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Objective To evaluate the safety and tolerability of multiple intravenous (IV) doses of sifalimumab in adults with moderate-to-severe systemic lupus erythematosus (SLE). Methods In this multicenter, double-blind, placebo-controlled, sequential dose-escalation study, patients were randomized 3:1 to receive IV sifalimumab (0.3, 1.0, 3.0, or 10.0 mg/kg) or placebo every 2 weeks to week 26, then followed up for 24 weeks. Safety assessment included recording of treatment-emergent adverse events (AEs) and serious AEs. Pharmacokinetics, immunogenicity, and pharmacodynamics were evaluated, and disease activity was assessed. Results Of 161 patients, 121 received sifalimumab (26 received 0.3 mg/kg; 25, 1.0 mg/kg; 27, 3.0 mg/kg; and 43, 10 mg/kg) and 40 received placebo. Patients were predominantly female (95.7%). At baseline, patients had moderate-to-severe disease activity (mean SLE Disease Activity Index score 11.0), and most (75.2%) had a high type I interferon (IFN) gene signature. In the sifalimumab group versus the placebo group, the incidence of ≥1 treatment-emergent AE was 92.6% versus 95.0%, ≥1 serious AE was 22.3% versus 27.5%, and ≥1 infection was 67.8% versus 62.5%; discontinuations due to AEs occurred in 9.1% versus 7.5%, and death occurred in 3.3% (n = 4) versus 2.5% (n = 1). Serum sifalimumab concentrations increased in a linear and dose-proportional manner. Inhibition of the type I IFN gene signature was sustained during treatment in patients with a high baseline signature. No statistically significant differences in clinical activity (SLEDAI and British Isles Lupus Assessment Group score) between sifalimumab and placebo were observed. However, when adjusted for excess burst steroids, SLEDAI change from baseline showed a positive trend over time. A trend toward normal complement C3 or C4 level at week 26 was seen in the sifalimumab groups compared with baseline. Conclusion The observed safety/tolerability and clinical activity profile of sifalimumab support its continued clinical development for SLE.

Objective: To investigate the relation between biochemical markers of bone, cartilage, and synovial remodelling and the structural progression of knee osteoarthritis. Methods: 62 patients of both sexes with knee osteoarthritis were followed prospectively for one year. From magnetic resonance imaging (MRI), done at baseline and after one year, the volume and thickness of cartilage of the femur, the medial tibia, and the lateral tibia were assessed. A whole organ magnetic resonance imaging score (WORMS) of the knee was calculated for each patient at baseline and at the one year visits. This score consists in a validated, semiquantitative scoring system for whole organ assessment of the knee in osteoarthritis using MRI. Biochemical markers (serum hyaluronic acid, osteocalcin, cartilage glycoprotein 39 (YKL-40), cartilage oligomeric matrix protein (COMP), and C-telopeptide of type I collagen (CTX-I), and urine C-telopeptide of type II collagen (CTX-II)) were measured at baseline and after three months. Results: Baseline markers were not correlated with one year changes observed in cartilage volume and thickness. However, an increase in CTX-II after three months was significantly correlated with a one year decrease in mean thickness of medial tibial and lateral tibial cartilage. Patients in the highest quartile of three month changes in CTX-II experienced a mean loss of 0.07 (0.08) mm of their medial thickness, compared with a mean increase of 0.05 (0.19) mm for patients in the lowest quartile (p = 0.04) Multiple regression analysis showed that high baseline levels of hyaluronic acid are predictive of a worsening in WORMS (p = 0.004). Conclusions: These results suggest that a single measurement of serum hyaluronic acid or short term changes in urine CTX-II could identify patients at greatest risk of progression of osteoarthritis.

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.

Our objective was to investigate the efficacy and tolerability of risedronate in postmenopausal women with low bone mass. Women with a mean lumbar spine T-score of -2 or less (n = 543) received 24 months of placebo or risedronate (2.5 or 5 mg/day). All received calcium (1 g/day). The principal outcome measures were bone mineral density (BMD) at the lumbar spine, femoral neck, and femoral trochanter. At 24 months, lumbar spine BMD increased from baseline by 4% with 5 mg risedronate and 1.4% in the 2.5-mg group, compared with no change with placebo. Efficacy was similar in women who were less than 5 yr and more than 5 yr postmenopausal. At 24 months, risedronate (5 mg) had also increased BMD at the femoral neck and trochanter, whereas BMD decreased in the placebo group. BMD increases were seen at all three sites with risedronate (5 mg) after only 6 months of therapy. Risedronate was well tolerated; upper gastrointestinal adverse events were similar to placebo. We conclude that risedronate (5 mg) increases BMD rapidly and effectively and is well tolerated in postmenopausal women with low bone mass, regardless of time since menopause.

Adherence to anti-osteoporosis medications is currently low and is associated with poor anti-fracture efficacy. This manuscript reviews the potential design of clinical studies that aim to demonstrate improved adherence, with new chemical entities to be used in the management of osteoporosis.Several medications have been unequivocally shown to decrease fracture rates in clinical trials. However, in real life settings, long-term persistence and compliance to anti-osteoporosis medication is poor, hence decreasing the clinical benefits for patients.An extensive search of Medline from 1985 to 2006 retrieved all trials including the keywords osteoporosis, compliance, persistence or adherence followed by a critical appraisal of the data obtained through a consensus expert meeting.The impact of non-adherence on the clinical development of interventions is reviewed, so that clinicians, regulatory agencies and reimbursement agencies might be better informed of the problem, in order to stimulate the necessary research to document adherence.Adherence to therapy is a major problem in the treatment of osteoporosis. Both patients and medication factors are involved. Adherence studies are an important aspect of outcomes studies, but study methodologies are not well developed at the moment and should be improved. Performing adherence studies will be stimulated when registration authorities accept the result of these studies and include the relevant information in Sect. 5.1 of the summary of product characteristics. Reimbursement authorities might also consider such studies as important information for decisions on reimbursement.

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.

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.

To assess the optimal dosage of oral tiludronate in Paget's disease of bone.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.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.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.

Summary 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 femoro-tibial 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.