A 2-year randomised, double-blind, placebo-controlled, multicentre study of oral selective iNOS inhibitor, cindunistat (SD-6010), in patients with symptomatic osteoarthritis of the knee.

OBJECTIVE: To determine if inhibition of inducible nitric oxide synthase (iNOS) with cindunistat hydrochloride maleate slows progression of osteoarthritis (OA) METHODS: This 2-year, multinational, double-blind, placebo-controlled trial enrolled patients with symptomatic knee OA (Kellgren and Lawrence Grade (KLG) 2 or 3). Standard OA therapies were permitted throughout. Patients were randomly assigned to cindunistat (50 or 200 mg/day) or placebo. Randomisation was stratified by KLG. Radiographs to assess joint space narrowing (JSN) were acquired using the modified Lyon-schuss protocol at baseline, week 48 and 96. RESULTS: Of 1457 patients (50 mg/day, n=485; 200 mg/day, n=486; placebo, n=486), 1048 (71.9%) completed the study. Patients were predominantly women; 56% had KLG3. The primary analysis did not demonstrate superiority of cindunistat versus placebo for rate of change in JSN. In KLG2 patients, JSN after 48 weeks was lower with cindunistat 50 mg/day versus placebo (p=0.032). Least-squares mean±SE JSN with cindunistat 50 mg/day ( -0.048±0.028 mm) and 200 mg/day (-0.062±0.028 mm) were 59.9% (95% CI 6.8% to 106.9%) and 48.7% (95% CI -8.4% to 93.9%) of placebo, improvement was not maintained at 96 weeks. No improvement was observed for KLG3 patients at either time-point. Cindunistat did not improve joint pain or function, but was generally well tolerated. CONCLUSIONS: Cindunistat (50 or 200 mg/day) did not slow the rate of JSN versus placebo. After 48-weeks, KLG2 patients showed less JSN; however, the improvement was not sustained at 96-weeks. iNOS inhibition did not slow OA progression in KLG3 patients. CLINICAL TRIAL LISTING: NCT00565812.

Malalignment and subchondral bone turnover in contralateral knees of overweight/obese women with unilateral osteoarthritis: implications for bilateral disease.

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. (99m)Tc-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.

The Relationship between Meniscal Tears and Meniscal Position.

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.

Etiopathogenesis of osteoarthritis.

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.

Etiopathogenesis of osteoarthritis.

In this article, the authors posit that, because osteoarthritis (OA) involves all of the tissues of the synovial joint, the emphasis on the loss of cartilage, in particular, is misguided. In contrast, the authors view OA as a process that is attempting to contain a mechanical problem in the joint. They argue that OA is best defined as failed repair of damage that has been caused by excessive mechanical stress on joint tissues. Because the body's innate mechanisms for repairing the damaged tissues cannot be effective in the face of the overwhelming mechanical abnormality, they cannot solve the problem of OA.

Urinary TIINE concentrations in a randomized controlled trial of doxycycline in knee osteoarthritis: implications of the lack of association between TIINE levels and joint space narrowing.

OBJECTIVE: To use the collagenase cleavage site neoepitope, TIINE, a marker of type II collagen breakdown in cartilage, to analyze the mechanism underlying the slowing of joint space narrowing (JSN) in patients with knee osteoarthritis treated with doxycycline. METHODS: The creatinine-adjusted urinary TIINE concentration was determined at baseline and every 6 months thereafter in a subset of patients who completed a 30-month randomized, placebo-controlled study of the effect of doxycycline on radiographic progression of JSN. The subset was selected a priori to permit comparison of 60 radiographic progressors with 60 radiographic nonprogressors. JSN was determined in highly standardized, semiflexed anteroposterior images. RESULTS: The coefficient of variation of TIINE concentrations over the 5 study visits was 30%. At the 5 semiannual followup visits, the mean TIINE concentration for doxycycline-treated patients was higher than that for the placebo group. In both treatment groups, the correlation between TIINE levels and JSN in the index knee was weak (for doxycycline, r(2) = 0.06, P = 0.08; for placebo, r(2) = 0.06, P = 0.05). CONCLUSION: High variability from visit to visit limits the sensitivity of the TIINE assay for detecting changes in individual patients and restricts its utility to group comparisons. The increase in TIINE concentration with treatment indicates that inhibition of collagenase-mediated breakdown of type II collagen in articular cartilage is unlikely to have accounted for the observed reduction of JSN in the index knees of patients in the doxycycline treatment group.

Risk factors for early radiographic changes of tibiofemoral osteoarthritis.

OBJECTIVE: To evaluate the risk factors for early radiographic changes of knee osteoarthritis. SUBJECTS: (n = 114) with unilateral or bilateral grade 0-1 knee osteoarthritis underwent x ray examination of the knees (semiflexed anteroposterior view) and assessment with the Western Ontario and McMaster Universities (WOMAC) Osteoarthritis Index at baseline and 30 months later. Severity of joint space narrowing (JSN) and osteophytosis were graded in randomly ordered serial radiographs by two readers, blinded to the sequence of the films, using standard pictorial atlases. RESULTS: The odds of an initial appearance of radiographic features of knee osteoarthritis at month 30 were more than threefold greater in African Americans than in whites (osteophytosis: odds ratio (OR) 3.30, 95% confidence interval (CI) 1.04 to 10.54; JSN: OR 3.49, 95% CI 1.16 to 10.68). In addition, the appearance of osteophytosis was positively related to baseline stiffness (OR 1.91/2.1 points on the 2-10 WOMAC scale, 95% CI 1.29 to 2.82). CONCLUSIONS: The distinction between incident and established, but early, radiographic knee osteoarthritis is difficult because of the limits to which all possible evidence of the disease can be ruled out in a conventional baseline knee radiograph. Nonetheless, our finding that African Americans were at greater risk of early osteophytosis and JSN than other subjects differs from the results of our previous analysis of risk factors for progressive knee osteoarthritis in the same subjects. The development of osteophytes also was associated with joint stiffness. Future investigations should focus on the systemic and local influences that these ostensible risk factors represent.

Effects of strength training on the incidence and progression of knee osteoarthritis.

OBJECTIVE: Quadriceps weakness is a risk factor for incident knee osteoarthritis (OA). We describe a randomized controlled trial of effects of lower-extremity strength training on incidence and progression of knee OA. METHODS: A total of 221 older adults (mean age 69 years) were stratified by sex, presence of radiographic knee OA, and severity of knee pain, and were randomized to strength training (ST) or range-of-motion (ROM) exercises. Subjects exercised 3 times per week (twice at a fitness facility, once at home) for 12 weeks, followed by transition to home-based exercise after 12 months. Assessments of isokinetic lower-extremity strength and highly standardized knee radiographs were obtained at baseline and 30 months. RESULTS: Subjects in both groups lost lower-extremity strength over 30 months; however, the rate of loss was slower with ST than with ROM. Compared with ROM, ST decreased the mean rate of joint space narrowing (JSN) in osteoarthritic knees by 26% (P = not significant). However, the difference between ST and ROM groups with respect to frequency of knee OA progression in JSN consensus ratings was marginally significant (18% versus 28%; P = 0.094). In knees that were radiographically normal at baseline, JSN >0.50 mm was more common in ST than in ROM (34% versus 19%; P = 0.038). Incident JSN was unrelated to exercise adherence or changes in quadriceps strength or knee pain. CONCLUSION: The ST group retained more strength and exhibited less frequent progressive JSN over 30 months than the ROM group. The increase in incident JSN >0.50 mm in ST is unexplained and requires confirmation.

Associations between joint space narrowing and molecular markers of collagen and proteoglycan turnover in patients with knee osteoarthritis.

OBJECTIVE: We examined whether plasma concentrations of biomarkers of the collagenase cleavage of type II collagen (C2C), types I and II collagens (C1,2C), type II collagen synthesis (CPII), proteoglycan aggrecan turnover (CS846), and the ratio C2C:CPII would distinguish subjects with progressive radiographic 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 clinical 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. Plasma samples were obtained every 6 months for determination of C2C, CPII, CS846, and C1,2C. RESULTS: None of the biomarkers was a significant predictor of progression of JSN. Over the interval from baseline to 16 months, the mean and the maximum of the intercurrent CS846 values were significantly associated with JSN (i.e., 0.12-0.14 mm of JSN per SD decrease in mean or maximum CS846; p < 0.01). The mean of serial CS846 levels was related to JSN also during the interval between months 16 and 30. CONCLUSION: Markers of type II collagen synthesis/degradation and of proteoglycan aggrecan turnover were not predictive of JSN in knee OA in this pilot study. However, serial concentrations of proteoglycan aggrecan epitope CS846 were associated with JSN during both the intervals studied.

Acetaminophen, like conventional NSAIDs, may reduce synovitis in osteoarthritic knees.

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 or=15 of 25 on the Western Ontario and McMaster Universities' pain scale underwent l.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 3 min 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 x 10(-12)) that was comparable with that seen after the reinstitution of NSAID (49%, P=6.0 x 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.

Experience with a placebo-controlled randomized clinical trial of a disease-modifying drug for osteoarthritis: the doxycycline trial.

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.

Glucosamine, chondroitin sulfate, and the two in combination for painful knee osteoarthritis.

BACKGROUND: Glucosamine and chondroitin sulfate are used to treat osteoarthritis. The multicenter, double-blind, placebo- and celecoxib-controlled Glucosamine/chondroitin Arthritis Intervention Trial (GAIT) evaluated their efficacy and safety as a treatment for knee pain from osteoarthritis. METHODS: We randomly assigned 1583 patients with symptomatic knee osteoarthritis to receive 1500 mg of glucosamine daily, 1200 mg of chondroitin sulfate daily, both glucosamine and chondroitin sulfate, 200 mg of celecoxib daily, or placebo for 24 weeks. Up to 4000 mg of acetaminophen daily was allowed as rescue analgesia. Assignment was stratified according to the severity of knee pain (mild [N=1229] vs. moderate to severe [N=354]). The primary outcome measure was a 20 percent decrease in knee pain from baseline to week 24. RESULTS: The mean age of the patients was 59 years, and 64 percent were women. Overall, glucosamine and chondroitin sulfate were not significantly better than placebo in reducing knee pain by 20 percent. As compared with the rate of response to placebo (60.1 percent), the rate of response to glucosamine was 3.9 percentage points higher (P=0.30), the rate of response to chondroitin sulfate was 5.3 percentage points higher (P=0.17), and the rate of response to combined treatment was 6.5 percentage points higher (P=0.09). The rate of response in the celecoxib control group was 10.0 percentage points higher than that in the placebo control group (P=0.008). For patients with moderate-to-severe pain at baseline, the rate of response was significantly higher with combined therapy than with placebo (79.2 percent vs. 54.3 percent, P=0.002). Adverse events were mild, infrequent, and evenly distributed among the groups. CONCLUSIONS: Glucosamine and chondroitin sulfate alone or in combination did not reduce pain effectively in the overall group of patients with osteoarthritis of the knee. Exploratory analyses suggest that the combination of glucosamine and chondroitin sulfate may be effective in the subgroup of patients with moderate-to-severe knee pain. (ClinicalTrials.gov number, NCT00032890.).

Use of the plasma stromelysin (matrix metalloproteinase 3) concentration to predict joint space narrowing in knee osteoarthritis.

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.