Intra-articular hyaluronic acid for the treatment of osteoarthritis of the knee: systematic review and meta-analysis

Background

Osteoarthritis of the knee affects up to 10% of the elderly population. The condition is frequently treated by intra-articular injection of hyaluronic acid. We performed a systematic review and meta-analysis of randomized controlled trials to assess the effectiveness of this treatment.

Methods

We searched MEDLINE, EMBASE, CINAHL, BIOSIS and the Cochrane Controlled Trial Register from inception until April 2004 using a combination of search terms for knee osteoarthritis and hyaluronic acid and a filter for randomized controlled trials. We extracted data on pain at rest, pain during or immediately after movement, joint function and adverse events.

Results

Twenty-two trials that reported usable quantitative information on any of the predefined end points were identified and included in the systematic review. Even though pain at rest may be improved by hyaluronic acid, the data available from these studies did not allow an appropriate assessment of this end point. Patients who received the intervention experienced a reduction in pain during movement: the mean difference on a 100-mm visual analogue scale was –3.8 mm (95% confidence interval [CI] –9.1 to 1.4 mm) after 2–6 weeks, –4.3 mm (95% CI –7.6 to –0.9 mm) after 10–14 weeks and –7.1 mm (95% CI –11.8 to –2.4 mm) after 22–30 weeks. However, this effect was not compatible with a clinically meaningful difference (expected to be about 15 mm on the visual analogue scale). Furthermore, the effect was exaggerated by trials not reporting an intention-to-treat analysis. No improvement in knee function was observed at any time point. Even so, the effect of hyaluronic acid on knee function was more favourable when allocation was not concealed. Adverse events occurred slightly more often among patients who received the intervention (relative risk 1.08, 95% CI 1.01 to 1.15). Only 4 trials explicitly reported allocation concealment, had blinded outcome assessment and presented intention-to-treat data.

Interpretation

According to the currently available evidence, intra-articular hyaluronic acid has not been proven clinically effective and may be associated with a greater risk of adverse events. Large trials with clinically relevant and uniform end points are necessary to clarify the benefit–risk ratio.Osteoarthritis affects about 10% of the population over 55 years of age. Of those, one-quarter are severely disabled.¹ The condition is characterized by degeneration of the articular cartilage and subsequent subchondral bone changes. The underlying mechanisms remain unknown, but the glycosaminoglycan–proteoglycan matrix may play a major role.²Hyaluronic acid, a glycosaminoglycan, is widely used for the treatment of osteoarthritis of the knee. A survey of 2 general practices in the United Kingdom showed that about 15% of patients with osteoarthritis received intra-articular treatment with glucosamine sulfates.³ The costs of such treatment are significant. At present, 1 syringe of hyaluronic acid costs at least Can$130 (US$110). The treatment of knee osteoarthritis is covered by the US Medicare program but not by provincial formularies in Canada. In Austria (which has 8 million inhabitants) more than 10 million euros (approximately US$12 million or Can$15 million) is spent by social insurance programs annually for hyaluronic acid preparations (excluding the cost of application).Hyaluronic acid has beneficial effects in vitro.⁴ Because of its viscoelastic quality, it may replace synovial fluid. Furthermore, it may reduce the perception of pain. Beneficial molecular and cellular effects have also been reported.^2,4 Hyaluronic acid is frequently applied by intra-articular injection, but the evidence concerning its clinical relevance is conflicting. The European League against Rheumatism (EULAR) recommends the intra-articular application of hyaluronic acid as “category 2” evidence (at least 1 controlled study without randomization).⁵ The American College of Rheumatology recommends intra-articular hyaluron therapy for patients with no response to nonpharmacologic therapy and simple analgesics.⁶ In contrast, other specialists have concluded that “hyaluronate sodium is not efficacious” in the treatment of osteoarthritis.⁷ The first state-of-the-art systematic review and meta-analysis was published recently,⁸ and its authors concluded “that intra-articular hyaluronic acid, at best, has a small effect.” We performed a systematic review and meta-analysis of the effect of intra-articular hyaluronic acid for the treatment of osteoarthritis of the knee. In contrast to 2 previous meta-analyses on this subject,^8,9 we used a different approach to data synthesis and interpretation: instead of analyzing a composite effect size over time, we allocated trial data, when possible, to 3 outcome groups that we assumed would be relevant for patients with osteoarthritis. We specifically looked at pain at rest, pain during exercise and joint function as distinct outcomes, measured repeatedly over time. In addition, we assessed adverse events and the impact of both trial quality and molecular mass of the product. This analysis allows us to provide important additional insight into the effects of intra-articular administration of hyaluronic acid for the treatment of osteoarthritis of the knee.     

Biomarkers of legume intake in human intervention and observational studies: a systematic review

There is a growing interest in assessing dietary intake more accurately across different population groups, and biomarkers have emerged as a complementary tool to replace traditional dietary assessment methods. The purpose of this study was to conduct a systematic review of the literature available and evaluate the applicability and validity of biomarkers of legume intake reported across various observational and intervention studies. A systematic search in PubMed, Scopus, and ISI Web of Knowledge identified 44 studies which met the inclusion criteria for the review. Results from observational studies focused on soy or soy-based foods and demonstrated positive correlations between soy intake and urinary, plasma or serum isoflavonoid levels in different population groups. Similarly, intervention studies demonstrated increased genistein and daidzein levels in urine and plasma following soy intake. Both genistein and daidzein exhibited dose-response relationships. Other isoflavonoid levels such as O-desmethylangolensin (O-DMA) and equol were also reported to increase following soy consumption. Using a developed scoring system, genistein and daidzein can be considered as promising candidate markers for soy consumption. Furthermore, genistein and daidzein also served as good estimates of soy intake as evidenced from long-term exposure studies marking their status as validated biomarkers. On the contrary, only few studies indicated proposed biomarkers for pulses intake, with pipecolic acid and S-methylcysteine reported as markers reflecting dry bean consumption, unsaturated aliphatic, hydroxyl-dicarboxylic acid related to green beans intake and trigonelline reported as marker of peas consumption. However, data regarding criteria such as specificity, dose-response and time-response relationship, reliability, and feasibility to evaluate the validity of these markers is lacking. In conclusion, despite many studies suggesting proposed biomarkers for soy, there is a lack of information on markers of other different subtypes of legumes. Further discovery and validation studies are needed in order to identify reliable biomarkers of legume intake.     

Diabetes mellitus increases the risk of active tuberculosis: a systematic review of 13 observational studies

Background

Several studies have suggested that diabetes mellitus (DM) increases the risk of active tuberculosis (TB). The rising prevalence of DM in TB-endemic areas may adversely affect TB control. We conducted a systematic review and a meta-analysis of observational studies assessing the association of DM and TB in order to summarize the existing evidence and to assess methodological quality of the studies.

Methods and Findings

We searched the PubMed and EMBASE databases to identify observational studies that had reported an age-adjusted quantitative estimate of the association between DM and active TB disease. The search yielded 13 observational studies (n = 1,786,212 participants) with 17,698 TB cases. Random effects meta-analysis of cohort studies showed that DM was associated with an increased risk of TB (relative risk = 3.11, 95% CI 2.27–4.26). Case-control studies were heterogeneous and odds ratios ranged from 1.16 to 7.83. Subgroup analyses showed that effect estimates were higher in non-North American studies.

Conclusion

DM was associated with an increased risk of TB regardless of study design and population. People with DM may be important targets for interventions such as active case finding and treatment of latent TB and efforts to diagnose, detect, and treat DM may have a beneficial impact on TB control.     

Selective serotonin reuptake inhibitors and risk of suicide: a systematic review of observational studies

Background

It is unclear whether the use of selective serotonin reuptake inhibitors (SSRIs) and other antidepressant drugs reduce the risk of suicide in people with depression. We explored the association between exposure to SSRIs and risk of suicide completion or attempt.

Methods

We conducted a systematic review of observational studies that reported completed or attempted suicide in depressed individuals who were exposed to SSRIs compared with those who were not exposed to antidepressants. We assessed the overall risk of completed or attempted suicide.

Results

Eight studies involving more than 200 000 patients with moderate or severe depression were included in the meta-analysis. Although exposure to SSRIs increased the risk of completed or attempted suicide among adolescents (odds ratio [OR] 1.92, 95% confidence interval [CI] 1.51–2.44), the risk was decreased among adults (OR 0.57, 95% CI 0.47–0.70). Among people aged 65 or more years, exposure to SSRIs had a protective effect (OR 0.46, 95% CI 0.27–0.79). Sensitivity analyses did not change these findings. In particular, for studies that used completed suicide as an outcome, exposure to SSRIs was associated with increased risk among adolescents (OR 5.81, 95% CI 1.57–21.51) and decreased risk among adults (OR 0.66, 95% CI 0.52–0.83) and older people (OR 0.53, 95% CI 0.26–1.06).

Interpretation

Based on data from observational studies, use of SSRIs may be associated with a reduced risk of suicide in adults with depression. Among adolescents, use of SSRIs may increase suicidality.There is uncertainty about the safety of selective serotonin reuptake inhibitors (SSRIs), which may cause worsening of suicidal thoughts in vulnerable people.^1,2 In 2005, a systematic review of published randomized controlled trials comparing SSRIs with another active treatment or placebo found an almost 2-fold increase in the odds of fatal and nonfatal suicide attempts among those exposed to SSRIs.³ No increase in risk was observed, however, when only fatal suicide attempts were included. Another systematic review,⁴ which included both published and unpublished randomized controlled trials submitted by pharmaceutical companies to the safety review of the Medicine and Healthcare products Regulatory Agency compared the use of SSRIs and placebo in adults with depression and other clinical conditions.⁴ This review showed no evidence of increased risk of completed suicide and only weak evidence of increased risk of self-harm.More recently, the US Food and Drug Administration (FDA) performed a meta-analysis of individual patient data from 372 randomized placebo-controlled trials of antidepressants with a total of nearly 100 000 patients.⁵ This study reported that the incidence of reported suicidal behaviour was strongly related to age.⁵ The risk associated with antidepressant use relative to placebo was increased among patients aged 25 or fewer years, and it was reduced among patients aged 65 or more years.⁵ The risk among patients aged 25–64 years was neutral; however, risk was reduced when suicidal behaviour and ideation were considered together.⁵ Based on these findings, in May 2007 the FDA ordered that all antidepressant drugs carry an expanded black-box warning on their label that included information about increased risk of suicidal behaviour in young adults aged 18–24 years.^6,7A controversial point of the FDA analysis is that the included trials were not primarily designed to measure suicidality (a composite outcome that includes suicide ideas, preparatory acts, suicide attempts and deaths by suicide).⁵ Of all suicidality events, less than 30% were serious suicide attempts or deaths. Additionally, considering that suicidality was self-reported rather than observed by others in most clinical trials, it is possible that antidepressant treatment, particularly in younger individuals, enhanced communication about suicidality, which may have allowed them to become more articulate and open about their thoughts and actions. Alternatively, antidepressant treatment might have enhanced communication about suicidality in all age groups, but increased attention to adverse effects might have led to enhanced detection of suicidality in younger individuals.⁵It is unlikely that individual randomized trials will be designed to primarily investigate the effect of antidepressant use on suicidality, and future systematic reviews of clinical trial data will not be able to overcome the limitations of the FDA analysis. Therefore, we sought to further explore the association between SSRI exposure and risk of completed or attempted suicide by conducting a systematic review and meta-analysis of observational studies. By including a large, broad spectrum of individuals followed under naturalistic circumstances, systematic reviews of observational studies may offer an added dimension in the evaluation of drug safety that is complementary to that provided by clinical trials.^8,9 Additionally, observational studies may allow researchers to move from the controversial concept of suicidality to hard outcomes such as suicide attempt and completion. Specifically, we set out to quantify the risk of completed or attempted suicide among people in different age groups with depression after exposure to SSRIs.     

Proximal gait adaptations in individuals with knee osteoarthritis: A systematic review and meta-analysis

Clarifying proximal gait adaptations as a strategy to reduce knee joint loading and pain for individuals with knee osteoarthritis (OA) contributes to understanding the pathogenesis of multi-articular OA changes and musculoskeletal pain in other joints. We aimed to determine whether biomechanical alterations in knee OA patients during level walking is increased upper trunk lean in the frontal and sagittal planes, and subsequent alteration in external hip adduction moment (EHAM) and external hip flexion moment (EHFM). A literature search was conducted in PubMed, PEDro, CINAHL, and Cochrane CENTRAL through May 2018. Where possible, data were combined into a meta-analysis; pooled standardized mean differences (SMD) of between knee OA patients and healthy adults were calculated using a random-effect model. In total, 32 articles (2037 participants, mean age, 63.0 years) met inclusion criteria. Individuals with knee OA had significantly increased lateral trunk lean toward the ipsilateral limb (pooled SMD: 1.18; 95% CI: 0.59, 1.77) along with significantly decreased EHAM. These subjects also displayed a non-significantly increased trunk/pelvic flexion angle and EHFM. The GRADE approach judged all measures as “very low.” These results may indicate that biomechanical alterations accompanying knee OA are associated with increased lateral trunk lean and ensuing alterations in EHAM. Biomechanical alterations in the sagittal plane were not evident. Biomechanical adaptations might have negative sequelae, such as secondary hip abductor muscle weakness and low back pain. Thus, investigations of negative sequelae due to proximal gait adaptations are warranted.     

Do early life factors affect the development of knee osteoarthritis in later life: a narrative review

Osteoarthritis (OA) mainly affects older populations; however, it is possible that early life factors contribute to the development of OA in later life. The aim of this review is to describe the association between childhood or early adulthood risk factors and knee pain, structural imaging markers and development of knee OA in later life. A narrative overview of the literature synthesising the findings of literature retrieved from searches of computerised databases and manual searches was conducted. We found that only a few studies have explored the long-term effect of childhood or early adulthood risk factors on the markers of joint health that predispose people to OA or joint symptoms. High body mass index (BMI) and/or overweight status from childhood to adulthood were independently related to knee pain and OA in later life. The findings regarding the association between strenuous physical activity and knee structures in young adults are still conflicting. However, a favourable effect of moderate physical activity and fitness on knee structures is reported. Childhood physical activity and performance measures had independent beneficial effects on knee structures including knee cartilage in children and young adults. Anterior knee pain syndrome in adolescence could lead to the development of patellofemoral knee OA in the late 40s. Furthermore, weak evidence suggests that childhood malalignment, socioeconomic status and physical abuse are associated with OA in later life. The available evidence suggests that early life intervention may prevent OA in later life.     

Cardiac complications in patients with community-acquired pneumonia: a systematic review and meta-analysis of observational studies

Background

Community-acquired pneumonia (CAP) is a leading cause of morbidity and mortality. CAP can trigger acute cardiac events. We sought to determine the incidence of major cardiac complications in CAP patients to characterize the magnitude of this problem.

Methods and Findings

Two investigators searched MEDLINE, Scopus, and EMBASE for observational studies of immunocompetent adults with clinical and radiological evidence of CAP that reported any of the following: overall cardiac complications, incident heart failure, acute coronary syndromes (ACS), or incident cardiac arrhythmias occurring within 30 days of CAP diagnosis. At a minimum, studies had to establish enrolment procedures and inclusion and exclusion criteria, enrol their patients sequentially, and report the incidence of cardiac complications as a function of their entire cohorts. Studies with focus on nosocomial or health care–associated pneumonia were not included. Review of 2,176 citations yielded 25 articles that met eligibility and minimum quality criteria. Seventeen articles (68%) reported cohorts of CAP inpatients. In this group, the pooled incidence rates for overall cardiac complications (six cohorts, 2,119 patients), incident heart failure (eights cohorts, 4,215 patients), acute coronary syndromes (six cohorts, 2,657 patients), and incident cardiac arrhythmias (six cohorts, 2,596 patients), were 17.7% (confidence interval [CI] 13.9–22.2), 14.1% (9.3–20.6), 5.3% (3.2–8.6), and 4.7% (2.4–8.9), respectively. One article reported cardiac complications in CAP outpatients, four in low-risk (not severely ill) inpatients, and three in high-risk inpatients. The incidences for all outcomes except overall cardiac complications were lower in the two former groups and higher in the latter. One additional study reported on CAP outpatients and low-risk inpatients without discriminating between these groups. Twelve studies (48%) asserted the evaluation of cardiac complications in their methods but only six (24%) provided a definition for them. Only three studies, all examining ACS, carried out risk factor analysis for these events. No study analyzed the association between cardiac complications and other medical complications or their impact on other CAP outcomes.

Conclusions

Major cardiac complications occur in a substantial proportion of patients with CAP. Physicians and patients need to appreciate the significance of this association for timely recognition and management of these events. Strategies aimed at preventing pneumonia (i.e., influenza and pneumococcal vaccination) in high-risk populations need to be optimized. Further research is needed to understand the mechanisms underlying this association, measure the impact of cardiac complications on other CAP outcomes, identify those patients with CAP at high risk of developing cardiac complications, and design strategies to prevent their occurrence in this population. Please see later in the article for the Editors'' Summary     

Effectiveness of physiotherapy exercise after knee arthroplasty for osteoarthritis: systematic review and meta-analysis of randomised controlled trials

Objective To evaluate the effectiveness of physiotherapy exercise after elective primary total knee arthroplasty in patients with osteoarthritis.Design Systematic review.Data sources Database searches: AMED, CINAHL, Embase, King''s Fund, Medline, Cochrane library (Cochrane reviews, Cochrane central register of controlled trials, DARE), PEDro, Department of Health national research register. Hand searches: Physiotherapy, Physical Therapy, Journal of Bone and Joint Surgery (Britain) Conference Proceedings.Review methods Randomised controlled trials were reviewed if they included a physiotherapy exercise intervention compared with usual or standard physiotherapy care, or compared two types of exercise physiotherapy interventions meeting the review criteria, after discharge from hospital after elective primary total knee arthroplasty for osteoarthritis.Outcome measures Functional activities of daily living, walking, quality of life, muscle strength, and range of motion in the knee joint. Trial quality was extensively evaluated. Narrative synthesis plus meta-analyses with fixed effect models, weighted mean differences, standardised effect sizes, and tests for heterogeneity.Results Six trials were identified, five of which were suitable for inclusion in meta-analyses. There was a small to moderate standardised effect size (0.33, 95% confidence interval 0.07 to 0.58) in favour of functional exercise for function three to four months postoperatively. There were also small to moderate weighted mean differences of 2.9 (0.61 to 5.2) for range of joint motion and 1.66 (−1 to 4.3) for quality of life in favour of functional exercise three to four months postoperatively. Benefits of treatment were no longer evident at one year.Conclusions Interventions including physiotherapy functional exercises after discharge result in short term benefit after elective primary total knee arthroplasty. Effect sizes are small to moderate, with no long term benefit.     

Risk factors for pre-eclampsia at antenatal booking: systematic review of controlled studies

Objective To determine the risk of pre-eclampsia associated with factors that may be present at antenatal booking.Design Systematic review of controlled studies published 1966-2002.Data synthesis Unadjusted relative risks were calculated from published data.Results Controlled cohort studies showed that the risk of pre-eclampsia is increased in women with a previous history of pre-eclampsia (relative risk 7.19, 95% confidence interval 5.85 to 8.83) and in those with antiphospholipids antibodies (9.72, 4.34 to 21.75), pre-existing diabetes (3.56, 2.54 to 4.99), multiple (twin) pregnancy (2.93, 2.04 to 4.21), nulliparity (2.91, 1.28 to 6.61), family history (2.90, 1.70 to 4.93), raised blood pressure (diastolic ≥ 80 mm Hg) at booking (1.38, 1.01 to 1.87), raised body mass index before pregnancy (2.47, 1.66 to 3.67) or at booking (1.55, 1.28 to 1.88), or maternal age ≥ 40 (1.96, 1.34 to 2.87, for multiparous women). Individual studies show that risk is also increased with an interval of 10 years or more since a previous pregnancy, autoimmune disease, renal disease, and chronic hypertension.Conclusions These factors and the underlying evidence base can be used to assess risk at booking so that a suitable surveillance routine to detect pre-eclampsia can be planned for the rest of the pregnancy.     

Exercise therapy for the management of osteoarthritis of the hip joint: a systematic review

Introduction

We aimed to replicate association of newly identified systemic lupus erythematosus (SLE) loci.

Methods

We selected the most associated SNP in 10 SLE loci. These 10 SNPs were analysed in 1,579 patients with SLE and 1,726 controls of European origin by single-base extension. Comparison of allele frequencies between cases and controls was done with the Mantel–Haenszel approach to account for heterogeneity between sample collections.

Results

A previously controversial association with a SNP in the TYK2 gene was replicated (odds ratio (OR) = 0.79, P = 2.5 × 10-⁵), as well as association with the X chromosome MECP2 gene (OR = 1.26, P = 0.00085 in women), which had only been reported in a single study, and association with four other loci, 1q25.1 (OR = 0.81, P = 0.0001), PXK (OR = 1.19, P = 0.0038), BANK1 (OR = 0.83, P = 0.006) and KIAA1542 (OR = 0.84, P = 0.001), which have been identified in a genome-wide association study, but not found in any other study. All these replications showed the same disease-associated allele as originally reported. No association was found with the LY9 SNP, which had been reported in a single study.

Conclusions

Our results confirm nine SLE loci. For six of them, TYK2, MECP2, 1q25.1, PXK, BANK1 and KIAA1542, this replication is important. The other three loci, ITGAM, STAT4 and C8orf13-BLK, were already clearly confirmed. Our results also suggest that MECP2 association has no influence in the sex bias of SLE, contrary to what has been proposed. In addition, none of the other associations seems important in this respect.     

Exercise therapy for the management of osteoarthritis of the hip joint: a systematic review

Introduction  

Recent guidelines pertaining to exercise for individuals with osteoarthritis have been released. These guidelines have been based primarily on studies of knee-joint osteoarthritis. The current study was focused on the hip joint, which has different biomechanical features and risk factors for osteoarthritis and has received much less attention in the literature. The purpose was to conduct a systematic review of the literature to evaluate the exercise programs used in intervention studies focused solely on hip-joint osteoarthritis, to decide whether their exercise regimens met the new guidelines, and to determine the level of support for exercise-therapy interventions in the management of hip-joint osteoarthritis.     

Amateur boxing and risk of chronic traumatic brain injury: systematic review of observational studies

Objective To evaluate the risk of chronic traumatic brain injury from amateur boxing.Setting Secondary research performed by combination of sport physicians and clinical academics.Design, data sources, and methods Systematic review of observational studies in which chronic traumatic brain injury was defined as any abnormality on clinical neurological examination, psychometric testing, neuroimaging studies, and electroencephalography. Studies were identified through database (1950 to date) and bibliographic searches without language restrictions. Two reviewers extracted study characteristics, quality, and data, with adherence to a protocol developed from a widely recommended method for systematic review of observational studies (MOOSE).Results 36 papers had relevant extractable data (from a detailed evaluation of 93 studies of 943 identified from the initial search). Quality of evidence was generally poor. The best quality studies were those with a cohort design and those that used psychometric tests. These yielded the most negative results: only four of 17 (24%) better quality studies found any indication of chronic traumatic brain injury in a minority of boxers studied.Conclusion There is no strong evidence to associate chronic traumatic brain injury with amateur boxing.     

Meniscal extrusion promotes knee osteoarthritis structural progression: protective effect of strontium ranelate treatment in a phase III clinical trial

IntroductionTo evaluate the impact of meniscal extrusion (Ext) on knee osteoarthritis (OA) structural progression and on response to strontium ranelate (SrRan) treatment at 36 months in patients with (+) or without (-) Ext, in association (+) or not (-) with bone marrow lesions (BML) in the medial compartment using X-rays (JSW) and qMRI.MethodsPatients from the qMRI substudy of the SEKOIA trial (SrRan 1 g/day, n = 113; SrRan 2 g/day, n = 105; placebo, n = 112) were stratified based on whether meniscal extrusion and/or BML were present or not in the medial compartment.ResultsIn the placebo group, Ext+ patients (n = 26) had more JSW loss (p = 0.002) and cartilage volume loss in the global knee (p = 0.034) and plateau (p = 0.005), and medial compartment (p = 0.0005) than Ext- patients (n = 86). Ext-BML+ patients (n = 18) demonstrated more JSW loss (p = 0.003) and cartilage volume loss in the global (p = 0.020) and medial femur (p = 0.055) than Ext-BML- (n = 68). Compared to Ext+ BML- (n = 14), Ext+ BML+ patients (n = 12) had more cartilage volume loss in the global femur (p = 0.028), with no change in JSW. The JSW loss (p = 0.0004) and cartilage volume loss (global knee, p = 0.033, medial compartment, p = 0.0005) were greater when Ext and BML were simultaneously present in the medial compartment. SrRan 2 g/day treatment demonstrated a reduction in OA knee structural progression with qMRI, but not with JSW, in which less cartilage volume loss was found in the plateaus (p = 0.007) in Ext+ patients (n = 15), and in the medial plateau (p = 0.046) in patients in whom both Ext and BML were co-localized.ConclusionThe findings of this study are novel and could have an impact on future strategies regarding clinical trials. Indeed, data first argue for a combined, cumulative effect of meniscal extrusion and bone marrow lesions on cartilage loss and, secondly, they showed that SrRan may have protective effects in OA patients with meniscal extrusion as well as when both meniscal extrusion and BML are co-localized.     

NSAID use selectively increases the risk of non-fatal myocardial infarction: a systematic review of randomised trials and observational studies

Background

Recent clinical trials and observational studies have reported increased coronary events associated with non steroidal anti-inflammatory drugs (NSAIDs). There appeared to be a disproportionate increase in non-fatal versus fatal events, however, numbers of fatal events in individual studies were too small, and event rates too low, to be meaningful.

Objectives

We undertook a pooled analysis to investigate the effect of NSAIDs on myocardial infarction (MI) risk with the specific aim to differentiate non-fatal from fatal events.

Methods

We searched Pubmed (January, 1990 to March, 2010) for observational studies and randomised controlled trials that assessed the effect of NSAIDs (traditional or selective COX-2 inhibitors [coxibs]) on MI incidence separately for fatal and non-fatal events. Summary estimates of relative risk (RR) for non-fatal and fatal MIs were calculated with a random effects model.

Results

NSAID therapy carried a RR of 1.30 (95% CI, 1.20–1.41) for non-fatal MI with no effect on fatal MI (RR 1.02, 95% CI, 0.89–1.17) in six observational studies. Overall, the risk increase for non-fatal MI was 25% higher (95% CI, 11%–42%) than for fatal MI. The two studies that included only individuals with prior cardiovascular disease presented risk estimates for non-fatal MI on average 58% greater (95% CI, 26%–98%) than those for fatal MI. In nine randomised controlled trials, all investigating coxibs, the pooled RR estimate for non-fatal MI was 1.61 (95% CI, 1.04–2.50) and 0.86 (95% CI 0.51–1.47) for fatal MIs.

Conclusions

NSAID use increases the risk of non-fatal MI with no substantial effect on fatal events. Such differential effects, with potentially distinct underlying pathology may provide insights into NSAID-induced coronary pathology. We studied the association between the use of nonsteroidal anti-inflammatory drugs (NSAIDs) and the risk of myocardial infarction (MI), separating non-fatal from fatal events, summarizing the evidence from both observational studies and randomised controlled trials. An increased risk of non-fatal MI was clearly found in both types of studies while use of NSAID did not confer an increased risk of fatal MI. Our findings provide support for the concept that thrombi generated under NSAID treatment could be different from spontaneous thrombi.     

Statins reduce all-cause mortality in chronic obstructive pulmonary disease: a systematic review and meta-analysis of observational studies

Background

Recent observational studies have suggested that use of statins reduces mortality in patients suffering from chronic obstructive pulmonary disease. However, no meta-analysis has reported the pooled hazard ratio of statins to all-cause mortality.

Methods

We searched for eligible articles using five databases. We included randomized controlled trials and cohort studies written in English using original data reporting the hazard ratio of statins to all-cause, cardiovascular-related, cancer-related, or respiratory-related mortality. A fixed model with the confidence interval method was used. Publication bias was evaluated by funnel plot and Begg’s test, and was corrected using Duval’s trim and fill method. Sensitivity analyses were also conducted.

Results

We included 10 out of 128 articles. The pooled hazard ratio of statins to all-cause mortality involving 16269 patients was 0.81 (95% CI: 0.75-0.86, P < 0.001) with moderate heterogeneity (I2 = 52%, P = 0.032). The sensitivity analysis and funnel plot suggested the existence of publication bias. After three possibly unpublished cohorts were imputed, the pooled hazard ratio of 0.83 (95% CI: 0.78-0.88, P < 0.001) still suggested a favorable prognosis in statin-treated patients. The pooled hazard ratio of statins to cardiovascular-related, cancer-related, and respiratory-related mortality were 0.52 (95% CI: 0.27-1.01, P = 0.052), 0.57 (95% CI: 0.32-1.01, P = 0.056), and 0.55 (95% CI: 0.43-0.78, P < 0.001), respectively, although these results were not conclusive as we could not find a sufficient number of original studies dealing with those forms of mortality.

Conclusions

The use of statins for patients suffering from chronic obstructive pulmonary disease may reduce all-cause mortality. This conclusion should be re-evaluated by a registered large-scale randomized controlled trial.     

Large-scale observational studies of hypericum extracts in patients with depressive disorders—a systematic review

We present a systematic review of observational studies of hypericum extracts in the treatment of depressive disorders. We included non-randomized studies with at least 100 patients suffering from depressive disorders treated with hypericum mono-preparations for at least 4 weeks, which reported clinical outcomes. Potentially relevant studies were identified through searches in electronic databases (Medline, PubMed), contacts with manufacturers, and handsearching of proceedings of phytomedicine congresses. Information on patients, interventions, methods an results were extracted by two reviewers. Sixteen studies including a total of 34,804 (range 101-11,296) patients met the inclusion criteria. Most studies investigated short-term effects (4-6 weeks) in patients with mild to moderate depression. Response rates (according to physician assessment) varied between 65% and 100%, the proportion of patients dropping out due to side effects varied between 0.0% and 2.8%. Two studies investigated long-term effects (52 weeks). Reponse rates were 60% and 69%, respectively, and the proportions of patients dropping out due to side effects were 3.4% and 5.7%, respectively. Serious side effects or interactions were not reported in any study. The quality of reporting was insufficient in the majority of publications. The available studies show that hypericum extract are well tolerated and seem to be effective in routine treatment of mild to moderate depressive disorders.     

A friend in knee: CCN3 may inhibit osteoarthritis progression

Osteoarthritis (OA) is a major clinical problem among the ageing population, yet no disease-modifying treatments currently exist. This issue arises, in part, due to the complex processes occurring in the microenvironment of articular cartilage that lead to osteoarthritic changes. Gaining a better understanding of these processes is crucial in developing a viable therapy for OA. A recent report in Journal of Bone Mineral Metabolism by Janune et al. (J Bone Miner Metab 35:582–597, 2016) suggests a novel role for CCN3 in maintaining the differentiated phenotype of articular cartilage. This report suggests that CCN3, a member of the CCN family of matricellular proteins, is important for proteoglycan accumulation, as well as expression of type II collagen, tenascin C, and lubricin in vitro. Furthermore, exogenous CCN3 increased tidemark integrity and lubricin protein expression in a rat model of OA. These results implicate the regulation of CCN3 as a potential therapeutic target in patients with OA.     

Epidemiological evidence for work load as a risk factor for osteoarthritis of the hip: a systematic review

Objective

Osteoarthritis of the hip (OA) is a common degenerative disorder of the joint cartilage that presents a major public health problem worldwide. While intrinsic risk factors (e.g, body mass and morphology) have been identified, external risk factors are not well understood. In this systematic review, the evidence for workload as a risk factor for hip OA is summarized and used to derive recommendations for prevention and further research.

Methods

Epidemiological studies on workload or occupation and osteoarthritis of the hip were identified through database and bibliography searches. Using pre-defined quality criteria, 30 studies were selected for critical evaluation; six of these provided quantitative exposure data.

Results

Study results were too heterogeneous to develop pooled risk estimates by specific work activities. The weight of evidence favors a graded association between long-term exposure to heavy lifting and risk of hip OA. Long-term exposure to standing at work might also increase the risk of hip OA.

Conclusions

It is not possible to estimate a quantitative dose-response relationship between workload and hip OA using existing data, but there is enough evidence available to identify job-related heavy lifting and standing as hazards, and thus to begin developing recommendations for preventing hip OA by limiting the amount and duration of these activities. Future research to identify specific risk factors for work-related hip OA should focus on implementing rigorous study methods with quantitative exposure measures and objective diagnostic criteria.