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The Open Dentistry Journal

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REVIEW ARTICLE

Effect of Pharmacological Methods in Accelerated Orthodontics: A Literature

Review
Abdullah Almalki1,*
1
Department of Preventive Dental Sciences, College of Dentistry, Majmaah University, Al-Majmaah 11952, Saudi Arabia

Abstract:
Aims:
This study aimed to perform a literature review on the effect of pharmacological methods in accelerated orthodontics and the evidence of published
studies.

Materials and Methods:

A search of the reported literature till December, 2020, was conducted using “PubMed,” “Google Scholar,” and “manual search.” The MesH terms
and keywords in the search criteria were “tooth movement,” “orthodontics,” “pharmacological,” and “drugs” in various combinations. The search
was confined to the English language. Data extraction was done under the heading authors, country and year, study design (level of evidence),
study type, and pharmacological agents. The level of evidence of included studies was in accordance with the National Health and Medical
Research Council.

Results:
Five hundred forty-seven studies were retrieved from different databases, and 12 were included in this review. Out of 12 included studies, 10 were
animal studies, and two were human trials. Pharmacological agents utilized for intervention were prostaglandin, followed by relaxin, vitamin D,
and parathyroid hormone. The level of evidence in the human study was reported as level II, and for animal studies, level III; all the included
studies recorded accelerated tooth movement. The risk of bias in the included animal studies was unclear, and the risk was low and moderate for
human studies.

Conclusion:
Prostaglandin, interleukins, parathyroid hormone, and vitamin D are commonly used in published literature for accelerating tooth movement.
Nonetheless, all these experimented drugs have few or other unsolicited adverse effects. Further studies with long-term follow-ups are
recommended to support the utilization of pharmacological methods in accelerated orthodontic movements.

Keywords: Orthodontics, Tooth movement, Prostaglandin, Interleukins, Parathyroid hormone, Vitamin D.

Article History Received: December 14, 2022 Revised: April 29, 2023 Accepted: May 21, 2023

1. INTRODUCTION compliance [3 - 5]. Orthodontists are constantly motivated

toward alternative approaches to minimize the duration of the
Accelerating orthodontic tooth movement minimizes the
treatment [6 - 9].
duration of the treatment with fewer side effects. It also has
numerous potential benefits, including differential tooth Cunningham first proposed vertical cuts in intra-dental
movement, the enhanced envelope of tooth movement, and areas while treating palatally inclined maxillary lateral incisors
better post-treatment retention. Fixed orthodontic treatment [10, 11]. A localized inflammatory response will be initiated by
usually takes 24 to 36 months [1, 2], and the enhanced duration creating a surgical wound in the bone [10, 12 - 15]. This
of treatment poses various complications that include procedure causes osteoclast differentiation, eventually leading
periodontal problems, external root resorption, and patient to bone resorption and accelerating tooth movement. This
acceleration of tooth movement might be possible in the
* Address correspondence to this author at the Department of Preventive Dental
Sciences, College of Dentistry, Majmaah University, Al-Majmaah 11952, presence of chemokines and cytokines through the
Saudi Arabia; E-mail: ae.almalki@mu.edu.sa prostaglandin E2 pathway and the RANK/RANKL pathway.

DOI: 10.2174/0118742106237691230920102859, 2023, 17, e187421062309182

2 The Open Dentistry Journal, 2023, Volume 17 Abdullah Almalki

Nevertheless, this outcome is not permanent and persists for addition, a manual search was performed on peer-reviewed
four months [14], and a repetition of this entire procedure is journals, and cross-referencing was done. Articles other than
required to allow accelerated tooth movement. the English language were excluded. The medical subject
headings [MesH] used for this review were “orthodontic
The need for a treatment approach is evident to minimize
patient,” OR “orthodontic therapy,” OR “orthodontic
the duration of orthodontic treatment without affecting the treatment,” OR “Orthodox,” OR “tooth movement” OR “teeth”
outcome. Subsequently, numerous methods have been AND “Pharmacological” OR “Drug,” OR “Local factor,” OR
introduced to enhance tooth movement in contemporary “Vitamin D,” OR “Prostaglandin,” OR “Cholecalciferol,”
orthodontics, including mechanical stimulation, surgical, and AND “Accelerated tooth movement,” OR “Fast treatment,” OR
pharmacological methods. Among these methods, “treatment time “OR “rapid tooth movement.”
pharmacological methods in accelerated orthodontics and their
effect have been evaluated only in a few published works of 2.2. Eligibility Criteria
literature. There is a need to study reported pharmacological
The inclusion criteria followed for this review were studies
approaches and their impact on accelerated orthodontics.
performing pharmacological interventions, such as
Therefore, this literature review aims to revise pharmacological
prostaglandin, vitamin D, hormone, interleukins, and
methods utilized in accelerated orthodontics and produce an
parathyroid for orthodontic tooth movement. All the included
evidence-based report of included studies [15]. articles were in the English language. There was no restriction
on the age of the patients, and animal studies were also
2. MATERIALS AND METHODS
included in this review. Exclusion criteria were studies that
As this is a literature review, PROSPERO registration was performed accelerated tooth movement without
not required. However, this review has followed the PRISMA pharmacological intervention.
guidelines to acquire evidence-based results. The PICO
question developed is “What are the effects of pharmacological 2.3. Study Selection
methods on accelerated tooth movement in humans and Evaluators independently reviewed and examined the
animals? Whether the population is humans or animals (P), abstract and titles of the articles. The full text was considered if
intervention is the pharmacological method (I), a comparison is the articles were potentially eligible, and the eligibility criteria
not applicable (C), and the outcome is orthodontic tooth were not determined by the abstract alone. Full-text articles
movement (O). In this review, the effects of pharmacological were assessed following inclusion-exclusion criteria.
methods on accelerated tooth movement are discussed.
The data extraction of full-text articles was done under the
However, no hypothesis has been developed.
following headings: authors, country, and year of publications,
pharmacological intervention, study design, level of evidence,
2.1. Data Extraction
and study type (animal or human study). The level of evidence
The literature was searched electronically on PubMed and was categorized according to the National Health and Medical
Google Scholar from inception till December, 2020. In Research Council [16] (Fig. 1).

Level Design
I A systematic review of randomized controlled trials (RCTs)
II Randomized controlled trials
III-1 A pseudo-randomized controlled trial
III-2 A comparative study with concurrent controls:
Non randomized, experimental trial
Cohort study
Case-control study
III-3 A comparative study without concurrent controls:
Historical control study
Two or more single-arm study
Interrupted time series without a parallel control group
IV Case series with either a post-rest or pre test/post-test outcomes

Fig. (1). Levels of evidence described by the national health and medical research council [16] (www.nhmrc.gov.au-2009).
Effect of Pharmacological Methods in Accelerated Orthodontics The Open Dentistry Journal, 2023, Volume 17 3

2.4. Risk of Bias methods on orthodontic tooth movements (Table 1). Five
The quality assessment of the included animal study was hundred eighteen articles were excluded after screening and
performed by the SYRCLE risk of bias tool. This tool is duplication removal. Fifteen articles were retrieved for full-text
designed to evaluate studies on animal experimental trials. reading, out of which three articles were excluded. Finally, 12
There are 10 questions related to the possible risk of bias from articles (2 studies on humans and 10 animal studies) were
the allocation of the sample to the publication of the study. The included in this review for data extraction [17 - 28].
answer on this scale is given as “Yes,” “No,” or “Unclear.” Table 2 demonstrates different pharmacological methods
The assessment of studies on humans, mainly randomized utilized in the included studies. Out of 12 studies, 5 studies
control trials, was performed by the Cochrane Collaboration utilized prostaglandin (Yamasaki et al. [26], Yamasaki et al.
tool. This tool has 7 questions evaluating risks from sample [27], Seifi et al. [25], Yamasaki et al. [28], Kale et al. [18]), 3
sequence allowance to outcome reporting. The answer on this studies used relaxin (Liu et al. [22], Madan et al. [23], Mc
scale is given as: “yes,” “no,” and “unclear.” Gorray et al. [24]), 3 studies utilized Vitamin D, and 2 studies
used parathyroid hormone (Soma et al. [19], Soma et al. [20],)
3. RESULTS as a pharmacological agent. The level of evidence determined
Fig. (2) illustrates the complete search of the included in human studies was level II, signifying that studies were
article with every step. A total of 540 articles were retrieved randomized controlled trials, and animal studies were level III,
from the databases searched (533 from electronic search and 7 indicating non-randomized experimental trials, case-control,
from manual search) (Fig. 2) on the effect of pharmacological and cohort studies.

Records identified through Additional records

identified from other
Identification

database searching sources (n = 7)

Records after duplicates removed (n = 540)

Records screened (n = 540) Records excluded (n =525)

Screening

Full-text articles assessed Full-text articles

Eligibility

for eligibility (n =15) excluded, with reasons

Studies included in
Included

qualitative synthesis

Fig. (2). Flow diagram of the study selection process.

Table 1. Retrieved articles based on search words in various combinations (n=number of studies).

Retrieved Articles and Search Combinations n

“Tooth movement” AND “pharmacological” 39
“Tooth movement “AND “drugs” 82
“Tooth movement” AND “orthodontics” AND “pharmacological” 23
“Tooth movement” AND “orthodontics” AND “pharmacological” and “drugs” 4
“Orthodontics” AND “pharmacological” 124
“Orthodontics” AND “drugs” 239
“Orthodontics” AND “pharmacological” AND “drugs” 15
4 The Open Dentistry Journal, 2023, Volume 17 Abdullah Almalki

Table 2. Details of pharmacological agents used in various studies.

Pharmacological Agent Studies

Parathyroid hormone Soma et al. [19], Soma et al. [20]
Relaxin Liu et al. [22], Madan et al. [23]. Mc Gorray et al. [24]
Prostaglandins Yamasaki et al. [26], Yamasaki et al. [27], Seifi et al. [25], Yamasaki et al. [28], Kale et al. [18]
Vitamin D Collins et al. [17], Kale et al. [18], Kawakami et al. [21]

Table 3. Studies performed using drugs for accelerated orthodontics in animals.

Authors, Year, Pharmacological Agent Level of Animals Overall Result Did the Drug
and Country Evidence assist
Accelerated
Orthodontics
Tooth
Movement
Yamasaki et al. Prostaglandins (PGs-PGE1 or Level III Sprague-Dawley A dose-dependent increase in the Yes
[26] 1980 PGE2) male rats appearance of osteoclasts when PGs
Japan were injected into the gingiva.
Yamasaki et al. Prostaglandins Level III Monkey Local administration of PGE1 or PGE2 Yes
[27] 1982 (Female Macaca (40 ug/site) in gingiva increased the rate
Japan fuscata) of tooth movement by 2-fold.
Collins et al. 1,25dihydroxycholecalciferol Level III Young adult cats Intra-ligamentous injections of a Yes
[17] (1,25D) solution of 1,25D moved teeth 60%
1988 USA further than matched control
teeth—increased numbers of
mononuclear osteoclasts.
Soma et al. [20] Parathyroid hormone Level III Male Wistar rats Continuous administration of PTH Yes
1999 Japan infusion (10 μg) doubled the rate of
tooth movement.
Soma et al. [19] Parathyroid hormone Level III Male Wistar rats PTH-MC injection (1 pg/400g body Yes
2000 Japan weight) increased tooth movement by
1.6-fold, along with active osteoclastic
bone resorption and a widened
periodontal space.
Seifi et al. [25] Prostaglandin E2 (PGE2) Level III 8-week-old male Significant acceleration of orthodontic Yes
2003 Iran Wistar rats tooth movement TM after PGE2
injection.
Kawakami et 1,25-dihydroxy vitamin D3 Level III 7-weeks old male Stimulated alveolar bone formation on Yes
al. [21] 2004 (1,25(OH)2D3) Wistar rats the mesial side. Significant increase in
Japan osteoblast surface value on the tension
surface.
Kale et al. [18] prostaglandin E2 (PGE2) and 1,25- Level III 6-week-old male Both PGE2 and 1,25-DHCC enhanced Yes
2004 Turkey dihydroxycholecalciferol Sprague- the amount of tooth movement
(1,25-DHCC) Dawley rats significantly.
Madan et al. Recombinant human relaxin Level III 45-day-old Sprague- Relaxin did not stimulate significantly No
[23] Dawley rats greater or more rapid tooth movement
2007 USA but reduced PDL fiber organization and
increased tooth mobility at the initial
stages.
Liu et al. [22] Human Relaxin Level III 45 days old Sprague- Both modes of application (minipumps Yes
2005 USA Dawley male rats and subcutaneous injections) accelerated
the initial stages of orthodontic tooth
movement.
Note: Level III- cross-sectional, case-control and cohort studies; Level II- randomized clinical trials.

Tables 3 and 4 demonstrate the findings of included animal prostaglandins (PGE1 or PGE2) resulted in a dose-dependent
and human studies. The results of this study show that increase of osteoclasts on proximal aspects [26] and almost
enhanced alveolar bone formation, higher levels of mineral double the rate of tooth movement [25, 27]. Recombinant
apposition rate and osteoblast surface [21], along with human relaxin either did not significantly stimulate rapid tooth
increased numbers of mononuclear osteoclasts [17], were movement [23] or had a mild effect [22]. 1,25-DHCC
found with the application of 1,25-dihydroxy vitamin D3 increased orthodontic tooth movement, and there was an
(1,25(OH)2D3) during tooth movement. Local application of increase in the number of Howship’s lacunae and capillaries on
Effect of Pharmacological Methods in Accelerated Orthodontics The Open Dentistry Journal, 2023, Volume 17 5

the pressure side [18].PTH infusion [20] and PTH-MC studies were considered to have an unclear risk of bias, except
injection [19] almost doubled the rate of tooth movement with 2 with moderate risk [18, 23]. Due to the inconsistency of
active osteoclastic bone resorption and a widened periodontal available data, it was difficult to determine the risk of bias in
space in these cases. In humans, locally administered most studies. The domains that represent an unclear risk of bias
prostaglandins in gingiva near the orthodontically treated teeth were random sequence generation, allocation concealment, and
caused almost double the rate of tooth movement [28], while blinding outcome of the study. The low risk of bias was
presented in the domain, namely random outcome assessment
relaxin did not significantly increase tooth movement [24].
and blinding. No information was provided on whether
investigators were blinded and animals were randomly
3.1. The Quality of the Studies Included
allocated for the research. Finally, it was difficult to determine
Table 5 summarizes the risk of bias amongst the included whether studies were free of any other issues that could
animal studies using the SYRCLE tool [29]. Most of the increase the risk of bias.

Table 4. Studies performed using drugs for accelerated orthodontics in humans.

Authors, Year, and Pharmacological Agent Level of Humans Overall Result Did the Drug assist
Country Evidence Accelerated
Orthodontics Tooth
Movement
Yamasaki et al. [28] Prostaglandins (PGE1) Level II Adults Local administration of PGE (10 pg per site) Yes
1984 Japan almost doubled the rate of tooth movement.
Mc Gorray et al. [24] Relaxin Level II Adults Tooth movement over the 8-week treatment No
2012 USA period did not differ for the relaxin group and
placebo.

Table 5. Risk of bias assessment of animal-controlled trial according to SYRCLE’s risk of bias tool [29].

Animal Sequence Basic Allocation Random Blinding Random Blinding Incomplete Selective Other
S.No. Studies Generation Characteristics Concealment Housing Outcome Outcome Outcome Sources
Assessment Data Data of Bias
1 Yamasaki et Unclear Unclear Unclear Unclear Unclear Unclear Unclear Unclear Unclear Unclear
al. [26] 1980
2 Yamasaki et Unclear Unclear Unclear Unclear Unclear Unclear Unclear Unclear Unclear Unclear
al. [27] 1982
3 Collinset al. Unclear Unclear Unclear Unclear Unclear Unclear Unclear Unclear Unclear Unclear
[17] 1988
4 Soma et al. Unclear Unclear Unclear Unclear Unclear Unclear Yes Unclear Unclear Unclear
[20] 1999
5 Soma et al. Unclear Unclear Unclear Unclear Unclear Unclear Yes Unclear Unclear Unclear
[19] 2000
6 Seifi et al. Unclear Unclear Unclear Unclear Unclear Yes Unclear Unclear Unclear Unclear
[25] 2003
7 Kawakami Unclear Unclear Unclear Unclear Unclear Unclear Unclear Unclear Unclear Unclear
et al. [21]
2004
8 Kale et al. Unclear Yes Unclear Yes Unclear Yes Yes Unclear Unclear Unclear
[18] 2004
9 Liu et al. Unclear Unclear Unclear Unclear Unclear Yes Unclear Unclear Unclear Unclear
[22]
2005
10 Madan et al. Unclear Unclear Unclear Unclear Unclear yes Yes yes Unclear Unclear
[23] 2007

Table 6. Quality of human clinical trials using Cochrane Collaboration’s tool [30].

Authors Sequence Allocation Blinding Blinding Incomplete Selective Outcome Free of Other
S.No.
Generation Concealment Outcome Data Reporting Bias
1 Yamasaki et al. [28] N/A N/A N/A N/A N/A N/A N/A
1984
6 The Open Dentistry Journal, 2023, Volume 17 Abdullah Almalki

(Table 6) contd.....
Authors Sequence Allocation Blinding Blinding Incomplete Selective Outcome Free of Other
S.No.
Generation Concealment Outcome Data Reporting Bias
2 Mc Gorray et al. Yes Unclear Yes Yes Yes Unclear Unclear
[24]
2012

Table 6 represents the risk of bias for included randomized Parathyroid hormones elevate serum calcium concentration
controlled trials by Cochrane collaboration tools [30]. Of the 2 by stimulating bone resorption and up-regulating calcium
included studies, one study by Mc Gorry et al. [24] represents a reabsorption. The enzyme 25-hydroxy D3 1-alpha-hydroxylase
low risk of bias, and another study by Yamasaki et al. [28] in the kidneys forms more than 1, 25 dihydroxy vitamin D3
represents an unclear risk. and increases calcium absorption in the small intestines. Soma
and co-workers [20] reported that the constant administration
4. DISCUSSION of parathyroid hormone accelerates tooth movement. It was
The present review established the relationship between suggested that administering PTH locally is more effective than
accelerated orthodontics and pharmacological agents. The systemic administration. Parathyroid hormone dissolved in gel
literature yielded very few studies reported in this context. form allows a slow release of the hormone, which causes faster
Prostaglandins are paracrine lipid inflammatory mediators that tooth acceleration compared to daily injecting PTH mixed in
act on nearby cells and encourage resorption of the bone by saline solution [34].
increasing the osteoclasts' number. In 1980, Yamasaki and Various investigations [17, 18, 21] established 1, 25-
colleagues [26] investigated the influence of local DHCC to modulate bone turnover during orthodontic tooth
prostaglandin administration in rats, and later, in 1984, human movement using vitamin D in rats. Vitamin D and parathyroid
clinical trials were conducted [28]. The authors concluded that hormone have similar features of calcium reabsorption. A
prostaglandin local administration is very effective and safe in comparative study investigating the effect of vitamin D and
humans. Based on these animal and human studies, Yamasaki PGE injections on accelerating tooth movement suggested no
and colleagues [28] recommended that the local administration statistical difference in both groups [18]. However, osteoblast
of prostaglandin effectively accelerated orthodontic tooth formation was recorded more on the site where vitamin D was
movement. Consequently, a systematic review by Eltimamy et injected. This finding indicates that vitamin D has a direct
al. [31] on human studies reported inconsistency in evidence effect on bone remodeling. The disadvantage is that vitamin D
supporting prostaglandin administration to accelerate tooth increases lactate dehydrogenase and creatine kinase enzyme
movement. Overall, studies have supported the use of levels when injected into the periodontal ligament. However,
prostaglandin to accelerate orthodontic tooth movement, yet safety remains a significant concern for the clinical application
more studies are required to support these findings. of pharmacological methods in orthodontic treatment.
Subsequently, Seifi and colleagues performed an animal Orthodontic treatment is in increasing demand nowadays
study to investigate the importance of prostaglandins in because of patients' interest in completing the treatment in less
association with calcium ions [25]. The authors found that time and reducing the number of visits [21 - 28, 32, 33, 35 -
combining calcium ions and prostaglandins will increase 37]. Accelerating orthodontic techniques can help fasten the
orthodontic tooth movement and stabilize root resorption. treatment [32, 33, 36]. Moreover, it has been observed that an
Human trials were not performed to support this combination, increased tooth movement rate decreases the treatment time.
as suggested by Seifi and colleagues [25]. The role of relaxin Numerous pharmacological agents were introduced to
was extensively studied in the remodeling of soft tissue rather accelerate orthodontic tooth movement and have achieved
than the remodeling of bone [32]. Relaxin is a hormone that successful results [38]. Kouskoura and colleagues hypothesized
helps during childbirth and is also present in the periodontal that the drug carriers that do not spread into a larger area from
ligament and cranial suture. Relaxin has the cumulative effect the application site are induced only at areas of bone
of decreasing collagen at the pressure site and increasing it at remodeling [39]. Another factor in successful orthodontic tooth
the tension site. movement includes treatment adjustment based on the patients'
age. It has been found that early-stage cellular responses are
Studies on the role of relaxin [22, 23] show that relaxin
delayed with increasing age [40].
does not enhance tooth movement in rats; it can reduce
periodontal ligament organization level, and periodontal Most of the reported studies were animal and case-control
ligament mechanical strength initially increases tooth studies, and only two randomized control trials performed in
movement. Few studies have suggested that remodeling humans were published on pharmacological methods used in
periodontal ligament by relaxin might reduce the chance of accelerated orthodontics. Based on the National Health and
relapse after orthodontic treatment [33]. A randomized control Medical Research Council, all the animal studies achieved
trial conducted by Mc Gorray et al. [24] recorded the tooth level III, while level II was reported for human trials. However,
movement weekly on polyvinyl siloxane impression, the available evidence is insufficient to support or contrary to
suggesting no significant difference between the relaxin group pharmacological methods in accelerating tooth movement.
and the control group. Authors opined that the low dosage of Furthermore, the adverse effects of the pharmacological agents
relaxin might have minimal effect on tooth movement. The role also need to be considered. This review establishes the
of the relaxin hormone on accelerated tooth movement is still relationship between pharmacological agents and accelerated
not fully understood. tooth movement in orthodontics. Prostaglandin, interleukins,
Effect of Pharmacological Methods in Accelerated Orthodontics The Open Dentistry Journal, 2023, Volume 17 7

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