The Effectiveness of Repetition or Multiplicity of Different Surgical and Non-Surgical Procedures Compared to a Single Procedure Application in Accelerating Orthodontic Tooth Movement: A Systematic Review and Meta-Analysis

In this study, we aimed to assess the current scientific evidence concerning the effectiveness of combining two acceleration techniques or repeating an acceleration procedure in comparison with the single application in terms of the speed of the orthodontic tooth movement (OTM). We performed a comprehensive electronic search to retrieve relevant studies on 10 databases. Randomized controlled trials (RCTs) on fixed orthodontic treatment patients who received multiple types of acceleration techniques or underwent a repeated acceleration procedure compared to a single application were included. Version 2 of the Cochrane risk-of-bias tool for randomized trials (RoB 2) was used for assessing the risk of bias of retrieved studies. A total of six RCTs were included in this review. Regarding multiple acceleration methods, it seems that the combination of low-level laser therapy (LLLT) with a surgical technique outperforms the single application of each technique separately. Additionally, the combination of two surgical interventions may have a synergistic effect leading to reduced treatment time compared to the application of a single intervention. Regarding acceleration method repetition, it seems that the re-application of surgical procedures twice is more efficient than the single application. The meta-analysis showed a non-significant difference in the canine retraction rate between the four-weekly micro-osteoperforations (MOPs) (three times of applications) and both the eight-weekly MOPs (two times of applications) [mean difference (MD) = 0.24; 95% CI: -0.2-0.77; p = 0.36], as well as 12-weekly MOPs (two times of applications) (MD = 0.06; 95% CI: -0.14-0.27; p = 0.55). Based on very low evidence, combining two acceleration techniques is superior over a single application in accelerating tooth movement. Again, very low evidence suggests that the efficacy of repetition of surgical procedures twice and three times is similar. Further high-quality RCTs are required to assess the benefit of repeating an acceleration procedure or combining two different methods. In addition, more insight is needed into the possible side effects associated with the repetition or multiplicity of procedures.


Introduction And Background
Comprehensive orthodontic treatment for moderate to severe cases of malocclusion usually lasts for more than 18 months, taking into account several factors that lead to a significant difference [1]. Elongating orthodontic treatment may lead to white spots formation, dental caries, apical root resorption, periodontal disease, pain, and discomfort [2,3]. Moreover, many adult patients wish to finish orthodontic treatment faster for aesthetic or social reasons [4]. Hence, many attempts have been made to shorten orthodontic duration: local or systemic administration of pharmacological substances, mechanical or physical stimulation, and surgical interventions [5].
Pharmacological interventions depend on the injection of local substances, which is related to the biological response occurring during tooth movement. The efficacy of pharmacological molecules has been investigated in many human and animal studies [6]. Many of these substances have proven their effectiveness, e.g., prostaglandins, which are inflammatory mediators that increase the number of osteoclasts leading to stimulating bone resorption and acceleration of the orthodontic tooth movement (OTM). Prostaglandin injection has been proven to be associated with pain and dose-dependent root resorption [7]. Also, pharmacological molecules that have proven effective in accelerating OTM include vitamin D [8] and hormones such as the parathyroid hormone (PTH) [9]. On the other hand, relaxin, which is considered to be a hormone, has many roles as it helps during childbirth as well as impacts some physiologic functions such as collagen turnover, angiogenesis, and antifibrosis, in addition to its role in soft tissue remodeling [10]. It affects the OTM by increasing the collagen in the tension site and decreasing it in the compression site. The mechanism of relaxin's effect on acceleration OTM remains unclear. However, one of the studies that investigated the effect of relaxin in humans showed that its injection was not effective in accelerating OTM [10].
The physical methods rely on using device-assisted therapy and include direct electric currents, pulsed electromagnetic field, vibration [11], and low-level laser, which has been widely investigated in many research projects [12] and has proven to be effective in its stimulating efficacy in alveolar bone resorption and formation processes by increasing osteoclast and osteoblast numbers, leading to the acceleration of OTM [13].
The surgical procedures are considered the most clinically effective methods, and they have been rigorously tested several times in terms of the possibility of significantly decreasing treatment duration [3]. However, the surgical intervention includes various procedures such as conventional corticotomy [5,14], dentoalveolar distraction [15], periodontal distraction [16], interseptal alveolar surgery [17], accelerated osteogenic orthodontics [18], piezocision [2,19], corticision [20], and micro-osteoperforations (MOPs) [21]. All these procedures depend on the same principle, "regional acceleratory phenomenon" (RAP), which was first described by Forest and is based on the principle that the occurrence of surgical injury to the alveolar bone may temporarily speed up OTM [22]. The RAP was described as a transient stage of localized soft and hard tissue remodeling that resulted in the rebuilding of the injured sites to a normal state through recruitment of osteoclasts and osteoblasts by way of local intercellular mediator mechanisms involving precursors [22]. This mechanism does not involve any secondary healing by fibrous tissue formation.
The focus of several recently published systematic reviews (SRs) has been on evaluating the effectiveness of different individual interventions for orthodontic acceleration, both surgical [23][24][25] and non-surgical [26,27]. Mohaghegh et al. [28], in their recent SR, discussed the effect of single and multiple MOPs on the rate of OTM. However, this SR was oriented only toward the MOPs procedure although repetition can be performed for other acceleration procedures such as traditional corticotomy, flapless corticision, flapless piezocision corticotomy, and high-intensity laser therapy-assisted corticotomy. In addition, no SR has evaluated the effect of combining different procedures, such as combining surgery with low-level laser therapy (LLLT) or surgery with vibrational devices. Hence, we performed this SR to address the following focused review question: Does the repetition of an acceleration procedure or the combination of different procedures outweigh a single application in patients undergoing fixed orthodontic treatment? In light of this objective, we aimed to critically appraise the available evidence regarding the effectiveness of multiplicity or repetition of acceleration procedures in comparison with the single application for speeding up orthodontic treatment.

Materials and methods
Initially, a PubMed® scoping search was carried out to verify the existence of similar SRs and to check out potentially eligible trials before writing the final SR protocol. The search results indicated the presence of one potentially eligible study and the absence of any similar SRs about the same topic. Registration of this review with PROSPERO was performed (https://www.crd.york.ac.uk/prospero/display_record.php?ID = CRD42021274314; 2021: CRD42021274314). This SR was prepared in accordance with the Cochrane Handbook for Systematic Reviews of Interventions [29], and the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines [30,31].

Criteria of Exclusion and Inclusion Were Applied According to the PICOS (Patient/Population, Intervention, Comparison, and Outcomes) Framework as Follows:
Participants: healthy patients of both genders (regardless of age, malocclusion type, and racial group) undergoing fixed orthodontic treatment (either extraction-or non-extraction-based treatments).
Type of interventions: first theme: multiple methods of acceleration [two or more different methods of acceleration even they fell within the same category of acceleration (e.g., corticision followed by MOPs, both being surgical interventions)]. Second theme: repeated acceleration using a single method of acceleration at different time intervals (in the interventional group) compared to a single application of this method (or less frequent applications) in the control group.
Comparisons: first theme: only a single method of acceleration from any category. Second theme: only one application of the acceleration procedure without repetition (or with less frequent applications compared to what was applied in the control group).
Outcomes: primary outcomes were the rate of tooth movement (RTM), the time of tooth movement (TTM), or any equivalent measurement. Secondary outcomes: a complication reported by patients (e.g., pain, discomfort, and other related experiences), or gingival and periodontal problems including periodontal index (PI), gingival index (GI), attachment loss (AT), gingival recession (GR), and periodontal depth (PD), or undesired tooth movement (tipping, torquing, rotation), or anchorage loss, or bone/root changes including bone density (BD), bone resorption (BR), root resorption (RR), or long-term treatment stability.
Study design: we took into account all randomized controlled trials (RCTs) without any restrictions regarding the publication year or the language used.
Exclusion criteria: retrospective studies, non-English language trials, in vitro studies, animal studies, reviews and technique description papers, editorials, personal opinions, case reports or case series reports, and finite element analysis articles were excluded.

Search strategy
An electronic search of databases [The Cochrane Central Register of Controlled Trials (CENTRAL), EMBASE®, Scopus®, PubMed®, Web of Science™, Google™ Scholar, Trip, OpenGrey (to determine the grey literature), and PQDT OPEN from pro-Quest® (to determine dissertations and theses)] was carried out in August 2021 in the English language only with no time limitation. Scrutiny of selected trials reference lists' was done to investigate if any scientific paper was inadvertently missed during electronic research. Also, manual searching was conducted in the same period; the American Journal of Orthodontics and Dentofacial Orthopedics, the European Journal of Orthodontics, and the Angle Orthodontist. ClinicalTrials.gov and World Health Organization International Clinical Trials Registry Platform Search Portal (ICTRP) were also screened electronically to recover any unpublished studies or recently completed research work. More details about the electronic search strategy are provided in Table 1.

Study selection and data extraction
Two reviewers (DTA and MYH) separately evaluated the studies' eligibility, and in instances of disagreement, a third author (OJ) helped in resolving this. At first, only titles and abstracts were checked. Subsequently, the full text of trials that appeared to be pertinent was evaluated and selected for inclusion, as well as titles or abstracts that were unclear to aid in decision-making. Failure to achieve one or more of the inclusion norms would have meant that the article was disqualified. In case of a need for more clarification or extra data, the specific author was e-mailed. Data extraction was independently achieved by the same two authors (DTA and MYH). A third author (OJ) was consulted to reach a solution when the two authors had disagreements. The data summary tables included the following items: general information (the name of authors, the year of publication, and study setting); methods (study design, treatment comparison); participants (sample size, age, and gender); intervention (the type of interventions, intervention site, and technical aspects of interventions); orthodontic aspects (malocclusion characteristics, type of movement, frequency of orthodontic adjustments, and follow-up time), and outcomes (primary and secondary outcomes mentioned, methods of outcome measurements, the statistical significance of reported differences in patients vs. controls).

Assessment of risk of bias in included studies and strength of evidence
The quality of the selected articles was estimated by two reviewers (DTA and MYH) using Version 2 of the Cochrane risk-of-bias tool for randomized trials (RoB 2) as the included studies were randomized trials [32]. Any conflict was resolved by discussion between the two reviewers. The following domains were evaluated as low, high risk, or some concern of bias for randomized trials: bias arising from the randomization process, bias due to deviations from intended interventions (effect of assignment to intervention; effect of adhering to intervention), bias due to missing outcome data, bias in the measurement of the outcome, and bias in the selection of the reported result. The overall risk-of-bias judgment of the included trials was assessed according to the following: "low risk of bias" if all fields were estimated as "at low risk of bias"; "some concerns" if at least one domain was assessed as "some concerns" but not to be at "high risk of bias" for any domain; "high risk of bias" if at least one or more fields were estimated as "at high risk of bias" or if there were some concerns for multiple domains in a way that substantially lowered confidence in the result. Grading of Recommendations Assessment, Development, and Evaluation (GRADE) approach was used to obtain a supplemental summary of the reliability of the conclusions and strength of the evidence [33] as follows: high, moderate, low, or very low.

Study Selection and Inclusion in the Review
A flow chart of study selection for this review is presented in Figure 1. A total of 1,967 articles were identified from the electronic databases. After taking off duplicates and reviewing titles and abstracts, full texts of 14 potentially relevant papers were evaluated in-depth. Ten completed studies and two of the ongoing studies did not meet the inclusion criteria. A summary of the excluded articles after full-text assessment with reasons for exclusion is illustrated in Table 2. Subsequently, six RCT trials were included in the SR.  The study did not apply surgical and non-surgical acceleration methods together, but they were applied separately in the same group of patients Effect of surgical corticotomy versus low-level laser therapy (LLLT) on the rate of canine retraction in orthodontic patients. Orthodontic Practice US. 9:1-11 The study did not apply surgical and non-surgical acceleration methods together, but they were applied separately in the same group of patients The study did not apply surgical and non-surgical acceleration methods together, but they were applied separately in the same group of patients The study did not apply surgical and non-surgical acceleration methods together, but they were applied separately in the same group of patients CTRI/2018/05/014328: Comparison of micro-osteoperforation and low-level laser therapy on the rate of retraction-an in vivo study Ongoing trial (protocol): the study is not applying surgical and non-surgical acceleration methods together, but they are applied separately in the same group of patients NCT03308851: Evaluation of the effects of osteoperforation and piezocorticision on canine retraction Ongoing trial (protocol): the study is not applying surgical and non-surgical acceleration methods together, but they are applied separately in the same group of patients

Characteristics of studies
The characteristics of the six included trials [16,[34][35][36][37][38] are illustrated in Table 3 and Table 4. Only two trial protocols were found; more information about those ongoing research projects is given in Table 5 and Table  6.
Authors       Six completed RCTs [16,[34][35][36][37][38], with a total of 152 patients, with ages ranging from 15 to 25 years, were included in this SR. One study included only female patients [36], three studies did not give information about sex distribution [16,34,35], while the other two studies included both genders, with a predominance of females [37,38]. Four of the involved studies were of a compound design (COMP) [a parallel-group design with a split-mouth design (SMD) in each group] [16,34,35,38], and the others were of SMD [36,37]. Three studies touched on the multiplicity of acceleration methods. Two of them combined LLLT and surgical interventions (MOPs, corticotomy) [34,36]. In one paper, the authors evaluated LLLT + MOPs versus each of these techniques separately [34], whereas, in the other study, only the comparison between LLLT + corticotomy versus corticotomy was performed [36]. Moreover, the third study combined multiple osteoperforation with a corticotomy procedure against multiple osteoperforation only [16]. On the other hand, the other three studies [35,37,38] discussed the efficacy of repeating the acceleration procedures. All three papers dealt with the repetition of MOPs at different time intervals. The surgical interventions in the retrieved studies ranged from invasive (traditional corticotomy [16,36], multiple osteoperforation with flap elevation [16]) to minimally invasive (MOPs [34,35,37,38]).
All the included studies [16,[34][35][36][37][38] involved extraction-based treatments and were primarily about accelerating canine retraction. Four papers studied the upper canines retraction [16,34,36,37], one studied the distalization of both upper and lower canines [38], and one trial assessed the retraction of lower canines [35]. The retraction was performed on canines after the first premolar extraction, which was performed before the beginning of orthodontic treatment in two papers [34,37], and after the completion of leveling and alignment in two trials [16,36], while this information was not mentioned in the other studies [35,38].

Risk of bias of the included studies
The risk of bias of the included trials is demonstrated in Figure 2, while Figure 3 shows the overall risk of bias for each field. More details about the assessment of the bias risk with supporting reasons for every assessment can be found in Table 7. Four of the included studies [34,[36][37][38] were assessed as "some concern of bias", but the other two trials [16,35] were at 'high risk of bias". Bias due to deviations from intended interventions (effect of assignment to intervention or effect of adhering to intervention) and bias in the measurement of the outcomes were the most questionable domains (100% of some concern of bias in all studies, and 50% in three studies, respectively).

FIGURE 2: Risk of bias summary of RCTs
+ sign: low risk of bias; -sign: some concern of bias; X sign: high risk of bias RCTs: randomized controlled trials

Effects of interventions
Primary outcomes: first theme: multiple methods of acceleration

Combining LLLT With a Surgical Intervention Against the Application of Each Technique Separately
Abdelhameed and Refai [34] estimated the impact of combined LLLT + MOPs versus the impact of the application of each technique separately on the RTM in a three-arm compound-design RCT. When comparing the accelerated sides with the non-accelerated sides, MOPs and LLLT, as well as MOPs + LLLT interventions, showed an increased rate of upper canine retraction. Statistically significant differences were found at all assessment times (p<0.05). On the other hand, the combination of ' MOPs + LLLT was found to be superior to the single application of MOPs or LLLT separately. According to GRADE, the overall quality of evidence supporting this outcome is low ( Table 8). The mean rate of canine retraction in the MOPs + LLLT side was the highest in the first, second, and third months (x ̅ = 2.83 ± 0.12 mm, x ̅ = 3.86 ± 0.27 mm, x ̅ = 4.87 ± 0.88 mm, respectively). Moreover, In the first, second, and third months, the mean rate of canine movement in MOPs side (x ̅ = 2.16 ± 0.27 mm, x ̅ = 3.43 ± 0.66 mm, x ̅ = 4.33 ± 0.64 mm, respectively) was significantly greater than the LLLT side (x ̅ = 1.81 ± 0.39 mm, x ̅ = 2.63 ± 0.87 mm, x ̅ = 3.72 ± 0.71 mm, respectively). The MOPs technique accelerated the canine retraction rate by 1.6 fold whereas LLLT achieved this by 1.3 fold compared with the non-accelerated sides. Nevertheless, the combination of MOPs + LLLT gained priority by increasing the canine retraction rate by 1.8 fold compared with the non-accelerated side.   [35,38], bias arising from the randomization process, bias in the measurement of the outcome, and bias in the measurement of the outcome [35]), one level for indirectness**, and one level for imprecision*** c, h, j Decline in one level for risk of bias (bias due to deviations from intended interventions), one level for imprecision*** [37] d Decline in one level for risk of bias (bias due to deviations from intended interventions, bias in the measurement of the outcome), one level for indirectness**, and one level for imprecision*** [35] e, g Decline in one level for risk of bias (bias due to deviations from intended interventions), one level for imprecision*** [36] f, g Decline in one level for risk of bias (bias arising from the randomization process, bias due to deviations from intended interventions, bias in the measurement of the outcome), one level for indirectness**, and one level for imprecision [16] *Differences in results; **Outcome is not directly related; ***Limited number of trials

Combining LLLT With a Surgical intervention Against a Single Application of the Latter
Farid et al. [36] evaluated the combined effect of LLLT + corticotomy versus corticotomy only on the RTM in a split-mouth RCT. In the first month of upper canine retraction, the results were opposite of what was expected. The mean rate of canine movement was greater in corticotomy only side (x ̅ = 1.16± 0.67 mm) compared with the LLLT + corticotomy side (x ̅ = 0.81± 0.58 mm) with a statistically significant difference (p = 0.019). Conversely, the mean rate of canine movement in the fourth month was greater in the LLLT + corticotomy side (x ̅ = 1.43± 1.18 mm) than corticotomy only side (x ̅ = 0.83± 1.03 mm) with a statistically significant difference (p = 0.033). However, there was no statistically significant difference between the sides of LLLT + corticotomy and corticotomy only regarding the rate of upper canine retraction in the second and third months (p = 0.064, p = 0.968), respectively. The high heterogeneity between the previous studies [34,36] did not allow for conduct quantitative synthesis of the findings.

Combining Two Different Surgical Interventions Against a Single Application of One of Them
The clinical trial by Yousif et al. [16] evaluated the effect of the combined multiple osteoperforation + corticotomy procedure against multiple osteoperforation on TTM in a three-arm compound-design RCT. The multiple osteoperforation side required less than three months (x ̅ = 85.1 ± 3.03 days) for the completion of canine retraction, whereas the multiple osteoperforation + corticotomy side took about two months only (x ̅ = 67.7 ± 3.09 days) to complete this procedure, with a statistically significant difference between the two sides (p = 0.001). According to GRADE, the overall quality of evidence supporting this outcome is low ( Table  8). The canine retraction was accelerated by 22% for the multiple osteoperforation side and 38.5% for the multiple osteoperforation + corticotomy side. Due to the use of a different outcome variable between this study and the previous, the meta-analyses were not performed.

Second theme: repetition of an acceleration method
Three of the included studies assessed the repetition of acceleration procedures. Moreover, all of these studies focused on the reapplication of MOPs [35,37,38]. Sivarajan et al. [38] and Asif et al. [35] in a threearm compound-design RCT evaluated the effect of multiple intervals of MOPs (every four, eight, or 12 weeks in groups 1, 2, and 3 respectively) on the RTM. The pooled estimate showed that there was no statistically significant difference between the four-week MOPs group (three times of application) and the eight-week MOPs group (two times of application) in the rate of canine retraction in one month (MD = 0.24; 95% CI: -0.28-0.77; p = 0.36, Figure 4). Heterogeneity between the two studies was high (χ2 = 6.57; p = 0.01; I2 = 85%). Also, the MD of 0.06 was found (95% CI: -0.14-0.27; p = 0.55, Figure 5) between the four-week MOPs group and the 12-week MOPs group, which was not statistically significant, with low heterogeneity (χ2 = 1.01; p = 0.31; I2 = 1%). According to GRADE, the overall quality of the evidence supporting this outcome is very low ( Table 8).
Jaiswal et al. [37] compared the efficacy of two-time MOPs versus one-time application on the RTM in an SMD RCT. In the first month of canine retraction, no significant differences were found between the two sides of the mouth (x ̅ = 1.37 ± 0.0.43 mm and x ̅ = 1.41 ± 0.43 mm, respectively; p = 0.840). On the contrary, the overall canine retraction rate was statistically greater in the two-time MOPs side than the one-time side (x ̅ = 6.12±0.76 mm and x ̅ = 4.57 ± 0.54 mm, respectively; p<0.001). According to GRADE, the overall quality of the evidence supporting this outcome is low ( Table 8). The difference in the repetition intervals between this study and the other two studies prevented its inclusion in the meta-analysis.

Secondary outcomes
The overall quality of evidence according to GRADE for secondary outcomes is illustrated in Table 8.

Secondary Outcomes Associated With Multiple Methods of Acceleration (Two or More Different Methods of Acceleration)
Two of the included papers in this hub [16,36] evaluated secondary outcomes. Farid et al. [36] assessed molar anchorage loss between the groups of corticotomy + LLLT and corticotomy only. The MD of anchorage loss was greater in the corticotomy only side than the corticotomy + LLLT side (MD: 0.46 ± 2.81 mm). However, this difference was statistically insignificant. Yousif et al. [16] evaluated pain and discomfort between the combined multiple osteoperforation + corticotomy side against the multiple osteoperforation side. No pain and discomfort were reported in both groups. Yousif et al. [16] also assessed canine angulation and inclination. They found that the mean canine angulation changes were greater in the multiple osteoperforation + corticotomy side (x ̅ = 15.2° ± 1.65°) compared to the multiple osteoperforation side (x ̅ = 11.0° ± 2.36°) with a statistically significant difference (p = 0.001). Moreover, the distal inclination of the canine was also greater in the multiple osteoperforation + corticotomy side compared to the multiple osteoperforation side with a statistically significant difference (p = 0.001). We could not pool the results of the secondary outcomes to quantitative synthesis due to the use of a different outcome variable between trials.

Secondary Outcomes Associated With Repetition of an Acceleration Method
Two studies in this hub [37,38] discussed the associated secondary outcomes. Sivarajan et al. [38] evaluated the pain and its impact on daily function between the multiple intervals of MOPs (every four, eight, and 12 weeks). Pain associated with MOP was reported in all groups. However, 60% of the MOP-4 patients' group reported moderate pain, with the highest mean pain score (x ̅ = 1.75 ± 0.72). Moreover, 70% of the MOP-8 patients' group and 75% of the MOP-12 patients' group reported only mild pain with a similar mean pain score (x ̅ = 1.35 ± 0.59 and x ̅ = 1.30 ± 0.57, respectively). The impact of this reported pain on daily function centered on speech and chewing; without any statistically significant effect on general activities, like mood and social interaction (p>0.05). Jaiswal et al. [37] estimated molar anchorage loss as well as canine angulation between one-time MOP and two-time MOP sides. Regarding the molar anchorage loss, a statistically insignificant difference (p = 0.657) was found between the one-time MOP side (0.31 ± 0.24 mm) and the side of the two-time MOP (0.30 ± 0.39 mm). Moreover, the canine tipping also demonstrated a statistically insignificant difference in the overall canine retraction intervals (p>0.05), which was 2° in the one-time MOP side and 3° in the two-time MOP. We could not pool the results of the secondary outcomes to quantitative synthesis due to the use of a different outcome variable between trials.

The Strength of the Evidence According to the GRADE Guidelines for the Included Trials
As per the GRADE recommendations, the evidence strength regarding the rate of orthodontics tooth movement as well as the adverse effects ranged from very low to low, as shown in Table 8. The decline in the evidence strength happened because of the risk of bias [16,[34][35][36][37][38], indirectness [16,34,35,38], and imprecision [16,[34][35][36][37][38].

Discussion
Acceleration of OTM has become a trend in the orthodontic field in recent decades. In the beginning, the trend was to assess the effectiveness of the methods used for OTM acceleration. Subsequently, some clinical trials have been conducted to evaluate the effectiveness of combining two methods or more or repeating a specific method to accelerate the OTM. This approach has not been widely accepted among orthodontic practitioners, and the effectiveness of this combination or repetition is still not known with any certainty.

First theme: multiple methods of acceleration
Unfortunately, the results of the two studies [34,36], which focused on the combination of LLLT with surgical intervention versus a single application of one of them, were contradictory. Abdelhameed and Refai [34] concluded that a combination of MOPs + LLLT achieved a synergistic effect with superior accelerated tooth movement compared to the sole application of each technique. On the contrary, Farid et al. [36] found that the combination of corticotomy + LLLT was not more efficient than the single application of corticotomy only in accelerating canine retraction. The dissimilarity in the findings could be attributed to the fact that the interventions were applied using different protocols. Abdelhameed and Refai [34] applied LLLT from the buccal and palatal surfaces along the root of the canines in addition to the application of MOPs six times over a period of three months, whereas in Farid et al.'s trial [36], the LLLT was applied at the middle point of the canine root on buccal and palatal surfaces, and the corticotomy procedure was performed only once. As mentioned before, the high heterogeneity between the previous studies [34,6] did not allow for quantitative synthesis of the findings.
However, Yousif et al. [16], who compared the combination of two different surgical interventions against a single application of one of them, reported that the combination outperformed the single surgical technique group as the mean TTM was less in the combination group (67.7 ± 3.09 days) compared to the singleprocedure group (85.1 ± 3.03 days). One possible explanation could be the synergistic effect of two surgical techniques with an increased RAP, i.e., increased cortical bone porosity with increased osteoclastic activity following the surgical healing of the cortical bone [39]. On the other hand, the combination of two surgical interventions (corticotomy + MOPs) reduced the treatment duration by 42.8%. This is superior to the acceleration of canine retraction with the MOPs only, which reduced the treatment duration by 25.4% when compared to conventional retraction. This is somewhat consistent with a previous trial, which suggested a possible reduction in the treatment duration of up to 30% [38]. Although surgical methods have been proven to be effective in accelerating OTM [24], different acceleration rates have been published in the literature. A study evaluating traditional corticotomy (with flap elevation) reported that canine retraction increased by two to four times when compared to the non-accelerated group [5], whereas a laser-assisted flapless corticotomy accelerated the canine retraction by 2.5 times when compared to the conventional retraction [40]. On the other hand, flapless piezocision-based corticotomy accelerated canine retraction by 1.5-2 times when compared to the non-accelerated group [2], whereas the application of MOPs produced OTM that was 2.3 times faster than the conventional retraction [41].

Second theme: repetition of an acceleration method
The results of the meta-analysis indicated that the rate of OTM was almost the same after repeated application of MOPs by three times (every four weeks) and two times (every eight or 12 weeks), as shown in Figures 4, 5. However, Jaiswal et al. [37] found the RTM was statistically greater in the two-time MOP side when compared with the one-time MOP side. The previous results could be explained by understanding the mechanism of RAP and the purpose of repeating the acceleration procedures. RAP is a transient phenomenon, beginning a few days after surgery, reaching its highest point at one to two months, and then declining over time [42]. Here is where the role of the repetition of intervention to ensure a continuous activation of the RAP biological response becomes important [43]. Since the purpose of the repetition is the same, which is to re-evoke the RAP and maintain the accelerated OTM, this could be the reason why there is no difference between repetition by two or three times.

The associated secondary outcomes
Considering the associated side effects, the anchorage loss was assessed in two trials, which concluded the same result. Farid et al. [36] found a statistically insignificant difference between the single acceleration method side (corticotomy) and the combined methods side (LLLT + corticotomy). Additionally, Jaiswal et al. [37] demonstrated that anchorage loss did not differ statistically between the sides of one-time MOP and two-time MOP. This could be attributed to the fact that the accelerating interventions were applied topically, leading to localized alveolar response without affecting the posterior segments, and hence anchorage loss did not differ between the two sides of the intervention.
Canine angulation was investigated in two studies. Yousif et al. [16] reported that more distal tipping and more buccal inclination of the canine were shown in the combined acceleration method side (multiple osteoperforation + corticotomy) than the single-method side (multiple osteoperforation). This result can be explained by understanding the biomechanical mechanism. It is known that in sliding techniques, an initial crown tipping is induced first, followed by root uprighting later [44]. The faster the OTM is done, the more tipping of the crown will occur. On the contrary, Jaiswal et al. [37] indicated that the canine tipping was minimal, with non-significant differences between the two sides of one-time MOP and two-time MOP. This can be attributed to the use of a rigid 0.019 x 0.025 stainless steel wire with a closed-coil spring for canine retraction. It is known that rectangular archwire provides good control for tipping during canine sliding; however, the looseness of the archwire fits in the bracket slot and causes a certain degree of tipping [45,46]. Although no important side effects were found in the included three studies, data on periodontal complications, postoperative infection, root resorption, tooth vitality loss, and possible morbidity are not available in the retrieved studies and further research is required.

Limitations of the current review
Only six RCTs (three studies in each theme), which fulfilled the eligibility criteria, were found and included in this SR; four of them were assessed to have some concern of bias, whereas the other two trials were at high risk of bias. The strength of evidence ranged from very low to low. Therefore, there is a need for highquality RCTs to assess the value of multiplicity or repetition in orthodontic acceleration. Canine retraction following premolar extraction was carried out in all included studies. We could not find trials evaluating acceleration in different treatment strategies such as decrowding of upper and lower teeth, incisors' retraction or intrusion, and en-masse retraction of anterior teeth. The high heterogeneity and the use of different outcome measures as well as treatment protocols prevented the inclusion of all of the retrieved studies in a meta-analysis and the results of only two studies were pooled. Not all included studies evaluated the side effects associated with the acceleration techniques. Moreover, the studied side effects reported were limited. Therefore, it was difficult to arrive at clear conclusions regarding the accompanying negative effects.

Conclusions
The combination of LLLT with a surgical technique seemed to outperform the application of each technique separately when accelerating tooth movement. The combination of two surgical interventions may produce a synergistic effect leading to a reduced treatment time compared to the application of a single surgical intervention. The quality of evidence of previous conclusions was very low. The double application of surgical procedures appears to be more effective than the single application but the quality of evidence in this aspect is low. As the strength of evidence of the reported results ranged from low to very low, we confirm the need for more well-conducted RCTs evaluating the benefits of combining several acceleration techniques throughout the treatment procedure or repeating specific methods in comparison with the single application. Future research should also consider the broad spectrum of possible side effects accompanying multiple or repeated applications.

Conflicts of interest:
In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work.