Efficacy and Safety of Tanezumab on Osteoarthritis Knee and Hip Pains: A Meta-Analysis of Randomized Controlled Trials.

Objectives: To evaluate the efficacy and safety of tanezumab for management of osteoarthritis (OA) knee and hip pain. Methods: Articles about management of OA knee and hip pains by tanezumab were systematically searched in PubMed, EBSCO, EMBASE, ScienceDirect, Web of Science, OVID, and Cochrane Library from the available date of inception until January 2016. Randomized controlled trials (RCTs) comparing the efficacy and safety of tanezumab with placebo/active comparator for management of OA knee and hip pains were included, and those with confounding conditions were excluded. Study quality was assessed using the Jadad five-point score. Finally, a meta-analysis of all eligible RCTs was performed on Review Manager 5.3 and STATA 12.0. Results: Nine studies with 10 RCTs that enrolled 7,665 patients were included. The reductions in pain intensity are significantly different between tanezumab-treated patients and placebo-treated patients (5,879 patients, mean difference [MD] = -0.98, 95% confidence interval [CI] = -1.18- -0.79). Both functional improvement (6,078 patients, MD = -1.10, 95% CI = -1.28- -0.92) and Patient's Global Assessment (PGA; 5,366 patients, MD = -0.27, 95% CI = -0.34- -0.20) are significantly different. There are significantly more discontinued patients due to adverse events (AEs) after treatment with tanezumab (6,537 patients, risk ratio = 1.62, 95% CI = 1.29-2.03). However, differences in serious AEs are not significant. Moreover, tanezumab-treated patients suffer from significantly more paraesthesia, arthralgia, hypoaesthesia, and peripheral edema. Conclusions: Tanezumab vs placebo provides superior pain relief and improvement in physical function and PGA in knee and hip osteoarthritis patients and is generally well tolerated with acceptable AEs. Low-dose tanezumab (10 or 25 µg/kg and 2.5 mg) provides similar effectiveness in reducing pain and improving function and is associated with fewer AEs. The long-term safety of tanezumab on osteoarthritis knee and hip pain needs further investigation.

Phenotypic Spectrum and Molecular Basis in a Chinese Cohort of Osteogenesis Imperfecta With Mutations in Type I Collagen.

Osteogenesis imperfecta (OI) is a rare inherited connective tissue dysplasia characterized with skeletal fragility, recurrent fractures and bone deformity, predominantly caused by mutations in the genes COL1A1 or COL1A2 that encode the chains of type I collagen. In the present study, clinical manifestations and genetic variants were analysed from 187 Chinese OI patients, majority of whom are of southern Chinese origin. By targeted sequencing, 63 and 58 OI patients were found carrying mutations in COL1A1 and COL1A2 respectively, including 8 novel COL1A1 and 7 novel COL1A2 variants. We validated a novel splicing mutation in COL1A1. A diverse mutational and phenotypic spectrum was observed, coupling with the heterogeneity observed in the transcriptomic data derived from osteoblasts of six patients from our cohort. Missense mutations were significantly associated (χ2 p = 0.0096) with a cluster of patients with more severe clinical phenotypes. Additionally, the severity of OI was more correlated with the quality of bones, rather than the bone mineral density. Bone density is most responsive to bisphosphonate treatment during the juvenile stage (10-15 years old). In contrast, height is not responsive to bisphosphonate treatment. Our findings expand the mutational spectrum of type I collagen genes and the genotype-phenotype correlation in Chinese OI patients. The observation of effective bisphosphonate treatment in an age-specific manner may help to improve OI patient management.

Patient-reported outcomes in a Chinese cohort of osteogenesis imperfecta unveil psycho-physical stratifications associated with clinical manifestations.

BACKGROUND: Osteogenesis imperfecta (OI) is a rare congenital disorder of the skeletal system, inflicting debilitating physical and psychological distress on patients and caregivers. Over the decades, much effort has been channeled towards understanding molecular mechanisms and developing new treatments. It has recently become more apparent that patient-reported outcome measurements (PROM) during treatment, healing and rehabilitation are helpful in facilitating smoother communication, refining intervention strategies and achieving higher quality of life. To date, systematic analyses of PROM in OI patients remain scarce. RESULTS: Here, utilizing a PROM Information System, we report a cross-sectional and longitudinal study in a southern Chinese cohort of 90 OI patients, covering both the child and adult age-groups. In the child group where both self and parental surveys were obtained, we identified two clusters of comparable sizes showing different outlooks in physical mobility and emotional experiences. One cluster (Cluster 1) is more negative about themselves than the other (Cluster 2). A concordance of 84.7% between self and parental assessments was recorded, suggesting the stability and validity of PROM-based stratification. Clinical subtyping, deformity, leg length discrepancy, and limited joint mobility were significantly associated with this stratification, with Cluster 1 showing higher percentages of severe phenotypes than Cluster 2. Since OI is a genetic disorder, we performed genetic testing on 72 of the 90 patients, but found no obvious association between genotypes and the PROM stratification. Analyses of longitudinal data suggested that patients tended to stay in the same psychological state, in both clusters. Adult patients also showed a continuous spectrum of self-evaluation that matches their clinical manifestations. CONCLUSION: By systematically analyzing patient-reported outcomes, our study demonstrated the link between the sociopsychological wellbeing of OI patients, and their clinical manifestations, which may serve as the basis for evaluating clinical interventions and help achieve better patient-centric medical practices. The lack of genotype-PROM association may be due to the diverse mutational spectrum in OI, which warrants further investigation when a larger sample size is available.

Knee muscle atrophy is a risk factor for development of knee osteoarthritis in a rat model.

OBJECTIVES: The objective of this study was to investigate the effect of botulinum toxin type A (BTX-A)-induced quadriceps muscle atrophy on the cartilage and subchondral bone in an otherwise intact rat joint model. METHODS: The rat right quadriceps muscle atrophy was established by intramuscular injection of BTX-A. Twenty-four rats were divided randomly into 3 groups: The BTX-A-treated 4-week group; the BTX-A-treated 8-week group; and the control group injected with phosphate buffer saline were observed for 8 weeks. Muscle atrophy level was measured by weighing and histology examinations. Serum interleukin-1ß level was tested by ELISA (enzyme linked immunosorbent assay); the subchondral bone was analysed by micro-computed tomography and the cartilage was measured by histology examinations (gross view, haematoxylin and eosin staining and Safranin-O/fast green staining) and immunohistochemistry test {collagen X [ColX]}. RESULTS: BTX-A intramuscular injection led to muscle atrophy. Characteristics of muscle atrophy appeared in two BTX-A-injected groups but not in the control group. Quadriceps atrophy did not affect interleukin-1ß level in serum, but resulted in subchondral bone abnormal changes with reduced bone volume/total tissue volume â€‹and increased Structure Model Index. Furthermore, the more the severe cartilage damage, the higher the histologic damage scores, followed by the higher the percentage of collagen X-positive chondrocytes caused by muscle atrophy. CONCLUSIONS: Quadriceps muscle atrophy triggered the subchondral bone abnormal change and cartilage degeneration, which would be a risk factor for development of osteoarthritis. THE TRANSLATIONAL POTENTIAL OF THIS ARTICLE: Our results indicate that anti-quadriceps muscle atrophy can be a candidate therapeutic target in the prevention of knee osteoarthritis.