Efficacy and safety of extracorporeal shock wave therapy combined with sodium hyaluronate in treatment of knee osteoarthritis: a systematic review and Meta-analysis

Abstract

OBJECTIVE:

To assess the efficacy and safety of extracorporeal shockwave therapy (ESWT) combined with sodium hyaluronate (HA) for the treatment of knee osteoarthritis (KOA).

METHODS:

PubMed, Embase, the Cochrane Library, Web of Science, China National Knowledge Infrastructure, Wanfang database, China Science and Technology Journal Database, and SinoMed were searched from inception to July 2020. The quality of the randomized controlled trials was evaluated independently by two reviewers according to the criteria in the Cochrane Collaboration for Systematic Reviews. The identified articles were then screened individually using EndnoteX9 for eligibility in this Meta-analysis. The heterogeneity among the articles was evaluated using I2.

RESULTS:

A total of 17 studies, comprising 2000 individuals, were included in this Meta-analysis. The results showed that a significant improvement was observed in knee pain and function based on the clinical efficacy of ESWT combined with HA. Statistical analysis of clinical efficacy showed that [relative risk (RR) = 1.21, 95% confidence interval (CI) (1.12, 1.30), P < 0.01]. Statistical analysis of visual analog scale showed that [standardized mean difference (SMD) = －2.84, 95%CI (－4.01, －1.66), P < 0.01]. Western Ontario and McMaster University osteoarthritis index statistical analysis showed that [SMD = －1.57, 95% CI (－2.52, －0.61), P < 0.01]. Lysholm score statistical analysis showed that [SMD = 1.71, 95% CI (0.98, 2.44), P < 0.01]. In addition, only minor side effects, such as redness and swelling of the skin, were observed.

CONCLUSIONS:

Medium to low quality evidence showed that ESWT combined with HA offers an inexpensive, well-tolerated, safe, and effective method to improve pain and functionality in patients with KOA. However, tightly controlled, randomized, large multicenter trials are warranted to validate the current findings.

1. INTRODUCTION

Knee osteoarthritis (KOA) is a common disease of the motor system occurring, manifested as local chronic pain, swelling, and stiffness. These findings can led to joint malformations, severely affecting the quality of life of some middle-aged and elderly people and also indicating a depressive predisposition.^1,2 With an accelerated aging process of the population, the prevalence of KOA is about 50% in people > 60-years-old, mainly females.^3,⇓-5

Currently, KOA is mostly treated with physical therapy and drug therapy in the early and middle stages, but the efficacy is not yet elucidated.^1,6,7 In order to improve joint function, play a protective role, sodium hyaluronate (HA) was used clinically to inhibit immune injury and promote cartilage repair. However, the effects of HA alone are slow and often require adjuvant treatment with hormone peripheral nerve block.^8,9 Extracorporeal shockwave therapy (ESWT) is a non-operative treatment between traditional physical therapy and surgical treatment that acts by producing and focusing shockwaves into a diseased region of the organization. It has a low risk for treating small body trauma, less complications and cost-effective.^10,⇓-12 Originally, ESWT was used for the treatment of urinary calculi and then gradually extended for the treatment of musculoskeletal system diseases. It is also effective in the treatment of KOA, thereby providing another option for the KOA.^{13,⇓,⇓-16} Several studies demonstrated that ESWT combined with HA in the treatment of KOA was better than HA alone, but no systematic review is yet available.

Meta-analysis (MA) is a quantitative statistical analysis method that obtains comprehensive conclusions through statistical processing of data through quantitative synthesis.^17,18 The systematic review and Meta-analyses are aimed to evaluate the efficacy and safety of ESWT combined with HA in the treatment of KOA to provide an evidence-based reference for clinical treatment.

2. MATERIAL AND METHODS

2.1. Search strategy

The systematic review was performed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses. Databases, such as PubMed, Embase, the Cochrane Library, Web of Science, China National Knowledge Infrastructure, Wanfang database, China Science and Technology Journal Database, and SinoMed, from inception to July 2021, were searched. All search algorithms were structured by Medical Subject Headings (MeSH) and free text terms as follows: “knee osteoarthritis”, “extracorporeal shock wave therapy”, “hyaluronate sodium”. In addition, the reference lists of the relevant articles and reviews were evaluated to identify the potentially eligible studies. The specific search strategy is presented in supplementary Text 1.

2.2. Inclusion and exclusion criteria

The studies were included in accordance with the following criteria: (a) The participants were diagnosed with KOA; (b) Intervention: intra-articular injection of HA combined with ESWT, and exclusion of different energies or modes (e.g. high energy vs low energy, focused vs diffuse) ESWT for comparison between clinical trials; (c) Control group: HA was injected into the joint cavity alone; (d) The primary outcomes were clinical efficacy, visual analog scale (VAS) and Western Ontario and McMaster University osteoarthritis index (WOMAC). The secondary outcomes were Lysholm score and incidence of adverse reactions; (e) Study design: randomized controlled trial (RCT).

Studies were excluded if they met the following criteria: (a) Studies with incomplete or unavailable data; (b) Studies that do not include any of the above outcome indicators; (c) Animal experiments; (d) Reviews, letters, conference papers, editorials, expert opinions, and comment protocols; (e) Languages other than Chinese and English.

2.3. Data extraction

Two researchers independently screened the literature and extracted experimental data. The discrepancies were settled through discussion or negotiation with a third investigator. After excluding duplicate literature through EndnoteX9 and manual screening, relevant data were extracted from the included articles, including author, year of publication, study design type, study sample size, basic patient characteristics (age, gender, and course of disease), intervention measures, treatment parameters, clinical efficacy, VAS, WOMAC, Lysholm score, and adverse events. If the articles did not provide detailed outcomes, the data were requested from the author via e-mail.

2.4. Assessment of risk of bias

Two researchers independently evaluated the risk of bias in the included study and cross-checked the results. The discrepancies could be resolved by discussion with a third investigator. The methodological quality of the RCT was assessed independently using the Cochrane Systematic Review Risk Assessment Tool¹⁸ with respect to randomization, concealment, blindness, data integrity, selective reporting, and other bias data. The risk of bias was determined to be low in the included literature. When one or more of the parameters are not described clearly, the risk of bias is considered unclear. When one or more of the parameters are missing, the risk of bias is high. The quality of evidence for each outcome was determined based on the risk of bias.

2.5. Data synthesis and analysis

Revman5.3 (Cochrane Collaboration, London, UK) and Stata 14.0 (StataCorp LP, Corpus Christi, TX, USA) statistical software were used for Meta-analysis. For continuous variables, mean difference (MD) or standardized mean difference (SMD) was used, while relative risk (RR) or odds ratio (OR) was used for categorical variables, and 95% confidence interval (CI) was provided for each effect.¹⁹ The heterogeneity between the results of the included studies was analyzed using χ ² test, and the heterogeneity was determined by using I ². I ² < 50% was considered as no statistical heterogeneity between the results, and a fixed-effects model was used for Meta-analysis, otherwise the random-effects model was used. Significant clinical heterogeneity was treated by subgroup analysis or sensitivity analysis or by descriptive analysis only.²⁰ On the other hand, sensitivity analysis explored the impact of individual studies by the sequential exclusion of each study.²¹ The test level for Meta-analysis was set as a = 0.05.

3. RESULTS

3.1. Study selection and characteristics

The current study generated 107 records from eights databases. The preliminary evaluation of the titles and abstracts identified 52 potentially eligible studies. Further screening of full texts excluded 35 articles, while 17 studies that met the eligibility criteria were included in the current Meta-analysis.^{22,⇓,⇓,⇓,⇓,⇓,⇓,⇓,⇓,⇓,⇓,⇓,⇓,⇓,⇓,⇓-38} Table 1 shows the basic characteristics of the included studies. Table 2 shows the ESWT parameters of the included studies. The study selection process is shown in Figure 1.

Table 1.

Characteristics of the included RCTs

Study	Sample size EG/CG	Sex (M/F)		Age (years)					Duration of disease (years)			Intervention		Outcome
		EG	CG	EG		CG			EG	CG		EG	CG
Wang KT et al 202022	57/55	28/29	26/29	57.4±10.10		62.18±7.89			4.57±3.24	4.58±3.02		ESWT+HA	HA	①②⑤
Wang GR et al 201923	48/48	20/28	21/27	64.94±4.75		65.28±4.83			5.61±2.26	5.49±2.30		ESWT+HA	HA	④
Sun LM et al 201524	40/38	22/18	20/18	64.10±9.70		63.40±9.50			9.10±7.60	9.60±7.50		ESWT+HA	HA	②④⑤
Su WZ et al 201825	80/80	28/52	24/56	58.35±12.56		57.65±10.53			3.13±0.94	3.22±1.01		ESWT+HA	HA	①②
Pan K et al 201826	25/25	NA	NA	NA		NA			NA	NA		ESWT+HA	HA	②
Meng Y et al 201627	67/65	NA	NA	NA		NA			NA	NA		ESWT+HA	HA	①④
Li ZC et al 201728	39/39	18/21	15/24	65.31±7.56		64.55±8.38			5.52±2.28	5.49±3.45		ESWT+HA	HA	③④
Huang SX et al 202029	27/27	10/17	12/15	48.30±9.60		46.90±6.80			NA	NA		ESWT+HA	HA	④
Han FM et al 201730	38/38	20/18	19/19	59.71±11.87		61.39±11.57			1.47±2.06	1.59±2.14		ESWT+HA	HA	④
Duan JF et al 201631	49/49	18/31	12/37	68.13±5.89		68.13±5.75			5.14±1.14	5.49±3.45		ESWT+HA	HA	①③④
Ding YY et al 201532	50/50	19/31	21/29	68.20±5.90		67.30±6.60			3.30±2.40	3.10±2.20		ESWT+HA	HA	①③④
Chi X et al 201833	43/43	19/24	22/21	60.30±4.70		60.80±4.90			8.50±1.50	8.80±1.70		ESWT+HA	HA	①③④
Liu SC et al 201934	35/35	13/22	15/20	66.80±9.10		68.20±10.30			14.00±3.80	15.20±4.20		ESWT+HA	HA	①②⑤
Yin Q et al 201535	25/25	0/25	0/25	71.34±5.22		71.34±5.22			7.53±2.21	7.53±2.21		ESWT+HA	HA	⑤
Shi CA et al 202036	40/40	14/26	13/27	66.40±9.20		65.40±9.90			8.40±2.10	8.10±2.90		ESWT+HA	HA	①②⑤
Xi FF et al 201937	30/30	14/16	15/15	68.00±7.00		64.00±9.00			6.50±2.20	6.40±2.30		ESWT+HA	HA	①②⑤
Xu H et al 202038	310/310	156/154	150/160	63.20±2.60		64.20±2.80			4.50±0.60	5.10±0.70		ESWT+HA	HA	①③④

Notes: data are presented as mean ± standard deviation. RCT: randomized controlled trial; EG: ESWT+HA; CG: HA; ESWT: extracorporeal shock wave combined with sodium hyaluronate; HA: sodium hyaluronate; M: male, F: female; NA: data not available. ①: visual analog scale, VAS; ②: Western Ontario and McMaster University osteoarthritis index, WOMAC; ③: Lysholm knee score; ④: total effective rate; ⑤: numeric rating scale, NRS.

Table 2.

Extracorporeal shock wave setting parameters

Study	Type	Frequency	Time	Interval of treatment (days)	Intensity of pressure (bar)
Wang KT et al 202022	Focused	2500	5	7	1.5-2.5
Wang GR et al 201923	Focused	1000	5	7	3.0
Sun LM et al 201524	Diffuse	2000-3000	5	7	1.4-3.0
Su WZ et al 201825	Focused	1000-2000	5	7	1.2-2.0
Pan K et al 201826	Focused	1000	5	7	3.0
Meng Y et al 201627	NA	3000-4000	4	2	1.5
Li ZC et al 201728	Diffuse	2000	5	7	3.0
Huang SX et al 202029	NA	NA	4	7	NA
Han FM et al 201730	NA	2500	5	7	3.0
Duan JF et al 201631	NA	2000	5	7	2.0-3.0
Ding YY et al 201532	NA	2000	5	7	2.0-3.0
Chi X et al 201833	NA	2000	10	7	NA
Liu SC et al 201934	NA	4000	8	7	2.5
Yin Q et al 201535	NA	2000	3	7	1.4-2.0
Shi CA et al 202036	Diffuse	2000	5	7	3
Xi FF et al 201937	NA	2000	5	7	2.5
Xu H et al 202038	Diffuse	2000	4	7	2

Notes: NA: data not available.

Figure 1. Process of literature screening.

CNKI: China National Knowledge Infrastructure Database; VIP: China Science and Technology Journal Database; CBM: Chinese Biomedical Literature Database.

3.2. Risk of bias

Among all randomized studies, 7 trials^{22,24,25,27,35-37} explicitly proposed the method of random number table for random grouping, while the other articles only mentioned “random grouping” and did not report the generation method of random sequence. Only one trial²³ mentioned the use of double-blind methods, while the other articles did not mention random occultation and blindness. Also, no dropouts or lost cases were described in any of the trials. In addition to the above methodological quality factors, no other bias was considered, and the risk of bias in the included study is shown in supplementary Figure 1. Overall, the studies were of medium-to-low quality.

3.3. Outcomes of the Meta-analysis

3.3.1. Clinical efficacy

A total of 9 studies^23,24,27-33 were included in this Meta-analysis, comprising 401 cases in the EXWT combined with HA group and 397 cases in the HA group alone. The Meta-analysis of the randomized effect model showed that the difference was statistically significant in the 1-month group^{23, 27, 29-31,33} of follow-up [RR =1.17, 95% CI (1.10, 1.25), P < 0.01] (Figure 2) and the difference was not statistically significant in the 6-months groups (24, 28, 32) of follow-up [RR = 1.33, 95% CI (1.02, 1.73), P = 0.03] (Figure 2). The efficacy of EXWT combined with HA in the treatment of KOA was significantly better than that of HA alone, but no significant advantage was recorded in long-term efficacy.

Figure 2. Meta-analysis of the effective rate of ESWT combined with HA treatment of KOA.

ESWT: extracorporeal shock wave combined with sodium hyaluronate; HA: sodium hyaluronate; CI: confidence interval.

3.3.2. VAS

A total of 10 studies^{22,25,27,31-33,36-38} were included, comprising of 761 cases in the EXWT combined with HA group and 757 cases of the pure HA group. The results of the Meta-analysis of the randomized effect model showed that the differences were statistically significant [SMD = －2.84, 95% CI (－4.01, －1.66), P < 0.01] (Figure 3), and EXWT combined with HA was better than the pure HA group in relieving the pain of KOA.

Figure 3. Meta-analysis of the VAS of ESWT combined with HA treatment of KOA.

ESWT: extracorporeal shock wave combined with sodium hyaluronate; HA: sodium hyaluronate; CI: confidence interval.

3.3.3. WOMAC

A total of 7 studies^{22,24-26,34,36,37} were included, consisting of 307 cases of EXWT combined with HA group and 303 cases of the pure HA group. The results of the random-effects model showed statistically significant differences [SMD = －1.5, 95% CI (－2.52, －0.61), P = 0.001] (Figure 4), and EXWT combined with HA relieved swelling and recovered the joint function better than pure HA in the treatment of KOA.

Figure 4. Meta-analysis of WOMAC of ESWT combined with HA treatment of KOA.

ESWT: extracorporeal shock wave combined with sodium hyaluronate; HA: sodium hyaluronate; CI: confidence interval.

3.3.4. Lysholm knee score, LKS

A total of 5 studies^28,31-33,38 were included, comprising 491 cases in EXWT combined with HA group and 481 of the pure HA group. The results of Meta-analysis of the randomized effect model showed statistically significant differences [SMD = 1.71, 95% CI (0.98, 2.44), P < 0.001]. The EXWT combined with HA in the treatment of KOA was better than pure HA.

3.3.5. Adverse effects (AE)

A total of 4 studies^22,34,36,37 reported AEs, such as aggravated symptoms or local subcutaneous ecchymosis, during the experiment. No AE reported in 2 studies,^24,35 while the remaining studies did not report such reactions. No serious AEs were described. Among these, 227 cases comprised the EXWT combined with HA group and 223 in the pure HA group. Meta-analysis of the fixed effects model showed that the differences were not statistically significant [OR = 0.84, 95% CI (0.44, 1.62), P = 0.61]. Therefore, no significant difference was observed in the incidence of adverse reactions between EXWT combined with HA and pure HA in the treatment of KOA.

3.4. Sensitivity analysis

Due to the obvious heterogeneity in VAS, WOMAC, and Lysholm scores, sensitivity analysis was conducted to determine the source of heterogeneity. After sequential exclusion of the studies, statistical analysis data did not show any directional change, indicating the credibility of the results.

4. DISCUSSION

KOA is a degenerative joint disease with an irreversible process, and the treatment of the early disease could be effectuated via pharmacological (oral and topical use of Traditional Chinese Medicine and nonsteroidal anti-inflammatory drugs) and non-pharmacological methods (acupuncture and massage, functional exercise, and joint cleaning) to relieve symptoms or delay the disease.^1,6,7 The late KOA often uses artificial knee joint replacement. ESWT was initially used to treat urinary calculi but has been extended to treat musculoskeletal disorders and has shown promising clinical results. Further studies indicated that ESWT could relieve joint pain, protect the cartilage, promote bone remodeling, and release soft tissue.^10,⇓-12 The synergistic effect of various mechanisms alleviated the pain and stiffness of the knee joint and improved the joint function in a short duration.^39,⇓-41 Its clinical efficacy was better than the traditional treatment methods, such as NSAIDs, blocking therapy, and cartilage protectants. In addition, some studies have also shown that ESWT has a good therapeutic effect on severe KOA patients.^42,43 The original studies have shown that the clinical effect of ESWT combined with HA in the treatment of KOA is better than HA alone.^{22,⇓,⇓,⇓,⇓,⇓,⇓,⇓,⇓,⇓,⇓,⇓,⇓,⇓,⇓,⇓-38} However, clinical evidence of ESWT combined with HA in the treatment of KOA is yet lacking, and the efficacy and safety of ESWT combined with HA have not been verified.

In this study, the systemic review was used to search for the major medical databases used commonly. The screening process and criteria were developed according to the PRISMA principle, and a total of 15 articles were included to evaluate the efficacy and safety of ESWT combined with HA in the treatment of KOA. Although the number included in this analysis was small, all of the references were clinical RCTs. The quality was evaluated in accordance with the bias risk assessment tools recommended by the Cochrane Guidelines to minimize the errors and reduce various biases.

This analysis showed that the clinical efficacy of ESWT combined with HA in the treatment of KOA was better than pure HA. Due to the varied follow-up time in the included studies, the subgroup analysis was conducted on the 1-month and the 6-months groups. The results showed that the efficacy of EXWT combined with HA in the treatment of KOA was significantly better than pure HA, but there was no significant advantage detected in the long-term efficacy. Also, VAS score analysis showed that ESWT combined with HA in the treatment of KOA was better than HA alone in alleviating joint pain. Ding et al ³² demonstrated that ESWT combined with HA in the treatment of KOA was better than HA alone in alleviating joint pain and improving joint function, with a faster curative effect and longer duration, which was consistent with the results of the present study. According to the WOMAC score, Lysholm scale, and adverse reaction analysis, ESWT combined with HA was better than HA alone in relieving pain and swelling of the joint and improving the joint function and quality of life in patients with no obvious adverse reactions. ESWT combined with HA has the advantages of simple operation, working fast, less injury, high safety, low cost, and no requirement of anesthesia. The follow-up clinical applications widely use ESWT combined with HA therapy for the conservative treatment of patients with KOA. In addition, one study compared the clinical effects of ESWT combined with HA, ESWT alone, and HA alone.²⁵ The results showed that the combined treatment was better than ESWT alone and HA alone in improving the clinical effect and reducing the VAS and WOMAC scores and no obvious adverse reactions. Therefore, to improve the effectiveness and shorten the course of clinical treatment, ESWT could be combined with other treatment methods to achieve a better therapeutic effect. Shi et al ³⁶ compared the clinical effects of ESWT combined with HA and HA alone in the treatment of KOA in elderly women. The results showed that ESWT combined with HA had an exact and lasting effect in the treatment of KOA, with improved knee joint function and no obvious adverse reactions, which was consistent with the results of the present study. Also, obvious heterogeneity was detected in this Meta-analysis, which might be related to the gender and age differences of the included samples. Yin et al ³⁵ assessed the efficacy and safety of ESWT combined with HA in females with KOA. Simultaneously, the heterogeneity could be increased due to the inconsistency of treatment parameters in the experimental group and different follow-up periods of each included study. Chi et al ³³ showed that the interval of ESWT was only 1 d, which was significantly different from other studies with an interval of 7 d. In future studies, the sample size would be increased to reduce the heterogeneity in the analysis.

Nevertheless, the present study has some limitations in this Meta-analysis: (a) Only Chinese and English literature were included, which may have morbidity bias; (b) The included studies were from China, which might affect the generalizability of the results; (c) Most of the included studies did not report randomized methods, allocation concealment, and blinding, which might have a high risk of selectivity and measurement bias; (d) There is a lack of a unified standard for the specifications and frequency of shock wave and hyaluronic acid in various studies that resulted in significant heterogeneity; (e) The evaluation indicators were scores, and the lack of imaging indicators or other significant cytokine-related data made it difficult to determine the clinical applications accurately.

In conclusion, it was rare that the efficacy and safety of ESWT combined with HA for the treatment of KOA were assessed using a systematic review and Meta-analysis. The results suggested that using ESWT combined with HA for treatment of KOA has a beneficial effect on pain relief, physical function, and quality of life, and only minor complications occurred after ESWT combined with HA treatment, which can be a clinical priority.

5. ACKNOWLEDGMENTS

The authors would like to thank all the members of the Center for Evidence-Based Medicine, Lanzhou University, for their help with this study.

6. SUPPORTING INFORMATION

Supporting data to this article can be found online at http://journaltcm.cn.