Gait risk factors for disease progression differ between non-traumatic and post-traumatic knee osteoarthritis.

OBJECTIVE: To examine if relationships between knee osteoarthritis (OA) progression with knee moments and muscle activation during gait vary between patients with non-traumatic and post-traumatic knee OA. DESIGN: This longitudinal study included participants with non-traumatic (n = 17) and post-traumatic (n = 18) knee OA; the latter group had a previous anterior cruciate ligament rupture. Motion capture cameras, force plates, and surface electromyography measured knee moments and lower extremity muscle activation during gait. Cartilage volume change were determined over 2 years using magnetic resonance imaging in four regions: medial and lateral plateau and condyle. Linear regression analysis examined relationships between cartilage change with gait metrics (moments, muscle activation), group, and their interaction. RESULTS: Measures from knee adduction and rotation moments were related to lateral condyle cartilage loss in both groups, and knee adduction moment to lateral plateau cartilage loss in the non-traumatic group only [ß = -1.336, 95% confidence intervals (CI) = -2.653 to -0.019]. Generally, lower levels of stance phase muscle activation were related to greater cartilage loss. The relationship between cartilage loss in some regions with muscle activation characteristics varied between non-traumatic and post-traumatic groups including for: lateral hamstring (lateral condyle ß = 0.128, 95%CI = 0.003 to 0.253; medial plateau ß = 0.199, 95%CI = 0.059 to 0.339), rectus femoris (medial condyle ß = -0.267, 95%CI = -0.460 to -0.073), and medial hamstrings (medial plateau; ß = -0.146, 95%CI = -0.244 to -0.048). CONCLUSION: Findings indicate that gait risk factors for OA progression may vary between patients with non-traumatic and post-traumatic knee OA. These OA subtypes should be considered in studies that investigate gait metrics as risk factors for OA progression.

Alternative and complementary therapies in osteoarthritis and cartilage repair.

Osteoarthritis (OA) is the most common joint condition and, with a burgeoning ageing population, is due to increase in prevalence. Beyond conventional medical and surgical interventions, there are an increasing number of 'alternative' therapies. These alternative therapies may have a limited evidence base and, for this reason, are often only afforded brief reference (or completely excluded) from current OA guidelines. Thus, the aim of this review was to synthesize the current evidence regarding autologous chondrocyte implantation (ACI), mesenchymal stem cell (MSC) therapy, platelet-rich plasma (PRP), vitamin D and other alternative therapies. The majority of studies were in knee OA or chondral defects. Matrix-assisted ACI has demonstrated exceedingly limited, symptomatic improvements in the treatment of cartilage defects of the knee and is not supported for the treatment of knee OA. There is some evidence to suggest symptomatic improvement with MSC injection in knee OA, with the suggestion of minimal structural improvement demonstrated on MRI and there are positive signals that PRP may also lead to symptomatic improvement, though variation in preparation makes inter-study comparison difficult. There is variability in findings with vitamin D supplementation in OA, and the only recommendation which can be made, at this time, is for replacement when vitamin D is deplete. Other alternative therapies reviewed have some evidence (though from small, poor-quality studies) to support improvement in symptoms and again there is often a wide variation in dosage and regimens. For all these therapeutic modalities, although controlled studies have been undertaken to evaluate effectiveness in OA, these have often been of small size, limited statistical power, uncertain blindness and using various methodologies. These deficiencies must leave the question as to whether they have been validated as effective therapies in OA (or chondral defects). The conclusions of this review are that all alternative interventions definitely require clinical trials with robust methodology, to assess their efficacy and safety in the treatment of OA beyond contextual and placebo effects.

Relationship between alignment and cartilage thickness in patients with non-traumatic and post-traumatic knee osteoarthritis.

OBJECTIVE: To compare cartilage thickness between patients with non-traumatic and post-traumatic knee osteoarthritis (OA) and healthy controls and to determine if disease severity and alignment impact these differences. DESIGN: Participants with non-traumatic (n = 22) and post-traumatic (n = 19) knee OA, and healthy controls (n = 22) were recruited for this cross-sectional study. Participants underwent 3T magnetic resonance imaging (T1-weighted, 3D sagittal gradient echo sequence) and cartilage thickness was determined in four regions: medial and lateral condyle, and medial and lateral plateau. Lower extremity alignment (mechanical axis angle) and disease severity (Kellgren-Lawrence scores) were measured from full length radiographs. Statistical analysis included one-way analysis of variance (ANOVA) and modified Bonferroni test adjusting for multiple pairwise comparisons. Linear regression analyses examined the relationship between cartilage thickness and knee OA group after controlling for disease severity, meniscal status, and alignment. RESULTS: In participants with predominantly medial compartment knee OA, compared to healthy controls, those with non-traumatic knee OA had diminished cartilage thickness in the medial plateau (p = 0.035) and those with post-traumatic knee OA had greater cartilage thickness in the lateral condyle (p = 0.044). In the lateral condyle, data revealed that alignment accounted for the variance in cartilage thickness (p = 0.035), in which a stronger relationship was found in the non-traumatic (r = -0.61) than the post-traumatic (r = -0.12) OA group. CONCLUSIONS: Emerging data demonstrated that participants with non-traumatic knee OA have a stronger relationship between alignment and cartilage thickness than those with post-traumatic knee OA. This indicates that factors involved in knee OA initiation and progression may differ between these OA subtypes.

The ratio adipsin/MCP-1 is strongly associated with structural changes and CRP/MCP-1 with symptoms in obese knee osteoarthritis subjects: data from the Osteoarthritis Initiative.

OBJECTIVE: There is a need to identify reliable biomarkers that can predict knee osteoarthritis (OA) progression. We investigated a panel of adipokines and some related inflammatory factors alone and their ratios for their associative value at assessing cartilage volume loss over time and symptoms in obese [High body mass index (BMI)] and non-obese (Low BMI) OA subjects. DESIGN: Human OA serum was from the Osteoarthritis Initiative Progression subcohort. Baseline levels of adiponectin (high and low molecular weight forms), adipsin, chemerin, leptin, visfatin, C-reactive protein (CRP), interleukin-8 (IL-8) and monocyte chemoattractant protein-1 (MCP-1) were evaluated with specific assays. Cartilage volume was assessed at baseline and 48 months by quantitative magnetic resonance imaging (MRI), and symptoms using baseline Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) scores. Data were analysed by linear regression with confounding factors at baseline, followed by multiple comparison adjustment. RESULTS: The levels of the nine biomarkers and their ratios (36) were studied. Among High BMI subjects, only the ratio adipsin/MCP-1 was associated with cartilage volume loss over time in the lateral compartment [ß, -2.95; 95% confidence interval (CI), -4.42, -1.49; P = 0.010], whereas MCP-1 was associated with WOMAC pain (-1.74; -2.75, -0.73; P = 0.030) and the ratio CRP/MCP-1 with WOMAC pain (0.76; 0.37, 1.14; P = 0.023), function (2.43; 1.20, 3.67; P = 0.020) and total (3.29; 1.58, 5.00; P = 0.027). No associations were found for biomarkers or ratios in Low BMI OA. CONCLUSION: In this study, the ratio adipsin/MCP-1 was found to be associated with the knee structural changes and that of CRP/MCP-1 with symptoms in obese OA subjects. Our data further underline the relevance of ratios as biomarkers to a stronger association to OA progression and symptoms.

Meniscal extrusion and bone marrow lesions are associated with incident and progressive knee osteoarthritis.

OBJECTIVE: Whether meniscal extrusion and bone marrow lesions (BMLs) are independently associated with the risk of knee osteoarthritis (OA) is unknown. METHODS: Data was extracted from the Osteoarthritis Initiative (OAI) cohort. Participants were grouped according to the absence (Kellgren-Lawrence (KL) grade ≤ 1, n = 2120) or presence (KL ≥ 2, n = 2249) of radiographic OA (ROA). Baseline meniscal extrusion and tibial BMLs were assessed. Tibial plateau cartilage volume was assessed at baseline and 72 months, while radiographic disease was assessed at baseline and 48 months. Total knee replacement (TKR) was assessed at 72 months. RESULTS: In those with ROA, the presence of a baseline meniscal extrusion (independent of BMLs) was associated with accelerated cartilage volume loss (medial tibia: -2.1%/annum vs -1.5%; lateral: -2.6%/annum vs -1.6%; both P < 0.001), progressive ROA and TKR (Odds ratio (OR) range 1.4-1.8; 95% CI range 1.1-2.9). The presence of a baseline BML was associated with accelerated cartilage volume loss (medial tibia: -2.1%/annum vs -1.6%; lateral: -1.9%/annum vs -1.6%; P ≤ 0.02), progressive ROA and joint replacement (OR range 1.5-2.4; 95% CI range 1.1-3.4). In those with no ROA, a baseline medial meniscal extrusion was associated with accelerated cartilage volume loss (medial tibia: -2.1%/annum vs -1.2%, P < 0.001), and a baseline medial BML with incident ROA (OR 1.7, 95% CI 1.1 to 2.9). CONCLUSIONS: The presence of baseline meniscal extrusion and BMLs are associated with incident and progressive knee of each other (OA) and represent important structural targets for the treatment and prevention of knee OA.

Deletion of 12/15-lipoxygenase accelerates the development of aging-associated and instability-induced osteoarthritis.

OBJECTIVE: 12/15-Lipoxygenase (12/15-LOX) catalyzes the generation of various anti-inflammatory lipid mediators, and has been implicated in several inflammatory and degenerative diseases. However, there is currently no evidence that 12/15-LOX has a role in osteoarthritis (OA). The aim of this study was to investigate the role of 12/15-LOX in the pathogenesis of OA. METHODS: The development of aging-associated and destabilization of the medial meniscus (DMM)-induced OA were compared in 12/15-LOX-deficient (12/15-LOX-/-) and wild-type (WT) mice. The extent of cartilage damage was evaluated by histology. The expression of OA markers was evaluated by immunohistochemistry and RT-PCR. Cartilage explants were stimulated with IL-1α in the absence or presence of the 12/15-LOX metabolites, 15-hydroxyeicosatetraenoic acids (15-HETE), 13-hydroxyoctadecadienoic acid (13-HODE) or lipoxin A4 (LXA4), and the levels of matrix metalloproteinases-13 (MMP-13), Nitric oxide (NO) and prostaglandin E2 (PGE2) were determined. The effect of LXA4 on the progression of OA was evaluated in wild type (WT) mice. RESULTS: The expression of 12/15-LOX in cartilage increased during the progression of DMM-induced OA and with aging in WT mice. Cartilage degeneration was more severe in 12/15-LOX-/- mice compared to WT mice in both models of OA, and this was associated with increased expression of MMP-13, a disintegrin and metalloproteinase with thrombospondin motifs, aggrecanases (ADAMTS5), inducible NO synthases (iNOS), and mPGES-1. Treatment of cartilage explants with 12/15-LOX metabolites, suppressed IL-1α-induced production of MMP-13, NO and PGE2, with LXA4 being the most potent. Intra-peritoneal injection of LXA4 reduced the severity of DMM-induced cartilage degradation. CONCLUSIONS: These data suggest an important role of 12/15-LOX in the pathogenesis of OA. They also suggest that activation of this pathway may provide a novel strategy for prevention and treatment of OA.

Diagnostic validity and triage concordance of a physiotherapist compared to physicians' diagnoses for common knee disorders.

BACKGROUND: Emergence of more autonomous roles for physiotherapists warrants more evidence regarding their diagnostic capabilities. Therefore, we aimed to evaluate diagnostic and surgical triage concordance between a physiotherapist and expert physicians and to assess the diagnostic validity of the physiotherapist's musculoskeletal examination (ME) without imaging. METHODS: This is a prospective diagnostic study where 179 consecutive participants consulting for any knee complaint were independently diagnosed and triaged by two evaluators: a physiotherapist and one expert physician (orthopaedic surgeons or sport medicine physicians). The physiotherapist completed only a ME, while the physicians also had access to imaging to make their diagnosis. Raw agreement proportions and Cohen's kappa (k) were calculated to assess inter-rater agreement. Sensitivity (Se) and specificity (Sp), as well as positive and negative likelihood ratios (LR+/-) were calculated to assess the validity of the ME compared to the physicians' composite diagnosis. RESULTS: Primary knee diagnoses included anterior cruciate ligament injury (n = 8), meniscal injury (n = 36), patellofemoral pain (n = 45) and osteoarthritis (n = 79). Diagnostic inter-rater agreement between the physiotherapist and physicians was high (k = 0.89; 95% CI:0.83-0.94). Inter-rater agreement for triage recommendations of surgical candidates was good (k = 0.73; 95% CI:0.60-0.86). Se and Sp of the physiotherapist's ME ranged from 82.0 to 100.0% and 96.0 to 100.0% respectively and LR+/- ranged from 23.2 to 30.5 and from 0.03 to 0.09 respectively. CONCLUSIONS: There was high diagnostic agreement and good triage concordance between the physiotherapist and physicians. The ME without imaging may be sufficient to diagnose or exclude common knee disorders for a large proportion of patients. Replication in a larger study will be required as well as further assessment of innovative multidisciplinary care trajectories to improve care of patients with common musculoskeletal disorders.

Familial effects on structural changes relevant to knee osteoarthritis: a prospective cohort study.

OBJECTIVE: Genetic factors play an important role in the pathogenesis of knee osteoarthritis (OA), but which knee structural changes mediate this is unclear. This study aimed to describe the differences in knee structural changes over 8-10 years between offspring having at least one parent with total knee replacement (TKR) for severe primary knee OA and controls with no family history of knee OA. DESIGN: 115 offspring (mean age 45 years) with a family history of TKR for severe knee OA were compared with 104 (mean age 46 years) controls. T1 or T2-weighted fat saturated magnetic resonance imaging (MRI) was performed respectively to evaluate knee cartilage defects, bone marrow lesions (BMLs), meniscal extrusion and tears at baseline and 10 years. Multivariate logistic regression model was used to adjust for potential confounders. RESULTS: Offspring had a greater increase in cartilage defect score (1.03 vs 0.52, P = 0.007) and meniscal extrusion score (0.28 vs 0.10, P = 0.027) over 10 years, and a greater increase in meniscal tear score (0.40 vs 0.10, P = 0.012) over 8 years in the medial but not the lateral tibiofemoral compartment. Changes in BMLs over 8-years were not different between the two groups. These associations were independent of potential confounders, and strengthened after further adjustment for each other. CONCLUSION: With the exception of BMLs, offspring with a family history of knee OA have a greater risk of increases in multiple knee structural abnormalities in the medial tibiofemoral compartment suggesting pleiotropic familial effects.

A family history of knee joint replacement increases the progression of knee radiographic osteoarthritis and medial tibial cartilage volume loss over 10 years.

OBJECTIVES: Osteoarthritis (OA) has a genetic component but it is uncertain if the offspring of those with knee OA are at a greater risk. The aim of this study was to describe radiographic OA (ROA) progression and cartilage loss over 10 years in a midlife cohort with some having a family history of OA and some community based controls. METHODS: 220 participants [mean-age 45 (26-61); 57% female] were studied at baseline and 10 years. Half were adult offspring of subjects who underwent knee replacement for OA and the remainder were randomly selected controls. Joint space narrowing (JSN) and osteophytes were assessed on radiographs and cartilage volume (tibial, femoral and patellar), cartilage defects, bone marrow lesions (BMLs) and meniscal tears were assessed on Magnetic resonance imaging (MRI). RESULTS: For ROA, there was a significant difference between offspring and controls in unadjusted analysis for change in total ROA, medial JSN, total medial, total lateral and total osteophyte scores. This difference persisted for medial JSN (difference in ratios = +1.93 (+1.04, +3.51)) only, after adjustment for confounders and baseline differences. In unadjusted analysis for cartilage loss, offspring lost more cartilage at the medial tibial (difference in means = -79.13 (-161.92, +3.71)) site only. This difference became of borderline significance after adjustment for baseline differences (P = 0.055). CONCLUSION: The offspring of subjects having a total knee replacement have a greater worsening of ROA (both JSN and osteophytes) and higher medial tibial cartilage volume loss over 10 years. Most of these changes are mediated by differences in baseline characteristics of offspring and controls except for increase in medial JSN.

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

Hand osteoarthritis (OA) is a very frequent disease, but yet understudied. However, a lot of works have been published in the past 10 years, and much has been done to better understand its clinical course and structural progression. Despite this new knowledge, few therapeutic trials have been conducted in hand OA. The last OARSI recommendations for the conduct of clinical trials in hand OA dates back to 2006. The present recommendations aimed at updating previous recommendations, by incorporating new data. The purpose of this expert opinion, consensus driven exercise is to provide evidence-based guidance on the design, execution and analysis of clinical trials in hand OA, where published evidence is available, supplemented by expert opinion, where evidence is lacking, to perform clinical trials in hand OA, both for symptom and for structure-modification. They indicate core outcome measurement sets for studies in hand OA, and list the methods and instruments that should be used to measure symptoms or structure. For both symptom- and structure-modification, at least pain, physical function, patient global assessment, HR-QoL, joint activity and hand strength should be assessed. In addition, for structure-modification trials, structural progression should be measured by radiographic changes. We also provide a research agenda listing many unsolved issues that seem to most urgently need to be addressed from the perspective of performing "good" clinical trials in hand OA. These updated OARSI recommendations should allow for better standardizing the conduct of clinical trials in hand OA in the next future.

OARSI Clinical Trials Recommendations: Hip imaging in clinical trials in osteoarthritis.

Imaging of hip in osteoarthritis (OA) has seen considerable progress in the past decade, with the introduction of new techniques that may be more sensitive to structural disease changes. The purpose of this expert opinion, consensus driven recommendation is to provide detail on how to apply hip imaging in disease modifying clinical trials. It includes information on acquisition methods/techniques (including guidance on positioning for radiography, sequence/protocol recommendations/hardware for magnetic resonance imaging (MRI)); commonly encountered problems (including positioning, hardware and coil failures, artifacts associated with various MRI sequences); quality assurance/control procedures; measurement methods; measurement performance (reliability, responsiveness, and validity); recommendations for trials; and research recommendations.

OARSI Clinical Trials Recommendations: Knee imaging in clinical trials in osteoarthritis.

Significant advances have occurred in our understanding of the pathogenesis of knee osteoarthritis (OA) and some recent trials have demonstrated the potential for modification of the disease course. The purpose of this expert opinion, consensus driven exercise is to provide detail on how one might use and apply knee imaging in knee OA trials. It includes information on acquisition methods/techniques (including guidance on positioning for radiography, sequence/protocol recommendations/hardware for magnetic resonance imaging (MRI)); commonly encountered problems (including positioning, hardware and coil failures, sequences artifacts); quality assurance (QA)/control procedures; measurement methods; measurement performance (reliability, responsiveness, validity); recommendations for trials; and research recommendations.

OARSI Clinical Trials Recommendations: Hand imaging in clinical trials in osteoarthritis.

Tremendous advances have occurred in our understanding of the pathogenesis of hand osteoarthritis (OA) and these are beginning to be applied to trials targeted at modification of the disease course. The purpose of this expert opinion, consensus driven exercise is to provide detail on how one might use and apply hand imaging assessments in disease modifying clinical trials. It includes information on acquisition methods/techniques (including guidance on positioning for radiography, sequence/protocol recommendations/hardware for MRI); commonly encountered problems (including positioning, hardware and coil failures, sequences artifacts); quality assurance/control procedures; measurement methods; measurement performance (reliability, responsiveness, validity); recommendations for trials; and research recommendations.

Republished: Value of biomarkers in osteoarthritis: current status and perspectives.

Osteoarthritis affects the whole joint structure with progressive changes in cartilage, menisci, ligaments and subchondral bone, and synovial inflammation. Biomarkers are being developed to quantify joint remodelling and disease progression. This article was prepared following a working meeting of the European Society for Clinical and Economic Aspects of Osteoporosis and Osteoarthritis convened to discuss the value of biochemical markers of matrix metabolism in drug development in osteoarthritis. The best candidates are generally molecules or molecular fragments present in cartilage, bone or synovium and may be specific to one type of joint tissue or common to them all. Many currently investigated biomarkers are associated with collagen metabolism in cartilage or bone, or aggrecan metabolism in cartilage. Other biomarkers are related to non-collagenous proteins, inflammation and/or fibrosis. Biomarkers in osteoarthritis can be categorised using the burden of disease, investigative, prognostic, efficacy of intervention, diagnostic and safety classification. There are a number of promising candidates, notably urinary C-terminal telopeptide of collagen type II and serum cartilage oligomeric protein, although none is sufficiently discriminating to differentiate between individual patients and controls (diagnostic) or between patients with different disease severities (burden of disease), predict prognosis in individuals with or without osteoarthritis (prognostic) or perform so consistently that it could function as a surrogate outcome in clinical trials (efficacy of intervention). Future avenues for research include exploration of underlying mechanisms of disease and development of new biomarkers; technological development; the 'omics' (genomics, metabolomics, proteomics and lipidomics); design of aggregate scores combining a panel of biomarkers and/or imaging markers into single diagnostic algorithms; and investigation into the relationship between biomarkers and prognosis.

Value of biomarkers in osteoarthritis: current status and perspectives.

Osteoarthritis affects the whole joint structure with progressive changes in cartilage, menisci, ligaments and subchondral bone, and synovial inflammation. Biomarkers are being developed to quantify joint remodelling and disease progression. This article was prepared following a working meeting of the European Society for Clinical and Economic Aspects of Osteoporosis and Osteoarthritis convened to discuss the value of biochemical markers of matrix metabolism in drug development in osteoarthritis. The best candidates are generally molecules or molecular fragments present in cartilage, bone or synovium and may be specific to one type of joint tissue or common to them all. Many currently investigated biomarkers are associated with collagen metabolism in cartilage or bone, or aggrecan metabolism in cartilage. Other biomarkers are related to non-collagenous proteins, inflammation and/or fibrosis. Biomarkers in osteoarthritis can be categorised using the burden of disease, investigative, prognostic, efficacy of intervention, diagnostic and safety classification. There are a number of promising candidates, notably urinary C-terminal telopeptide of collagen type II and serum cartilage oligomeric protein, although none is sufficiently discriminating to differentiate between individual patients and controls (diagnostic) or between patients with different disease severities (burden of disease), predict prognosis in individuals with or without osteoarthritis (prognostic) or perform so consistently that it could function as a surrogate outcome in clinical trials (efficacy of intervention). Future avenues for research include exploration of underlying mechanisms of disease and development of new biomarkers; technological development; the 'omics' (genomics, metabolomics, proteomics and lipidomics); design of aggregate scores combining a panel of biomarkers and/or imaging markers into single diagnostic algorithms; and investigation into the relationship between biomarkers and prognosis.

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.

A pilot randomized controlled trial evaluating outdoor community walking for knee osteoarthritis: walk.

OBJECTIVES: To determine the feasibility of a randomized controlled trial (RCT) examining outdoor walking on knee osteoarthritis (KOA) clinical outcomes and magnetic resonance imaging (MRI) structural changes. METHOD: This was a 24-week parallel two-arm pilot RCT in Tasmania, Australia. KOA participants were randomized to either a walking plus usual care group or a usual care control group. The walking group trained 3 days/week. The primary outcome was feasibility assessed by changes being required to the study design, recruitment, randomization, program adherence, safety, and retention. Exploratory outcomes were changes in symptoms, physical performance/activity, and MRI measures. RESULTS: Forty participants (mean age 66 years (SD 1.4) and 60% female) were randomized to walking (n = 24) or usual care (n = 16). Simple randomization resulted in a difference in numbers randomized to the two groups. During the study, class sizes were reduced from 10 to 8 participants to improve supervision, and exclusion criteria were added to facilitate program adherence. In the walking group, total program adherence was 70.0% and retention 70.8% at 24 weeks. The walking group had a higher number of mild adverse events and experienced clinically important improvements in symptoms (e.g., visual analogue scale (VAS) knee pain change in the walking group: - 38.7 mm [95% CI - 47.1 to - 30.3] versus usual care group: 4.3 mm [- 4.9 to 13.4]). CONCLUSIONS: This study supports the feasibility of a full-scale RCT given acceptable adherence, retention, randomization, and safety, and recruitment challenges have been identified. Large symptomatic benefits support the clinical usefulness of a subsequent trial. TRIAL REGISTRATION NUMBER: 12618001097235. Key Points • This pilot study is the first to investigate the effects of an outdoor walking program on knee osteoarthritis clinical outcomes and MRI joint structure, and it indicates that a full-scale RCT is feasible. • The outdoor walking program (plus usual care) resulted in large improvements in self-reported knee osteoarthritis symptoms compared to usual care alone. • The study identified recruitment challenges, and the manuscript explores these in more details and provides recommendations for future studies.

The associations between parity, other reproductive factors and cartilage in women aged 50-80 years.

OBJECTIVE: Sex hormones and reproductive factors may be important for osteoarthritis (OA). The aim of this study was to describe the associations of parity, use of hormone replacement therapy (HRT) and oral contraceptives (OCs) with cartilage volume, cartilage defects and radiographic OA in a population-based sample of older women. DESIGN: Cross-sectional study of 489 women aged 50-80 years. Parity, use of HRT and OC was assessed by questionnaire; knee cartilage volume and defects by magnetic resonance imaging and knee joint space narrowing (JSN) and osteophytes by X-ray. RESULTS: Parity was associated with a deficit in total knee cartilage volume [adjusted ß=-0.69 ml, 95% confidence interval (CI) -1.34, -0.04]. Increasing parity was associated with decreasing cartilage volume in both the tibial compartment and total knee (both P trend <0.05). Parity was also associated with greater cartilage defects in the patella compartment [adjusted odds ratio (OR)=2.87, 95% CI=1.39, 5.93] but not other sites. There was a consistent but non-significant increase in knee JSN (OR=2.78, 95% CI=0.75, 10.31) and osteophytes (OR=1.69, 95% CI=0.59, 4.82) for parous women. Use of HRT and/or OC was not associated with cartilage volume, cartilage defects or radiographic change. CONCLUSIONS: Parity (but not use of HRT or OC) is independently associated with lower cartilage volume primarily in the tibial compartment and higher cartilage defects in the patella compartment in this population-based sample of older women.

Decrease in serum level of matrix metalloproteinases is predictive of the disease-modifying effect of osteoarthritis drugs assessed by quantitative MRI in patients with knee osteoarthritis.

OBJECTIVES: To explore the impact of disease-modifying osteoarthritis drug (DMOAD) treatment on biomarker levels and their correlation with cartilage volume loss and disease symptoms in a 2-year phase III clinical trial in patients with knee OA. METHODS: 161 patients with knee OA (according-to-protocol population) were selected from a 2-year DMOAD trial studying the effect of licofelone (200 mg twice daily) versus naproxen (500 mg twice daily). Clinical evaluation of patients was carried out using the Western Ontario and McMaster Universities (WOMAC) questionnaire. Biomarker measurements of matrix metalloproteinase (MMP)-1, MMP-3, interleukin (IL)-6, C reactive protein (CRP), cartilage oligomeric matrix protein (COMP) and type I collagen C-terminal telopeptide (CTX-I) in serum, type II collagen C-terminal telopeptide (CTX-II) in urine, and knee MRI were performed at baseline and 2 years. RESULTS: Over time an increase occurred in all biomarker levels with the exception of IL-6, CRP and CTX-II which decreased. The increase in MMP-1 and MMP-3 was significantly less (p = 0.05; p < 0.01, respectively) in the licofelone group. The baseline MMP-1 level was significantly but inversely predictive of cartilage volume loss for the medial compartment in both univariate (p = 0.04) and multivariate (p ≤ 0.04) regression analyses, and COMP, a predictor for the lateral compartment, in both univariate and multivariate models (p < 0.01). Baseline levels of IL-6 and CRP also showed a significant relationship with volume loss for the medial compartment (univariate analysis, p = 0.04 and p = 0.01, respectively; multivariate analysis, p = 0.03, p = 0.01). A significant association (univariate) was observed between the change in the levels of MMP-1 (p = 0.03) and MMP-3 (p = 0.02) and cartilage volume loss (lateral compartment) over 2 years. Baseline levels of CTX-I correlated (p = 0.02) with an increase in the size of the bone marrow lesion in the medial compartment. The baseline CRP levels correlated with worsening of symptoms: WOMAC total index (p < 0.01), pain (p < 0.01) and function (p < 0.01). CONCLUSION: Higher baseline values of IL-6, CRP and COMP are predictive of greater risk of cartilage loss in OA. However, over time a reduction in MMP-1 and MMP-3 levels correlated best with reduction in cartilage volume loss and the effect of drug treatment. Baseline CRP was found to be a good predictor of the symptomatic response to treatment.

Cartilage, bone and synovial histomorphometry in animal models of osteoarthritis.

OBJECTIVE: This review focuses on histomorphometry for assessing the pathological changes in various compartments of the joint including cartilage, bone and synovium in animal models of osteoarthritis (OA). METHODS: Different methodological approaches are presented concerning sampling, embedding, sectioning, staining, mounting of stained sections and measurement of histomorphometric parameters using automated and semi-automated methods. Notes are provided describing some methods in greater detail. RESULTS: Histomorphometry allows a significant gain of objectivity, accuracy and reproducibility in the quantification of the main histological parameters which best characterize OA in the affected joint (cartilage thickness (CT), chondrocyte size and density, cartilage fissure, proteoglycan (PG) content, subchondral bone plate thickness (SBPT), thickness of synovial living cell layer) in animal models. CONCLUSION: Use of histomorphometry could contribute to a better quantification of histological differences between control and OA animals. Contributing also to the introduction of normative data, it is a major advantage for therapeutic assessments in experimental OA and particularly for the analytical comparison of the efficacy of disease modifying OA drugs (DMOAD).