probability of cost-effectiveness at $50 000 willingness-to-pay per QALY. Conclusions STEP-KOA improves QOL and has a high probability of cost-effectiveness. Resources needed to implement the program will decline as ownership of mobile health devices increases.

Objective The study aimed to explore patient perceptions of and motivations for physical activity after total knee joint replacement. Methods Participants were purposively sampled after completing a public outpatient rehabilitation exercise group. Semi-structured interviews were completed with 22 participants (mean age 70 years, 45% women) 6 to 12 months after total knee joint replacement. Interviews were audiotaped and transcribed verbatim. Themes were identified by an inductive and iterative process of data analysis. Results The main theme to emerge was participants were in the dark about physical activity. Participants were typically not familiar with physical activity guidelines and had difficulty distinguishing between low and moderate-intensity physical activity. Three subthemes were identified: (1) people prioritise participation in meaningful life situations after total knee joint replacement; (2) rehabilitation was perceived to not explicitly address moderate-intensity physical activity levels; and (3) other health and social reasons replaced knee osteoarthritis as barriers to physical activity. Conclusion Limited understanding of physical activity recommendations, prioritisation of participation in meaningful life situations, rehabilitation that was impairment focused and other health and social reasons appeared to contribute to low levels of moderate-intensity physical activity for adults after knee joint replacement. Addressing being in the dark about physical activity may be an important first step to increase the effectiveness of behavioural interventions designed to promote physical activity after total knee joint replacement.

Duloxetine is a treatment approved by the US Food and Drug Administration for both osteoarthritis (OA) pain and depression, though uptake of duloxetine in knee OA management varies. We examined the cost-effectiveness of adding duloxetine to knee OA care in the absence or presence of depression screening.We used the Osteoarthritis Policy Model, a validated computer microsimulation of knee OA, to examine the value of duloxetine for patients with knee OA who have moderate pain by comparing 3 strategies: 1) usual care, 2) usual care plus duloxetine for patients who screen positive for depression on the Patient Health Questionnaire 9 (PHQ-9), and 3) usual care plus universal duloxetine. Outcome measures included quality-adjusted life years (QALYs), lifetime direct medical costs, and incremental cost-effectiveness ratios (ICERs), discounted at 3% annually. Model inputs, drawn from the published literature and national databases, included annual cost of duloxetine ($721-937); average pain reduction for duloxetine (17.5 points on the Western Ontario and McMaster Universities Osteoarthritis Index pain scale [0-100]), and likelihood of depression remission with duloxetine (27.4%). We considered 2 willingness-to-pay (WTP) thresholds of $50,000/QALY and $100,000/QALY. We varied parameters related to the PHQ-9 and the cost of duloxetine, efficacy, and toxicities to address uncertainty in model inputs.The screening strategy led to an additional 17 QALYs per 1,000 subjects and increased costs by $289/subject (ICER = $17,000/QALY). Universal duloxetine led to an additional 31 QALYs per 1,000 subjects and $1,205 per subject (ICER = $39,300/QALY). Under the majority of sensitivity analyses, universal duloxetine was cost-effective at the $100,000/QALY threshold.The addition of duloxetine to usual care for knee OA patients with moderate pain, regardless of depressive symptoms, is cost-effective at frequently used WTP thresholds.

Objective Several current and many emerging osteoarthritis (OA) treatments are intra-articular (IA) injections. However, little is known about physicians' perceptions and beliefs regarding IA injections or their considerations when deciding whether to recommend them to patients. We aimed to investigate physician-perceived benefits and drawbacks of offering IA injections. Methods We conducted individual interviews with orthopedic surgeons, rheumatologists, and physiatrists who treat patients with knee OA. We conducted a thematic analysis to identify factors that physicians weigh when making IA injection recommendations. Results We interviewed 18 physicians from academic and community practices. We identified four categories of themes that influenced providers' recommendations to their patients regarding injections: 1) the physician's knowledge, beliefs, and concerns, including their propensity to rely on guidelines versus clinical experience, and understanding of the efficacy and risks associated with injectables, such as possible cartilage damage; 2) the characteristics of the injectable product, such as ease or number of administrations needed; 3) individual patient-specific factors, including OA severity, comorbidities, and patient preference for and expectations of specific IA injections; and 4) financial and administrative factors, including insurance coverage and out-of-pocket costs. Conclusion Physicians factor the uncertain efficacy of injectable treatments and the need to manage patient expectations into their decision to offer IA therapies. Some providers relied on evidence and guidelines while others were swayed more by clinical experience. High out-of-pocket costs were seen as a barrier to use. These findings may help in the delivery of IA injections for OA and in development of injectable products.

BACKGROUND: Physical therapy and exercise programs are frequently used in the treatment of knee osteoarthritis (OA). However, it is not known at what stage of knee OA it is more effective. OBJECTIVE: The purpose of this work was to determine the relationship between the effectiveness of the physical therapy and exercise programs and the radiological findings presence/grade of knee OA. MATERIAL AND METHODS: Overall, 92 patients (65F, 27M) with knee OA were enrolled in the retrospective study. Standard knee radiographs were graded according to Kellgren-Lawrence. Pain and functional status were evaluated using a visual analog scale (VAS) and the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) at baseline, at the end of the physical therapy program (first month), and at third-month control visits. The demographic characteristics and VAS/WOMAC scores of the subjects were obtained from patient files. RESULTS: We analyzed 131 knees of 92 patients with knee OA (65F, 27M, mean age 53.02 ± 11.13 years). The mean total VAS and WOMAC scores on the first and third months were significantly lower than the initial values (all p< 0.001). The mean VAS scores on the first and third months were significantly lower than the initial values in the group without radiological damage, but WOMAC scores were similar between the evaluations (p= 0.009, p 50 = 0.003, respectively). The mean VAS and WOMAC scores on the first and third months were significantly lower than the initial values in the grade 1 according to the Kellgren-Lawrence radiological grades (all p< 0.001). CONCLUSIONS: According to the results of our study, physical therapy and exercise was effective on pain in all patients with knee OA, but only effective on knee functional capacity in the group with radiological findings, and especially more effective in patients with Kellgren-Lawrence grade 1.

INTRODUCTION: Radiofrequency (RF) treatment of the genicular nerves is a promising treatment for chronic osteoarthritic and persistent postsurgical knee pain (PPSP), refractory to conventional medical management. METHODS: The RECORGEN study is a retrospective single-center cohort study of patients treated with ultrasound-guided conventional RF of the genicular nerves for chronic knee pain in Hospital Oost-Limburg, Genk from September 2017 to June 2020. Subgroup analysis based on etiology of pain (PPSP and degenerative knee pain) was performed in addition to the total study population analysis. Outcome parameters were global perceived effect (GPE), Numeric Rating Scale for pain, consumption of strong opioids, and safety of the treatment at 6 weeks and cross-sectionally at a variable time point. Treatment success was defined as GPE≥50%. RESULTS: Sixty-eight cases were screened of which 59 (46 diagnosed with PPSP and 13 with degenerative knee pain) were included in the study. Treatment success at 6 weeks was achieved in 19 of 59 interventions (32.2%) and was similar in both groups. Seventeen responders were evaluated at follow-up. 45.1% (8/17) continued to have a positive effect at the second time point. The mean duration of effect of the RF treatment was 8.3 months. Safety analysis at 6 weeks and at the second time point showed a good safety profile of the treatment. CONCLUSION: Conventional RF of the genicular nerves was clinically successful in more than 30% of the study population refractory to conventional medical management. Overall, the treatment was well tolerated. The mean duration of effect was 8.3 months. ispartof: PAIN PRACTICE vol:22 issue:3 pages:340-348 ispartof: location:United States status: published

Primary knee osteoarthritis remains a difficult-to-control degenerative disease. With the rise in average life expectancy and the incidence of obesity, osteoarthritis has brought an increasing economic and physical burden on people. This article summarizes the latest understanding of platelet-rich plasma in the treatment of knee osteoarthritis, and reviews the economic issues of PRP.The literatures in Pubmed, Embase, Cochrane library, Web-science and other databases were searched, and literature inclusion and exclusion criteria were formulated. According to the Cochrane systematic reviewer's manual, the included literatures were grouped, and qualitative descriptions and quantitative meta-analysis were performed. Continuous statistical methods were used to compare the effects and adverse effects of PRP before and after treatment, as well as between PRP and other conservative treatments.A total of 12 randomized controlled trials were included in this study. A total of 959 KOA patients (1070 knees) were enrolled and followed for 3-12 months. PRP total knee scores were significantly better than baseline at 1, 2, 3, 6 and 12 months after treatment (1 month: SMD = 0.60, P 0.01; 2 months: SMD = 0.98, P 0.01; 3 months: SMD = 1.16, P 0.01; 6 months: SMD = 1.49, P 0.01; 12 months: SMD = 1.47, P 0.01). In terms of adverse reactions, PRP did not increase the risk of adverse events compared with HA (OR = 0.96, P = 0.85).Compared with many other treatment methods, intra-articular injection of PRP has been proven to be safe and effective to improve the quality of life of patients with KOA.

Summary Objective Osteoarthritis (OA) pathogenesis involves the interaction of articular cartilage with surrounding tissues, which are innervated by tyrosine hydroxylase-positive (TH+) sympathetic nerve fibers suggesting a role of the sympathetic nervous system (SNS) during OA progression. We analyzed the effects of sympathectomy (Syx) in a murine OA model. Methods Peripheral Syx was generated by 6-hydroxydopamine (6-OHDA) injections in male C57BL/6 mice. OA was induced in wild-type (WT) and Syx mice by destabilization of the medial meniscus (DMM). TH+ fibers and splenic NE were analyzed to evaluate Syx efficiency. OA progression was examined by OARSI and synovitis scores and micro-CT. Expression of TH, α2A- and β2-adrenergic receptors (AR), and activity of osteoblasts (ALP) and osteoclasts (TRAP) was investigated by stainings. Results Syx resulted in synovial TH+ fiber elimination and splenic NE decrease. Cartilage degradation and synovitis after DMM were comparably progressive in both WT and Syx mice. Calcified cartilage (CC) and subchondral bone plate (SCBP) thickness and bone volume fraction (BV/TV) increased in Syx mice due to increased ALP and decreased TRAP activities compared to WT 8 weeks after DMMWT and Syx mice developed osteophytes and meniscal ossicles without any differences between the groups. AR numbers decreased in cartilage but increased in synovium and osteophyte regions after DMM in both WT and Syx mice. Conclusion Peripheral dampening of SNS activity aggravated OA-specific cartilage calcification and subchondral bone thickening but did not influence cartilage degradation and synovitis. Therefore, SNS might be an attractive target for the development of novel therapeutic strategies for pathologies of the subchondral bone.

Purpose To analyze the clinical outcomes and survival curve of arthroscopic lateral patellar facetectomy and lateral release for isolated patellofemoral osteoarthritis (PFOA). Methods All patients undergoing arthroscopic lateral patellar facetectomy and lateral release between January 2008 and January 2018 were evaluated retrospectively. The inclusion criteria were 1) diagnosis of isolated symptomatic lateral PFOA, 2) PFOA with kissing lesions (defined as a lesion on both the patella and trochlea, which were in direct contact, 3) arthroscopic lateral patellar facetectomy and lateral release, and 4) two-year minimum follow-up. Evaluation included preoperative and postoperative subjective International Knee Documentation Committee (IKDC), Knee Injury and Osteoarthritis Outcome Score (KOOS) scores, and visual analogue pain scale (VAS). The primary end point determining the survival curve was revision of lateral facetectomy. Results A retrospective analysis was conducted of 61 consecutive arthroscopic lateral patellar facetectomy and lateral release procedures, performed in 55 patients for a diagnosis of isolated PFOA. Five patients were lost to follow-up, leaving 56 knees (50 patients) available at a mean follow up of 7.5 years (range: 2-10). The cohort included 37 women and 13 men with a mean age of 59 years (range: 34-87). Nine patients (18%) underwent revision surgery: six total knee replacements (TKR), two high tibial osteotomies, and one revision arthroscopic lateral patellar facetectomy. The mean time from arthroscopic facetectomy to TKR was 51 months (range: 10-114). The survival curve rate was 86% at 7.5 years. Both KOOS and IKDC scores improved significantly. These results are confirmed by an analysis of MCID. The mean VAS decreased from 6.98 ± 1.2 preoperatively to 2.06 ± 1.6 at the last follow-up (ΔCI95% = [−5.6; −4.4]; P = .0001). Conclusion Arthroscopic lateral patellar facetectomy and lateral release for isolated PFOA demonstrates sustained significant improvement in knee clinical outcome scores and pain with a low rate of complications and revision surgery at mid-term follow-up. This operation can be recommended in cases of symptomatic isolated PFOA. Level of Evidence IV, case series

Background Primary hyperparathyroidism (HPT) is commonly underdiagnosed and undertreated. Joint pain is a nonspecific symptom associated with osteoarthritis or primary HPT. We hypothesize that patients treated for osteoarthritis are underdiagnosed with primary HPT. Methods Adult patients diagnosed with hip/knee osteoarthritis at the Medical College of Wisconsin from January 2000 to October 2020 were queried. Patients with a calcium level drawn within 1 year of diagnosis of osteoarthritis were included. Patients who had undergone prior parathyroidectomy were excluded. Patients were stratified by serum calcium level, HPT diagnosis, and PTH level. Arthroplasty rates were compared between groups. Results Of 54,788 patients, 9,967 patients (18.2%) had a high serum calcium level, of whom 1,089 (10.9%) had a diagnosis of HPT. Only 76 (7.0%) patients with HPT underwent parathyroidectomy, 208 (19.1%) underwent knee/hip arthroplasty, and 14 (1.3%) underwent both. Arthroplasty was performed in 1,793 patients without evaluation and/or definitive treatment for HPT. There were higher rates of arthroplasty performed in patients with a high serum calcium level compared with those without (21.2% vs 17.4%, P Conclusion Patients with high serum calcium levels were more likely to undergo arthroplasty than those with normocalcemia. Hypercalcemia in the setting of hip or knee osteoarthritis should prompt a full evaluation for primary HPT.

Purpose To compare 5-year outcomes among patients with and without unstable chondral lesions undergoing arthroscopic partial meniscectomy (APM). Methods Using data from the Chondral Lesions And Meniscal Procedures (ChAMP) Trial, we compared outcomes for patients with unstable chondral lesions found at the time of APM and left in situ (CL-noDeb, N = 71) versus patients without unstable chondral lesions (NoCL, N = 47) at 5 years after APM. Outcomes included the Western Ontario and McMaster Universities Arthritis Index (WOMAC), Knee Injury and Osteoarthritis Outcome Score (KOOS), visual analog pain scale, Short-form Health Survey (SF-36), physical knee measurements, progressive joint space narrowing on radiographs, and the rate of additional knee surgery. Multivariate linear regression was used to obtain mean differences (MDs) with corresponding 95% confidence intervals (CIs) adjusted for age, body mass index, and preoperative score (for postoperative scores). Results Compared with CL-noDeb, NoCL subjects had significantly greater improvement at 5 years in the KOOS score for function in sport and recreation (MD = 9.9 [95% CI, 0.7-19.1]), SF-36 pain (MD = 13.9 [95% CI, 5.5-22.3]), knee extension (MD = 0.8 [95% CI, 0.1-1.5]), and decreased quadriceps circumference at the mid-portion of the patella (MD = −1.5 [95% CI, −2.7 to −0.3). A greater proportion of patients in the NoCL group achieved the MCID for all outcome scores except for the WOMAC pain score (89% CL-NoDeb vs 87% NoCL) and SF-36 general (29% CL-NoDeb vs 23% NoCL). There were no significant group differences in measures of progressive radiographic joint space narrowing in any compartments of the operative knee and no significant difference in the rate of additional knee surgery within 5 years of the initial APM. Conclusions Patients undergoing APM without unstable chondral lesions had statistically significantly better outcomes than patients with unstable chondral lesions at 5 years after surgery; however, there were no group differences in progressive radiographic joint space narrowing. Level of Evidence Level II, prospective comparative study.

We developed and validated a set of composite scores that combine quantitative magnetic resonance imaging (MRI)-based measurements of hyaline cartilage damage, bone marrow lesions (BMLs), and effusion-synovitis into composite scores.We selected 300 participants (n = 100 for development cohort; n = 200 for validation cohort) from the Osteoarthritis Initiative with complete clinical, radiographic, and MRI data at baseline and 24 months. We used semiautomated programs to quantify tibiofemoral and patellar cartilage damage, BML volume, and whole-knee effusion-synovitis volume. The candidate composite scores were formed by summing changes from baseline to 24 months based on prespecified methods. We evaluated the candidate composite scores for 1) the ability to differentiate groups with and without knee osteoarthritis progression (17 radiographic and patient-reported definitions), 2) sensitivity to change (standardized response means), and 3) relative performance relating to legacy outcome measures of knee osteoarthritis progression.Three of 13 developed composite scores qualified for testing in the validation cohort (ranked by sensitivity to change): whole-knee cumulative cartilage damage, unweighted total knee score, and BML plus effusion-synovitis volume. Change in cumulative cartilage damage associated with radiographic progression (Kellgren/Lawrence grade: odds ratio [OR] 1.84; joint space width progression: OR 2.11). Changes in the unweighted total knee score (OR 1.97) and BML plus effusion-synovitis score (OR 1.92) associated with Western Ontario and McMaster Universities Osteoarthritis Index knee pain progression.Two composite scores emerged, reflecting discrete domains of knee osteoarthritis progression. First, cumulative damage, which is measured by a whole-knee cartilage damage score, reflects the damage accrued over time. Second, dynamic disease activity, which is measured by a BML plus effusion-synovitis score, relates to changes in a patient's state of disease and symptoms.

OBJECTIVE To compare the prevalence of participants meeting different patient-reported criteria for early osteoarthritis (OA) illness after anterior cruciate ligament reconstruction (ACLR). METHODS Participants completed the Knee Injury and Osteoarthritis Outcomes Score (KOOS) at a single time-point at 5.0-7.9 months post-ACLR. We used established KOOS subscale criteria (i.e., Luyten_Original and Englund_Original) to define patient-reported early OA illness. A two-by-two contingency table and McNemar's test were used to compare the prevalence of participants that met the Luyten_Original versus Englund_Original KOOS criteria for early OA illness. These analyses were repeated using KOOS subscale thresholds based on established population-specific patient acceptable symptom state (PASS) within the Luyten and Englund KOOS criteria (i.e., Luyten_PASS and Englund_PASS). RESULTS A greater prevalence of participants with ACLR met the Luyten_Original criteria (n=165, 54%) compared to those who met the Englund_Original criteria (n=128, 42%; χ2 =19.3, p

To compare the clinical efficacy of the patients with medial compartment knee osteoarthritis who underwent either opening-wedge high tibial osteotomy alone (HTO) or simultaneous HTO and pure platelet-rich plasma therapy (HTO+P-PRP).Eighty patients were divided into 2 groups randomly, the HTO-alone group (n = 41) and the HTO+P-PRP group (n = 39). Patients were matched for preoperative age, sex, and body mass index. The outcomes studied included visual analogue scale (VAS) score, Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC), and Lysholm score. The minimum width of medial knee joint (MJSW), medial proximal tibial angle (MPTA), femoral tibial angle (FTA), and weightbearing line (WBL) were measured preoperatively, immediately postoperatively, and 1, 6, 12, and 24 months postoperatively. Paired t test and chi-squared test were used for statistical analysis.All patients were followed up at 1, 6, 12, and 24 months postoperatively. At 1, 6, and 12 months, pain and function scores in the HTO+P-PRP group were better than those in the HTO-alone group, especially at 6 months in Lysholm score (HTO alone, 72.5 ± 10.6; HTO+P-PRP, 83.1 ± 14.7; P = .003, 95% CI -14.13 to -10.42) and WOMAC (HTO alone, 90.3 ± 11.9; HTO+P-PRP, 75.6 ± 15.4; P.001, 95% CI 13.36 to 20.11). For both groups, no difference was found preoperatively (HTO alone, varus 3.5 ± 3.9; HTO+P-PRP, varus 4.1 ± 4.0; P = .898) or postoperatively (HTO alone, valgus 6.7 ± 4.5; HTO+P-PRP, valgus 7.7 ± 2.3; P = .768) in FTA or WBL. The increase of the MJSW in the HTO+P-PRP group was significantly greater than that in the HTO-alone group during the first year, especially at 6 months (HTO alone, 3.8 ± 1.2 mm; HTO+P-PRP, 4.6 ± 1.1 mm; P = .001, 95% CI -1.27 to -0.35).Compared with HTO alone, HTO combined with intra-articular P-PRP improved the minimum medial knee joint space width during the first year postoperatively. Clinically, a higher proportion of patients in the HTO+P-PRP group exceeded the minimal clinically important difference (MCID) in the first year, especially at 6 months in Lysholm score (HTO alone, 65.9%; HTO+P-PRP, 97.4%) and WOMAC (HTO alone, 82.9%; HTO+P-PRP, 100.0%).2, prospective comparative study.

Summary Objective To develop a machine learning-based prediction model for incident radiographic osteoarthritis (OA) of the knee over 8 years using MRI-based cartilage biochemical composition and knee joint structure, demographics, and clinical predictors including muscle strength and symptoms. Design Individuals (n=1044) with baseline Kellgren Lawrence (KL) grade 0-1 in the right knee from the Osteoarthritis Initiative database were analyzed. 3T MRI at baseline was used to quantify knee cartilage T2, and Whole-Organ Magnetic Resonance Imaging Scores (WORMS) were obtained for cartilage, meniscus, and bone marrow. The outcome was set as true if a subject developed KL grade 2-4 OA in the right knee over 8 years (n=183) and false if the subject remained at KL 0-1 over 8 years (n=861). We developed and compared three models: Model 1: 112 predictors based on OA risk factors; Model 2: top ten predictors based on feature importance score from Model 1 and clinical relevance; Model 3: Model 2 without the imaging predictors. We compared the models using the area under the R OC curve derived from hold-out data. Results The 10-predictor model (Model 2, that includes cartilage and meniscus WORMS scores and cartilage T2) had a slightly lower AUC (0.772) compared to the model with 112 predictors (Model 1: AUC=0.792, p=0.739); and had a significantly higher AUC compared to the model without MR imaging predictors (Model 3, AUC=0.669, p=0.011). Conclusions A 10-predictor model including MRI parameters coupled with demographics, symptoms, muscle, and physical activity scores provides good prediction of incident radiographic OA over 8 years.

Osteoarthritis (OA) is the most common degenerative disease in older adults and its treatment remains unsatisfactory. This study aimed to evaluate the effectiveness and explore the therapeutic mechanisms of the combination of platelet-rich plasma (PRP) and ozone (O3) for knee OA.Thirty male rabbits were randomly divided into five groups (Control group, OA group, PRP group, O3 group, and PRP + O3 group). Rabbit model of OA were induced by improved Hulth surgery. Gross articular observation, histopathological examination and cartilage scoring system were used to assess the articular cartilage destruction. The bone morphogenetic protein-2 (BMP-2) mRNA expression in joint fluid was determined by quantitative reverse transcription polymerase chain reaction (qRT-PCR). The expression of type II collagen, matrix metalloproteinase-1 (MMP-1) of cartilage was detected via Immunohistochemistry. Pain behavior was observed by percent ipsilateral weight-bearing (PIW) asymmetry.The content of platelet in PRP was increased by 6.2-times that in whole blood. Among induced OA groups (the OA, PRP, O3 and PRP + O3 group), PRP + O3 significantly inhibited the surgically induced increase in gross articular alterations, histopathological damage of cartilage and Mankin score when compared to the OA, PRP and O3 groups (P0.05). Observed pain behavior by weight-bearing asymmetry, in the PRP + O3 group was reversed at 3 and 6 weeks after the administration of PRP + O3 (PIW asymmetry: -10.66%±1.172%). In addition, surgery-induced BMP-2 mRNA expression was significantly downregulated after the treatment of PRP, O3 and PRP + O3 (P0.01). PRP + O3 group significantly increased the expression of type II collagen but decreased MMP-1 of cartilage in comparison to OA, PRP and O3 groups (P0.05) by immunohistochemical analysis.PRP combined with O3 may prevent cartilage destruction and improve weight-bearing asymmetry by restoring homeostasis between anabolism and catabolism of extracellular matrix in progressive OA. Furthermore, a combination of PRP and O3 might achieve even better results than the two agents alone.

Summary Objective To explore clinicians’ attitudes and beliefs about physical activity and exercise therapy as treatment for individuals with knee and/or hip osteoarthritis (OA). Method This was a scoping review, mapping available knowledge about the topic derived from qualitative research designs and methods. A comprehensive search of selected databases (MEDLINE, EMBASE; CINAHL; Web of Science) was conducted and data were analysed thematically. Results Twelve articles met inclusion criteria. Thematic analysis identified three interrelated main themes: 1) Understandings of OA and its trajectory and management; 2) Attitudes to activity and exercise as part of OA management; 3) Clinicians’ perceived knowledge of and expertise in OA management. Findings highlight that many clinicians involved in knee/hip OA management, particularly general practitioners and physiotherapists, perceive OA to be a low priority ‘wear-and-tear’ disease with expected progression of symptoms, making joint replacement surgery eventually inevitable. Further, many clinicians appear to lack knowledge about and interest in physical activity and exercise therapy in the management of knee/hip OA, and seem to show uncertainty about the effectiveness and safety of physical activity and exercise therapy on joint health. Conclusion Clinicians’ attitudes and beliefs about physical activity and exercise therapy in OA seem to reflect an outdated narrative which describes OA as a wear-and-tear disease with inevitable disease progression to joint replacement surgery. Clinicians need to adopt a contemporary narrative, which accurately reflects current knowledge and evidence-based practice, thereby ensuring consistent utilisation of exercise therapy as first-line care as recommended in OA guidelines. Objective: To explore clinicians’ attitudes and beliefs about physical activity and exercise therapy as treatment for individuals with knee and/or hip osteoarthritis (OA). Method: This was a scoping review, mapping available knowledge about the topic derived from qualitative research designs and methods. A comprehensive search of selected databases (MEDLINE, EMBASE; CINAHL; Web of Science) was conducted and data were analysed thematically. Results: Twelve articles met inclusion criteria. Thematic analysis identified three interrelated main themes: 1) Understandings of OA and its trajectory and management; 2) Attitudes to activity and exercise as part of OA management; 3) Clinicians' perceived knowledge of and expertise in OA management. Findings highlight that many clinicians involved in knee/hip OA management, particularly general practitioners and physiotherapists, perceive OA to be a low priority ‘wear-and-tear’ disease with expected progression of symptoms, making joint replacement surgery eventually inevitable. Further, many clinicians appear to lack knowledge about and interest in physical activity and exercise therapy in the management of knee/hip OA, and seem to show uncertainty about the effectiveness and safety of physical activity and exercise therapy on joint health. Conclusion: Clinicians’ attitudes and beliefs about physical activity and exercise therapy in OA seem to reflect an outdated narrative which describes OA as a wear-and-tear disease with inevitable disease progression to joint replacement surgery. Clinicians need to adopt a contemporary narrative, which accurately reflects current knowledge and evidence-based practice, thereby ensuring consistent utilisation of exercise therapy as first-line care as recommended in OA guidelines.

Osteoarthritis (OA) is the most prevalent type of arthritis worldwide, resulting in pain and often chronic disability and a significant burden on healthcare systems globally. Non-steroidal anti-inflammatory drugs (NSAIDs), analgesics, intra-articular corticosteroid injections are of little value in the long term, and opioids may have ominous consequences. Radiotherapy of knee OA has no added value. Physical therapy, exercises, weight loss, and lifestyle modifications may give pain relief, improve physical functioning and quality of life. However, none of them has articular cartilage regenerating potential. Due to a better understanding of osteoarthritis, innovative new treatment options have been developed. In this narrative review, we focus on emerging OA knee treatments, relieving symptoms, and regenerating damaged articular cartilage that includes intra-articular human serum albumin, conventional disease-modifying anti-rheumatic drugs (DMARDs), metformin, lipid-lowering agents (statin), nerve growth factors antagonists, bone morphogenetic protein, fibroblast growth factors, Platelet-Rich Plasma (PRP), Mesenchymal Stem Cells (MSC), exosomes, interleukin-1 blockers, gene-based therapy, and bisphosphonate.

Background A socioeconomic gradient exists in the utilisation of total hip replacements (THR) and total knee replacements (TKR) for osteoarthritis. However, the relations between socioeconomic status (SES) and time to THR or TKR is unknown. Aim To describe the association between SES and time to THR and TKR. Methods 1072 older-adults residing in Tasmania, Australia were studied. Incident primary THR and TKR were determined by data linkage to the Australian Orthopaedic Association National Joint Replacement Registry. At baseline, each participant's area-level SES was determined by the Index of Relative Socioeconomic Advantage and Disadvantage (IRSAD), from the Australian Bureau of Statistics' 2001 census data. IRSAD was analysed in two ways; 1) categorised into quartiles, whereby quartile 1 represented the most socioeconomically disadvantaged group, 2) the cohort dichotomised at the quartile 1 cut-point. Results The mean age was 63.0 (±7.5) years, and 51% were women. Over the median follow-up of 12.9 (Interquartile range: 12.2-13.9) years, 56 (5%) participants had a THR, and 79 (7%) had a TKR. Compared to the most disadvantaged quartile, less disadvantaged participants were less likely to have a THR (i.e. less disadvantaged participants had a longer time to THR) (HR: 0.56, 95% CI 0.32, 1.00) but not TKR (HR: 0.90, 95% CI 0.53, 1.54). However, the former became non-significant after adjustment for pain and radiographic osteoarthritis, suggesting that the associations may be mediated by these factors. Conclusions This study suggests that time to joint replacement was determined according to the symptoms/need of the participants rather than their SES. This article is protected by copyright. All rights reserved.

For individuals with knee osteoarthritis (OA), stair negotiation is a challenging task and the first task during which they report pain due to the high knee loading required. The use of lateral wedge insole (LWI) has been found to reduce loading in patients with OA but not to reduce pain, whereas the use of knee sleeve has been shown to result in good pain reduction. Understanding the effect of combining LWI and knee sleeve use on healthy individuals before testing on individuals with knee OA is an important step.The current study aimed to evaluate the effect of combining the use of LWI and knee sleeve and compare the results with the application of each treatment separately and with the control condition.This randomised cross-over study included 17 healthy participants who underwent 3D gait analysis. Participants performed ascending and descending stair activities with the following four treatment conditions: five-degree LWI, off-the-shelf knee sleeve, both LWI and knee sleeve and control condition. External knee adduction moment (EKAM) and knee frontal plane range of motion (ROM) were evaluated as primary outcomes. Repeated measure ANOVA or the Friedman test was selected based on meeting the assumption followed by multiple pairwise comparisons with Bonferroni correction.In general, the use of LWI reduced the first peak EKAM significantly (p 0.001) compared to the control condition in stir ascending (12% reduction) but not in stair descending (p 0.05). Interestingly, knee sleeve use did not result in any reduction in the first peak EKAM compared to the control or any other condition. However, knee sleeve use led to a significant reduction in the knee frontal plane ROM during stair descending. The combined treatment was not superior to the LWI use when compared to control in the EKAM reduction.Combined knee sleeve and LWI use was not superior to LWI use alone in reducing the knee loading, but it may be beneficial for individuals with knee OA since it helped in reduction of the knee frontal plane ROM during stair descending. Importantly, the effect of LWI use or any other treatment must be investigated for each different activity, and the results found in one activity must not be generalised across other activities.

Summary Objective In knee cartilage from patients with osteoarthritis (OA), both preserved cartilage and damaged cartilage are observed. In this study, we aim to compare preserved with damaged cartilage to identify the molecule(s) that may be responsible for the mechanical loading-induced differences within cartilage degradation. Methods Preserved and damaged cartilage were harvested from the same OA knee joint. RNA Sequencing was performed to examine the transcriptomic differences between preserved and damaged cartilage cells. Estrogen receptor-α (ERα) was identified, and its function of was tested through gene knockin and knockout. The role of ERα in mediating chondrocyte response to mechanical loading was examined via compression of chondrocyte-laded hydrogel in a strain-controlled manner. Findings from the studies on human samples were verified in animal models. Results Level of estrogen receptor α (ERα) was significantly reduced in damaged cartilage compared to preserved cartilage, which were observed in both human and mice samples. Knockdown of ESR1, the gene encoding ERα, resulted in an upregulation of senescence- and OA-relevant markers in chondrocytes. Conversely, knockin of ESR1 partially reversed the osteoarthritic and senescent phenotype of OA chondrocytes. Using a three-dimensional (3D) culture model, we demonstrated that mechanical overload significantly suppressed ERα level in chondrocytes with concomitant upregulation of osteoarthritic phenotype. When ESR1 expression was suppressed, mechanical loading enhanced hypertrophic and osteogenic transition. Conclusion Our study demonstrates a new estrogen-independent role of ERα in mediating chondrocyte phenotype and its response to mechanical loading, and suggests that enhancing ERα level may represent a new method to treat osteoarthritis.

Objectives: The aim of this study was to estimate the costs of primary hip and knee replacement in individuals with osteoarthritis up to 2 years post-surgery, compare costs before and after the surgery, and identify predictors of hospital costs. Methods: Patients aged 18 years or over with primary planned hip or knee replacements and osteoarthritis in England between 2008 and 2016 were identified from the National Joint Registry and linked with Hospital Episode Statistics data containing inpatient episodes. Primary care data linked with hospital outpatient records were also used to identify patients aged 18 years or over with primary hip or knee replacements between 2008 and 2016. All healthcare resource use was valued using 2016/17 costs and non-parametric censoring methods were used to estimate total 1-year and 2-year costs. Results: We identified 854,866 individuals undergoing hip or knee replacement. The mean censor-adjusted 1-year hospitalisation costs for hip and knee replacement were £7,827 (95% CI £7,813 to £7,842) and £7,805 (95% CI £7,790 to £7,818), respectively. Complications and revisions were associated with up to a three-fold increase in 1-year hospitalisation costs. The censor-adjusted 2-year costs were £9,258 (95 % CI £9,233 to £9,280) and £9,452 (95%CI £9,430 to £9,475) for hip and knee replacement. Adding primary and outpatient care, the mean total hip and knee replacement 2-year costs were £11,987 and £12,578, respectively. Conclusions: There are significant costs following joint replacement. Revisions and complications accounted for considerable costs and there is a significant incentive to identify best approaches to reduce these.

OBJECTIVE. To test the hypothesis that an altered gut microbiota (dysbiosis) plays a role in obesity-associated osteoarthritis (OA). METHODS. Stool and blood samples were collected from 92 participants with BMI ≥ 30 kg/m(2) recruited from the Johnston County Osteoarthritis Project. OA cases (n=50) had hand plus knee OA (Kellgren-Lawrence [KL] grade ≥2 or arthroplasty). Controls (N=42) had no hand OA and KL grade 0–1 knees. Compositional analysis of stool samples was carried out by 16S rRNA amplicon sequencing. Alpha and beta diversity and differences in taxa relative abundances were determined. Blood samples were used for multiplex cytokine analysis and measures of lipopolysaccharide (LPS) and LPS binding protein. Germ-free mice were gavaged with case or control pooled fecal samples and placed on a 40% fat, high sucrose diet for 40 weeks. Knee OA was evaluated histologically. RESULTS. OA cases were slightly older with more females and higher BMI, WOMAC pain and KL grades than controls. There were no significant differences in alpha or beta diversity or genus level composition between cases and controls. Cases had higher plasma levels of osteopontin (p=0.01) and serum LPS (p

Osteoarthritis (OA) is one of the most prevalent disorders in today's society, resulting in significant socio-economic costs and morbidity. MRI is widely used as a non-invasive imaging tool for OA of the knee. However, conventional knee MRI has limitations to detect subtle early cartilage degeneration before morphological changes are visually apparent. Novel MRI pulse sequences for cartilage assessment have recently received increased attention due to newly developed compositional MRI techniques, including: T2 mapping, T1rho mapping, delayed gadolinium-enhanced MRI of cartilage (dGEMRIC), sodium MRI, diffusion-weighted imaging (DWI)/ diffusion tensor imaging (DTI), ultrashort TE (uTE), and glycosaminoglycan specific chemical exchange saturation transfer (gagCEST) imaging. In this article, we will first review these quantitative assessments. Then, we will discuss the variations of quantitative values of knee articular cartilage with cartilage layer (depth)- and angle (regional)-dependent approaches. Multiple MRI sequence techniques can discern qualitative differences in knee cartilage. Normal articular hyaline cartilage has a zonal variation in T2 relaxation times with increasing T2 values from the subchondral bone to the articular surface. T1rho values were also higher in the superficial layer than in the deep layer in most locations in the medial and lateral femoral condyles, including the weight-bearing portion. Magic angle effect on T2 mapping is clearly observed in the both medial and lateral femoral condyles, especially within the deep layers. One of the limitations for clinical use of these compositional assessments is a long scan time. Recent new approaches with compressed sensing (CS) and MR fingerprinting (MRF) have potential to provide accurate and fast quantitative cartilage assessments.

Background Despite the success rate of Total Knee Arthroplasty (TKA), many patients undergo contralateral TKA. It is possible that altered gait mechanics after unilateral TKA play a role in the progression of contralateral OA progression. Research question The purpose of this study was to identify biomechanical predictors of radiographic OA progression in the contralateral (non-surgical) knee after unilateral (primary/initial) TKA. In addition, this study quantified for patients who had contralateral OA progression. Methods Biomechanical outcomes were collected 6–24 months after unilateral primary TKA and were used to predict changes in contralateral OA severity at follow-up. Participants were divided into “Progressor” and “Non-Progressor” groups based on changes in Kellgren-Lawrence (KL) OA grade and Joint Space Width (JSW) between baseline and follow-up testing sessions. Biomechanical factors during walking were peak knee adduction moment, knee flexion/extension excursions, knee angle at initial foot contact, and peak knee flexion/extension. Multiple independent t-tests were used to examine the magnitude of differences in biomechanical variables between the groups. Logistic regression was used to examine the association between the biomechanical predictors and change in KL scores and JSW. Results The mean time between surgery and follow-up x-rays was 8.8 (2.4) years. Of 40 participants, 62.5–78% had contralateral radiographic knee OA progression by follow-up. There were no significant differences in the biomechanical variables between groups. For the regression analysis, none of the biomechanical variables were found to be predictors for contralateral OA progression. Significance Although abnormal biomechanics are known risk factors for primary knee OA, it is possible that the mechanisms that result in OA progression of the contralateral limb are different than primary knee OA progression. Future work should evaluate other objective measures of OA progression and determine if cumulative measures of joint loading are related to OA worsening.

Background/Aims: Conventional disease-modifying anti-rheumatic drugs have been trialed in osteoarthritis (OA). Hydroxychloroquine (HCQ), which has shown its effectiveness in rheumatoid arthritis, has been trialed for the treatment of OA; however, its efficacy and safety remain unclear. This systematic review and meta-analysis evaluate efficacy and safety of HCQ for the treatment of OA.Methods: MEDLINE, EMBASE, and Cochrane Central were searched from inception through June 2020. Two reviewers independently screened for randomized controlled trials (RCTs) comparing HCQ with placebo or other active-comparators for the treatment of knee, hand, or hip OA, extracted data, and performed Cochrane risk of bias assessments.Results: Six RCTs, four in hand OA, two in knee OA, consisting of 842 patients (436 in HCQ arm, 406 in control arm) were included. RCTs were conducted between 2012 and 2020, one each at UK, Netherlands, Germany, Italy, Iran, and Egypt; follow-up period ranged 24 to 52 weeks. High-quality evidence showed no clinically important pain reduction with HCQ compared to placebo/active-control in hand OA (standardized mean difference [SMD], 0.14; 95% confidence interval [CI], –0.20 to 0.48). Effect on pain reduction in knee and hand OA was small and non-significant (SMD, –0.09; 95% CI, –0.44 to 0.25). High-quality evidence showed no improvement in dysfunction with HCQ compared to placebo in hand OA patients (SMD, 0.08; 95% CI, –0.23 to 0.40). Effect on dysfunction improvement in knee and hand OA was modest and statistically non-significant (SMD, –0.20; 95% CI,–0.57 to 0.18). No improvement in quality of life was observed in hand OA.Conclusions: HCQ has no benefit in reducing pain and improving physical function in hand or knee OA patients.

Graphical abstract, Highlights • Synovial fibrosis was positively correlated with pain sensitivity in KOA rats. • Synovial fibrosis was most prominent in DMM group 14 days after modeling. • ACLT replaced DMM to be the most typical at 28 days after modeling. • Increased synovial sensory innervation followed the same trend as fibrosis. • ACLT is more applicable for KOA pain research., Introduction Knee osteoarthritis (KOA) showed synovial fibrosis and hyperalgesia, although the correlation between the two is unclear. Besides, the specific changes of sensory innervation in animal models are still controversial, which makes it difficult to choose the modeling methods for KOA pain research. Objectives Study the characteristics of sensory innervation within three commonly used KOA rat models and the correlation between synovial fibrosis and hyperalgesia. Methods KOA models were induced by destabilization of medial meniscus (DMM), anterior cruciate ligament transection (ACLT), and monoiodoacetate (MIA), respectively. Mechanical, cold and thermal withdrawal threshold (MWT, CWT and TWT) were measured. The harvested tissues were used for pathological sections, immunofluorescence and quantitative analysis. Results KOA synovium showed more type I collagen deposition, increased expression of CD31, VEGF and TGF-β. These changes were most pronounced in surgical models, with DMM presenting the most prominent at Day 14 and ACLT at Day 28. Day 14, changes in mechanical hyperalgesia and cold hyperalgesia were most typical in DMM model and statistically different from MIA. There was a negative correlation between the percentage of type I collagen and MWT value (r = −0.88), as well as CWT value (r = −0.95). DMM synovium showed more axonal staining, upregulated CGRP, TRPV1, NGF and Netrin1 compared with MIA. Above changes were also observed at Day 28, but ACLT replaced DMM as the most typical. In DRG, only the levels of CGRP and NGF were different among KOA models at Day 14, and the highest in DMM, which was statistically different compared with MIA. Conclusions This study described the details of sensory innervation in different KOA model of rats, and the degree of synovial fibrosis was positively correlated with the pain sensitivity of KOA model rats. Additionally, surgical modeling especially ACLT method is more recommended for KOA pain research.

Summary Objective To explore mechanisms of mechanoinflammation, we investigated the association between the presence of knee synovial perivascular edema and gait biomechanics that serve as surrogate measures of knee load in patients with knee osteoarthritis (OA). Design Patients with symptomatic, radiographic knee OA and neutral to varus alignment undergoing total knee arthroplasty or high tibial osteotomy participated in this cross-sectional analysis. All participants underwent 3D gait analysis prior to surgery. Synovial biopsies were obtained during surgery for histopathological assessment. The association between the presence of synovial perivascular edema (predictor) and the external knee moment (outcome) in each orthogonal plane was analyzed using multivariate linear regression and polynomial mixed effects regression models, while adjusting for age, sex, BMI, and gait speed. Results Ninety-two patients with complete gait and histopathological data were included. When fitted over 100% of stance, regression models indicated substantial differences between patients with and without synovial perivascular edema for knee moments in frontal, sagittal and transverse planes. The knee adduction moment was higher in patients with edema from 16 to 74% of stance, with the largest difference at 33% of stance (β = 6.87 Nm [95%CI 3.02, 10.72]); whereas the knee flexion-extension moment differed from 15 to 92% of stance, with the largest difference in extension at 60% of stance (β = −10.80 Nm [95%CI -16.20, −5.40]). Conclusions In patients with knee OA, the presence of synovial perivascular edema identified by histopathology is associated with aberrant patterns of knee loading throughout stance, supporting the link between biomechanics and synovial inflammation.

Background Total knee arthroplasty (TKA) by the trivector approach is less invasive to the knee extensor mechanism; early quadriceps training is possible and a good prognosis is expected after surgery. However, investigations regarding lower limb muscle activity during gait have not been reported after using the trivector approach. To determine an effective postoperative rehabilitation program, we analyzed the recovery processes of leg muscle activities during walking. Methods Fourteen subjects with severe knee osteoarthritis (OA) who underwent early exercises after TKA by trivector approach were included in the TKA group. The control group consisted of eight patients with mild knee OA. Surface electromyography of the vastus medialis (VM), vastus lateralis (VL), and rectus femoris (RF) muscles were recorded and gait speed and step length were measured. The TKA group was measured postoperatively at 3, 12, and 24 weeks. Results Gait speed of TKA group significantly increased at 12 weeks post-surgery and recovered equal to the control group at 24 weeks. Additionally, step length reached the level of control subjects at 24 weeks. Postoperative activity of VM returned to that of the control group at 12 weeks. VL continued decreasing until 12 weeks compared with the preoperative values, but gradually increased and became equal to the control group at 24 weeks. RF slightly increased at 3 weeks postoperation and remained stable. Conclusions VM injury by the trivector approach might be small and temporary.Functional recovery of VL was important and early starting rehabilitation program up to 24 weeks is appropriate.

Introduction: Knee Osteoarthritis (OA) is a weight-bearing joint disease and is more common in overweight and obese persons. The objective of the study was to assess the feasibility and acceptability of Instructions of Daily Care (IDC) on pain, mobility, and Body Mass Index (BMI) among knee OA participants who are overweight or obese. Material and Method: The study was an open-label randomized controlled trial of six weeks. Forty overweight and obese participants with knee OA were randomly divided into two groups by a computer-generated number. The participants in the Instruction Group (IG) were provided with leaflets explaining IDC for the duration of six weeks. Both groups were instructed to take low doses of the non-steroid anti-inflammatory drug (NSAIDs) on alternate days. The outcome measures were pain, mobility and BMI. The feasibility and acceptability of knee pain and mobility were assessed using a questionnaire designed by experts in rehabilitation. Results: Participants in the IG reported more statistically significant pain relief as assessed by the Western Ontario and McMaster Universities Osteoarthritis Index score (p=0.001) and improvement in mobility (p=0.000) assessed by the Timed Up and Go test score after six weeks compared to the Control Group (CG). Both groups did not demonstrate any significant change in BMI (p-value > 0.05). The results of descriptive statistics showed a significantly higher satisfaction score for participants who received a combination of IDC and NSAIDs, indicating an acceptable intervention. Conclusion: The IDC is effective and acceptable in terms of improving pain and mobility and should be recommended as the usual care of treatment.

Objectives To examine the cross-sectional association of ascending pain mechanisms (APM), implicated in pain sensitization (PS), and descending pain modulation with pain patterns and unpredictability of pain. Methods The Multicenter Osteoarthritis (OA) Study is a longitudinal cohort of older adults with or at risk of knee OA. Peripheral and central APM were assessed using quantitative sensory tests (QST); pressure pain thresholds (PPTs) using a handheld pressure algometer (knee/peripheral and wrist/central), temporal summation (TS) using weighted probes (wrist/central). Descending modulation was assessed by conditioned pain modulation (CPM) using PPTs and a forearm ischemia test. Pain patterns were characterized based on responses to the Intermittent and Constant OA Pain (ICOAP) questionnaire: 1) no intermittent or constant pain; 2) intermittent pain only; 3) constant pain only; and 4) combined constant and intermittent pain. A question regarding frequency assessed unpredictable pain. We assessed the association of QST measures to pain patterns using regression models with generalized estimating equations. Results There were 2794 participants (mean age 63.9, BMI 29.5 kg/m2 , 57% female). Lower PS (by wrist PPT) OR = 0.80 (95% CI 0.68, 0.93) and adequate CPM, OR = 1.45 (1.10, 1.92) were associated with having constant +/- intermittent pain compared with intermittent pain only. Higher PS (by PPT and TS) was associated with higher likelihood of unpredictable pain. Conclusions Knee pain patterns appear to be related to peripheral +/- central facilitated APM, and descending modulatory mechanisms. These findings highlight the need for a broader approach to understanding pain mechanisms by symptomatic disease progression.

Background: The use of symptomatic slow-acting drugs for osteoarthritis (OA) (e.g., glucosamine, chondroitin) is largely debated in the scientific literature. Indeed, multiple formulations of these agents are available, both as pharmaceutical-grade products and as nutritional supplements , but while all preparations may claim to deliver a therapeutic effect, not all are supported by clinical evidence. Moreover, few data are available regarding the cost-effectiveness of all these formulations. Usually, access to individual patient data is required to perform economic evaluations of treatments, but it can be challenging to obtain. We previously developed a model to simulate individual health utility scores from aggregated data obtained from published OA trials. Objective: In the present study, using our new simulation model, we investigated the costeffectiveness of different glucosamines used in Germany. Methods: We used our validated model to simulate the utility scores of 10 published trials that used different glucosamine preparations. Using the simulated utility scores, the quality-adjusted life years (QALYs) were calculated using the area-under-the-curve method. We used the 2018 public costs of glucosamine products available in Germany to calculate the Incremental Cost/Effectiveness Ratio (ICER). We performed analyses for pharmaceutical-grade Crystalline Glucosamine Sulfate (pCGS) and other formulations of glucosamine (OFG). A cost-effectiveness cut-off of 30,000 €/QALY was considered. Results: Of 10 studies in which utility was simulated, four used pCGS, and six used OFG. The ICER analyses showed that pCGS was cost-effective compared to a placebo, with an ICER of 4489 €/QALY at month 3, 4112 €/QALY at month 6, and 9983 €/QALY at year 3. The use of OFG was not cost-effective at any of the time points considered. Conclusion: Using our previously published model to simulate the individual health utility scores of patients, we showed that, in the German context, the use of pCGS could be considered costeffective, while the use of OFG could not. These results highlight the importance of the formulation of glucosamine.

Background: A significant number of high tibial osteotomies (HTOs) result in an overcorrected tibia and subsequent excessive lateral joint line obliquity (JLO). The correlation between excessive JLO and poor outcomes is controversial. Purpose: To evaluate the prognostic factors (including a pathological postoperative JLO) related with the outcomes of opening wedge HTO at 10 years of follow-up. Study Design: Case series; Level of evidence, 4. Methods: All patients undergoing HTO between 2004 and 2017 for medial osteoarthritis and with a postoperative hip-knee-ankle angle between 176° and 185° were included. Clinical evaluation included Knee Society Score (KSS; knee score and function score), Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC), and visual analog scale for pain. Several mechanical and anatomic angles were measured pre- and postoperatively on long-leg weightbearing radiographs. Abnormal JLO was defined as a Mikulicz–joint line angle (MJL) ≥94° or a mechanical medial proximal tibial angle (mMPTA) ≥95°. Regression analysis was performed to evaluate the association between independent variables and each outcome. A Kaplan-Meier cumulative survival analysis was performed. Results: A total of 92 knees in 76 patients were included. The mean age of the patients was 53.5 years (SD, 9.7 years), and the mean follow-up was 129.4 months (SD, 44.4 months). Increased JLO was associated with a significant preoperative varus deformity (small preoperative hip-knee-ankle angle), increased mechanical lateral distal femoral angle, increased joint line congruency angle, and increased knee-ankle joint angle. Male sex was associated with better WOMAC scores ( P = .0277), and increased body mass index (BMI) was associated with inferior WOMAC scores ( P = .0024). A good preoperative range of motion was associated with better knee score ( P = .0399) and function score ( P = .0366) on the KSS. An increased BMI was associated with inferior KSS function scores ( P = .0317). MJL ≥94° and mMPTA ≥95° were not associated with inferior WOMAC or KSS outcomes. With indication to total knee arthroplasty as an endpoint, Kaplan-Meier analysis showed a survival rate of 98.7% at 5 years, 95.5% at 10 years, and 92.7% at 12 years. Conclusion: Increased lateral JLO (MJL ≥94° or mMPTA ≥95°) was not correlated with the clinical outcomes of opening wedge HTO at 10 years of follow-up.

GLPG1972/S201086 is a disintegrin and metalloproteinase with thrombospondin motif-5 (ADAMTS-5) inhibitor in development as an osteoarthritis disease-modifying therapy. We report the safety, tolerability, pharmacokinetics, and pharmacodynamics (turnover of plasma/serum ARGS-aggrecan neoepitope fragments [ARGS]) of GLPG1972 in 3 randomized, double-blind, placebo-controlled phase 1 trials. Study A, a first-in-human trial of single (≤2100 mg [fasted] and 300 mg [fed]) and multiple (≤1050 mg once daily [fed]; 14 days) ascending oral (solution) doses, investigated GLPG1972 in healthy men (N = 41; NCT02612246). Study B investigated multiple ascending oral (tablet) doses of GLPG1972 (≤300 mg once daily [fed]; 4 weeks) in male and female participants with osteoarthritis (N = 30; NCT03311009). Study C investigated single (Japanese: ≤1500 mg; White: 300 mg [fasted]) and multiple (Japanese, ≤1050 mg once daily; White, 300 mg once daily [fed]; 14 days) ascending oral (tablet) doses of GLPG1972 in healthy Japanese and White men (N = 88). The pharmacokinetic profile of GLPG1972 was similar between healthy participants and participants with osteoarthritis, with low to moderate interindividual variability. GLPG1972 was rapidly absorbed (median time to maximum concentration, 4 hours), and eliminated with a mean apparent terminal elimination half-life of ≈10 hours. Steady state was achieved within 2 days of dosing, with minimal accumulation. Steady-state plasma exposure after 300 mg of GLPG1972 showed no or minor differences between populations. Area under the plasma concentration-time curve (56.8-67.6 μg · h/mL) and time to maximum concentration (4 hours) were similar between studies. Urinary excretion of GLPG1972 (24 hours) was low (

Background Many patients choose complementary and alternative medicine (CAM) to treat various conditions. Among osteoarthritis patients, acupressure is a popular CAM treatment. In Iran, Ghamz (a Persian acupressure technique) uses for musculoskeletal ailments like knee pain. Aims To examine the potential efficacy of Ghamz on osteoarthritis outcomes. Design Clinical Trial. Settings Randomized, single-blind, sham-controlled clinical trial. Participants/Subjects Eighty patients with diagnosed knee osteoarthritis, age over 35 years old. Methods Eighty adult patients with confirmed knee osteoarthritis from three outpatient clinics were recruited. Participants were randomly assigned either to intervention or placebo groups using sham acupressure. The primary outcomes included Knee injury and Osteoarthritis Outcome Score (KOOS) parameters and pain scores measured using the visual analog scales (VAS). Results Seventy-two individuals completed the trial and were included in the analysis. At baseline, there was no difference between the mean scores of both outcomes. After the intervention, the group receiving Ghamz therapy experienced an improvement in KOOS parameters, including symptoms, pain, activity daily livings, sport, recreation function, and quality of life. The mean pain score in the intervention group was significantly decreased from 5.89 at the beginning study to 4.11 at the end of the study, while the pain score did not change substantially in the sham group. These findings remained consistent after adjusting for covariates of age, weight, and pre-treatment. Conclusions This study supports evidence that Ghamz therapy provides an effective option for short-term knee pain relief in patients with knee osteoarthritis. Additional studies are recommended to confirm these findings.