Effect of bisphosphonate vs. osteoprotegerin during orthodontic tooth movement: A systematic review and meta-analysis

Kuri Tupak Sarango-Quishpe; María Isabel Cabrera-Padrón; José Esteban Torracchi-Carrasco; Gloria Andrade-Medina; Cesar Heriberto Juela-Moscoso

doi:10.4041/kjod24.049

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Sarango-Quishpe, Cabrera-Padrón, Torracchi-Carrasco, Andrade-Medina, and Juela-Moscoso: Effect of bisphosphonate vs. osteoprotegerin during orthodontic tooth movement: A systematic review and meta-analysis

Original Article

Korean J Orthod 2025;55(2):120-130.

Published online: 2 December 2024

DOI: https://doi.org/10.4041/kjod24.049

Effect of bisphosphonate vs. osteoprotegerin during orthodontic tooth movement: A systematic review and meta-analysis

Kuri Tupak Sarango-Quishpe^a

, María Isabel Cabrera-Padrón^a

, José Esteban Torracchi-Carrasco^b,

, Gloria Andrade-Medina^a

, Cesar Heriberto Juela-Moscoso^a

^aCollege of Dentistry, Catholic University of Cuenca, Cuenca, Ecuador

^bCenter for Research, Innovation and Technology Transfer (CIITT), Catholic University of Cuenca, Cuenca, Ecuador

Corresponding author: José Esteban Torracchi-Carrasco. Research Professor, Center for Research, Innovation and Technology Transfer (CIITT), Catholic University of Cuenca, Av. de las Américas, y Humboldt, Cuenca 010101, Ecuador., Tel +593-07-4134-750 e-mail kuri011@hotmail.com

How to cite this article: Sarango-Quishpe KT, Cabrera-Padrón MI, Torracchi-Carrasco JE, Andrade-Medina G, Juela-Moscoso CH. Effect of bisphosphonate vs. osteoprotegerin during orthodontic tooth movement: A systematic review and meta-analysis. Korean J Orthod 2025;55(2):-130. https://doi.org/10.4041/kjod24.049

Received 25 March 2024 Revised 16 November 2024 Accepted 26 November 2024

(open-access):

This is an open-access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

Objective

Orthodontic appliances are commonly used to achieve anchorage during orthodontic treatments; however, their use can contribute to oral diseases. Studies have shown that bisphosphonates and osteoprotegerin are highly effective in reducing orthodontic tooth movement. To determine the efficacy of bisphosphonates and osteoprotegerin in reducing orthodontic tooth movement.

Methods

A comprehensive search was conducted across five databases—MEDLINE-PubMed, Scopus, Google Scholar, ScienceDirect, and Taylor & Francis—up to August 2, 2023. Clinical trials conducted in healthy animals, where bisphosphonates and osteoprotegerin were administered during tooth movement, were included. The search identified 3,099 articles, which underwent a two-phase screening process, resulting in twelve studies for the systematic review and seven for the meta-analysis. Risk of bias was assessed using the SYRCLE tool, and Egger’s regression was used to evaluate publication bias.

Results

The administration of bisphosphonates was more effective than osteoprotegerin in reducing mesiodistal orthodontic movement. However, osteoprotegerin did not significantly reduce orthodontic tooth movement.

Conclusions

The findings align with previous studies, confirming the superior efficacy of bisphosphonates over osteoprotegerin. Further research is required to determine the optimal dosage and mechanism of action for these drugs in clinical practice, considering the specific objectives of orthodontic treatments.

Keywords: Orthodontic anchorage, Bisphosphonate, Osteoprotegerin, Animal

INTRODUCTION

Orthodontic tooth movement (OTM) is a biological response involving the periodontal ligament and alveolar bone, driven by an inflammatory process triggered by external stimuli. This process promotes blood revascularization, which leads to the secretion of chemical mediators such as cytokines, growth factors, and arachidonic acid metabolites, ultimately resulting in bone remodeling.¹

Reduced tooth movement occurs due to deficiencies in bone remodeling.² This reduction, known as anchorage, is necessary to perform different types of biomechanical movements during orthodontic treatment. Anchorage can be achieved mechanically or pharmacologically. There are several mechanisms to reduce dental movement such as the union of some dental pieces as an anchorage point, the use of orthopedic appliances and/or micro-implants,³ but these can alter the oral microbiota, periodontal health,⁴ gingival hyperplasia, appearance of white spots, among others, due to the accumulation of dental plaque on the dental surfaces and of the auxiliary anchorage devices.⁵

To address these issues, various drugs have been investigated for their potential to reduce OTM.² Among these are bisphosphonates (BFs), which are used to treat diseases associated with excessive bone resorption.⁶ There are two types of BFs: nitrogen-containing and non-nitrogen-containing. The presence of nitrogen confers a greater potency of action.⁷ Non-nitrogenated BFs bind to non-hydrolyzable analogs of adenosine triphosphate (ATP), causing osteoclastic apoptosis, while non-nitrogenated BFs inhibit the enzyme farnesyl pyrophosphate synthase in the mevalonate pathway, which inhibits the enzymatic modification of small guanosine triphosphate-binding proteins in osteoclasts.^8,9 However, long-term use of BFs is associated with adverse effects such as atypical fractures of the femur and spine.¹⁰

Osteoprotegerin (OPG) is a soluble protein produced by osteoblasts and bone marrow stromal cells,¹¹ which has been shown to interfere with bone turnover because it inhibits the interaction between RANKL factors and the RANK receptor.¹² This prevents osteoclast differentiation and activation,^12,13 reducing bone turnover. OPG has been implicated in physiological and pathological processes, including dental eruption, OTM, and periodontal diseases.¹⁴

Justification

Numerous studies highlight the effectiveness of BFs and OPG in reducing OTM. However, their efficacy depends on factors such as dosage, time of administration, and the systemic health of the study population. Therefore, it is essential to carry out a systematic review and meta-analysis to determine the clinical effectiveness of these drugs.

This study aims to minimize bias and provide reliable insights by selecting studies that share consistent inclusion criteria. The findings will help elucidate the clinical implications of BFs and OPG in reducing OTM, ultimately guiding their use in achieving specific treatment goals.

MATERIALS AND METHODS

Objective

To determine the effectiveness of BF and OPG in reducing OTM.

Null hypothesis (H0)

There was no significant difference in the reduction of OTM between the administration of BFs and OPG, and no administration of these drugs.

Alternative hypothesis (H1)

There was a significant difference in the reduction of OTM between the administration of BFs and OPG, and no administration of these drugs.

Protocol and registry

The methodology for this review was registered in PROSPERO under the identification number CRD42024488437. This systematic review and meta-analysis adhered to the following guidelines: PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses), PRISMA-S, PRISMA for Abstracts, and the Cochrane Handbook for Systematic Reviews of Interventions (2nd ed.).^15-17

PICO format

P: Health animals.

I: Biphosphonate.

C: Osteoprotegerin.

O: Minor tooth movement or orthodontic anchorage.

Inclusion and exclusion criteria

Inclusion criteria

Clinical trials on pharmacological reduction of OTM in animals.
Clinical trials conducted on healthy animals with both a control group (placebo) and an intervention group.
Articles related to the reduction of tooth movement with BFs or OPG.

Exclusion criteria

Clinical trials involving micro-screws.
Clinical trials administering drugs other than BFs or OPG.
Clinical trials involving human subjects.
Clinical trials that did not mention the sample size.
Review articles, systematic reviews, meta-analyses, books, or commentaries.

Search strategy

An exhaustive search of scientific articles was performed independently using the following databases: MEDLINE-PubMed, Scopus, ScienceDirect, Google Scholar, and Taylor & Francis. Articles published up to August 2, 2023, in any language were included, with no time restrictions. The search terms were selected from the Medical Subject Headings (MeSH) based on the keywords of the PICO question: How does the administration of bisphosphonates and osteoprotegerin affect orthodontic tooth movement compared to the control group?

Boolean operators “OR” and “AND” were used in the search strategies. Keywords used were: "anchorage orthodontic”, “minor tooth movement”, “bisphosphonate”, “osteoprotegerin”, and “animal”. To ensure comprehensive coverage, the authors alternated keywords and Boolean operators while conducting simultaneous searches.

Selection process and data collection

The search equation was designed to capture the maximum number of relevant articles. Duplicate entries were removed using Mendeley Reference Manager for Windows version 2.101.0 (Elsevier, Amsterdam, Netherlands). Subsequently, the selection process was divided into two parts. The first part involved reading the title and abstract of each article on the Rayyan Web program (Rayyan, Cambridge, MA, USA),¹⁸ where the reasons for their inclusion were specified and left for consideration by the second reviewer for approval or correction. In the second section, a complete reading of each article was performed, indicating the reasons for its inclusion for the subsequent approval of the second reviewer. Discrepancies were resolved through discussion between the two reviewers.

Analysis of the risk of bias

The risk of bias assessment of individual studies was performed with the Systematic Review Centre for Laboratory Animal Experimentation (SYRCLE) tool.

In the first domain, all clinical trials were randomized and sequenced. In the second domain, there was one study in which the experimental group was larger than the control group. In the third and fourth domains, most studies did not clearly state how they concealed the allocation and blinding of the assessor. In the fifth domain, most investigations were not clear whether the investigators were blinded. In the other domains, there was a low level of bias.

Quantitative analysis

Studies with compatible quantitative data were included in the meta-analysis. This analysis was conducted using R studio 2023.12.0+369 “Ocean Storm” Release (33206f75bd14d07d84753f965eaa24756eda97b7, 2023-12-14) for windows (R Foundation for Statistical Computing, Vienna, Austria). Qualitative data were separated according to the drugs: BF (alendronate, pamidronate, risedronate, AHBuBP, clodronate, and zoledronate) and OPG. Meta-analysis data included sample size, drug used, source of strength, final OTM (mean and standard deviation), dose administered, time of experiment, study effect, and study population (Table 1).^7,19-24

The studies included in the meta-analysis presented different clinical methods to measure OTM. Hence, a random effects model with the inverse variance method was applied. The confidence interval was set at 95% with statistical significance defined as P ≤ 0.05. The study was performed at the drug effectiveness level because the levels of effectiveness between the BFs and OPG were compared. Heterogeneity was calculated using τ², I², and H statistics. Publication bias was visualized with a funnel plot and assessed through Egger’s regression.

RESULTS

The systematic search identified 836 records from MEDLINE-PubMed, 520 from ScienceDirect, 1,720 from Google Scholar, 87 from Scopus, and 10 from Taylor & Francis, resulting in a total of 3,173 records. After removing duplicates, 3,099 records remained. Titles and abstracts were analyzed, and 63 studies met the inclusion criteria. Subsequently, the complete articles were read, and 30 were excluded for being review articles, 13 for using incorrect active ingredients (different drugs), 4 for being studies in humans and ex vivo, 2 for comparing two drugs without a control group, and 2 for not presenting the results of the trials in a clear manner. Finally, 12 articles were included in the systematic review. For the meta-analysis, 5 additional studies were excluded because they presented a different experimental design, leaving seven articles or inclusion (Figure 1).

Orthodontic tooth movement reduction under the administration of bisphosphonates

Among the 7 studies reporting BF administration, all had a prospective study design with both experimental and control groups.^6,7,19-22,25 The applied tensile or thrust force to produce the OTM reported in the studies ranged from 10 g to 100 g, with helical springs and orthodontic anchorage devices used in all studies. Most studies were conducted on rats with the exception of two trials that were performed in rabbits.^7,20

Orthodontic tooth movement reduction under the administration of the osteoprotegerin

The five studies on OPG also utilized a prospective design with experimental and control groups. All studies were conducted on rats.^23,24,26-28 The force applied between the studies ranged from 17 g to 54 g, as in previous studies, and coil springs and orthodontic anchorage devices were applied.

Risk of bias

The risk of bias was assessed across ten domains.²⁹ A graphical description of the domains is provided below (Table 2).^6,7,19-28

Meta-analysis

Seven studies valuating OTM were included in the meta-analysis. To evaluate the efficacy of each drug during OTM, statistical significance was set at P < 0.01. The results are presented in a forest plot (Figure 2),³⁰ and the overall risk ratio of OTM (95%) was –0.88 (–1.45, –0.31), suggesting that the administration of the studied drugs significantly reduced OTM compared to the control group. However, it is important to point out that the degree of heterogeneity in this study was 97%, due to the different populations, forms of drug administration, and diastema measurements.³⁰

Five studies were selected to evaluate the efficacy of BFs in the movement. The results were presented as forest plots (Figure 3).³⁰ The overall risk ratios (95%) was -0.98 (–1.76, –0.20) with P < 0.01, indicating that the administration of BFs significantly reduced OTM compared to the control group.

Two studies were selected to evaluate the efficacy of OPG in OTM. The results are presented in the forest plot (Figure 4).³⁰ The overall risk ratio of the OTM (95%) was –0.63 (–1.30, 0.03) with P < 0.01, which means that the administration of OPG significantly reduced the OTM compared to the control group. However, the position of the diamond suggests that the magnitude of the effect is not significant.

The application of BFs and OPG significantly reduced OTM by 12% compared with the control group, with a relative risk of 0.88. Additionally, the absolute reduction was 91 cases per 100 treated cases, indicating a high clinical impact. The high certainty of these findings supports the efficacy of these treatments in reducing tooth movement and improving the predictability of orthodontic treatment. However, it is essential to consider the possible adverse effects associated with their use, which underlines the importance of careful evaluation of each clinical case (Table 3).

A funnel plot was constructed to evaluate publication bias (Figure 5). The presence of funnel plot asymmetry was evaluated by Egger’s regression (mixed effects) using the standard error as a predictor. The test for asymmetry resulted in a value of z = –1.7059, and the confidence interval was (–1.073 to 1.859) at 95% with P = 0.0880. There was an asymmetric trend, but it was not statistically significant. In this study, the P value was greater than 5%, indicating that no publication bias.

The findings of this study suggest that the administration of these drugs significantly reduces OTM. Among the two, BFs demonstrated greater efficacy than OPG.

Caution is advised when interpreting these results due to the high level of heterogeneity in this study. Future research should consider specific aspects of variability to strengthen the clinical recommendations and robustness of the findings.

DISCUSSION

The present study aimed to evaluate whether drug use reduces OTM through a systematic review and meta-analysis. The study identified the effects of different drug doses, focusing on the mode of administration, drug quantity, and force application methods, to understand their impact on OTM. Although orthodontic diagnosis and treatment rely heavily on clinical evaluation and diagnostic records, understanding drug efficacy is crucial for enhancing orthodontic techniques and methods.

The application of optimal forces and drugs can positively or negatively influence treatment outcomes, depending on how they are administered. Improper administration can lead to adverse effects, such as altered bone physiology or complications in treatment.³¹ Studies have shown that patients who underwent orthodontic treatment while taking BFs presented with sclerotic changes in the alveolar bone. However, the evidence linking these drugs to such alterations remains inconclusive due to contradictory findings at experimental and clinical levels.^32,33

The effectiveness of BFs in reducing OTM is primarily attributed to their inhibition of bone resorption by osteoclasts.³⁴ This underscores the importance of controlled bone resorption for successful treatment outcomes. While the literature generally supports the efficacy of BFs, some studies highlight associated complications, emphasizing the need for careful administration tailored to individual patient characteristics.³⁵

The characteristics of the BFs, as well as their preventive nature in the loss of bone density can have an impact on the delay of some orthodontic treatments. Therefore, clinicians must weigh these effects when considering their use for OTM. In relation to the most commonly used BFs to reduce OTM, the literature agrees with the findings of this study, where the most common BFs are alendronate, risedronate, clodronate, pandronate, and zoledronate, the latter being one of the most potent in the market today.^31,33-35

BFs reduce the tendency for root resorption during orthodontic treatment, while others warn that they produce alterations in the cementum surface through their inhibitory effect on the formation of acellular cementum, generating a greater vulnerability of the root surface to absorption processes. Consequently, a detailed medical history is essential, including information on drug type, route of administration, duration, dose, and frequency to evaluate orthodontic treatment and risk of osteoclastic inhibition.³⁶

This study also highlights the effectiveness of OPG in reducing OTM. OPG acts as an osteoclast function inhibitor, enhancing anchorage during orthodontic force application.³⁷ However, the reduction in OTM observed with OPG was less pronounced than with BFs.³⁷ Despite this, OPG provides notable benefits, including reduced relapse rates, which enhance the long-term efficacy of treatment.³⁸ Contrary to this study’s findings, some authors have reported OPG to be more effective than BFs in reducing OTM.³⁷ However, this discrepancy may stem from differences in clinical protocols, formulations, side effects, and drug mechanisms.³⁹

This level of effectiveness occurs because BFs can be incorporated into the spaces of active bone remodeling, which increases their concentration in the trabecular bone, where significant alveolar bone changes occur.⁴⁰

However, most authors stress the need for further research to refine our understanding of drug efficacy in orthodontics. Future research should aim to identify optimal doses for improved treatment outcomes, investigate localized and long-term effects of drugs on bone physiology, and consider case-specific characteristics to develop personalized treatment plans. Greater specificity in research is essential to explore the complex interactions between drugs and osteoclast behavior, a fundamental aspect of dental movement.³⁷

This study has some limitations. The high heterogeneity (97%) across included studies, arising from variations in populations, drug administration methods, and force application, complicates generalizability. Additionally, the reliance on animal models, such as rats^19,22 and rabbits,^7,20 limits direct applicability to human orthodontics. Inconsistent reporting of dosages and outcomes among studies also poses challenges. Future research should focus on standardizing methodologies and exploring long-term effects in diverse human populations.

CONCLUSIONS

Recent studies on the use of pharmacological agents in orthodontics emphasize the importance of understanding their side effects and adverse outcomes. The goal is not only to achieve orthodontic objectives but also to provide sustainable solutions with minimal side effects.

While BFs are more effective than OPG in reducing OTM, OPG presents fewer adverse effects and relapse risks, making it a viable alternative. Further research is necessary to determine the effective dosage and mechanisms of these drugs to align with clinical goals.

Additionally, prolonged use of BFs has systemic repercussions, underscoring the need for proper clinical records and effective communication between physicians and orthodontists. This collaborative approach is crucial to minimizing side effects and ensuring safe and effective treatment outcomes.

Notes

AUTHOR CONTRIBUTIONS

Conceptualization: KTSQ, MICP. Data curation: KTSQ, MICP, GAM, CHJM. Formal analysis: KTSQ, MICP, GAM, CHJM. Funding acquisition: KTSQ, MICP. Investigation: KTSQ, JETC. Methodology: KTSQ, MICP, GAM, CHJM. Project administration: KTSQ, MICP. Resources: KTSQ, JETC. Software: KTSQ, JETC. Supervision: KTSQ, MICP. Validation: All authors. Visualization: KTSQ, JETC. Writing–original draft: KTSQ. Writing–review & editing: KTSQ, MICP, GAM, CHJM.

CONFLICTS OF INTEREST

No potential conflict of interest relevant to this article was reported.

FUNDING

This article was paid for by the authors of the article privately but the research was carried out at Catholic University of Cuenca.

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Figure 1

Flow diagram of the selection and analysis of the studies included in the systematic review and meta-analysis.

Figure 2

Studies included in the meta-analysis represented in a forest plot.

SD, standard deviation; MD, mean difference; CI, confidence interval.

Figure 3

Studies performed with bisphosphonates included in the meta-analysis.

SD, standard deviation; MD, mean difference; CI, confidence interval.

Figure 4

Studies performed with osteoprotegerin included in the meta-analysis.

SD, standard deviation; MD, mean difference; CI, confidence interval.

Figure 5

Studies included in the publication bias risk assessment.

Table 1

Data collected from the studies included in the meta-analysis

Study	Number of partici- pants	Power source	Result of the control group (mm)	Results of the experimental group (mm)	Evalu-ation time (wk)	Effect	Drug used	Dosage used	Unit of study
Karras et al. (2009)¹⁹	50	Helical spring	1.06 ± 0.33	0.45 ± 0.38	4	OTM (diastema)	Bisphosphonate (alendronate)	7 mg	Rats
Venkataramana et al. (2014)⁷	20	Helical spring	3.75 ± 0.54	3.05 ± 0.55	3	OTM (diastema)	Bisphosphonate (pamidronate)	1.5 mg/1 mL	Rabbits
Ortega et al. (2012)²¹	30	Helical spring	0.94 ± 0.45	0.24 ± 0.21	3	OTM (diastema)	Bisphosphonate (zolendronate)	16 mg	Rats
Kanzaki et al. (2004)²³	20	Helical spring	0.53 ± 0.03	0.22 ± 0.03	3	OTM (diastema)	Osteoprotegerin	215 g	Rats
Zhao et al. (2012)²⁴	18	Helical spring	1.53 ± 0.23	0.55 ± 0.13	3	OTM (diastema)	Osteoprotegerin	5 mL	Rats
Kirschneck et al. (2014)²²	48	Helical spring	0.88 ± 0.28	0.52 ± 0.21	4	OTM (diastema)	Bisphosphonate (ranelate from strontium)	900 mg	Rats
Venkataramana et al. (2012)²⁰	20	Helical spring	4.96 ± 0.45	2.38 ± 0.36	3	OTM (diastema)	Bisphosphonate (pamidronate)	1.5 mg/0.5 mL	Rabbits

OTM, orthodontic tooth movement.

Table 2

Risk of bias assessment of individual animal studies according to SYRCLE

Study	1	2	3	4	5	6	7	8	9	10	Summary
Venkataramana et al. (2012)²⁰	Low	Low	Unclear	Unclear	Low	Low	Unclear	Low	Low	Low	Unclear
Kirschneck et al. (2014)²²	Low	Low	Unclear	Low	Low	Low	Unclear	Low	Low	Low	Unclear
Sydorak et al. (2019)²⁸	Low	Low	Unclear	Unclear	Low	Low	Low	Low	Low	Low	Unclear
Schneider et al. (2015)²⁷	Low	Low	Unclear	Unclear	Low	Low	Unclear	Low	Low	Low	Unclear
Zhao et al. (2012)²⁴	Low	Low	Unclear	Unclear	Unclear	Low	Unclear	Low	Low	Low	Unclear
Dunn et al. (2007)²⁶	Low	Low	Unclear	Low	Low	Low	Low	Low	Low	Low	Unclear
Ortega et al. (2012)²¹	Low	Low	Low	Low	Low	Low	Low	Low	Low	Low	Low
Venkataramana et al. (2014)⁷	Low	Low	Low	Unclear	Low	Low	Unclear	Low	Low	Low	Unclear
Kaipatur et al. (2013)⁶	Low	Low	Unclear	Low	Low	Low	Unclear	Low	Low	Low	Unclear
Karras et al. (2009)¹⁹	Low	Low	Low	Low	Low	Low	Low	Low	Low	Low	Low
Igarashi et al. (1994)²⁵	Low	Low	Low	Unclear	Low	Low	Unclear	Low	Low	Low	Unclear
Kanzaki et al. (2004)²³	Low	High	Unclear	Low	Unclear	Low	Low	Low	Low	Low	Unclear

Systematic Review Centre for Laboratory Animal Experimentation (SYRCLE)’s risk of bias tool.²⁹

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 from selective outcome reporting?; 10, Was the study free of other problems that could result in a high risk of bias?

Table 3

Evidence table (GRADE analysis)

Certainty assessment								No. of patients			Effect		Certainty	Importance
No. of studies	Study design	Risk of bias	Inconsistency	Indirectness	Imprecision	Other considerations		Biphosphonates or osteoprotegerin	Placebo		Relative (95% CI)	Absolute (95% CI)	Certainty	Importance
7	Randomized trials	Not serious	Not serious	Not serious	Not serious	None		99/192 (51.6%)	93/192 (48.4%)		RR –0.88 (–1.45 to –0.31)	91 fewer per 100 (from 100 fewer to 63 fewer)	⨁⨁⨁⨁ High	CRITICAL

CI, confidence interval; RR, risk ratio.

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