Viscosupplementation with High Molecular Weight Hyaluronic Acid for Hip Osteoarthritis: a Systematic Review and Meta-Analysis of Randomised Control Trials of the Efficacy on Pain, Functional Disability, and the Occurrence of Adverse Events.

PURPOSE OF THE STUDY: Hip osteoarthritis (OA) has a prevalence of around 6.4% and is the second most commonly affected joint. This review aims to assess the clinical outcomes of intra-articular high molecular weight hyaluronic acid (HMWHA) in the management of hip osteoarthritis. MATERIAL AND METHODS: We conducted a comprehensive search across PubMed, Google Scholar, and the Cochrane Library for randomised trials investigating the effectiveness of high molecular weight hyaluronic acid (HMWHA) in the treatment of hip osteoarthritis. Quality and risk of bias assessments were performed using the Cochrane RoB2 tool. To synthesise the data, we utilised the Standardised Mean Difference (SMD) for assessing pain relief through the Visual Analogue Scale (VAS) and the Lequesne index (LI) for evaluating functional outcomes. Risk Ratio (RR) was calculated to assess the occurrence of complications. RESULTS: A total of four studies involving HMWHA and control groups were included. The standardised mean difference (SMD) for the Visual Analogue Scale (VAS) (SMD -0.056; 95% CI; -0.351, 0.239; p = 0.709) and the Lequesne index (SMD -0.114; 95% CI; -0.524, 0.296; p = 0.585) were not statistically significant. Analysis for complications demonstrated an overall relative risk ratio (RR) of 0.879 (95% CI; 0.527, 1.466; p = 0.622), and was not statistically significant. DISCUSSION AND CONCLUSIONS: Intra-articular HMWHA in hip OA can significantly reduce pain and improve functional recovery when compared with the condition before treatment. However, there is no significant difference between HMWHA, or saline, or other therapeutic treatments. Currently, available evidence indicates that intra-articular HMWHA in hip OA would not increase the risk of adverse events. KEY WORDS: hip osteoarthritis, hyaluronic acid, intra-articular, molecular weight, viscosupplementation.

Gait kinematics of osteoarthritic knees after intra-articular viscosupplementation: A double-blinded randomized controlled trial.

BACKGROUND: The utilization of subjective questionnaires for assessing conservative treatment in knee osteoarthritis may present challenges in identifying differences due to inadequate statistical power. Objective tools, such as three-dimensional (3D) kinematic analysis, are accurate and reproducible methods. However, no high-quality studies assessing the effects of intra-articular viscosupplementation (VS) have been published. Therefore, the objective of the study was to evaluate gait kinematics of patients with advanced knee osteoarthritis after VS. METHODS: Forty-two patients were randomized to receive either VS or saline injection (placebo). They underwent 3D kinematic gait analysis before and at 1, 6, and 12 weeks after treatment and knee angles during stance phase were determined. Patients and the healthcare team responsible for data collection, processing, and analysis were blinded to group allocation. Between-group comparisons were conducted using linear mixed models. RESULTS: Compared with placebo, the VS increased the maximum knee extension (3.2° (0.7-5.7)) and decreased the maximum knee flexion (-3.6° (-6.1 to -1.2)) on the sagittal plane at 1 week. At 6 weeks, the VS group sustained a reduced maximum knee flexion (-2.6° (-5.2 to 0.0)). On the axial plane, the VS group demonstrated an increase in maximum internal rotation at 12 weeks (3.9° (0.3 to 7.7)). The VS group exhibited reduced single-leg stance time at 1 week and increased total stance time at 12 weeks. CONCLUSIONS: VS led to short- and long-term kinematic improvements in the sagittal and axial planes, leading to a gait pattern closer to that observed in individuals with less severe osteoarthritic knees.

Platelet-Rich Plasma, Bone Marrow Aspirate Concentrate, and Hyaluronic Acid Injections Outperform Corticosteroids in Pain and Function Scores at a Minimum of 6 Months as Intra-Articular Injections for Knee Osteoarthritis: A Systematic Review and Network Meta-analysis.

PURPOSE: To compare the efficacy of common intra-articular injections used in the treatment of knee osteoarthritis, including corticosteroid (CS), hyaluronic acid (HA), platelet-rich plasma (PRP), and bone marrow aspirate concentrate (BMAC), with a minimum follow-up of 6-months. METHODS: A literature search was conducted using the 2020 Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines in August 2022 in the following databases: PubMed/MEDLINE, Scopus, Cochrane Database of Controlled Trials, and the Cochrane Database of Systematic Reviews. Level I to II randomized clinical trials with a minimum follow-up of 6 months that investigated the treatments of interest were included. Patient-reported outcome scores for pain and function at baseline and at latest follow-up were extracted, and the change in scores was converted to uniform 0 to 100 scales. Arm-based Bayesian network meta-analysis using a random-effects model was created to compare the treatment arms in pain and function. RESULTS: Forty-eight studies comprising a total of 9,338 knees were included. The most studied intra-articular injection was HA (40.9%), followed by placebo (26.2%), PRP (21.5%), CS (8.8%), and then BMAC (2.5%). HA and PRP both led to a significant improvement in pain compared with placebo. HA, PRP, and BMAC all led to a significant improvement in function scores when compared with placebo. Surface under the cumulative ranking curves (SUCRAs) of the interventions revealed that PRP, BMAC, and HA were the treatments with the highest likelihood of improvement in both pain and function, with overall SUCRA scores of 91.54, 76.46, and 53.12, respectively. The overall SUCRA scores for CS and placebo were 15.18 and 13.70, respectively. CONCLUSIONS: At a minimum 6-month follow-up, PRP demonstrated significantly improved pain and function for patients with knee osteoarthritis compared with placebo. Additionally, PRP exhibited the highest SUCRA values for these outcomes when compared with BMAC, HA, and CS. LEVEL OF EVIDENCE: Level II, meta-analysis of Level I to II studies.

Intra-articular Hyaluronic Acid Treatments for Knee Osteoarthritis: A Systematic Review of Product Properties.

INTRODUCTION: There are many intra-articular hyaluronic acid (IA-HA) products on the market that have known intrinsic differences in molecular size, source, and structure. The current review summarizes existing evidence describing and assessing these differences, while also identifying whether these differences have an impact on clinical outcomes. METHODS: This systematic review summarized all literature that specifically addresses IA-HA product differences. Included studies summarized basic science and mechanism of action comparisons of IA-HA product differences, or systematic reviews that assess differences in clinical outcomes between IA-HA product differences. RESULTS: A total of 20 investigations assessed basic science differences between IA-HA products, while 20 investigations provided assessments of the clinical outcome differences between IA-HA product characteristics. The published basic science literature provided a differentiation between low molecular weight (LMW) and high molecular weight (HMW) HA with regard to changes within the synovial fluid, driven by the interactions that these molecules have with receptors in the joint space. These differences in receptor interaction manifest within clinical outcomes, as meta-analyses comparing pain relief after IA-HA suggest that pain reduction is superior in patients who receive HMW HA as opposed to LMW HA. CONCLUSION: This review highlights differences between IA-HA characteristics, and how important the molecular weight, derivation of the product, and structure are to variances in reported clinical outcomes to treat osteoarthritis (OA) of the knee. HMW IA-HAs have shown greater efficacy compared to the alternative of LMW products, while avian-derived and cross-linked products have potentially demonstrated an increase in inflammatory events over non-avian-derived, non-cross-linked HAs.

A composite device for viscosupplementation treatment resistant to degradation by reactive oxygen species and hyaluronidase.

Osteoarthritis (OA) is one of the most common musculoskeletal disorders in the world. OA is often associated with the loss of viscoelastic and tribological properties of synovial fluid (SF) due to degradation of hyaluronic acid (HA) by reactive oxygen species (ROS) and hyaluronidases. Viscosupplementation is one of the ways how to effectively restore SF functions. However, current viscosupplementation products provide only temporal therapeutic effect because of short biological half-life. In this article we describe a novel device for viscosupplementation (NV) based on the cross-linked tyramine derivative of HA, chondroitin sulfate (CS), and high molecular weight HA by online determination of viscoelastic properties loss during degradation by ROS and hyaluronidase. Rheological and tribological properties of developed viscosupplement were compared with HA solutions with different molecular weights in the range 500-2000 kDa, which are currently commonly used as medical devices for viscosupplementation treatment. Moreover, based on clinical practice and scientific literature all samples were also diluted by model OA SF in the ratio 1:1 (vol/vol) to better predict final properties after injection to the joint. The observed results confirmed that NV exhibits appropriate rheological properties (viscosity, elastic, and viscous moduli) comparable with healthy SF and maintain them during degradation for a significantly longer time than HA solutions with molecular weight in the range 500-2000 kDa and cross-linked material without CS.

Intra-articular Injectates: What to Use and Why.

Intra-articular injections are a nonsurgical treatment modality that can be used to manage osteoarthritis, naturally occurring or surgically induced acute synovitis, and intra-articular ligamentous or tendon injury. This option may be assistive for patients in which other conservative modalities are ineffective, or in conjunction with other forms of treatment. It may also be used as the primary treatment. Injectates labeled for use in companion animal joints include corticosteroids and viscosupplements. Additional injectates, that are not specifically approved for use in companion animals are but are reported in the literature, include orthobiologics and a radioisotope of Tin-117m.

Different changes in the biomarker C-terminal telopeptides of type II collagen (CTX-II) following intra-articular injection of high molecular weight hyaluronic acid and oral non-steroidal anti-inflammatory drugs in patients with knee osteoarthritis: a multi-center randomized controlled study.

OBJECTIVES: We previously reported, based on a multicenter randomized-control study, that the efficacy of intra-articular injections of hyaluronic acid (IA-HA) was not inferior to that of oral non-steroidal anti-inflammatory drugs (NSAIDs) in patients with knee osteoarthritis (OA). However, the molecular effects on the pathophysiology of knee OA remain unclear. C-terminal telopeptides of type II collagen (CTX-II) is reported to primarily originate from the interface between articular cartilage and subchondral bone, which is a site of potential remodeling in OA. We performed a predefined sub-analysis of the previous study to compare the changes of urinary CTX-II (uCTX-II) in response to IA-HA to those in response to NSAID for knee OA. DESIGN: A total of 200 knee OA patients were registered from 20 hospitals and randomized to receive IA-HA (2,700 kDa HA, 5 times at 1-week intervals) or NSAID (loxoprofen sodium, 180 mg/day) for 5 weeks. The uCTX-II levels were measured before and after treatment. RESULTS: The uCTX-II levels were significantly increased by IA-HA treatment (337.7 ± 193.8 to 370.7 ± 234.8 ng/µmol Cr) and were significantly reduced by NSAID treatment (423.2 ± 257.6 to 370.3 ± 250.9 ng/µmol Cr). The %changes of uCTX-II induced by IA-HA (11.6 ± 29.5%) and NSAID (-9.0 ± 26.7%) was significantly different (between-group difference: 20.6, 95% confidence intervals: 10.6 to 30.6). CONCLUSIONS: While both IA-HA and NSAID improved symptoms of knee OA, uCTX-II levels were increased by IA-HA and reduced by NSAIDs treatment, suggesting these treatments may improve symptoms of knee OA through different modes of action.

Retreatment with Hyaluronic Acid Viscosupplementation in Knee Osteoarthritis: Agreement between EUROVISCO Guidelines and Current Medical Practice.

OBJECTIVES: This work studied if and how current clinical practice agrees with European Viscosupplementation Consensus Group (EUROVISCO) recommendations and how this agreement might be different according to physician's specialization. In addition, this work aimed to identify key decision factors that practitioners consider in their decision to retreat or not a patient with hyaluronic acid viscosupplementation. METHODS: Practitioners have been invited by e-mail to participate in an online exercise on viscosupplementation retreatment. They received a fictional patient case at random among a set of predefined fictional cases. The platform asked the practitioner if he/she would retreat the patient with viscosupplementation or not. To take a decision, the practitioner could select questions among a list of predefined questions. Among them, some were related to criteria used in the EUROVISCO decision tree and others served as confounding factors. RESULTS: A total of 506 practitioners participated to the exercise, of which 399 gave their decision about the case assigned to them by the platform. The observed agreement between practitioner decisions and EUROVISCO recommendations was 58.89 ± 4.95% (95% confidence interval [CI]). Overall, the decision to retreat was taken in 47.87% of the cases, while the EUROVISCO guidelines follow-up would have led to 55.89% retreatment for the same cases (P = 0.03). CONCLUSIONS: In current practice, physicians tended to reinject their patients less than recommended, although EUROVISCO guidelines for viscosupplementation retreatment consider decision criteria that clearly correspond to those of practitioners in real life. These include the patients' willingness to be treated or the patients' perception of the effectiveness of the treatment.

Evolution of the Hyaluronic Acid in Viscosupplementation - from Linear Particles to Hybrid Complexes.

The discovery of unique properties of the hyaluronic acid and learning about the role of this aid in pathophysiology of extracellular matrices resulted in using this substance in pharmacological support in cases of tissue dysfunction due to numerous disease units. Therefore, the products containing this substance are now widely used in medicine including dermatology and aesthetic medicine, ophthalmology, facial-mandibular surgery and orthopedics, being among the most effective products used in the treatment of numerous cases of function impairment and deformation of tissues and organs. There are applied in both post-traumatic and post-inflammatory conditions as well as in symptoms due to chronic conditions. Their therapeutic effects result from joint surface moisturizing, reduction of the coefficient of friction (COF) and good bio-tolerance and biocompatibility confirmed by a low percentage of side effects and biocompatibility. The introduction of hyaluronic acid hybrid complexes with high and low molecular mass (H/L-HA) has increased the clinical usefulness of hyaluronic acid products thanks to their increased viscoelasticity, increased anti-inflammatory and chondroprotective properties and thermodynamic stabilization of the product guaranteeing its half-life. Thanks to the above mentioned pro-perties it becomes more effective in the non-surgical treatment of osteoarthritis.

Effects of adipose tissue-derived stromal vascular fraction on osteochondral defects treated by hyaluronic acid-based scaffold: An experimental study.

OBJECTIVES: This study aims to evaluate the effect of adipose-derived stromal vascular fraction (SVF) on osteochondral defects treated by hyaluronic acid (HA)-based scaffold in a rabbit model. MATERIALS AND METHODS: Eighteen white New Zealand rabbits were randomly grouped into the experimental group (n=9) and control group (n=9). In all groups, osteochondral defects were induced on the weight-bearing surfaces of the right femoral medial condyles, and a HA-based scaffold was applied to the defect area with microfractures (MFs). In this study, 1 mL of adipose-derived SVF was injected into the knee joints of the rabbits in the experimental group. For histological and macroscopic evaluation, four rabbits were randomly selected from each group at Week 4, and the remaining rabbits were sacrificed at the end of Week 8. Macroscopic assessments of all samples were performed based on the Brittberg scoring system, and microscopic evaluations were performed based on the O'Driscoll scores. RESULTS: Samples were taken at Weeks 4 and 8. At Week 4, the O'Driscoll scores were significantly higher in the control group than the experimental group (p=0.038), while there was no significant difference in the Brittberg scores between the two groups (p=0.108). At Week 8, the O'Driscoll score and Brittberg scores were statistically higher in the experimental group than in the control group (p=0.008 and p=0.007, respectively). According to the microscopic evaluation, at the end of Week 8, the cartilage thickness was greater in the experimental group, and nearly all of the defect area was filled with hyaline cartilage. CONCLUSION: Application of adipose-derived SVF with MF-HA-based scaffold was better than MF-HA-based scaffold treatment in improving osteochondral regeneration. Therefore, it can be used in combination with microfracture and scaffold to accelerate cartilage regeneration, particularly in the treatment of secondary osteoarthritis.

A randomized study protocol comparing the platelet-rich plasma with hyaluronic acid in the treatment of symptomatic knee osteoarthritis.

BACKGROUND: In recent years, intra articular injection of platelet rich plasma has attracted increasing attention. The major aim of our current randomized controlled double-blind study was to compare long-term outcomes of intra-articular injection of hyaluronic acid or platelet rich plasma in the treatment of the patients with knee osteoarthritis. METHODS: This is a kind of double-blind, randomized, prospective, and comparative clinical investigation with the allocation ratio of 1:1 and was approved by our institutional review Committee. Between 2020 and 2021, altogether 2 hundred patients will be selected to participate in our present study. We will report the randomized experiments in accordance with the guidelines of Consolidated Standards of Reporting Trials and then offer the Consolidated Standards of Reporting Trials flow chart. The inclusion criteria were: patients aged from 40 to 70 years old, patients with chief complaint history of at least 1 month and knee joint pain for nearly 6 months, need the analgesic drug treatment, and radiology confirmed knee osteoarthritis. The eligible patients would be randomly divided into 2 groups through applying the random numbers generated by computer before surgery. Outcomes after treatment were assessed using the Western Ontario and McMaster University and the scoring systems of visual analogue scale which were recorded through questionnaires accomplished via the patients prior to the first injection and then at three and six months, 1 and 2 years follow-up. Any adverse events occurred within 1 year after surgery were recorded during follow-up. RESULTS: This should suggest whether biological methods can offer more lasting outcomes than the viscosification. TRIAL REGISTRATION: This study protocol was registered in Research Registry (researchregistry6265).

Tackling osteoarthritis during COVID-19 pandemic.

In this opinion article, we would like to draw attention to the fact that COVID-19 has a significant impact not only on immune-mediated arthritis but also on osteoarthritis (OA), the most common rheumatic disease. We suggest herein strategies for pain relief and symptom prevention in patients with OA during COVID-19 pandemic.

Evaluation of Hylan G-F 20 Treatment with Opioid Prescriptions and Intraarticular Corticosteroid Injections in Patients with Osteoarthritis of the Knee Using a Claims Database.

OBJECTIVE: Assess how treatment with the viscosupplement hylan G-F 20 relates to opioid prescriptions and intraarticular corticosteroid injections (IACS) in patients with osteoarthritis of the knee (OAK). DESIGN: Case-crossover; adult patients with OAK identified in a claims database were treated with hylan G-F 20 from July 1, 2007, to June 29, 2017. Opioid or IACS prescriptions in the 6 months before treatment were compared to the 6 months after. Patients with comorbid conditions requiring pain medications were excluded, resulting in a 29,395-patient cohort. Four subgroups were investigated: patients with (1) opioids before hylan G-F 20 (OB; n = 6,609); (2) opioids before and after hylan G-F 20 (OBF; n = 3,320); (3) IACS before hylan G-F 20 (CB; n = 11,162); and (4) IACS before and after hylan G-F 20 (CBF; n = 2,810). All opioids were converted to morphine milligram equivalents (MME). RESULTS: OB subgroup patients had a significant decrease (P < 0.01) in total MME (-14.0%), MME per day (-14.2%) and opioid prescription days (-12.6%) after treatment versus before. Only 50.2% of patients prescribed opioids before hylan G-F 20 were prescribed an opioid after treatment. OBF subgroup patients had a significant increase (P < 0.01) in opioid prescription days (7.8%) before versus after treatment. There was a significant decrease (P < 0.01) in the number of IACS after versus before treatment for the Total Cohort (-56.1%), and subgroups CB (-72.6%) and CBF (-4.1%). A total of 74.8% of patients receiving an IACS before treatment did not receive an IACS after treatment. CONCLUSIONS: Hylan G-F 20 is associated with a reduction in opioid prescriptions and IACS in OAK patients.

Visual Analogue Scale has higher assay sensitivity than WOMAC pain in detecting between-group differences in treatment effects: a meta-epidemiological study.

OBJECTIVE: To compare assay sensitivity of the Visual Analogue Scale (VAS) for global osteoarthritis pain and the Western Ontario and McMaster University (WOMAC) pain subscale, and the associated between-trial heterogeneity in effect sizes (ES). DESIGN: We included trials with placebo, sham or non-intervention control that included at least 100 patients with hip or knee osteoarthritis per arm, reporting both VAS and WOMAC pain scores. ES were calculated as between-group difference in means divided by the pooled standard deviation and compared using a paired t-test. ES and τ2 as a measure of between-trial heterogeneity were combined using random-effects meta-regression with robust variance estimation to account for the correlation of data within trials and meta-analyses. RESULTS: Twenty-eight trials with 44 randomized comparisons were included. In 28 comparisons (64%), ES from VAS favoured the intervention more than those from WOMAC pain (P = 0.003). Twenty-six p-values (59%) were smaller according to VAS (P = 0.008). The 44 comparisons contributed to 12 meta-analyses. Eleven meta-analyses (92%) showed larger benefits of interventions according to VAS, with a combined overall difference in ES of -0.08 (95% CI -0.14 to -0.02). τ2 was similar for VAS and WOMAC pain (difference in τ2, -0.003, 95% CI -0.009 to 0.004). CONCLUSION: The VAS for global pain had slightly higher assay sensitivity at trial and meta-analysis levels than the WOMAC pain subscale without relevant increase in between-trial heterogeneity.

Effects of a Thermosensitive Antiadhesive Agent on Single-Row Arthroscopic Rotator Cuff Repair.

BACKGROUND: Postoperative stiffness after rotator cuff repair is a common complication that can lead to poor outcomes and patient discomfort. The application of an antiadhesive agent at the time of repair recently became an option for clinicians, but little information is available on its effects. PURPOSE: To evaluate and compare retear rates, the incidence of postoperative stiffness, and the clinical outcomes of patients who underwent cuff repair with or without the application of an antiadhesive agent. STUDY DESIGN: Cohort study; Level of evidence, 3. METHODS: Among 296 patients who underwent arthroscopic rotator cuff repair surgery, we compared the outcomes of those injected with a thermosensitive gel antiadhesive agent into the subacromial space (112 cases) versus noninjected controls (184 cases). Retear rates in the 2 groups were determined by magnetic resonance imaging at 1 year after surgery. Shoulder joint range of motion and functional scores were evaluated serially. RESULTS: The rate of retear was significantly lower in the injection group (20/112 cases; 17.9%) than the control group (53/184 cases; 28.8%) (P = .034). Postoperative stiffness was not significantly different between the 2 groups (P = .710). Among the data regarding range of motion, only forward flexion at 6 months after surgery showed superior results in the injection group. Functional scores showed conflicting results: The control group had better visual analog scale scores for pain (injection vs control: 2.17 vs 1.68 at 6 months; 1.82 vs 1.28 at 12 months), American Shoulder and Elbow Surgeons scores (79.89 vs 89.64 at 12 months), and simple shoulder test scores (8.70 vs 10.06 at 12 months), whereas the injection group had better Constant-Murley scores (injection vs control: 59.49 vs 55.60 at 3 months; 77.35 vs 71.98 at 6 months; 87.28 vs 81.56 at 12 months). CONCLUSION: The tendon healing rate was significantly higher in the group receiving an antiadhesive agent than in the control group. No intergroup difference was seen in the occurrence of postoperative stiffness. However, the pain-related functional score showed inferior results in the injection group at 12 months. The biological action of antiadhesive agents in rotator cuff repair should be further evaluated.

Knee OA cost comparison for hyaluronic acid and knee arthroplasty.

BACKGROUND: Limiting treatment to those recommended by the American Academy of Orthopaedic Surgeon Clinical Practice Guidelines has been suggested to decrease costs by 45% in the year prior to total knee arthroplasty, but this only focuses on expenditures leading up to, but not including, the surgery and not the entire episode of care. We evaluated the treatment costs following knee osteoarthritis (OA) diagnosis and determined whether these are different for patients who use intra-articular hyaluronic acid (HA) and/or knee arthroplasty. METHODS: Claims data from a large commercial database containing de-identified data of more than 100 million patients with continuous coverage from 2012 to 2016 was used to evaluate the cumulative cost of care for over 2 million de-identified members with knee OA over a 4.5-year period between 2011 and 2015. Median cumulative costs were then stratified for patients with or without HA and/or knee arthroplasty. RESULTS: Knee OA treatment costs for 1,567,024 patients over the 4.5-year period was $6.60 billion (mean $4210/patient) as calculated by the authors. HA and knee arthroplasty accounted for 3.0 and 61.5% of the overall costs, respectively. For patients who underwent knee arthroplasty, a spike in median costs occurred sooner for patients without HA use (around the 5- to 6-month time point) compared to patients treated with HA (around the 16- to 17-month time point). CONCLUSIONS: Non-arthroplasty therapies, as calculated by the authors, accounted for about one third of the costs in treating knee OA in our cohort. Although some have theorized that limiting the use of HA may reduce the costs of OA treatment, HA only comprised a small fraction (3%) of the overall costs. Among patients who underwent knee arthroplasty, those treated with HA experienced elevated costs from the surgery later than those without HA, which reflects their longer time to undergoing knee arthroplasty. The ability to delay or avoid knee arthroplasty altogether can have a substantial impact on the cost to the healthcare system.