[Study on the occurrence of adverse health events in nursing homes : contributions from the Liège SENIOR cohort]. / Étude de la survenue des événements de santé indésirables en maison de repos : apports de la cohorte Liégeoise SENIOR.

The SENIOR study followed a cohort of older people living in nursing homes for 8 years and examined their adverse health events. The results were analysed after 1, 3 and 8 years to identify predictive factors and improve care. After 1 year, residents with poorer motor and muscle function had a higher incidence of adverse health events such as death and falls. Sarcopenia predicted mortality, while poor physical performance was associated with falls. At 3 years, poor nutritional status and poor balance were important predictors of mortality, falls and loss of independence. At 8 years, younger age, higher body mass index, and good physical and cognitive performance were associated with longer survival. The study also examined the impact of the COVID-19 pandemic in nursing homes and found no significant association between frailty, nutrition, muscle strength and COVID-19. In conclusion, functional capacity and nutrition play a crucial role in predicting adverse events in nursing home residents. The results will guide public health policies and clinical interventions to improve quality of life.

L'étude SENIOR a suivi pendant 8 ans une cohorte de personnes âgées en maison de repos, examinant leurs événements de santé indésirables. Les résultats ont été analysés à 1 an, 3 ans et 8 ans pour identifier les facteurs déterminants et améliorer la prise en charge. Après 1 an, les résidents ayant de moins bonnes capacités motrices et musculaires présentaient une fréquence plus élevée d'événements indésirables tels que les décès et les chutes. La sarcopénie prédisait la mortalité, tandis que des performances physiques médiocres étaient liées aux chutes. Après 3 ans, un mauvais état nutritionnel et un équilibre affaibli étaient des prédicteurs majeurs de mortalité, chutes et perte d'autonomie. Après 8 ans, un âge plus jeune, un indice de masse corporelle élevé et de bonnes performances physiques et cognitives étaient associés à une survie prolongée. L'étude a également examiné l'impact de la pandémie de COVID-19 en maison de repos, ne trouvant pas de lien significatif entre fragilité, nutrition, force musculaire et COVID-19. En conclusion, les capacités fonctionnelles et la nutrition jouent un rôle crucial dans la prédiction d'événements indésirables chez les résidents de maisons de repos. Les résultats guideront les politiques de santé publique et les interventions cliniques pour améliorer la qualité de vie.

Risk factors predicting the 'time to first fracture' and its association with imminent fractures: a substudy of the FRISBEE cohort.

Only previous glucocorticoid use and rheumatoid arthritis were predictors of an early fracture (< 2 years after inclusion). A shorter 'time to first fracture' was not an independent clinical risk factor for imminent fractures. PURPOSE: Risk factors for fragility fractures independent of BMD were assessed in several prediction models. However, predictors of a shorter 'time to first fracture' and its impact on imminent fractures are unknown. METHODS: We studied the concept of 'time to first fracture' in the FRISBEE ("Fracture RIsk Brussels Epidemiological Enquiry") cohort (3560 postmenopausal women). Validated fractures were divided into 3 groups: first fracture < 2 years, 2-5 years, and > 5 years after inclusion. Factors associated with first fracture risk were evaluated with uni- and multivariate analyses using Cox modeling. We examined 'time to first fracture' as a risk factor for imminent fractures in untreated subjects and in those receiving pharmacological treatment. RESULTS: Classical risk factors (age, prior fracture, fall history and low BMD) were associated with first fracture in all groups. Previous glucocorticoids and rheumatoid arthritis (RA) were predictors for fracture < 2 years. Imminent fractures were similar in subjects with or without osteoporosis treatment, despite a higher estimated 10-year risk of fragility fracture in those treated, suggesting that treatment is efficient. 'Time to first fracture' was not an independent risk factor for imminent fractures. CONCLUSION: Among the risk factors considered, previous glucocorticoid use and RA were predictors for early fracture, consistent with the concept of very high risk. The 'time to first validated fracture' was not an independent risk factor for imminent fractures. Patients with a first osteoporotic fracture should thus be considered at very high risk for re-fracture, independent of the 'time to first fracture'.

External validation of FRISBEE 5-year fracture prediction models: a registry-based cohort study.

Five-year fracture risk prediction from the Fracture Risk Brussels Epidemiological Enquiry (FRISBEE) models was externally tested in 9716 Canadian women and demonstrated good discrimination but consistently overestimated risk. INTRODUCTION: Five-year risk prediction models for all fractures, major osteoporotic fractures (MOFs) and central fractures (proximal to forearm and ankle) from the FRISBEE cohort demonstrated good performance in the original derivation cohort. Our aim was to externally validate the FRISBEE-based 5-year prediction models in routine practice. METHODS: Using the population-based Manitoba Bone Mineral Density (BMD) registry, we identified women aged 60-85 years undergoing baseline BMD assessment from September 1, 2012 to March 31, 2018. Five-year probabilities of all fractures, MOFs and central fractures were calculated using the FRISBEE prediction models. We identified incident non-traumatic fractures up to 5 years from population-based healthcare data sources. Performance characteristics included area under the receiver operating characteristic curve (AUROC), gradient of risk (hazard ratio [HR] per SD increase and across risk tertiles) from Cox regression analysis, and calibration (ratio 5-year observed cumulative incidence to predicted fracture probability). RESULTS: We included 9716 women (mean age 70.7 + / - SD 5.3 years). During a mean observation time of 2.5 years, all fractures, MOFs and central fractures were identified in 377 (3.9%), 264 (2.7%) and 259 (2.7%) of the women. AUROC showed significant fracture risk stratification with the FRISBEE models (all fractures 0.69 [95%CI 0.67-0.72], MOFs 0.71 [95%CI 0.68-0.74], central fractures 0.72 [95%CI 0.69-0.75]). There was a strong gradient of risk for predicting fracture outcomes per SD increase (HRs from 1.98 to 2.26) and across risk tertiles (HRs for middle vs lowest from 2.25 to 2.41, HRs for highest vs lowest from 4.70 to 6.50). However, risk was overestimated for all fractures (calibration-in-the-large 0.63, calibration slope 0.63), MOF (calibration-in-the-large 0.51, calibration slope 0.57) and central fractures (calibration-in-the-large 0.55, calibration slope 0.60). CONCLUSIONS: FRISBEE 5-year prediction models were externally validated to stratify fracture risk similar to the derivation cohort, but would need recalibration for Canada as risk was overestimated.

Fragility Fractures in Postmenopausal Women: Development of 5-Year Prediction Models Using the FRISBEE Study.

CONTEXT: Individualized fracture risk may help to select patients requiring a pharmacological treatment for osteoporosis. FRAX and the Garvan fracture risk calculators are the most used tools, although their external validation has shown significant differences in their risk prediction ability. OBJECTIVE AND METHODS: Using data from the Fracture Risk Brussels Epidemiological Enquiry study, a cohort of 3560 postmenopausal women aged 60 to 85 years, we aimed to construct original 5-year fracture risk prediction models using validated clinical risk factors (CRFs). Three models of competing risk analysis were developed to predict major osteoporotic fractures (MOFs), all fractures, and central fractures (femoral neck, shoulder, clinical spine, pelvis, ribs, scapula, clavicle, sternum). RESULTS: Age, a history of fracture, and hip or spine BMD were predictors common to the 3 models. Excessive alcohol intake and the presence of comorbidities were specific additional CRFs for MOFs, a history of fall for all fractures, and rheumatoid arthritis for central fractures. Our models predicted the fracture probability at 5 years with an acceptable accuracy (Brier scores ≤ 0.1) and had a good discrimination power (area under the receiver operating curve of 0.73 for MOFs and 0.72 for central fractures) when internally validated by bootstrap. Three simple nomograms, integrating significant CRFs and the mortality risk, were constructed for different fracture sites. In conclusion, we derived 3 models predicting fractures with an acceptable accuracy, particularly for MOFs and central fractures. The models are based on a limited number of CRFs, and we constructed nomograms for use in clinical practice.

Prediction of an Imminent Fracture After an Index Fracture - Models Derived From the Frisbee Cohort.

Patients who sustain a fracture are at greatest risk of recurrent fracture during the next 2 years. We propose three models to identify subjects most at risk of an imminent fracture, according to fracture site (any fracture, major osteoporotic fracture [MOF] or central). They were constructed using data of the prospective Frisbee cohort, which includes 3560 postmenopausal women aged 60 to 85 years who were followed for at least 5 years. A total of 881 subjects had a first incident validated fragility fracture before December 2018. Among these, we validated 130 imminent fractures occurring within the next 2 years; 79 were MOFs, and 88 were central fractures. Clinical risk factors were re-evaluated at the time of the index fracture. Fine and Gray proportional hazard models were derived separately for each group of fractures. The following risk factors were significantly associated with the risk of any imminent fracture: total hip bone mineral density (BMD) (p < 0.001), a fall history (p < 0.001), and comorbidities (p = 0.03). Age (p = 0.05 and p = 0.03, respectively) and a central fracture as the index fracture (p = 0.04 and p = 0.005, respectively) were additional predictors of MOFs and central fractures. The three prediction models are presented as nomograms. The calibration curves and the Brier scores based on bootstrap resampling showed calibration scores of 0.089 for MOF, 0.094 for central fractures, and 0.132 for any fractures. The predictive accuracy of the models expressed as area under the receiver operating characteristic (AUROC) curve (AUC) were 0.74 for central fractures, 0.72 for MOFs, and 0.66 for all fractures, respectively. These AUCs compare well with those of FRAX and Garvan to predict the 5- or 10-year fracture probability. In summary, five predictors (BMD, age, comorbidities, falls, and central fracture as the incident fracture) allow the calculation with a reasonable accuracy of the imminent risk of fracture at different sites (MOF, central fracture, and any fracture) after a recent sentinel fracture. © 2021 American Society for Bone and Mineral Research (ASBMR).

Independent External Validation of FRAX and Garvan Fracture Risk Calculators: A Sub-Study of the FRISBEE Cohort.

Probabilistic models including clinical risk factors with or without bone mineral density (BMD) have been developed to estimate the 5- or 10-year absolute fracture risk. We investigated the performance of the FRAX and Garvan tools in a well-characterized population-based cohort of 3560 postmenopausal, volunteer women, aged 60 to 85 years at baseline, included in the Fracture Risk Brussels Epidemiological Enquiry (FRISBEE) cohort, during 5 years of follow-up. Baseline data were used to calculate the estimated 10-year risk of hip and major osteoporotic fractures (MOFs) for each participant using FRAX (Belgium). We computed the 5-year risk according to the Garvan model with BMD. For calibration, the predicted risk of fracture was compared with fracture incidence across a large range of estimated fracture risks. The accuracy of the calculators to predict fractures was assessed using the area under the receiver operating characteristic curves (AUC). The FRAX tool was well calibrated for hip fractures (slope 1.09, p < 0.001; intercept -0.001, p = 0.46), but it consistently underestimated the incidence of major osteoporotic fractures (MOFs) (slope 2.12, p < 0.001; intercept -0.02, p = 0.06). The Garvan tool was well calibrated for "any Garvan" fractures (slope 1.05, p < 0.001; intercept 0.01, p = 0.37) but largely overestimated the observed hip fracture rate (slope 0.32, p < 0.001; intercept 0.006, p = 0.05). The predictive value for hip fractures was better for FRAX (AUC: 0.841, 95% confidence interval [CI] 0.795-0.887) than for Garvan (AUC: 0.769, 95% CI 0.702-0.836, p = 0.01). The Garvan AUC for "any Garvan" fractures was 0.721 (95% CI 0.693-0.749) and FRAX AUC for MOFs was 0.708 (95% CI 0.675-0.741). In conclusion, in our Belgian cohort, FRAX estimated quite well hip fractures but underestimated MOFs, while Garvan overestimated hip fracture risk but showed a good estimation of "any Garvan" fractures. Both models had a good discriminatory value for hip fractures but only a moderate discriminatory ability for MOFs or "any Garvan" fractures. © 2021 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.

Role of Collagen Derivatives in Osteoarthritis and Cartilage Repair: A Systematic Scoping Review With Evidence Mapping.

INTRODUCTION: There is currently no disease-modifying drug for osteoarthritis (OA), and some safety concerns have been identified about the leading traditional drugs. Therefore, research efforts have focused on alternatives such as supplementation with collagen derivatives. The objective of this scoping review is to examine the extent, range, and nature of research, and to summarize and disseminate research findings on the effects of collagen derivatives in OA and cartilage repair. The purpose is to identify gaps in the current body of evidence in order to further help progress research in this setting. METHODS: The databases Medline, Scopus, CENTRAL, TOXLINE, and CDSR were comprehensively searched from inception to search date. After studies selection against eligibility criteria, following recommended methods, data were charted from the retrieved articles and these were subsequently synthesized. Numerical and graphical descriptive statistical methods were used to show trends in publications and geographical distribution of studies. RESULTS: The systematic literature search identified a total of 10,834 records. Forty-one published studies were ultimately included in the review, 16 of which were preclinical studies and 25 were clinical studies (including four systematic reviews/meta-analyses). Collagen hydrolysate (CH) and undenatured collagen (UC) were the two types of collagen derivatives studied, with a total of 28 individual studies on CH and nine on UC. More than a third of studies originated from Asia, and most of them have been published after 2008. Oral forms of collagen derivatives were mainly studied; three in vivo preclinical studies and three clinical trials investigated intra-articularly injected CH. In most of the clinical trials, treatment durations varied between 3 and 6 months, with the shortest being 1.4 months and the longest 11 months. All in vivo preclinical studies and clinical trials, regardless of their quality, concluded on beneficial effects of collagen derivatives in OA and cartilage repair, whether used as nutritional supplement or delivered intra-articularly, and whatever the manufacturers of the products, the doses and the outcomes considered in each study. CONCLUSIONS: Although current evidence shows some potential for the use of CH and UC as an option for management of patients with OA, there is still room for progress in terms of laboratory and clinical research before any definitive conclusion can be made. Harmonization of outcomes in preclinical studies and longer randomized placebo-controlled trials in larger populations with the use of recommended and validated endpoints are warranted before collagen derivatives can be recommended by large scientific societies.

Motivational climate of group exercise sessions in nursing homes.

BACKGROUND: Motivational climate in exercise group environments would have an impact on adherence, effort and enjoyment. We examined the motivational climate among nursing home residents who were involved in group exercise sessions. METHODS: This cross-sectional study was conducted in 10 nursing homes of Liège area that offer group exercise sessions. Sociodemographic data (age, sex, body mass index), cognitive status (by the Mini Mental State Examination) and independence in activities of daily living (by the Katz Scale) were retrieved in the medical records. The "Abbreviated-Perceived Motivational Climate in Exercise Questionnaire" was translated into French and then administered face to face with a clinical researcher. This is composed of 6 ego-involving climate items (corresponding to rivalry, comparison and favoritism) and 6 task-involving climate items (corresponding to valorization, individual efforts, self-improvement and cooperation). Each item is ranged on a 5-point Likert scale ranging from 1 (not at all focused on ego or task) to 5 (totally focused on ego or task). Each subscale has a total score expressed as an average. RESULTS: A total of 102 subjects of exercise group sessions were included (84.3 ± 7.7 years and 83 (81.4%) women). The mean score of task-involving and ego-evolving motivational climate was respectively 3.57 (SD = 0.67) and 1.52 (SD = 0.49), suggesting that the motivational climate was more focused on the task-involving climate than on ego-involving climate. Some items results were of particular interest: 55.9% of the respondents found that the instructor doesn't remark/reward when they try hard, 63.7% said that the instructor doesn't encourage mutual aid and 38.2% found that instructor doesn't encourage to do new exercises. CONCLUSIONS: Participants tended to perceive motivational climate as more task-involving than ego-involving. The absence of individual positive feedback, new exercises and mutual aid were also highlighted.

Senior physical activity contests in nursing homes: a feasibility study.

BACKGROUND: Competition has been shown to improve motivation and physical performance in young people. This method has been rarely studied in older people. AIMS: To evaluate the feasibility of senior physical activity (PA) contests between two nursing homes and to assess changes in the motivational level and physical performance of the residents over time. METHODS: Residents from two Belgian nursing homes were invited to participate in PA contests. A pretest and three contest sessions were organized over a period of 3 months. The activities proposed were body balance, gait speed, sit-to-stand performance, arm curl and address tests. Feasibility was measured by contest session adherence (expected score > 80%), difficulty scores (expected score < 40%) and appreciation scores (expected score > 80%). Motivational questionnaires were administered: the BREQ-2 (assessing amotivation, introjected regulation, identified regulation, intrinsic motivation and external motivation) and the A-PMCEQ (assessing ego- and task-involving climates). Friedman's analysis of variance was performed to evaluate the changes in physical performance and motivational levels. RESULTS: Of the 24 participants, seven did not complete all sessions because of medical or personal reasons not related to the study. During the three sessions, the adherence was 86%, the mean difficulty score was 30.8% and the satisfaction score was 87%. After three sessions, residents experienced a significant decrease ranged from 3 to 0 point for amotivation (p = 0.03), 1 to 0 point for external motivation (p = 0.03) and 2.5 to 2 points for ego-involving climate (p = 0.02) and a significant improvement ranged from 0.7 to 0.9 m/s for gait speed (p < 0.001), 18.5 to 15.6 s for sit-to-stand performance (p < 0.001) and 11.5 to 15 curls for arm curl scores (p < 0.001). CONCLUSIONS: In nursing home settings, senior PA contests are feasible and may improve the motivational climate and physical performance.

Physical performance trajectories and mortality among nursing home residents: results of the SENIOR cohort.

BACKGROUND: Previous studies have shown that older people can experience a considerable change in their physical performance (PP) over time. OBJECTIVES: To identify PP trajectories and their association with mortality among nursing home residents who were followed up for 3 years. DESIGN: Three-year longitudinal observational study. SETTING: Subjects of the SENIOR cohort. SUBJECTS: Six hundred and four nursing home residents with a mean age of 82.9 ± 9.1 years. METHODS: Baseline characteristics and the date of death were collected from the medical records. PP was assessed annually by the short physical performance battery (SPPB) test. Multiple imputations were performed to manage the missing data. PP trajectory groups were estimated using latent growth curve analysis. Cox proportional hazard regression models were applied to examine the risk of mortality according to the PP trajectory groups. RESULTS: Three PP trajectory groups were identified: slow decline (N = 96), moderate decline (N = 234) and fast decline (N = 274). After adjustments for potential confounding variables and the baseline SPPB scores, the residents in the fast decline and moderate decline trajectory groups had an increased risk of mortality compared to those in the slow decline trajectory group, with hazard ratio values of 1.78 (95% confidence interval [CI] = 1.34-2.26) and 1.37 (95% CI = 1.10-1.66), respectively. CONCLUSIONS: PP trajectories provide value-added information to baseline geriatric assessments and could be used for predicting 3-year mortality among nursing home residents. It may be important to regularly monitor the SPPB score and signal an alert when a fast decline in PP is detected in older people.

Prediction of Adverse Outcomes in Nursing Home Residents According to Intrinsic Capacity Proposed by the World Health Organization.

BACKGROUND: This study aimed to evaluate the predictive value of the domains of intrinsic capacity (ie, cognition, locomotion, sensory, vitality, and psychosocial) proposed by the World Health Organization (WHO) on the 3-year adverse health outcomes of nursing home residents. METHODS: A 3-year incidence of mortality, falls, repeated falls, and autonomy decline (ie, a one-unit increase in the Katz score) was assessed in a cohort of Belgian nursing home residents. Cognition was assessed using the Mini-Mental State Examination (MMSE). For locomotion, balance, gait speed and chair stand performance were evaluated by the Short Physical Performance Battery test. The sensory domain was measured using the Strawbridge questionnaire for audition and vision. For vitality, abdominal circumference, body mass index, nutritional status (by Mini Nutritional Assessment [MNA]) and handgrip strength were assessed. Psychosocial status was evaluated by the EQ-5D and the Center for Epidemiological Studies Depression scale. Missing data were handled by multiple imputations. Cox proportional hazard models, logistic regressions, and analysis of variance were used for the analyses. RESULTS: In the multivariable model, a one-unit increase in balance performance and in the nutrition score decreased the probability of death by 12% (Hazard ratio [HR] = 0.88; 95% confidence interval [CI] 0.78-0.99) and 4% (HR = 0.96; 95% CI 0.93-0.99), respectively. The risk of falling decreased when there was a one-unit increase in balance performance (HR = 0.87, 95% CI 0.79-0.96) and in the nutrition score (HR = 0.96, 95% CI 0.93-0.98). No association was found for intrinsic capacity and repeated falls. Low scores in nutrition (odds ratio = 0.86, 95% CI 0.77-0.96) were associated with a higher probability of autonomy decline. CONCLUSION: Some domains of intrinsic capacity predicted health outcomes among nursing home residents. Nutrition and balance should be regularly checked among this population.

Normative data for isometric strength of 8 different muscle groups and their usefulness as a predictor of loss of autonomy among physically active nursing home residents: the SENIOR cohort.

OBJECTIVES: To provide normative values for isometric strength of 8 different muscle groups among nursing home residents and to investigate their predictive value for the decline of autonomy. METHODS: This is an analysis of the 1-year follow-up of the SENIOR cohort. At baseline, isometric muscle strength of residents has been assessed for 8 muscle groups using the MicroFET2. The cut-off threshold for low relative isometric muscle strength was defined as the lower quartile. The outcome was the 1-year loss of autonomy (i.e. a decrease of ≥1 point on the ADL scale between baseline and 12-month follow-up). Logistic regressions were carried out to assess the predictive value of isometric muscle strength for the loss of autonomy. RESULTS: 204 subjects (83.2±8.99 years, 72.5% women) were included. Threshold values of isometric strength were: knee flexors=0.94, knee extensors=1.07, ankle flexors=0.77, ankle extensors=0.88, hip abductors=0.78, hip extensors=0.79, elbow flexors=0.99 and elbow extensors= 0.71 N/kg. After adjustment for age and sex, the cut-off values for knee extensors (p=0.04) and for ankle extensors (p=0.03) were significantly predictive of loss of autonomy. CONCLUSIONS: The normative values for knee extensors and ankle extensors are independent predictors for loss of autonomy.

Relationship between peak expiratory flow and incidence of frailty, deaths and falls among nursing home residents: Results of the SENIOR cohort.

OBJECTIVE: To correlate peak expiratory flow (PEF) with the incidence of frailty, deaths and falls among nursing home residents. METHODS: This is a 1-year longitudinal analysis performed on the clinical data of the SENIOR cohort. PEF, measured by peak flow meter, was considered as "low" when the observed value was ≤80% of the theoretical value. Physical capacity was evaluated using Short Physical Performance Battery, balance and gait using Tinetti test and muscle strength using a dynamometer. The incidence of frailty was defined as the transition from a "robust" or "prefrail" status to a "frail" status following Fried's criteria. Deaths and falls were also collected. RESULTS: Among 646 subjects included at baseline (83.2 ± 9 years and 72.1% women), 297 (45.7%) displayed a low PEF. In this subgroup, physical capacity (p-values from 0.01 to <0.001), muscle strength (p < 0.001), balance and gait score (p < 0.001) were significantly lower compared to subjects displaying normal PEF. Subjects who became frail after one year displayed a lower % of the theoretical PEF value compared to those that did not (88.52 ± 45.06 vs 102.78 ± 50.29, respectively, p = 0.03). After adjustment for potential confounding variables (calf circumference, Tinetti test, SPPB test and handgrip strength), PEF was no longer associated with the occurrence of frailty. There was no association between PEF and mortality and falls. CONCLUSION: In a nursing home setting, PEF is not an independent factor associated with the incidence of frailty, deaths and falls.

Safety of Topical Non-steroidal Anti-Inflammatory Drugs in Osteoarthritis: Outcomes of a Systematic Review and Meta-Analysis.

OBJECTIVE: We aimed to assess the safety of topical non-steroidal anti-inflammatory drugs (NSAIDs) in the management of osteoarthritis (OA) in a systematic review and meta-analysis of randomized, placebo-controlled trials. METHODS: A comprehensive literature search was undertaken in the MEDLINE, Cochrane Central Register of Controlled Trials (CENTRAL), and Scopus electronic databases. Randomized, double-blind, placebo-controlled, parallel-group trials that assessed adverse events (AEs) with topical NSAIDs in patients with OA were eligible for inclusion. Authors and/or study sponsors were contacted to obtain the full report of AEs. The primary outcomes were overall severe and serious AEs, as well as the following MedDRA System Organ Class (SOC)-related AEs: gastrointestinal, vascular, cardiac, nervous system, skin and subcutaneous tissue, musculoskeletal and connective tissue. RESULTS: The search strategy identified 1209 records, from which 25 papers were included in the qualitative synthesis and 19 were included in the meta-analysis, after exclusions. Overall, more total AEs (odds ratio [OR] 1.16, 95% confidence interval [CI] 1.04-1.29; I2 = 0.0%) and more withdrawals due to AEs (OR 1.49, 95% CI 1.15-1.92; I2 = 0.0%) were observed with topical NSAIDs compared with placebo. The same results were achieved with topical diclofenac, largely driven by an increase in skin and subcutaneous tissue disorders (OR 1.73, 95% CI 0.96-3.10), although the difference was not statistically significant compared with placebo. No significant difference in the odds for gastrointestinal disorders was observed between topical NSAIDs and placebo (OR 0.96, 95% CI 0.73-1.27). CONCLUSIONS: Topical NSAIDs may be considered safe in the management of OA, especially with regard to low gastrointestinal toxicity. The use of topical NSAIDs in OA should be considered, taking into account their risk: benefit profile in comparison with other anti-OA treatments.

Safety of Intra-articular Hyaluronic Acid Injections in Osteoarthritis: Outcomes of a Systematic Review and Meta-Analysis.

BACKGROUND: Some controversy exists regarding the safety of intra-articular hyaluronic acid (IAHA) in the management of osteoarthritis (OA). OBJECTIVE: The objective of this study was to re-assess the safety profile of IAHA in patients with OA, through a comprehensive meta-analysis of randomized, placebo-controlled trials. METHODS: A comprehensive literature search was undertaken in the databases MEDLINE, Cochrane Central Register of Controlled Trials (CENTRAL), and Scopus. Randomized, double-blind, placebo-controlled, parallel-group trials that assessed adverse events (AEs) with IAHA in patients with OA were eligible for inclusion. Authors and/or study sponsors were contacted to obtain the full report of AEs. The primary outcomes were overall severe and serious AEs, as well as the following MedDRA System Organ Class (SOC)-related AEs: gastrointestinal, cardiac, vascular, respiratory, nervous system, skin and subcutaneous tissue disorders, musculoskeletal, renal and urinary disorders, infections and infestations, and hypersensitivity reaction. RESULTS: Database searches initially identified 1481 records. After exclusions according to the selection criteria, 22 studies were included in the qualitative synthesis, and nine studies having adequate data were ultimately included in the meta-analysis. From the studies excluded according to the pre-specified selection criteria, 21 with other pharmacological OA treatments permitted during the trials were a posteriori included in a parallel qualitative synthesis, from which eight studies with adequate data were finally included in a parallel meta-analysis. Since this meta-analysis was designed to assess safety, the exclusion criterion on concomitant anti-OA medication was crucial. However, due to the high number of studies that allowed mainly concomitant oral non-steroidal anti-inflammatory drugs (NSAIDs), we decided to include them in a post hoc parallel analysis in order to compare the results from the two analyses. No statistically significant difference in odds was found between IAHA and placebo for all types of SOC-related disorders, except for infections and infestations, for which significantly lower odds were found with IAHA compared with placebo, both overall (odds ratio [OR] = 0.61, 95% confidence interval [CI] 0.40-0.93; I2 = 0%) and in studies without concomitant anti-OA medication (OR = 0.49, 95% CI 0.27-0.89). There were significant increased odds of reporting serious AEs with IAHA compared with placebo, both overall (OR = 1.78, 95% CI 1.21-2.63; I2 = 0%) and in studies with concomitant anti-OA medication (OR = 1.78, 95% CI 1.10-2.89), but not in studies without concomitant anti-OA medication (OR = 1.78, 95% CI 0.92-3.47). CONCLUSIONS: Using the available data on studies without any concomitant anti-OA medication permitted during clinical trials, IAHA seems not to be associated with any safety issue in the management of OA. However, this evidence was associated with only a "low" to "moderate" certainty. A possible association with increased risk of serious AEs, particularly when used with concomitant OA medications, requires further investigation.

Safety of Symptomatic Slow-Acting Drugs for Osteoarthritis: Outcomes of a Systematic Review and Meta-Analysis.

BACKGROUND: Symptomatic slow-acting drugs for osteoarthritis (SYSADOAs) are an important drug class in the treatment armamentarium for osteoarthritis (OA). OBJECTIVE: We aimed to re-assess the safety of various SYSADOAs in a comprehensive meta-analysis of randomized placebo-controlled trials, using, as much as possible, data from full safety reports. METHODS: We performed a systematic review and random-effects meta-analyses of randomized, double-blind, placebo-controlled trials that assessed adverse events (AEs) with various SYSADOAs in patients with OA. The databases MEDLINE, Cochrane Central Register of Controlled Trials (Ovid CENTRAL) and Scopus were searched. The primary outcomes were overall severe and serious AEs, as well as AEs involving the following Medical Dictionary for Regulatory Activities (MedDRA) system organ classes (SOCs): gastrointestinal, cardiac, vascular, nervous system, skin and subcutaneous tissue, musculoskeletal and connective tissue, renal and urinary system. RESULTS: Database searches initially identified 3815 records. After exclusions according to the selection criteria, 25 studies on various SYSADOAs were included in the qualitative synthesis, and 13 studies with adequate data were included in the meta-analyses. Next, from the studies previously excluded according to the protocol, 37 with mainly oral nonsteroidal anti-inflammatory drugs (NSAIDs) permitted as concomitant medication were included in a parallel qualitative synthesis, from which 18 studies on various SYSADOAs were included in parallel meta-analyses. This post hoc parallel inclusion was conducted because of the high number of studies allowing concomitant anti-OA medications. Indeed, primarily excluding studies with concomitant anti-OA medications was crucial for a meta-analysis on safety. The decision for parallel inclusion was made for the purpose of comparative analyses. Glucosamine sulfate (GS), chondroitin sulfate (CS) and avocado soybean unsaponifiables (ASU; Piascledine®) were not associated with increased odds for any type of AEs compared with placebo. Overall, with/without concomitant OA medication, diacerein was associated with significantly increased odds of total AEs (odds ratio [OR] 2.22; 95% confidence interval [CI] 1.58-3.13; I2 = 52.8%), gastrointestinal disorders (OR 2.85; 95% CI 2.02-4.04; I2 = 62.8%) and renal and urinary disorders (OR 3.42; 95% CI 2.36-4.96; I2 = 17.0%) compared with placebo. In studies that allowed concomitant OA medications, diacerein was associated with significantly more dermatological disorders (OR 2.47; 95% CI 1.42-4.31; I2 = 0%) and more dropouts due to AEs (OR 3.18; 95% CI 1.85-5.47; I2 = 13.4%) than was placebo. No significant increase in serious or severe AEs was found with diacerein versus placebo. CONCLUSIONS: GS and CS can be considered safe treatments for patients with OA. All eligible studies on ASU included in our analysis used the proprietary product Piascledine® and allowed other anti-OA medications; thus, the safety of ASU must be confirmed in future studies without concomitant anti-OA medications. Given the safety concerns with diacerein, its usefulness in patients with OA should be assessed, taking into account individual patient characteristics.