Abstract
Purpose
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The combination of pharmacological and non-pharmacological interventions is strongly recommended by current guidelines for knee osteoarthritis. However, few systematic reviews have validated their combined efficacy. In this study, we investigated the effects of the combination of pharmacological agents and exercise on knee osteoarthritis.
Methods
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Randomized controlled trials that investigated the efficacy of pharmacological agents combined with exercise for knee osteoarthritis were searched in PubMed, Embase, and Cochrane Library up to February 2024. The network meta-analysis was performed within the frequentist framework. Standardized mean difference (SMD) with 95% CI was estimated for pain and function. Grading of recommendations, assessment, development, and evaluations were used to evaluate the certainty of evidence.
Results
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In total, 71 studies were included. The combination therapy outperformed pharmacological or exercise therapy alone. Among the various pharmacological agents combined with exercise, mesenchymal stem cell injection was ranked the best for short-term pain reduction (SMD: −1.53, 95% CI: −1.92 to −1.13, high certainty), followed by botulinum toxin A, dextrose, and platelet-rich plasma. For long-term pain relief, dextrose prolotherapy was the optimal (SMD: −1.76, 95% CI: −2.65 to −0.88, moderate certainty), followed by mesenchymal stem cells, platelet rich in growth factor, and platelet-rich plasma.
Conclusion
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Exercise programs should be incorporated into clinical practice and trial design. For patients undergoing exercise therapies, mesenchymal stem cell, dextrose, platelet-rich plasma, platelet rich in growth factor, and botulinum toxin A may be the optimal agents.
Introduction
Knee osteoarthritis is a common cause of disability in older adults. Current treatment strategies for knee osteoarthritis can be classified as surgical and non-surgical interventions. Total knee arthroplasty is an effective procedure for end-stage knee osteoarthritis; however, it is associated with the risks of various complications, including intraoperative and postoperative infections, instability, fractures, pain, and discomfort (1). For patients unsuitable for surgery or with mild-to-moderate disease severity, non-surgical interventions are considered (2). According to the European Society for Clinical and Economic Aspects of Osteoporosis, Osteoarthritis and Musculoskeletal Diseases and the Osteoarthritis Research Society International 2019 guidelines (3, 4), the combination of non-pharmacological and pharmacological therapies is strongly recommended as a non-surgical approach. Among the non-pharmacological treatments, exercise programs (aerobic or resistance exercises), patient education, and weight loss (if overweight) comprise the core treatments (3, 4). For symptoms that cannot be alleviated by these non-pharmacological treatments, pharmacological agents have been subsequently added to the treatment regimen (3, 4).
Although the relevant guidelines recommend pharmacological therapies as add-on treatments to exercise, exercise is underused in practice (3). Most systematic reviews and meta-analyses have focused on the efficacy of either exercise or pharmacological treatments; few have investigated their combined effects. Thus, we identified a gap between evidence synthesis from systematic reviews and guideline recommendations. In this systematic review and network meta-analysis, we aimed to investigate (1) the efficacy of the combinations of various pharmacological agents and exercise and (2) the comparative efficacy of pharmacological agents and exercise for knee osteoarthritis.
Methods
Search strategy and selection criteria
This systematic review and network meta-analysis was planned, conducted, and reported in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines (5). The protocol of this study (Method S1 in the Supplement, see section on supplementary materials given at the end of this article) was registered in PROSPERO (CRD42022316479).
Three electronic databases (PubMed, Embase, and Cochrane Library) and three clinical trial registries (ClinicalTrials.gov registry, International Clinical Trials Registry Platform (ICTRP), and International Standard Randomised Controlled Trial Number registry (ISRCTN)) were searched for relevant clinical trials up to February 2024. Randomized controlled trials (RCTs) that examined (1) the efficacy of the combination of pharmacological treatments and exercise or (2) the comparative efficacy of pharmacological treatments and exercise for knee osteoarthritis were included. The search strategy and keywords are summarized in Method S2 in the Supplement. Because exercise is the core treatment in the aforementioned guidelines, (3, 4) exercise served as a reference group in this study. The detailed inclusion criteria of the studies were summarized with the Patient, Intervention, Comparison, Outcomes, and Study criteria (Supplementary Table 1 in the Supplement).
Two reviewers (HYC and CWL) independently extracted important data and resolved disagreements regarding trial inclusion and data extraction by consulting with the other reviewers (CDL and SWH). The following information was collected from each study: bibliography, country, grouping, patient age, patient sex, sample size, Kellgren–Lawrence (KL) grade, disease duration, patients’ body mass index (BMI) values at baseline, pharmacological treatment dosage and duration, exercise program, exercise frequency, other interventions, measured time points, and outcomes.
Network geometry assessment
Network graphs were constructed to visualize the overall structure of the comparison. Each node represented a treatment option. Because of their similar efficacy levels, various nonsteroidal anti-inflammatory drug (NSAID) agents (ibuprofen, diclofenac, tenoxicam, meloxicam, and naproxen) were combined into a single node; similarly, different corticosteroids (methylprednisolone and triamcinolone) and hyaluronic acid agents (low- and high-molecular-weight agents) were combined into their corresponding nodes.
Risk of bias assessment within individual studies
Using the revised Cochrane risk-of-bias (RoB) tool for randomized trials (RoB 2; released on August 22, 2019), two reviewers (HYC and CWL) independently assessed the risk of bias of the included studies (6). Any disagreements between the reviewers regarding the risk of bias appraisal were resolved by consultation with the other reviewers (CDL and SWH). To validate the robustness of the results, sensitivity analyses were performed by excluding studies with a high risk of bias.
Outcome measures
The primary outcome was pain. The secondary outcome was function. The hierarchy of the scales used in the outcome measures is summarized in Method S1 in the Supplement.
Data synthesis and analysis
The data used in this network meta-analysis comprised information of the postintervention scores. For the unreported standard deviations (s.d .), we calculated the values on the basis of standard errors, interquartile ranges, P-values, or 95% CIs using the method described by the Cochrane Handbook (7) and Wan et al. (8) The analysis was based on the timeframe of follow-up. We defined short-term outcomes as those at <6 months and long-term outcomes as those at ≥6 months. For studies with multiple time points, the data obtained at the last follow-up was preferentially used.
A random-effects network meta-analysis was performed within a frequentist framework using the netmeta package of R (version 4.0.4). The effect estimates of pain and function are presented as standardized mean differences (SMDs) with 95% CIs.
Heterogeneity (within designs) was assessed using the T2 and I2statistics. T20.04 indicated low heterogeneity, T2 0.09 indicated moderate heterogeneity, and T2 0.16 indicated high heterogeneity (9). Regarding I2 statistics, I2 25% indicated low heterogeneity, I2 50% indicated moderate heterogeneity, and I2 75% indicated high heterogeneity (9).
Inconsistency (between designs) were assessed using the design-by-treatment model and the Cochrane’s Q test, with P < 0.1 indicating significant global inconsistency. We also used the separate indirect from direct evidence with back-calculation methods to examine local inconsistency between direct and indirect evidence.
To evaluate the relative efficacy of the treatments, the network forest plots were constructed. The ranking probabilities of the treatments’ effect estimates were calculated by evaluating the surfaces under cumulative ranking curves. The results were presented comparing each intervention with a common control group, which was the combination of placebo and exercise.
To identify publication bias, comparison-adjusted funnel plots were constructed, and Egger’s regression asymmetry tests were performed (10). A P-value of <0.1 in Egger’s regression asymmetry tests indicated significant publication bias.
Evaluation of certainty in evidence
The certainty in evidence was evaluated using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach, and the method described by Salanti et al. (11). The evaluation was performed using the online application Confidence in Network Meta-Analysis (CINeMA). Six domains, namely risk of bias, reporting bias, indirectness, imprecision, heterogeneity, and incoherence, were assessed. To help interpret the results, we back-transformed the SMDs to a 100 mm visual analogue scale assuming an s.d. of 25 mm. The minimal clinically important difference of pain was determined to be −0.37 SMD, which corresponds to 9 mm on a 100 mm visual analog scale (12, 13).
Results
Study selection
Figure 1 illustrates the identification, screening, and selection of relevant studies. Potentially relevant studies were retrieved from electronic databases and clinical trial registries. A total of 1627 records were retained after duplicate results were removed. Subsequently, a total of 1564 articles were excluded. Among the excluded studies, 19 seemingly met the inclusion criteria. The reasons for their exclusion are summarized in Supplementary Table 2. In total, 71 studies met the eligibility criteria.
Characteristics and risk of bias of the included studies
A total of 71 studies with 5414 patients were included (Supplementary Table 3). The publication year ranged from 2002 to 2023. The mean age of the patients was mostly from 50–70 years. Their KL grades were mostly between grades II and III. The patients were generally overweight, with a mean baseline BMI of >25 in most studies. Regarding interventions, the following pharmacological agents were used in the treatment arms: glucosamines, chondroitin, intra-articular corticosteroids, NSAIDs (oral, intra-articular, and topical), acetaminophen, opioids, capsaicin, hyaluronic acids, platelet-rich plasma (PRP), platelet rich in growth factor (PRGF), botulinum toxin A, O2–O3, dextrose, and mesenchymal stem cell (MSC). Regarding exercise, most studies included resistance training programs to strengthen the quadriceps femoris muscle. A few studies also added range of motion recovery, stretching, flexibility, aerobic, and balance training in the exercise programs (Supplementary Table 4). However, aquatic exercise was not used in any of the included studies. Supplementary Table 5 summarizes the risk of bias of the included studies.
Primary outcome: pain
Figure 2 illustrates the overall structure of the comparisons. The results of the pairwise meta-analysis of the direct comparisons are depicted in Supplementary Figs 1 and 2 in the Supplement. We performed the network meta-analysis by combining results from both direct and indirect comparisons.
Network graphs. Each node represents a treatment option, and the edges represent the direct comparisons. The size of the nodes was determined by the number of patients in the treatment arm. The thickness of the edges were determined by the number of direct comparisons. BTX-A, botulinum toxin A; CS, chondroitin sulfate; Ex, exercise; GlcN, glucosamine; GRADE, Grading of Recommendations, Assessment, Development, and Evaluations; HA, hyaluronic acid; IA, intra-articular; MSC, mesenchymal stem cell; NSAID, non-steroidal anti-inflammatory drug; PLA, placebo; PO, orally; PP, phonophoresis; PRGF, platelet rich in growth factor; PRP, platelet-rich plasma; SMD, standardized mean difference; SUCRA, surface under the cumulative ranking curve; TOP, topical; UC, usual care.
Citation: EFORT Open Reviews 9, 7; 10.1530/EOR-23-0136
Based on 54 RCTs with 3841 patients, the network meta-analysis of the short-term pain outcome revealed that exercise had equivalent or even superior effects than monotherapy of pharmacological agents (Fig. 3 and Supplementary Table 6). Furthermore, the combination therapy of pharmacological agents and exercise exerted generally greater effects than monotherapies of pharmacological agents or exercise. When combined with exercise, intra-articular injection of MSC (vs placebo plus exercise: SMD: −1.53, 95% CI: −1.92 to −1.13, high certainty), botulinum toxin A (vs placebo plus exercise: SMD: −1.39, 95% CI: −1.79 to −0.98, moderate certainty), dextrose (vs placebo plus exercise: SMD: −1.19, 95% CI: −1.48 to −0.90, moderate certainty), and PRP (vs placebo plus exercise: SMD: −0.98, 95% CI: −1.20 to −0.76, moderate certainty) were the optimal treatments for short-term pain reduction.
Forest plot of the short-term primary outcome. BTX-A, botulinum toxin A; CS, chondroitin sulfate; Ex, exercise; GlcN, glucosamine; GRADE, Grading of Recommendations, Assessment, Development, and Evaluations; HA, hyaluronic acid; IA, intra-articular; MSC, mesenchymal stem cell; NSAID, non-steroidal anti-inflammatory drug; PLA, placebo; PO, orally; PP, phonophoresis; PRGF, platelet rich in growth factor; PRP, platelet-rich plasma; SMD, standardized mean difference; SUCRA, surface under the cumulative ranking curve; TOP, topical; UC, usual care.
Citation: EFORT Open Reviews 9, 7; 10.1530/EOR-23-0136
Based on 38 RCTs and 3067 patients, the network meta-analysis of the long-term pain outcome revealed that when combined with exercise, dextrose (vs placebo plus exercise: SMD: −1.76, 95% CI: −2.65 to −0.88, moderate certainty), MSC (vs placebo plus exercise: SMD: −1.61, 95% CI: −2.08 to −1.04, high certainty), PRGF (vs placebo plus exercise: SMD: −1.19, 95% CI: −1.74 to −0.65, high certainty), intra-articular NSAIDs (vs placebo plus exercise: SMD: −1.12, 95% CI: −1.75 to −0.48, low certainty), and PRP (vs placebo plus exercise: SMD: −1.06, 95% CI: −1.41 to −0.71, moderate certainty) exerted the strongest effects on pain relief (Fig. 4 and Supplementary Table 6). We were unable to evaluate the efficacy of botulinum toxin A for the long-term outcome.
Forest plot of the long-term primary outcome. BTX-A, botulinum toxin A; CS, chondroitin sulfate; Ex, exercise; GlcN, glucosamine; GRADE, Grading of Recommendations, Assessment, Development, and Evaluations; HA, hyaluronic acid; IA, intra-articular; MSC, mesenchymal stem cell; NSAID, non-steroidal anti-inflammatory drug; PLA, placebo; PO, orally; PP, phonophoresis; PRGF, platelet rich in growth factor; PRP, platelet-rich plasma; SMD, standardized mean difference; SUCRA, surface under the cumulative ranking curve; TOP, topical; UC, usual care.
Citation: EFORT Open Reviews 9, 7; 10.1530/EOR-23-0136
Secondary outcome: function
Based on 54 RCTs with 3845 patients and 38 RCTs with 2983 patients for the short- and long-term outcomes, respectively, the results of the network meta-analysis of function mirrored those of the network meta-analysis of pain. When combined with exercise, MSC, botulinum toxin A, dextrose, and PRP were ranked the best for the short-term function improvement, and dextrose, MSC, PRGF, intra-articular NSAIDs, and PRP were the optimal treatments for the long-term outcome (Supplementary Figs 3 and 4).
Placebo effect
To investigate the potential placebo effects, we revised the study protocol and separated the group of placebo plus exercise from that of exercise alone (Method S1 in the Supplement). Compared with exercise alone, the combination of placebo and exercise was not found to be more efficacious (short-term pain: SMD: 0.27, 95% CI: 0.05 to 0.49; long-term pain: SMD: 0.30, 95% CI: −0.13 to 0.73; short-term function: SMD: 0.04, 95% CI: −0.22 to 0.30; long-term function: SMD: 0.19, 95% CI: −0.16 to 0.54; Figs 3 and 4, and Supplementary Figs 3 and 4 in the Supplement), indicating that the placebo effect may not be substantial in our analysis.
Sensitivity analysis
To evaluate the impact of risk of bias on the results, we performed sensitivity analyses that only included RCTs with low risk of bias arising from the randomization process, bias due to deviations from intended interventions, and bias due to missing outcome data. The results of the sensitivity analyses were consistent with those of the main analyses (Supplementary Table 6), indicating the robustness of our results.
Heterogeneity, inconsistency, and publication bias
The network analysis exhibited low heterogeneity and nonsignificant inconsistency (Figs 3 and 4). Comparison-adjusted funnel plots were constructed (Supplementary Fig. 5 and 6). Egger’s regression asymmetry test revealed no significant publication bias.
Discussion
This network meta-analysis revealed the superiority of the combination of pharmacological and exercise interventions over single therapeutic approaches. Among the combination therapies, MSC, dextrose, PRP, PRGF, and botulinum toxin A were the pharmacological agents that exhibited the highest efficacies for pain reduction and physical function restoration with moderate-to-high certainty. The results exhibited low heterogeneity, inconsistency, and publication bias. The sensitivity analyses confirmed the robustness of the results.
According to the aforementioned guidelines, different exercise modalities, including resistant, aerobic, aquatic, and even mind–body approaches, are all strongly recommended and form the core treatment for knee osteoarthritis (3, 4). The prescription of pharmacological agents is also suggested to be accompanied with non-pharmacological treatments (3, 4). Despite the benefits, exercise is clinically underused. In this study, the combination of pharmacological and exercise interventions outperformed the single therapies, which supported the guideline recommendations. Therefore, exercise programs should be routinely incorporated in clinical practice and the study design of future clinical trials.
Prior to the present study, few systematic reviews have been performed on the combination of pharmacological treatments and exercise for knee osteoarthritis. Monticone et al. systematically reviewed the efficacy of the combination of intra-articular hyaluronic acid and exercise (14). Intra-articular hyaluronic acid alone and in combination with exercise alleviated joint disability and pain (14); however, the two included trials were inconsistent regarding whether the combination therapy or injection therapy alone outperformed the other (15, 16). A scoping review (17) conducted in 2022 investigated the efficacy of injection therapies (intra-articular hyaluronic acid or PRP) for athletes. The injection therapies improved both joint pain and physical function. However, the findings could not be generalized because only soccer athletes with early osteoarthritis were included (17). Liao et al. (18) performed a network meta-analysis to investigate the efficacy of the combination of injection therapies and physical therapies. The results supported the use of MSC, dextrose, PRP, PRGF, and botulinum toxin A in combination with physical therapy. However, because of the wide variety and heterogeneity of the physical therapy modalities, the effect of exercise therapy could not be evaluated. Two previous network meta-analyses have compared the analgesic effect of NSAIDs with exercise (19, 20). Exercise showed equivalent effects to those of NSAIDs, a result that was consistent with those of our study. However, the authors did not evaluate the combined efficacy of NSAIDs and exercise. To our knowledge, this network meta-analysis is the first study to comprehensively review the effects of the combination of various pharmacological agents and exercise on knee osteoarthritis.
Of the pharmacological agents, our findings suggest that intra-articular injections, including MSC, dextrose, PRP, PRGF, and botulinum toxin A, are suitable for patients undergoing exercise therapy. In a network meta-analysis conducted in 2021, Anil et al. compared the efficacy of various intra-articular injections (21). Hyaluronic acids with corticosteroids, PRP, and stromal vascular fractions were optimal for pain and functional outcomes in short-, mid-, and long-term follow-ups, respectively (21). Our findings support the benefits of PRP. However, in our study, the combination of exercise and hyaluronic acids or corticosteroids exhibited an efficacy similar to that of exercise alone. We found no clinical trials on the effects of stromal vascular fractions combined with exercise and thus could not evaluate the effects of stromal vascular fractions in the present study. Notably, the role of exercise in combination with pharmacological treatments was not investigated by Anil et al. Therefore, the treatment strategies for knee osteoarthritis may be different for patients who exercise and those who do not.
In the clinical trials on knee osteoarthritis, placebo effect is a well-documented occurrence (22, 23). However, in this study, no substantial placebo effects were identified in the efficacy of combined pharmacological and exercise interventions compared with exercise monotherapy. Previous studies have suggested that the therapeutic effects of exercise on osteoarthritis may partially stem from the placebo effect (24). Therefore, when exploring the role of the placebo effect in the combination therapy of medication and exercise, it may not be as significant as expected.
This network meta-analysis has some limitations. First, the sample size of the included studies were generally small (<50 patients per treatment arm). Although no significant publication bias (small-study bias) was detected in our analysis, RCTs with larger sample sizes are warranted to validate our findings. Second, we noted a lack of long-term follow-up data regarding the effects of the combination of exercise with botulinum toxin A. Therefore, although botulinum toxin A showed promising results in the short-term outcomes, its long-term effects on knee osteoarthritis remained unknown. Third, although a few included studies focused on the efficacy of the combination of MSC and exercise. The data regarding other cell- or tissue-based therapies were lacking. We were also unable to perform subgroup analyses to investigate the comparative efficacy of different sources and preparations of MSC as this may hinder the statistical power of our analysis. More studies should focus on the combination of cell- or tissue-based therapies and exercise.
In conclusion, the combination of pharmacological and exercise interventions outperformed single therapeutic approaches for the treatment of knee osteoarthritis. Among the pharmacological agents in combination with exercise, MSC, dextrose, PRP, PRGF, and botulinum toxin A are the optimal treatment options with moderate-to-high certainty in evidence. Future studies on knee osteoarthritis are warranted to evaluate the long-term effects of botulinum toxin A as well as cell- and tissue-based therapies in patients undergoing exercise therapy. Large and high-quality clinical studies are required to solidify the current evidence.
Supplementary materials
This is linked to the online version of the paper at https://doi.org/10.1530/EOR-23-0136.
ICMJE Conflict of Interest Statement
The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research reported.
Funding Statement
This work did not receive any specific grant from any funding agency in the public, commercial, or not-for-profit sector.
Author contribution statement
Hsiao-Yi Cheng and Chun-Wei Liang contributed equally to this work. Chun-De Liao and Shih-Wei Huang contributed equally to this work. Conceptualization: Hsiao-Yi Cheng, Chun-Wei Liang, Yu-Hao Lee, Timporn Vitoonpong, Chun-De Liao, and Shih-Wei Huang; data curation: Hsiao-Yi Cheng and Chun-Wei Liang; formal analysis, validation, and visualization: Hsiao-Yi Cheng, Chun-Wei Liang, and Chun-De Liao; writing – original draft: Hsiao-Yi Cheng and Chun-Wei Liang; writing – review and editing: Yu-Hao Lee, Timporn Vitoonpong, Chun-De Liao, and Shih-Wei Huang.
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