Comparison of the effects of once-monthly versus once-daily risedronate in postmenopausal osteoporosis: a phase II, 6-month, multicenter, randomized, double-blind, active-controlled, dose-ranging study.

BACKGROUND: Risedronate 5 mg/d is approved by the US Food and Drug Administration for the treatment and prevention of postmenopausal osteoporosis. Once-monthly dosing options might increase treatment compliance and persistence. OBJECTIVE: The aim of this study was to compare the tolerability and efficacy of 3 once-monthly risedronate dosing regimens with those of risedronate 5 mg/d. METHODS: This Phase II, 6-month, randomized, double-blind, active-controlled, dose-ranging study was conducted at 13 clinical research centers and hospitals in Croatia, Poland, Canada, and the United States between April 2004 and June 2005. Post-menopausal women aged 50 to 85 years with a lumbar spine T-score <-2.0 were randomly assigned to 1 of 4 treatment groups: risedronate 100, 150, or 200 mg/mo or 5 mg/d (active control), administered PO for 6 months. Evaluation of tolerability, the primary study objective, was based on adverse-event (AE) profiles and clinical laboratory values. Efficacy evaluation, a secondary objective, was a noninferiority comparison of the changes from baseline in bone mineral density (BMD) and bone turnover markers (BTMs). RESULTS: Of 370 patients randomized (91, 88, 88, and 103 patients in the risedronate 100-, 150-, and 200-mg/mo and 5-mg/d groups, respectively), 57% were > or =65 years of age and 99% were white; 316 patients (85.4%) completed the study. Completion rates were not significantly different across treatment groups, nor were reasons for discontinuation. Between-group differences in the incidences of treatment-emergent AEs, serious AEs, and upper gastrointestinal (GI) AEs were nonsignificant. Overall, 6 (7%), 14 (16%), 6 (7%), and 9 patients (9%) withdrew because of AEs in the 100-, 150-, and 200-mg/mo and 5 mg/d groups, respectively. GI disorders were the AEs that most frequently led to study withdrawal (5 [5.5%], 7 [8.0%], 4 [4.5%], and 6 [5.8%]). No trends were observed in the nature or frequency of other AEs causing withdrawal. All serious AEs were considered unrelated to treatment, with the exception of erosive esophagitis in 1 patient (1%) who received the 5-mg/d dose. Mean percentage increases in BMD were 2.10%, 2.99%, and 3.38% with risedronate 100, 150, and 200 mg/mo, respectively, versus 3.05% with 5 mg/d. At the 2 higher monthly doses, the changes from baseline in BMD were not significantly different from those in the 5-mg/d group. Mean BTM values were decreased significantly from baseline in all 4 treatment groups, and the changes from baseline at 6 months at the 2 higher monthly doses were not significantly different from those at 5 mg/d. CONCLUSIONS: Overall, in this study, the safety profiles of risedronate 100, 150, and 200 mg/mo were not different from that of risedronate 5 mg/d. Changes in efficacy measures in the monthly treatment groups were considered dose related and were not significantly different between the 5-mg/d group and the 150- and 200-mg/mo groups; similarity was greatest with 150 mg/mo.

Efficacy and safety of risedronate 150 mg once a month in the treatment of postmenopausal osteoporosis.

INTRODUCTION: Risedronate has been shown to be effective in the treatment of postmenopausal osteoporosis when given orally in daily or weekly doses or on 2 consecutive days per month. This randomized, double-blind, multi-center study was designed to assess the efficacy and safety of a single 150 mg risedronate once-a-month oral dose compared with the 5 mg daily regimen. METHODS: Women with postmenopausal osteoporosis were randomly assigned to receive risedronate 5 mg daily (n=642) or 150 mg once a month (followed by daily placebo) (n=650) in a double-blind fashion for 2 years. Study drug was taken on an empty stomach at least 30 min before breakfast. Bone mineral density, bone turnover markers, fractures, and adverse events were evaluated. The primary efficacy endpoint was the mean percent change from baseline in lumbar spine bone mineral density after 1 year. RESULTS: 538 patients in the daily group (83.8%) and 556 patients in the once-a-month group (85.5%) completed 1 year. The mean percent change in lumbar spine bone mineral density was 3.4% (95% confidence interval, 3.03% to 3.82%) in the daily group and 3.5% (95% confidence interval, 3.15% to 3.93%) in the once-a-month group. The difference between groups was -0.1% (95% confidence interval, -0.51% to 0.27%). The once-a-month regimen was determined to be non-inferior to the daily regimen based on prospectively defined criteria. The mean percent changes in bone mineral density at sites in the hip (total proximal femur, femoral neck, femoral trochanter) were also similar in both dose groups, as were the changes in biochemical markers of bone turnover. The incidence of adverse events, adverse events leading to withdrawal, and upper gastrointestinal tract adverse events were similar in the 2 treatment groups. Both regimens were well tolerated; the percent of patients who withdrew from treatment as a result of an adverse event was 9.5% in the daily group and 8.6% in the once-a-month group. CONCLUSIONS: Risedronate 150 mg once a month is similar in efficacy and safety to daily dosing and may provide an alternative for patients who prefer once-a-month oral dosing.

Development of musculoskeletal toxicity without clear benefit after administration of PG-116800, a matrix metalloproteinase inhibitor, to patients with knee osteoarthritis: a randomized, 12-month, double-blind, placebo-controlled study.

We performed a randomized, double-blind, placebo-controlled, multicenter, parallel-group, dose-response study of the efficacy and safety of the oral administration of PG-116800, a matrix metalloproteinase (MMP) inhibitor, in patients with mild to moderate knee osteoarthritis. The primary efficacy endpoints included the progression of joint space narrowing in the osteoarthritic knee, as measured by microfocal radiography with fluoroscopic positioning, and the reduction of symptoms (pain and stiffness) and/or the improvement of function, as measured by the Western Ontario and McMaster Universities osteoarthritis index (WOMAC). Four hundred and one patients were randomly assigned to either placebo (n = 80) or one of fourdoses of PG-116800: 25 mg (n = 81), 50 mg (n = 80), 100 mg (n = 80), or 200 mg (n = 80) taken twice daily for 12 months. During the study, the 200-mg dose was discontinued based on an increased frequency of musculoskeletal adverse effects. After 1 year of treatment, no statistically significant difference was observed between placebo and PG-116800 with regard to mean changes in minimum joint space width of the knee or to WOMAC scores. The most frequent adverse effect was arthralgia (35%). Twenty-three percent of evaluable patients had at least a 30% decrease from baseline of at least onerange-of-motion measurement of either shoulder at a follow-up visit. The percentage of patients with reduction in range of motion was significantly greater in the twohighest dose groups relative to placebo. Thirteen percent of patients, half of whom were in the 200-mg group, reported hand adverse events (oedema, palmar fibrosis, Dupuytren contracture, or persistent tendon thickness or nodules). The threemost frequent shoulder adverse events were reversible arthralgia, stiffness, and myalgia, which mostly affected the twohighest dose groups. The unfavorable risk-benefit balance of the MMP inhibitor PG-116800 in patients with knee osteoarthritis precludes further development of the compound for this indication. This study adds to the weight of evidence suggesting that side effect profiles of MMP inhibitors in general make them unsuitable for use in osteoarthritis.

Risk factors associated with the loss of cartilage volume on weight-bearing areas in knee osteoarthritis patients assessed by quantitative magnetic resonance imaging: a longitudinal study.

The objective of this study was to identify, on a symptomatic knee osteoarthritis (OA) cohort, the risk factors associated with the progression of the disease. More specifically, we investigated the correlation between knee cartilage volume loss from subregions over the span of 24 months by means of quantitative magnetic resonance imaging (qMRI) with demographic, clinical, radiological, and MRI structural changes. A cohort of 107 patients with knee OA selected from a large trial evaluating the effect of a bisphosphonate underwent x-rays and MRI of the knee at baseline and 24 months. Joint space width (JSW) and joint space narrowing (JSN) and cartilage volume loss over time in subregions of the tibial plateaus and femoral condyles were quantitated. Structural changes in the subchondral bone (hypersignal) and in the menisci (tear and extrusion) were also evaluated. The greatest cartilage volume loss was found in the medial compartment, and risk factors included female gender, JSW, meniscal lesions, and bone changes at baseline. Subregion analysis revealed that the greatest cartilage volume loss at 24 months was found in the central area of the medial tibial plateau (15%; p < 0.0001) and of the medial femoral condyle (12%; p < 0.0001). These findings were associated with the presence at baseline of meniscal extrusion, particularly severe meniscal extrusion, medial and severe meniscal tear, bone hypersignal, high body mass index (BMI), smaller JSW, increases in Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) pain and patient global scores over time, and greater JSN. Parameters predicting medial central femoral condyle cartilage volume loss at 24 months were lateral meniscal tear, SF-36 and BMI at baseline, and JSN. At the medial central tibial plateau, the parameters were severe meniscal extrusion, severe lateral meniscal tear, and bone hypersignal in the lateral compartment at baseline, and WOMAC pain change. Meniscal damage and bone changes are the features most closely associated with the greatest subregional cartilage volume loss. Interestingly, for the first time, JSN was strongly associated with cartilage loss in the central areas of plateaus and condyles. This study also further confirms the correlation between cartilage volume loss and JSN and symptomatic changes at 24 months.

Risedronate decreases biochemical markers of cartilage degradation but does not decrease symptoms or slow radiographic progression in patients with medial compartment osteoarthritis of the knee: results of the two-year multinational knee osteoarthritis structural arthritis study.

OBJECTIVE: Bisphosphonates have slowed the progression of osteoarthritis (OA) in animal models and have decreased pain in states of high bone turnover. The Knee OA Structural Arthritis (KOSTAR) study, which is the largest study to date investigating a potential structure-modifying OA drug, tested the efficacy of risedronate in providing symptom relief and slowing disease progression in patients with knee OA. METHODS: The study group comprised 2,483 patients with medial compartment knee OA and 2-4 mm of joint space width (JSW), as determined using fluoroscopically positioned, semiflexed-view radiography. Patients were enrolled in 2 parallel 2-year studies in North America and the European Union. These studies evaluated the efficacy of risedronate at dosages of 5 mg/day, 15 mg/day, 35 mg/week (in Europe), and 50 mg/week (in North America) compared with placebo in reducing signs and symptoms, as measured by the Western Ontario and McMaster Universities Osteoarthritis (WOMAC) index and patient global assessment (PGA) scores, and in slowing radiographic progression. RESULTS: A reduction of approximately 20% in signs and symptoms, as measured by WOMAC subscales and PGA scores, was observed in all groups, with no treatment effect of risedronate demonstrated. Risedronate did not significantly reduce radiographic progression as measured by decreased JSW or using a dichotomous definition of progression (joint space loss of >or=0.6 mm). Thirteen percent of patients receiving placebo demonstrated significant disease progression over 2 years. A dose-dependent reduction in the level of C-terminal crosslinking telopeptide of type II collagen, a cartilage degradation marker associated with progressive OA, was seen in patients who received risedronate. No increase in the number of adverse events was demonstrated for risedronate compared with placebo. CONCLUSION: Although risedronate (compared with placebo) did not improve signs or symptoms of OA, nor did it alter progression of OA, a reduction in the level of a marker of cartilage degradation was observed. A sustained clinically relevant improvement in signs and symptoms was observed in all treatment and placebo groups.

Comparison of fixed flexion, fluoroscopic semi-flexed and MTP radiographic methods for obtaining the minimum medial joint space width of the knee in longitudinal osteoarthritis trials.

OBJECTIVE: To compare three radiographic techniques (fluoroscopic semi-flexed [Fluoro], fixed flexion [FF], and semi-flexed metatarsophalangeal joint [MTP] views) for measuring medial joint space width (JSW) of the knee in longitudinal osteoarthritis (OA) trials and to identify the percentage of patients with detectable progression. DESIGN: Retrospective summary of the progression and variability of the change in JSW in knee OA. MATERIAL AND METHODS: Data from the placebo arms of three separate, structure modifying, knee OA trials were compared including gender, age, baseline JSW, change from baseline in JSW, duration of observation, and number and percent of patients with joint space narrowing of various degrees. Computer evaluation of the joint space at its narrowest point in the medial compartment was used in the studies. It is important to note that the narrowest joint space at baseline may not be in the same anatomic location at subsequent evaluations. No statistical tests were performed. RESULTS: The average observation times were 0.98, 0.68 and 0.82 years for the Fluoro, FF, and MTP studies, respectively. The amount of progression was different among the three studies. The Fluoro study showed the greatest magnitude of OA structural progression and the lowest variability. The Fluoro study was expected to show the greatest magnitude of structural progression since it was conducted for the longest duration. For all patients, the standard deviation of the change in JSW was 0.42, 0.63, and 0.53 mm for the Fluoro, FF, and MTP studies, respectively. The percent of patients with detectable progression was similar across studies. CONCLUSION: With these data, information was not sufficient to control for duration of observation and differences in inclusion criteria for the three study populations. Therefore, no definitive conclusions can be made regarding the degree of progression of OA over specific time intervals. However, the data indicate that all three studies contain a cohort of patients that exhibit detectable progression.

Prevalence of exposure to Salmonella spp in finishing swine marketed in Iowa.

OBJECTIVE: To describe the prevalence of antibodies against Salmonella spp in swine marketed in Iowa. ANIMALS: Swine marketed by 1,044 low-volume producers and 45 high-volume producers. PROCEDURE: Samples of diaphragm muscle collected from swine carcasses were tested by an indirect ELISA based on lipopolysaccharides from Salmonella spp, in particular Salmonella serovar Typhimurium. Prevalence of positive results for antibodies against Salmonella spp for carcasses, lots, and swine for each producer was determined. Producer-level seroprevalence was used to classify swine from producers as having negligible, low, moderate, or widespread evidence of previous or historical exposure to Salmonella spp. RESULTS: From low-volume producers, 23,609 of 25,478 (92.7%; 95% confidence interval [CI], 92.4% to 92.9%) samples had negative results, and 1,863 (7.3%; 95% CI, 7.05% to 7.56%) had antibodies against Salmonella spp. Of the 6,299 lots of swine tested, 1,191 (18.9%) contained at least 1 sample with positive results. From high-volume producers, 203 of 2,486 (8.1%; 95% CI, 6.8% to 9.3%) samples had antibodies against Salmonella spp, and 124 of 629 lots had at least 1 sample with positive results for antibodies against Salmonella spp. CONCLUSIONS AND CLINICAL RELEVANCE: Less than 10% of pigs marketed in Iowa are apparently exposed to Salmonella spp. Most swine marketed by low-volume producers had negligible or little evidence of exposure to Salmonella spp, whereas a higher percentage of swine marketed by high-volume producers had positive results when tested to detect antibodies against Salmonella spp.

Long term evaluation of disease progression through the quantitative magnetic resonance imaging of symptomatic knee osteoarthritis patients: correlation with clinical symptoms and radiographic changes.

The objective of this study was to further explore the cartilage volume changes in knee osteoarthritis (OA) over time using quantitative magnetic resonance imaging (qMRI). These were correlated with demographic, clinical, and radiological data to better identify the disease risk features. We selected 107 patients from a large trial (n = 1,232) evaluating the effect of a bisphosphonate on OA knees. The MRI acquisitions of the knee were done at baseline, 12, and 24 months. Cartilage volume from the global, medial, and lateral compartments was quantified. The changes were contrasted with clinical data and other MRI anatomical features. Knee OA cartilage volume losses were statistically significant compared to baseline values: -3.7 +/- 3.0% for global cartilage and -5.5 +/- 4.3% for the medial compartment at 12 months, and -5.7 +/- 4.4% and -8.3 +/- 6.5%, respectively, at 24 months. Three different populations were identified according to cartilage volume loss: fast (n = 11; -13.2%), intermediate (n = 48; -7.2%), and slow (n = 48; -2.3%) progressors. The predictors of fast progressors were the presence of severe meniscal extrusion (p = 0.001), severe medial tear (p = 0.005), medial and/or lateral bone edema (p = 0.03), high body mass index (p < 0.05, fast versus slow), weight (p < 0.05, fast versus slow) and age (p < 0.05 fast versus slow). The loss of cartilage volume was also slightly associated with less knee pain. No association was found with other Western Ontario McMaster Osteoarthritis Index (WOMAC) scores, joint space width, or urine biomarker levels. Meniscal damage and bone edema are closely associated with more cartilage volume loss. These data confirm the significant advantage of qMRI for reliably measuring knee structural changes at as early as 12 months, and for identifying risk factors associated with OA progression.

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

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 >or= 25% or >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.