Lasers Med Sci DOI 10.1007/s10103-014-1538-z
REVIEW ARTICLE
Efficacy of low-level laser therapy for accelerating tooth movement during orthodontic treatment: a systematic review and meta-analysis M. K. Ge & W. L. He & J. Chen & C. Wen & X. Yin & Z. A. Hu & Z. P. Liu & S. J. Zou
Received: 29 April 2013 / Accepted: 3 February 2014 # Springer-Verlag London 2014
Abstract This review aimed to evaluate the efficacy of lowlevel laser therapy (LLLT) for accelerating tooth movement during orthodontic treatment. An extensive electronic search was conducted by two reviewers. Randomized controlled trials (RCTs) and quasi-RCTs concerning the efficacy of LLLT for accelerating tooth movement during orthodontic treatment were searched in CENTRAL, Medline, PubMed, Embase, China Biology Medicine Disc (CBM), China National Knowledge Infrastructure (CNKI), and Google Scholar. Six RCTs and three quasi-RCTs, involving 211 patients from six countries, were selected from 173 relevant studies. All nine articles were feasible for the systematic review and meta-analysis, five of which were assessed as moderate risk of bias, while the rest were assessed as high risk of bias. The mean difference and the 95 % confidence interval (95 % CI) of accumulative moved distance of teeth were observed among all the researches. The results showed that the LLLT could accelerate orthodontic tooth movement (OTM) in 7 days (mean difference 0.19, 95 % CI [0.02, 0.37], p=0.03) and 2 months (mean difference 1.08, 95 % CI [0.16, 2.01], p=0.02). Moreover, a relatively lower energy density (5 and 8 J/cm2) was
M. K. Ge : J. Chen : X. Yin : Z. A. Hu : Z. P. Liu : S. J. Zou (*) State Key Laboratory of Oral Diseases, Department of Orthodontics, West China Hospital of Stomatology, Sichuan University, 14 Section 3 South Ren Min Road, 610041 Chengdu, China e-mail: [email protected] W. L. He Department of Orthodontics, Guangdong Provincial Stomatological Hospital, the Affiliated Stomatological Hospital of Southern Medical University, Guangzhou, China C. Wen State Key Laboratory of Oral Diseases, Department of Prosthodontics, West China Hospital of Stomatology, Sichuan University, Chengdu, China
seemingly more effective than 20 and 25 J/cm2 and even higher ones. Keywords Low-level laser therapy . Tooth movement . Orthodontic . Systematic review . Meta-analysis
Introduction Orthodontic treatment, based on tooth movement, is a timeconsuming procedure which usually takes 20–30 months treatment duration. This long-term treatment is not only burdensome for patients, resulting in decreasing compliance of patients throughout the duration, but also is apt to cause a variety of side effects, such as alveolar bone resorption [1], root resorption [2], caries [3], etc. Therefore, shortening the orthodontic treatment duration is desired. Reducing orthodontic treatment time requires increasing the rate of tooth movement. Many studies have researched different methods to accelerate tooth movement, including drug injections [4–6], electric stimulation [7, 8], pulsed electromagnetic fields [9], and corticotomy [10, 11]. Although these methods could speed up the tooth movement, there are some drawbacks; for example, they could cause some unpleasant experience on patients; the required apparatuses were not in common use in dental practice, or the chemicals used to accelerate the tooth movement could cause negative effects on bone and root resorption [12]. However, compared with chemicals or operations mentioned above, low-level laser therapy (LLLT) has not been reported negative systematic effects on the subjects yet. It is deemed to be a promising technique in dentistry owing to its multiple bio-stimulatory effect, non-invasive manner, and easy access. It was recognized for its use in teeth whitening [13], caries detection [14], pain relief for aphthous ulcers [15], increasing osseointegration of implants [16, 17], etc. Besides, the non-invasive manner provided better experience for patients.
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Several experiments based on animal models [18–21] and human subjects [22–30] have investigated the effect of LLLT on accelerating orthodontic tooth movement (OTM). Therefore, a systematic review of the present knowledge seems desirable. The purpose of this review was to comprehensively evaluate, in an evidence-based way, the effectiveness of LLLT on accelerating tooth movement in orthodontic treatment for human subjects.
Materials and methods This systematic review and meta-analysis were carried out referring to Cochrane Handbook for Systematic Reviews of Interventions and Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA). Two reviewers (M.K. Ge and W.L. He) independently conducted the search and the work of extracting data and assessing the risk of bias and eligibilities of the retrieved articles. Any disagreement was resolved by discussing with a third reviewer (S.J. Zou). Search strategy An extensive electronic search for randomized controlled trials (RCTs) and quasi-RCTs (where nonrandom allocation method was applied) was made through CENTRAL (up to Issue 1. 2013), PubMed, MEDLINE(via OVID, up to Feb 2013), Embase (up to Feb 2013), China National Knowledge Infrastructure (CNKI) (up to Feb 2013), and China Biology Medicine Disc (CBM) (up to Feb 2013). Ongoing clinical trials were searched in World Health Organization International Clinical Trials Registry Platform. Hand-searching was performed in relevant Chinese journals. Terms used in the search included “orthodontic,” “tooth movement/orthodontic movement,” “laser/low-level laser/low-intensity laser/soft or cold laser,” and “irradiation/light/phototherapy.” Reference lists of the retrieved articles were also checked. There was no language restriction in the search.
Exclusion criteria: 1. Reviews, cohort studies, case reports, descriptive studies, letters, opinion articles, or abstracts 2. Participants have system disease, or dental, pulp, or periodontal problems 3. Participants are under medical treatment that could interfere with bone metabolism or orthodontic movement (e.g., analgesics, anti-inflammatory medicine (NSAIDs), or antibiotics) 4. Animal experiments
Methodological quality and risk of bias Risk of bias assessment was performed referring to Cochrane Handbook for Systematic Reviews of Interventions. All included articles were assessed on the following domains: sequence generation, allocation concealment, blinding, incomplete outcome, selective reporting, and other bias. The qualities of included studies were categorized as follows: 1. Low risk of bias: with six domains assessed as “low risk” 2. Moderate risk of bias: with one or more domains assessed as “unclear” 3. High risk of bias: with one or more domains assessed as “high risk” Modified Jadad score was also utilized to quantize the assessment. The modified Jadad score scale was listed in Table 1. Data extraction Relevant information were extracted independently by two reviewers including method of randomization, concealment and blindness, and the studies’ eligibility (study designs, demographic data, duration of follow-ups, orthodontic treatment, laser parameters, outcome measurements, laser treatment intervals).
Selection criteria Outcome measures Inclusion criteria: Primary outcome measures: 1. Studies that evaluated efficacy of LLLT for OTM 2. Study design: RCTs and quasi-RCTs. Relevant data should be provided 3. All participants received orthodontic treatment with the same management 4. Subjects were assigned to experimental group or control/ placebo group based on using LLLT or not 5. Outcome variables were accumulative moved distance or speed of the tooth movement in treatment duration
1. Distance of tooth movement 2. Speed of tooth movement Secondary outcome measures: 1. The wavelengths, doses, and frequencies of LLLT 2. Adverse events: damage to the root, alveolar bone, or periodontal tissues
Lasers Med Sci Table 1 Modified Jadad score Item assessed
Response
Score
Was the study described as randomized?
Yes No Yes Not described No Yes No Yes Not described No Yes No Yes No Yes No Yes
+1 0 +1 0 −1 +1 0 +1 0 −1 +1 0 +1 0 +1 0 +1
No
0
Was the method of randomization appropriate? Was the study described as blinded? Was the method of blinding appropriate? Was there a description of withdrawals and dropouts? Was there a clear description of the inclusion/exclusion criteria? Was the method used to assess adverse effects described? Was the method of statistical analysis described?
adopted if non-significant heterogeneity was observed (I2 ≤ 50 %).The statistical significance for the hypothesis test was set at p 50 %); fixed-effects model would be
Six random controlled trials [22–24, 26–28] and three quasiRCTs [25, 29, 30] were finally included. All of the enrolled participants completed their treatment without any dropouts or withdrawals. Table 2 showed the characteristics of the included studies. In addition, summary details of laser parameters and treatment regimen were shown in Table 3.
Fig. 1 Flow diagram of the study inclusion of the systematic review and meta-analysis
RCT, split-mouth design
Sousa 2011 [27] Brazil
30/30
17/17
36/36
12/12
20 participants
10 participants 10.5–20.2 years
30/30
13/13
90 participants 60/30 Mean age 19.08 years 20 participants 20/20 Mean age 14.5 years
36 participants 11.0–13.5 years
12 participants Mean age 20.11± 3.4 years
11/11
N (I/C)
Maxillary first premolar extraction, maxillary canine retraction using NiTi closed-coil springs, modified Nance arch used for anchorage reinforcement 3 months after maxillary first premolar extraction, maxillary canine retraction using NiTi closed-coil springs, vertical loop stops for anchorage reinforcement Maxillary first premolar extractions. Canine retraction using NiTi closedcoil springs, Nance arch used for anchorage reinforcement Maxillary first premolar extractions. Canine retraction using NiTi closedcoil springs, modified Nance arch used for anchorage reinforcement 14 days after extraction of 4 first premolars, maxillary canine retraction using Ricketts springs, both upper and lower jaws included Separators were placed at the mesial and distal contacts of the maxillary first molars in 90 patients Extraction of maxillary first premolars, canine retraction using elastomeric chains. Nance arch used for anchorage reinforcement 3 months after maxillary first premolar extractions (in 3 patients, mandibular premolars also extracted), canine retraction using NiTi coil springs Maxillary first premolar extractions (in 10 patients mandibular premolars also extracted), canine retraction using NiTi closed-coil springs, transpalatal arch used for anchorage reinforcement
Orthodontic treatment
M male, F female, N number of participants, I LLLT group, C control/placebo group
Doshi-Mehta RCT, split-mouth 2012 [23] India design
Quasi-RCT, splitmouth design
Youssef 2008 [30] Quasi-RCT, splitSyria mouth design
Gui 2008 [25] China
RCT, split-mouth design
Wang 2007 [28] China
RCT
15 participants 14–23 years
Quasi-RCT, splitmouth design
Xu 2006 [29] China
Fujiyama 2008 [24] Japan
17 participants 11–16 years
RCT, split-mouth design
Limpanichkul 2006 [26] Thailand
11 participants 12–18 years
RCT, split-mouth design
Cruz 2004 [22] Brazil
Participants/age
Study design
Study ID
Table 2 General information of recruited studies and methodological assessment score
4
1
Measurement was performed on 3 dental casts with a Vernier caliper
Measurement was performed on dental casts with a computer image analyzer
Measurement of dental casts using a 5 stereo microscope
Measurement in loco with a digital electronic caliper
Modified Jadad score
Measurements performed with the 6 Geomagic Studio 5 software after casts being 3D scanned
Measurement was performed on 2 dental casts with a Vernier caliper
Measurement of dental casts using a 3 digital caliper
4.5 months/150 g initial Measurements on models performed 8 force with a digital caliper
3 months/150 g initial force (activated monthly)
28 days/150 g initial force
7 days
9 weeks/150 g initial Measurement of dental casts using a 4 force (activated every digital electronic caliper 21 days)
8 weeks/125 g initial force
21 days/1.37 N initial force
3 months/150 g initial force (activated monthly)
2 months/150 g initial force (activated monthly)
Follow-up/force applied Tooth movement measurement
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Lasers Med Sci Table 3 Laser parameters and treatment regimen of included studies Study ID
Type of laser
Limpanichkul 2006a [26] Thailand GaAlAs semiconductor diode laser Gui 2008a [25] China
GaAs semiconductor laser
Doshi-Mehta 2012a [23] India
GaAlAs semiconductor diode laser
Youssef 2008b [30] Syria
GaAlAs semiconductor diode laser
Cruz 2004b [22] Brazil
GaAlAs semiconductor diode laser
b
Wang 2007 [28] China Sousa 2011b [27] Brazil Xu 2006 [29] China Fujiyama 2008 [24] Japan
Wavelength/ Power output/ Frequency of laser treatment energy density total time per tooth(s) 860 nm 25 J/cm2 650 nm 25 J/cm2 810 nm 20 J/cm2 809 nm 8 J/cm2 780 nm
5 J/cm2 GaAlAs semiconductor diode laser 780 nm 5 J/cm2 GaAlAs semiconductor diode laser 780 nm 5 J/cm2 He–Ne laser with CO2 laser assisted 632 nm 2.5 J/cm2 CO2 laser, 5 pulses per 1,000 s Not specified
a
Studies included in high energy density groups
b
Studies included in low energy density groups
Methodological and quality assessment Randomization was performed among all included RCTs. All three quasi-RCTs used split-mouth design and took right side as experimental group. Five of the included studies showed a moderate risk of bias, and four of them exhibited a high risk of bias. Quantized assessment was made using the Jadad score. Results of the studies’ Jadad scores were listed in Table 2. Review authors’ judgments (referring to Cochrane Handbook for Systematic Reviews of Interventions) about risk of bias for each included study were exhibited in Fig. 2. The effect of LLLT on OTM Eight included studies reported distance of tooth movement according to different follow-ups, respectively. Youssef et al. [30] reported the mean speed in the duration; therefore, the distance was calculated manually. With regard to the existence of considerable heterogeneity, random-effect model was adopted. Feasible data of included studies were pooled, and meta-analysis was made to investigate the overall efficacy of LLLT regarding four follow-ups (7 days, 1 month, 2 months, and 3 months). The results showed that accumulative moved distance was statistically increased in the LLLT group in
100 mW 184 s/tooth 20 mW 1,200 s 80 mW 100 s/tooth 100 mW 80 s/tooth 20 mW
Days 1, 2, 3 of every month For 3 months Once a week For 4 weeks Days 0, 3, 7, 14 of every 15 days For 4.5 months Days 0, 3, 7, 14 of every stage(3 weeks) For 3 stages (9 weeks) Days 0, 3, 7, 14 of each month
100 s/tooth 20 mW 100 s/tooth 20 mW 100 s/tooth 20 mW
For 2 months Once a week For 8 weeks Days 0, 3, 7 of each month For 4 months Days 1, 2, 3, 4, 5 in 21 days
2W 60 s/tooth
Once (immediately after separation)
7 days (mean difference 0.17, 95 % CI [0.02, 0.37], p=0.03) and 2 months (mean difference 1.08, 95 % CI [0.16, 2.01], p= 0.02). Marginal significance was found in 3 months (mean difference 0.49, 95 % CI [0.00, 0.98], p=0.05). Besides, Doshi-Mehta and Bhad-Patil [23] reported the moved distance in 4.5 months, and the mean difference is 1.53 (95 % CI [1.03, 2.03], p=0.0000). No statistical difference between LLLT group and control/placebo group was found in 1-month follow-up (mean difference 0.32, 95 % CI [−0.04, 0.68], p= 0.08). Figure 3 showed forest plots of the overall efficacy with respect to each follow-up as well as subgroup analysis regarding energy densities. Some participants had both their jaws involved in the test in several studies. Difference of moved distance between maxillary and mandibular canines was tested by Sousa et al. [27] utilizing the three-way analysis of variance, and no statistical difference was observed. Youssef et al. [30] stated that there was not any statistical difference between the mean speed of the upper and lower canines in both control and experimental group. Doshi-Mehta and Bhad-Patil [23] provided the data for both upper and lower canines, and both upper and lower ones had a “high significance” in accumulative moved distance between control and experimental group within 3 months as well as 4.5 months.
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cemento-enamel junction. No statistical difference was detected between them.
Discussion
Fig. 2 Risk of bias summary. Review of author’s judgments about each risk of bias item for each included study. Red, green, and yellow refer to high risk of bias, low risk of bias, and unclear risk of bias, respectively
Adverse effect There was no evidence that LLLT would do damage to roots, alveolar bone, and periodontal tissues based on radiographs [22, 28]. Doshi-Mehta and Bhad-Patil [23] investigated adverse effect in adjacent periodontal ligaments and alveolar bone based on periapical radiographs, and no undesirable changes were found. Gui and Qu [25] suggested that there was no harmful response of gingiva and mucosa following LLLT. Particularly, Sousa et al. [27] analyzed the alveolar bone resorption of the canines and the first molars in both irradiated group and non-irradiated group by means of measuring the distance between the alveolar bone ridge and the
The LLLT has been introduced into dentistry for various clinical practices for its bio-stimulatory effect which contributed to wound healing [31, 32], muscle relaxation [33], immune system modulation [31], fibroblast proliferation [34, 35], and nerve regeneration [36]. In the field of orthodontics, researchers proposed a positive effect of LLLT in managing orthodontic pain [37] and increasing bone deposition in midpalatal suture during RPE in rats [38]. Currently, some reports [18–21] have shown that LLLT could accelerate tooth movement in animals. Several studies evaluated the influence of LLLT on the speed of OTM by means of clinical trials, but the results turned out to be divergent and the laser dosage was different. Therefore, a systematic review of the present knowledge seems desirable. Cruz et al. [22] first conducted a research on human subjects, and the results showed that LLLT could enhance the speed of OTM, which was similar to the previous animal experiments. But Limpanichkul et al. [26] stated that there was no significant difference between the LLLT side and the placebo side by means of measuring the canine distal movement. Moreover, subsequent researches did not reach a full consensus with these initial two studies. Recently, Genc et al. [39] also investigated the effect of LLLT on OTM. Although no data of accumulative moved distance was reported, a positive result for its accelerating effect was demonstrated. The tooth movement in the laser group was 20–40 % faster than that in the control group, which was similar to some of previous studies [19, 30, 38]. In our review, the LLLT statistically enhanced the accumulative moved distance in the duration of 7 days, 2 months, and 4.5 months, while no significant difference was observed between LLLT group and control/placebo group in the duration of 1 month and a marginal significance was found in the duration of 3 month. According to our analysis, LLLT have some positive effects in reducing orthodontic treatment duration. Investigators have been focusing on the mechanisms of LLLT in accelerating tooth movement for years. Generally, the LLLT enhanced the vitality actions of the cell by upregulating the ATP production of mitochondria [40]. Thus, the bio-stimulatory effect of LLLT turned out to be a result of activation of cells. The basic process of orthodontic treatment is bone absorption and deposition which is defined as bone remodeling that is promoted by forces. In this process, osteoclasts and osteoblasts, which are responsible for bone resorption and bone formation, respectively, are pivotal points [41, 42].
Lasers Med Sci Fig. 3 Forest plots of comparison. LLLT group versus control/placebo group. Outcome: accumulative moved distance. Subgroup analysis: high energy density versus low energy density
Several studies [18, 19, 42] have confirmed that the LLLT had an effect in stimulating this bone remodeling process. A promotion in the speed of orthodontic movement after the use of laser irradiation could be observed as being a result of increased osteoclast number and/or activity in laser treated area of the animal models [19, 20, 43]. Similar results in proliferation of osteoclasts and osteoblasts, which might influence each other’s activity, were widely reported in other
relevant studies, and this process seemed accompanied by bone healing and vascularization [18]. Recently, deeper understandings have been elaborated that the LLLT increased the speed of tooth movement via stimulation of RANK/RANKL/ OPG system [18, 42, 43] which reflected osteoclasts’ differentiation level and was essential for bone remodeling. One important and difficult issue for LLLT is to define the optimal dose or energy density in orthodontic treatment. Many
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investigators have discovered that the bio-stimulation of LLLT followed a dose dependency [44–47]. Long-term cryopreserved peripheral blood progenitor cell exhibited variable activities under exposure of LLLT in different energy densities [44]. By observing colony-forming units (CFU) number, the activities of long-term cryopreserved peripheral blood progenitor were evaluated. The highest activity was observed at the dose of 1.0 J/cm2. Energy densities lower or higher than 1.0 J/cm2 would reduce the bio-stimulatory effect, showing no statistical difference between experiment group and control group. Notably, the highest energy density (2.0 J/cm2) of LLLT employed in this study inhibited the cell activity instead. Such bell-shaped dose–effect curve was also found in several previous preliminary studies based on various cells and tissues [46, 48]. As mentioned previously, excessive exposure of LLLT could run a risk of generating a bio-inhibitory effect on irradiated tissues [34, 47], of which some undesirable outcomes in orthodontic treatment could be a result. In the study of Goulart et al. [45], two densities (5.25 and 35.0 J/cm2) were employed to investigate the speed of tooth movement in dogs. A statistically significant increased speed of OTM was found in 5.25 J/cm2 group, and a delay of OTM was found in 35.0 J/cm2 group. This phenomenon was similar with our analysis. In this review, the employed energy densities varied from 2.5 to 25 J/cm2 (one employed 2.5 J/cm2, three employed 5 J/cm2, one employed 8 J/cm2, one employed 20 J/cm2, and two employed 25 J/cm2) which varied in a great scale. Thus, the studies were divided into two subgroups (low energy density and high energy density) for each follow-up (subgroup analysis of 7 days was unavailable due to the lack of data in Fujiyama’s study). Three studies that employed energy density of 20 or 25 J/cm2 fell into high energy density group which was close to that of the study of Goulart et al., and the rest of the studies (5 and 8 J/cm2) fell into low energy group which was close to 5 J/cm2 employed by Goulart et al. Notably, in each follow-up, the low energy density subgroup exhibited a higher mean difference than that of the high energy density subgroup. Furthermore, accumulative moved distance was statistically increased in all low energy density subgroups, while in high energy subgroups, no statistical difference was observed between LLLT group and control/placebo group. It seemed that the results of studies of high energy density subgroups probably hindered the overall effect. This could explain why in 1-month follow-up no statistical difference between groups was detected and in 3-month follow-up a marginal significance was observed. Thus, we considered that there possibly existed an optimal density for the promotion effect of LLLT. Densities higher or lower than the optimal density would reduce its efficacy for accelerating OTM. The adverse effect of laser therapy is mainly concerned as potential risk of retinal damage [49]. Covering the laser probe with a sheath or filter plate might prevent the operator and
patient from this risk. When applied in orthodontics, the mainly concerned potential adverse effect of LLLT is damage to alveolar bone, periodontal tissues, and root, which is generally considered undesirable in orthodontic treatment. According to our findings, no obvious damage was observed in the alveolar bone, periodontal tissues, and root. Therefore, there was no evidence demonstrating the insecurity or adverse effects caused by LLLT according to our knowledge. A systematic review of interventions for accelerating orthodontic tooth movement by Hu Long et al. [50] also investigated the accelerating effect of LLLT for OTM. The power of our meta-analysis compared with that one was increased by three factors. First, we included more studies in our metaanalysis which could possibly enhance the internal validity of the results. Second, that review discussed five different interventions, but we focused specially on LLLT’s accelerating effect for OTM; as a result, we provided more detailed evidence. Third, we first tested the hypothesis that the efficacy of LLLT might be related with its dose or energy density. The subgroup analysis revealed a dose–effect response of the LLLT. According to current evidence, an energy density of 20 or 25 J/cm2 or even higher was not suggested. However, there were still some limitations in this review which deserved further discussion. The qualities of the recruited studies varied in a considerable scale. Our methodological and quality assessments revealed that the deficiency of the included studies mainly lay in insufficient description for method of randomization and/or method of blinding. Additionally, one of the studies [30] reported continuous data without standard deviations, resulting in incomplete use of the data. Although we tried to contact the investigators, no response was received. Finally, some of the study samples were considerably undersized, and all of the included studies had moderate to high risk of bias. Despite the limitations mentioned above, we still considered this review provided the best evidence of the efficacy of LLLT for accelerating OTM up to now. More qualified RCTs in human subjects are required to define the optimal dose or density of LLLT in order to maximize the efficacy of this promising treatment.
Conclusions This systematic review and meta-analysis demonstrated that LLLT might speed up the tooth movement in orthodontic treatment. It seemed that this accelerating effect showed no statistical difference between upper and lower jaws. No obvious adverse effect was detected in this review. Moreover, a relatively lower energy density (2.5, 5, and 8 J/cm2) was seemingly more effective than 20 J/cm 2, 25 J/cm 2, and even higher ones, although the optimal dose remained undetermined.
Lasers Med Sci Acknowledgement This work was supported by the National Nature Science Foundation of China (grant number 81271178).
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REVIEW ARTICLE
Efficacy of low-level laser therapy for accelerating tooth movement during orthodontic treatment: a systematic review and meta-analysis M. K. Ge & W. L. He & J. Chen & C. Wen & X. Yin & Z. A. Hu & Z. P. Liu & S. J. Zou
Received: 29 April 2013 / Accepted: 3 February 2014 # Springer-Verlag London 2014
Abstract This review aimed to evaluate the efficacy of lowlevel laser therapy (LLLT) for accelerating tooth movement during orthodontic treatment. An extensive electronic search was conducted by two reviewers. Randomized controlled trials (RCTs) and quasi-RCTs concerning the efficacy of LLLT for accelerating tooth movement during orthodontic treatment were searched in CENTRAL, Medline, PubMed, Embase, China Biology Medicine Disc (CBM), China National Knowledge Infrastructure (CNKI), and Google Scholar. Six RCTs and three quasi-RCTs, involving 211 patients from six countries, were selected from 173 relevant studies. All nine articles were feasible for the systematic review and meta-analysis, five of which were assessed as moderate risk of bias, while the rest were assessed as high risk of bias. The mean difference and the 95 % confidence interval (95 % CI) of accumulative moved distance of teeth were observed among all the researches. The results showed that the LLLT could accelerate orthodontic tooth movement (OTM) in 7 days (mean difference 0.19, 95 % CI [0.02, 0.37], p=0.03) and 2 months (mean difference 1.08, 95 % CI [0.16, 2.01], p=0.02). Moreover, a relatively lower energy density (5 and 8 J/cm2) was
M. K. Ge : J. Chen : X. Yin : Z. A. Hu : Z. P. Liu : S. J. Zou (*) State Key Laboratory of Oral Diseases, Department of Orthodontics, West China Hospital of Stomatology, Sichuan University, 14 Section 3 South Ren Min Road, 610041 Chengdu, China e-mail: [email protected] W. L. He Department of Orthodontics, Guangdong Provincial Stomatological Hospital, the Affiliated Stomatological Hospital of Southern Medical University, Guangzhou, China C. Wen State Key Laboratory of Oral Diseases, Department of Prosthodontics, West China Hospital of Stomatology, Sichuan University, Chengdu, China
seemingly more effective than 20 and 25 J/cm2 and even higher ones. Keywords Low-level laser therapy . Tooth movement . Orthodontic . Systematic review . Meta-analysis
Introduction Orthodontic treatment, based on tooth movement, is a timeconsuming procedure which usually takes 20–30 months treatment duration. This long-term treatment is not only burdensome for patients, resulting in decreasing compliance of patients throughout the duration, but also is apt to cause a variety of side effects, such as alveolar bone resorption [1], root resorption [2], caries [3], etc. Therefore, shortening the orthodontic treatment duration is desired. Reducing orthodontic treatment time requires increasing the rate of tooth movement. Many studies have researched different methods to accelerate tooth movement, including drug injections [4–6], electric stimulation [7, 8], pulsed electromagnetic fields [9], and corticotomy [10, 11]. Although these methods could speed up the tooth movement, there are some drawbacks; for example, they could cause some unpleasant experience on patients; the required apparatuses were not in common use in dental practice, or the chemicals used to accelerate the tooth movement could cause negative effects on bone and root resorption [12]. However, compared with chemicals or operations mentioned above, low-level laser therapy (LLLT) has not been reported negative systematic effects on the subjects yet. It is deemed to be a promising technique in dentistry owing to its multiple bio-stimulatory effect, non-invasive manner, and easy access. It was recognized for its use in teeth whitening [13], caries detection [14], pain relief for aphthous ulcers [15], increasing osseointegration of implants [16, 17], etc. Besides, the non-invasive manner provided better experience for patients.
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Several experiments based on animal models [18–21] and human subjects [22–30] have investigated the effect of LLLT on accelerating orthodontic tooth movement (OTM). Therefore, a systematic review of the present knowledge seems desirable. The purpose of this review was to comprehensively evaluate, in an evidence-based way, the effectiveness of LLLT on accelerating tooth movement in orthodontic treatment for human subjects.
Materials and methods This systematic review and meta-analysis were carried out referring to Cochrane Handbook for Systematic Reviews of Interventions and Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA). Two reviewers (M.K. Ge and W.L. He) independently conducted the search and the work of extracting data and assessing the risk of bias and eligibilities of the retrieved articles. Any disagreement was resolved by discussing with a third reviewer (S.J. Zou). Search strategy An extensive electronic search for randomized controlled trials (RCTs) and quasi-RCTs (where nonrandom allocation method was applied) was made through CENTRAL (up to Issue 1. 2013), PubMed, MEDLINE(via OVID, up to Feb 2013), Embase (up to Feb 2013), China National Knowledge Infrastructure (CNKI) (up to Feb 2013), and China Biology Medicine Disc (CBM) (up to Feb 2013). Ongoing clinical trials were searched in World Health Organization International Clinical Trials Registry Platform. Hand-searching was performed in relevant Chinese journals. Terms used in the search included “orthodontic,” “tooth movement/orthodontic movement,” “laser/low-level laser/low-intensity laser/soft or cold laser,” and “irradiation/light/phototherapy.” Reference lists of the retrieved articles were also checked. There was no language restriction in the search.
Exclusion criteria: 1. Reviews, cohort studies, case reports, descriptive studies, letters, opinion articles, or abstracts 2. Participants have system disease, or dental, pulp, or periodontal problems 3. Participants are under medical treatment that could interfere with bone metabolism or orthodontic movement (e.g., analgesics, anti-inflammatory medicine (NSAIDs), or antibiotics) 4. Animal experiments
Methodological quality and risk of bias Risk of bias assessment was performed referring to Cochrane Handbook for Systematic Reviews of Interventions. All included articles were assessed on the following domains: sequence generation, allocation concealment, blinding, incomplete outcome, selective reporting, and other bias. The qualities of included studies were categorized as follows: 1. Low risk of bias: with six domains assessed as “low risk” 2. Moderate risk of bias: with one or more domains assessed as “unclear” 3. High risk of bias: with one or more domains assessed as “high risk” Modified Jadad score was also utilized to quantize the assessment. The modified Jadad score scale was listed in Table 1. Data extraction Relevant information were extracted independently by two reviewers including method of randomization, concealment and blindness, and the studies’ eligibility (study designs, demographic data, duration of follow-ups, orthodontic treatment, laser parameters, outcome measurements, laser treatment intervals).
Selection criteria Outcome measures Inclusion criteria: Primary outcome measures: 1. Studies that evaluated efficacy of LLLT for OTM 2. Study design: RCTs and quasi-RCTs. Relevant data should be provided 3. All participants received orthodontic treatment with the same management 4. Subjects were assigned to experimental group or control/ placebo group based on using LLLT or not 5. Outcome variables were accumulative moved distance or speed of the tooth movement in treatment duration
1. Distance of tooth movement 2. Speed of tooth movement Secondary outcome measures: 1. The wavelengths, doses, and frequencies of LLLT 2. Adverse events: damage to the root, alveolar bone, or periodontal tissues
Lasers Med Sci Table 1 Modified Jadad score Item assessed
Response
Score
Was the study described as randomized?
Yes No Yes Not described No Yes No Yes Not described No Yes No Yes No Yes No Yes
+1 0 +1 0 −1 +1 0 +1 0 −1 +1 0 +1 0 +1 0 +1
No
0
Was the method of randomization appropriate? Was the study described as blinded? Was the method of blinding appropriate? Was there a description of withdrawals and dropouts? Was there a clear description of the inclusion/exclusion criteria? Was the method used to assess adverse effects described? Was the method of statistical analysis described?
adopted if non-significant heterogeneity was observed (I2 ≤ 50 %).The statistical significance for the hypothesis test was set at p 50 %); fixed-effects model would be
Six random controlled trials [22–24, 26–28] and three quasiRCTs [25, 29, 30] were finally included. All of the enrolled participants completed their treatment without any dropouts or withdrawals. Table 2 showed the characteristics of the included studies. In addition, summary details of laser parameters and treatment regimen were shown in Table 3.
Fig. 1 Flow diagram of the study inclusion of the systematic review and meta-analysis
RCT, split-mouth design
Sousa 2011 [27] Brazil
30/30
17/17
36/36
12/12
20 participants
10 participants 10.5–20.2 years
30/30
13/13
90 participants 60/30 Mean age 19.08 years 20 participants 20/20 Mean age 14.5 years
36 participants 11.0–13.5 years
12 participants Mean age 20.11± 3.4 years
11/11
N (I/C)
Maxillary first premolar extraction, maxillary canine retraction using NiTi closed-coil springs, modified Nance arch used for anchorage reinforcement 3 months after maxillary first premolar extraction, maxillary canine retraction using NiTi closed-coil springs, vertical loop stops for anchorage reinforcement Maxillary first premolar extractions. Canine retraction using NiTi closedcoil springs, Nance arch used for anchorage reinforcement Maxillary first premolar extractions. Canine retraction using NiTi closedcoil springs, modified Nance arch used for anchorage reinforcement 14 days after extraction of 4 first premolars, maxillary canine retraction using Ricketts springs, both upper and lower jaws included Separators were placed at the mesial and distal contacts of the maxillary first molars in 90 patients Extraction of maxillary first premolars, canine retraction using elastomeric chains. Nance arch used for anchorage reinforcement 3 months after maxillary first premolar extractions (in 3 patients, mandibular premolars also extracted), canine retraction using NiTi coil springs Maxillary first premolar extractions (in 10 patients mandibular premolars also extracted), canine retraction using NiTi closed-coil springs, transpalatal arch used for anchorage reinforcement
Orthodontic treatment
M male, F female, N number of participants, I LLLT group, C control/placebo group
Doshi-Mehta RCT, split-mouth 2012 [23] India design
Quasi-RCT, splitmouth design
Youssef 2008 [30] Quasi-RCT, splitSyria mouth design
Gui 2008 [25] China
RCT, split-mouth design
Wang 2007 [28] China
RCT
15 participants 14–23 years
Quasi-RCT, splitmouth design
Xu 2006 [29] China
Fujiyama 2008 [24] Japan
17 participants 11–16 years
RCT, split-mouth design
Limpanichkul 2006 [26] Thailand
11 participants 12–18 years
RCT, split-mouth design
Cruz 2004 [22] Brazil
Participants/age
Study design
Study ID
Table 2 General information of recruited studies and methodological assessment score
4
1
Measurement was performed on 3 dental casts with a Vernier caliper
Measurement was performed on dental casts with a computer image analyzer
Measurement of dental casts using a 5 stereo microscope
Measurement in loco with a digital electronic caliper
Modified Jadad score
Measurements performed with the 6 Geomagic Studio 5 software after casts being 3D scanned
Measurement was performed on 2 dental casts with a Vernier caliper
Measurement of dental casts using a 3 digital caliper
4.5 months/150 g initial Measurements on models performed 8 force with a digital caliper
3 months/150 g initial force (activated monthly)
28 days/150 g initial force
7 days
9 weeks/150 g initial Measurement of dental casts using a 4 force (activated every digital electronic caliper 21 days)
8 weeks/125 g initial force
21 days/1.37 N initial force
3 months/150 g initial force (activated monthly)
2 months/150 g initial force (activated monthly)
Follow-up/force applied Tooth movement measurement
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Lasers Med Sci Table 3 Laser parameters and treatment regimen of included studies Study ID
Type of laser
Limpanichkul 2006a [26] Thailand GaAlAs semiconductor diode laser Gui 2008a [25] China
GaAs semiconductor laser
Doshi-Mehta 2012a [23] India
GaAlAs semiconductor diode laser
Youssef 2008b [30] Syria
GaAlAs semiconductor diode laser
Cruz 2004b [22] Brazil
GaAlAs semiconductor diode laser
b
Wang 2007 [28] China Sousa 2011b [27] Brazil Xu 2006 [29] China Fujiyama 2008 [24] Japan
Wavelength/ Power output/ Frequency of laser treatment energy density total time per tooth(s) 860 nm 25 J/cm2 650 nm 25 J/cm2 810 nm 20 J/cm2 809 nm 8 J/cm2 780 nm
5 J/cm2 GaAlAs semiconductor diode laser 780 nm 5 J/cm2 GaAlAs semiconductor diode laser 780 nm 5 J/cm2 He–Ne laser with CO2 laser assisted 632 nm 2.5 J/cm2 CO2 laser, 5 pulses per 1,000 s Not specified
a
Studies included in high energy density groups
b
Studies included in low energy density groups
Methodological and quality assessment Randomization was performed among all included RCTs. All three quasi-RCTs used split-mouth design and took right side as experimental group. Five of the included studies showed a moderate risk of bias, and four of them exhibited a high risk of bias. Quantized assessment was made using the Jadad score. Results of the studies’ Jadad scores were listed in Table 2. Review authors’ judgments (referring to Cochrane Handbook for Systematic Reviews of Interventions) about risk of bias for each included study were exhibited in Fig. 2. The effect of LLLT on OTM Eight included studies reported distance of tooth movement according to different follow-ups, respectively. Youssef et al. [30] reported the mean speed in the duration; therefore, the distance was calculated manually. With regard to the existence of considerable heterogeneity, random-effect model was adopted. Feasible data of included studies were pooled, and meta-analysis was made to investigate the overall efficacy of LLLT regarding four follow-ups (7 days, 1 month, 2 months, and 3 months). The results showed that accumulative moved distance was statistically increased in the LLLT group in
100 mW 184 s/tooth 20 mW 1,200 s 80 mW 100 s/tooth 100 mW 80 s/tooth 20 mW
Days 1, 2, 3 of every month For 3 months Once a week For 4 weeks Days 0, 3, 7, 14 of every 15 days For 4.5 months Days 0, 3, 7, 14 of every stage(3 weeks) For 3 stages (9 weeks) Days 0, 3, 7, 14 of each month
100 s/tooth 20 mW 100 s/tooth 20 mW 100 s/tooth 20 mW
For 2 months Once a week For 8 weeks Days 0, 3, 7 of each month For 4 months Days 1, 2, 3, 4, 5 in 21 days
2W 60 s/tooth
Once (immediately after separation)
7 days (mean difference 0.17, 95 % CI [0.02, 0.37], p=0.03) and 2 months (mean difference 1.08, 95 % CI [0.16, 2.01], p= 0.02). Marginal significance was found in 3 months (mean difference 0.49, 95 % CI [0.00, 0.98], p=0.05). Besides, Doshi-Mehta and Bhad-Patil [23] reported the moved distance in 4.5 months, and the mean difference is 1.53 (95 % CI [1.03, 2.03], p=0.0000). No statistical difference between LLLT group and control/placebo group was found in 1-month follow-up (mean difference 0.32, 95 % CI [−0.04, 0.68], p= 0.08). Figure 3 showed forest plots of the overall efficacy with respect to each follow-up as well as subgroup analysis regarding energy densities. Some participants had both their jaws involved in the test in several studies. Difference of moved distance between maxillary and mandibular canines was tested by Sousa et al. [27] utilizing the three-way analysis of variance, and no statistical difference was observed. Youssef et al. [30] stated that there was not any statistical difference between the mean speed of the upper and lower canines in both control and experimental group. Doshi-Mehta and Bhad-Patil [23] provided the data for both upper and lower canines, and both upper and lower ones had a “high significance” in accumulative moved distance between control and experimental group within 3 months as well as 4.5 months.
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cemento-enamel junction. No statistical difference was detected between them.
Discussion
Fig. 2 Risk of bias summary. Review of author’s judgments about each risk of bias item for each included study. Red, green, and yellow refer to high risk of bias, low risk of bias, and unclear risk of bias, respectively
Adverse effect There was no evidence that LLLT would do damage to roots, alveolar bone, and periodontal tissues based on radiographs [22, 28]. Doshi-Mehta and Bhad-Patil [23] investigated adverse effect in adjacent periodontal ligaments and alveolar bone based on periapical radiographs, and no undesirable changes were found. Gui and Qu [25] suggested that there was no harmful response of gingiva and mucosa following LLLT. Particularly, Sousa et al. [27] analyzed the alveolar bone resorption of the canines and the first molars in both irradiated group and non-irradiated group by means of measuring the distance between the alveolar bone ridge and the
The LLLT has been introduced into dentistry for various clinical practices for its bio-stimulatory effect which contributed to wound healing [31, 32], muscle relaxation [33], immune system modulation [31], fibroblast proliferation [34, 35], and nerve regeneration [36]. In the field of orthodontics, researchers proposed a positive effect of LLLT in managing orthodontic pain [37] and increasing bone deposition in midpalatal suture during RPE in rats [38]. Currently, some reports [18–21] have shown that LLLT could accelerate tooth movement in animals. Several studies evaluated the influence of LLLT on the speed of OTM by means of clinical trials, but the results turned out to be divergent and the laser dosage was different. Therefore, a systematic review of the present knowledge seems desirable. Cruz et al. [22] first conducted a research on human subjects, and the results showed that LLLT could enhance the speed of OTM, which was similar to the previous animal experiments. But Limpanichkul et al. [26] stated that there was no significant difference between the LLLT side and the placebo side by means of measuring the canine distal movement. Moreover, subsequent researches did not reach a full consensus with these initial two studies. Recently, Genc et al. [39] also investigated the effect of LLLT on OTM. Although no data of accumulative moved distance was reported, a positive result for its accelerating effect was demonstrated. The tooth movement in the laser group was 20–40 % faster than that in the control group, which was similar to some of previous studies [19, 30, 38]. In our review, the LLLT statistically enhanced the accumulative moved distance in the duration of 7 days, 2 months, and 4.5 months, while no significant difference was observed between LLLT group and control/placebo group in the duration of 1 month and a marginal significance was found in the duration of 3 month. According to our analysis, LLLT have some positive effects in reducing orthodontic treatment duration. Investigators have been focusing on the mechanisms of LLLT in accelerating tooth movement for years. Generally, the LLLT enhanced the vitality actions of the cell by upregulating the ATP production of mitochondria [40]. Thus, the bio-stimulatory effect of LLLT turned out to be a result of activation of cells. The basic process of orthodontic treatment is bone absorption and deposition which is defined as bone remodeling that is promoted by forces. In this process, osteoclasts and osteoblasts, which are responsible for bone resorption and bone formation, respectively, are pivotal points [41, 42].
Lasers Med Sci Fig. 3 Forest plots of comparison. LLLT group versus control/placebo group. Outcome: accumulative moved distance. Subgroup analysis: high energy density versus low energy density
Several studies [18, 19, 42] have confirmed that the LLLT had an effect in stimulating this bone remodeling process. A promotion in the speed of orthodontic movement after the use of laser irradiation could be observed as being a result of increased osteoclast number and/or activity in laser treated area of the animal models [19, 20, 43]. Similar results in proliferation of osteoclasts and osteoblasts, which might influence each other’s activity, were widely reported in other
relevant studies, and this process seemed accompanied by bone healing and vascularization [18]. Recently, deeper understandings have been elaborated that the LLLT increased the speed of tooth movement via stimulation of RANK/RANKL/ OPG system [18, 42, 43] which reflected osteoclasts’ differentiation level and was essential for bone remodeling. One important and difficult issue for LLLT is to define the optimal dose or energy density in orthodontic treatment. Many
Lasers Med Sci
investigators have discovered that the bio-stimulation of LLLT followed a dose dependency [44–47]. Long-term cryopreserved peripheral blood progenitor cell exhibited variable activities under exposure of LLLT in different energy densities [44]. By observing colony-forming units (CFU) number, the activities of long-term cryopreserved peripheral blood progenitor were evaluated. The highest activity was observed at the dose of 1.0 J/cm2. Energy densities lower or higher than 1.0 J/cm2 would reduce the bio-stimulatory effect, showing no statistical difference between experiment group and control group. Notably, the highest energy density (2.0 J/cm2) of LLLT employed in this study inhibited the cell activity instead. Such bell-shaped dose–effect curve was also found in several previous preliminary studies based on various cells and tissues [46, 48]. As mentioned previously, excessive exposure of LLLT could run a risk of generating a bio-inhibitory effect on irradiated tissues [34, 47], of which some undesirable outcomes in orthodontic treatment could be a result. In the study of Goulart et al. [45], two densities (5.25 and 35.0 J/cm2) were employed to investigate the speed of tooth movement in dogs. A statistically significant increased speed of OTM was found in 5.25 J/cm2 group, and a delay of OTM was found in 35.0 J/cm2 group. This phenomenon was similar with our analysis. In this review, the employed energy densities varied from 2.5 to 25 J/cm2 (one employed 2.5 J/cm2, three employed 5 J/cm2, one employed 8 J/cm2, one employed 20 J/cm2, and two employed 25 J/cm2) which varied in a great scale. Thus, the studies were divided into two subgroups (low energy density and high energy density) for each follow-up (subgroup analysis of 7 days was unavailable due to the lack of data in Fujiyama’s study). Three studies that employed energy density of 20 or 25 J/cm2 fell into high energy density group which was close to that of the study of Goulart et al., and the rest of the studies (5 and 8 J/cm2) fell into low energy group which was close to 5 J/cm2 employed by Goulart et al. Notably, in each follow-up, the low energy density subgroup exhibited a higher mean difference than that of the high energy density subgroup. Furthermore, accumulative moved distance was statistically increased in all low energy density subgroups, while in high energy subgroups, no statistical difference was observed between LLLT group and control/placebo group. It seemed that the results of studies of high energy density subgroups probably hindered the overall effect. This could explain why in 1-month follow-up no statistical difference between groups was detected and in 3-month follow-up a marginal significance was observed. Thus, we considered that there possibly existed an optimal density for the promotion effect of LLLT. Densities higher or lower than the optimal density would reduce its efficacy for accelerating OTM. The adverse effect of laser therapy is mainly concerned as potential risk of retinal damage [49]. Covering the laser probe with a sheath or filter plate might prevent the operator and
patient from this risk. When applied in orthodontics, the mainly concerned potential adverse effect of LLLT is damage to alveolar bone, periodontal tissues, and root, which is generally considered undesirable in orthodontic treatment. According to our findings, no obvious damage was observed in the alveolar bone, periodontal tissues, and root. Therefore, there was no evidence demonstrating the insecurity or adverse effects caused by LLLT according to our knowledge. A systematic review of interventions for accelerating orthodontic tooth movement by Hu Long et al. [50] also investigated the accelerating effect of LLLT for OTM. The power of our meta-analysis compared with that one was increased by three factors. First, we included more studies in our metaanalysis which could possibly enhance the internal validity of the results. Second, that review discussed five different interventions, but we focused specially on LLLT’s accelerating effect for OTM; as a result, we provided more detailed evidence. Third, we first tested the hypothesis that the efficacy of LLLT might be related with its dose or energy density. The subgroup analysis revealed a dose–effect response of the LLLT. According to current evidence, an energy density of 20 or 25 J/cm2 or even higher was not suggested. However, there were still some limitations in this review which deserved further discussion. The qualities of the recruited studies varied in a considerable scale. Our methodological and quality assessments revealed that the deficiency of the included studies mainly lay in insufficient description for method of randomization and/or method of blinding. Additionally, one of the studies [30] reported continuous data without standard deviations, resulting in incomplete use of the data. Although we tried to contact the investigators, no response was received. Finally, some of the study samples were considerably undersized, and all of the included studies had moderate to high risk of bias. Despite the limitations mentioned above, we still considered this review provided the best evidence of the efficacy of LLLT for accelerating OTM up to now. More qualified RCTs in human subjects are required to define the optimal dose or density of LLLT in order to maximize the efficacy of this promising treatment.
Conclusions This systematic review and meta-analysis demonstrated that LLLT might speed up the tooth movement in orthodontic treatment. It seemed that this accelerating effect showed no statistical difference between upper and lower jaws. No obvious adverse effect was detected in this review. Moreover, a relatively lower energy density (2.5, 5, and 8 J/cm2) was seemingly more effective than 20 J/cm 2, 25 J/cm 2, and even higher ones, although the optimal dose remained undetermined.
Lasers Med Sci Acknowledgement This work was supported by the National Nature Science Foundation of China (grant number 81271178).
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