Effect of local administration of bisphosphonate on orthodontic anchorage – A systematic review of animal studies Harikrishnan S, Ramasamy N

SYSTEMATIC REVIEW

Year : 2022 | Volume : 11 | Issue : 1 | Page : 31

Effect of local administration of bisphosphonate on orthodontic anchorage – A systematic review of animal studies

Sruthi Harikrishnan, Navaneethan Ramasamy
Department of Orthodontics and Dentofacial Orthopaedics, Saveetha Dental College and Hospital, Saveetha Institute of Medical and Technical Sciences (SIMATS), Saveetha University, Chennai, Tamil Nadu, India

Date of Submission	23-Nov-2021
Date of Decision	03-Jun-2022
Date of Acceptance	06-Jun-2022
Date of Web Publication	24-Aug-2022

Correspondence Address:
Sruthi Harikrishnan
Department of Orthodontics and Dentofacial Orthopaedics, Saveetha Dental College and Hospital, Saveetha Institute of Medical and Technical Sciences (SIMATS), Saveetha University, Chennai - 600 077, Tamil Nadu
India

Source of Support: None, Conflict of Interest: None

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DOI: 10.4103/jos.jos_189_21

Abstract

BACKGROUND: Pharmacological means of anchorage control can improve patient compliance. Bisphosphonates could be helpful in orthodontic anchorage control if their actions could be localized to limit (or control) unwanted tooth movement while not interfering with the desired tooth movement.
OBJECTIVE: This systematic review aimed to examine and evaluate the quality of all animal studies that reported the effect of locally administered bisphosphonate on limiting orthodontic tooth movement.
DATA SOURCES: An electronic search was conducted in the PubMed-Medline, Scopus, Google Scholar, and Cochrane databases till May 2022, using the keywords anchorage, anchorage loss, molar movement, posterior tooth movement, incisor movement, incisor retraction, anterior retraction, unwanted tooth movement, tooth displacement, tooth movement forward, bisphosphonate, local bisphosphonate administration, bisphosphonate injection, and bbisphosphonate vestibular induction. Only studies involving localized bisphosphonate administration for anchorage purposes were taken into account.
DATA SELECTION: Animal studies that simulated orthodontic tooth movement after localized injection of bisphosphonate and evaluated the rate of tooth movement were included in the review.
DATA EXTRACTION AND ANALYSIS: The quality of the studies was assessed by using ARRIVE guidelines (Animal Research: Reporting of In Vivo Experiments). Bias in the studies was analyzed by SYRCLE's tool (Systematic Review Centre for Laboratory Animal Experimentation) for risk of bias.
RESULTS: The search strategy yielded 925 titles. After screening, 908 articles were discarded because they did not fulfill the inclusion/exclusion criteria based on the title and abstract. The remaining 16 articles were read entirely, of which nine were excluded as they involved systemic administration of bisphosphonates. Finally, after careful consideration, seven papers that met our inclusion criteria were included in the qualitative analysis. The majority of studies were assessed to have an uncertain risk of bias, with just one deemed low risk of bias.
CONCLUSION: This systematic review found that bisphosphonates limit orthodontic tooth movement around the application site without affecting adjacent sites. More potent bisphosphonates in smaller doses or less potent bisphosphonates in higher frequencies have been proposed to improve outcomes. However, the data quality is insufficient to recommend a protocol for bisphosphonate administration for anchoring control. Long-term studies evaluating various types, frequencies, and dosages of bisphosphonates are required to clarify the effects on orthodontic tooth movement.
REGISTRATION NUMBER FOR PROSPERO: CRD42021224033

Keywords: Animals, orthodontic anchorage procedures, orthodontics, pharmaceutical preparations

How to cite this article:
Harikrishnan S, Ramasamy N. Effect of local administration of bisphosphonate on orthodontic anchorage – A systematic review of animal studies. J Orthodont Sci 2022;11:31

How to cite this URL:
Harikrishnan S, Ramasamy N. Effect of local administration of bisphosphonate on orthodontic anchorage – A systematic review of animal studies. J Orthodont Sci [serial online] 2022 [cited 2023 May 29];11:31. Available from: https://www.jorthodsci.org/text.asp?2022/11/1/31/354500

Introduction

Orthodontics subjects teeth to a variety of forces. These operational forces generate a corresponding reciprocal force, generating tooth movement. Thus, “anchorage” refers to the opposition to such undesirable tooth movement.^[1] Good treatment outcomes require anchorage control. Newton's Third Law of Motion states that every action has a counter-reaction. The “action” is indeed the movement of the targeted teeth, whereas the “counter-reaction” is the displacement of the anchoring unit. Extensive research has been done on improving anchoring control using various techniques such as headgears, transpalatal arch, Nance palatal arch, lingual stabilizing arch, interpapillary elastics, miniscrews, mini-plates, mini implants, pharmacological agents, etc.^{[2],[3],[4],[5],[6]}

Pharmacological management of the anchorage unit has the potential to alter the underlying biological mechanisms that occur all through orthodontic tooth movement, resulting in equivalent results while enhancing patient compliance. Bisphosphonate is a critical pharmacological substance that has been extensively researched in the literature for orthodontic anchoring. Several skeletal metabolic conditions can be addressed with bisphosphonates. This drug class was first developed in the middle of the nineteenth century and is now routinely used to treat osteoporosis, Paget's disease, malignant bone metastasis, and osteogenesis imperfecta. Bisphosphonates are inorganic pyrophosphate analogs. Two phosphonates (PO3) linked to an oxygen molecule make up pyrophosphates found in body fluids such as saliva. Bisphosphonates are classified into two groups: non-nitrogenous (clodronate, etidronate, and tiludronate) and nitrogenous (alendronate, pamidronate, risedronate, ibandronate, zoledronate, etc.). The presence of the nitrogen atom enhances the drug's potency. Both kinds of bisphosphonates have anti-osteoclastic properties. However, they work through different methods. Non-nitrogenous bisphosphonates bind to non-hydrolyzable analogs of adenosine triphosphate (ATP), interfering with ATP-dependent pathways and causing osteoclast apoptosis, whereas nitrogenous bisphosphonates inhibit the mevalonate pathway enzyme farnesyl pyrophosphate synthase, which inhibits the enzymatic modification of small guanosine triphosphate-binding proteins in osteoclast.^{[7],[8],[9],[10],[11]}

Several studies have investigated the effect of systemically administered bisphosphonates in osteoporotic animals on orthodontic tooth movement. These studies revealed that orthodontic tooth movement was hampered in subjects receiving systemic bisphosphonate administration.^{[12],[13],[14],[15]} Bisphosphonate's adverse effects could be used to advantage in orthodontics on a local level to limit (or) prevent unwanted movement while not interfering with beneficial tooth movement.

Objective

This systematic review aimed to examine and evaluate the quality of all animal studies that reported on the effect of locally administered bisphosphonate on limiting orthodontic tooth movement.

Materials and Method

Protocol and registration

The International Prospective Register of Systematic Reviews (PROSPERO) was used to register the protocol (CRD42021224033). The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement was followed in the formulation of the protocol, as well as during its execution and reporting.^{[16],[17],[18]}

PICO analysis

P- Experimental animals with orthodontic appliances for simulating tooth movement

I – Local administration of bisphosphonate

C- Local administration of other pharmacological agents/Placebo

O- Orthodontic Tooth movement

Eligibility criteria

Inclusion criteria

Experiments on healthy animals using the orthodontic appliance
Administration of bisphosphonate injection before force application
Studies reporting rate of tooth movement following administration of bisphosphonate locally compared with a saline injection or any other control group
Qualitative data on the rate of molar displacement

Exclusion criteria

No control group
Systemic administration of bisphosphonate
Review articles, systematic reviews, and meta-analysis

Search strategy

An electronic search was conducted in the PubMed-Medline, Scopus, Google Scholar, and Cochrane databases till May 2022, using the keywords anchorage, anchorage loss, molar movement, posterior tooth movement, incisor movement, incisor retraction, anterior retraction, unwanted tooth movement, tooth displacement, tooth movement forward, bisphosphonate, local bisphosphonate administration, bisphosphonate injection, and bisphosphonate vestibular induction. Only studies involving localized bisphosphonate administration for anchorage purposes were taken into account. Two calibrated reviewers conducted the search, independently applying the inclusion and exclusion criteria to each article with adequate concordance. To broaden the search for relevant articles, selected article references were reviewed. The following factors were considered: sample size, dose, frequency, route, administration, the validity of measurement-taking techniques, suitable statistics, method error analysis, and measurement blinding.

Result

The flow of records through the reviewing process is shown in [Figure 1]. The search strategy yielded 925 titles. After screening, 908 articles were discarded because they did not fulfill the inclusion/exclusion criteria based on the title and abstract. The remaining 16 articles were read entirely, of which nine were excluded as they involved systemic administration of bisphosphonates^{[13],[14],[19],[20],[21],[22],[23],[24],[25]} [Table 1]. Finally, after careful consideration, seven papers that met our inclusion criteria were included in the qualitative analysis.^{[26],[27],[28],[29],[30],[31],[32]}

Figure 1: PRISMA flow chart showing the process of study inclusion

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Table 1: Description of excluded studies

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[Table 2] summarizes the research's general features. Coil springs were frequently used to promote orthodontic tooth movement by putting them between the incisors and molars. Likewise, springs that provided expansion stresses to the incisors or molars were utilized. The appliances applied forces ranging from 10 to 100 g, and the duration between applications varied from 2 weeks to 24 days.

Table 2: Study characteristics of included studies

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Clodronate was administered over a 7-day and 21-day period by Nakaš et al. (2017)^[31] and Liu et al. (2004)^[27], respectively, at increasing concentrations of 10m mol per day and 50 ul per day. On average, Nakaš et al. (2017)^[31] found a 0.88 mm decrease in tooth movement on the third day and a 2.31 mm decrease on the seventh day, whereas Liu et al. (2004)^[27] found a 0.02 mm decrease in tooth movement on the tenth day, 0.10 mm decrease on the fifteenth day, and 0.17 mm decrease on the twenty-first day. Both these studies demonstrated that increasing concentrations of clodronate inhibited tooth movement. Relatively small doses of clodronate administered more frequently produced better outcomes. In Adachi et al. (1994)^[26] study, risedronate was used at increasing concentrations of 50 ul for 21 days. On the 10^th, 15^th, and 21^st days, tooth movement was reduced by an average of 0.07 mm, 0.1 mm, and 0.2 mm. This research confirms that inhibition of tooth movement is more concentration-dependent. Venkataramana, Kumar et al. (2014)^[32] administered 1.2 mg of ibandronate as a single dose. The results of this study indicated a 0.2 mm reduction in tooth movement. In Fernández-González et al. (2016)^[30] and Ortega et al. (2012)^[29] studies, 16 ug of zoledronate was administered as a single dose preparation. The result indicated that tooth movement was inhibited by an average of 0.69 mm and 0.55 mm. [Table 3] displays the results obtained from the listed research. All the studies showed a decrease in tooth movement irrespective of the type and dosage of the locally administered bisphosphonate used.

Table 3: Summation of results of the included studies

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The Systematic Review Centre for Laboratory Animal Experimentation (SYRCLE's) risk of bias tool was used to assess the risk of bias in individual studies.^[33] Results of risk-of-bias assessments are summarized in [Table 4]. The majority of studies were assessed to have an uncertain risk of bias, with just one deemed to have a low risk of bias.^[29] In general, the majority of studies assessed had an uncertain risk of bias in the areas of random sequence generation, allocation concealment, and outcome assessor blinding due to insufficient evidence to construct a strong judgment on the risk of bias. Nonetheless, the majority of studies used groups that were similar in terms of gender, age, and weight of the participants at baseline, and so were deemed to have a low risk of bias in the relevant domain. There was no information on whether animals were housed randomly or whether caregivers and investigators were blinded to the intervention each animal received, leaving the majority of trials at risk of bias.^[29] Due to a lack of data, it was impossible to determine if the trials were free of publication bias, and subgroup analyses were not performed. [Table 5] summarizes theAnimal Research Reporting of In Vivo Experiments (ARRIVE) quality of evidence assessment.^[34] Overall, the quality of available evidence on the impact of various types of bisphosphonates on orthodontic tooth movement was rated as low at best.

Table 4: Summary of risk of bias assessment according to SYRCLE (Systematic Review Centre for Laboratory Animal Experimentation)

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Table 5: Quality assessment of included studies using Animal Research: Reporting of In Vivo Experiments (ARRIVE) Guidelines^[34]

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Discussion

Various studies retrieved for qualitative analysis in this systematic review used different types of bisphosphonates at various doses. All trials, on the other hand, consistently showed that local administration of all types of bisphosphonates impeded orthodontic tooth mobility. The amount of tooth movement varied according to the potency and dosage of the bisphosphonate type. The evidence was deemed to be of poor quality, compelling the clinician to proceed with caution when making relevant recommendations. There were no adverse reactions reported in any of the studies. However, conclusive evidence is still lacking in the majority of cases. Our final qualitative analysis included seven studies, which evaluated the effect of locally administered bisphosphonate on anchorage control. The various types of bisphosphonate used in the study are Clodronate^[27],[31] Zoledronate,^[29],[30] Risedronate,^[26] and Ibandronate.^[32] The type of bisphosphonate used was not mentioned in Fujimura et al. (2009)^[28] study. The method of Tooth movement evaluation varied among the studies.

Naka et al. (2017)^[31] evaluated the role of localized clodronate administration in the incisor area (Rat) by placing separators between the upper incisors. He proved that localized clodronate treatment significantly inhibits tooth movement and that the period between applications should be shortened to reduce dosage concentration. Fernández-González et al.^[30] compared the effect of locally administered zoledronate and osteoprotegerin near the first moral area (Rat) in limiting its movement when retracted with a mini implant. He demonstrated that a single, locally applied dosage of zoledronate or a high, twice-weekly dose of Osteoprotegerin allowed for maximum anchoring when orthodontic force was applied. Ibandronate was examined for its effect on molar movement during retraction (Rabbit) by Venkataramana, Kumar et al. (2014).^[32] They demonstrated that ibandronate is an antiresorptive drug that, when applied locally, reduces molar tooth movement in rabbits and can be used to improve pharmacological anchorage. Ortega et al. (2012)^[29] evaluated the influence of zoledronate on molar displacement during retraction (Rat). Local use in preventing molar movement during retraction. They demonstrated that a single, small, locally administered dosage of zoledronate was sufficient for maximal anchoring in extraction space closure. Zoledronate reduced periodontal bone loss around the second and third molars as well as at the extraction site without causing any side effects. Fujimura et al. (2009)^[28] studied the effect of locally administered bisphosphonate on maxillary molar anchorage and observed that bisphosphonates administered rats had less tooth movement, osteoclasts, and root resorption than nondrug administered animals. The sort of bisphosphonate utilized, however, was not disclosed in the article. Liu et al. (2004)^[27] and Adachi et al. (1994)^[26] studied the effect of locally administered clodronate and residronate in similar study settings. The bisphosphonate was injected near the upper first molar with the contralateral molar functioning as a control, tooth movement was stimulated using a standard expansion spring with the right and left molar movement buccally. Both investigations discovered significantly less molar tooth movement in the local bisphosphonate-administered side during expansion, as well as reduced relapse when the expansion force was released, confirming the pharmacologically produced anchoring and retention phenomenon.

The method of evaluating tooth movement also differed between studies. Pre and post-plaster models magnified with a profile projector were used by Liu et al. (2004)^[27] and Adachi et al. (1994)^[26] Fernández-González et al. (2016)^[30] used imaging software to make measurements of models. Nakas et al. (2017)^[31] performed measurements on scanned digital models. Fujimura et al. (2009)^[28] evaluated the model using a stereoscopic microscope. Pre and post-lateral cephalograms were superimposed by Venkataramana, Kumar et al. (2014)^[32] and Ortega et al. (2012)^[29]. However, the results of all the studies are incomparable due to the method's heterogeneity and the wide range of bisphosphonates used. As shown, high-potency bisphosphonates such as zoledronate and ibandronate were able to inhibit tooth movement at low concentrations and single dosage, whereas low-potency bisphosphonates such as clodronate are effective at low concentrations but only when used at a higher frequency. Numerous authors have reported on the use of bisphosphonates at low doses to prevent adverse effects such as osteonecrosis (30–32).

The review's well-established methodology is one of its most notable features. There were no preconceived limits on language, publication date, or status of publication for gathering data from electronic and manual sources through May 2022. In addition, screening, eligibility verification, information abstraction, bias risk assessment, and evidence quality evaluation were all carried out in duplicate to reduce bias. Disagreements were resolved through dialogue, and a final agreement was reached.

It is also worth noting that the existing evidence is not only derived from animal studies but also entails administering bisphosphonate in a variety of forms and doses that are difficult to compare between species. The data's universal application to human clinical conditions is restricted by the employment of specialized techniques to induce orthodontic tooth movement. Also included in this research is the distribution of the medication to healthy animals, which may have ramifications for tissue homeostasis. Although orthodontic tooth movement occurs in three dimensions, the majority of research examined the presence and extent of tooth movement using traditional, lateral cephalograms and two-dimensional measurement in models. It has been hypothesized that cone-beam computed tomography would be useful in this regard. Finally, the lack of power sample estimates in most studies raises concerns regarding the precision of empirical estimations and the clinical significance of the results if the retrieved animal information is extended to typical clinical conditions in people.

Before applying these findings to human studies, it is preferable to examine the dosage and frequency of different types of bisphosphonates in similar settings. It is also critical to do animal research to determine the effect of locally administered bisphosphonate's long-term local and systemic effects. It would also be significant if such research were to become more standardized and the approach for evaluating the outcome events was more relevant to the tooth movement's three-dimensional aspect. Additionally, potential sources of bias should be resolved, and future research should replicate as closely as possible, scenarios encountered in clinical practice in humans in terms of duration, dose equivalence, and route of administration, as well as the characteristics of the biomechanical systems used to apply force.

Conclusion

This systematic review found that bisphosphonates effectively limit orthodontic tooth movement around the application site without affecting adjacent sites. More potent bisphosphonates in smaller doses or less potent bisphosphonates in higher frequencies have been proposed to improve outcomes. However, the data quality is insufficient to recommend a protocol for bisphosphonate administration for anchoring control. Long-term studies evaluating various types, frequencies, and dosages of bisphosphonates are required to clarify the effects on orthodontic tooth movement.

Data availability

Data available on request

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

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