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

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. Copyright:

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.[23456]

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.[7891011]

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.[12131415] 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.[161718]

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[131419202122232425] Table 1. Finally, after careful consideration, seven papers that met our inclusion criteria were included in the qualitative analysis.[26272829303132]

Figure 1

PRISMA flow chart showing the process of study inclusion

Table 1

Description of excluded studies

Author name	Year	Reason for exclusion
Wu et al. (2019)[24]	2019	Systemic administration of the drug
Suzuki et al. (2019)[23]	2019	Systemic administration of the drug
Franzoni et al. (2017)[22]	2017	Systemic administration of the drug
Brunet et al. (2016)[21]	2016	Systemic administration of the drug
Salazar et al. (2015)[20]	2015	Systemic administration of the drug
Venkataramana et al. (2014)[25]	2014	Systemic administration of the drug
Kaipatur et al. (2013)[19]	2013	Systemic administration of the drug
Karras et al. (2009)[14]	2009	Systemic administration of the drug
Keles et al. (2007)[13]	2007	Systemic administration of the drug

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

Study (Name of the first author and year of study)	Subject characteristics (Species, sex, age, weight, total number)	Tooth movement model	Group characteristics (number, injecting agent, dosage, frequency, route, administration)	Assessment of tooth movement
Nakaš et al. (2017)[31]	Adult winter Rat, 14 Males, 46 Females, 8-6 weeks, 343-233g, 60	Elastic band - Between the incisors 3 days 7 days	The experimental group (E1)- 15, application of 10 mMol of clodronate in 3-day intervals. E2-15, application of 2.5 mMol of clodronate in 3-day intervals E3-15, application of 10 mMol of clodronate in 7-day intervals E4-15, application of 2.5 mMol of clodronate in 7-day intervals Control: Split Mouth-Contra lateral incisor Site of injection: Subperiosteal area is adjacent to the right maxillary incisor. Needle: Disposable insulin syringe Sample size calculation: nil	Impression -Plaster model - scanned Digital measurements of incisor movements (O3DM software package) The maxillary incisor movements were evaluated according to the fixed position of the molars. Teeth movements were calculated by measuring the distance between incisors and molars on the treated and control sides: Point 1 - The middle of the distal proximal surface of incisors on the right side 2 mm from the gingiva Point 1’ - The middle of the mesial proximal ridge of the first molar on the right side Point 2 - The middle of the distoproximal surface of incisors on the left side 2 mm from the gingiva Point 2’ - The middle of the mesial proximal ridge of the first molar on the left side. Distance between points 1 and 1’ and 2 and 2’ was used to represent tooth movement in millimeters.
Fernandez-Gonzalez et al. (2016)[30]	Sprague-Dawley Rat, Male, 420-460 g, 36	Niti coil Spring between Maxillary molar and 6-mm-length mini-screw between the roots of the upper incisors. 50 g force, 7, 14, and 21 days	Experimental group 1-12,16 ug of zoledronate, Experimental group 2-12, 5 mg/kg of human OPG-Fc, Control group 3-12, untreated Site of injection Sample size calculation is done.	PVS Impressions- diastema distal to the right maxillary first molar -Models were scanned with a 100 mm ruler and then magnified 100, and diastema was measured using imaging software (Adobe Photoshop)
Venkataramana, Kumar SS, et al. (2014)[32]	New Zealand rabbits, 16 weeks, 3.5-4 kg, 20	NiTi closed coil springs between the mandibular molar and incisors. 100 g force. 21 days.	Group-1 (control)-10, 1 ml Saline. Group-2 (experimental)- 10, Ibandronate 0.3 mg/kg Site of injection: mesial aspect of mandibular 1st molar mucoperiosteum Sample size calculation: nil	Lateral cephalogram- 1st and 21st days. The magnitude of molar tooth movement in the mesial direction was measured manually using a standard metric scale based on two reference points that are, a mesio-occlusal tip of the second molar (M1) to the disto-occlusal tip of the first molar (M2)
Ortega et al. (2012)[29]	Retired breederSprague-Dawley rats, Male, 30	NiTi closed coil spring between incisor and second molar. 1st molar extracted. 10g force. 21 days	Group-1 (control)-15, 50 ul Saline Group-2 (experimental)- 15,16 ug of zoledronate Site of injection: 1/3rd injection e mesiopalatal and distopalatal aspects of the maxillary left second molar and the vestibule above the first molar. Sample size calculation: 30	Lateral cephalogram at 1st, 7th, and 21st day. The lines N-Po and occlusal plane were drawn, and a perpendicular line was constructed from N to intersect the occlusal plane (N0). A line perpendicular to N-Po was constructed through the most distal point of the wire (W) until it intersected the occlusal plane (W0). Measurement A was the distance N to a perpendicular from N-Po through W, measurement B was the distance N0-W0, and
				measurement C was the distance from the most anterior-inferior point on the maxilla posterior to the incisors to W
Fujimura et al. (2009)[28]	C57BL mice, male, 8 weeks, 12	NiTi closed coil spring between the anterior alveolar bone and first molar. 10 g force. 12 days	Group-1 (control)-6, 1 ml Saline daily Group-2 (experimental)-6, 2 ug/20 ml daily Site of injection: adjacent to upper molar. Sample size calculation: nil	The animal sacrificed-12 days-maxilla removed-injection type PVS Impression of maxilla- Distance between the 1st and second molar measured in impression on a stereoscopic microscope
Liu et al. (2004)[27]	adult winter Rat, 8-9 weeks old, 180 g, 26	Standard expansion Spring right and left molar moved buccally. force- 120 mN, 3 weeks	Split mouth Group-1 (control) -26,1 ml Saline Group-2 (experimental) - 13,50 ul of clodronate Site of injection: sub-periosteum adjacent to upper 1st molar Sample size calculation: Nil	Silicon Impression-plaster model upper jaw was magnified×10 with a profile projector and traced. The contours of the palatal cusps of the second and third molars of the tracings were then superimposed on those of the second and third molars on tracings from a pre-treatment plaster model. The distance between the crests of the mesiopalatal cusps of the first molars before and after tooth movement was measured with sliding calipers.
Adachi et al. (1994)[26]	ale Wistar rats, 9 to 10 weeks old, 227 g, 126	Standard expansion Spring right and left molar moved buccally. force- 165 mN, 3 weeks	Split mouth Group-1 (control)-41, 1 ml Saline Group-2 (experimental)- 41, 50 ul of Residonate Site of injection: sub-periosteum adjacent to upper 1st molar Sample size calculation: Nil	Silicon Impression-plaster model upper jaw was magnified×10 with a profile projector and traced. The contours of the palatal cusps of the second and third molars of the tracings were then superimposed on those of the second and third molars on tracings from a pre-treatment plaster model. The distance between the crests of the mesiopalatal cusps of the first molars before and after tooth movement was measured with sliding calipers.

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 10th, 15th, and 21st 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

Study	Nakas et al. (2017)[31]	Fernandez-González et al. (2015)[30]	Venkataramana, Kumar et al. (2014)[32]	Ortega et al. (2012)[29]	Fujimura et al. (2009)[28]	Liu et al. (2004)[27]	Adachi et al. (1994)[26]
Result	After 3 days Experimental group 1: 97.37+2.74 mm Experimental group 2: 98.25+1.82 mm After 7 days Experimental group 3: 98.29+2.7 mm Experimental group 4: 100.6+2.03 mm	Day 14 Experimental group 1:0.25+0.01 Experimental group 2:0.17+0.01 mm Control group -0.54+0.01 mm Day 21 Experimental group 1: 0.30+0.01 Experimental group 2: 0.21+0.01 mm Control group -0.99+0.01 mm zoledronate group-tooth displacement decreased significantly with 52%, 46% and 30%, to observed in control rats at 7, 14, and 21 days, respectively (*P <0.001)	Day21 Group-1 (control) -4.650±0.363 mm Group-2 (experimental) -2.030±0.291 mm	Days 21 Measurement N-PO: Control group: 0.13+0.39 mm Experimental group: 0.18+0.46 mm Measurement A: Control group: -0.83+0.45 mm Experimental group: -0.118+0.23 mm Measurement B: Control group: -0.81+0.45 mm Experimental group: -0.06+0.28 mm Measurement c: Control group: -0.94+0.45 mm Experimental group:-0.24+0.21 mm	Days 12 Control group: 126±60 u m. Experimental Group: 61±18 um	3 weeks Day 10: Control group: 0.27 mm Experimental group: 025 mm Day 15: Control group: 0.37 mm Experimental group: 0.27 mm Day 21: Control group: 0.477 mm Experimental group: 0.3 mm	3 weeks Day 10: Control group: 0.277 mm Experimental group: 0.22 mm Day 15: Control group: 0.35 mm Experimental group: 0.23 mm Day 21: Control group: 0.47 mm Experimental group: 0.2.3 mm

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)

Study	1	2	3	4	5	6	7	8	9	10	Summary
Nakaš et al. (2017)[31]	Low	Low	Unclear	Low	Unclear	Unclear	Unclear	Low	Low	Low	Unclear
Fernández-González et al. (2016)[30]	Low	Low	Unclear	Low	Unclear	Low	Unclear	Low	Low	Low	Unclear
Venkataramana, Kumar, et al. (2014)[32]	Unclear	Low	Unclear	Unclear	Unclear	Unclear	Unclear	Unclear	Low	Unclear	Unclear
Ortega et al. (2012)[29]	Low	Low	Low	Low	Low	Low	Low	Low	Low	Low	Low
Fujimura et al. (2009)[28]	Unclear	Low	Unclear	Unclear	Unclear	Unclear	Unclear	Unclear	Unclear	Unclear	Unclear
Liu et al. (2004)[27]	Unclear	Low	Unclear	Unclear	Unclear	Unclear	Unclear	Low	Unclear	Unclear	Unclear
Adachi et al. (1994)[26]	Unclear	Low	Unclear	Unclear	Low	Low	Low	Low	Low	Low	Unclear

1-Was the allocation sequence adequately generated and applied?; 2- Were the groups similar at baseline or were they adjusted for confounders in the analysis? ; 3- Was the allocation to different groups adequately concealed during the study? ; 4-Were the animals randomly housed during the assessment?; 5- Were the caregivers and/or investigators blinded from knowledge of which intervention each animal received during the experiment?; 6- Were animals selected at random for outcome assessment?; 7- Was the outcome assessor-blinded?; 8. Were incomplete outcome data adequately addressed?; 9- Are reports of the study free of selective outcome reporting?; 10. Was the study free of other problems that could result in a high risk of bias?- SYRCLE’s risk of bias tool[33]

Table 5

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

Item		Recommendation	Nakas et al. (2017)[31]	Fernandez-Gonzalez et al. (2016)[30]	Venkataramana, Kumar et al. (2014)[32]	Ortega et al. (2012)[29]	Fujimura et al. (2009)[28]	Liu et al. (2004)[27]	Adachi et al. (1994)[26]
Title	1	Provide as accurate and concise a description of the content of the article as possible	Yes	Yes	Yes	Yes	Yes	Yes	Yes
Abstract	2	Provide an accurate summary of the background and research objectives, including details of the species or strain of animal used, key methods, principal findings, and conclusions of the study	Yes	Yes	Yes	Yes	Yes	Yes	Yes
Background	3	a. Include sufficient scientific background (including relevant references to previous work) to understand the motivation and context for the study, and explain the experimental approach and rationale. b. Explain how and why the animal species and model being used can address the scientific objectives and, where appropriate, the study’s relevance to human biology.	Yes	Yes	Yes	Yes	Yes	Yes	Yes
Objectives	4	Clearly describe the primary and any secondary objectives of the study, or specific hypotheses being tested.	Yes	Yes	Yes	Yes	Yes	No	Yes
Ethical statement	5	Indicate the nature of the ethical review permissions, relevant licenses (e.g. Animal [Scientific Procedures] Act 1986), and national or institutional guidelines for the care and use of animals, that cover the research.	Yes	Yes	Yes	Yes	Yes	Yes	Yes
Experimental animals	6	For each experiment, give brief details of the study design, including a. The number of experimental and control groups. b. Any steps taken to minimize the effects of subjective bias when allocating animals to treatment (e.g. randomization procedure) and when assessing results (e.g. if done, describe who was blinded and when). c. The experimental unit (e.g. a single animal, group, or cage of animals). A time-line diagram or flow chart can be useful to illustrate how complex study designs were carried out	Yes	Yes	Yes	Yes	No	No	Yes
Experimental animals	7	For each experiment and each experimental group, including controls, provide precise details of all procedures carried out. For example, a. How (e.g. drug formulation and dose, site and route of administration, anesthesia, and analgesia used [including monitoring], surgical procedure, method of euthanasia). Provide details of any specialist equipment used, including supplier (s). b. When (e.g. time of day). c. Where (e.g. home cage, laboratory, water maze). d. Why (e.g. rationale for the choice of specific anesthetic, route of administration, drug dose used).	Yes	Yes	Yes	Yes	Yes	Yes	Yes
Housing and husbandry	8	Provide details of a. Housing (type of facility, e.g., specific pathogen-free [SPF]; type of cage or housing; bedding material; some cage companions; tank shape and material, etc., for fish). b. Husbandry conditions (e.g. breeding program, light/dark cycle, temperature, quality of water, etc., for fish, type of food, access to food and water, environmental enrichment). c. Welfare-related assessments and interventions that were carried out before, during, or after the experiment	Yes	Yes	Yes	Yes	Yes	Yes	Yes
Sample size	9	a. Specify the total number of animals used in each experiment, and the number of animals in each experimental group. b. Explain how the number of animals was arrived at. Provide details of any sample size calculation used. c. Indicate the number of independent replications of each experiment, if relevant.	No	Yes	No	Yes	No	No	Yes
Allocating animals to an experimental group	10	a. Give full details of how animals were allocated to experimental groups, including randomization or matching if done. b. Describe the order in which the animals in the different experimental groups were treated and assessed.	Yes	Yes	No	Yes	No	No	No
Experimental outcomes	11	Clearly define the primary and secondary experimental outcomes assessed (e.g. cell death, molecular markers, behavioral changes).	Yes	Yes	Yes	Yes	Yes	Yes	Yes
Statistical methods	12	a. Provide details of the statistical methods used for each analysis. b. Specify the unit of analysis for each dataset (e.g. single animal, group of animals, single neuron). c. Describe any methods used to assess whether the data met the assumptions of the statistical approach.	Yes	Yes	Yes	Yes	Yes	Yes	Yes
Baseline data	13	For each experimental group, report relevant characteristics and health status of animals (e.g. weight, microbiological status, and drug or test naïve) before treatment or testing. (This information can often be tabulated).	Yes	Yes	Yes	Yes	No	Yes	Yes
Numbers analyzed	14	a. Report the number of animals in each group included in each analysis. Report absolute numbers (e.g. 10/20, not 50%). b. If any animals or data were not included in the analysis, explain why.	Yes	Yes	Yes	Yes	Yes	Yes	Yes
Outcomes and estimation	15	Report the results for each analysis carried out, with a measure of precision (e.g. standard error or confidence interval).	Yes	Yes	Yes	Yes	Yes	Yes	Yes
Adverse events	16	a. Give details of all important adverse events in each experimental group. b. Describe any	No	Yes	No	No	No	No	No
		modifications to the experimental protocols made to reduce adverse events.
Interpretation/scientific implications	17	a. Interpret the results, taking into account the study objectives and hypotheses, current theory, and other relevant studies in the literature. b. Comment on the study limitations, including any potential sources of bias, any limitations of the animal model, and the imprecision associated with the results. c. Describe any implications of your experimental methods or findings for the replacement, refinement, or reduction (the 3 Rs) of the use of animals in research.	Yes	Yes	Yes	Yes	Yes	Yes	Yes
Generalizability ty/translation	18	Comment on whether and how the findings of this study are likely to translate to other species or systems, including any relevance to human biology.	No	Yes	Yes	No	Yes	Yes	No
Funding	19	List all funding sources (including grant number) and the under (s) role in the study.	No	No	No	Yes	Yes	No	No

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[2731] Zoledronate,[2930] 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.