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Summary Objective Abnormal metabolic activities of chondrocytes may cause articular cartilage (AC) degradation, but key transcription factors regulating metabolic activities in AC of aging individuals remain unknown. This study aimed to investigate the role of transcription factor NFAT1 in regulating the expression of anabolic and catabolic molecules in AC of aged mice. Methods The hip, knee, and shoulder joints of BALB/c mice were harvested at 6, 12, 15, 18, and 24 months of age for histopathological and immunohistochemical (IHC) analyses. Total RNA was isolated from AC for gene expression. Genomic DNA and chromatin were prepared from AC for methylated DNA immunoprecipitation (MeDIP) and chromatin immunoprecipitation (ChIP) assays. Results NFAT1 expression in AC of mice was significantly decreased after 12 months of age, which was associated with reduced proteoglycan staining, decreased expression of chondrocyte markers, and increased expression of interleukin-1β. Forced Nfat1 expression in chondrocytes from aged mice significantly reversed the abnormal metabolic activities. ChIP assays confirmed that NFAT1 bound to the promoter of the Acan , Col2a1 , Col9a1 , Col11a1 , Il1b , Mmp13 and Tnfa genes in articular chondrocytes of aged mice. ChIP and MeDIP assays revealed that reduced NFAT1 expression in AC of aged mice was regulated by epigenetic histone methylation at the promoter region and was correlated with increased DNA methylation at introns 1 and 10 of the Nfat1 gene. Conclusion NFAT1 is a transcriptional regulator of multiple anabolic and catabolic genes in AC of aged mice. Epigenetically mediated reduction of NFAT1 expression causes imbalanced metabolic activities of articular chondrocytes in aged mice.

Resume Objectif Verifier l’importance de l’alignement du plateau tibial interne (PTI), determine par la distance entre le bord anterieur et posterieur du plateau (distance inter-bords [DIB]), pour la mesure de l’epaisseur de l’interligne articulaire (EIA) sur les radiographies de genoux normaux. Methodes L’EIA et la DIB ont ete mesurees sur des radiographies de genoux appariees (au debut de l’etude et apres 12 mois) chez 122 patients de l’osteoarthritis initiative (OAI). Les relations entre l’EIA et la DIB, et entre la variation de l’EIA et la variation de la DIB, ont ete evaluees. Resultats Dans une analyse transversale, une relation non lineaire a ete mise en evidence entre l’EIA et la DIB. Avec un mauvais alignement du PTI (DIB > 1,7 mm), une augmentation de 1,0 mm de la DIB entrainait une augmentation de 0,16 mm de l’EIA (IC 95 % : 0,11–0,21) ( p p Initiale et le DIB 12 mois a ete associee a une variation de 0,10 mm de l’EIA (IC 95 % : 0,06–0,13), avec des variations de l’EIA et de la DIB evoluant dans le meme sens. La variation acceptable de la DIB pour une evaluation precise de l’EIA sur des series radiographiques a ete determinee inferieure ou egale a 1,0 mm. Conclusion L’erreur de mesure de l’EIA causee par une variation de la DIB sur des series radiographiques de genoux normaux peut etre aussi importante, voir plus importante, que la variation du pincement de l’interligne articulaire a 12 mois de genoux arthrosiques. L’alignement du PTI et la reproduction de cet alignement dans des series de radiographies de genoux sont necessaires pour une evaluation precise du pincement de l’interligne articulaire des genoux arthrosiques.

Objective To explore whether the risk of incident tibiofemoral (TF) osteoarthritis (OA) in the radiographically normal contralateral knee of overweight/obese women with unilateral knee OA is mediated by malalignment and/or preceded by increased turnover of subchondral bone. Methods We used data of post hoc analyses from a randomized controlled trial. Cross-sectional analyses evaluated the baseline association between frontal plane alignment and bone turnover in the medial TF compartment in 78 radiographically normal contralateral knees. Longitudinal analyses ascertained whether incident radiographic OA (TF osteophyte formation within 30 months) was associated with malalignment and/or increased bone turnover at baseline. Alignment subcategories (varus/neutral/valgus) were based on the anatomic axis angle. 99mTc–methylene diphosphonate uptake in a late-phase bone scan was quantified in regions of interest in the medial tibia (MT) and medial femur (MF) and adjusted for uptake in a reference segment of the ipsilateral tibial shaft (TS). Results MF and MT uptake in varus contralateral knees was 50–55% greater than in the TS. Adjusted MT uptake in varus contralateral knees was significantly greater than that in neutral and valgus contralateral knees (mean 1.55 versus 1.38 and 1.43, respectively; P < 0.05). Among 69 contralateral knees followed longitudinally, 22 (32%) developed TF OA. Varus angulation was associated with a marginally significant increase in the odds of incident OA (adjusted odds ratio 3.98, P = 0.067). Conclusion While the small sample size limited our ability to detect statistically significant risk factors, these data suggest that the risk of developing bilateral TF OA in overweight/obese women may be mediated by varus malalignment.

Summary Objective To respond to a pre-specified set of questions posed by the United States Food and Drug Administration (FDA) on defining the disease state to inform the clinical development of drugs, biological products, and medical devices for the prevention and treatment of osteoarthritis (OA). Methods An Osteoarthritis Research Society International (OARSI) Disease State working group was established, comprised of representatives from academia and industry. The Working Group met in person and by teleconference on several occasions from the Spring of 2008 through the Autumn of 2009 to develop consensus-based, evidence-informed responses to these questions. A report was presented at a public forum in December 2009 and accepted by the OARSI Board of Directors in the Summer of 2010. Results An operational definition of OA was developed incorporating current understanding of the condition. The structural changes that characterize OA at the joint level were distinguished from the patients' experience of OA as the ‘disease' and ‘illness', respectively. Recommendations were made regarding the evaluation of both in future OA clinical trials. The current poor understanding of the phenotypes that characterize OA was identified as an important area for future research. Conclusions The design and conduct of clinical trials for new OA treatments should address the heterogeneity of the disease, treatment-associated structural changes in target joints and patient-reported outcomes.

Objective: To investigate how different types of meniscal tears predispose to different patterns of meniscal position in subjects with and without symptomatic knee osteoarthritis (OA). Methods: A cross-sectional analysis of 161 women participating in an observational study to evaluate knee OA progression was performed using baseline MRI data. Meniscal morphologic features were scored in three separate locations. Meniscal position measures were determined for extrusion and proportion of coverage. Analysis was performed using multiple linear regression models treating each tear type as an individual variable with a binary response. Results: Complex tears, cysts and maceration of the medial meniscus were associated with more medial ( p = 0.0004, p = 0.004, p < 0.0001, respectively) and anterior extrusion ( p = 0.03, p = 0.03, p < 0.0001, respectively) than normal menisci. Horizontal tears of the lateral meniscus had more lateral ( p = 0.005) and anterior extrusion ( p < 0.0001) than normal menisci. Anterior and body tears of the medial meniscus were associated with more anterior extrusion ( p = 0.0006, p = 0.01, respectively), whereas meniscal body tears alone had more medial extrusion than normal menisci ( p = 0.0002). Meniscal body tears of the lateral meniscus had more lateral extrusion than normal menisci ( p = 0.01). Conclusion: Anterior horn and meniscal body tears and the more severe macerated and complex tear types predisposed to more medial meniscal extrusion. Laterally, only meniscal body and horizontal tears significantly affected extrusion, potentially reflecting a lower overall prevalence of lateral meniscal tears. These results may have important implications in identifying tear types associated with more meniscal dysfunction, with the ultimate goal of identifying those at greatest risk for knee OA progression.

Anterior cruciate ligament transection (ACLT) in the dog results in osteophyte formation and in morphologic, metabolic, biochemical, and biomechanical changes in the articular cartilage of the unstable knee that mimic those of human osteoarthritis (OA). However, in dogs studied up to 2 years after ACLT, the changes have appeared to be self-limiting, which has led to the suggestion that this is a model of cartilage damage and repair, rather than of OA. To ascertain whether changes in articular cartilage and subchondral bone of dogs subjected to ACLT lead to progressive changes of OA, we studied 3 dogs for 54 months after ACLT. Arthrotomy was performed in the dogs to visualize and then transect the anterior cruciate ligament. When the dogs were killed, full-thickness ulceration of the articular cartilage was seen on the medial femoral condyle and tibial plateau of the unstable knee, while cartilage in other regions was thicker than that of the contralateral knee, consistent with hypertrophic cartilage repair. Synovial infiltration by mononuclear cells was not more severe than that seen in dogs killed at earlier intervals after ACLT, although gross fibrotic thickening of the capsule was apparent in each dog. Histomorphometric studies revealed a marked increase in subchondral bone volume and active bone formation. These findings show that the changes that develop in the canine knee joint after ACLT are progressive and are unambiguously those of OA.

summary Objective: To update evidence for available therapies in the treatment of hip and knee osteoarthritis (OA) and to examine whether research evidence has changed from 31 January 2006 to 31 January 2009. Methods: A systematic literature search was undertaken using MEDLINE, EMBASE, CINAHL, AMED, Science Citation Index and the Cochrane Library. The quality of studies was assessed. Effect sizes (ESs) and numbers needed to treat were calculated for efficacy. Relative risks, hazard ratios (HRs) or odds ratios were estimated for side effects. Publication bias and heterogeneity were examined. Sensitivity analysis was undertaken to compare the evidence pooled in different years and different qualities. Cumulative meta-analysis was used to examine the stability of evidence. Results: Sixty-four systematic reviews, 266 randomised controlled trials (RCTs) and 21 new economic evaluations (EEs) were published between 2006 and 2009. Of 51 treatment modalities, new data on efficacy have been published for more than half (26/39, 67%) of those for which research evidence was available in 2006. Among non-pharmacological therapies, ES for pain relief was unchanged for selfmanagement, education, exercise and acupuncture. However, with new evidence the ES for pain relief for weight reduction reached statistical significance, increasing from 0.13 [95% confidence interval (CI) � 0.12, 0.36] in 2006 to 0.20 (95% CI 0.00, 0.39) in 2009. By contrast, the ES for electromagnetic therapy which was large in 2006 (ES ¼ 0.77, 95% CI 0.36, 1.17) was no longer significant (ES ¼ 0.16, 95% CI � 0.08, 0.39). Among pharmacological therapies, the cumulative evidence for the benefits and harms of oral and topical non-steroidal anti-inflammatory drugs, diacerhein and intra-articular (IA) corticosteroid was not greatly changed. The ES for pain relief with acetaminophen diminished numerically, but not significantly, from 0.21 (0.02, 0.41) to 0.14 (0.05, 0.22) and was no longer significant when analysis was restricted to high quality trials (ES ¼ 0.10, 95% CI � 0.0, 0.23). New evidence for increased risks of hospitalisation due to perforation, peptic ulceration and bleeding with acetaminophen >3 g/day have been published (HR ¼ 1.20, 95% CI 1.03, 1.40). ES for pain relief from IA hyaluronic acid, glucosamine sulphate, chondroitin sulphate and avocado soybean unsponifiables also diminished and there was greater heterogeneity of outcomes and more evidence of publication bias. Among surgical treatments further negative RCTs of lavage/debridement were published and the pooled results demonstrated that benefits from this modality of therapy were no greater than those obtained from placebo. Conclusion: Publication of a large amount of new research evidence has resulted in changes in the calculated risk–benefit ratio for some treatments for OA. Regular updating of research evidence can help to guide best clinical practice.

Summary Objective To identify subregional differences in femorotibial cartilage morphology between healthy controls and women with different grades of radiographic knee osteoarthritis (OA). Design 158 women aged ≥40 years were studied. Weight-bearing extended anterior-posterior (AP) and Lyon schuss radiographs were obtained and the Kellgren Lawrence grade (KLG) determined. 97 women had a body mass index (BMI)≤28, no symptoms, and were AP KLG0. 61 women had a BMI≥30, symptoms in the target knee, and mild (KLG2=31) to moderate (KLG3=30) medial femorotibial radiographic OA in the AP views. Coronal spoiled gradient echo water excitation sequences were acquired at 3.0 Tesla. Total plate and regional measures of cartilage morphology of the weight-bearing femorotibial joint were quantified. Results KLG2 participants displayed, on average, thicker cartilage than healthy controls in the medial femorotibial compartment (particularly anterior subregion of the medial tibia (MT) and peripheral [external, internal] subregions of the medial femur), and in the lateral femur. KLG3 participants displayed significantly thinner cartilage than KLG0 participants in the medial weight-bearing femur (central subregion), in the external subregion of the MT, and in the internal subregion of the lateral tibia. These differences were generally unaffected when possible effects of demographic covariates were considered. Conclusions The results indicate that in femorotibial OA regional cartilage thickening and thinning may occur, dependent on the (radiographic) disease status of the joint. These changes appear to display a heterogeneous spatial pattern, where certain subregions are more strongly affected than others.

Summary Background Joint space width (JSW) evaluated in millimeters on plain X-rays is the currently optimal recognized technique to evaluate osteoarthritis (OA) structural progression. Data obtained can be presented at the group level (e.g., mean±standard deviation of the changes). Such presentation makes difficult the interpretation of the clinical relevance of the reported results. Therefore, a presentation at the individual level (e.g., % progressors) seems more attractive but requires to determining a cut-off. Several methodologies have been proposed to define cut-offs in JSW: arbitrary chosen cut-off, cut-off based on the validity to predict a relevant end-point such as the requirement of total articular replacement or cut-off based on the measurement error such as smallest detectable difference (SDD). Objectives The objective of this OARSI–OMERACT initiative was to define a cut-off evaluated in millimeters on plain X-rays above which a change in JSW could be considered as relevant in patients with hip and knee OA. Methods The first step consisted in a systematic literature research performed using Medline database up to July 2007 to obtain all manuscripts published between 1990 and 2007 reporting a cut-off value in JSW evaluated in millimeters at either the knee or hip level. The second step consisted in a consensus based on the best knowledge of the 11 experts with the support of the available evidence. Results Among the 506 articles selected by the search, 47 articles reported cut-off of JSW in millimeters. There was a broad heterogeneity in cut-off values, whatever the methodologies or the OA localization considered (e.g., from 0.12 to 0.84mm and from 0.22 to 0.78mm for Knee (seven studies) and hip (seven studies), respectively when considering the data obtained based on the reliability). Based on the data extracted in the literature, the expert committee proposed a definition of relevant change in JSW based on plain X-rays, on an absolute change of JSW in millimeters and on the measurement error e.g., calculation of the SDD using the Bland and Altman technique. The results of the analysis of JSW should be expressed in terms of a dichotomous variable (e.g., progressors yes/no): a patient with a change in JSW during the study over such SDD will fulfill the definition of "progressor". Moreover, the pilot study aimed at evaluating the measurement error should be designed to reflect the different characteristics of the primary study in which the analysis of the radiological findings will be based on (patient's characteristics, centers characteristics, readers). Conclusion This initiative based on both an Evidence Based Medicine (Systematic Literature Research) and Expert Opinion approach resulted in a proposal of definition of relevant radiological progression in OA to be used as end-point in clinical trials and also recommendations on the conduct of the reliability study allowing such definition.

Summary Background Measurement of radiographic joint space width (JSW) and of joint space narrowing (JSN) is the currently recommended method for assessment of anatomical severity and structural progression of osteoarthritis (OA), respectively. A standard radiographic view of the pelvis is commonly used for measurement of hip OA but other views are available. Objectives To evaluate the inter–intra reader reproducibility and the sensitivity to change of a new automated method of measurement of the hip JSW and to assess which radiographic view [pelvis anteroposterior (AP) view, hip AP view, hip oblique view] provides the greatest accuracy for JSW and JSN measurements. Material and methods An AP pelvis radiograph, an AP radiograph centered on the target hip (AP hip) and an oblique view were performed at baseline (M0) and 3 years later (M36) in 50 hip OA patients. Two readers, blinded to each other's results and time sequence, measured twice, at a minimum 15 day interval, the six radiographs of each patient, using a novel version of a previously validated software program whose edge-based algorithm automatically detects the joint space contours. Inter-observer cross-sectional (M0+M36) and longitudinal (M0−M36) reproducibility of JSW measurement was assessed by the intra-class correlation coefficient (ICC) and the Bland–Altman method. Sensitivity to change was estimated by the standardized response mean (SRM). An ANOVA was used to analyze differences related to the observer and the view. Results Intra-observer reproducibility : For JSW measurement, the ICC value, for observers 1 and 2 respectively, were 0.92 and 0.83 for the pelvic view, 0.96 and 0.88 for the hip AP view, and 0.90 and 0.86 for the oblique view. For JSN, ICC was 0.94 and 0.82 for the pelvic view, 0.97 and 0.78 for the hip AP view, and 0.95 and 0.86 for the oblique view. Inter-observer reproducibility : For JSW measurement, ICC was 0.87 for the pelvic view, 0.98 for the hip AP view, and 0.87 for the oblique view. The mean inter-observer difference (SD) was 0.0 (0.31), −0.01 (0.15) and −0.04 (0.4)mm for pelvic, AP and oblique views respectively. For JSN, ICC was 0.91 for the pelvic view, 0.93 for the hip AP view, and 0.90 for the oblique view. Sensitivity to change : SRM values were 0.61 (observer 1) and 0.65 (observer 2) for the pelvic view, 0.68 and 0.75, respectively, for the hip AP view, 0.64 and 0.66, respectively, for the oblique view. JSN did not vary significantly with the observer and the view. In 27% of cases intervention by the observer was necessary to correct the computer's identification of the acetabular edge in the area of interest. Conclusion Computer measurement of the radiographic hip joint space provided good intra- and inter-observer reproducibility and good sensitivity to change. However, it was necessary for the observer to intervene frequently to select the area of interest and adjust detection of the bone edge. The hip AP view performed better than the pelvis and oblique views, but not significantly so.

Because of the implications for prevention and treatment, how a clinician views osteoarthritis (OA) matters. We view OA as an attempt to contain a mechanical problem in the joint and as failed repair of damage caused by excessive mechanical stress on the joint. OA is organ failure of the synovial joint. Because of insufficient focus on reduction of the habitually loaded contact area of the joint and on aberrant loading, we believe that therapeutic efforts aimed at pathogenetic mechanisms in OA have been misdirected: neither the large role that a reduction of excessive levels of mechanical stress plays in promoting the healing response in OA nor the evidence that relief of joint pain and improvement in function, rather than the appearance of the articular surface, are the most important outcomes of the healing process have been sufficiently emphasized. Various mechanical abnormalities can trigger the processes involved in repair and attempts by the joint to contain the mechanical insult, but without a return to mechanical normality, attempts at healing will fail. In our view, drugs may be helpful symptomatically, but cannot accomplish this. In our view, as long as the joint remains in the same adverse mechanical environment that got it into trouble in the first place, it is unlikely that a drug that inhibits a specific enzyme or cytokine in the pathways of cartilage breakdown, or further stimulates the already increased synthesis of cartilage matrix molecules will solve the problem of OA. Also, because the subchondral bone is critically important in containing the mechanical abnormalities that damage the cartilage, emphasis on cartilage repair alone is likely to be futile. On the other hand, if the abnormal stresses on the joint are corrected, intervention with a structure-modifying drug may be superfluous.

To evaluate the validity of using the conventional anteroposterior (AP) radiograph of the knee in order to identify joint space narrowing (JSN) at an early stage of osteoarthritis (OA).Grading of JSN using a 0-5 score and quantitative measurement of joint space width (JSW) of the medial and lateral compartments of the tibiofemoral joint in AP and fluoroscopically assisted posteroanterior Lyon schuss (LS) radiographs of 202 patients with knee OA.Knees without definite JSN (score2) were twice as common in AP than in LS radiographs (36.1% vs 18.8%). The number of knees showing definite medial JSN was identical in both views but four knees showing a medial OA in AP view were classified differently in the LS radiographs (three bicompartmental OA and one lateral OA). The frequency of lateral JSN was approximately twice as great in the LS view as in the AP view. JSN score was significantly higher (p0.001) and JSW was significantly smaller (p0.01) in the LS view than in the AP view. In knees with definite JSN, JSW of the compartment with no narrowing was significantly (p0.04) larger than in knees that did not exhibit definite JSN. Medial JSW and lateral JSW were inversely correlated (p0.001).The standing AP radiograph performed poorly in identifying both the location of JSN in patients with early tibiofemoral OA (especially, lateral OA) and the severity of JSN. The LS radiographs are preferable to standing AP views for the selection of patients for therapeutic trials of structure-modifying OA drugs.

Summary Objective To examine whether urine concentrations of type II collagen neoepitope (uTIINE) distinguish subjects with progressive radiographic and/or symptomatic knee osteoarthritis (OA) from those with stable disease. Methods Subjects were 120 obese middle-aged women with unilateral knee OA who participated in a 30-month randomized-controlled trial of structure modification with doxycycline, in which a standardized semiflexed anteroposterior view of the knee was obtained at baseline, 16 months and 30 months. Subjects were selected from a larger sample to permit a priori comparisons between 60 OA progressors and 60 nonprogressors, as defined by joint space narrowing (JSN) in the medial tibiofemoral compartment. Each group contained 30 subjects who exhibited clinically significant increases in knee pain over 30 months and 30 who did not. Urine samples were obtained every 6 months for determination of the creatinine (Cr)-adjusted uTIINE concentration. Results Baseline uTIINE levels were unrelated to JSN in the placebo group. However, among subjects in the active treatment group, a 1-standard deviation increment in baseline uTIINE (68ng/mM Cr) was associated with a marginally significant, two-fold increase in the odds of progression of JSN (odds ratio 2.04, 95% confidence interval 0.98–4.28). The within-subject mean of uTIINE values at baseline, 6 months and 12 months was associated with concurrent JSN measured at 16 months (0.10mm of JSN per 69ng/mM Cr, P =0.008). Similar results were seen in the interval between months 16 and 30 and in analyses using the maximum of intercurrent uTIINE levels. Conclusion Baseline uTIINE was not a consistent predictor of JSN in subjects with knee OA. However, serial measurements of uTIINE reflect concurrent JSN.

Objective. To determine the extent to which treatment of patients with symptomatic knee osteoarthritis (OA) with non-steroidal anti-inflammatory drugs (NSAIDs) and acetaminophen (ACET) reduces total effusion volume and synovial tissue volume, as quantified by magnetic resonance imaging (MRI). Methods. Sequential pilot studies used subjects whose knee OA was treated with NSAIDs (n=10) or with ACET ≤4 g/day (n=20), respectively. After a five half-lives washout of their pain medication, the OA knee with the higher pain score >15 of 25 on the Western Ontario and McMaster Universities' pain scale underwent 1.5T MRI. Effusion was quantified in axial short tau inversion recovery images; to measure synovial tissue volume, fat-suppressed T1-weighted axial images were obtained 3min after i.v. injection of gadolinium contrast. After the initial MRI examination, patients resumed their customary pain medications until the severity of knee pain returned to baseline, when pain was again measured and the MRI was repeated. Results. Pain severity after washout was similar in subjects taking ACET and NSAIDs. Reinstitution of ACET resulted in a 50% decrease in the mean of pain scores (P= 1.7 × 10 -12 ) that was comparable with that seen after the reinstitution of NSAID (49%, P=6.0 × 10 -7 ). The mean total effusion volume measured during the flare of knee pain induced by the withdrawal of the two drugs was comparable (ACET 16.9 ml, NSAID 16.2 ml; P= 0.884). Significant decreases in mean total effusion volume were observed after reinstitution of both ACET (-4.5 ml, P=0.009) and NSAID (-3.3 ml, P=0.013); the difference between drugs was not significant. Analyses of synovial volume yielded similar results. Conclusion. While uncontrolled and derived from small samples, these data suggest that ACET may have a significant anti-inflammatory effect in patients with knee OA, comparable with that achieved with NSAIDs, possibly through an effect on neurogenic inflammation. Joint pain is the clinical feature of OA that most often leads the affected individual to seek medical attention. Because many patients with OA improve symptomatically with the use of NSAIDs, it has been widely assumed that the pain of OA is due to synovial inflammation. However, the origins of OA pain are numerous and may vary from patient to patient and, within the same subject, from visit to visit. Although the articular cartilage is usually the site of the most obvious pathological changes in this disease, it is aneural and, therefore, is not the source of joint pain. However, in addition to the synovium, the subchondral bone, joint capsule, osteophytes, menisci, ligaments, periarticular tendons, entheses and bursae all contain nociceptive nerve endings, stimulation of which by chemical or physical mediators may be a basis for OA pain.

Little effort has gone into the development of more effective analgesics for osteoarthritic pain. Efforts to improve symptomatic therapy for osteoarthritis have been deflected or diluted by a decision to pursue the development of disease-modifying OA drugs (DMOADs). These agents' main mechanism of action is directed not at the relief of joint pain but at slowing the progression of structural damage. This article describes the results of a recent randomized placebo-controlled designed to examine the DMOAD effect in humans of the tetracycline antibiotic doxycycline, and reviews the experience gained from other recent DMOAD trials in humans.

Objective: To compare quantitative estimates of change in joint space width (JSW) with semiquantitative ratings of the progression of joint space narrowing (JSN) with respect to sensitivity to change over time. Methods: 431 obese women 45 to 64 years old with unilateral radiographic knee osteoarthritis were randomised to 30 months’ treatment with doxycycline 100 mg twice daily or placebo. Quantitative estimates of change in JSW in the medial tibiofemoral compartment from fluoroscopically assisted semiflexed AP radiographs were obtained at baseline and 16 and 30 months after randomisation. Radiographic JSN was rated (0–3 scale) in the same images by two readers using a standard atlas. Changes in overall severity of knee osteoarthritis were derived from gradings of conventional standing AP radiographs at baseline and 30 months, with blinding to treatment group and chronological order of examination. Results: Follow up radiographs were obtained from 381 subjects (88%) at 16 months and from 367 (85%) at 30 months. The treatment groups did not differ in the frequency of significant loss of JSW by dichotomous criteria (⩾0.5 mm, ⩾1.0 mm, ⩾20%, or ⩾50% of baseline JSW). Progressors and non-progressors, as defined by each of the dichotomous outcomes, differed significantly in mean value for quantitative measurement of change in JSW at 30 months (p⩽0.001). Conclusions: Quantitative and semiquantitative indicators of progression of osteoarthritis in fluoroscopically standardised radiographs of osteoarthritic knees are highly related, but the effect of doxycycline on articular cartilage thickness was more easily detected with quantitative measurements of change in JSW than with semiquantitative ratings of JSN.

SummaryObjectiveRecent studies using various standardized radiographic acquisition techniques have demonstrated the necessity of reproducible radioanatomic alignment of the knee to assure precise measurements of medial tibiofemoral joint space width (JSW). The objective of the present study was to characterize the longitudinal performance of several acquisition techniques with respect to long-term reproducibility of positioning of the knee, and the impact of changes in positioning on the rate and variability of joint space narrowing (JSN).MethodsEighty subjects were randomly selected from each of three cohorts followed in recent studies of the radiographic progression of knee osteoarthritis (OA): the Health ABC study (paired fixed-flexion [FF] radiographs taken at a 36-month interval); the Glucosamine Arthritis Intervention Trial (GAIT) (paired metatarsophalangeal [MTP] radiographs obtained at a 12-month interval), and a randomized clinical trial of doxycycline (fluoroscopically assisted semiflexed anteroposterior (AP) radiographs taken at a 16-month interval).Manual measurements were obtained from each radiograph to represent markers of radioanatomic positioning of the knee (alignment of the medial tibial plateau and X-ray beam, knee rotation, femorotibial angle) and to evaluate minimum JSW (mJSW) in the medial tibiofemoral compartment. The effects on the mean annualized rate of JSN and on the variability of that rate of highly reproduced vs variable positioning of the knee in serial radiographs were evaluated.ResultsParallel or near-parallel alignment was achieved significantly more frequently with the fluoroscopically guided positioning used in the semiflexed AP protocol than with either the non-fluoroscopic FF or MTP protocol (68% vs 14% for both FF and MTP protocols when measured at the midpoint of the medial compartment; 75% vs 26% and 34% for the FF and MTP protocols, respectively, when measured at the site of mJSW; P

Objective To confirm preclinical data suggesting that doxycycline can slow the progression of osteoarthritis (OA). The primary outcome measure was joint space narrowing (JSN) in the medial tibiofemoral compartment. Methods In this placebo-controlled trial, obese women (n = 431) ages 45–64 years with unilateral radiographic knee OA were randomly assigned to receive 30 months of treatment with 100 mg doxycycline or placebo twice a day. Tibiofemoral JSN was measured manually in fluoroscopically standardized radiographic examinations performed at baseline, 16 months, and 30 months. Severity of joint pain was recorded at 6-month intervals. Results Seventy-one percent of all randomized subjects completed the trial. Radiographs were obtained from 85% of all randomized subjects at 30 months. Adherence to the dosing regimen was 91.8% among subjects who completed the study per protocol. After 16 months of treatment, the mean ± SD loss of joint space width in the index knee in the doxycycline group was 40% less than that in the placebo group (0.15 ± 0.42 mm versus 0.24 ± 0.54 mm); after 30 months, it was 33% less (0.30 ± 0.60 mm versus 0.45 ± 0.70 mm). Doxycycline did not reduce the mean severity of joint pain, although pain scores in both treatment groups were low at baseline and remained low throughout the trial, suggesting the presence of a floor effect. However, the frequency of followup visits at which the subject reported a ≥20% increase in pain in the index knee, relative to the previous visit, was reduced among those receiving doxycycline. In contrast, doxycycline did not have an effect on either JSN or pain in the contralateral knee. In both treatment groups, subjects who reported a ≥20% increase in knee pain at the majority of their followup visits had more rapid JSN than those whose pain did not increase. Conclusion Doxycycline slowed the rate of JSN in knees with established OA. Its lack of effect on JSN in the contralateral knee suggests that pathogenetic mechanisms in that joint were different from those in the index knee.

Objective To determine whether baseline or serial plasma concentrations of stromelysin (matrix metalloproteinase 3 [MMP-3]) protein might distinguish subjects with progressive radiographic knee osteoarthritis (OA) from those with stable disease. Methods Subjects were 120 women with unilateral knee OA who participated in a 30-month randomized, placebo-controlled trial of structure modification with doxycycline. Anteroposterior views of both knees in a semiflexed position were obtained at baseline, 16 months, and 30 months. Subjects were selected to obtain comparisons of plasma MMP-3 levels between 60 progressors (21 taking doxycycline, 39 taking placebo) and 60 nonprogressors (30 taking doxycycline, 30 taking placebo) with respect to medial joint space narrowing (JSN) in the index knee. Each group consisted of 30 subjects who exhibited significant increases in knee pain. Blood samples were obtained semiannually for MMP-3 assay. Results Subjects in the placebo group whose MMP-3 concentration was in the upper tertile of the baseline distribution showed a 4-fold increase in the odds of progression of JSN as compared with the lower tertile (odds ratio 4.12, P = 0.037). Baseline MMP-3 levels were unrelated to knee pain. The within-subject mean of serial MMP-3 concentrations was associated with concurrent JSN in the placebo group over the 0–16-month interval (b = 0.18 mm/SD increase in the mean MMP-3, P < 0.01) and over the 16–30-month interval (b = 0.15, P < 0.05). Similar evidence of concurrent validity was found in the placebo group for the maximum of intercurrent MMP-3 values. Conclusion The baseline MMP-3 level was a significant predictor of JSN in this pilot study. Moreover, serial plasma MMP-3 levels reflected concurrent JSN in the placebo group over the 30-month period of observation.

Objective To describe the methods by which remarkable levels of subject retention and adherence were achieved in a 30-month multicenter randomized placebo-controlled trial (RCT) of a disease-modifying osteoarthritis drug (DMOAD). Methods Subjects were obese 45–64-year-old women with unilateral knee osteoarthritis. Before randomization, each volunteer completed a 4-week “faintness-of-heart” (FOH) test, during which she was required to demonstrate reliable appointment keeping and ≥80% adherence to the dosing regimen. Subjects who passed the FOH test were randomized to treatment with doxycycline or placebo for 30 months. The double-blind phase entailed 15 bimonthly followup visits; intervisit adherence data were downloaded from the dosing monitor and used to estimate therapeutic coverage and to identify correctable patterns of nonadherence. Subjects received token incentives and a small cash payment at each followup visit. Measures to prevent or treat side effects of doxycycline were dispensed free of charge. Study coordinators monitored safety and reinforced participation through between-visit telephone calls. Results Of 463 eligible volunteers, 32 (7%) failed the FOH test and were excluded from the double-blind phase. Among the 431 subjects randomized to treatment groups, 307 (71%) completed the 30-month RCT and 124 discontinued the study drug prematurely. Nearly half of the dropouts returned for their 16- and 30-month radiographs, resulting in loss to followup of 14.8% of randomized subjects. The 2 treatment groups did not differ significantly with respect to rates of discontinuation or retention. Therapeutic coverage over 30 months was very high in both groups. Conclusion The rate of discontinuation in this 30-month RCT (29%) was lower than that of any DMOAD trial of ≥2 years duration published to date. The proportion of subjects for whom 30-month radiographs were available (85%) and adherence to the dosing regimen (mean >80%) also were remarkably high.

Drugs should be used as adjuncts to non-pharmacological measures In the 1950s and early 60s Sir John Charnley succeeded in developing components for total hip arthroplasty and demonstrated the remarkable success that could be achieved with this procedure in patients with osteoarthritis (OA). Charnley’s adaptation of polymethylmethacylate as a fixation interface between the metallic or plastic implant and the bone served as a major advance in the surgical treatment of severe OA.1,2 Development of total knee arthroplasty followed. The materials and surgical techniques have improved steadily so that both of these procedures are associated with a high level of patient satisfaction. Most patients with OA of the hip or knee who undergo total joint arthroplasty experience clinically significant improvement in joint pain, function, and quality of life.3,4 Recommendation of total joint arthroplasty for the patient with OA, however, is tantamount to an acknowledgement of the failure of medical management. The surgical procedure is often performed after the patient has experienced years, or even decades, of pain and disability. Among all the pharmacological and non-pharmacological interventions promoted for treatment of OA in the half century since Charnley directed his attention to replacement of the arthritic hip, none approximates the effectiveness of arthroplasty. The 1963 edition of the Cecil-Loeb textbook of medicine,5 in discussing the treatment of OA, noted: “Analgesics, particularly salicylates, are useful in controlling the symptoms of osteoarthritis. Phenylbutazone is sometimes helpful when salicylates have failed, but the potential toxic reactions rarely justify its use in such a mild disorder. Systemic corticosteroid treatment is not recommended for osteoarthritis. Intra-articular injections of hydrocortisone acetate ... may be helpful for joints which fail to respond to simpler measures.” Despite enormous increases in our understanding of pain mechanisms and of the metabolism, biochemistry, and molecular biology of articular …

Objective Computerized measurement of changes in joint space width (JSW) on serial radiographs of the knee in the semiflexed, anteroposterior (SF-AP) view has been used recently as a primary outcome measure in clinical trials of disease-modifying osteoarthritis drugs (DMOADs). In the use of fluoroscopy to achieve reproducible alignment of the medial tibial plateau and x-ray beam, the SF-AP radiographic protocol affords greater sensitivity in the detection of joint space narrowing (JSN) than that achieved by conventional radiographic positioning techniques. However, the utility of the SF-AP view is compromised by the variation in x-ray penetration in each examination, which may confound the correction of the automated measurement of JSW for the radiographic magnification inherent in an AP view of the knee. A recent DMOAD trial using the SF-AP protocol showed an improbable increase in JSW of ≥0.50 mm (i.e., greater than the measurement error). The present report provides an analysis of this problem, and the study aim was to demonstrate that substitution of the automated estimates of JSW with precise manual measurements can markedly reduce the problem attributable to radiographic magnification. Methods SF-AP radiographs were obtained at baseline and at 16 months and 30 months thereafter from subjects enrolled in a 6-center DMOAD trial. For each examination, a 6.35-mm steel ball was affixed to the skin over the head of the fibula to permit estimation of the percentage of radiographic magnification (%Mag) and correction of JSW measurements. Measurements of the minimum interbone distance (IBD) in the medial tibiofemoral compartment and the %Mag were obtained by an automated method (edge detection) and manually. Combinations of automated and manual measurements of the IBD and %Mag in estimates of magnification-corrected JSW were compared with respect to their reproducibility, agreement, and sensitivity to JSN. Results With fully automated measurements, variations in x-ray penetration in analog radiographs and edge enhancement in digital radiographs resulted in the computer “seeing” a metal ball whose diameter was artifactually reduced, resulting in an inflated measurement of JSW. Use of manual measurement of the IBD and %Mag largely eliminated these problems and reduced, from 16% to 2%, the frequency of knees exhibiting an increase in JSW ≥0.50 mm. In 14 of the 15 knees in which a significant increase in JSW was noted with the manual method, this increase in JSW could be explained by the development of significant lateral compartment narrowing during the study or poor alignment of the medial plateau. Conclusion Although automated and manual methods of JSW measurement of the knee in the SF-AP view possess comparable intrareader reproducibility, the manual method is less susceptible to technical factors that affect the correction of raw JSW estimates for radiographic magnification. Until we can identify practical, effective solutions to these technical problems, use of any radiographic protocol involving AP imaging of the knee in a DMOAD trial must be viewed with caution.

Recent research on the radiographic imaging of knee OA has helped clarify the features of imaging protocols that contribute to accurate representation of disease severity--specifically, the thickness of articular cartilage--and to sensitive detection of disease progression. The absence of standards for reproducible positioning of the knee in the conventional standing AP view obscures the true rate and variability of JSN in knee OA. Moreover, the standing AP view is susceptible to systematic bias insofar as longitudinal changes in knee pain might lead to over- or underestimation of radiographic JSW depending on the direction of change in pain. More recent protocols for standardized knee radiography have been designed to achieve reproducible alignment of the medical tibial plateau and x-ray beam. As a group these protocols permit measurement of tibiofemoral JSW with remarkable precision--the sine qua non of sensitivity to change--however, only limited longitudinal data is available to permit a direct evaluation of the suitability of these protocols for use in clinical DMOAD trials. Longitudinal studies published to date suggest that fluoroscopic positioning methods are superior to nonfluoroscopic methods with respect to reproducing the position of the knee in serial examinations performed several years apart. Fluoroscopic methods also appear to be superior with respect to achieving parallel alignment of the medial tibial plateau and x-ray beam in serial radiographs, a positioning marker strongly associated with sensitive detection of JSN in knee OA. It is important to note that while the various standardization protocols described in this article perform with great success in short-term demonstrations of the reproducibility of positioning and radiographic JSW, differences clearly exist between protocols in the quality of performance over intervals relevant to clinical DMOAD trials. Over intervals of 2 to 3 years, changes in patient characteristics (e.g., severity of knee pain, body weight, load bearing, varus--valgus deformity) and uncontrollable events related to radiography (e.g., technologist turnover, equipment upgrades) have ample opportunity to affect the technical quality of a radiological knee examination. It is difficult, therefore, to conclude whether or not an apparent difference with respect to sensitivity to OA progression between specific radiographic protocols, implemented in separate locations with different cohorts, reflects a robust difference in technical quality or uncontrollable patient variables and events. The most informative recent studies have provided the results of head-to-head longitudinal comparisons of alternative standardization protocols or conventional examination methods performed concurrently in the same subjects [20,22]. Additional comparative studies of this nature are needed, however, to fully characterize the strengths and weaknesses of currently available alternatives in a way that will permit generalizable conclusions regarding the best radiographic methods for multicenter DMOAD trials.

Most of the treatments used today for OA have a relatively weak evidence base to support their use, and their effect size is small. Many key questions about OA management remain unanswered, in part because of the strong bias toward research on single pharmaceutical agents rather than nonpharmacologic interventions and a comprehensive package of care involving pharmacologic and nonpharmacologic measures. Good management of OA involves the coordination of several different types of interventions provided by health care professionals; however, while a great deal of research is available on the use of individual treatments, there is a lack of information on how health services for patients who have OA should be organized. The problem is compounded by the fact that many people who have OA use complementary therapy as well as, or instead of, allopathic treatments despite the fact that most of the evidence suggests that many such interventions are no better than placebo [123], which might be because of the relatively small effects of most conventional nonsurgical treatment for OA and to the need for a more holistic, individualized approach to treatment than most conventional health professionals usually provide. For many people who have OA, the fear of side effects is a major barrier to the use of pharmacologic interventions [11]. The authors believe that future research in OA therapeutics should concentrate more on behavioral and physical interventions than on drugs, should examine packages of care involving combinations of treatment modalities, and should include a consideration of patient preferences. The authors also believe that the academic community striving to provide help for people who have OA should bear in mind the concept that there is "too much medicine" [37].

Objective To evaluate the effectiveness of tidal irrigation (TI) in comparison with a well-matched sham irrigation (SI) procedure as a treatment for knee osteoarthritis (OA). Methods One hundred eighty subjects with knee OA were randomized to receive TI or SI, with clinical followup over the ensuing 12 months. The primary outcomes of interest were change in pain and function, as measured by the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC). Subjects and the nurse assessor were blinded, and success of blinding was assessed. Results Although the study groups were otherwise comparable, the baseline WOMAC pain and physical functioning scores were higher (worse) in the SI group. After adjustment for baseline, there were no differences between the effects of SI and TI. Blinding was successful, with ∼90% of SI and TI subjects stating that they had received the TI procedure. Conclusion Most, if not all, of the effect of TI appears to be attributable to a “placebo response.”

Objective To estimate the reproducibility of the semiflexed metatarsophalangeal (MTP) view in repeat radiographic examinations of the knee of subjects with osteoarthritis (OA) with respect to radioanatomic alignment of the medial tibial plateau and the central x-ray beam and the precision of measurements of minimum medial tibiofemoral joint space width (JSW). Methods Thirty-eight subjects with definite knee OA underwent 2 semiflexed MTP examinations on the same day. Radioanatomic alignment of the medial tibial plateau and the x-ray beam (distance between anterior and posterior margins of the plateau) was measured manually (Lequesne method). Manual measurements of the JSW in repeat radiographs also were obtained. The reproducibility of JSW measurements was estimated by the method of Bland and Altman. Results Only 29% of the initial semiflexed MTP radiographs exhibited satisfactory radioanatomic alignment (intermargin distance ≤1 mm). However, intermargin distances in initial and repeat radiographs were highly correlated (r = 0.86, P< 0.01). In 89% of knees, the intermargin distance in the first examination was reproduced (±1 mm) in the second examination. The standard error of measurement (mean of within-knee standard deviations of repeat JSW values) was 0.30 mm. The magnitude of discrepancy between repeat measurements of JSW was related positively to overall radiographic severity of knee OA (P< 0.05). Conclusion The semiflexed MTP protocol affords highly reproducible radioanatomic positioning of the knee, although misalignment of the medial tibial plateau and the x-ray beam occurs in >70% of cases. Precision of measurement of JSW in the semiflexed MTP view approaches that associated with fluoroscopically assisted positioning protocols. However, the consequences of poor, albeit reproducible, alignment of the knee in serial semiflexed MTP radiographs in longitudinal studies of OA progression are currently unknown.

In patients with knee osteoarthritis (OA) the real problem, for the clinician and the patient, is not radiographic OA but painful OA. As noted by Liang, ‘x-rays don't weep'.1 Patients weep. In this issue of the Annals , Snijders et al 2 report results of a randomised controlled (RCT), placebo-controlled trial of doxycycline (doxy) in patients with symptomatic knee OA. Their primary end point was the difference in the proportion of subjects in the two treatment groups who achieved a clinical response at 24 weeks, as judged by OMERACT-OARSI responder criteria. Secondary outcomes included joint pain, stiffness, function, quality of life, OA-related medication use and side effects of treatment. The results showed no difference between doxy and placebo with respect to symptomatic benefit; about one-third of each treatment group met the responder criteria. The authors conclude that doxy is ineffective in reducing symptoms of knee OA over 24 weeks. The study was prompted by our 2005 report that doxy slowed the rate of joint space narrowing (JSN) over 30 months in patients with knee OA; significant differences from placebo were seen as early as 16 months.3 In contrast to the study by Snijders et al ,2 our primary outcome measure was the effect of doxy on radiographic progression of OA, not on symptoms. Specifically, our intent was to ascertain whether a fluoroscopically assisted semiflexed radiographic view of the knee4 was suitable for use in a multicentre clinical trial of a putative structure-modifying OA drug (SMOAD). Subjects enrolled in the study, which was implemented in 1997, were recruited chiefly from the community, rather than from clinics for patients with joint pain. Our inclusion criteria did not contain a threshold for severity of joint pain and levels of knee pain at entry were low. Post hoc comparison showed …

A prospective, multicenter, randomized, double-blind, controlled trial was conducted in 226 patients with knee osteoarthritis to evaluate the safety and efficacy of intraarticular injections of sodium hyaluronate. Patients were randomized to three weekly injections of 30 mg sodium hyaluronate or physiologic saline (control) and were observed for an additional 25 weeks. In comparison with the control group, among patients who completed at least 15 weeks of the study and whose Western Ontario and McMaster Universities Osteoarthritis Index pain score for the contralateral knee was less than 12 at baseline, sodium hyaluronate injection resulted in improvement in Western Ontario and McMaster Universities Osteoarthritis Index pain score, patient and investigator global assessments, and pain on standing from Weeks 7 to 27. Fifty-eight percent of patients treated with sodium hyaluronate achieved a 5-unit or greater improvement in mean pain score from Weeks 7 through 27, compared with 40% of control patients. In addition, nearly twice as many patients treated with sodium hyaluronate as with saline (30% versus 17%, respectively) achieved a net improvement of at least 7 units. In contrast to treatment with saline, Western Ontario and McMaster Universities Osteoarthritis Index pain score for the contralateral knee was inversely related to the magnitude of improvement after treatment with sodium hyaluronate. Few side effects were attributed to treatment, and no differences between treatment groups were seen in this respect (sodium hyaluronate, nine [8%]; saline, 11 [10%]). The incidence of injection site reactions was low (sodium hyaluronate, 1.2 %; saline, 1.5%). The results indicate that sodium hyaluronate treatment is well tolerated and produces statistically and clinically significant improvement of symptoms in patients with mild to moderate knee osteoarthritis in whom pain in the contralateral knee is relatively modest.

Pyomyositis is an uncommon condition that may present a difficult problem in diagnosis. We report the development of Streptococcus pneumoniae pyomyositis involving the iliacus, iliopsoas, and gluteus muscles in a patient with elevated serum levels of antinuclear and antiphospholipid antibodies but without clinical evidence of connective tissue disease. Magnetic resonance imaging demonstrated rapid evolution of the infection, with progression from muscle edema to abscess formation over a period of 10 days. The diagnosis was initially missed, and osteomyelitis and sacroiliitis developed. Pyomyositis should be suspected in patients with the acute onset of severe, localized muscle pain and fever. As in this case, failure to promptly diagnose and treat this infection can result in significant morbidity.

Objective Previous studies of knee osteoarthritis (OA) have yielded variable estimates of the rate of joint space narrowing (JSN) in the standing anteroposterior (AP) radiograph, due largely to longitudinal changes in the alignment of the medial tibial plateau (MTP) and x-ray beam. To characterize this bias, we examined serial radiographs of subjects with knee OA in population-based and clinical OA cohorts from 3 locations in the United States and the United Kingdom. Methods Radiographic features of knee OA (e.g., osteophytosis, JSN) and MTP alignment in 428 OA knees were evaluated by consensus of 2 readers. Alignment was considered satisfactory if the anterior and posterior margins of the MTP were superimposed within 1 mm. Readers were blinded to subject identity, and films were read in random order. The minimum medial joint space width was also measured manually (standard error of repeated measurements 0.20 mm) in serial knee images. Results Only 14% of serial radiographs exhibited alignment of the MTP in both images. In OA knees with satisfactory alignment in both images, the mean rate of JSN over 2–3 years (0.26 mm/year) was significantly larger (P = 0.004) than that in OA knees with misalignment in 1 or both radiographs and was 86% more rapid than the mean JSN in all OA knees. Moreover, the within-group standard deviation of JSN was significantly smaller among knees with reproduced alignment of the MTP than in knees in which misalignment occurred in 1 or both images (P = 0.006). Conclusion Poor standardization of knee positioning in serial standing AP radiographs in previous studies of OA progression has obscured the rate and variability of articular cartilage loss in subjects with knee OA. True JSN (i.e., JSN that is not attributable to longitudinal changes in the alignment of the MTP with the x-ray beam in serial radiographic examinations) may occur more rapidly, and with less between-subject variability, than that previously thought to be characteristic of knee OA.

Objective and Design We characterized the mean peak vertical forces (MFz) in five groups of dogs which underwent transection of the left anterior cruciate ligament (ACLT) or sham ACLT and ipsilateral dorsal root ganglionectomy or sham-ganglionectomy, and the relationship of these forces to the severity of osteoarthritis (previously reported) 72 weeks after arthrotomy. Group I ( N =7) underwent ACLT; Group II ( N =8) underwent ACLT followed 52 weeks later by ganglionectomy; Group III ( N =7) underwent ganglionectomy followed 2 weeks later by ACLT; Group IV ( N =7) underwent sham-ganglionectomy followed 2 weeks later by ACLT; Group V ( N =8) underwent ganglionectomy followed 2 weeks later by sham-ACLT. The dogs were evaluated 2, 6, 12, 24, 52 and 72 weeks after arthrotomy. Results From 6 weeks after arthrotomy until death, the left hindlimb MFz in Group V was significantly greater ( P 0.05) than that in the other four groups. The MFz of all groups which underwent ACLT decreased after arthrotomy. While the MFz of Group III (very severe OA) was about 10–20% greater than that of Groups I, II and IV (mild OA) 6 and 12 weeks after ACLT, and generally about 5–10% greater subsequently, this difference was not statistically significant. The MFz of Group II returned to pre-ganglionectomy levels, rather than to baseline levels, following ganglionectomy. Conclusions (1) since the ipsilateral limb of dogs with ganglionectomy+sham ACLT bore normal amounts of weight throughout most of the postsurgical period, and its knee did not develop OA, one cannot argue that the knee was protected from OA because the limb was not used; (2) the fact that the MFz of dogs which underwent ACLT+ganglionectomy returned to pre-ganglionectomy levels, rather than baseline, is consistent with the hypothesis that the unstable joint was protected from accelerated breakdown by a central nervous system that was reprogramed by sensation from the unstable limb; (3) the slightly—but consistently—greater MFz of dogs which underwent ganglionectomy+ ACLT may contribute to the acceleration of OA in this model.

Objective To investigate the inhibition of matrix metalloproteinase 1 (MMP-1), MMP-8, and MMP-13 by doxycycline, and to determine whether the variable hemopexin-like domain of each MMP was responsible for the differences in susceptibility to doxycycline inhibition among these collagenases. Methods Recombinant human MMP-1 (collagenase 1), MMP-8 (collagenase 2), and MMP-13 (collagenase 3), truncated forms of MMP-8 and MMP-13 lacking the hemopexin-like domain, and a mutant form of truncated MMP-13 were used in these studies. The activity of the full-length MMP in the presence of doxycycline was tested against type II collagen, a natural substrate for the enzymes. A small peptolide substrate was used to determine which structural features of the MMPs were related to sensitivity to doxycycline inhibition. Results The activity of MMP-13 and MMP-8 against type II collagen was inhibited by 50-60% by 30 microM doxycycline, while that of MMP-1 was inhibited only 18% by 50 microM doxycycline. In contrast, in experiments with the peptolide substrate, neither full-length nor truncated MMP-13 was inhibited until the concentration of the drug exceeded 90 microM. MMP-8 and truncated MMP-8 were sensitive to inhibition by 30 microM doxycycline, while MMP-1 was slightly inhibited (14%) by 90 microM doxycycline. For MMP-8, inhibition was reversible upon dilution and was independent of the order in which the reagents were added. Kinetic analysis of the inhibition constant (K(i)) of MMP-8 (K(i) = 36 microM) and truncated MMP-8 (K(i) = 77 microM) indicated that inhibition was noncompetitive. Conclusion Significant inhibition of MMP-13 and MMP-8 activity against collagen occurred in vitro at concentrations that were near the concentrations achieved in serum after oral dosing. Studies with truncated enzymes and 2 substrates suggest that doxycycline disrupts the conformation of the hemopexin-like domain of MMP-13 and the catalytic domain of MMP-8.

Objective To determine the extent to which the cost of an effective self-care intervention for primary care patients with knee osteoarthritis (OA) was offset by savings resulting from reduced utilization of ambulatory medical services. Methods In an attention-controlled clinical trial, 211 patients with knee OA from the general medicine clinic of a municipal hospital were assigned arbitrarily to conditions of self-care education (group E) or attention control (group AC). Group E (n = 105) received individualized instruction and followup emphasizing nonpharmacologic management of joint pain. Group AC (n = 106) received a standard public education presentation and attention-controlling followup. A comprehensive clinical database provided data concerning utilization and cost of health services during the following year. Results Only 25 subjects (12%) were lost to followup. The 94 subjects remaining in group E made 528 primary care visits during the year following intervention, compared with 616 visits by the 92 patients remaining in group AC (median visits 5 versus 6, respectively; P < 0.05). Fewer visits translated directly into reduced clinic costs in group E, relative to controls (median costs [1996 dollars] $229 versus $305, respectively; P < 0.05). However, self-care education had no significant effects on utilization and costs of outpatient pharmacy, laboratory, or radiology services over the ensuing year. The cost per patient to deliver the self-care intervention was estimated to be $58.70. Conclusion Eighty percent of the cost of delivering effective self-care education to the knee OA patients in this study was offset within 1 year by the reduced frequency and costs of primary care visits. For >50% of patients receiving the intervention, the savings associated with fewer primary care visits exceeded the cost of self-care education.

The identification of pharmacologic agents that inhibit matrix metalloproteinase activity and may serve as effective disease-modifying osteoarthritis drugs (DMOADs) in humans has led to interest in the ability of plain radiographic methods to detect early cartilage damage and assess progressive cartilage changes of knee osteoarthritis (OA). Conventional knee radiography lacks sufficient standardization of key elements of the radioanatomic positioning of the knee to avoid significant, probably insurmountable, error variation in the measurement of tibiofemoral joint space width (JSW), the surrogate for the thickness of articular cartilage in radiographic images. Recently, several protocols for the use of fluoroscopy to standardize the radioanatomic position of the knee in a plain radiograph have been shown to afford notably more precise measurement of medial tibiofemoral JSW than can be derived from unstandardized, conventional techniques. A field test of one of these protocols suggests that DMOAD trials with respect to sample size or duration of treatment necessary to detect true OA progression and demonstrate a drug effect may be more feasible.

Objective To determine if diacerhein protects against the early stages of joint damage in a canine model of osteoarthritis (OA). Methods OA was induced in 20 adult mongrel dogs by transection of the anterior cruciate ligament of the left knee. Beginning the day after surgery, dogs in the active treatment group were dosed twice a day with capsules of diacerhein, providing a total daily dose of 40 mg/kg, for 32 weeks. Dogs in the control group received placebo capsules on the same schedule. Pathology in the unstable knee was assessed arthroscopically 16 weeks after surgery and by direct observation when the dogs were killed 32 weeks after surgery. The severity of gross joint pathology was recorded, and samples of the medial femoral condyle cartilage and the synovial tissue adjacent to the central portion of the medial meniscus were collected for histologic evaluation. Water content and uronic acid concentration of the articular cartilage from the femoral condyle were determined, and collagenolytic activity in extracts of cartilage pooled from the medial and lateral tibial plateaus was assayed against 14C-labeled collagen fibers. Results Diacerhein treatment slowed the progression of OA, as measured by grading of gross changes in the unstable knee at arthroscopy 16 weeks after cruciate ligament transection (P = 0.04) and at the time the animals were killed, 32 weeks after surgery (P = 0.05). However, 32 weeks after ACL transection, the mean proteoglycan concentration and water content of the OA cartilage and the level of collagenolytic activity in extracts of the cartilage were not significantly different in the diacerhein treatment group than in the placebo treatment group. Conclusion Diacerhein treatment significantly reduced the severity of morphologic changes of OA compared with placebo. These findings support the view that diacerhein may be a disease-modifying drug for OA.

Objective To determine whether baseline lower extremity muscle weakness is a risk factor for incident radiographic osteoarthritis (OA) of the knee. Methods This prospective study involved 342 elderly community-dwelling subjects (178 women, 164 men) from central Indiana, for whom baseline and followup (mean interval 31.3 months) knee radiographs were available. Lower extremity muscle strength was measured by isokinetic dynamometry and lean tissue (i.e., muscle) mass in the lower extremities by dual x-ray absorptiometry. Results Knee OA was associated with an increase in body weight in women (P = 0.0014), but not in men. In both sexes, lower extremity muscle mass exhibited a strong positive correlation with body weight. In women, after adjustment for body weight, knee extensor strength was 18% lower at baseline among subjects who developed incident knee OA than among the controls (P = 0.053), whereas after adjustment for lower extremity muscle mass, knee extensor strength was 15% lower than in the controls (P not significant). In men, in contrast, adjusted knee extensor strength at baseline was comparable to that in the controls. Among the 13 women who developed incident OA, there was a strong, highly significant negative correlation between body weight and extensor strength (r = -0.740, P = 0.003), that is, the more obese the subject, the greater the reduction of quadriceps strength. In contrast, among the 14 men who developed incident OA, a modest positive correlation existed between weight and quadriceps strength (r = 0.455, P = 0.058). No correlation between knee flexor (hamstring) strength and knee OA was seen in either sex. Conclusion Reduced quadriceps strength relative to body weight may be a risk factor for knee OA in women.

Treatment of the patient with osteoarthritis should be comprehensive, with nonpharmacologic approaches considered as primary therapy, and analgesics and nonsteroidal anti-inflammatory drugs (NSAIDs) assigned to an adjunctive role. These nonmedicinal approaches can include joint protection strategies; the use of thermal modalities (heat and cold) and transcutaneous electrical nerve stimulation (TENS); the development of exercise programs (that focus not only on the localized impairment, but on the functional limitations and disability secondary to inactivity); weight loss programs; the use of patellar tapping, wedged insoles, tidal irrigation (of the knee); and the introduction of coping skills and social support.

Objective To determine if intraarticular injections of hyaluronan (HA) protect against the early stages of joint damage in a canine model of osteoarthritis (OA). Methods OA was induced in adult mongrel dogs by transection of the anterior cruciate ligament of the left knee. One group of dogs (n = 7) was treated with 5 weekly injections of HA (MW 1,500,000) into the operated knee beginning 1 day after ligament transection. The control group (n = 6) was injected with saline on the same schedule. Twelve weeks after surgery, all dogs were killed, the severity of pathologic changes of OA was graded, and composition of the cartilage and extent of aggregation of proteoglycans (PGs) synthesized in vitro by cartilage slices were determined. Results All dogs showed gross morphologic changes typical of OA in the unstable knee. The severity of joint pathology in HA-treated dogs was comparable with that in the saline-injected controls. In OA cartilage from the saline-treated group, the mean uronic acid concentration was 30-60% greater than that in the contralateral knee. In sharp contrast, the uronic acid concentration in OA cartilage from the HA-treated dogs was 10-30% lower than that in cartilage from the contralateral knee (P = 0.02 and P = 0.03, respectively, for samples from the medial and lateral femoral condyle). The extent of aggregation of PG synthesized in vitro by cartilage from HA-injected animals was similar to that synthesized by cartilage from the saline-injected dogs. Conclusion In this canine model of OA, the series of intraarticular injections of HA did not alter development of osteophytosis or fibrillation. However, the PG concentration of cartilage in the OA knee was significantly reduced by this treatment, suggesting that HA therapy might adversely affect the biomechanical properties of the cartilage.

Objective. To evaluate the nature, risks, and benefits of osteoarthritis (OA) management by primary care physicians and rheumatologists. Methods. Subjects were 419 patients followed for symptoms of knee OA by either a specialist in family medicine (FM) or general internal medicine (GIM) or by a rheumatologist (RH). Management practices were characterized by in-home documentation by a visiting nurse of drugs taken to relieve OA pain or to prevent gastrointestinal side effects of nonsteroidal anti-inflammatory drugs (NSAIDs) and by patient report (self-administered survey) of nonpharmacologic treatments. Changes in outcomes (knee pain and physical function) over 6 months were measured with the Western Ontario and McMaster Universities Osteoarthritis Index. Results. Patients of RHs were 2-3 years older (P = 0.035) and tended to exhibit greater radiographic severity of OA (P = 0.064) and poorer physical function (P = 0.076) at baseline than the other 2 groups. In all 3 groups, knee pain and physical function improved slightly over 6 months; however, between-group differences were not significant. Compared to drug management of knee pain by FMs or RHs, that by the GIMs was distinguished by greater utilization of acetaminophen and nonacetylated salicylates (P = 0.008), lower prescribed doses of NSAIDs (P = 0.007), and, therefore, lower risk of iatrogenic gastroenteropathy (P < 0.001). In contrast, patients of RHs were more likely than those of FMs and GIMs to report that they had been instructed in use of isometric quadriceps and range-of-motion exercises (P ≦ 0.001), application of heat (P = 0.051) and cold (P < 0.001) packs, and in the principles of joint protection (P = 0.016). Neither physician specialty nor specific management practices accounted for variations in patient outcomes. Conclusion. This observational study identified specialty-related variability in key aspects of the management of knee OA in the community (i.e., frequency and dosing of NSAIDs, use of nonpharmacologic modalities) that bear strong implications for long-term safety and cost. However, changes in knee pain and function over 6 months were unrelated to variations in management practices.

Objective. To characterize, for the first time, periosteal new bone formation in a well-established canine model of accelerated osteoarthritis (OA) with features of neuropathic arthropathy. Methods. Seven dogs underwent left L4-S1 dorsal root ganglionectomy (DRG), followed 3 weeks later by transection of the anterior cruciate ligament of the ipsilateral knee (ACLT). Eight weeks thereafter, a postmortem examination was performed to assess the severity of cartilage changes of OA and the formation of new bone on the distal femur and proximal tibia in the cruciate-deficient limb. Results. As described previously, extensive fullthickness ulceration of the articular cartilage was present in the unstable knee of every dog. The femoral shaft immediately proximal to the condyles in the unstable limb was consistently wider (mean ± SD diameter 22.4 ± 2.2 mm) than that in the contralateral limb (19.9 ± 1.3 mm; P = 0.01). Xeroradiography and histologic examination of the distal femur revealed extensive formation of woven bone on the periosteal surfaces of the medial, lateral, and anterior aspects of the femoral shaft in the OA limb of every dog. These bony changes were not seen in radiographs of dogs that underwent DRG with the cruciate ligament left intact (n = 8) or of neurologically intact dogs that underwent ACLT (n = 7) and were examined 24 weeks after surgery. Conclusion. Formation of new periosteal bone on the distal femur and tibia is a feature of this model of accelerated OA that is not seen in the conventional ACLT model of OA in the neurologically intact dog. This observation suggests that interruption of sensory input from the limb may affect the regulation of osteogenesis in the mechanically unstable joint.

Objective. To evaluate a concise program of self-care education delivered by an arthritis nurse specialist as an adjunct to primary care for inner-city patients with knee osteoarthritis (OA). Methods. An attention-controlled clinical trial; 211 inner-city patients with knee OA were assigned arbitrarily to education (E) or attention-control (AC) conditions. Group E received an individualized 30-60-minute educational intervention that emphasized non-pharmacologic management of joint pain, preservation of function by problem-solving, and practice of principles of joint protection. Brief telephone contacts 1 week and 4 weeks later monitored and reinforced new self-care activities. Group AC viewed a 20-minute standardized public education presentation on arthritis and received followup telephone calls (only to encourage continued participation in the study). Outcomes included the Health Assessment Questionnaire (HAQ) Disability and Discomfort Scales, 10-cm visual analog scales measuring knee pain at rest and while walking, and the Quality of Well-Being (QWB) scale. Assessments were made at baseline and at 4-month intervals for 1 year. Results. A total of 165 subjects (78%) completed all assessments. After control for baseline status, group E had significantly lower scores for disability and resting knee pain throughout the year of postintervention followup (P < 0.05 for both). Effects were somewhat discordant. By 12 months, functional benefits had begun to wane, while the effect on resting knee pain had grown. The overall effects of education on walking knee pain, overall joint pain (by HAQ), and general health status (by QWB) were not significant. Conclusion. Self-care education for inner-city patients with knee OA, delivered as an adjunct to primary care, was found to result in notable preservation of function and control of resting knee pain. The magnitude of the observed effects compares well with those of more labor-intensive and time-consuming intervention models. However, more sustained preservation of function and consistent effects on pain may require prolonged, more proactive followup, either by the patient educator or by a trained clinical assistant dedicated to the task of supporting self-care by patients with knee OA.