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See detailLongitudinal study of magnetic resonance imaging and standard X-rays to assess disease progression in osteoarthritis
Bruyère, Olivier ULg; Genant, H.; Kothari, M. et al

in Osteoarthritis and Cartilage (2007), 15(1), 98-103

Objective: To investigate, over 1-year, the relationship between X-ray and magnetic resonance imaging (MRI) findings in patients with knee osteoarthritis (OA). Methods: Sixty-two osteoarthritic patients ... [more ▼]

Objective: To investigate, over 1-year, the relationship between X-ray and magnetic resonance imaging (MRI) findings in patients with knee osteoarthritis (OA). Methods: Sixty-two osteoarthritic patients (46 women) were followed for 1 year. At baseline and after 1 year, volume and thickness of cartilage of the medial tibia, the lateral tibia and the femur were assessed by MRI. A global score from the multi-feature whole-organ MRI scoring system (WORMS) was calculated for each patient at baseline and after 1 year. This score combined individual scores for articular cartilage, osteophytes, bone marrow abnormality, subchondral cysts and bone attrition in 14 locations. It also incorporated scores for the medial and lateral menisci, anterior and posterior cruciate ligaments, medial and lateral collateral ligaments and synovial distension. Lateral and medial femorotibial joint space width (JSW) measurements, performed by digital image analysis, were assessed from fixed-flexion, postero-anterior knee radiographs. Results: One-year changes in medial femoro-tibial JSW reach 6.7 (20.5) % and changes in medial cartilage volume and thickness reach 0.4 (16.7) % and 2.1 (11.3) %, respectively. Medial femoro-tibial joint space narrowing (JSN) after 1 year, assessed by radiography, was significantly correlated with a loss of medial tibial cartilage volume (r = 0.25, P = 0.046) and medial tibial cartilage thickness (r = 0.28, P = 0.025), over the same period. We found also a significant correlation between the progression of the WORMS and radiographic medial JSN over 1 year (r = -0.35, P = 0.006). All these results remained statistically significant after adjusting for age, sex and body mass index. Conclusion: This study shows a moderate but significant association between changes in JSW and changes in cartilage volume or thickness in knee joint of osteoarthritic patients. (C) 2006 Osteoarthritis Research Society International. Published by Elsevier Ltd. All rights reserved. [less ▲]

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See detailRecommendations for the use of new methods to assess the efficacy of disease-modifying drugs in the treatment of osteoarthritis
Abadie, Eric ULg; Ethgen, Dominique ULg; Avouac, Bernard ULg et al

in Osteoarthritis and Cartilage (2004), 12(4), 263-268

Background: Recent innovations in the pharmaceutical drug discovery environment have generated new chemical entities with the potential to become disease modifying drugs for osteoarthritis (DMOAD's ... [more ▼]

Background: Recent innovations in the pharmaceutical drug discovery environment have generated new chemical entities with the potential to become disease modifying drugs for osteoarthritis (DMOAD's). Regulatory agencies acknowledge that such compounds may be granted a DMOAD indication, providing they demonstrate that they can slow down disease progression; progression would be calibrated by a surrogate for structural change, by measuring joint space narrowing (JSN) on plain X-rays with the caveat that this delayed JSN translate into a clinical benefit for the patient. Recently, new technology has been developed to detect a structural change of the OA joint earlier than conventional X-rays. Objective: The Group for the Respect of Ethics and Excellence in Science (GREES) organized a working party to assess whether these new technologies may be used as surrogates to plain x-rays for assessment of DMOADs. Methods: GREES includes academic scientists, members of regulatory authorities and representatives from the pharmaceutical industry. After an extensive search of the international literature, from 1980 to 2002, two experts meetings were organized to prepare a resource document for regulatory authorities. This document includes recommendations for a possible update of guidelines for the registration of new chemical entities in osteoarthritis. Results: Magnetic resonance imaging (MRI) is now used to measure parameters of cartilage morphology and integrity in OA patients. While some data are encouraging, correlation between short-term changes in cartilage structure observed with MRI and long-term radiographic or clinical changes are needed. Hence, the GREES suggests that MRI maybe used as an outcome in phase II studies, but that further data is needed before accepting MRI as a primary end-point in phase III clinical trials. Biochemical markers of bone and cartilage remodelling are being tested to predict OA and measure disease progression. Recently published data are promising but validation as surrogate end-points for OA disease progression requires additional study. The GREES suggests that biochemical markers remain limited to 'proof of concept' studies or as secondary end-points in phase II and III clinical trials. However, the GREES emphasizes the importance of acquiring additional information on biochemical markers in order to help better understand the mode of action of drugs to be used in OA. Regulatory agencies consider that evidence of improvement in clinical outcomes is critical for approval of DMOAD. Time to total joint replacement surgery is probably the most relevant clinical end-point for the evaluation of efficacy of a DMOAD. However, at this time, time to surgery can not be used in clinical trials because of bias by non disease-related factors like patient willingness for surgery or economic factors. At this stage, it appears that DMOAD should demonstrate a significant difference compared to placebo. Benefit should be measured by 3 co-primary end-points: JSN, pain and function. Secondary end-points should include the percentage of patients who are 'responder' (or 'failure'). The definition of a 'failure' patient would be someone with progression of JSN>0.5 mm over a period of 2-3 years or who has a significant worsening in pain and/or function, based on validated cut-off values. The definition of the clinically relevant cut-off points for pain and function must be based on data evaluating the natural history of the disease (epidemiological cohorts or placebo groups from long-term studies). These cut-offs points should reflect a high propensity, for an individual patient, to later require joint replacement. Conclusion: GREES has outlined a set of guidelines for the development of a DMOAD for OA. Although these guidelines are subject to change as new information becomes available, the information above is based on the present knowledge in the field with the addition of expert opinion. (C) 2004 OsteoArthritis Research Society International. Published by Elsevier Ltd. All rights reserved. [less ▲]

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See detailEffect of High Doses of Oral Risedronate (20 Mg/Day) on Serum Parathyroid Hormone Levels and Urinary Collagen Cross-Link Excretion in Postmenopausal Women with Spinal Osteoporosis
Zegels, Brigitte ULg; Eastell, R.; Russell, R. G. et al

in BONE (2001), 28(1), 108-12

The present study describes the biological effects of risedronate, a pyridinyl bisphosphonate, on bone and assesses the safety and tolerability of risedronate when given at high doses, with or without ... [more ▼]

The present study describes the biological effects of risedronate, a pyridinyl bisphosphonate, on bone and assesses the safety and tolerability of risedronate when given at high doses, with or without calcium, to postmenopausal women with spinal osteoporosis. This single-center descriptive, double-blind, placebo-controlled, randomized, parallel group study included 32 postmenopausal white women with at least one radiographically confirmed vertebral compression fracture. Patients were randomized to one of four different dose regimen groups: (i) R-P, risedronate 20 mg/day for 14 days, followed by placebo for 42 days; (ii) R-CP-P, risedronate 20 mg/day for 14 days, followed by elemental calcium 1000 mg/day and placebo for 14 days, then by placebo for 28 days; (iii) R-CP-R-CP, risedronate 20 mg/day for 7 days, followed by elemental calcium 1000 mg/day and placebo for 21 days, then risedronate 20 mg/day for 7 days, and finally elemental calcium 1000 mg/day and placebo for 21 days; and (iv) P, placebo for 56 days. The biological response was investigated by measuring serum calcium, parathyroid hormone (PTH), and 2 h urinary pyridinoline/creatinine (Pyr/Cr) and deoxypyridinoline/creatinine (DPyr/Cr) ratios at baseline and at days 3, 7, 14, 21, 28, 35, 42, 49, 56, and 84. Overall, there were no consistent trends observed between the active group and placebo for serum calcium. In groups R-P, R-CP-P, and R-CP-R-CP, mean serum PTH levels were elevated above baseline values for the entire 56 day treatment period and remained elevated, although to a lesser extent, at the day 84 follow-up visit. The effect of calcium supplementation on PTH was variable. Urinary Pyr/Cr and DPyr/Cr ratios were decreased from baseline over the entire study period in all groups receiving risedronate. The maximum observed percent decreases from baseline for Pyr/Cr and DPyr/Cr were -46.9% and -58.8%, respectively, at day 49 in the R-CP-R-CP group. In conclusion, risedronate given orally at a dose of 20 mg/day, continuously for 7 or 14 days, resulted in the expected biological response in osteoporotic women. The time course of changes in PTH levels following cessation of dosing was unaffected by calcium supplementation. There was no evidence of a PTH-mediated rebound in bone resorption following cessation of therapy. Furthermore, based on collagen cross-link data, patients did not show an excessive reduction in bone turnover. [less ▲]

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See detailEfficacy and Tolerability of a New Formulation of Oral Tiludronate (Tablet) in the Treatment of Paget's Disease of Bone
Reginster, Jean-Yves ULg; Treves, R.; Renier, J. C. et al

in Journal of Bone and Mineral Research : The Official Journal of the American Society for Bone and Mineral Research (1994), 9(5), 615-9

We sought to assess efficacy and safety of a new oral formulation (tablet) of tiludronate in Paget's disease of bone. We studied 128 patients with Paget's disease in an open-label uncontrolled trial ... [more ▼]

We sought to assess efficacy and safety of a new oral formulation (tablet) of tiludronate in Paget's disease of bone. We studied 128 patients with Paget's disease in an open-label uncontrolled trial. Patients received a daily dose of 400 mg oral tiludronate (two tablets). Treatment was for 6 months. Serum alkaline phosphatase activity (SAP) and fasting urinary excretion of hydroxyproline/creatine (OH/Cr) were measured every 3 months, as were biochemical parameters reflecting renal, hepatic, and hematologic functions. Analgesic efficacy was self-evaluated from a visual analog scale (VAS). Statistical analysis revealed a significant reduction from baseline in SAP and OH/Cr levels, as well as VAS scores. In the whole population with evaluation under treatment, there was a reduction in initial SAP activity after 3 months (47.2 +/- 2.2%, mean +/- SEM) and 6 months (58.3 +/- 2.3%). In the population with SAP levels above twice the upper limit at inclusion and with evaluation at month 3 and month 6 (n = 96), the reduction in SAP levels was 49.3 +/- 2.4% after 3 months and of 59.5 +/- 2.6% after 6 months (ANOVA time effect, p = 0.0001). Aside from mild gastrointestinal disturbances, as experienced with other oral bisphosphonates, clinical tolerance was good. Exhaustive biochemical investigation failed to reveal significant toxicity of tiludronate tablets at the dose of 400 mg/day. The dose of 400 mg daily of this new formulation appears to be a satisfactory tiludronate regimen for the treatment of Paget's disease of bone. [less ▲]

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See detailPaget's Disease of Bone Treated with a Five Day Course of Oral Tiludronate
Reginster, Jean-Yves ULg; Lecart, Marie-Paule ULg; Deroisy, Rita ULg et al

in Annals of the Rheumatic Diseases (1993), 52(1), 54-7

Chloro-4-phenyl thiomethylene bisphosphonate (tiludronate) is a new drug which can be used as an inhibitor of bone resorption. As it remains in bone for a long time, and as mineralisation defects have ... [more ▼]

Chloro-4-phenyl thiomethylene bisphosphonate (tiludronate) is a new drug which can be used as an inhibitor of bone resorption. As it remains in bone for a long time, and as mineralisation defects have only been seen at doses much higher than those required to decrease osteoclastic activity, it could be given at high doses over a short period of time. Eighteen patients with Paget's disease of bone were randomly allocated to three therapeutic groups receiving respectively 600, 800, and 1200 mg/day tiludronate for five days. Serum alkaline phosphatase activity and the urinary hydroxyproline/creatinine ratio were quickly and drastically reduced in all three groups. A significant reduction of serum alkaline phosphatases and the hydroxyproline/creatinine ratio was still present six months after the five day therapeutic course, reflecting a sustained activity of tiludronate even after stopping treatment. Dose dependent short and long term reductions of bone turnover rate were observed. Biochemical assessment of haematological, renal, or hepatic tolerance did not show any toxicity of tiludronate. Fifty per cent of patients treated by a dose of 1200 mg/day reported gastrointestinal disturbances, however, making this dosage unsuitable for clinical practice. [less ▲]

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See detailEvaluation of the Efficacy and Safety of Oral Tiludronate in Paget's Disease of Bone. A Double-Blind, Multiple-Dosage, Placebo-Controlled Study
Reginster, Jean-Yves ULg; Colson, F.; Morlock, G. et al

in Arthritis & Rheumatism : Arthritis Care & Research (1992), 35(8), 967-74

OBJECTIVE. To assess the optimal dosage of oral tiludronate in Paget's disease of bone. METHODS. We studied 149 patients with Paget's disease, in a double-blind, randomized, placebo-controlled trial ... [more ▼]

OBJECTIVE. To assess the optimal dosage of oral tiludronate in Paget's disease of bone. METHODS. We studied 149 patients with Paget's disease, in a double-blind, randomized, placebo-controlled trial. Patients were randomly assigned to 1 of 5 therapeutic groups: a daily dose of 100 mg, 200 mg, 400 mg, or 800 mg of oral tiludronate, or a placebo. Treatment was for 3 months, followed by 3 months of placebo-controlled followup. Serum alkaline phosphatase activity (SAP) and fasting urinary excretion of hydroxyproline/creatinine (OH/Cr) were measured monthly, as were biochemical parameters reflecting renal, hepatic, and hematologic functions. Analgesic efficacy was self-evaluated from a visual analog scale and a global pain index. RESULTS. Statistical analysis revealed that beginning at a dosage of 200 mg/day, there was a direct dose-dependent effect on the reduction of SAP and OH/Cr levels. Reduction of SAP levels was clinically significant at a dosage of 400 mg (44.9 +/- 4.2% reduction at 90 days and 49.2 +/- 4.5% at 180 days, mean +/- SEM) and at 800 mg (53.4 +/- 5% at 90 days and 59.3 +/- 4.6% at 180 days). There was a significant reduction in pain in all groups, including the group taking placebo. In only those taking 800 mg/day of tiludronate was there a significant frequency of complete resolution of pain (versus placebo). Aside from mild gastrointestinal disturbances, as experienced with other oral bisphosphonates, clinical tolerance of all 5 regimens was good. Exhaustive biochemical investigations failed to reveal significant toxicity of tiludronate up to the 800-mg daily dose investigated. CONCLUSION. Because of its significantly better antiresorptive effects and greater analgesic properties (compared with lower dosages), combined with the excellent clinical and biochemical tolerance, the 800-mg daily dose of tiludronate appears to be optimal for the treatment of Paget's disease of bone. [less ▲]

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See detailPrevention of Postmenopausal Bone Loss by Tiludronate
Reginster, Jean-Yves ULg; Lecart, M. P.; Deroisy, Rita ULg et al

in Lancet (1989), 2(8678-8679, Dec 23-30), 1469-71

76 healthy women, who had been menopausal for less than 96 months and who had never received any form of treatment to prevent bone loss, were entered into a randomised double-blind study. For the first 6 ... [more ▼]

76 healthy women, who had been menopausal for less than 96 months and who had never received any form of treatment to prevent bone loss, were entered into a randomised double-blind study. For the first 6 months, half the patients received tiludronate 100 mg daily, while the others received placebo. During the second 6 months, all patients received placebo. Bone mineral density of the lumbar spine decreased significantly by 2.1% (SE 0.8%) in the placebo group and did not significantly change in the tiludronate group (+1.33 [0.8]%). The difference in response between the groups was significant, as were the differences between values for corrected urinary hydroxyproline and calcium. Treatment with tiludronate was not followed by increased secretion of parathyroid hormone. A 6 month course of oral tiludronate may counteract postmenopausal bone loss for at least a year by decreasing bone resorption. [less ▲]

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