Effectiveness of Mobilization with Movement on the Management of Knee Osteoarthritis: A Systematic Review of Randomized Controlled Trials

Background Osteoarthritis is becoming a global major cause of pain and functional disability worldwide, especially in the elderly population. Nowadays, evidence shows that mobilization with movement (MWM) has a beneficial effect on knee osteoarthritis subjects. However, its adequacy remains unclear. Objective To review the best available evidence for the effectiveness of MWMs on pain reduction and functional improvement in patients with knee osteoarthritis. Methods A comprehensive search of literature was conducted using the following electronic databases: Google Scholar, PubMed, Physiotherapy Evidence Database (PEDro), Science Direct, Cochrane Library, and Scopus. Only randomized controlled trials (RCTs) were included, and the methodological quality of the studies was appraised using the PEDro scale. It was reported according to the guideline of the PRISMA statement. Results A total of 15 RCTs having 704 participants were included. The present systematic review suggests that there were significant differences between MWM groups and control groups in terms of visual analogue scale (VAS), Western Ontario and MacMaster Universities Osteoarthritis Index (WOMAC) scale, and flexion range of motion. Conclusions This systematic review demonstrated that MWM was effective to improve pain, range of motion, and functional activities in subjects with knee osteoarthritis.


Introduction
Osteoarthritis (OA) is a chronic degenerative disease characterized by the deterioration of the cartilage in the joints, creating stiffness, pain, and impaired movement [1,2]. Osteoarthritis a leading cause of pain and functional disability in both developed and developing countries, especially in the elderly population [3,4]. e knee joint is the most commonly affected joint by OA due to its weight-bearing requirement, high mobility, and lack of intrinsic stability [5]. It leads to limitations in activities of daily life and impairment in the quality of life because of the accompanying pain and morning stiffness in the joint [6].
According to the World Health Organization (WHO), OA affects 9.6% of men and 18% of women over 60 years of age [7]. Generally, 43.4 million people in the world were affected by OA associated with a disability by the year 2020 [8,9]. Moreover, there is an increasing need for urgent attention to this disease because of the societal trends in the population such as aging, obesity prevalence, and joint injury, estimating that the number of people affected by OA will increase by about 50% over the next 20 years [10,11]. e management of knee OA needs a multidisciplinary approach. e conservative treatment forms for knee OA comprise pharmacological and nonpharmacological modalities. Nonsteroidal anti-inflammatory drugs are mostly used for pain relief and stiffness caused by OA with their numerous side effects, particularly on the gastrointestinal tract, making the treatment unsustainable [12,13], whereas the nonpharmacological treatments such as manual therapy, weight management strategies, kinesiotherapy, resistance strengthening exercise, aerobic conditioning, and physical agent modalities such as electrotherapy were used to relieve pain, to reduce or eliminate complications, and to prevent disease progression for knee OA [14][15][16][17][18][19][20][21].
Mobilization with movement (MWM) is a manual therapy technique that is used most frequently for the management of musculoskeletal conditions [22]. It was initially advocated by Brian Mulligan and has been proposed as a novel manual therapy technique to treat a variety of upper and lower limb joint-related soft tissue conditions [23,24]. In this technique, the physiological movement is performed in a pain-free manner [24] with accessory glides being applied in the direction towards the opposite of the previously painful movement to have the greatest improvement [25].
MWMs has shown promising various therapeutic benefits such as reduction of pain and improved range of motion [23,26]. e rationale for the use of MWM techniques is directed towards correcting positional faults at the joint [27].
Previous evidence has furnished the beneficial effects of MWM on different peripheral joints [23,25,28]. Nowadays, studies mentioned that MWM had a beneficial effect on knee OA patients. Nevertheless, its adequacy remains unclear. erefore, the aim of this review was to analyze the effectiveness of MWM on pain reduction and functional improvement in patients with knee OA.

Design and Protocol Registration.
is systematic review was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guideline [29] with International Prospective Register of Systematic Reviews (PROSPERO) registration number CRD/42020193092.

Search
Strategy. An extensive literature search was performed to identify all eligible randomized controlled trials from inception to September 2020. Systematic and comprehensive searches were conducted in electronic databases such as Google Scholar, Physiotherapy Evidence Database (PEDro), Scopus, Science Direct, Cochrane Library, and PubMed. e search was made using the following keywords: mobilization with movement, knee osteoarthritis, and randomized controlled trial. As the topic titles speckled among the databases, various combinations of the keywords were used: "Mulligan's mobilization/mobilization with movement/sham/placebo mobilization with movement" and "osteoarthritis/knee joint pain/Arthritis/ degenerative knee arthritis" and "randomized controlled trial."

Exclusion Criteria.
e exclusion criteria established for this review were observational studies, quasiexperimental studies, studies not having full access, and RCTs published in other than English languages, and results obtained from theses/dissertations, conference proceedings, abstracts, and websites were excluded from this review.

Study Selection.
e study selection process was performed by four reviewers (G. G, M. H, T. T, and H. M). Only randomized control trials and studies intervening knee OA with MWM were included in this review. Any disagreement between the reviewers should be consulted by two reviewers (G. S and A. A) to reach a consensus.

Hierarchy of Evidence.
Four reviewers independently assessed all sources of the papers, and the level of each study was determined according to the hierarchical system of Lloyd-Smith. e level of evidence reveals the degree to which bias has been considered within study design, with a lower rating on the hierarchy indicating less bias. Merely studies that scored between 1b and 2a on the Lloyd-Smith scale were included in this systematic review. In this approach, we could ensure that MWM for knee OA supported by this review was based on results of high-level evidence.

Data Extraction.
Based on a predetermined extraction tool, three authors (G.G, A.A, and G.S) independently extracted relevant data from each article. e following data were extracted from each trial: general study information (title, authors' name, year of publication, and country of study), OA definition (severity measure, type, and duration), number of participants in the treatment and control group, mean follow-up time, type of treatment, mean age of the participants, inclusion and exclusion criteria of the participants, primary outcome measures, study design, study findings, and conclusions.

Risk-of-Bias Assessment.
e qualities of the eligible studies were assessed using the Physiotherapy Evidence Database (PEDro) Scale [30]. e PEDro scale includes 11 items, in which the first item assesses the external validity and the remaining 10 items assess the internal validity, examining random allocation, concealment of allocation, baseline equivalence, blinding procedure, 'intention to treat' analysis, adequacy of follow-up, between-group statistical analysis, and measurement of data variability. is review considered trials with a score of 5 to 7 as moderate quality and a score of ≥8 as a high-quality study ( Table 1).

Literature Search.
A total of 1198 articles were identified by the searching strategy. After adjusting for duplicates, 768 remained. After the title and abstract screening of studies, 365 studies were expelled. Subsequently, by full content screening out of 38 articles, 15 randomized controlled trials were included in this review (1).

Description of the Studies.
e characteristics of the included studies are illustrated in Table 2.
e included studies were published between 2010 and September 2020. Overall, 704 participants with knee OA aged from 40 to 70 years were included. e average age of the participants ranged from 47.47 ± (0.61) to 58.5 ± (4.36) in the experimental group [38,44] and 47.47 ± (0.61) to 59.4 ± (6.57) [38,44] in the control group. e follow-up duration of the experimental and control group ranged from two days to twelve months [36,40], with the majority of the studies having a follow-up duration of around two to three weeks. e mean PEDro score of the studies was 6.7 (range: 5-9) ( Table 3). Two trials [36,44] scored 8, and four trials [5,35,39,40] scored 9 on the PEDro scale, which was the highest possible score given the intervention, as it would not be feasible to blind clinicians.

Risk of Bias within the Studies.
e methodological qualities of the included studies are summarized and reported in Table 3. Out of the 15 randomized controlled trials, 9 articles reported about the procedure of proper randomization sequence and six randomized controlled trials conducted by Shenouda [31], Gupta and Heggannavar [33], Kulkarni and Kamat [34], Kiran et al. [38], Saddam Hussain Shaik et al. [41], and Pawar et al. [42] had not stated the randomization method. Six trials reported concealed allocation, and the majority of the articles had not clearly reported a concealed allocation method. In study performance bias, merely 3 of the randomized controlled trials were found to be double-blinded and the other remaining articles are single-blinded. Six randomized controlled trials conducted by Lalnunpuii et al. [5], Rao et al. [35], Kaya Mutlu et al. [36], Bhagat et al. [39], Alkhawajah and Alshami [40], and Nigam et al. [44] had a blinded outcome assessor.

Interventions.
Randomized control trials comparing the effectiveness of MWM, MWM combined with conventional physiotherapy and comparison/control group: sham/placebo MWM, and/or conventional physiotherapy, usual care, myofascial release, KT, exercise, McConnell patella taping, and Maitland mobilization intervention were included.

Outcome Measures.
e outcome measures for each of the fifteen trials are presented in Table 2 All the studies included outcome measures for pain and functional disability status. e pain intensity was measured by the Visual Analogue Scale (VAS) in eleven studies [5, 31-34, 36-38, 40, 42, 44], Numerical Pain Rating Scale (NPRS) in three studies [35,39,43], and KOOS in one study [41]. Functional disability status was measured by the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) in ten studies [5, 31-33, 36-38, 40, 43, 44], Time Up and Go in three studies [35,39,44], and 6-minute walk test in one trial [34] for subjects with knee OA.

Effects of MWM on Pain Reduction.
e effects of MWM intervention in subjects with knee OA are summarized in Table 2. Out of the 15 included trials, 14 of them reported that knee pain was significantly improved in the MWM groups compared to the control group [5,31,[33][34][35][36][37][38][39][40][41][42][43][44]. Only one study reported that the MWM group had no improvement in knee pain compared to the control groups [32].

Effects of MWM on Knee Joint ROM.
From the total included trials, nine of them had assessed knee ROM. Out of these, eight trials reported that MWM has positive effects on joint range of motion for OA patients compared to the control groups [5,31,33,36,38,40,43,44]. Conversely, only one study reported that the MWM group had no improvement of knee ROM compared to the control group [32].

Effects of MWM on Functional Status.
Out of the included trials, fourteen of them had assessed functional status. Out of these trials, thirteen of them had reported that MWM has positive effects on functional activities in OA patients compared to the control groups [5, 31, 33-39, 41, 43, 44]. However, two studies reported that the MWM group had no significant effect on knee functional status in patients with knee OA [32,40].

Discussion
is review of RCTs has been designed to investigate the effectiveness of MWM in subjects with knee OA. To the extent of our knowledge, this is the preliminary review to Pain Research and Management  Most of the included studies published that MWMs is effective in improving pain, range of motion, and physical functioning in patients with knee OA. Most of the studies used the same outcome measure, particularly VAS, WOMAC, and knee ROM, for pain and functional impairment. Ten of the trials had assessed pain using a VAS [5, 31-34, 36-38, 40, 44], three trials used the NPRS [35,39,43], and the Knee injury and Osteoarthritis Outcome Scores (KOOS) pain subscale in one study [41] suggested that MWM had positive effects for subjects with knee OA on pain reduction. e results in this review are consistent with the previous systematic reviews on peripheral joints reporting positive clinical effects of MWM [23,25,28].
Shenouda [31] reported that MWM had positive effects for subjects with knee OA on pain reduction and functional disability. Besides, MWM has no statistically significant difference in the improvement of knee ROM in both the interventional and control groups. However, in within-and between-group analysis of pre-and posttreatment, there was statistical significance in all outcome measures. In contrast, a study conducted by Kandada andHeggannavar [32] showed that the intergroup analysis shows an insignificant difference in all the outcome measures. But, the intragroup comparison shows a significant difference in pain reduction, functional improvement, and knee ROM.
Another study investigated by Gupta et al. [33] showed that MWM had significant improvement in pain reduction, functional disability, and knee joint proprioception in OA knee participants. is could mean MWM may have had beneficial effects on joint nutrition because of the squeezing out of the fluid during each compression and imbibing of fluid when the compression is removed [45]. Normally, squeezing occurs when the mobilization technique is performed and imbibing of fluid occurs when the joint is relaxed. is could possibly be the reason for a reduction in pain and a subsequent improvement in ROM and function that was found at the end of the treatment session. Likewise, Lalnunpuii et al. [5] reported more significant relieving pain, increasing ROM, and functional capacity were found in the intervention group compared to the control group in females with knee OA. is could be beacuse MWM might provide a stretching effect on the joint capsules and muscles, thus restoring normal arthrokinematics or decreasing pain by stimulation of joint mechanoreceptors, which consequently inhibits nociceptive stimuli and improved motor control [46,47]. Kulkarni and Kamat [34] showed that significant reductions in pain (P < 0.05) and improvement in 6-minute walk test distance covered during posttreatment sessions in both groups. However, posttreatment distance covered in the experimental group (mean � 37, SD � 16.882) was greater than that in the control group (mean � 35, SD � 23.146). Besides, Rao et al. [35] reported that both groups have shown a significant effect in reducing pain and improving functional mobility in subjects with knee OA immediately after treatment. Similarly, the study by Kaya Mutlu et al. [36] showed that MWM is superior in reducing pain, improving quadriceps muscle strength, knee range of motion, and functional level than the control group in knee OA participants. is could be due to the repeated motion of   Pain Research and Management MWM, which might alter the concentrations of anti-inflammatory mediators in the joint, which might consequently inhibit nociceptors [48]. Another possible reason could be due to psychological effects such as a reduction in fear avoidance associated with movement [49]. Varma and Purohit [37] found that MWM combined with conventional exercise groups showed better significant improvement in reducing pain, improving function than the conventional exercise group after 2 weeks of intervention. In the intervention group, the improvements could be because of biomechanical and neurophysiological mechanisms of MWM that may produce pain at the spinal level (pain gate mechanisms) [50]. Besides, a study by Kiran et al. [38] found that both groups showed a significant effect on the improvement of pain, knee range of motion, and functional ability after two weeks of intervention in patients with knee OA.

Pain Research and Management
Bhagat et al. [39] investigated that MWM produced direct effects in reducing knee pain and improving functional mobility in knee OA as compared with the placebo group. is could be because of the biomechanical mechanisms in Mulligan's MWM concept [51,52]. e correction of positional faults by the treatment glides used in the intervention group could have quickly repaired the normal kinematics of the osteoarthritic knee producing instant pain relief. Furthermore, a study conducted by Alkhawajah and Alshami [40] suggested that MWM had a superior effect in reducing pain, improving physical function (TUG), and knee flexion than the sham group. However, WOMAC (P � 0.067) has no significant effect on patients with knee OA. is could be because the grade of OA was relatively low, which may denote a nonmajor limitation of functional activity and the duration of the follow-up was short (2 days) which might not be sufficient for a perceived improvement in daily activities.
Another study conducted by Saddam Hussain Shaik et al. [41] reported that MWM had a significant improvement in pain reduction and quadriceps peak torque compared to the control group. In the intervention group for pain, the reduction may be because of the inspiration that MWM sedates an agitated, expedited system, significantly the dorsal horn, by offending it with painless normality it is been freckled to receive. Another attainable reason may be central mechanisms area unit concerned as there is activation of the nonopioid mediate drizzling pain restrictive system [25,53]. In addition, the mechanism responsible for the improvement of quadriceps peak torque is believed to be the arthrokinetic reflex, defined as the influence of joint mechanoreceptor afferents on muscles around the joint [54]. Pawar et al. studied the effect of MWM in subjects with knee OA. A randomized control trial shows that the MWM group showed greater improvement when compared with the control group on pain [42].
Shamim et al. [43] investigated that reduction of pain and ROM showed a significant effect in the MWM group compared to the control group. In the study conducted by Nigam et al. [44] MWM combined with usual care suggested that there is a significant effect of MWM in favor of the intervention group for WOMAC and VAS compared to the control group. e superior pain reduction in the experimental group could be because MWM may decrease nociceptive inputs while increasing nonnociceptive inputs via activation of peripheral mechanoreceptors [53]. However, there were no significant differences between groups for functional mobility as measured with the TUG immediately after the intervention. e improvement seen in both groups could be due to the positive effects of exercise. Exercise reduces pain, increases muscle strength, and improves control around the affected joint [55].

Limitations.
is systematic review has some limitations. e first limitation of this review is that a language bias is possible as only those studies that were available as full text in English were included. e second limitation of this review is that the outcome measures were not similar across the RCTs included in this review. A meta-analysis was not conducted because of the heterogeneous nature of the studies, and this could have been valuable for the effect of mobilization with movement.
ird, studies with short follow-up duration were included because a longer treatment duration could likely result in a significant intergroup difference. Lastly, only one of the available studies scrutinized the long-term effects of the MWMs on knee OA [44]. Based on the systematic appraisal of the current literature, any future research studies should consider the limitations of the previous studies in order to improve the quality of evidence in this field.

Clinical Implication.
is review suggests that MWM appears to reduce pain, improves knee range of motion, and improve physical functioning in subjects with knee osteoarthritis.

Conclusions
e findings of this systematic review suggest that Mulligan's MWM could be a treatment option among subjects with knee osteoarthritis. is review supports the evidence that Mulligan's MWM reduces pain, improves knee range of motion, and physical functioning of subjects with knee osteoarthritis.

Ethical Approval
It does not require ethical approval since the present study was a review of previously published literature.

Conflicts of Interest
e authors report no potential conflicts of interest in this work with respect to the research, authorship, and/or publication of this article.

Authors' Contributions
All authors have contributed to the work reported, the conception, study design, execution, acquisition of data, analysis, and interpretation, and writing or critically reviewing the article, agreed on the journal to which the article was submitted, and reviewed and agreed on all versions of the article before submission. Finally, the authors agree to take responsibility and be accountable for the contents of this article.