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      Effect of risedronate on joint structure and symptoms of knee osteoarthritis: results of the BRISK randomized, controlled trial [ISRCTN01928173]

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          Abstract

          To determine the efficacy and safety of risedronate in patients with knee osteoarthritis (OA), the British study of risedronate in structure and symptoms of knee OA (BRISK), a 1-year prospective, double-blind, placebo-controlled study, enrolled patients (40–80 years of age) with mild to moderate OA of the medial compartment of the knee. The primary aims were to detect differences in symptoms and function. Patients were randomized to once-daily risedronate (5 mg or 15 mg) or placebo. Radiographs were taken at baseline and 1 year for assessment of joint-space width using a standardized radiographic method with fluoroscopic positioning of the joint. Pain, function, and stiffness were assessed using the Western Ontario and McMaster Universities (WOMAC) OA index. The patient global assessment and use of walking aids were measured and bone and cartilage markers were assessed. The intention-to-treat population consisted of 284 patients. Those receiving risedronate at 15 mg showed improvement of the WOMAC index, particularly of physical function, significant improvement of the patient global assessment ( P < 0.001), and decreased use of walking aids relative to patients receiving the placebo ( P = 0.009). A trend towards attenuation of joint-space narrowing was observed in the group receiving 15 mg risedronate. Eight percent ( n = 7) of patients receiving placebo and 4% ( n = 4) of patients receiving 5 mg risedronate exhibited detectable progression of disease (joint-space width ≥ 25% or ≥ 0.75 mm) versus 1% ( n = 1) of patients receiving 15 mg risedronate ( P = 0.067). Risedronate (15 mg) significantly reduced markers of cartilage degradation and bone resorption. Both doses of risedronate were well tolerated. In this study, clear trends towards improvement were observed in both joint structure and symptoms in patients with primary knee OA treated with risedronate.

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          Evidence for increased bone resorption in patients with progressive knee osteoarthritis: longitudinal results from the Chingford study.

          Several studies have suggested that increased subchondral bone turnover is a determinant of progression of osteoarthritis (OA). To test this hypothesis, the level of urinary N-terminal type I collagen telopeptides (NTx) and C-terminal type I collagen telopeptides (CTx), which are validated markers of bone resorption, was measured at 3 different time points in a subset of patients from the Chingford study. The original Chingford study population comprised 1,003 women. From this group, postmenopausal women not receiving any bone-modifying medication who had a baseline knee radiograph and a repeat radiograph 4 years later, and for whom a baseline lumbar spine bone mineral density (BMD) measurement was available, were identified and separated into 4 groups as follows: controls (n = 50), progressive OA (n = 71), nonprogressive OA (n = 36), and osteoporosis (n = 59). NTx and CTx were measured in urine samples collected at baseline, year 1, and year 2. Patient age and years since menopause were similar among groups at baseline. As expected, both body mass index (BMI) and BMD were lowest in patients with osteoporosis. Median resorption marker levels over the 3 time points were 31-87% higher in patients with either progressive OA or osteoporosis than in controls and patients with nonprogressive OA (P < 0.01, except for levels of CTx in patients with progressive OA versus nonprogressive OA). Levels of NTx and CTx did not differ significantly between women with progressive OA (defined either by the presence of osteophytes or by joint space narrowing) and those with osteoporosis or between controls and women with nonprogressive OA. Results were essentially unchanged after adjustment for age, BMI, BMD, and past use of hormone replacement therapy, or when NTx and CTx values at each time point were analyzed separately. Our data demonstrate that bone resorption is increased in patients with progressive knee OA and is not increased in those with nonprogressive knee OA. The increase in bone resorption seen in patients with progressive knee OA is similar to that observed in patients with osteoporosis. Altered bone turnover may be a diagnostic or therapeutic target in patients with progressive OA.
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            Six-month results of a double-blind, placebo-controlled trial of etanercept treatment in patients with active ankylosing spondylitis.

            There is increasing evidence that tumor necrosis factor alpha (TNFalpha) is centrally involved in the pathogenesis of ankylosing spondylitis (AS) and other spondylarthritides. This study was designed to investigate the efficacy of anti-TNFalpha therapy with etanercept, a 75-kd receptor fusion protein, in active AS. This multicenter trial had 2 phases: an initial placebo-controlled period of 6 weeks' duration and an observational phase lasting 24 weeks. Thirty patients with active AS were included. They were randomized into 2 groups, which received either etanercept (25 mg twice weekly) (n = 14) or placebo (n = 16) for 6 weeks. Then both groups were treated with etanercept. Nonsteroidal antiinflammatory drug (NSAID) treatment could be continued, but disease-modifying antirheumatic drugs (DMARDs) and steroids had to be withdrawn prior to the study. All patients received etanercept for a total of 12 weeks and were followed up for at least 24 weeks. The Bath AS Disease Activity Index (BASDAI), Bath AS Functional Index, Bath AS Metrology Index, pain level on a numeric rating scale, quality of life by the Short Form 36, and C-reactive protein (CRP) level were assessed. The primary outcome parameter was a >or=50% improvement in the BASDAI. Treatment with etanercept resulted in at least a 50% regression of disease activity in 57% of these patients at week 6, versus 6% of the placebo-treated patients (P = 0.004). After the placebo-treated patients switched to etanercept, 56% improved. The mean +/- SD BASDAI improved from 6.5 +/- 1.2 at baseline to 3.5 +/- 1.9 at week 6 in the etanercept group, with no improvement in the placebo group (P = 0.003 between groups). Similarly, pain, function, mobility, and quality of life improved with etanercept but not with placebo at week 6 (P < 0.05). Mean CRP levels decreased significantly with etanercept but not with placebo (P = 0.001). There was ongoing improvement in all parameters in both groups until week 12 and week 18, respectively (i.e., throughout the period of etanercept treatment). Disease relapses occurred a mean +/- SD of 6.2 +/- 3.0 weeks after cessation of etanercept. No severe adverse events, including major infections, were observed during the trial. This study shows that on a short-term basis (3 months), treatment with etanercept is clearly efficacious in patients with active AS who are receiving NSAID therapy but not DMARDs or steroids. After cessation of therapy, almost all patients experienced a relapse within a few weeks. Thus, it seems probable that etanercept must be administered continuously in most AS patients to achieve permanent inhibition of the inflammatory process.
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              A specific immunoassay for monitoring human bone resorption: quantitation of type I collagen cross-linked N-telopeptides in urine.

              Peptides of low molecular weight that contain pyridinoline cross-links were isolated from adolescent human urine. A fraction was selected that was enriched in the N-telopeptide-to-helix intermolecular cross-linking domain of bone type I collagen. Mouse monoclonal antibodies were generated against these urinary peptides conjugated to a carrier protein as immunogen. A high-affinity antibody was identified that specifically bound to the trivalent peptides derived from the N-telopeptide-to-helix pyridinoline cross-linking site in type I collagen of human bone. This was confirmed by the direct isolation from human bone collagen of similar fragments recognized selectively by the antibody. A sensitive inhibition ELISA was established on microtiter plates that could quantify the bone-derived peptides in human urine. The assay, which can be run directly on untreated urine, was thoroughly tested against samples from normal subjects and from patients with metabolic bone disease. For example, strong correlations with urinary hydroxyproline and total pyridinoline cross-links were found in patients with Paget's disease of bone. The method shows considerable promise as a rapid and specific index of human bone resorption rates, with greatly improved specificity and convenience over total pyridinoline analysis. Potential applications include the study of normal metabolism, the diagnosis and monitoring of bone disease, and evaluating the effectiveness of antiresorption therapies.
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                Author and article information

                Journal
                Arthritis Res Ther
                Arthritis Research & Therapy
                BioMed Central (London )
                1478-6354
                1478-6362
                2005
                24 March 2005
                : 7
                : 3
                : R625-R633
                Affiliations
                [1 ]Twin Research & Genetic Epidemiology Unit, St Thomas' Hospital, London, UK
                [2 ]Academic Unit of Musculoskeletal Disease, University of Leeds, UK
                [3 ]King's College London, School of Biomedical Sciences, London, UK
                [4 ]SYNARC, Lyon, France
                [5 ]Procter & Gamble Pharmaceuticals, Mason, OH, USA
                Article
                ar1716
                10.1186/ar1716
                1174954
                15899049
                91b9f2e7-31c8-4d4d-9f52-24189c895390
                Copyright © 2005 Spector et al.; licensee BioMed Central Ltd.

                This is an Open Access article distributed under the terms of the Creative Commons Attribution License ( http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                : 20 December 2004
                : 20 January 2005
                : 1 February 2005
                : 15 February 2005
                Categories
                Research Article

                Orthopedics
                Orthopedics

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