Background Guidelines recommend exercise as a core treatment for osteoarthritis (OA). However, it is unclear which type of exercise is most effective, leading to inconsistency between different recommendations. Objectives The aim of this systematic review and network meta-analysis was to investigate the relative efficacy of different exercises (aerobic, mind–body, strengthening, flexibility/skill, or mixed) for improving pain, function, performance and quality of life (QoL) for knee and hip OA at, or nearest to, 8 weeks. Methods We searched nine electronic databases up until December 2017 for randomised controlled trials that compared exercise with usual care or with another exercise type. Bayesian network meta-analysis was used to estimate the relative effect size (ES) and corresponding 95% credibility interval (CrI) (PROSPERO registration: CRD42016033865). Findings We identified and analysed 103 trials (9134 participants). Aerobic exercise was most beneficial for pain (ES 1.11; 95% CrI 0.69, 1.54) and performance (1.05; 0.63, 1.48). Mind–body exercise, which had pain benefit equivalent to that of aerobic exercise (1.11; 0.63, 1.59), was the best for function (0.81; 0.27, 1.36). Strengthening and flexibility/skill exercises improved multiple outcomes at a moderate level. Mixed exercise was the least effective for all outcomes and had significantly less pain relief than aerobic and mind–body exercises. The trend was significant for pain (p = 0.01), but not for function (p = 0.07), performance (p = 0.06) or QoL (p = 0.65). Conclusion The effect of exercise varies according to the type of exercise and target outcome. Aerobic or mind–body exercise may be the best for pain and function improvements. Strengthening and flexibility/skill exercises may be used for multiple outcomes. Mixed exercise is the least effective and the reason for this merits further investigation.

Exercise is an effective treatment for osteoarthritis. However, the effect may vary from one patient (or study) to another. To evaluate the efficacy of exercise and its potential determinants for pain, function, performance, and quality of life (QoL) in knee and hip osteoarthritis (OA). We searched 9 electronic databases (AMED, CENTRAL, CINAHL, EMBASE, MEDLINE Ovid, PEDro, PubMed, SPORTDiscus and Google Scholar) for reports of randomised controlled trials (RCTs) comparing exercise-only interventions with usual care. The search was performed from inception up to December 2017 with no language restriction. The effect size (ES), with its 95% confidence interval (CI), was calculated on the basis of between-group standardised mean differences. The primary endpoint was at or nearest to 8 weeks. Other outcome time points were grouped into intervals, from<1 month to≥18 months, for time-dependent effects analysis. Potential determinants were explored by subgroup analyses. Level of significance was set at P≤0.10. Data from 77 RCTs (6472 participants) confirmed statistically significant exercise benefits for pain (ES 0.56, 95% CI 0.44-0.68), function (0.50, 0.38-0.63), performance (0.46, 0.35-0.57), and QoL (0.21, 0.11-0.31) at or nearest to 8 weeks. Across all outcomes, the effects appeared to peak around 2 months and then gradually decreased and became no better than usual care after 9 months. Better pain relief was reported by trials investigating participants who were younger (mean age<60 years), had knee OA, and were not awaiting joint replacement surgery. Exercise significantly reduces pain and improves function, performance and QoL in people with knee and hip OA as compared with usual care at 8 weeks. The effects are maximal around 2 months and thereafter slowly diminish, being no better than usual care at 9 to 18 months. Participants with younger age, knee OA and not awaiting joint replacement may benefit more from exercise therapy. These potential determinants, identified by study-level analyses, may have implied ecological bias and need to be confirmed with individual patient data.

Prostaglandin E₂ (PGE₂) can increase thelial vascular endogrowth factor A (VEGF-A) production but the mechanisms involved are unclear. Here we characterized the transcriptional mechanisms involved in human airway smooth muscle cells (HASMC). PGE₂ increased VEGF-A mRNA and protein but not mRNA stability. PGE₂ stimulated the activity of a transiently transfected 2068-bp (–2018 to +50) VEGF-A promoter-driven luciferase construct. Functional 5′ deletional analysis mapped the PGE₂ response element to the 135-bp sequence (–85/ +50) of the human VEGF-A promoter. PGE₂-induced luciferase activity was reduced in cells transfected with a 135-bp VEGF promoter fragment containing mutated Sp-1 binding sites but not in cells transfected with a construct containing mutated EGR-1 binding sites. Electrophoretic mobility shift assay and chromatin immunoprecipitation assay confirmed binding of Sp-1 to the VEGF promoter. PGE₂ increased phosphorylation of Sp-1 and luciferase activity of a transfected Sp-1 reporter construct. PGE receptor agonists EP₂ (ONO-AE1 259) and EP₄ (ONO-AE1 329) mimicked the effect of PGE₂, and reverse transcription-PCR, Western blotting, and flow cytometry confirmed the presence of EP₂ and EP₄ receptors. VEGF protein release and Sp-1 reporter activity were increased by forskolin and isoproterenol, which increase cytosolic cAMP, and the cAMP analogue, 8-bromoadenosine-3′,5′-cyclophosphoric acid. These studies suggest that PGE₂ increases VEGF transcriptionally and involves the Sp-1 binding site via a cAMP-dependent mechanism involving EP₂ and EP₄ receptors.

To compare the efficacy of topical non-steroidal anti-inflammatory drugs (NSAIDs) with topical capsaicin for pain relief in osteoarthritis (OA). A systematic literature search was conducted for randomised controlled trials (RCTs) examining any topical NSAID or capsaicin in OA. Pain relief at or nearest to 4 weeks was pooled using a random-effects network meta-analysis (NMA) in a Frequentist and Bayesian setting. Analysis was conducted for all trials and for trials using drugs listed as licensed for OA in the British National Formulary (BNF). The trial network comprised 28 RCTs (7372 participants), of which 17 RCTs (3174 participants) were included in the as licensed analyses. No RCTs directly compared topical NSAIDs with capsaicin. Placebo was the only common comparator for topical NSAIDs and capsaicin. Frequentist and Bayesian effect size (ES) estimates were in agreement. Topical NSAIDs were statistically superior to placebo overall (ES 0.30, 95% confidence interval [CI] 0.19 to 0.41) and as licensed (ES 0.32, 95% CI 0.24 to 0.39). However, capsaicin was only statistically superior to placebo when used at licensed doses (ES 0.41, 95% CI 0.17 to 0.64). No significant differences were observed in pain relief between topical NSAIDs and capsaicin (overall: ES 0.04, 95% CI -0.26 to 0.33; as licensed: ES-0.09, 95% CI -0.34 to 0.16). Current evidence indicates that topical NSAIDs and capsaicin in licensed doses may be equally effective for pain relief in OA. Whether the equivalence varies between individuals remains unknown.