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Review Article
2023
:2;
100157
doi:
10.1016/j.jorep.2023.100157

Efficacy of hyaluronic acid in rotator cuff pathology compared to other available treatment modalities: A Systematic Review and meta-analysis

, , , , , ,
Department of Orthopedics, AIIMS, Rishikesh, Uttarakhand, 249203, India

∗Corresponding author: Mohit Dhingra. modisbanu77@gmail.com

Received: , Accepted: ,
Disclaimer:
This article was originally published by Reed Elsevier India Pvt. Ltd. and was migrated to Scientific Scholar after the change of Publisher.

Abstract

Abstract

Rotator cuff tendinopathy is associated with decreased function and restricted range of motion (ROM) of the shoulder. Hyaluronic acid(HA) injections have been used for the management and pain relief. The objective of this study is to compare the efficacy of HA with steroids, Placebo(normal saline), physical therapy, Lignocaine, PRP, and ESWT.

PRISMA guidelines were followed for the literature search. The literature search was done on PubMed, Embase and Cochrane, using multiple search terms or derivatives until 20th March 2023. 18 RCTs meeting the eligibility criteria were included. Quality assessment was done using the Newcastle Ottawa score and GRADE criteria and risk assessment using risk of bias 2 tool. Quantitative analysis was done on VAS and constant murphy score whereas Qualitative analysis was done on ROM, DASH, UCLA and ASES. The follow-up period was up to 12 months.

Eighteen studies (1773 rotator cuffs) were pooled in the Systematic Review and Meta-analysis. GRADE assessment had high quality for VAS and Constant score. The Newcastle Ottawa Score ranged from 4 to 6. Significant improvement (p ​< ​0.05) in VAS and constant murphy score was seen on comparing HA with Physical therapy and PRP on short-term follow-up(1 & 3 months) with insignificant results on comparing HA with placebo(normal saline) and steroids. Significant improvement in DASH scores on comparing HA with physiotherapy. No significant change was seen in ROM, UCLA and ASES scores on comparing HA with steroid injections.

Intra-articular HA injection in RC tendinopathy is associated with improved VAS score and functional outcome score. HA as well as steroids both are found to be effective with no significant difference. But the risk of complications is more with steroids as suggested by the literature. More specific RCT between the two might be needed to provide a clear picture in terms of both efficacy and complications.

Therapeutic Level I.

Systematic Review and Meta-analysis.

Keywords

Rotator cuff tendinopathy
Shoulder pain
Hyaluronic acid
Shoulder range of motion
VAS score
Constant shoulder score
RCT
HA
LMW
HMW
PT
PRP
NS
ESWT
PubMed
1

1 Introduction

Rotator cuff pathology is seen in all ages with tears having a progressive incidence as age increases,1,2 with incidence ranging from 0.3 to 5.5%.3 They may be symptomatic in a few and may be asymptomatic in others as per the morphology of the tears. However, the progression of these tears is well documented and long-standing tears may eventually progress to cuff tear arthropathy.4 The initial management of symptomatic cuff tears includes rest, oral NSAIDs (Non-Steroidal Anti Inflammatory Drugs),5 physical therapy,6 joint rehabilitation exercises, topical agents,7 TENS (Transcutaneous Electric Nerve Stimulation) and ultrasound therapy,8 injection of steroids,9 hyaluronic acid, Platelet Rich Plasma,10 Dextrose11 and Local Anesthetics(LA).12 Magnetic resonant imaging and ultrasonography could aid in diagnosis.13,14

Hyaluronic acid (HA) is a glycosaminoglycan made of repeating units of N-acetyl glucosamine and D-glucuronic acids.15 It binds with molecules such as CD-44, Intracellular adhesion molecule-1 (ICAM-1), and other various molecules to modulate cell migration and proliferation.16 HA injection is useful for tendon disorders as shown by many clinical trials. In Achilles tendinopathy, HA improves tendon healing and reduces adhesion. Also in hand surgery, HA improves ROM, reduces friction and adhesion, and provides lubrication on tendon surfaces.17–19 High molecular weight HA, mobile reticulum HA, and crosslinked HA is considered useful for the treatment of Osteoarthritis.20 These molecules reduce the need for NSAIDs and delay the need for joint replacement. The role of HA in cuff tear lesions is less understood in terms of the outcomes and complications. There exists minimal evidence to support the use of HA in rotator cuff lesions. The current literature lacks a well-structured, high quality and outcome-based assessment of the use of HA in rotator cuff lesions.

The current study aims to mitigate the above lacunae in the literature concerning the use of HA in rotator cuff lesions. The review further aims to assess the outcomes and compare the use of HA with other modalities of treatment using randomized controlled trials. Though there is a wide spectrum of intra-articular injections being used for such patients, no clear-cut literature states the most effective therapy. With this study, we aim to provide a clear picture using the various functional scores. It was hypothesized that hyaluronic acid reports better functional outcomes in patients with rotator cuff tendinopathy compared to conservative management, physical therapy and other injectable modalities like corticosteroids, local anaesthetics and placebo.

2

2 Materials and method

2.1

2.1 Eligibility criteria

All the studies in the English language which fulfilled the inclusion criteria were included. These include 1) Randomized control trials 2) A minimum of 1 month of follow up 3) Comparison of HA vs any other modalities in rotator cuff lesions. The exclusion criteria included duplicates, articles in other languages, case reports, case series, posters, and articles with no comparison groups. We also excluded studies having low Newcastle Ottawa scores and studies with outcomes that were given low GRADE for quality.

2.2

2.2 Search strategy

PRISMA guidelines (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) were followed for the literature search.21 PICO algorithm was used to guide the search (Table 1). The literature search was done on data platforms like PubMed, Embase, and Cochrane, using search terms or derivatives until 20th March 2023. The search was done using the terms ("HA" OR "Hyaluronic acid" OR "Sodium Hyaluronate" OR "Hylan" OR "Hyaluronate Sodium" OR "hyaluronan") AND ("rotator cuff" OR "rotator cuff lesions" OR "RC tear" OR "Shoulder tendinopathy"). To increase the efficiency of the search outcomes, Boolean operators “AND” or “OR” were utilized in various combinations possible. Pubmed listed 172 results, Embase listed 465 results and Cochrane listed 52 results using these search terms. With this, all relevant abstracts and bibliographies were extracted. Full-text articles were obtained after screening the title and abstract which fulfilled the inclusion criteria.

Table 1 PICO algorithm.
Population Rotator Cuff tendinopathy
Rotator Cuff tear
Gleno-humeral osteoarthritis
Osteoarthritis
Adhesive capsulitis
Intervention Intra-articular injections (Steroid, PRP, LA, HA-LMW or HMW, Normal saline – placebo); Physical therapy; ESWT
Comparison HA vs Steroid; HA vs placebo; HA vs PRP; HA vs physical therapy; HA vs LA
Outcomes VAS score; Constant Murphy score; Shoulder ROM; DASH; UCLA; ASES score
2.3

2.3 Selection and data collection

We used the same set of search terms for all the databases. After the removal of duplicates, 3 independent reviewers screened the titles and abstracts. In case the study appeared potentially eligible, full texts were derived. All the relevant articles were screened for our criteria mentioned earlier. A collaborated MS excel sheet was used to club results with different colour backgrounds. Using an excel sheet the reviewers assessed the study design, methodology, intervention, follow up and demographic data. Only the randomized trials fitting the criteria were included in this study.

2.4

2.4 Data items

For all the studies included, data were extracted by two independent reviewers: Author, year of publication, type of study, age of control and intervention group, sex, sample size, follow-up period, the intervention done and the outcome measurements. Quality assessment was done for all the studies included. Newcastle and Ottawa Score was used to evaluate the quality of each study (Table 2). It includes a set of 8 questions for comparative studies. It includes selection, comparability, and study outcomes and analyses up to adequate statistical data with each question giving 0 or 1 point according to fulfilment of question by study. The quality appraisal for all the studies was done, and in case of any disagreements, it was reassessed by the second author and finalized.

Table 2 Newcastle and Ottawa score.
S.N. Author(Year) Selection Comparability Outcomes Total Remarks
1 Shibata et al. 200136 ∗∗ ∗ ∗∗∗ 6 Fair
2 Blaine et al. 200822 ∗∗ ∗ ∗∗ 5 Fair
3 Meloni et al. 201830 ∗∗ ∗ ∗∗ 5 Fair
4 Chou et al. 201025 ∗∗ ∗ ∗ 4 Poor
5 Ozgen et al. 201034 ∗∗ ∗ ∗ 4 Poor
6 Byun et al. 201123 ∗∗ ∗ ∗∗ 5 Fair
7 Kim et al. 201229 ∗∗ ∗ ∗ 4 Poor
8 Penning et al. 201235 ∗∗ ∗ ∗∗ 5 Fair
9 Moghtaderi et al. 201332 ∗∗ ∗ ∗∗ 5 Fair
10 Merolla et al. 201331 ∗∗ ∗ ∗∗∗ 6 Fair
11 Huang et al. 201628 ∗∗ ∗ ∗∗ 5 Fair
12 Flores et al. 201726 ∗∗ ∗ ∗∗ 5 Fair
13 Frizziero et al. 201727 ∗∗ ∗ ∗∗∗ 6 Fair
14 Cai et al. 201824 ∗∗ ∗ ∗∗ 5 Fair
15 Mohebbi et al. 202133 ∗∗ ∗ ∗∗∗ 6 Fair
16 Esmaily et al.(2021)37 ∗∗ ∗ ∗∗∗ 6 Fair
17 Rezasoltani et al. (2021)38 ∗∗ ∗ ∗∗ 5 Fair
18 Pellegrino et al. (2022)42 ∗∗ ∗ ∗∗ 5 Fair
2.5

2.5 Assessment of risk of bias

To assess the bias, we used Cochrane's Risk of bias tool (Version 2.0, Denmark)22 using Revman web (version 1.22.0, Cochrane Collaboration) for all the RCTs. 3 studies showed a high risk of bias, 6 studies resulted in some concerns whereas 8 studies had a low risk of overall bias. The highest bias was seen in the measurement of the outcome followed by selection of the reported results (Table 3).

Table 3 Risk of Bias 2 tool.
2.6

2.6 Assessment of quality of recommendation

We performed the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) to rate the quality of the evidence for the outcomes using Grade pro (McMaster University, 2022).23 The level of evidence is divided into high, moderate, low and very low. The studies included are randomized trials, with consistent and precise results. Confounding factors were eliminated.24 (Table 4).

Table 4 Author(s): Question: Hyaluronic acid compared to other modalities for [health problem and/or population].
Certainty assessment № of patients Effect Certainty Importance
№ of studies Study design Risk of bias Inconsistency Indirectness Imprecision Other considerations Hyaluronic acid other modalities Relative (95% CI) Absolute (95% CI)
VAS (follow-up: range 1 months to 6 months)
8 randomised trials not serious not serious not serious not serious none -/298 -/268 not estimable ⨁⨁⨁⨁High
Constant Murphy Score (follow-up: range 1 months to 6 months)
5 randomised trials not serious not serious not serious not serious none -/165 -/171 not estimable ⨁⨁⨁⨁High
Shoulder Range of Motion (follow-up: range 1 months to 12 months)
7 randomised trials seriousa not serious not serious not serious none -/267 -/258 not estimable ⨁⨁⨁◯Moderate
Disability of Arm shoulder and hand (follow-up: range 1 months to 6 months)
4 randomised trials seriousa not serious not serious not serious none -/126 -/125 not estimable ⨁⨁⨁◯Moderate
University of California at Los Angeles (follow-up: range 1 months to 6 months)
1 randomised trials seriousa not serious not serious not serious none -/38 -/40 not estimable ⨁⨁⨁◯Moderate
American shoulder and elbow surgeons standardised shoulder assessment (follow-up: range 1 months to 6 months)
2 randomised trials seriousa not serious not seriousa seriousa none -/86 -/89 not estimable ⨁⨁◯◯Low
a Measurement of the outcomes not adequate.
2.7

2.7 Data synthesis

The data were extracted and included demographic details, intervention details, type of injection, the mean follow-up, and outcome measures on follow-up. Guidelines of the Oxford Centre for Evidence-based Medicine were followed to find out the level of evidence of all the studies included in the review. Continuous data were expressed as mean and standard deviation and the dichotomous data as events and total. The mean difference (MD) with a 95% confidence interval is reported for continuous variables and the odds ratio (OR) for dichotomous variables.

The data was extracted using Microsoft Excel software (Version 2019, United States) and a meta-analysis was performed using Revman software (Version 5.3, Denmark). The random-effects model was utilized assuming that there is a mean specific population effect size about which the study-specific effect varies, taking into account the heterogeneity between the studies including the study designs and it provides a conservative evaluation than the fixed effects for the significance of the association.

3

3 Results

3.1

3.1 Search results

Of the 689 citations identified through literature searches, 145 were assessed for eligibility. Eighteen studies25–42 met all of our inclusion criteria stated previously. A total of 1773 rotator cuffs were included in these seventeen studies. The search results have been depicted by a flowchart (Fig. 1).

PRISMA flowchart of Study.
Fig. 1 PRISMA flowchart of Study.
3.2

3.2 Study characteristics

The mean age of the patients was 51.67 years and 52.53 years in the intervention and control groups respectively. 851 were males and 922 were females. 1102 interventions in the form of Subacromial injections (HA, steroid, PRP, ESWT) and 671 were controls (placebo/physical therapy). The mean postoperative follow-up was 4.5 months. The study characteristics and patient characteristics are listed in Table 5. The various outcome measures reported by these studies are listed in Table 6. The comparison is done on a funnel plot (Fig. 2).

Table 5 Study Characteristics of the participants in the study.
S.N. Author(year) Type of study(prospective vs retrospective) Age(Mean) Sex(female/male) Sample Follow-up duration (months) Intervention done
1 Shibata et al. 200139 Prospective RCT Control ​= ​62.4 ​± ​8.6, HA ​= ​59.5 ​± ​9.1 Control ​= ​12/28, HA ​= ​11/27( Control ​= ​40, HA ​= ​38 6 HA Vs Steroid (control)
2 Blaine et al. 200825 Double blind RCT Control ​= ​63.6 ​± ​12.3; for HA= At 3 doses of HA(62.3 ​± ​12.7), 5 doses of HA(63.4 ​± ​12.4) Control ​= ​118/103,HA ​= ​111/107 ​at 3 doses, 114/107 ​at 5 doses Control ​= ​221, HA ​= ​218 ​at 3 doses and 221 ​at 5 doses. 6.5 HA vs Saline(control)
3 Meloni et al. 200833 Prospective RCT N/A N/A Control ​= ​28, HA ​= ​28 26 HA vs Saline(control
4 Chou et al. 201028 Double blind RCT Control ​= ​52.38 ​± ​8.95, HA ​= ​51.16 ​± ​7.84 Control ​= ​16/10, HA ​= ​16/9 Control ​= ​26, HA ​= ​25 1.5 HA vs Saline(control
5 Ozgen et al. 201037 Prospective RCT Control ​= ​52.50 (8.83 ​± ​2.55), HA ​= ​58.67 (9.80 ​± ​2.83) Control ​= ​9/3, HA ​= ​9/3 Control ​= ​12, HA ​= ​12 27 HA vs Physical therapy(control)
6 Byun 201126 Prospective RCT Control ​= ​55.4 ​± ​10.0, HA ​= ​55.5 ​± ​12.1 Control ​= ​10/3, HA ​= ​10/3 Control ​= ​13, HA ​= ​13 1 HA ​+ ​Steroid ​+ ​lignocaine vs Steroid ​+ ​Lignocaine(control)
7 Kim et al. 201232 Prospective RCT Control ​= ​54.1 ​± ​7.7, HA ​= ​55.9 ​± ​7.9 Control ​= ​25/17, HA ​= ​27/11 Control ​= ​42, HA ​= ​38 3 HA Vs Steroid (control)
8 Penning et al. 201238 Prospective RCT Control ​= ​54, HA ​= ​53, steroid ​= ​52 Control ​= ​31/24, HA ​= ​27/24, steroid ​= ​27/26 Control ​= ​55, HA ​= ​51, steroid ​= ​53 6.5 HA vs Steroid vs Saline(control)
9 Moghtaderi et al. 201335 Double blind RCT N/A Control ​= ​12/8, HA ​= ​12/8 Control ​= ​20, HA ​= ​20 3 HA vs Saline(control
10 Merolla et al. 201334 Prospective, randomized Control ​= ​51 ​± ​2.64, HA ​= ​49 ​± ​2.35 Control ​= ​11/12, HA ​= ​11/14 Control ​= ​23, HA ​= ​25 6 HA vs Physical therapy(control)
11 Huang et al. 201631 Double blind RCT Control ​= ​62.5, HA ​= ​61, Control ​= ​3/7,HA ​= ​6/10 Control ​= ​10, HA ​= ​16 1 HA vs Saline(control
12 Flores et al. 201729 Prospective RCT Control ​= ​38.0 (13.1), HA ​+ ​PT ​= ​42.3 (11.5) Control ​= ​22/20, HA ​+ ​PT ​= ​17/24 Control ​= ​42, HA ​+ ​PT ​= ​41 3 HA ​+ ​Physical therapy vs Physical therapy(control)
13 Frizziero et al. 201730 Prospective single blind RCT Control ​= ​58.5, HA ​= ​58.2 Control ​= ​13/4, HA ​= ​13/4 Control ​= ​17, HA ​= ​17 3 HA vs ESWT(control)
14 Cai et al. 201827 Prospective RCT Control ​= ​39.87 ​± ​8.96, Intervnetion; HA ​= ​38.93 ​± ​7.35, PRP ​= ​40.56 ​± ​7.85, HA ​+ ​PRP ​= ​39.63 ​± ​7.65 Control ​= ​20/27, intervention; HA ​= ​24/20, PRP ​= ​23/22 HA ​+ ​PRP ​= ​22/26 Control ​= ​47, intervention; SH ​= ​44, PRP ​= ​45, HA ​+ ​PRP ​= ​48 12 HA vs PRP vs HA ​+ ​PRP vs NS(control)
15 Mohebbi et al. 202136 Triple blind RCT Control ​= ​47.1 (13.2), LMW HA ​= ​48.4 (12.5) Control ​= ​17/11, i LMW HA ​= ​19/9 Control ​= ​28, LMW HA ​= ​28 3 LMW HA vs HMW HA(control)
16 Esmaily et al. 202140 Triple blind RCT Control ​= ​54.1 (11.4), LMW HA ​= ​48.4 (12.5), HMW HA ​= ​46.6 (13.2), Control ​= ​14/10, LMW HA ​= ​17/11, HMW HA ​= ​19/8, Control ​= ​24, intervention with lmw HA ​= ​28, HMW HA ​= ​27, 6 LMW HA vs HMW HA vs Physical therapy(control)
17 Rezasoltani et al. 202141 Randomized RCT Control ​= ​47.07 (13.23), HA ​= ​55.52 (8.16) Control ​= ​12/11, HA ​= ​19/9 Control ​= ​23, HA ​= ​28 6 HA vs Physical therapy(control)
18 Pellegrino et al. 202242 Randomized RCT 50.8 17/23 Control ​= ​20, HA ​= ​20 2 ESWT vs ESWT ​+ ​HA
Table 6 Study intervention and outcome measures.
Author Intervention Outcome measures
Shibata et al. 200139 Sodium Hyaluronate injection Vs Steroid injection UCLA score; Range of motions
Blaine et al. 200825 Sodium hyaluronate injection(3 and 5 weekly) vs control group(saline) Night pain reduction; Range of motion; global assessment score
Chou et al. 201028 Sodium Hyaluronate injection Vs Sodium chloride Constant score; VAS score; global assessment score; global tolerability assessment
Ozgen et al. 201037 Sodium Hyaluronate vs physical therapy VAS score; range of motion and functional evaluation; Patients global effectiveness
Byun 201126 Sodium hyaluronate ​+ ​steroid vs steroid VAS of shoulder pain, active range of motion (AROM), shoulder function assessment scale (SFA), shoulder disability questionnaire (SDQ)
Kim et al. 201232 Sodium Hyaluronate injection Vs Steroid injection VAS; ASES score; Range of motion
Penning et al. 201238 Sodium Hyaluronate injection Vs Steroid injection Vs Saline VAS; Constant score; shoulder disability questionnaire (SDQ); Shoulder pain score; Functional Mobility test(FMT); Patient specific disability(PSD); Range of movements
Moghtaderi et al. 201335 Sodium Hyaluronate injection Vs Sodium chloride VAS; Constant score
Merolla et al. 201334 Sodium Hyaluronate vs physical therapy VAS score for pain (0–100), Oxford Shoulder Score (OSS), and Constant–Murley Score (CS)
Huang et al. 201631 Sodium Hyaluronate injection Vs Sodium chloride VAS score; range of motion; Fugl-Meyer assessment (FMA-UE)
Flores et al. 201729 physical therapy ​+ ​subacromial HA injections vs physical therapy only VAS; activity of daily life (ADL); Tampa Scale for Kinesiophobia (TSK)
Frizziero et al. 201730 LMW-HA VS low-energy ESWT DASH scale; Constant Murley scale
Meloni et al. 201833 Sodium Hyaluronate injection Vs Sodium chloride VAS, Range of motion
Cai et al. 201827 NS vs SH vs PRP vs PRP ​+ ​SH VAS; Constant score; ASES score
Mohebbi et al., 202136 HMW-HA vs LMW-HA VAS; DASH; Quality of life (QOL); ROM
Rezasoltani et al. 202141 LMW HA vs Physiotherapy VAS; DASH; Quality of life (QOL); ROM
Esmaily et al. 202140 HMW HA vs LMW HA vs Physiotherapy VAS; DASH; Quality of life (QOL); ROM
Pellegrino et al. 202242 ESWT vs ESWT ​+ ​HA Self-perceived pain, Disability of arm
Funnel plot of study.
Fig. 2 Funnel plot of study.

The GRADE of this study was found to be high for VAS and Constant murphy, moderate for ROM, DASH and UCLA scores and low for ASES scores.

4

4 Synthesis of results

4.1

4.1 Quantitative outcomes

4.1.1

4.1.1 VAS score

It was used to compare pain perception before and after the intervention. 6 studies27,28,32,34,35,38 compared VAS less than equal to 1 month which revealed no added benefit in the experimental group over the control group(M.D. of 0, 95% CI of −0.80 to 0.80). According to the forest plot, statistically significant results in comparing HA with physical therapy and PRP at 1 month were seen, with no effective results compared to steroid or placebo (Fig. 3). 7 studies27,28,32,34,38,40,41 were used to compare at 3 months (MD ​= ​−0.63; 95% CI of −1.57 to 0.31) and forest plot derived. Statistically significant results (p ​< ​0.05) favouring HA over PRP and physical therapy were seen (Fig. 4). 3 studies27,34,38 at 6 months or more (MD ​= ​−0.40; 95% CI of −1.97 to 1.18) showed more reduction in VAS score compared to control groups on long term follow-ups, however, none of them was statistically significant (Fig. 5). Heterogeneity was found to be high (I2 - 99%). The model takes random effects and determines that the comparability is statistically insignificant (p ​> ​0.05).

Analysis of VAS score at 1 month or less.
Fig. 3 Analysis of VAS score at 1 month or less.
Analysis of VAS score at 3 months.
Fig. 4 Analysis of VAS score at 3 months.
Analysis of VAS score at 6 months or more.
Fig. 5 Analysis of VAS score at 6 months or more.
4.1.2

4.1.2 Constant murphy score

This scale was used to determine the level of pain and functionality after treatment for rotator cuff tendinopathy. The test consists of 4 parameters – 1) Pain, 2) activities of daily living, 3) range of motions HA and 4) strength.

3 studies27,28,38 compared constant scores at 1 month (MD ​= ​−0.76; 95% CI of −9.86 to 8.35). No significant result seen as depicted by forest plot (Fig. 6). 4 studies27,34,35,38 at 3 months (MD ​= ​1.00; 95% CI of −7.41 to 9.42) depicted HA to be superior to physical therapy but inferior to steroids, both statistically significant (Fig. 7). 2 studies27,38 at 6 months or more (MD ​= ​−0.82; 95% CI of - 11.94 to 10.30) depicted higher efficacy of steroids over HA with no difference when compared to placebo/normal saline (Fig. 8). Heterogeneity was found to be high (I2 - 100%). The model takes random effects and determines that the comparability is statistically insignificant (p ​> ​0.05).

Analysis of Constant score at 1 month.
Fig. 6 Analysis of Constant score at 1 month.
Analysis of Constant score at 3 months.
Fig. 7 Analysis of Constant score at 3 months.
Analysis of Constant score at 6 months or more.
Fig. 8 Analysis of Constant score at 6 months or more.
4.2

4.2 Qualitative outcomes

4.2.1

4.2.1 Shoulder range of motion (ROM)

The Shoulder Range of Motion was compared in 7 studies. 3 studies compared HA with steroids. A study by Shibata et al.(2001)39 showed significant improvement in Abduction in both groups with poor results in External and internal rotation of the shoulder. In a study by Byun et al.(2011),26 no added benefit was seen with HA at the 1-month follow-up. A study by Kim et al.(2012)32 showed no benefit of HA over Steroid injections up to 3 months of follow-up. 3 studies compared HA with physiotherapy. Ozgen et al. (2010)37 showed statistically significant improvement in the HA group over physiotherapy. Esmaily et al. (2021)40 showed clinically better results in the HA group though not statistically significant. Rezasoltani et al.(2021)41 showed statistically significant improvement in the HA group. Huang et al. (2016)31 showed significant improvement in flexion and abduction in the HA group over the normal saline group.

4.2.2

4.2.2 Disability of the arm shoulder and hand (DASH)

Four studies discussed DASH (Esmaily et al., 2021, Rezasoltani et al., 2021, Mohebbi et al., 2021, Frizziero et al., 2017). According to Esmaily et al. 2021,40 HA preparation (HMW HA & LMW HA) showed significant differences compared with physiotherapy alone. Despite the success of all treatments, HA preparations decreased shoulder disability more quickly than other treatments. Rezasoltani et al. 202141 compared the DASH score between LMW HA and Physiotherapy. HA was significantly more successful in controlling shoulder pain than PT. HA was more effective in decreasing DASH-sports/art scores than PT was in decreasing total DASH and DASH-work scores. Mohebbi et al. 202136 compared the DASH score between LMW HA and HMW HA. DASH scores decreased significantly between baseline and three months in both groups. Frizziero et al. 201730 compared DASH between LMW and ESWT. DASH scores did not differ between the two groups over time.

4.2.3

4.2.3 The University of California at Los Angeles (UCLA) score

Only one author discussed the UCLA score (Shibata et al., 2001),39 he compared Sodium Hyaluronate injection Vs Steroid injection. UCLA scores at 1 month and 6 months were significantly higher, indicating that both groups continued to benefit from the therapeutic effect.

4.2.4

4.2.4 American shoulder and elbow surgeons standardized shoulder assessment (ASES)

ASES discussed by two authors. Kim et al. 201232 compared HA with Steroids. At three weeks, the ASES scores in the hyaluronate and dexamethasone groups began to improve significantly, but at 3 and 6 months, there were no significant differences. Both groups also improved functionally. Cai et al. 201827 compared normal saline, HA, Platelets Rich Plasma (PRP), or SH ​+ ​PRP. A significant increase in ASES score was observed in the HA group after three months, followed by a gradual decline over the next few months. In the PRP and the SH ​+ ​PRP groups, ASES scores had a similar upward trend after the final injection. ASES scores in the SH and SH ​+ ​PRP groups improved significantly over time compared to those in the NS group at 1 and 3 months.

5

5 Discussion

Shoulder pain causes serious disability to one's day-to-day activities with a great amount of morbidity concerning pain and limitation of shoulder movements. It could be due to glenohumeral arthritis (prevalence of 4–26% in the general population),43 rotator cuff tendinopathies like tendonitis, adhesive capsulitis and subacromial bursitis.44 The incidence of adhesive capsulitis in the general population is 3–5%, up to 20% in the diabetic.45

In the literature, there is a paucity of evidence to support the use of Hyaluronic acid for rotator cuff pain. Hyaluronic acid acts as a lubricant, shock absorber and anti-inflammatory substance by reducing leukotrienes and prostaglandin levels, chondroprotection, proteoglycan synthesis, and cartilage matrix alteration.46 Some authors have described the use of Hyaluronic Acid(HA) in degeneration conditions such as osteoarthritis of the Hip, Knee and Ankle.47–50 Pre-operative use of HA in patients undergoing arthroscopic rotator cuff repair increased functional outcomes.51 HA in these studies has been shown to reduce pain and disability however the efficacy may not be long-lasting.

This study identified 689 citations for patients with shoulder pain. The main analysis of primary outcome included 18 large controlled trials which included 1773 patients with rotator cuff tendinopathy comparing the efficacy and functional outcome of Hyaluronic acid injections with corticosteroids, physical therapy, plasma-rich platelets and placebo-like normal saline. We found that intra-articular HA injections were significantly associated with a reduction in pain intensity up to 6 months compared to physical therapy and up to 3 months compared to intra-articular plasma-rich platelets injection. The patients also perceived better functionality according to the constant murphy score when compared to physical therapy. The steroid injections were found to be equally effective in pain reduction when compared to HA injections with perhaps a better constant murphy score. A study by Osti et al. using 11 prospective studies also concluded that HA injections are effective in reducing pain and improving function, without any major complication and could be used as an alternative to cortisone or oral drugs.52

In a recent study by Pellegrino et al., results concluded that ESWT along with HA injections has better functional outcomes compared to ESWT alone and more reduction in pain perception.42 Another review by Mao et al. with 7 RCTs supported the use of HA in frozen shoulder patients. It showed better functionality with similar VAS scores compared to other modalities.53 Both steroid and HA injection improved ROM comparing the pre-treatment condition but no significant results in long-term follow-up. DASH score was also used to assess the improvement in functionality and showed comparable results. HA significantly decreased disability compared to physical therapy. But no benefit was seen over Energy shock wave therapy. Studies show better results when steroids and HA were combined compared to when given alone.54,55

Though the efficacy of steroids is comparable to HA, literature shows evidence of higher complication rates with intra-articular steroid injections ranging from mild-like skin rash to dreadful like septic arthritis,56,57 tendon rupture,58–60 and risk of osteonecrosis.61

Other scores were used like UCLA score, FMT score, Shoulder pain score, FMA-UE, Functional evaluation degree variation, ASES score, OSS score, ADL score, TSK score, PDS-VAS, SDQ and SFA scores showing variable results with no clear-cut proven efficacy. Based on these outcomes we found that HA injections improve the quality of life when compared to physical therapy, PRP and LA injections. Lin et al. in a network meta-analysis concluded that steroids work well in short-term follow-up however, PRP and prolotherapy have better long-term results(>24 weeks).62

The current meta-analysis has the following strengths, 1) This study includes 18 prospective randomized trials including 1773 rotator cuff patients. To the best of our knowledge, this is the highest sample size described in the literature. 2) 15 studies reported ‘Fair’ outcomes according to the Newcastle and Ottawa score of quality assessment. GRADE for outcome quality assessment reported high quality for quantitative outcomes for VAS and Constant murphy. The study has some shortcomings. Firstly, the study has high heterogeneity and the use of various outcome scores made it difficult to evaluate results. The follow-up period also varied in the studies included. Secondly, due to a lack of ample data, the study did not compare complications in various management modalities. Thirdly, 3 studies showed high risk and 6 studies showed some concerns with the risk of bias. There is a need for further studies to compare complications of steroids and HA over a long course of time as both have similar efficacy.

Authors in this study favour use of early intra-articular HA injections over conservative management and physical therapy to improve Quality of life (QOL) and reduce years lived with disability (YLD). Our hypothesis holds partially in this aspect.

6

6 Conclusion

Intra-articular HA injection in RC tendinopathy is associated with improved VAS score and functional outcome score. HA as well as steroids both are found to be effective with no significant difference. But the risk of complications is more with steroids as suggested by the literature. More specific RCT between the two might be needed to provide a clear picture in terms of both efficacy and complications.

Financial support and sponsorship:

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

Conflict of interest statement

The author(s) declared no potential conflicts of interest concerning the research, authorship, and/or publication of this article.

Ethical review committee statement:

Not applicable

Consent to participation:

Not applicable.

Authors’ contribution

B.S.R. - Planning of study, literature search, writing the manuscript, quality assessment of the included studies. S.B. - Data management, outcome assessment, manuscript preparation, revising the manuscript, B.B.N - Literature search, writing the manuscript, quality assessment of the included studies. A.R. - Data management, outcome assessment, manuscript preparation. D.S. - Planning of study, writing and revising the manuscript. M.D. - Planning of study, revising the manuscript, and a corresponding author.

Funding/sponsorship

No funds were provided for this study.

Institutional ethical committee approval

Not applicable to our study.

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