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OBJECTIVE: To evaluate the efficacy and safety of the anti-catabolic ADAMTS-5 inhibitor S201086/GLPG1972 for the treatment of symptomatic knee osteoarthritis. DESIGN: ROCCELLA (NCT03595618) was a randomized, double-blind, placebo-controlled, dose-ranging, phase 2 trial in adults (aged 40-75 years) with knee osteoarthritis. Participants had moderate-to-severe pain in the target knee, Kellgren-Lawrence grade 2 or 3 and Osteoarthritis Research Society International joint space narrowing (grade 1 or 2). Participants were randomized 1:1:1:1 to once-daily oral S201086/GLPG1972 75, 150 or 300 mg, or placebo for 52 weeks. The primary endpoint was change from baseline to week 52 in central medial femorotibial compartment (cMFTC) cartilage thickness assessed quantitatively by magnetic resonance imaging. Secondary endpoints included change from baseline to week 52 in radiographic joint space width, Western Ontario and McMaster Universities Osteoarthritis Index total and subscores, and pain (visual analogue scale). Treatment-emergent adverse events (TEAEs) were also recorded. RESULTS: Overall, 932 participants were enrolled. No significant differences in cMFTC cartilage loss were observed between placebo and S201086/GLPG1972 therapeutic groups: placebo vs 75 mg, P = 0.165; vs 150 mg, P = 0.939; vs 300 mg, P = 0.682. No significant differences in any of the secondary endpoints were observed between placebo and treatment groups. Similar proportions of participants across treatment groups experienced TEAEs. CONCLUSIONS: Despite enrolment of participants who experienced substantial cartilage loss over 52 weeks, during the same time period, S201086/GLPG1972 did not significantly reduce rates of cartilage loss or modify symptoms in adults with symptomatic knee osteoarthritis.
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Osteoartrite do Joelho , Adulto , Humanos , Método Duplo-Cego , Articulação do Joelho/diagnóstico por imagem , Articulação do Joelho/patologia , Osteoartrite do Joelho/diagnóstico por imagem , Osteoartrite do Joelho/tratamento farmacológico , Dor/patologia , Resultado do TratamentoRESUMO
Objective: To assess onset of effect in three placebo- or nonsteroidal anti-inflammatory drug (NSAID)-controlled trials of tanezumab in patients with moderate-to-severe osteoarthritis. Methods: Post-hoc nonparametric Kaplan-Meier analyses were used to estimate median time to first improvement and to sustained improvement in Western Ontario and McMaster Universities Osteoarthritis Index domain (Pain, Physical Function, Stiffness) scores across a range of improvement thresholds (0-100%, in 5% increments). Time to first improvement was defined as the first week scores met the pre-specified threshold. Time to sustained improvement was defined as the first week scores met the pre-specified threshold and were sustained (on average) for the remainder of the treatment period. Results: Across all domains, tanezumab-treated patients had shorter median times to first improvement (at most thresholds) and reached higher levels of improvement than placebo-treated patients. No substantial differences were observed between tanezumab doses (2.5 and 5 âmg), or between tanezumab and NSAIDs. Most patients experiencing an event of first improvement went on to experience a sustained event. At low thresholds, sustained improvement occurred simultaneously with, or shortly after, first improvement. At higher thresholds, median time to sustained improvement was longer than median time to first improvement. Conclusions: Following initiation of tanezumab treatment, first improvement of osteoarthritis symptoms of 30% was evident within 2-4 weeks and sustained improvement was evident within 2-8 weeks. Time to improvement of 50% was more variable, with first and sustained events expected within 4-16 and 8-24 weeks, respectively. ClinicalTrialsgov identifiers: NCT02697773; NCT02709486; NCT02528188.
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Computed tomography and finite element modeling were used to assess bone structure at the knee as a function of time after spinal cord injury. Analyzed regions experienced degradation in stiffness, mineral density, and content. Changes were well described as an exponential decay over time, reaching a steady state 3.5 years after injury. INTRODUCTION: Spinal cord injury (SCI) is associated with bone fragility and an increased risk of fracture around the knee. The purpose of this study was to investigate bone stiffness and mineral content at the distal femur and proximal tibia, using finite element (FE) and computed tomography (CT) measures. A cross-sectional design was used to compare differences between non-ambulatory individuals with SCI as a function of time after injury (0-50 years). METHODS: CT scans of the knee were obtained from 101 individuals who experienced an SCI 30 days to 50 years prior to participation. Subject-specific FE models were used to estimate stiffness under axial compression and torsional loading, and CT data was analyzed to assess volumetric bone mineral density (vBMD) and bone mineral content (BMC) for integral, cortical, and trabecular compartments of the epiphyseal, metaphyseal, and diaphyseal regions of the distal femur and proximal tibia. RESULTS: Bone degradation was well described as an exponential decay over time (R2 = 0.33-0.83), reaching steady-state levels within 3.6 years of SCI. Individuals at a steady state had 40 to 85% lower FE-derived bone stiffness and robust decreases in CT mineral measures, compared to individuals who were recently injured (t ≤ 47 days). Temporal and spatial patterns of bone loss were similar between the distal femur and proximal tibia. CONCLUSIONS: After SCI, individuals experienced rapid and profound reductions in bone stiffness and bone mineral at the knee. FE models predicted similar reductions to axial and torsional stiffness, suggesting that both failure modes may be clinically relevant. Importantly, CT-derived measures of bone mineral alone underpredicted the impacts of SCI, compared to FE-derived measures of stiffness. TRIAL REGISTRATION: ClinicalTrials.gov (NCT01225055, NCT02325414).
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Densidade Óssea/fisiologia , Fêmur/fisiopatologia , Fraturas por Osteoporose/etiologia , Traumatismos da Medula Espinal/complicações , Tíbia/fisiopatologia , Adolescente , Adulto , Idoso , Força Compressiva , Estudos Transversais , Diáfises/fisiopatologia , Epífises/fisiopatologia , Feminino , Fêmur/diagnóstico por imagem , Análise de Elementos Finitos , Humanos , Articulação do Joelho/diagnóstico por imagem , Articulação do Joelho/fisiopatologia , Masculino , Pessoa de Meia-Idade , Fraturas por Osteoporose/diagnóstico por imagem , Fraturas por Osteoporose/fisiopatologia , Traumatismos da Medula Espinal/fisiopatologia , Tíbia/diagnóstico por imagem , Fatores de Tempo , Tomografia Computadorizada por Raios X/métodos , Adulto JovemRESUMO
OBJECTIVE: This study tested whether galcanezumab, a humanized monoclonal antibody with efficacy against migraine, was superior to placebo for the treatment of mild or moderate osteoarthritis (OA) knee pain. METHOD: In a multicenter, double-blind, placebo- and celecoxib-controlled trial, patients with moderate to severe OA pain were randomized to placebo; celecoxib 200 mg daily for 16 weeks; or galcanezumab 5, 50, 120, and 300 mg subcutaneously every 4 weeks, twice. The primary outcome was change from baseline at Week 8 in Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) pain subscore measured by 100 mm visual analog scale (VAS). The trial was considered positive if ≥1 dose of galcanezumab demonstrated ≥95% Bayesian posterior probability of superiority to placebo and ≥50% posterior probability of superiority to placebo by ≥9 mm. A planned interim analysis allowed termination of the study if posterior probability of superiority to placebo by ≥9 mm was ≤5%. Secondary endpoints included WOMAC function subscore and Patient Global Assessment (PGA) of OA. Safety and tolerability were also assessed. RESULTS: The study was terminated after interim analysis suggested inadequate efficacy. Celecoxib significantly reduced WOMAC pain subscore compared with placebo [-12.0 mm; 95% confidence interval (CI) -23 to -2 mm]. None of the galcanezumab arms demonstrated clinically meaningful improvement (range: 1.5 to -5.0 mm) or met the prespecified success criteria. No improvement in any secondary objective was observed. Galcanezumab was well tolerated by OA patients. CONCLUSIONS: This study failed to demonstrate sufficient statistical evidence that galcanezumab was efficacious for treating OA knee pain. STUDY IDENTIFICATION: NCT02192190.
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Anticorpos Monoclonais Humanizados/administração & dosagem , Peptídeo Relacionado com Gene de Calcitonina/antagonistas & inibidores , Osteoartrite do Joelho/tratamento farmacológico , Adulto , Idoso , Anticorpos Monoclonais Humanizados/farmacologia , Anticorpos Monoclonais Humanizados/uso terapêutico , Celecoxib/uso terapêutico , Relação Dose-Resposta a Droga , Método Duplo-Cego , Esquema de Medicação , Feminino , Humanos , Injeções Subcutâneas , Masculino , Pessoa de Meia-Idade , Osteoartrite do Joelho/complicações , Dor/tratamento farmacológico , Dor/etiologia , Manejo da Dor/métodos , Medição da Dor/métodos , Índice de Gravidade de Doença , Resultado do TratamentoRESUMO
OBJECTIVE: To evaluate intraarticular onabotulinumtoxinA 400 U and 200 U in reducing symptoms of knee osteoarthritis (OA) in patients with nociceptive pain. DESIGN: A multicenter, double-blind, randomized, placebo-controlled study was conducted in adults with knee OA and a painDETECT questionnaire score of ≤12 (indicating nociceptive pain). Patients were randomized to receive intraarticular onabotulinumtoxinA 400 U or 200 U or placebo (saline) in the study knee on a 1:1:2 ratio and were followed-up for 24 weeks posttreatment. The primary efficacy measure was the daily average numeric rating scale pain score for the study knee over 7 days at week 8. Secondary efficacy measures included the Western Ontario and McMaster Universities Osteoarthritis Index pain and physical function scores, the patient global impression of change score and the 7-day average worst pain score. RESULTS: Of the 176 enrolled patients, 158 completed the study. The daily average pain score was reduced by approximately two points for all treatments (week 8); the reduction was sustained throughout follow-up, with no significant between-group difference between onabotulinumtoxinA and placebo (both doses: 0.22 [95% confidence interval (CI): -0.33, 0.76]; 400 U: 0.42 [95% CI: -0.26, 1.10]; 200 U: -0.03 [95% CI: -0.70, 0.64]). Similar results were found for all secondary efficacy measures. Treatment-related adverse events occurred in 3.4% of the pooled onabotulinumtoxinA group and placebo group; none were serious. CONCLUSIONS: There were no significant differences between onabotulinumtoxinA and placebo in reducing average pain score at week 8 compared with baseline in patients with knee OA. No safety concerns were identified. CLINICALTRIALS. GOV IDENTIFIER: NCT02230956.
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Artralgia/tratamento farmacológico , Toxinas Botulínicas Tipo A/administração & dosagem , Articulação do Joelho/fisiopatologia , Osteoartrite do Joelho/tratamento farmacológico , Adulto , Idoso , Artralgia/diagnóstico , Artralgia/etiologia , Relação Dose-Resposta a Droga , Método Duplo-Cego , Feminino , Seguimentos , Humanos , Injeções Intra-Articulares , Masculino , Pessoa de Meia-Idade , Fármacos Neuromusculares/administração & dosagem , Osteoartrite do Joelho/fisiopatologia , Amplitude de Movimento Articular/fisiologia , Estudos Retrospectivos , Resultado do TratamentoRESUMO
Human neuroimaging studies and complementary animal experiments now identify the gross elements of the brain involved in the chronification of pain. We briefly review these advances in relation to somatic and orofacial persistent pain conditions. First, we emphasize the importance of reverse translational research for understanding chronic pain-that is, the power of deriving hypotheses directly from human brain imaging of clinical conditions that can be invasively and mechanistically studied in animal models. We then review recent findings demonstrating the importance of the emotional brain (i.e., the corticolimbic system) in the modulation of acute pain and in the prediction and amplification of chronic pain, contrasting this evidence with recent findings regarding the role of central sensitization in pain chronification, especially for orofacial pain. We next elaborate on the corticolimbic circuitry and underlying mechanisms that determine the transition to chronic pain. Given this knowledge, we advance a new mechanistic definition of chronic pain and discuss the clinical implications of this new definition as well as novel therapeutic potentials suggested by these advances.
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Encéfalo/diagnóstico por imagem , Encéfalo/fisiopatologia , Dor Crônica/fisiopatologia , Dor Crônica/psicologia , Emoções , Dor Facial/fisiopatologia , Dor Facial/psicologia , Sistema Límbico/fisiopatologia , Neuroimagem , Animais , Humanos , Manejo da Dor , Medição da DorRESUMO
BACKGROUND: Dual anti-platelet therapy with clopidogrel and low-dose aspirin increases the risk for gastrointestinal clinical events. Omeprazole has been shown to significantly reduce these events without compromising cardiovascular safety in patients treated with dual anti-platelet therapy. Whether or not omeprazole improves patient-reported outcomes is undetermined. AIM: To assess the impact of prophylactic omeprazole with background dual anti-platelet therapy on patient-reported symptoms of dyspepsia compared to placebo. METHODS: We analysed results of the Severity of Dyspepsia Assessment questionnaires collected in the Clopidogrel and the Optimization of Gastrointestinal Events Trial. RESULTS: Patient-reported outcome data from 3759 subjects were available for analysis. At 4 weeks, the mean scores of pain intensity and nonpain symptoms were lower in the omeprazole group (5.61 ± 0.17 vs. 6.40 ± 0.17, P = 0.001, and 10.61 ± 0.07 vs. 11.00 ± 0.07, P < 0.001 respectively). These differences were maintained at 24 weeks (5.91 ± 0.35 vs. 7.10 ± 0.37, P = 0.020 for pain intensity; 10.36 ± 0.12 vs. 10.93 ± 0.13, P = 0.001 for nonpain symptoms). After adjusting for covariates there were no statistically significant differences between the groups in the percent of patients with dyspepsia during follow-up. CONCLUSIONS: In addition to reducing the risk of gastrointestinal bleeding, statistically significant benefits with prophylactic omeprazole use on both pain and nonpain symptoms were evident at 4 weeks and sustained through 24 weeks. The clinical significance of these overall results is unclear, but greater in patients with pain at baseline.
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Aspirina/efeitos adversos , Dispepsia/tratamento farmacológico , Inibidores da Bomba de Prótons/uso terapêutico , Ticlopidina/análogos & derivados , Adulto , Idoso , Idoso de 80 Anos ou mais , Aspirina/uso terapêutico , Plaquetas , Clopidogrel , Método Duplo-Cego , Quimioterapia Combinada , Feminino , Hemorragia Gastrointestinal/induzido quimicamente , Humanos , Masculino , Pessoa de Meia-Idade , Omeprazol/uso terapêutico , Inibidores da Agregação Plaquetária/efeitos adversos , Inibidores da Agregação Plaquetária/uso terapêutico , Ticlopidina/efeitos adversos , Ticlopidina/uso terapêutico , Adulto JovemRESUMO
To highlight methodologic challenges pertinent to design, analysis, and reporting of results of randomized clinical trials in OA and offer practical suggestions to overcome these challenges. The topics covered in this paper include subject selection, randomization, approaches to handling missing data, subgroup analysis, sample size, and issues related to changing design mid-way through the study. Special attention is given to standardizing the reporting of results and economic analyses. Key findings include the importance of blinding and concealment, the distinction between superiority and non-inferiority trials, the need to minimize missing data, and appropriate analysis and interpretation of subgroup effects. Investigators may use the findings and recommendations advanced in this paper to guide design and conduct of randomized controlled trials of interventions for osteoarthritis.
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Osteoartrite/terapia , Guias de Prática Clínica como Assunto/normas , Ensaios Clínicos Controlados Aleatórios como Assunto/estatística & dados numéricos , Relatório de Pesquisa/normas , HumanosRESUMO
The goal of this document is to update the original OARSI recommendations specifically for the design, conduct, and reporting of clinical trials that target symptom or structure modification among individuals with knee osteoarthritis (OA). To develop recommendations for the design, conduct, and reporting of clinical trials for knee OA we initially drafted recommendations through an iterative process. Members of the working group included representatives from industry and academia. After the working group members reviewed a final draft, they scored the appropriateness for recommendations. After the members voted we calculated the median score among the nine members of the working group who completed the score. The document includes 25 recommendations regarding randomization, blocking and stratification, blinding, enhancing accuracy of patient-reported outcomes (PRO), selecting a study population and index knee, describing interventions, patient-reported and physical performance measures, structural outcome measures, biochemical biomarkers, and reporting recommendations. In summary, the working group identified 25 recommendations that represent the current best practices regarding clinical trials that target symptom or structure modification among individuals with knee OA. These updated recommendations incorporate novel technologies (e.g., magnetic resonance imaging (MRI)) and strategies to address the heterogeneity of knee OA.
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Ensaios Clínicos como Assunto/normas , Gerenciamento Clínico , Osteoartrite do Joelho/terapia , Guias de Prática Clínica como Assunto , Ensaios Clínicos como Assunto/métodos , HumanosRESUMO
To evaluate the efficacy and safety of anti-NGF antibody treatment in hip and knee osteoarthritis (OA), a systematic review and meta-analysis was undertaken utilizing the criteria described by the Cochrane collaboration. Both published and unpublished trials were identified for tanezumab, fulranumab and fasinumab in hip and knee OA; sponsors were contacted to provide and confirm data. Study quality was assessed by Jadad criteria; efficacy and safety data were extracted independently by two individuals and meta-analyses were performed using Revman 5.2. 13 randomized, controlled trials were identified: 10 of tanezumab, two of fulranumab and one with fasinumab. All agents demonstrated superiority in efficacy compared to placebo. The highest doses in the phase II studies of tanezumab had a standardized effect size for WOMAC pain of 0.73 (CI, 0.51, 0.95). Subsequent phase III studies of tanezumab and phase II studies of fulranumab and fasinumab reported standardized effect sizes for WOMAC pain of -0.15-0.5, with no clear distinction among dose levels. Tanezumab compared to NSAIDs and opioids showed greater efficacy with a standardized effect size for WOMAC pain of 0.23 (CI 0.17-0.29). WOMAC function and PGA results were similar to WOMAC pain. Safety, determined by odds ratios of withdrawals from studies due to adverse events (AEs), was better at the lower doses than higher doses and similar among all agents. These results demonstrate that antibodies to NGF provide efficacy in OA and that general safety at the lower doses appears similar to placebo. Additional data on both efficacy and safety of these antibodies are needed to define the optimal dose to maximize benefit to risk.
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Anticorpos Monoclonais/uso terapêutico , Fator de Crescimento Neural/antagonistas & inibidores , Osteoartrite do Quadril/tratamento farmacológico , Osteoartrite do Joelho/tratamento farmacológico , Anticorpos Monoclonais/efeitos adversos , Humanos , Resultado do TratamentoRESUMO
STUDY DESIGN: Comparison of diagnostic tests; methodological validation. OBJECTIVES: Primary: to investigate the precision and reliability of a knee bone mineral density (BMD) assessment protocol that uses an existing dual energy X-ray absorptiometry (DXA) forearm acquisition algorithm in individuals with spinal cord injury (SCI). Secondary: to correlate DXA-based knee areal BMD with volumetric BMD assessments derived from quantitative computed tomography (QCT). SETTING: Academic medical center, Chicago, IL, USA. PARTICIPANTS: a convenience sample of 12 individuals with acute SCI recruited for an observational study of bone loss and 34 individuals with chronic SCI who were screened for a longitudinal study evaluating interventions to increase BMD. MAIN OUTCOME MEASURES: Root-mean-square standard deviation (RMS-SD) and intra/inter-rater reliability of areal BMD acquired at three knee regions using an existing DXA forearm acquisition algorithm; correlation of DXA-based areal BMD with QCT-derived volumetric BMD. RESULTS: The RMS-SD of areal BMD at the distal femoral epiphysis, distal femoral metaphysis and proximal tibial epiphysis averaged 0.021, 0.012 and 0.016 g cm(-2), respectively, in acute SCI and 0.018, 0.02 and 0.016 g cm(-2) in chronic SCI. All estimates of intra/inter-rater reliability exceeded 97% and DXA-based areal BMD was significantly correlated with QCT-derived volumetric BMD at all knee regions analyzed. CONCLUSIONS: Existing DXA forearm acquisition algorithms are sufficiently precise and reliable for short-term assessments of knee BMD in individuals with SCI. Future work is necessary to quantify the reliability of this approach in longitudinal investigations and to determine its ability to predict fractures and recovery potential. SPONSORSHIP: This work was funded by the Department of Defense, grant number DOD W81XWH-10-1-0951, with partial support from Merck & Co, Inc.
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Absorciometria de Fóton , Doenças Ósseas/etiologia , Joelho/diagnóstico por imagem , Traumatismos da Medula Espinal/complicações , Traumatismos da Medula Espinal/patologia , Tomógrafos Computadorizados , Adolescente , Adulto , Doenças Ósseas/diagnóstico , Estudos de Coortes , Feminino , Antebraço/diagnóstico por imagem , Antebraço/patologia , Humanos , Masculino , Pessoa de Meia-Idade , Reprodutibilidade dos Testes , Adulto JovemRESUMO
SUMMARY: Computed tomography and finite element modeling were used to assess bone mineral and stiffness loss at the knee following acute spinal cord injury (SCI). Marked bone mineral loss was observed from a combination of trabecular and endocortical resorption. Reductions in stiffness were 2-fold greater than reductions in integral bone mineral. INTRODUCTION: SCI is associated with a rapid loss of bone mineral and an increased rate of fragility fracture. The large majority of these fractures occur around regions of the knee. Our purpose was to quantify changes to bone mineral, geometry, strength indices, and stiffness at the distal femur and proximal tibia in acute SCI. METHODS: Quantitative computed tomography (QCT) and patient-specific finite element analysis were performed on 13 subjects with acute SCI at serial time points separated by a mean of 3.5 months (range 2.6-4.8 months). Changes in bone mineral content (BMC) and volumetric bone mineral density (vBMD) were quantified for integral, trabecular, and cortical bone at epiphyseal, metaphyseal, and diaphyseal regions of the distal femur and proximal tibia. Changes in bone volumes, cross-sectional areas, strength indices and stiffness were also determined. RESULTS: Bone mineral loss was similar in magnitude at the distal femur and proximal tibia. Reductions were most pronounced at epiphyseal regions, ranging from 3.0 % to 3.6 % per month for integral BMC (p < 0.001) and from 2.8 % to 3.4 % per month (p < 0.001) for integral vBMC. Trabecular BMC decreased by 3.1-4.4 %/month (p < 0.001) and trabecular vBMD by 2.7-4.7 %/month (p < 0.001). A 3.8-5.4 %/month reduction was observed for cortical BMC (p < 0.001); the reduction in cortical vBMD was noticeably lower (0.6-0.8 %/month; p ≤ 0.01). The cortical bone loss occurred primarily through endosteal resorption, and reductions in strength indices and stiffness were some 2-fold greater than reductions in integral bone mineral. CONCLUSIONS: These findings highlight the need for therapeutic interventions targeting both trabecular and endocortical bone mineral preservation in acute SCI.
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Fêmur/fisiopatologia , Osteoporose/etiologia , Traumatismos da Medula Espinal/complicações , Tíbia/fisiopatologia , Absorciometria de Fóton , Doença Aguda , Adulto , Densidade Óssea/fisiologia , Força Compressiva/fisiologia , Diáfises/fisiopatologia , Epífises/fisiopatologia , Feminino , Fêmur/diagnóstico por imagem , Seguimentos , Humanos , Articulação do Joelho/diagnóstico por imagem , Articulação do Joelho/fisiopatologia , Masculino , Pessoa de Meia-Idade , Osteoporose/diagnóstico por imagem , Osteoporose/fisiopatologia , Traumatismos da Medula Espinal/fisiopatologia , Tíbia/diagnóstico por imagem , Tomografia Computadorizada por Raios X/métodos , Adulto JovemRESUMO
BACKGROUND: The vascular and gastrointestinal effects of non-steroidal anti-inflammatory drugs (NSAIDs), including selective COX-2 inhibitors (coxibs) and traditional non-steroidal anti-inflammatory drugs (tNSAIDs), are not well characterised, particularly in patients at increased risk of vascular disease. We aimed to provide such information through meta-analyses of randomised trials. METHODS: We undertook meta-analyses of 280 trials of NSAIDs versus placebo (124,513 participants, 68,342 person-years) and 474 trials of one NSAID versus another NSAID (229,296 participants, 165,456 person-years). The main outcomes were major vascular events (non-fatal myocardial infarction, non-fatal stroke, or vascular death); major coronary events (non-fatal myocardial infarction or coronary death); stroke; mortality; heart failure; and upper gastrointestinal complications (perforation, obstruction, or bleed). FINDINGS: Major vascular events were increased by about a third by a coxib (rate ratio [RR] 1·37, 95% CI 1·14-1·66; p=0·0009) or diclofenac (1·41, 1·12-1·78; p=0·0036), chiefly due to an increase in major coronary events (coxibs 1·76, 1·31-2·37; p=0·0001; diclofenac 1·70, 1·19-2·41; p=0·0032). Ibuprofen also significantly increased major coronary events (2·22, 1·10-4·48; p=0·0253), but not major vascular events (1·44, 0·89-2·33). Compared with placebo, of 1000 patients allocated to a coxib or diclofenac for a year, three more had major vascular events, one of which was fatal. Naproxen did not significantly increase major vascular events (0·93, 0·69-1·27). Vascular death was increased significantly by coxibs (1·58, 99% CI 1·00-2·49; p=0·0103) and diclofenac (1·65, 0·95-2·85, p=0·0187), non-significantly by ibuprofen (1·90, 0·56-6·41; p=0·17), but not by naproxen (1·08, 0·48-2·47, p=0·80). The proportional effects on major vascular events were independent of baseline characteristics, including vascular risk. Heart failure risk was roughly doubled by all NSAIDs. All NSAID regimens increased upper gastrointestinal complications (coxibs 1·81, 1·17-2·81, p=0·0070; diclofenac 1·89, 1·16-3·09, p=0·0106; ibuprofen 3·97, 2·22-7·10, p<0·0001; and naproxen 4·22, 2·71-6·56, p<0·0001). INTERPRETATION: The vascular risks of high-dose diclofenac, and possibly ibuprofen, are comparable to coxibs, whereas high-dose naproxen is associated with less vascular risk than other NSAIDs. Although NSAIDs increase vascular and gastrointestinal risks, the size of these risks can be predicted, which could help guide clinical decision making. FUNDING: UK Medical Research Council and British Heart Foundation.
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Anti-Inflamatórios não Esteroides/efeitos adversos , Gastroenteropatias/induzido quimicamente , Doenças Vasculares/induzido quimicamente , Vasos Sanguíneos/efeitos dos fármacos , Doença das Coronárias/induzido quimicamente , Inibidores de Ciclo-Oxigenase 2/efeitos adversos , Diclofenaco/efeitos adversos , Trato Gastrointestinal/efeitos dos fármacos , Humanos , Ibuprofeno/efeitos adversos , Infarto do Miocárdio/induzido quimicamente , Naproxeno/efeitos adversos , Acidente Vascular Cerebral/induzido quimicamenteRESUMO
UNLABELLED: This study used quantitative computed tomography to assess changes in bone mineral at the proximal femur after acute spinal cord injury (SCI). Individuals with acute SCI experienced a marked loss of bone mineral from a combination of trabecular and endocortical resorption. Targeted therapeutic interventions are thus warranted in this population. INTRODUCTION: SCI is associated with a rapid loss of bone mineral and an increased rate of fragility fracture. Some 10 to 20% of these fractures occur at the proximal femur. The purpose of this study was to quantify changes to bone mineral, geometry, and measures of strength at the proximal femur in acute SCI. METHODS: Quantitative computed tomography analysis was performed on 13 subjects with acute SCI at serial time points separated by a mean of 3.5 months (range, 2.6-4.8 months). Changes in bone mineral content (BMC) and volumetric bone mineral density (vBMD) were quantified for integral, trabecular, and cortical bone at the femoral neck, trochanteric, and total proximal femur regions. Changes in bone volumes, cross-sectional areas, and surrogate measures of compressive and bending strength were also determined. RESULTS: During the acute period of SCI, subjects experienced a 2.7-3.3%/month reduction in integral BMC (p < 0.001) and a 2.5-3.1 %/month reduction in integral vBMD (p < 0.001). Trabecular BMC decreased by 3.1-4.7 %/month (p < 0.001) and trabecular vBMD by 2.8-4.4 %/month (p < 0.001). A 3.9-4.0 %/month reduction was observed for cortical BMC (p < 0.001), while the reduction in cortical vBMD was noticeably lower (0.8-1.0 %/month; p ≤ 0.01). Changes in bone volume and cross-sectional area suggested that cortical bone loss occurred primarily through endosteal resorption. Declines in bone mineral were associated with a 4.9-5.9 %/month reduction in surrogate measures of strength. CONCLUSIONS: These data highlight the need for therapeutic interventions in this population that target both trabecular and endocortical bone mineral preservation.
Assuntos
Osteoporose/etiologia , Traumatismos da Medula Espinal/complicações , Absorciometria de Fóton , Doença Aguda , Adulto , Densidade Óssea/fisiologia , Feminino , Fêmur/diagnóstico por imagem , Fêmur/fisiopatologia , Colo do Fêmur/diagnóstico por imagem , Colo do Fêmur/fisiopatologia , Humanos , Masculino , Pessoa de Meia-Idade , Variações Dependentes do Observador , Osteoporose/fisiopatologia , Traumatismos da Medula Espinal/fisiopatologia , Tomografia Computadorizada por Raios X/métodos , Adulto JovemRESUMO
OBJECTIVE: This study was designed to evaluate the long-term safety and effectiveness of repeated doses of the humanized anti-nerve growth factor antibody, tanezumab, during open-label treatment of patients with OA knee pain. DESIGN: The current study (clinicaltrials.gov identifier: NCT00399490) was a multicenter, phase II, open-label, multiple-dose extension of an earlier randomized clinical trial. All patients (N=281) received infusions of tanezumab 50µg/kg on Days 1 and 56 with subsequent doses administered at 8-week intervals (up to a total of eight infusions). The primary endpoint of this study was safety. Effectiveness evaluations included overall knee pain, Western Ontario and McMaster Universities Osteoarthritis (WOMAC) index subscales, and subject global assessment (SGA) of response to therapy on 0-100 point visual analog scales. RESULTS: Repeated administration of tanezumab resulted in a low incidence of treatment-related adverse events (AEs; 7.5%). The rate of serious AEs was also low (2.8%) with none considered treatment-related. Few AEs of abnormal peripheral sensation were reported; hypoesthesia was reported by nine patients (3.2%), paresthesia by seven patients (2.5%), and hyperesthesia, peripheral neuropathy, and sensory disturbance were each reported by one patient (0.4% for each). Most AEs of abnormal peripheral sensation were rated as mild (95%) and the majority (65%) resolved before study completion. At Week 8, overall knee pain and SGA improved from baseline by a mean (± standard error) of -12.8 (±1.78) and 8.0 (±1.66), respectively. Similar improvements occurred for WOMAC subscales. CONCLUSIONS: Repeated injections of tanezumab in patients with moderate to severe knee OA provide continued pain relief and improved function with a low incidence of side effects. Additional studies to define the efficacy and duration of pain reduction and to provide a more complete assessment of long-term safety are warranted.
Assuntos
Anticorpos Monoclonais/uso terapêutico , Osteoartrite do Joelho/tratamento farmacológico , Dor/tratamento farmacológico , Receptor de Fator de Crescimento Neural/antagonistas & inibidores , Idoso , Anticorpos Monoclonais Humanizados , Feminino , Humanos , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Osteoartrite do Joelho/complicações , Osteoartrite do Joelho/fisiopatologia , Dor/etiologiaRESUMO
OBJECTIVE: To evaluate the efficacy and safety of the cyclooxygenase-inhibiting nitric-oxide donator, naproxcinod, compared with naproxen and placebo in patients with osteoarthritis (OA) of the knee. METHOD: 918 eligible patients were randomly assigned to double-blind treatment with either naproxcinod 375 mg, naproxcinod 750 mg, naproxen 500 mg or placebo, twice daily for 13 weeks. The primary objective was to show superiority of naproxcinod compared to placebo. Main efficacy criteria were assessment of pain and physical function using the Western Ontario and MacMaster Universities Osteoarthritis Index (WOMAC) and patients' overall rating of disease status (Likert scale). The main secondary objectives were to show that naproxcinod was non-inferior to naproxen 500 mg and to evaluate overall safety. RESULTS: Both doses of naproxcinod were statistically and clinically superior to placebo in relieving signs and symptoms of OA of the knee after 13 weeks of treatment, as demonstrated by all three co-primary endpoints (P< or =0.0003). The evaluation of the other secondary efficacy measures was consistent with the primary endpoint results. Naproxcinod 750 mg was non-inferior to equimolar doses of naproxen 500 mg in the Intent-to-Treat (ITT) population. 24.5% of patients discontinued prematurely, with a higher incidence in the placebo group (18.6%) than the active groups (4.3-7.1%) discontinuing due to lack of efficacy. Both doses of naproxcinod were well-tolerated, with most adverse events being mild or moderate. Compared to placebo, naproxcinod 750 mg and 375 mg showed a similar blood pressure (BP) profile in contrast to naproxen which increased BP. CONCLUSIONS: These results demonstrated the clinical efficacy and safety of naproxcinod in the management of the signs and symptoms of OA. Naproxcinod was well-tolerated, with BP effects similar to placebo and different from naproxen. Clinical Trials.gov identifier: NCT00542555.
Assuntos
Anti-Inflamatórios não Esteroides/uso terapêutico , Inibidores de Ciclo-Oxigenase/uso terapêutico , Naproxeno/análogos & derivados , Doadores de Óxido Nítrico/uso terapêutico , Osteoartrite do Joelho/tratamento farmacológico , Idoso , Anti-Inflamatórios não Esteroides/administração & dosagem , Anti-Inflamatórios não Esteroides/efeitos adversos , Pressão Sanguínea/efeitos dos fármacos , Inibidores de Ciclo-Oxigenase/administração & dosagem , Inibidores de Ciclo-Oxigenase/efeitos adversos , Relação Dose-Resposta a Droga , Esquema de Medicação , Feminino , Frequência Cardíaca/efeitos dos fármacos , Humanos , Masculino , Pessoa de Meia-Idade , Naproxeno/administração & dosagem , Naproxeno/efeitos adversos , Naproxeno/uso terapêutico , Doadores de Óxido Nítrico/administração & dosagem , Doadores de Óxido Nítrico/efeitos adversos , Osteoartrite do Joelho/complicações , Osteoartrite do Joelho/fisiopatologia , Dor/tratamento farmacológico , Dor/etiologia , Dor/fisiopatologia , Medição da Dor , Estudos Prospectivos , Índice de Gravidade de DoençaRESUMO
OBJECTIVE: Cartilage morphology displays sensitivity to change in osteoarthritis (OA) with quantitative MRI (qMRI). However, (sub)regional cartilage thickness change at 3.0 Tesla (T) has not been directly compared with radiographic progression of joint space narrowing in OA participants and non-arthritic controls. METHODS: A total of 145 women were imaged at 7 clinical centres: 86 were non-obese and asymptomatic without radiographic OA and 55 were obese with symptomatic and radiographic OA (27 Kellgren-Lawrence grade (KLG)2 and 28 KLG3). Lyon-Schuss (LS) and fixed flexion (FF) radiographs were obtained at baseline, 12 and 24 months, and coronal spoiled gradient echo MRI sequences at 3.0 T at baseline, 6, 12 and 24 months. (Sub)regional, femorotibial cartilage thickness and minimum joint space width (mJSW) in the medial femorotibial compartment were measured and the standardised response means (SRMs) determined. RESULTS: At 6 months, qMRI demonstrated a -3.7% "annualised" change in cartilage thickness (SRM -0.33) in the central medial femorotibial compartment (cMFTC) of KLG3 subjects, but no change in KLG2 subjects. The SRM for mJSW in 12-month LS/FF radiographs of KLG3 participants was -0.68/-0.13 and at 24 months was -0.62/-0.20. The SRM for cMFTC changes measured with qMRI was -0.32 (12 months; -2.0%) and -0.48 (24 months; -2.2%), respectively. CONCLUSIONS: qMRI and LS radiography detected significant change in KLG3 participants at high risk of progression, but not in KLG2 participants, and only small changes in controls. At 12 and 24 months, LS displayed greater, and FF less, sensitivity to change in KLG3 participants than qMRI.
Assuntos
Cartilagem Articular/patologia , Osteoartrite do Joelho/patologia , Adulto , Idoso , Cartilagem Articular/diagnóstico por imagem , Progressão da Doença , Feminino , Seguimentos , Humanos , Articulação do Joelho/diagnóstico por imagem , Imageamento por Ressonância Magnética/métodos , Pessoa de Meia-Idade , Osteoartrite do Joelho/diagnóstico por imagem , Radiografia , Índice de Gravidade de DoençaRESUMO
OBJECTIVE: To identify subregional differences in femorotibial cartilage morphology between healthy controls and women with different grades of radiographic knee osteoarthritis (OA). DESIGN: 158 women aged > or =40 years were studied. Weight-bearing extended anterior-posterior (AP) and Lyon schuss radiographs were obtained and the Kellgren Lawrence grade (KLG) determined. 97 women had a body mass index (BMI)< or =28, no symptoms, and were AP KLG0. 61 women had a BMI> or =30, symptoms in the target knee, and mild (KLG2=31) to moderate (KLG3=30) medial femorotibial radiographic OA in the AP views. Coronal spoiled gradient echo water excitation sequences were acquired at 3.0 Tesla. Total plate and regional measures of cartilage morphology of the weight-bearing femorotibial joint were quantified. RESULTS: KLG2 participants displayed, on average, thicker cartilage than healthy controls in the medial femorotibial compartment (particularly anterior subregion of the medial tibia (MT) and peripheral [external, internal] subregions of the medial femur), and in the lateral femur. KLG3 participants displayed significantly thinner cartilage than KLG0 participants in the medial weight-bearing femur (central subregion), in the external subregion of the MT, and in the internal subregion of the lateral tibia. These differences were generally unaffected when possible effects of demographic covariates were considered. CONCLUSIONS: The results indicate that in femorotibial OA regional cartilage thickening and thinning may occur, dependent on the (radiographic) disease status of the joint. These changes appear to display a heterogeneous spatial pattern, where certain subregions are more strongly affected than others.
Assuntos
Cartilagem Articular/patologia , Articulação do Joelho/patologia , Osteoartrite do Joelho/patologia , Adulto , Idoso , Cartilagem Articular/diagnóstico por imagem , Estudos Transversais , Feminino , Fêmur/diagnóstico por imagem , Fêmur/patologia , Humanos , Articulação do Joelho/diagnóstico por imagem , Estudos Longitudinais , Imageamento por Ressonância Magnética/métodos , Pessoa de Meia-Idade , Osteoartrite do Joelho/diagnóstico por imagem , Radiografia , Estatística como Assunto , Tíbia/diagnóstico por imagem , Tíbia/patologiaRESUMO
OBJECTIVE: To compare the safety and efficacy of acetaminophen extended-release (APAP ER) with rofecoxib for the management of pain associated with knee osteoarthritis (OA). METHODS: Four hundred and three adult patients with moderate pain secondary to knee OA were randomized to receive APAP ER 1300 mg three times daily, rofecoxib 12.5mg once daily, or rofecoxib 25mg once daily. Primary end point was change from baseline at week 4 in the Western Ontario and McMaster Universities Osteoarthritis Index pain subscale score using a visual analog scale. This 4-week study was conducted at 23 US research sites from October 1999 to October 2000. RESULTS: APAP ER was noninferior to rofecoxib 12.5mg because the upper 95% confidence limit (CL) for the least squares mean (LSM) change from baseline (35.27 mm at week 4) did not exceed the prespecified noninferiority limit of 50mm. The upper CL (57.39 mm) exceeded the noninferiority limit for APAP ER compared with rofecoxib 25mg at week 4. There were no significant differences among groups in the overall incidence of adverse events. CONCLUSION: APAP ER 3900 mg daily was noninferior to rofecoxib 12.5mg daily, but noninferiority was not established to rofecoxib 25mg daily. APAP ER was well tolerated and no safety issues were identified. Based on the results of this study, APAP ER 3900 mg daily is an alternative to nonsteroidal anti-inflammatory drugs (NSAIDs), such as rofecoxib, in treating pain associated with knee OA.
Assuntos
Acetaminofen/uso terapêutico , Analgésicos não Narcóticos/uso terapêutico , Inibidores de Ciclo-Oxigenase 2/uso terapêutico , Lactonas/uso terapêutico , Osteoartrite do Joelho/tratamento farmacológico , Sulfonas/uso terapêutico , Acetaminofen/administração & dosagem , Idoso , Analgésicos não Narcóticos/administração & dosagem , Preparações de Ação Retardada , Método Duplo-Cego , Esquema de Medicação , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Medição da Dor/métodos , Índice de Gravidade de Doença , Resultado do TratamentoRESUMO
OBJECTIVE: This study evaluated the longitudinal performance of a modified Lyon schuss (LS) knee examination in the detection of radiographic joint space narrowing (JSN) in knees with osteoarthritis (OA). The modified LS exam entails two to four iterative acquisitions with empirically adjusted angulation of the X-ray beam to achieve superimposition of the anterior and posterior margins of the medial tibial plateau (MTP), a marker of parallel radioanatomic alignment that the original LS exam achieves with fluoroscopically guided beam angulation. METHODS: Seventy-four obese women with symptomatic knee OA underwent LS and fixed-flexion (FF, caudal 10 degrees beam angulation) X-ray exams at baseline and 1 year later. For 47 subjects, beam angulation for both LS exams was guided by fluoroscopy. For 27 subjects, the modified LS exam was performed at one or both times. Modified and original LS procedures were evaluated relative to concurrent FF radiographs with respect to the inter-margin distance (IMD) at the MTP midpoint (quality and reproducibility of alignment) and sensitivity to JSN. RESULTS: Compared to FF radiographs, modified LS radiographs afforded a smaller mean IMD at baseline (0.89 vs 2.06 mm, P=0.002), more reproducible IMD (mean change=0.49 vs 0.91 mm, P=0.007) and more rapid JSN (mean=0.25 vs 0.02 mm/yr, P=0.005). These differences paralleled those observed between original LS and FF procedures with respect to baseline alignment (0.96 vs 1.94 mm, P<0.001), reproducibility of alignment (0.49 vs 1.00 mm, P<0.001) and sensitivity to JSN (0.16 vs -0.01 mm/yr, P=0.007). CONCLUSION: In clinical centers where the absence of fluoroscopy equipment precludes use of the original LS protocol, a modified procedure employing iterative, empirical adjustment of the beam angle to achieve parallel radioanatomic alignment with the MTP affords a degree of superiority over the FF protocol with respect to quality and reproducibility of positioning and sensitivity to JSN in OA knees similar to that of the original.