Faculty Bibliography

OBJECTIVE: To evaluate the risk factors for early radiographic changes of knee osteoarthritis. METHODS: 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

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=4 g/day (n=20), respectively. After a five half-lives washout of their pain medication, the OA knee with the higher pain score >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

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

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

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.)

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 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