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CADTH Health Technology Review
Authors; Angela M. Barbara, Lindsay Ritchie, and Melissa Severn.
Osteoarthritis (OA) is a progressive disorder of the joint.1,2 It is the most common type of arthritis that causes damage to the articular cartilage and underlying bone.1 The most frequently affected joints include the knee and hip, and the less commonly affected joints include the shoulder (glenohumeral) and ankle.1 In response to OA, the body produces additional synovial fluid to offset the affected joint.3 The increased fluid causes inflammation and pain.3 OA can also cause other symptoms, such as limitation of movement, stiffness, and disability.4 Risk factors for OA include older age (due to progressive degeneration), female sex, family history, excess body weight, joint trauma, and repeated stress on a particular joint (e.g., through sport or work-related activities).1,5 Approximately 219,000 Canadians aged 20 years and older (8.7 per 1,000 persons per year) were newly diagnosed with OA from 2016 to 2017.2 The prevalence of OA during these years was 13.6% and is projected to increase to 18.6% among adults in Canada and the direct cost of OA (including hospitalization, physician and outpatient services, alternative care, out-of-pocket costs, drugs, rehabilitation, home care, formal caregiver, and side effects of drugs) to increase from CAD $2.9 billion to CAD $7.6 billion (2010 values).2,6
OA is a chronic disease, and there is no cure.7 Therefore, treatment focuses on reducing pain and improving functional outcomes.4 Front-line treatment includes exercise, physical therapy, local analgesics, and nonsteroidal anti-inflammatory drugs to relieve pain and inflammation.1,8,9 Conservative treatment before surgery includes injections of glucocorticoids, corticosteroids, and platelet-rich plasma.1,8,9 Operative treatments include arthroscopy, joint preserving surgery, joint fusion, and joint replacement.10 Surgery is often considered a last resort option for end-stage OA due to the risks of surgical complications (e.g., infectious disease, nerve injuries, dislocation).4,11 Surgery is especially problematic in patients 35 years of age and younger because of the requirement for longer implant survival and the need for revision surgery.12 None of these interventions have been shown to stop disease progression or reverse cartilage deterioration.4
HA is a natural component of synovial fluid.4,11 Intra-articular (IA-) HA injections (also called viscosupplementation) are gel-like fluid injections that help lubricate the joint and protect the cartilage and surrounding soft tissues.4,11 HA has been approved in Canada for treating mild to moderate knee OA since 1992.13 IA-HA injections have been accepted as an alternative treatment for OA in people who do not respond to front-line interventions, such as physical therapy or pain medication.14-16 However, most evidence on the clinical effectiveness of IA-HA comes from research on knee OA,17,18, while the effects reported for the hip, shoulder, and ankle joints are limited.17 The evidence suggests that IA-HA products with high MW; defined as greater than 3,000 kDa) have better effectiveness and safety for OA of the knee than lower MW products.13,18,19
In 2019, CADTH produced 2 Rapid Reviews on IA-HA to manage OA of the hip and ankle,14 and the shoulder.15 In 1 report,14 the evidence suggested no effect of IA-HA compared to placebo on pain and adverse events for hip OA, and a potential benefit of IA-HA compared to saline on pain and disability for ankle OA. In the other report,15 there were no significant differences between IA-HA and placebo on pain reduction and functional outcomes for shoulder OA. Adverse events were considered unrelated to the study products.
These 2 CADTH reports14,15 focused on older populations with degenerative OA. For this report, we focus on adults between the ages of 18 and 55 years. While the average age of diagnosis in Canadian adults is 50 years, many experience symptoms of OA years earlier and nearly 1/3 of people with OA have been diagnosed before the age of 45 years.20 OA is prevalent within specific occupations such as the military, sports, construction, mining, and other types of physical labour due to extreme activities and demands,1,5,21 and joint trauma is increasingly being recognized as a common cause of OA.22 The burden of OA on younger adults is similar to and potentially worse than that on older adults.20 Surgery for OA in patients 55 years and younger is problematic, especially total joint replacement, due to the need for long-term durability and the possibility of multiple revisions.12,22 Therefore, effective conservative treatment options for younger patients are required, but the effectiveness of high MW IA-HA for this patient population has not yet been established.
To support decision-making about the use of HA for OA in younger adults, we prepared this Rapid Review to summarize and critically appraise the most recent clinical effectiveness studies on high MW IA-HA in adults between the ages of 18 and 55 years with OA of the hip, shoulder, or ankle joints.
What is the clinical effectiveness of intra-articular hyaluronic acid for people with osteoarthritis of the hip, glenohumeral, or ankle (i.e., tibiotalar or subtalar) joints?
An information specialist conducted a literature search on key resources including MEDLINE, Embase, the Cochrane Database of Systematic Reviews, the International HTA Database, the websites of Canadian and major international health technology agencies, and a focused internet search. The search approach was customized to retrieve a limited set of results, balancing comprehensiveness with relevancy. The search strategy comprised both controlled vocabulary, such as the National Library of Medicine’s MeSH (Medical Subject Headings), and keywords. Search concepts were developed based on the elements of the research questions and selection criteria. The main search concepts were hyaluronic acid and hip, shoulder, and ankle osteoarthritis. The search was completed on December 12, 2023, and limited to English-language documents published since January 1, 2013.
One reviewer screened citations and selected studies. In the first screening level, titles and abstracts were reviewed and potentially relevant articles were retrieved and assessed for inclusion. No comparative randomized or nonrandomized studies meeting the selection criteria were identified from the literature search results. Therefore, 1 reviewer re-screened for single-arm studies (i.e., without a relevant comparator group) with before-and-after data published since 2018. Based on the volume of relevant evidence from before-and-after studies published since 2018, literature screening was not extended further.
Several systematic reviews (SRs) with similar eligibility criteria met our inclusion criteria. Still, they did not include any comparative studies that met our inclusion criteria (i.e., SRs with no relevant primary studies). Therefore, 1 recent and comprehensive SR was selected to include in this Rapid Review. The other SRs with no relevant primary studies are listed in Appendix 5.
The final selection of full-text articles was based on the inclusion criteria presented in Table 1.
Selection Criteria.
The following were excluded:
The included publications were critically appraised by 1 reviewer using the following tools as a guide: A MeaSurement Tool to Assess systematic Reviews 2 (AMSTAR 2)23 for systematic reviews, and the Downs and Black checklist24 for randomized and nonrandomized studies. We assessed only the relevant items in the critical appraisal tools. Summary scores were not calculated for the included studies; rather, the strengths and limitations of each included publication were described narratively.
This report includes 3 SRs with relevant primary studies,26-28 1 SR without relevant studies,25 and 4 nonrandomized open-label before-and-after studies.12,29-31 Study selection details are presented in Appendix 1.
We selected the SR by the National Institute for Health and Care Excellence (NICE)25 to include in our Rapid Review as the most recent, comprehensive, and high-quality SR of comparative studies that met our inclusion criteria but did not include any relevant primary studies. The other SRs that met our selection criteria but with no relevant primary studies are listed in Appendix 5.
Six publications12,25-30 had broader inclusion criteria than the present review:
Additional details regarding the characteristics of included publications are provided in Appendix 2.
The NICE SR25 searched multiple databases for comparative studies from inception to November 2021.
The SR by Boffa et al.27 on ankle diseases queried the electronic databases from inception to March 2020. The 2 SRs26,28 on hip OA searched the electronic databases from January 2000 to January 202028 and from inception to April 2020.26 These 3 SRs26-28 included 4 relevant primary studies (single-arm before-and-after studies) published between 2002 and 2008.
The 4 primary studies12,29-31 were observational open-label studies with uncontrolled before-and-after data. Two studies were prospective30,31 and 2 were retrospective designs.12,29
One study reported in 1 SR26 and another study reported in another SR28 included patients with hip OA. The mean age was 55 years in 1 study in 1 SR,26 but not reported in the other SR (though young adults were eligible for this primary study).28 The sample sizes were 2226 and 78.28 Three primary studies12,30,31 identified for this Rapid Review also included patients with hip OA. The severity of OA in these studies ranged from mild30,31 to severe.12 The studies were conducted at a single site each in Australia,31 Italy,12 and Japan.30 Samples sizes ranged from 930 to 87.31 Mean ages ranged from 3312 to 54 years.31
One primary study29 included 88 patients with OA of the shoulder (glenohumeral joint) from multiple centres in France. Patients with posttraumatic OA (fracture sequalae) or OA following rotator cuff tear were excluded. The mean age was 40 years (range 20 to 65).29
Two studies reported in the SR by Boffa et al.27 included patients with ankle OA and mean ages were 41 and 45 years. The sample sizes were 21 and 55.27 The SR27 did not specify whether tibiotalar or subtalar joints were affected.
The 3 SRs26-28 did not report the countries where the relevant primary studies were conducted.
Most studies assessed single or multiple high MW (6,000 kDa) injections of 2 mL IA-HA (Hylan G-F 2012,26,28,30 or Synvisc brand27,29). One study assessed a single ultra-high MW (> 100,000 kDa) injection of 3 mL HA (Durolane brand).31
The HA injections were guided by fluoroscopy,26 ultrasound,12,29,31 radioscopy,29 or air arthrogram.30 No imaging guidance was used in the 2 studies included in the SR by Boffa et al.27 The SR by Acuna et al.28 did not report whether imaging was used to guide the HA injection.
Clinical benefits included:
Harms were assessed by adverse events.12,26,27,29-31 Follow-up ranged from 6 weeks to 15 years.29
Brief descriptions of the tools used to measure clinical effectiveness outcomes are presented as footnotes in the Summary of Findings tables in Appendix 4.
The 4 SRs25-28 provided some description of the inclusion criteria; however, 3 reviews26-28 did not report establishing an a priori method or developing a review protocol. A preestablished review method is important for informing the conduct of reviews and allows readers to assess any protocol deviations that could introduce potential risk of bias to the findings of the review. The authors of the 4 SRs25-28 performed literature searches in 2 or more electronic databases. The NICE SR25 described the search strategies in detail, while the other 3 SRs26-28 provided the search string27 or key search terms.26,28 This increases the transparency and reproducibility of the literature searches and article selection process. All SRs25-28 presented a flow chart illustrating the study selection process. Study selection was performed in duplicate in 3 SRs;25-27 thus, reducing the likelihood that relevant studies were missed.
There were several limitations that were common to the included SRs.25-28 None incorporated searches of the grey literature25-28 and only the NICE review25 searched trial registries. Of the 3 SRs that included relevant studies,26-28 2 SRs,26,28 did not report that data extraction was performed in duplicate, thus, increasing the possibility of errors in data extraction in those 2 SRs.26,28 Two SRs26,28 did not provide a list of excluded studies. One SR28 did not assess risk of bias of included studies or quality of evidence, and another SR26 did not indicate if risk of bias was accounted for in their findings. The clarity of reporting is fundamental to understand the results and assess the validity of the results. However, 1 SR reported only narrative findings per study,27 and another SR28 did not report effect estimates. The statement of conflicts of interest helps readers understand the potential bias of study funders. However, 2 SRs26,27 did not report the funding sources for the relevant studies included in their review. The authors of 2 SRs25,26 received government funding to conduct the reviews, another SR27 did not report whether financial support was received, and 3 authors of another SR28 disclosed ties with pharmaceutical companies.
The 4 primary studies12,29-31 reported the study objective, inclusion and exclusion criteria, interventions used, and demographics of included participants. Because HA was administered by study personnel, it was assumed that each study's adherence to the intervention was reliable. Outcomes of interest were assessed using validated scales.12,29-31 All 4 studies12,29-31 reported adverse events associated with the intervention.
There were many limitations across the included studies.12,29-31 The 4 studies12,29-31 were open-label with either 1-arm cohort27-29 or without a relevant comparator group.19 Therefore, the risk of confounding is high, and, in the absence of a frame of reference for comparison, we cannot determine how much the intervention, a placebo effect, or the natural history of the disease have contributed to study outcomes. The lack of blinding could result in bias in outcomes favouring the intervention, particularly since most outcomes were based on self-reported measures. All studies12,29-31 had sample sizes less than 89 patients that might not represent the entire population from which they were recruited. In all studies,12,29-31 the outcome data were not adequately described or lacked clarity, which makes interpretation of the results challenging. While 2 studies12,30 declared no conflicts of interest, the authors of another study29 disclosed ties with pharmaceutical companies (consultant or royalties), but not with the manufacturer of the HA (Sanofi) used in their study. One of the authors of the other study31 had previously been on the medical advisory board for Bioventus Global, the manufacturer of the HA assessed in the study.
Additional details regarding the strengths and limitations of the included publications are provided in Appendix 3.
The main study findings are presented in Appendix 4.
Two SRs26,28 and 2 primary studies12,30 assessed the effect of HA on pain in adults with hip OA.
The following effects were reported with single injections of high MW IA-HA guided by imaging (fluoroscopy,26 ultrasound,12 or air arthrogram30):
The following effect was also reported with single injections of high MW IA-HA (imaging guidance NR):
The cohort study by De Lucia et al.12 reported that pain was reduced from baseline at 6 months with multiple ultrasound-guided injections of high MW IA-HA (data presented graphically only, statistical significance not reported). At the 2-year follow-up, pain response differed according to the type of hip OA:
One study30 reported no statistically significant difference from baseline in hip joint function with single injection of high MW HA (guided by air arthrogram) at 4 or 12 weeks in patients with mild hip OA.
One study30 reported the following effects on health-related quality of life with a single injection of high MW HA guided by air arthrogram in patients with mild hip OA:
Two SRs26,28 and 2 primary studies12,31 assessed the effect of HA on composite measures of pain, function, and/or other outcomes in adults with hip OA.
The following effects were reported with a single injection of high MW weight IA-HA:
The cohort study by De Lucia et al.12 reported that pain, stiffness, and function was improved from baseline at 6 months with multiple ultrasound-guided injections of high MW IA-HA (data presented graphically only, statistical significance not reported). At 2 years, treatment response differed according to type of hip OA:
One study29 assessed ultrasound or radioscopy-guided injections of high MW IA-HA in adults with shoulder OA.
There was an improvement from baseline of 12 points on functional quality and 14% on shoulder self-assessment at 12 to 182 months follow-up (statistical significance and clinical importance not reported).29
Eighty-six percent of patients had no arthroscopy at a minimum 4 years’ follow-up (range 12 to 321 months), indicating treatment success according to study authors.29
No complications were reported in 88 patients.29
Two studies reported in the SR by Boffa et al.27 studied the effectiveness and safety of unguided high MW HA in adults with OA of the ankle.
The SR authors27 narratively reported that a single injection of IA-HA was effective at reducing pain from baseline at 6 months (within-group difference and statistical significance not reported, 1 study in 1 SR).27
The SR authors27 narratively reported that 3 weekly injections (1 per week over 3 weeks) of IA-HA provided pain relief from baseline at 18 months (within-group difference and statistical significance not reported, 1 study in 1 SR).27
The SR authors27 narratively reported that 3 injections of IA-HA were effective at providing functional improvement from baseline at 18 months (within-group difference and statistical significance not reported, 1 study in 1 SR).27
No treatment-related adverse events were reported in 76 patients with OA of the ankle.27
We did not identify any clinical effectiveness studies with a relevant comparator group (placebo, wait list, or sham treatment); instead, all identified studies reported a within-group change from baseline (before-and-after treatment). The placebo effect has been demonstrated with therapies for OA.33-35 Without a comparator group, it is not possible to attribute the reported effects to the intervention alone due to potential confounding. With the exception of 1 primary study,31 the minimally important differences on the patient-reported scales were not reported in the evidence; therefore, it is unknown whether the results of pain, function, and composite outcomes were clinically meaningful to patients.
Of the 4 included studies in the 3 SRs, 2 studies from 2 of the SRs26,27 were good quality as assessed by the SR authors and 1 study in 1 SR26 was fair quality. One study included in another SR28 was not assessed for risk of bias by the review authors.
None of the primary studies12,29-31 were conducted in Canada, which may limit the generalizability of the findings of this Rapid Review to the Canadian health care context. The 3 SRs with relevant studies26-28 did not identify the countries in which the studies were conducted; therefore, the generalizability (or directness) of their findings is unknown.
There was variability in patient populations (e.g., OA diagnosis, disease severity), interventions (e.g., number of injections, method of guidance), and outcomes (e.g., instruments used to assess function and compositive outcomes, end points) across included studies. There was also substantial heterogeneity regarding how adverse events were categorized, reported, and presented.
For each outcome, there were very few events or patients included in the results. All included studies had very small sample sizes, ranging from 930 to 88 patients.29 The evidence also had inadequate or unclear reporting of findings. The effect estimates and/or confidence intervals were not reported for several outcomes.27-31 Thus, the results presented in this Rapid Review are generally imprecise.
This report comprises 4 SRs25-28 and 4 observational before-and-after studies12,29-31 on the clinical effectiveness of high MW IA-HA for adults between 18 and 55 years of age with OA of the hip, shoulder, or ankle joints.
In adults with hip OA, compared to baseline, high MW IA-HA may have a favourable effect on pain at 1 month12,26,30 and on pain and disability at 6 months12,26,31 and 1 year28 following treatment. However, these findings are uncertain due to high risk of bias and imprecision. Also, our confidence in the results of the 2 SRs26,28 is very low (based on our assessment using AMSTAR 2).
High MW IA-HA had a neutral effect (e.g., not statistically significant within-group difference) on pain, hip function, and health-related quality of life at 3 months following treatment, but this finding is uncertain due to high risk of bias, imprecision, and indirectness.26,30
High MW IA-HA may have a favourable effect from baseline on pain, stiffness and function at 2 years in patients with primary hip OA, but a neutral effect on these outcomes in patients with OA secondary to juvenile idiopathic arthritis.12 However, these results are uncertain due to high risk of bias, imprecision, and indirectness.12
There were no severe adverse events reported for high MW IA-HA in patients with hip OA.30,31
While 1 study29 reported improvement in function scores after treatment with high MW IA-HA in patients with shoulder OA, the certainty in the evidence is reduced due to high risk of bias, imprecision, and potential indirectness.29 There were no complications reported with high MW IA-HA in patients with shoulder OA.29
In adults with ankle OA, high MW IA-HA may have a favourable effect from baseline on pain at 6 months and 18 months after treatment and on pain and function at 18 months following treatment, but these findings are uncertain due to imprecision and low confidence in the results of the SR.27 There were no treatment-related adverse events with high MW IA-HA in patients with ankle OA.27
The evidence in this report was from limited certainty evidence in nonrandomized before-and-after studies. High-quality data from randomized placebo-controlled trials in large populations are needed to conclusively determine the effectiveness and safety of high MW IA-HA in adults between the ages of 18 and 55 years with OA of the hip, shoulder, and ankle. Many SRs were excluded from this report because the authors did not describe the included studies in adequate details. Specifically, the age of the population and/or the HA MW were not described. Future SRs must provide sufficient information about the populations and interventions (e.g., product name, MW, guidance used) of their included studies. While this was a reporting issue, we also suspect that younger adults are a less studied population, as we did find 12 SRs without relevant primary studies.
To help address health equity concerns in future studies, researchers should consider collecting equity-relevant population characteristics (e.g., gender, education, socioeconomic status, place of residence) to assess potential health inequities related to IA-HA treatment for OA. Compared to older adults, adults younger than 45 years with OA report a great proportion of poor mental health.20 Therefore, future research could assess the impact of high MW IA-HA on psychological outcomes.
While there may be improvements in pain and function up to 2 years following high MW IA-HA in younger adults with hip, shoulder, or ankle OA, the evidence is limited in quantity and quality, and we are uncertain whether high MW IA-HA is clinically effective compared to no treatment. Given this uncertainty, health care providers and decision-makers may wish to consider other factors when considering high MW IA-HA as part of an overall treatment approach for their patients with hip, shoulder, or ankle OA. These factors include acceptability by younger adults and clinicians administering the intervention, feasibility of implementing high MW IA-HA in clinical practice, cost of treatment and other resources required, health equity, and patient values and preferences.
hyaluronic acid
intra-articular
molecular weight
National Institute for Health and Care Excellence
osteoarthritis
systematic review
Contributors: Elizabeth Carson, Calvin Young
Selection of Included Studies.
Characteristics of Included Systematic Reviews.
Characteristics of Included Primary Clinical Studies.
Note that this appendix has not been copy-edited.
Strengths and Limitations of Systematic Reviews Using AMSTAR 223.
Strengths and Limitations of Clinical Studies Using the Downs and Black Checklist.
Summary of Findings by Outcome — Pain.
Summary of Findings by Outcome — Function.
Summary of Findings by Outcome: Health-Related Quality of Life.
Summary of Findings by Outcome: Composite and Other Outcomes.
Summary of Findings by Outcome: Adverse Events.
Note that this appendix has not been copy-edited.
Disclaimer: The information in this document is intended to help Canadian health care decision-makers, health care professionals, health systems leaders, and policy-makers make well-informed decisions and thereby improve the quality of health care services. While patients and others may access this document, the document is made available for informational purposes only and no representations or warranties are made with respect to its fitness for any particular purpose. The information in this document should not be used as a substitute for professional medical advice or as a substitute for the application of clinical judgment in respect of the care of a particular patient or other professional judgment in any decision-making process. The Canadian Agency for Drugs and Technologies in Health (CADTH) does not endorse any information, drugs, therapies, treatments, products, processes, or services.
While care has been taken to ensure that the information prepared by CADTH in this document is accurate, complete, and up-to-date as at the applicable date the material was first published by CADTH, CADTH does not make any guarantees to that effect. CADTH does not guarantee and is not responsible for the quality, currency, propriety, accuracy, or reasonableness of any statements, information, or conclusions contained in any third-party materials used in preparing this document. The views and opinions of third parties published in this document do not necessarily state or reflect those of CADTH.
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About CADTH: CADTH is an independent, not-for-profit organization responsible for providing Canada’s health care decision-makers with objective evidence to help make informed decisions about the optimal use of drugs, medical devices, diagnostics, and procedures in our health care system.
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Questions or requests for information about this report can be directed to ac.HTDAC@stseuqeR
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