Effect of low-intensity laser therapy on levels of biomarkers during orthodontic tooth movement – A systematic review

Protocol and registration

Protocol of this systematic review was registered on National Institute for Health Research, Prospero international prospective register of systematic reviews (PROSPERO: registration number: CRD42022355520). The review was conducted following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines 2020 and Cochrane Handbook for Systematic Reviews of Interventions version 6.3.

Eligibility criteria

Information sources, search strategy, and selection process

To conduct a comprehensive and systematic review on the effect of LILT on levels of biomarkers during OTM, a broad range of electronic databases such as PubMed, Central of the Cochrane Library, and Google Scholar were searched from January 2000 to March 2023. A hand search was also undertaken in orthodontic journals. Unpublished literature was searched on ClinicalTrials.gov. In addition, reference lists of relevant studies, meta-analyses, systematic reviews, and other review articles were screened for potential inclusion.

Search Strategy: The search strategy was developed using relevant Medical Subject Headings (MeSH) terms, keywords, and Boolean operators “AND” and “or” combination. The following search terms and their combinations were used in the search strategy: “low-intensity laser,” “low-level laser,” “low-power laser,” “semiconductor diode laser,” “tooth movement,” “orthodontic tooth movement,” “accelerated tooth movement,” “accelerated orthodontic tooth movement,” “biomarkers,” “molecular biomarkers,” “transforming growth factor,” “TGF,” “matrix metalloproteinase,” “MMP,” “interleukin,” “IL-1,” “IL-6,” “prostaglandin,” “prostaglandin E2,” “Receptor activator of nuclear factor kappa B ligand,” “RANKL,” “Osteoprotegerin”, “OPG” with Boolean characters “AND,” and “OR” combination. The search strategy was adapted to the specific syntax and subject headings of each electronic database.

Data collection process and data items

Once the relevant studies were identified, data were extracted from each study using a pre-designed data extraction form. The data items extracted included the study design, name of author, year of publication, study design, age and sex of participants. Additionally, description of participants and grouping, type of tooth movement, description of intervention site, type of laser, wavelength of laser, power output were also extracted. Furthermore the total time of irradiation, frequency of LILT, biomarker analyzed, method of analyzing the biomarker, main outcome (level of biomarker), and additional outcome (rate of OTM) were other data items that were extracted.

Risk of bias (RoB) assessment in animal studies

RoB assessment for animal intervention studies done using Systematic Review Centre for Laboratory Animal Experimentation’s (SYRCLE’s) RoB tool.

RoB assessment in human studies

RoB assessment for human studies was done using Revised Cochrane RoB tool.

Study selection

Electronic screening of PubMed and Google scholar identified 32 articles. After adjusting the duplicates, 25 articles were scrutinized for inclusion in the study. Majority of them were excluded as they did not have relevant title and abstract, leaving 15 articles. Subsequent to excluding two review article and two descriptive studies, only 11 original articles remained, which were included in this systematic review. The PRISMA flowchart of the electronic database search is represented in [Figure 1].

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Figure 1:

Preferred Reporting Items for Systematic Reviews and Meta-Analyses flow diagram of study selection, n: Number of articles, *: records identified are total number of records across all databases, **: automation tools were not used, records were excluded by the reviewers.

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Study characteristics

RoB

The RoB assessment for animal studies is summarized in [Figures 2 and 3] and for human studies in [Figures 4 and 5]. On overall assessment, all animal studies^[1,2,18-20] had high RoB and out of six human studies, one study had low RoB^[3] with remaining five having high RoB^{[16,17,21-23]}

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Figure 2:

Risk of bias summary for animal studies.

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Figure 3:

Risk of bias graph for animal studies.

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Figure 4:

Risk of bias summary for human studies.

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Figure 5:

Risk of bias graph for human studies.

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Animal studies

Out of the five animal studies analyzed in this systematic review, four of them concluded that LILT led to an acceleration in tooth movement.^[2,18-20] However, one study reported that there was no significant difference in the rate of tooth movement between the experimental group and the control group.^[1]

Kawasaki and Shimizu^[2] found that low-energy laser irradiation during experimental tooth movement in rats increased the amount of tooth movement and osteoclast formation on the pressure side. They used the expression of tartrate resistant acid phosphatase as a lineage marker to identify the macrophage/osteoclast lineage.^[2]

Fujita et al.^[18] and Yamaguchi et al.^[19] showed that low-energy laser irradiation increased the velocity of tooth movement by promoting the expressions of receptor activator of nuclear factor-kappa B (RANK)/RANK ligand (RANKL) and macrophage colony-stimulating factor/colony-stimulating factor-1 receptor, respectively, which are essential for osteoclastogenesis and bone resorption. These factors are necessary and sufficient for bone resorption, which is the rate-limiting step in OTM.^[18,19]

Yamaguchi et al.^[20] conducted a study on the impact of LILT on OTMs in rats, focusing on the roles of matrix metalloproteinase (MMP)-9, cathepsin K, and alpha(v) beta (3) integrin. Their research indicated that MMP-9 is involved in the invasive activity of osteoclasts, cathepsin K plays a critical part in the degradation of the bone organic matrix through osteoclasts, and alpha(v) beta (3) integrin is responsible for the tight attachment of osteoclasts to the bone matrix. They observed higher expression of MMP-9, cathepsin K, and alpha(v) beta (3) integrin on the pressure side, as well as a significant increase in the velocity of OTM on the laser-treated side.^[20]

In their research on rats, Kim et al.^[1] determined that the experimental group exhibited a significant increase in the expression of fibronectin and collagen type I from day 1, with a more uniform distribution compared to the control group. These differences were maintained until the conclusion of the study. Based on these findings, the authors concluded that LILT aids in the rearrangement of connective tissues during tooth movement in rats.^[1]

However, in all these studies, animals were sacrificed within one or two weeks to obtain tissue samples, which prevented the determination of the long-term effects of the laser treatment. Therefore, it was necessary to conduct studies on humans to assess the changes in biomarker levels over a longer period during orthodontic treatment with LILT.

Human studies

Out of the six human studies analyzed in this systematic review, five studies^[3,16,21-23] concluded that LILT resulted in a higher rate of tooth movement. However, one study^[17] did not find a significant difference in the average rate of tooth movement between the experimental and control group.

Interleukin-1beta (IL-1β) is a powerful cytokine that promotes osteoclast activity and is produced in sufficient quantities by the PDL to diffuse into the GCF. IL-1β is considered a biomarker of OTM.^[3] Üretürk et al.^[21] found that low-level laser therapy (LILT) had a significant effect on the levels of IL-1β in GCF. Twenty-four hours after LILT, there was a significant difference in IL-1β levels between the laser and control groups, but only at the site of compression due to increased osteoclastic activity in that area.^[21] According to Jose et al. and Zheng and Yang, IL-1β levels peaked on day 7 after LILT, and the laser group had significantly higher levels on day 21.^[16,23] All these observations were attributed to the role of IL-1β in bone resorption, which is the limiting factor in OTM.

Varella et al.^[3] demonstrated a four-fold increase in IL-1β levels after four weeks and a ten-fold increase after eight weeks in patients who received continuous laser irradiation compared to those who did not receive LILT. This finding suggests that the accumulation of IL-1β in response to laser therapy may increase over time, possibly due to the extended application of laser irradiation during canine retraction.^[3]

The production of osteoclast precursors and osteoclast proliferation is stimulated by inflammatory cytokines like IL-6, which also play a crucial role in regulating bone remodeling activity in specific regions and initiating the acute inflammatory response at the onset of orthodontic treatment.^[17] Yassaei et al.^[17] conducted a study on the effect of LILT on the level of IL-6 in GCF and determined that there was no significant difference in the average concentration of IL-6 during various stages of canine distalization treatment between the groups. However, this result could be because the second GCF sample was collected six months after stage 0, whereas other studies have examined the increase in cytokine levels over shorter periods of time, such as 24 h or 1 week.^[17]

Osteoclasts produce MMP-9, which is primarily a marker for bone resorption.^[20] This marker can be analyzed on the pressure side during tooth movement. Jivrajani and Bhad Patil^[22] studied the impact of LILT on MMP9 levels in GCF and found that LILT increased MMP-9 expression in GCF during the initial three months of canine retraction. However, this effect declined after three months as there was no significant difference in the change of MMP-9 concentration between the experimental and control groups.^[22] This result suggests that LILT may be more effective in the early stages of OTM, as demonstrated by previous studies conducted by Doshi-Mehta and Bhad-Patil,^[24] and Saito and Shimizu.^[25]

RANKL plays a crucial role in the formation of osteoclasts, which are responsible for bone resorption.

When RANKL binds to its receptor, RANK, it triggers a series of internal signaling events that ultimately lead to the breakdown of bone tissue. Osteoprotegerin (OPG), a soluble decoy receptor, inhibits this interaction. During the early stages of OTM, the previous clinical studies have found that OPG levels tend to remain the same or decrease while RANKL levels tend to increase.^[22,23] However, Zheng and Yang^[23] recently investigated the impact of LILT on the levels of RANKL and OPG in GCF and found that the RANKL level was significantly higher at day 21 in the laser group, while it remained constant in the control group. This is because the binding of RANKL to RANK initiates bone resorption, which is prevented by OPG.

Several studies have pointed out the interaction between biomarkers. Üretürk et al.^[21] investigated how LILT affects the levels of IL-1β and transforming growth factor-beta 1 (TGF-β1) in GCF. Although IL-1β levels exhibited a significant difference between the laser and control groups at 24 h only in the compression site due to increased osteoclastic activity in the same area, TGF-β1 levels showed no significant difference between the two groups, possibly due to reduced gene and protein expression of TGF-β1 in cells exposed to IL-1β.^[21] In contrast, Jose et al. also studied IL-1β and prostaglandin E2 (PGE2) in GCF and concluded that the levels of both IL-1β and PGE2 reached their peak at the 7 and 21 day after LILT, indicating that PGE2 was upregulated by IL-1β.^[16] The GCF collection protocol recommended by Jivrajani and Bhad Patil^[22] offers valuable insights for future research, particularly in exploring the prolonged effects of LILT on biomarker levels and the rate of OTM.