Viscosupplementation for knee osteoarthritis: systematic review and meta-analysis.

OBJECTIVE: To evaluate the effectiveness and safety of viscosupplementation for pain and function in patients with knee osteoarthritis. DESIGN: Systematic review and meta-analysis of randomised trials. DATA SOURCES: Searches were conducted of Medline, Embase, and the Cochrane Central Register of Controlled Trials (CENTRAL) databases from inception to 11 September 2021. Unpublished trials were identified from the grey literature and trial registries. ELIGIBILITY CRITERIA FOR STUDY SELECTION: Randomised trials comparing viscosupplementation with placebo or no intervention for knee osteoarthritis treatment. MAIN OUTCOME MEASURES: The prespecified primary outcome was pain intensity. Secondary outcomes were function and serious adverse events. Pain and function were analysed as standardised mean differences (SMDs). The prespecified minimal clinically important between group difference was -0.37 SMD. Serious adverse events were analysed as relative risks. METHODS: Two reviewers independently extracted relevant data and assessed the risk of bias of trials using the Cochrane risk of bias tool. The predefined main analysis was based only on large, placebo controlled trials with ≥100 participants per group. Summary results were obtained through a random effects meta-analysis model. Cumulative meta-analysis and trial sequential analysis under a random effects model were also performed. RESULTS: 169 trials provided data on 21 163 randomised participants. Evidence of small study effects and publication biases was observed for pain and function (Egger's tests with P<0.001 and asymmetric funnel plots). Twenty four large, placebo controlled trials (8997 randomised participants) included in the main analysis of pain indicated that viscosupplementation was associated with a small reduction in pain intensity compared with placebo (SMD -0.08, 95% confidence interval -0.15 to -0.02), with the lower bound of the 95% confidence interval excluding the minimal clinically important between group difference. This effect corresponds to a difference in pain scores of -2.0 mm (95% confidence interval -3.8 to -0.5 mm) on a 100 mm visual analogue scale. Trial sequential analysis for pain indicated that since 2009 there has been conclusive evidence of clinical equivalence between viscosupplementation and placebo. Similar conclusions were obtained for function. Based on 15 large, placebo controlled trials on 6462 randomised participants, viscosupplementation was associated with a statistically significant higher risk of serious adverse events than placebo (relative risk 1.49, 95% confidence interval 1.12 to 1.98). CONCLUSION: Strong conclusive evidence indicates that viscosupplementation leads to a small reduction in knee osteoarthritis pain compared with placebo, but the difference is less than the minimal clinically important between group difference. Strong conclusive evidence indicates that viscosupplementation is also associated with an increased risk of serious adverse events compared with placebo. The findings do not support broad use of viscosupplementation for the treatment of knee osteoarthritis. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42021236894.

Molecular Weight of Hyaluronic Acid Has Major Influence on Its Efficacy and Safety for Viscosupplementation in Hip Osteoarthritis: A Systematic Review and Meta-Analysis.

BACKGROUND: This study aimed to compare the efficacy and safety of intra-articular hyaluronic acid (HA) injection with different molecular weights (MWs) for treating hip osteoarthritis (OA). METHODS: A systematic literature search for relevant studies was conducted in 3 electronic databases, including PubMed, BMJ Journals, and Cochrane Library, from inception to April 2020. Extracted outcomes included visual analogue scale (VAS) (1, 3, and 6 months), Lequesne index (3 and 6 months), and adverse effects. HAs were classified into low-molecular-weight (LMW), moderate-molecular-weight (MMW), high-molecular-weight (HMW), and ultra-high-molecular-weight (UHMW) groups. Meta-analysis was performed using Review Manager 5.3. RESULTS: A total of 15 studies with 614 patients were included. Our meta-analysis showed that the HMW HA group had the best improvement in VAS and Lequesne index compared with other HA groups for all the follow-up visits. Moreover, the HMW group demonstrated significantly better improvement than the other groups in VAS at 6-month follow-up and in Lequesne index at 3- and 6-month follow-ups. Analysis for adverse effects revealed low rates of systemic adverse effects (≤0.6%) in all groups and similar rate of local adverse effects (around 10%) among the groups except for UHMW HA group (37.5%). CONCLUSION: Among different MWs of HA for treating hip OA, HMW HA injection demonstrated the best efficacy for up to 6 months after treatment without increased risk of adverse effects. Further studies with more comprehensive data and a higher level of evidence are required to prove our results.

A placebo-controlled study comparing the efficacy of intra-articular injections of hyaluronic acid and a novel hyaluronic acid-platelet-rich plasma conjugate in a canine model of osteoarthritis.

BACKGROUND: The objective of this study was to assess the efficacy of intra-articular injections of hyaluronic acid (HA) and a novel, on-site conjugate of HA with autologous fibrinogen in platelet-rich plasma (HA-PRP) in a canine model of osteoarthritis (OA) METHODS: Twelve beagle dogs underwent a unilateral resection of the cranial cruciate ligament (CrCL) of the stifle joint. Clinical and radiographic signs of OA were confirmed in all dogs 8 weeks following CrCL resection and prior to treatment. The dogs were randomized into three groups: saline (n = 4), HA (n = 4), and HA-PRP (n = 4). Each dog received intra-articular injections of the respective substance into the affected joint at pre-determined time points. The dogs were assessed for adverse effects for 3 days after each injection and for lameness, pain, range of motion, kinetics, and radiographic OA severity prior to treatment and 3 months after injection. OA severity as determined by radiographic examination was not significantly different among the groups at any time point. The dogs were then humanely euthanatized and the stifle joint assessed by gross and histological examinations. RESULTS: Dogs treated with four weekly injections of HA or two biweekly injections of HA-PRP were significantly (p < 0.05) better than dogs treated with four weekly injections of saline at 2-, 4-, and 12-week time points based on a comfortable range of motion (CROM) and clinical lameness score. Gait analysis measuring symmetry and weight distribution on pressure sensor walkway showed significantly (p < 0.05) improved limb function for dogs treated with HA and HA-PRP compared with dogs treated with saline yet with better clinical outcome for the HA-PRP-treated group at 12 and 20 weeks follow-up. Gross and histological analysis of synovium and articular cartilage demonstrated significant (p < 0.05) improvement by both treatments groups compared to controls. There was however significantly (p < 0.05) less damage to the cartilage in the HA-PRP group compared to the HA-treated group. CONCLUSIONS: These data suggest that while injection of HA and HA-PRP may be sufficient for short-term amelioration of the symptoms associated with OA, treatment with HA-PRP conjugates may be superior, providing significantly better long-term cartilage preservation.

Intra-Articular Viscosupplementation for Patients with Hip Osteoarthritis: A Meta-Analysis and Systematic Review.

BACKGROUND The aim of this study was to review the efficacy and safety of intra-articular (IA) viscosupplementation (VS) for hip osteoarthritis (OA). MATERIAL AND METHODS We searched Medline, Clinical Trial Register Center, EMBASE, and Cochrane databases for randomized controlled trials (RCTs) comparing VS with placebo injection for hip OA. We included suitable studies, assessed the quality of studies, and extracted data on pain reduction, function improvement at different time points, and safety profiles. The comparisons of pain and function outcome were performed by meta-analysis. RESULTS Five high-quality randomized controlled studies trials (RCTs) with 591 patients with hip OA were identified. Although several trials demonstrated a significant decline in pain in VS groups during follow-up compared to baseline, without severe adverse events, the pooled analysis did not show VS was superior to placebo at any time windows [7-14 days: standardized mean difference (SMD): -0.18; 95% CI, -0.47 to 0.10, p=0.21; 28-30 days: 0.02 (-0.15, 0.19), p=0.82; or at final visit: -0.14 (-0.46, 0.18), p=0.38]. Similar results were also observed in the combined data of functional results. CONCLUSIONS IA VS does not reduce pain or improve function significantly better than placebo in a short-term follow-up. The benefits and safety of VS should be further assessed by sufficiently-sized, methodologically sound studies with validated assessment of more clinically relevant end-points.

Long-term efficacy of repeated sodium hyaluronate injections in adult patients with Kashin-Beck disease of the knee.

AIM: To prospectively evaluate the long-term efficacy and safety of repeated sodium hyaluronate injections for the treatment of knee pain due to Kashin-Beck disease (KBD). METHODS: A total of 85 patients with KBD-based knee pain were treated with two cycles of a 5-week course of sodium hyaluronate and received clinical assessments with a follow-up period of 24 months after the first cycle. The primary efficacy measure was the visual analogue scale (VAS) pain score. The second efficacy measure included the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) scores; and the patients' and physicians' global assessments. Tolerability was evaluated based on adverse events (AEs). RESULTS: Seventy-one patients (83.5%) completed the final study. The VAS was significantly reduced from 65.06 ± 12.21 mm (mean ± standard deviation [SD]) at baseline to 30.17 ± 11.92 mm at 6 months and was maintained for 24 months (35.79 ± 7.92 mm, P < 0.01 vs baseline). This finding was supported by the secondary variables (the WOMAC A, B and C scores; the total WOMAC scores; and the global assessments of the patients and their physicians at months 6, 12, 18 and 24). The overall incidence of AEs during the first and second cycles was 8 (9.4%) and 7 patients (8.2%), respectively. No serious AEs were reported. CONCLUSIONS: Repeated once yearly cycles of intra-articular sodium hyaluronate injections may improve knee KBD symptoms during the inbetween cycle period as well as exert a significant carry-over effect for at least 1 year after the repeated cycle. Other randomized double-blind studies are needed to confirm the findings from our study.

Long-Term Health and Economic Value of Improved Mobility among Older Adults in the United States.

BACKGROUND: Mobility impairments have substantial physical and mental health consequences, resulting in diminished quality of life. Most studies on the health economic consequences of mobility limitations focus on short-term implications. OBJECTIVES: To examine the long-term value of improving mobility in older adults. METHODS: Our six-step approach used clinical trial data to calibrate mobility improvements and estimate health economic outcomes using a microsimulation model. First, we measured improvement in steps per day calibrated with clinical trial data examining hylan G-F 20 viscosupplementation treatment. Second, we created a cohort of patients 51 years and older with osteoarthritis. In the third step, we estimated their baseline quality of life. Fourth, we translated steps-per-day improvements to changes in quality of life using estimates from the literature. Fifth, we calibrated quality of life in this cohort to match those in the trial. Last, we incorporated these data and parameters into The Health Economic Medical Innovation Simulation model to estimate how mobility improvements affect functional status limitations, medical expenditures, nursing home utilization, employment, and earnings between 2012 and 2030. RESULTS: In our sample of 12.6 million patients, 66.7% were female and 70% had a body mass index of more than 25 kg/m2. Our model predicted that a 554-step-per-day increase in mobility would reduce functional status limitations by 5.9%, total medical expenditures by 0.9%, and nursing home utilization by 2.8%, and increase employment by 2.9%, earnings by 10.3%, and monetized quality of life by 3.2% over this 18-year period. CONCLUSIONS: Interventions that improve mobility are likely to reduce long-run medical expenditures and nursing home utilization and increase employment.

Is the Addition of a Polyol to Hyaluronic Acid a Significant Advance in the Treatment of Osteoarthritis?

Viscosupplementation with intra-articular injections of hyaluronic acid is recommended as a second line treatment for knee OA, after failure of non-pharmacological modalities and usual pain killers. Nevertheless there are still controversies regarding clinical relevance of its effects. Research is looking for the best way to improve the performance of viscosupplementation in order to obtain a faster, longer-lasting and more pronounced effect. Antioxidants have been assessed in combination with hyaluronic acid because the injected hyaluronate is rapidly degraded by the reactive oxygen species, present in large amounts in the OA synovial fluid, limiting its residence time into the joint. Sorbitol and mannitol which have intrinsic free radical scavenger properties have been the most studied antioxidants. Sodium hyaluronate and polyols develop together a complex based on a dense network of hydrogen bonds which do not modify the visco-elsatic properties of hyaluronic acid. The oxygen free radicals neutralization by mannitol has been proven to delay the degradation of both linear and cross-linked HA in several in vitro models of oxidative stress. The antioxidant effect of these polyols may also play a role in accelerating onset of analgesia, as demonstrated in a double blind controlled trial comparing a mannitol-modified viscosupplement to regular hyaluronic acid. The addition of mannitol and sorbitol to hyaluronic acid does not alter the safety and local tolerability. In summary, adding a polyol to hyaluronic acid may improve the effects of viscosupplementation by reducing the rate of degradation of HA leading to a faster effect on pain relief without increasing the risk of adverse effect.

Decision Algorithms for the Retreatment with Viscosupplementation in Patients Suffering from Knee Osteoarthritis: Recommendations from the EUROpean VIScosupplementation COnsensus Group (EUROVISCO).

Background Viscosupplementation (VS) is a symptomatic treatment of knee osteoarthritis. Although systematic reviews of its repeat use showed favorable benefit/risk ratio, no study has focused on the indication of retreatment. Methods A task force was created to look at issues regarding retreatment with VS in knee osteoarthritis. An attempt was made to reach consensus on several issues: (1) to define treatment "success" and "failure," (2) to determine when to retreat patients successfully treated by a previous VS, (3) to determine how to retreat patients in whom VS failed, (4) to define what to do in case of adverse reaction following previous VS, and (5) to examine the interests of soluble biomarkers to manage retreatment. After debate and review of literature the working group voted on 88 issues. Two "decision trees" were built based on the results of the votes. Results In case of failure, the authors draw attention to the need of a rigorous clinical and radiological analysis, and consider evidence-based medicine. When VS was previously successful, retreatment can be considered after recurrence or increase in pain. However, in subjects with high risk of disease progression, in young patients, and in professional sportsmen, retreatment could be considered systematically, because of the probability of hyaluronic acid to slow osteoarthritis progression. Evidence on soluble biomarkers was not considered as enough strong to support their use as decision tools for patient retreatment. Conclusion The decision algorithms are intended to facilitate consideration of the therapeutic options, in patients with knee osteoarthritis previously treated with VS.

Intra-articular hyaluronic acid injection in treating knee osteoarthritis: assessing risk of bias in systematic reviews with ROBIS tool.

OBJECTIVES: Intra-articular injection of hyaluronic acid (HA) is a common, yet controversial therapeutic option in treating knee osteoarthritis (OA). The purpose of the present study was to assess the risk of bias (RoB) of systematic reviews (SRs) and to summarize available evidence of HA in treating knee OA. METHODS: A systematic search of SRs published through to December 2016 was conducted using the MEDLINE, EMBASE and Cochrane Library. The RoB of included SRs was assessed by ROBIS tool. In addition, the methodological quality of primary studies in SRs with low RoB was evaluated according to the Cochrane Handbook. The evidence quality of each primary outcome of SRs with low RoB was determined by the GRADE (Grading of Recommendations, Assessment, Development, and Evaluation) system. RESULTS: Thirty-one SRs were eligible for inclusion. According to the ROBIS tool, there were 13 SRs with low RoB, 16 with high RoB and two with unclear RoB. The methodological quality of a total of 135 primary studies was evaluated and summarized. Forty-two outcomes from these 13 SRs were classified into the four following quality levels based on the GRADE approach: three outcomes with high quality, eight with moderate quality, 12 with low quality and 19 with very low quality. CONCLUSIONS: This study evaluated RoB in SRs for managing knee OA with HA and assessed the evidence quality of each primary outcome in SRs with low RoB. These results can help users of SRs to improve the process of SR assessment in developing overviews or guidelines, leading to more reliable recommendations for improvements in treating knee OA. Registration: PROSPERO ((http://www.crd.york.ac.uk/PROSPERO) [CRD42017057384].

Hyaluronic acid in knee osteoarthritis: preliminary results using a four months administration schedule.

AIM: To evaluate the therapeutic trajectory of intra-articular injections of hyaluronic acid at high concentration (2%) performed at 4-month intervals. METHODS: Subjects with knee osteoarthritis received, after a weekly injection of 32 mg/2 mL hyaluronic acid for 3 weeks, a single injection of 50 mg/2.5 mL hyaluronic acid (not cross-linked, molecular weight 800-1200 kDa) at 4-month interval (4, 8 and 12 months). Clinical assessment (visual analogic scale [VAS] for pain at rest and during activities, Lequesne Index [LI], Knee Injury and Osteoarthritis Outcome Score (KOOS), and monthly non-steroidal anti-inflammatory drug consumption) was performed at baseline, and after 1, 4, 6, 8, 12 and 14 months. RESULTS: In the 15 knees treated, pain decreased (baseline vs. 14 months: VAS at rest, 3.7 ± 1.7 vs. 1 ± 0.7 [P < 0.000]; VAS activities, 6.2 ± 1.7 vs. 2.6 ± 1.3 [P < 0.000]) and function improved (baseline vs. 14 months: KOOS, 51.9 ± 15.3 vs. 70.2 ± 13.7 [P < 0.000]; LI, 10 ± 3.8 vs. 5.4 ± 2.4 [P < 0.000]) significantly. CONCLUSIONS: This schedule provides persistent positive results in terms of reduced pain and improved function, optimizing the protective properties of the hyaluronic acid used.

Can viscosupplementation be used in the hip? An Italian perspective.

Viscosupplementation is the intra-articular administration of preparations containing hyaluronic acid or hyaluronate intended to restore the normal biological properties of hyaluronic acid normally found in synovial fluid. Infiltration of hyaluronic acid in the arthritic hip is a more recent technique than viscosupplementation of the knee due to the greater technical difficulty of infiltration to the hip, which requires fluoroscopic or ultrasound guidance. The introduction of high-molecular-weight hyaluronic acid in the treatment permits a single administration and has helped diffuse hip infiltration treatment. A single infiltration reduces patient discomfort caused by the procedure and allows treatment of a larger number of patients. Although the literature has unequivocally proven the possibility of reducing pain in patients affected by hip arthritis following infiltration, the molecular weight and density, the number of infiltrations required for long-term results, and the most appropriate indications for infiltration treatment have yet to be clarified. Selecting the patient is the first obstacle to be overcome. Therefore, infiltration should be considered as an option for patients with initial pain symptoms who have not yet been listed for joint prosthesis surgery. The radiographic criteria require at least a partly preserved joint space, and the clinical criteria of persistent hip pain and full joint mobility seem to be sufficiently effective for selection.

Viscosupplementation for knee osteoarthritis.

PURPOSE: To provide an overview of the diagnosis and pathophysiology of osteoarthritis (OA), and to describe appropriate treatments for knee OA, with a focus on the efficacy and safety of viscosupplementation. Because nurse practitioners (NPs) can inject viscosupplements, a section on injection technique is included. DATA SOURCES: Manuscripts were identified using PubMed and EMBASE with a review of the reference lists from retrieved articles. CONCLUSIONS: Viscosupplements are safe and effective at improving function and alleviating knee pain from OA for up to 26 weeks. IMPLICATIONS FOR PRACTICE: As the number of patients with OA is increasing, NPs need to be prepared to prescribe various treatment options to alleviate osteoarthritic knee pain, including viscosupplementation.

[Intra-articular use of sodium hyaluronate (2,2,-2,7 MDa) in the treatment of Moroccan patients with knee osteoarthritis: randomized controlled trial]. / Intérêt de la viscosupplémentation a l'hyaluronate de sodium (2,2-2,7 MDa) dans le traitement de la gonarthrose chez des patients marocains: etude randomisée contrôlée.

OBJECTIVE: To assess the efficacy of intra-articular sodium hyaluronate, administred once weekly for 3 weeks (3 injections) in Moroccan patients with knee osteoarthritis over 6-month period. MATERIAL AND METHODS: We prospectively studied the outcome of 75 patients with painful knee osteoarthritis in grade 1, 2 and 3 on ACR radiological criteria in our rheumatology clinic in Morocco. Group 1: 45 patients were treated with 3-weekly injections of intra-articular sodium hyaluronate (1%; 2,2-2,7 MDa). Group 2 : 30 patients treated with symptomatic slow-acting drugs for osteoarthritis (SYSADOA). The efficacy parameters were Visual Analogue Scale (VAS) and Lequesne index. RESULTS: In group 1: 35/45 were female, a mean age of patients was 57.2 (± 8.2) years, and a mean Body Mass Index (BMI) was 28 (± 1.4) kg/m2. In group 2: 23/30 were female, a mean age of patients was 58.6 (± 2.8) years, and a mean of BMI was 27.8 (± 1.4) kg/m2. Before treatment in group 1, the mean of VAS was 6.5 cm (± 1), and of Lequesne index 10.5 (± 2.1). At 3 and 6 months after the third injection of sodium hyaluronate, there was a significant improvement from baseline of Lequesne index and VAS (P = 0.001). In group 2 before treatment, the mean of VAS was 7 cm (± 0,7), and of Lequesne index 8 (+ 1.1), but the improvement from baseline at 3 and 6 months of treatment was lower than group 1. CONCLUSION: The results of this prospective study, showed the efficacy of 3-weekly injections of sodium hyaluronate in the treatment of knee osteoarthritis in Moroccan patients over a 6-month period.

Viscosupplementation for knee osteoarthritis: current evidence and recommendations.

Osteoarthritis (OA) is the most common joint disorder worldwide and is a leading cause of pain and disability. Appropriate management of younger patients with milder disease remains a challenging area of intense research. Viscosupplementation attempts to restore the biomechanical and biochemical functions of normal synovial fluid hyaluronic acid. Several preparations with varying characteristics are currently available. The literature suggests a small benefit and relative safety, but several recent large meta-analyses have reported conflicting results. Major clinical guidelines provide inconclusive recommendations. Viscosupplementation may be a viable option in younger patients with milder OA where other non-operative modalities are also only modestly successful, but further investigation is clearly warranted. Limitations due to study heterogeneity, outcome reporting, and bias can each be addressed with improved research methodology.

Acute pseudo-septic arthritis following viscosuplementation of the knee.

A 70-year-old woman with a history of medial femoro-tibial compartment of knee osteoarthritis was admitted for acute arthritis six days after a second intra-articular injection of Hyaluronic acid. The joint fluid was inflammatory, with no crystals, and laboratory tests showed marked inflammation leading to antibiotic treatment for suspected septic arthritis. The persistent symptoms and negative results of joint fluid and blood cultures led to discontinuation of the antibiotic therapy after 10 days. Anti-inflammatory with rehabilitation therapy of the knee relieved the symptoms, and the patient was discharged home 3 weeks after her admission. Aseptic arthritis induced by repeated Hyaluronic acid injection is the most likely diagnosis. Physicians should be conscious of this extremely severe complication.