Evaluation of S201086/GLPG1972, an ADAMTS-5 inhibitor, for the treatment of knee osteoarthritis in ROCCELLA: a phase 2 randomized clinical trial.

OBJECTIVE: To evaluate the efficacy and safety of the anti-catabolic ADAMTS-5 inhibitor S201086/GLPG1972 for the treatment of symptomatic knee osteoarthritis. DESIGN: ROCCELLA (NCT03595618) was a randomized, double-blind, placebo-controlled, dose-ranging, phase 2 trial in adults (aged 40-75 years) with knee osteoarthritis. Participants had moderate-to-severe pain in the target knee, Kellgren-Lawrence grade 2 or 3 and Osteoarthritis Research Society International joint space narrowing (grade 1 or 2). Participants were randomized 1:1:1:1 to once-daily oral S201086/GLPG1972 75, 150 or 300 mg, or placebo for 52 weeks. The primary endpoint was change from baseline to week 52 in central medial femorotibial compartment (cMFTC) cartilage thickness assessed quantitatively by magnetic resonance imaging. Secondary endpoints included change from baseline to week 52 in radiographic joint space width, Western Ontario and McMaster Universities Osteoarthritis Index total and subscores, and pain (visual analogue scale). Treatment-emergent adverse events (TEAEs) were also recorded. RESULTS: Overall, 932 participants were enrolled. No significant differences in cMFTC cartilage loss were observed between placebo and S201086/GLPG1972 therapeutic groups: placebo vs 75 mg, P = 0.165; vs 150 mg, P = 0.939; vs 300 mg, P = 0.682. No significant differences in any of the secondary endpoints were observed between placebo and treatment groups. Similar proportions of participants across treatment groups experienced TEAEs. CONCLUSIONS: Despite enrolment of participants who experienced substantial cartilage loss over 52 weeks, during the same time period, S201086/GLPG1972 did not significantly reduce rates of cartilage loss or modify symptoms in adults with symptomatic knee osteoarthritis.

Reflections from the 2021 OARSI clinical trial symposium: Considerations for understanding biomarker assessments in osteoarthritis drug development - Should future studies focus on disease activity, rather than status?

Objective: Osteoarthritis (OA) is heterogeneous disease, for which drug development has proven to be challenging, both facilitated and hampered by changing guidelines. This is evident by the current lack of approved treatments, which improve joint function and delay joint failure. There is a need to bring together key stakeholders to discuss, align and enhance the processes for OA drug development to benefit patients. Design: To facilitate drug development, the Osteoarthritis Research Society International (OARSI) initiated a series of annual clinical trials symposia (CTS). The aim of these symposia was to bring together academics, translational and clinical scientists, regulators, drug developers, and patient advocacy groups to share, refine and enhance the drug development process for the benefit of patients. Results: OARSI is now considered the leading organization to facilitate open dialogue between all these stakeholders, in the intersection of understanding of the pathologies and drug development. Clearly, such a pivotal task needs an annual forum to allow stakeholders to share and discuss information, as possible solutions are joint efforts rather than a single stakeholder contribution. Conclusions: The main topic of the 2021 CTS was how to improve clinical studies to help patients through overcoming barriers to development of new disease modifying treatments for OA. One key aspect was the focus on definitions of disease activity, status and the definitions of "illness vs disease". There is a clear medical need to couple a given disease activity with the optimal intervention for the right patient.

A Phase 2b randomized trial of lorecivivint, a novel intra-articular CLK2/DYRK1A inhibitor and Wnt pathway modulator for knee osteoarthritis.

OBJECTIVE: Lorecivivint (LOR; SM04690), an investigational Wnt pathway modulator, previously demonstrated patient-reported and radiographic outcome improvements vs placebo in clinically relevant subjects with moderate to severe knee osteoarthritis (OA). This study's objective was to identify effective LOR doses. DESIGN: Subjects in this 24-week, Phase 2b, multicenter, randomized, double-blind, placebo (PBO)-controlled trial received an intra-articular injection of 2 mL LOR (0.03, 0.07, 0.15, or 0.23 mg), PBO, or dry-needle sham. The primary efficacy endpoints were changes in Pain NRS [0-10], WOMAC Pain [0-100], WOMAC Function [0-100], and radiographic mJSW outcomes, which were measured using baseline-adjusted analysis of covariance at Week 24. Multiple Comparison Procedure-Modeling (MCP-Mod) was performed for dose modeling. RESULTS: In total, 695/700 subjects were treated. Pain NRS showed significant improvements vs PBO after treatment with 0.07 mg and 0.23 mg LOR at Weeks 12 (-0.96, 95% CI [-1.54, -0.37], P = 0.001; -0.78 [-1.39, -0.17], P = 0.012) and 24 (-0.70 [-1.34, -0.06], P = 0.031; -0.82 [-1.51, -0.12], P = 0.022). Additionally, 0.07 mg LOR significantly improved WOMAC Pain and Function subscores vs PBO at Week 12 (P = 0.04, P = 0.021), and 0.23 mg LOR significantly improved both WOMAC subscores at Week 24 (P = 0.031, P = 0.017). No significant differences from PBO were observed for other doses. No radiographic progression was observed in any group at Week 24. MCP-Mod identified 0.07 mg LOR as the lowest effective dose. CONCLUSION: This 24-week Phase 2b trial demonstrated the efficacy of LOR on PROs in knee OA subjects. The optimal dose for future studies was identified as 0.07 mg LOR.

Evaluating the structural effects of intra-articular sprifermin on cartilage and non-cartilaginous tissue alterations, based on sqMRI assessment over 2 years.

OBJECTIVE: Sprifermin (recombinant human fibroblast growth factor-18), a potential disease-modifying osteoarthritis (OA) drug, demonstrated dose-dependent effects on femorotibial cartilage thickness (by quantitative magnetic resonance imaging [MRI]) in the phase II FORWARD study. This post-hoc analysis evaluated the potential effects of sprifermin on several articular structures in the whole joint over 24 months using semi-quantitative MRI assessment. DESIGN: Patients aged 40-85 years with symptomatic radiographic knee OA, Kellgren-Lawrence grade 2 or 3, and medial minimum joint space width ≥2.5 mm in the target knee were randomized (1:1:1:1:1) to receive three double-blinded, once-weekly, intra-articular injections of sprifermin 30 µg or 100 µg or placebo every 6 (q6mo) or 12 months. 1.5- or 3 T MRIs were read using the Whole-Organ Magnetic Resonance Imaging Score (WORMS) system at baseline and 24 months. Change from baseline at 24 months on compartment and/or whole knee level was assessed for cartilage morphology, bone marrow lesions (BMLs), and osteophytes by delta-subregional and delta-sum (DSM) approaches. Menisci, Hoffa-synovitis, and effusion-synovitis were also evaluated for worsening. RESULTS: 549 patients were included. Dose-dependent treatment effects from baseline to 24 months were observed on cartilage morphology (sprifermin 100 µg q6mo vs placebo; mean DSM (95% confidence interval [CI]) -0.6 (-1.5, 0.2); less cartilage worsening) in the entire knee and BMLs sprifermin 100 µg q6mo vs placebo; mean DSM (95% CI) -0.2 (-0.5, 0.1) in the patellofemoral compartment. No effects over 24 months were observed on osteophytes, menisci, Hoffa-synovitis or effusion-synovitis. CONCLUSIONS: Positive effects associated with sprifermin were observed for cartilage morphology changes, and BML improvement. There were no meaningful negative or positive effects associated with sprifermin in the other joint tissues examined.

Predicting knee replacement in participants eligible for disease-modifying osteoarthritis drug treatment with structural endpoints.

OBJECTIVE: Evaluate associations between 2-year change in radiographic or quantitative magnetic resonance imaging (qMRI) structural measures, and knee replacement (KR), within a subsequent 7-year follow-up period. METHOD: Participants from the Osteoarthritis Initiative were selected based on potential eligibility criteria for a disease-modifying osteoarthritis (OA) drug trial: Kellgren-Lawrence grade 2 or 3; medial minimum joint space width (mJSW) ≥2.5 mm; knee pain at worst 4-9 in the past 30 days on an 11-point scale, or 0-3 if medication was taken for joint pain; and availability of structural measures over 2 years. Mean 2-year change in structural measures was estimated and compared with two-sample independent t-tests for KR and no KR. Area under the receiver operating characteristic curve (AUC) was estimated using 2-year change in structural measures for prediction of future KR outcomes. RESULTS: Among 627 participants, 107 knees underwent KR during a median follow-up of 6.7 years after the 2-year imaging period. Knees that received KR during follow-up had a greater mean loss of cartilage thickness in the total femorotibial joint and medial femorotibial compartment on qMRI, as well as decline in medial fixed joint space width on radiographs, compared with knees that did not receive KR. These imaging measures had similar, although modest discrimination for future KR (AUC 0.62, 0.60, and 0.61, respectively). CONCLUSIONS: 2-year changes in qMRI femorotibial cartilage thickness and radiographic JSW measures had similar ability to discriminate future KR in participants with knee OA, suggesting that these measures are comparable biomarkers/surrogate endpoints of structural progression.

Examining Differences in Recovery Outcomes between Male and Female Hip Fracture Patients: Design and Baseline Results of a Prospective Cohort Study from the Baltimore Hip Studies.

BACKGROUND: Incidence of hip fractures in men is expected to increase, yet little is known about consequences of hip fracture in men compared to women. It is important to investigate differences at time of fracture using the newest technologies and methodology regarding metabolic, physiologic, neuromuscular, functional, and clinical outcomes, with attention to design issues for recruiting frail older adults across numerous settings. OBJECTIVES: To determine whether at least moderately-sized sex differences exist across several key outcomes after a hip fracture. DESIGN, SETTING, AND PARTICIPANTS: This prospective cohort study (Baltimore Hip Studies 7th cohort [BHS-7]) was designed to include equal numbers of male and female hip fracture patients to assess sex differences across various outcomes post-hip fracture. Participants were recruited from eight hospitals in the Baltimore metropolitan area within 15 days of admission and were assessed at baseline, 2, 6 and 12 months post-admission. MEASUREMENTS: Assessments included questionnaire, functional performance evaluation, cognitive testing, measures of body composition, and phlebotomy. RESULTS: Of 1709 hip fracture patients screened from May 2006 through June 2011, 917 (54%) were eligible and 39% (n=362) provided informed consent. The final analytic sample was 339 (168 men and 171 women). At time of fracture, men were sicker (mean Charlson score= 2.4 vs. 1.6; p<0.001) and had worse cognition (3MS score= 82.3 vs. 86.2; p<0.05), and prior to fracture were less likely to be on bisphosphonates (8% vs. 39%; p<0.001) and less physically active (2426 kilocalories/week vs. 3625; p<0.001). CONCLUSIONS: This paper provides the study design and methodology for recruiting and assessing hip fracture patients and evidence of baseline and pre-injury sex differences which may affect eventual recovery one year later.

Pain severity as a mediator of the association between depressive symptoms and physical performance in knee osteoarthritis.

OBJECTIVE: Depressive symptoms in knee osteoarthritis (OA) are associated with increased pain severity and declines in physical performance. This study examined whether pain severity mediates the association between depressive symptoms and physical performance in persons with radiographic knee OA. METHOD: Three years of annual data from participants (n = 1,463) with radiographic knee OA in the Osteoarthritis Initiative (OAI) were analyzed. Depressive symptoms were measured using the Center for Epidemiological Studies Depression (CES-D) scale. Pain severity was evaluated with the Western Ontario and McMaster Universities Arthritis Index. Physical performance was assessed via standardized gait speed. Marginal structural models were used to assess the direct (unmediated) effects of depressive symptoms on physical performance and indirect (mediated) effects through pain severity. RESULTS: Direct and indirect effects for a difference in CES-D score of 0-1 were -0.0051 (95% confidence intervals (CI): -0.0053, -0.0049) and -0.0016 (95% CI: -0.0024, -0.0007) standard deviations in gait speed, respectively. Higher depressive symptom severity exhibited diminishing, incremental, direct and indirect effects and for a difference in CES-D score of 15-16 were -0.0045 (95% CI: -0.0047, -0.0042) and -0.0009 (95% CI: -0.0014, -0.0004) standard deviations in gait speed, respectively. Therefore, the magnitude of the mediated, indirect effect, was never larger than 24%. CONCLUSION: Pain severity mediated approximately one-fifth of the association between depressive symptoms and physical performance in persons with radiographic knee OA, and the diminishing incremental effects may explain why unimodal treatment strategies with a single disease target are often ineffective in depressed OA patients.

Factors associated with the orthopaedic surgeon's decision to recommend total joint replacement in hip and knee osteoarthritis: an international cross-sectional study of 1905 patients.

OBJECTIVE: To determine factors associated with orthopaedic surgeons' decision to recommend total joint replacement (TJR) in people with knee and hip osteoarthritis (OA). DESIGN: Cross-sectional study in eleven countries. For consecutive outpatients with definite hip or knee OA consulting an orthopaedic surgeon, the surgeon's indication of TJR was collected, as well as patients' characteristics including comorbidities and social situation, OA symptom duration, pain, stiffness and function (Western Ontario and McMaster Universities Osteoarthritis Index [WOMAC]), joint-specific quality of life, Osteoarthritis Research Society International (OARSI) joint space narrowing (JSN) radiographic grade (0-4), and surgeons' characteristics. Univariable and multivariable logistic regressions were performed to identify factors associated with the indication of TJR, adjusted by country. RESULTS: In total, 1905 patients were included: mean age was 66.5 (standard deviation [SD], 10.8) years, 1082 (58.0%) were women, mean OA symptom duration was 5.0 (SD 7.0) years. TJR was recommended in 561/1127 (49.8%) knee OA and 542/778 (69.7%) hip OA patients. In multivariable analysis on 516 patients with complete data, the variables associated with TJR indication were radiographic grade (Odds Ratio, OR for one grade increase, for knee and hip OA, respectively: 2.90, 95% confidence interval [1.69-4.97] and 3.30 [2.17-5.03]) and WOMAC total score (OR for 10 points increase: 1.65 [1.32-2.06] and 1.38 [1.15-1.66], respectively). After excluding radiographic grade from the analyses, on 1265 patients, greater WOMAC total score was the main predictor for knee and hip OA; older age was also significant for knee OA. CONCLUSION: Radiographic severity and patient-reported pain and function play a major role in surgeons' recommendation for TJR.

Older men who sustain a hip fracture experience greater declines in bone mineral density at the contralateral hip than non-fractured comparators.

Men experience declining bone mineral density (BMD) after hip fracture; however, changes attributable to fracture are unknown. This study evaluated the excess BMD decline attributable to hip fracture among older men. Older men with hip fracture experienced accelerated BMD declines and are at an increased risk of secondary fractures. INTRODUCTION: The objective was to determine whether bone mineral density (BMD) changes in men after hip fracture exceed that expected with aging. METHODS: Two cohorts were used: Baltimore Hip Studies 7th cohort (BHS-7) and Baltimore Men's Osteoporosis Study (MOST). BHS-7 recruited older adults (N = 339) hospitalized for hip fracture; assessments occurred within 22 days of admission and at 2, 6, and 12 months follow-up. MOST enrolled age-eligible men (N = 694) from population-based listings; data were collected at a baseline visit and a second visit that occurred between 10 and 31 months later. The combined sample (n = 452) consisted of Caucasian men from BHS-7 (n = 89) and MOST (n = 363) with ≥ 2 dual-energy X-ray absorptiometry scans and overlapping ranges of age, height, and weight. Mixed-effect models estimated rates of BMD change, and generalized linear models evaluated differences in annual bone loss at the total hip and femoral neck between cohorts. RESULTS: Adjusted changes in total hip and femoral neck BMD were - 4.16% (95% CI, - 4.87 to - 3.46%) and - 4.90% (95% CI, - 5.88 to - 3.92%) in BHS-7 participants; - 1.57% (95% CI, - 2.19 to - 0.96%) and - 0.99% (95% CI, - 1.88 to - 0.10%) in MOST participants; and statistically significant (P < 0.001) between-group differences in change were - 2.59% (95% CI, - 3.26 to - 1.91%) and - 3.91% (95% CI, - 4.83 to - 2.98%), respectively. CONCLUSION: Hip fracture in older men is associated with accelerated BMD declines at the non-fractured hip that are greater than those expected during aging, and pharmacological interventions in this population to prevent secondary fractures may be warranted.

A novel Wnt pathway inhibitor, SM04690, for the treatment of moderate to severe osteoarthritis of the knee: results of a 24-week, randomized, controlled, phase 1 study.

OBJECTIVE: To assess the safety, pharmacokinetics, and exploratory efficacy of SM04690, a novel Wnt pathway inhibitor, as a potential disease modifying treatment for knee osteoarthritis (OA). DESIGN: Subjects with Kellgren-Lawrence grade 2-3 knee OA were randomized in successive dose-escalation cohorts to receive a knee intra-articular (IA) injection with 0.03, 0.07, or 0.23 mg SM04690, or placebo (PBO) (4:1 ratio). Safety, pharmacokinetics, efficacy (WOMAC Total/Function/Pain, Pain VAS, Physician Global Assessment [MDGA], and OMERACT-OARSI Response), OA-related biomarker (P1NP, ß-CTX, and cartilage oligomeric matrix protein [COMP]), and radiographic/imaging data were collected at baseline and during 24-week follow-up. RESULTS: 61 subjects (SM04690 n = 50; PBO n = 11) enrolled. Two dose limiting toxicities (DLTs), increased pain following injection and paroxysmal tachycardia (also the single serious AE), were reported in the 0.07 mg cohort. A total of 72 AEs were reported; Sixteen (occurring in eight subjects) were considered related to study medication. There were three discontinuations; one due to an AE (0.03 mg cohort). Bone marrow edema (BME) remained constant for most subjects. No doses were excluded from further study due to DLT criteria. Plasma levels of SM04690 were below the limit of detection at all time points. At Week 24, improvements from baseline were seen in all cohorts for the exploratory measures WOMAC Total, WOMAC Function, WOMAC Pain, MDGA, Pain VAS, and OMERACT-OARSI response. Joint space width (JSW) improvement was observed in the 0.07 mg cohort (P = 0.02 vs PBO). CONCLUSION: SM04690 appeared safe and well tolerated, with no evidence of systemic exposure. Exploratory efficacy analyses suggested positive trends for measurements of OA pain, function and disease-modifying osteoarthritis drug (DMOAD) properties. CLINICALTRIALS. GOV REGISTRATION: NCT02095548.

Clinical algorithms to aid osteoarthritis guideline dissemination.

BACKGROUND: Numerous scientific organisations have developed evidence-based recommendations aiming to optimise the management of osteoarthritis (OA). Uptake, however, has been suboptimal. The purpose of this exercise was to harmonize the recent recommendations and develop a user-friendly treatment algorithm to facilitate translation of evidence into practice. METHODS: We updated a previous systematic review on clinical practice guidelines (CPGs) for OA management. The guidelines were assessed using the Appraisal of Guidelines for Research and Evaluation for quality and the standards for developing trustworthy CPGs as established by the National Academy of Medicine (NAM). Four case scenarios and algorithms were developed by consensus of a multidisciplinary panel. RESULTS: Sixteen guidelines were included in the systematic review. Most recommendations were directed toward physicians and allied health professionals, and most had multi-disciplinary input. Analysis for trustworthiness suggests that many guidelines still present a lack of transparency. A treatment algorithm was developed for each case scenario advised by recommendations from guidelines and based on panel consensus. CONCLUSION: Strategies to facilitate the implementation of guidelines in clinical practice are necessary. The algorithms proposed are examples of how to apply recommendations in the clinical context, helping the clinician to visualise the patient flow and timing of different treatment modalities.

Changes in bone mineral density over time by body mass index in the health ABC study.

UNLABELLED: Obesity appears protective against osteoporosis in cross-sectional studies. However, results from this longitudinal study found that obesity was associated with bone loss over time. Findings underscore the importance of looking at the longitudinal relationship, particularly given the increasing prevalence and duration of obesity among older adults. INTRODUCTION: Cross-sectional studies have found a positive association between body mass index (BMI) and bone mineral density (BMD), but little is known about the longitudinal relationship in US older adults. METHODS: We examined average annual rate of change in BMD by baseline BMI in the Health, Aging, and Body Composition Study. Repeated measurement of BMD was performed with dual-energy X-ray absorptiometry (DXA) at baseline and years 3, 5, 6, 8, and 10. Multivariate generalized estimating equations were used to predict mean BMD (femoral neck, total hip, and whole body) by baseline BMI (excluding underweight), adjusting for covariates. RESULTS: In the sample (n = 2570), 43 % were overweight and 24 % were obese with a mean baseline femoral neck BMD of 0.743 g/cm(2), hip BMD of 0.888 g/cm(2), and whole-body BMD of 1.09 g/cm(2). Change in total hip or whole-body BMD over time did not vary by BMI groups. However, obese older adults lost 0.003 g/cm(2) of femoral neck BMD per year more compared with normal weight older adults (p < 0.001). Femoral neck BMD change over time did not differ between the overweight and normal weight BMI groups (p = 0.74). In year 10, adjusted femoral neck BMD ranged from 0.696 g/cm(2) among obese, 0.709 g/cm(2) among normal weight, and 0.719 g/cm(2) among overweight older adults. CONCLUSIONS: Findings underscore the importance of looking at the longitudinal relationship between body composition and bone mineral density among older adults, indicating that high body mass may not be protective for bone loss over time.

OARSI Clinical Trials Recommendations: Design and conduct of clinical trials for hip osteoarthritis.

The ability to assess the efficacy and effectiveness of an intervention for the treatment of hip osteoarthritis (OA) requires strong clinical trial methodology. This consensus paper provides recommendations based on a narrative literature review and best judgment of the members of the committee for clinical trials of hip OA. We provide recommendations on clinical trial design, outcome measures, including structural (radiography), and patient and physician global assessments, performance based measures, molecular markers and experimental endpoints including MRI imaging. This information can be utilized by sponsors of trials for new therapeutic agents for hip OA.

Disease activity in rheumatoid arthritis and the risk of cardiovascular events.

OBJECTIVE: Use of several immunomodulatory agents has been associated with reduced numbers of cardiovascular (CV) events in epidemiologic studies of rheumatoid arthritis (RA). However, it is unknown whether time-averaged disease activity in RA correlates with CV events. METHODS: We studied patients with RA whose cases were followed in a longitudinal US-based registry. Time-averaged disease activity was assessed during followup using the area under the curve of the Clinical Disease Activity Index (CDAI), a validated measure of RA disease activity. Age, sex, presence of diabetes mellitus, hypertension, or hyperlipidemia, body mass index, family history of myocardial infarction (MI), use of aspirin or nonsteroidal antiinflammatory drugs (NSAIDs), presence of CV disease, and baseline use of an immunomodulator were assessed at baseline. Cox proportional hazards regression models were examined to determine the risk of a composite CV end point that included MI, stroke, and death from CV causes. RESULTS: A total of 24,989 patients who had been followed up for a median of 2.7 years were included in these analyses. During followup, we observed 534 confirmed CV end points, for an incidence rate of 7.8 per 1,000 person-years (95% confidence interval [95% CI] 6.7-8.9). In models adjusted for variables noted above, a 10-point reduction in the time-averaged CDAI was associated with a 21% reduction in CV risk (95% CI 13-29). These results were robust in subgroup analyses stratified by the presence of CV disease, use of corticosteroids, use of NSAIDs or selective cyclooxygenase 2 inhibitors, and change in RA treatment, as well as when restricted to events adjudicated as definite or probable. CONCLUSION: Our findings showed that reduced time-averaged disease activity in RA is associated with fewer CV events.

Serious joint-related adverse events in randomized controlled trials of anti-nerve growth factor monoclonal antibodies.

BACKGROUND: Reports of serious joint adverse events (AEs) due to osteonecrosis were noted during randomized placebo-controlled clinical trials of monoclonal antibodies to nerve growth factor (NGF), including tanezumab and fulranumab. METHODS: All available medical records from subjects with reported cases of osteonecrosis, as well as records of subjects who underwent joint replacement during these studies, were reviewed by an independent adjudication committee that was established by each company; the committees were different for each company and included distinct individual experts. Cases were categorized as having definite osteonecrosis, normal or rapid progression of osteoarthritis (OA), another diagnosis or unable to determine the underlying diagnosis. RESULTS: The vast majority of investigator reported cases of osteonecrosis were adjudicated as either normal or rapid progression of OA. Indeed, the syndrome of rapid progression of OA associated with chondrolysis and bone destruction appears to be a safety signal that is associated with not only increasing doses of anti-NGF antibodies but also concomitant therapy with nonsteroidal anti-inflammatory drugs. CONCLUSIONS: These results have implications for future clinical trials of anti-NGF agents in OA and other painful conditions.

Sedentary behavior and blood pressure control among osteoarthritis initiative participants.

OBJECTIVE: To examine the association between sedentary behavior and blood pressure (BP) among Osteoarthritis Initiative (OAI) participants. DESIGN: We conducted a cross-sectional analysis of the OAI 48-month visit participants whose physical activity was measured using accelerometers. Participants were classified into four quartiles according to the percentage of wear time that was sedentary (<100 activity counts per min). Users of antihypertensive medications or non-steroidal anti-inflammatory drugs (NSAIDs) were excluded. Our main outcomes were systolic and diastolic blood pressures (SBP and DBP) and "elevated BP" defined as BP ≥ 130/85 mm Hg. RESULTS: For this study cohort (N = 707), mean BP was 121.4 ± 15.6/74.7 ± 9.5 mm Hg and 33% had elevated BP. SBP had a graded association with increased sedentary time (P for trend = 0.02). The most sedentary quartile had 4.26 mm Hg higher SBP (95% confidence interval (CI), 0.69-7.82; P = 0.02) than the least sedentary quartile, adjusting for age, moderate-to-vigorous (MV) physical activity, and other demographic and health factors. The probability of having elevated BP significantly increased in higher sedentary quartiles (P for trend = 0.046). There were no significant findings for DBP. CONCLUSION: A strong graded association was demonstrated between sedentary behavior and increased SBP and elevated BP, independent of time spent in MV physical activity. Reducing daily sedentary time may lead to improvement in BP and reduction in cardiovascular risk.

What is the predictive value of MRI for the occurrence of knee replacement surgery in knee osteoarthritis?

Knee osteoarthritis is associated with structural changes in the joint. Despite its many drawbacks, radiography is the current standard for evaluating joint structure in trials of potential disease-modifying osteoarthritis drugs. MRI is a non-invasive alternative that provides comprehensive imaging of the whole joint. Frequently used MRI measurements in knee osteoarthritis are cartilage volume and thickness; others include synovitis, synovial fluid effusions, bone marrow lesions (BML) and meniscal damage. Joint replacement is considered a clinically relevant outcome in knee osteoarthritis; however, its utility in clinical trials is limited. An alternative is virtual knee replacement on the basis of symptoms and structural damage. MRI may prove to be a good alternative to radiography in definitions of knee replacement. One of the MRI parameters that predicts knee replacement is medial compartment cartilage volume/thickness, which correlates with radiographic joint space width, is sensitive to change, and predicts outcomes in a continuous manner. Other MRI parameters include BML and meniscal lesions. MRI appears to be a viable alternative to radiography for the evaluation of structural changes in knee osteoarthritis and prediction of joint replacement.

Responsiveness of the Intermittent and Constant Osteoarthritis Pain (ICOAP) scale in a trial of duloxetine for treatment of osteoarthritis knee pain.

OBJECTIVE: To assess the change in the Intermittent and Constant Osteoarthritis Pain (ICOAP)-scale scores in patients taking duloxetine or placebo and to characterize the responsiveness of the ICOAP by comparing the effect size associated with its scales to effect sizes seen with other pain scales used in this study. METHODS: This was a secondary analysis of data from a 10-week, double-blind, randomized, flexible-dose, placebo-controlled trial that enrolled patients who had persistent moderate pain due to osteoarthritis (OA) of the knee, despite having received nonsteroidal anti-inflammatory drug (NSAID) therapy. The pain measures used in this study (focusing on the drug-placebo difference at week 8) were patient-rated pain severity, the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC), the Brief Pain Inventory (BPI), and the ICOAP. RESULTS: The mean difference between duloxetine and placebo at week 8 for patient-rated pain severity, the BPI average pain, WOMAC pain, and each ICOAP scale was statistically significant (P < 0.001 for each). The ICOAP total showed a moderate effect size of 0.53, whereas the constant and intermittent scores showed effect sizes of 0.47 and 0.49, respectively. The patient-rated pain severity and the BPI average pain showed similar moderate effect sizes of 0.59 and 0.53, respectively. CONCLUSION: The study demonstrated efficacy of duloxetine compared with placebo when using the ICOAP scale in a placebo-controlled trial. The observed treatment effect size for the ICOAP scores was similar to that for other reliable, valid and responsive pain assessments. CLINICAL TRIALS REGISTRATION: ClinicalTrial.gov Identifier: NCT01018680.

Osteoarthritis year 2012 in review: clinical.

Epidemiologic and clinical research in osteoarthritis (OA) continues to focus on analytic and descriptive epidemiology, and the role of both nonpharmacologic and pharmacologic therapies in the management of OA, respectively. A systematic literature review was conducted using PubMed for the period between September 1, 2011 and March 31, 2012. Selected articles in these areas are discussed in this narrative review article.