SYSTEMATIC REVIEW

Effectiveness of biologic methods of inhibiting

orthodontic tooth movement in animal studies
~ ez-Vico,b Enrique Solano-Reina,c and Alejandro Iglesias-Linaresd
Maria Cadenas-Perula,a Rosa M. Yan
Seville and Madrid, Spain

Introduction: A number of biologic methods leading to decreased rates of orthodontic tooth movement (OTM)
can be found in the recent literature. The aim of this systematic review was to provide an overview of biologic
methods and their effects on OTM inhibition. Methods: An electronic search was performed up to January
2016. Two researchers independently selected the studies (kappa index, 0.8) using the selection criteria estab-
lished in the PRISMA statement. The methodologic quality of the articles was assessed objectively according to
the Methodological Index for Non-Randomized Studies scale. Results: We retrieved 861 articles in the initial
electronic search, and 57 were finally analyzed. Three biologic techniques were identified as reducing the rate
of OTM: chemical methods, low-level laser therapy, and gene therapy. When the experimental objective was
to slow down OTM, pharmacologic modulation was the most frequently described method (53 articles). Rats
were the most frequent model (38 of 57 articles), followed by mice (9 of 57), rabbits (4 of 57), guinea pigs (2 of
57), dogs (2 of 57), cats (1 of 57), and monkeys (1 of 57). The sample sizes seldom exceeded 25 subjects per
group (6 of 57 articles). The application protocols, quality, and effectiveness of the different biologic methods
in reducing OTM varied widely. Conclusions: OTM inhibition was experimentally tested with various biologic
methods that were notably effective at bench scale, although their clinical applicability to humans was rarely
tested further. Rigorous randomized clinical trials are therefore needed to allow the orthodontist to improve
the effect of translating them from bench to clinic. (Am J Orthod Dentofacial Orthop 2016;150:33-48)

A
bsolute control over tooth movement is a key
factor in orthodontics.1-7 One main remaining
limitation of past and current orthodontic
treatments is the inability to completely prevent the
unexpected movement of certain teeth; this is
frequently defined as loss of anchorage during
treatment or relapse during the retention phase.7 At
present, auxiliary devices such as temporary anchorage
devices are used to provide additional biomechanical
resistance and help prevent undesirable tooth
a
Postdoctoral student, Department of Stomatology, Dentistry School, University
of Seville, Seville, Spain.
b
Associate professor (Plan Propio Investigacion US), Department of Stomatology,
Dentistry School, University of Seville, Seville, Spain.
c
Head of orthodontics and program director, Department of Stomatology,
Dentistry School, University of Seville, Seville, Spain.
d
Associate professor, Department of Orthodontics, School of Dentistry, Complu-
tense University of Madrid, Madrid, Spain.
All authors have completed and submitted the ICMJE Form for Disclosure of Po-
tential Conflicts of Interest, and none were reported.
Supported by a grant (PI13/00310) from the National Institute of Health Carlos
III of Spain.
Address correspondence to: Alejandro Iglesias-Linares, Department of Orthodon-
tics, School of Dentistry, Complutense University of Madrid, Plaza Ramon y Cajal
s/n PC 28040, Madrid, Spain; e-mail, aleigl01@ucm.es.
Submitted, January 2015; revised and accepted, January 2016.
0889-5406/$36.00
Copyright Ó 2016 by the American Association of Orthodontists. All rights
reserved.
http://dx.doi.org/10.1016/j.ajodo.2016.01.015
movement. Similarly, in recent decades, a number of
biologic methods have emerged that can decrease the
rate of orthodontic tooth movement (OTM) or even
inhibit it completely4-7 by interfering with osteoclast
cell activity during the bone remodeling on which
OTM depends.2-4
In this respect, chemical methods, including hor-
mones, drugs, and various synthetic molecules, have
been used from the earliest to the most recent studies
on OTM. Bisphosphonates3,4 (inhibitors of bone
resorption) and prostaglandin inhibitors, such as
ibuprofen2 and acetylsalicylic acid,1 have been widely
studied because of their activity in slowing OTM. Apart
from the administration of specific drugs, other methods
proposed in the literature to reduce the rate of OTM
include processes that modify the biologic substrate,
such as low-level laser therapy5,6 or gene therapy.7 The
doses, protocols, and hypotheses are as varied as the
studies themselves; this makes it difficult for the clini-
cian to establish useful comparisons between studies
and their relevance, if any, to the clinical field.
The purposes of this review were (1) to compile,
analyze, and summarize the data available in the liter-
ature regarding experimental studies in animals that
used biologic methods against a control group that
resulted in a decreased rate of OTM or its inhibition;
33
34
(2) to compare the different methods and their out-
comes; and (3) to give the clinician a clear overview
of the scientific evidence available in the literature
with a quality analysis of the methodologies used in
the articles reviewed, thus facilitating research for
professionals with an interest in this area. The main
specific questions asked in this review were the
following: Which experimental biologic methods
have a decreasing or inhibitory effect on OTM? How
efficient are these methods?
MATERIAL AND METHODS
Protocol
The structure of the review protocol was developed
before the start of the study, and the reporting of find-
ings followed the PRISMA guidelines (www.
prisma-statement.org). Because the experimental
studies on which this systematic review was based
were on animals, our protocol could not be registered
in the PROSPERO database.
Information resources
A search was made of the MedLine (Entrez PubMed,
www.ncbi.nim.nih.gov), SCOPUS (www.scopus.com),
and Web of Science (www.isiknowledge.com) databases
to find possible studies matching our established selec-
tion criteria, including all articles published up to
January 21, 2016. We searched for gray literature by
exploring the OpenGrey database, European Association
for Grey Literature Exploitation, also up to January 21,
2016, without applying language restrictions.
Search strategy
Our search strategy used the medical subject heading
term “tooth movement” crossed with “inhibition,”
“inhibit,” or “decrease” and excluded the terms “relapse”
or “increase” or “enhance” or “promotion.”
Supplementary Table I summarizes the full search strat-
egy, including animal search filters, in all databases
used.8 Some main orthodontic journals not indexed in
the Journal Citation Report index were also hand
searched to identify potential studies not found in the
electronic search (Supplementary Table I).
Eligibility
Articles selected for this study fulfilled the following
criteria for inclusion, according to the PICOS format.
1. Population: animals; any experimental study or
clinical investigation that included at least 1 exper-
imental group with a minimum of 5 animals or sam-
ples per group.
July 2016  Vol 150  Issue 1 American Journal of Orthodontics and Dentofacial Orthopedics
Cadenas-Perula et al
2. Intervention: biologic methods of decreasing or in-
hibiting tooth movement using orthodontic or or-
thopedic devices to apply forces.
3. Comparison: control group without a biologic
method.
4. Outcome: rate of OTM deceleration or inhibition.
5. Study design: experimental controlled trials.
Excluded from the selection were case reports, case
series, descriptive studies, review articles, opinion arti-
cles, letters, and articles that did not correspond to the
objectives of this review or did not have an adequate
description of the technique or the administration dose.
Study selection
Eligibility was assessed by 2 observers (M.C-P. and
R.M.Y-V.) acting independently. Articles were initially
selected on the basis of the title and abstract, with the
complete article reviewed whenever there was doubt
about whether it should be included. Disagreements
were resolved by consensus or by a third experienced
reviewer who was requested to arbitrate (A.I-L.). After
the 2 reviewers had separately applied the inclusion
and exclusion criteria to each article, concordance be-
tween them was measured using the kappa index.
Data collection and analysis
Data were extracted by 1 observer (M.C-P.). A data
extraction sheet was developed and piloted. Conflicts
during data collection were resolved by discussion with
a second (R.M.Y-V.) or a third experienced observer
(A.I-L.). Data were extracted for the following items:
author and year, study design, sample (size, species,
age, and sex), a brief description of the methods, applied
force, total treatment or experimentation time, decrease
in the rate of OTM, and clinical applicability.
Methodologic quality and risk of bias of individual
studies
The methodologic quality of the selected articles was
assessed using the Methodological Index for Non-
Randomized Studies (MINORS).9 The 12 variables
analyzed were clearly stated: aim, inclusion of consecu-
tive patients, prospective collection of data, end points
appropriate to the aim of the study, unbiased assessment
of the study end point, follow-up period appropriate to
the aim of the study, loss to follow-up less than 5%, pro-
spective calculation of the study size, adequate control
group, contemporary groups, baseline equivalence of
the groups, and adequate statistical analysis. After this
analysis, every item scored 0 when not reported, 1
when it was reported but inadequate, and 2 when it
Cadenas-Perula et al
Fig. PRISMA flow diagram.
was reported and adequate. Articles obtaining between
0 and 7 points were assessed as low quality and therefore
had a high risk of bias; studies with 8 to 15 points were
considered as medium quality and with a medium risk of
bias; and articles obtaining 16 to 24 points were classed
as high quality and with a low risk of bias.
RESULTS
Study selection
Two independent observers selected the studies, and
good concordance was shown (kappa index, 0.8). A com-
plete flow diagram of the search is given in the Figure.
Study characteristics and quality assessment
Rats were the most frequently used models in the
sample (38 of 57 articles: 25 Wistar, 13 Sprague Dawley),
followed by mice (9 of 57) and rabbits (4 of 57); guinea
pigs and dogs were used in 2 articles each, and cats and
monkeys in 1 each. The sample sizes seldom exceeded
25 subjects per group (6 of 57 articles).10-15
Randomization of the samples was mentioned in 24
American Journal of Orthodontics and Dentofacial Orthopedics
35
articles,1,5,6,10-14,16-32 and blinding measures were
found in only 14 studies1,10,13,16,22,24,27,29,31,33-37
(Table I).
The most commonly used biologic method leading to
reduced orthodontic tooth movement was pharmacologic
administration, and a wide range of substances were used
(53 of 57 articles). The main substances evaluated in the
selected articles were nonsteroidal anti-inflammatory drugs
(NSAIDS) in 14 articles,1,2,12,14,19,24,25,30,35,36,38,45,56,58
followed by cytokines15,17,28,31,33,34,37,40,44,52 and
bisphosphonates3,4,11,13,16,41,42,47,49,55 in 10 articles each.
Three articles were based on antihistamines,46,50,51 and 2
articles each on hormones,18,23 fluoride,21,57 and beta
blockers.20,29 Finally, 10 articles concentrated on other
substances, such as immunosuppressants,10 morphine,22
nitric oxide,26 phenytoin,27 nicotine,43 simvastatin,32,48
endothelin,53 and tetracycline,54 or Nrf2 activators.39
Twenty-five studies were categorized as high quality with
a low risk of bias (over 16 points), although on the
24-point scale used, no article scored more than 20 points.
The remaining articles were considered to be medium
quality.
July 2016  Vol 150  Issue 1
 Table I. Methodological quality of the selected articles with the Methodological Index for Nonrandomized Studies (MINORS)
July 2016  Vol 150  Issue 1

36
Follow-up
End points Unbiased period Loss to
Clearly Inclusion Prospective appropriate assessment appropriate follow-up Prospective Adequate Adequate
stated of consecutive collection to aim of study to aim of less calculation control Contemporary Baseline statistical
Authors, year aim sample of data of study end point study than 5% of study size group groups equivalence analysis Total Q B
Chemical methods
Olteanu et al,38 2015 2 2 2 2 0 2 0 0 2 0 0 2 14 M M
Kanzaki et al,39 2015 2 2 2 2 0 2 0 0 2 0 0 1 13 M M
Hakami et al,40 2015 2 2 2 2 0 2 0 0 2 0 0 2 14 M M
Fernandez-Gonzalez 2 2 2 2 0 2 0 2 2 2 2 2 20 H L
et al,31 2015
Venkataramana et al,41 2 2 2 2 0 2 0 0 2 0 0 1 13 M M
2014b
Venkataramana et al,42 2 2 2 2 0 2 0 0 2 0 0 1 13 M M
2014a
Oliveira et al,29 2014 2 2 2 2 1 2 0 0 2 2 0 1 16 H L
Nagaie et al,43 2014 2 0 2 2 0 2 0 0 1 2 1 1 13 M M
Toro et al,4 2013 2 0 2 2 1 2 0 0 2 2 0 1 14 M M
Kaipatur et al,16 2013 2 2 2 2 1 2 1 0 2 2 1 1 18 H L
Yabumoto et al,17 2 2 2 2 0 1 0 0 2 2 0 1 14 M M
2013
American Journal of Orthodontics and Dentofacial Orthopedics

Olyaee et al,18 2013 2 2 2 2 0 2 0 0 2 2 0 2 16 H L

Sodagar et al,19 2013 2 2 2 2 0 2 0 0 2 2 0 1 15 M M
Kondo et al,20 2013 2 2 2 2 0 2 0 0 1 2 0 1 14 M M
Esfahani et al,32 2013 2 2 2 2 0 1 0 0 2 2 0 1 14 M M
Yoshimatsu et al,33 2 2 2 2 1 2 0 0 2 2 0 1 16 H L
2012
Kohara et al,44 2012 2 1 2 2 0 2 0 0 1 2 0 1 13 M M
Hammad et al,45 2012 2 2 2 2 0 2 0 0 2 0 0 1 13 M M
Meh et al,46 2011 2 2 2 2 0 2 0 0 2 2 0 1 15 M M
Hao and Hua,34 2011 2 2 2 2 1 2 0 0 2 2 0 1 16 H L
Gonzales et al,21 2011 2 2 2 2 0 2 0 0 2 2 0 1 15 M M
Shoji et al,47 2010 2 2 2 2 0 1 0 0 2 0 0 2 13 M M
Santos et al,10 2010 2 2 2 2 1 2 0 0 2 2 0 1 16 H L
Han et al,48 2010 2 2 2 2 0 2 0 0 2 2 0 1 15 M M
Choi et al,3 2010 2 2 2 2 0 2 0 0 2 2 0 1 15 M M
Baysal et al,23 2010 2 2 2 2 0 2 0 0 2 2 0 2 16 H L
Akhoundi et al,22 2010 2 2 2 2 0 2 0 0 2 2 0 1 15 M M

Cadenas-Perula et al
Karras et al,11 2009 2 2 2 2 0 2 1 0 2 2 0 1 16 H L
Fujimura et al,49 2009 2 1 2 2 0 2 0 0 2 2 0 1 14 M M
Sprogar et al,50 2008 2 2 2 2 0 2 0 0 2 2 0 2 16 H L
Kriznar et al,51 2008 2 2 2 2 0 2 0 0 2 2 0 2 16 H L
Kitaura et al,52 2008 2 2 2 2 0 2 0 0 2 2 0 2 16 H L
Hauber Gameiro 2 2 2 2 1 2 0 0 2 2 0 1 16 H L
et al,24 2008
 Table I. Continued
American Journal of Orthodontics and Dentofacial Orthopedics

Cadenas-Perula et al
Follow-up
End points Unbiased period Loss to
Clearly Inclusion Prospective appropriate assessment appropriate follow-up Prospective Adequate Adequate
stated of consecutive collection to aim of study to aim of less calculation control Contemporary Baseline statistical
Authors, year aim sample of data of study end point study than 5% of study size group groups equivalence analysis Total Q B
Sprogar et al,53 2007 2 2 2 2 0 2 0 0 2 2 0 1 15 M M
Keles et al,15 2007 2 2 2 2 0 1 0 0 2 2 0 1 14 M M
Dunn et al,28 2007 2 2 2 2 0 2 1 0 2 2 0 1 16 H L
de Carlos et al,36 2007 2 2 2 2 1 1 0 1 2 2 0 2 17 H L
Bildt et al,54 2007 2 2 2 2 0 2 0 0 2 2 0 2 16 H L
de Carlos et al,35 2006 2 2 2 2 1 1 0 0 2 2 0 2 16 H L
Arias and 2 2 2 2 1 1 0 0 2 2 0 1 15 M M
Marquez-Orozco,1
2006
J€ager et al,37 2005 2 2 2 2 1 2 0 0 2 2 0 2 17 H L
Liu et al,55 2004 2 2 2 2 0 2 0 0 2 2 0 1 15 M M
Gurton et al,25 2004 2 2 2 2 0 1 0 0 2 2 0 2 15 M M
Shirazi et al,26 2002 2 2 2 2 0 2 0 0 2 2 0 2 16 H L
Zhou et al,12 1997 2 2 2 2 0 1 0 1 2 2 0 1 15 M M
Karsten and Hellsing,27 2 2 2 2 1 2 0 1 2 2 0 2 18 H L
1997
Kehoe et al,2 1996 2 2 2 2 0 1 0 0 2 1 0 1 13 M M
Igarashi et al,13 1994 2 2 2 2 1 2 0 0 2 2 0 1 16 H L
Wong et al,56 1992 2 2 2 2 0 2 0 0 1 2 0 0 13 M M
Hellsing and 2 2 2 2 1 2 0 1 2 2 0 2 18 H L
Hammarstrom,57
1991
Mohammed et al,14 2 2 2 2 0 2 0 0 2 2 0 1 16 H L
1989
Chumbley and 2 2 2 2 0 2 0 0 2 2 0 1 13 M M
Tuncay,30 1986
Sandy and Harris,58 2 2 2 2 0 1 0 1 2 2 0 2 14 M M
1984
Low-level laser therapy
July 2016  Vol 150  Issue 1

Kim et al,59 2015 2 2 2 2 1 2 0 0 2 2 0 1 16 H L

Kim et al,5 2009 2 2 2 2 0 2 0 0 2 2 0 1 15 M M
Seifi et al,6 2007 2 2 2 2 1 2 0 0 2 2 0 1 15 M M
Gene therapy
Kanzaki et al,7 2004 2 2 2 2 1 2 2 0 2 2 0 1 16 H L
Q, Quality; B, risk of bias; H, high; L, low; M, medium.

37
38
Outcomes
The methods included in this review fall into 3 major
categories: chemical or pharmacologic methods, gene
therapy, and low-level laser therapy (Table II). Fifty-
three of the 57 studies were classed as chemical
methods. These comprised a wide range of substances,
ranging from NSAIDs to bisphosphonates and cytokines,
and were mainly administered in 1 of 2 forms: local or
systemic. NSAIDS and other selective COX-2 inhibitors
were the most frequently described substances (14 of
53 studies). Diclofenac seems to have the strongest
inhibitory effect on OTM; de Carlos et al,35 in a study
rated as high quality, described complete inhibition
when diclofenac was used on rats under 100 and 50 g
of force (P \0.01), and partial inhibition with rofecoxib
under 50 g of force (P\0.01), although some movement
was found (a reduction of approximately 70%) with ro-
fecoxib and 100 g of force, compared with the controls
(P\0.05). In another article by the same authors, no sta-
tistically significant reduction in OTM was found with
parecoxib or celecoxib compared with the controls at
50 g of force.36 However, short-term use of celecoxib
slowed down OTM by 30% and long-term use by 46%
(P \0.01), as determined by a study of high methodo-
logic quality,24 whereas in another, assessed as medium
quality, 50% less tooth movement was found with the
same drug (P \0.01).19 However, a higher decrease in
OTM was found by Hammad et al45 with paracetamol
and ketorolac than with celecoxib (P \0.01). Indometh-
acin obtained different results; it was reported to reduce
the rate of OTM by half compared with the controls
(P\0.01), as described in a study rated as high quality,30
and to reduce OTM by 40% (P \0.05)12 and 25%
(P \0.01) in 2 studies of medium methodologic qual-
ity.25 In the latter study, the prostaglandin (PG) analogs,
prostacyclin (PGI2) and thromboxane A2 (TxA2), were
compared with 2 PG inhibitors, indomethacin (a PGI2 in-
hibitor) and imidazole (a TxA2 inhibitor). The PG ana-
logs—PGI2 much more than TxA2—significantly
increased the rate of OTM in rats, whereas indomethacin
and imidazole reduced OTM, with no significant
differences in their inhibitory effects.25 Leukotriene
inhibitors—and not only PG—were also reported to
decrease OTM (application of AA861 resulted in 29.8%
less OTM and 36% less tooth movement combined
with indomethacin) (P \0.05), as 1 high-quality study
demonstrated (Table II).14
On the other hand, the authors of several studies
found contradictory results for ibuprofen. Whereas Arias
and Marquez-Orozco1 and Kehoe et al2 found 42%
(P\0.01) and 22% (P\0.001) decreases in OTM in Wis-
tar rats and guinea pigs, respectively, Sandy and Harris58
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Cadenas-Perula et al
found no significant differences in rabbits, all in studies
rated as medium quality. Similarly, in the study of Arias
and Marquez-Orozco, acetylsalicylic acid caused a
decrease of 38.75% (P \0.05), whereas Wong et al,56
in another medium-quality study, reported no differ-
ences. A dose-dependent effect may account for some
differences in the measured OTM. There does, however,
appear to be consensus about acetaminophen, which
was twice reported as not affecting OTM (Table II).1,2
Inflammatory cytokines, in 10 of 53 articles, were the
second most studied chemical substance. Two high-
quality studies described that soluble IL-1 and TNF-a re-
ceptors produced 60% less OTM (P \0.05),37 whereas
various concentrations of recombinant soluble TNF re-
ceptor (rhsTNF-R1), administered both systemically
and locally, reduced OTM by 40% (P \0.01).34 Injec-
tions of IL-1233 and IL-444 at doses of up to 1.5 mg
per day significantly reduced OTM because of the inhib-
itory effect of IL-12 on TNF-mediated osteoclastogene-
sis (P \0.001), as determined in high-quality
studies.33,40 In a similar line of research with a high-
quality methodologic design involving TNF mediators,
mice were injected with an antibody against the macro-
phage colony-stimulating factor receptor, c-Fms,
causing a decrease in OTM of approximately 37%
(P \0.05) by blocking TNF-a-induced osteoclastogene-
sis (Table II).52 A commonly targeted cytokine was osteo-
protegerin (OPG).15,28,31,60 The authors of a high-quality
study concluded that local injections of recombinant
OPG inhibited OTM by 70% in the higher-dose group
(P \0.001) and by 31.8% in the lower-dose group
(P \0.05) (Table II).28
Bisphosphonates were studied in 10 of the 53 articles
on chemical methods in this review. Most of the exper-
imental studies with bisphosphonates were performed
on rats, and 50% less OTM on average was found
when the drugs were injected locally (Table II). Clodro-
nate (40, 10, and 2.5 mg/mol) was reported to reduce
the rate of OTM by 81%, 61%, and 56% (P \0.001) in
a medium-quality study,55 whereas another, rated as
medium quality, reported 36.2% and 32% less OTM us-
ing 10 and 2.5 mg per mole (P \0.05).3 Alendronate
completely inhibited OTM in some experiments
(P \0.05) of medium methodologic quality.4,47 Other
authors reported a 65% reduction (P 5 0.05) in OTM
when alendronate was injected during OTM and an
86% reduction (P \0.01) after 8 weeks when it was
administered 3 months before the forces were
applied16; others reported 42% less OTM if it was in-
jected daily (P \0.001)11; both results were from high-
quality studies. In a similar high-quality study, another
nitrogen-containing bisphosphonate, AhBuBP, resulted
 American Journal of Orthodontics and Dentofacial Orthopedics

Cadenas-Perula et al
Table II. Summary of articles included in the review
Human
clinical
Study Sample Force Time applicability
Authors, year design (n) Description of groups Species Age, sex (g) (d) Decrease in rate of OTM tested
Chemical methods
Olteanu et al,38 2015 CS 24 G1) CG: OTM only; G2) 1.5 mL aspirin by gastric WR NM, 24 M 25 28 Decrease of OTM with aspirin Yes
gavage 1 OTM; G3) 1.2 mL algocalmin by and algocalmin (P 5 0.0001)
gastric gavage 1 OT
Kanzaki et al,39 2015 CS 20 G1) CG: no OTM; G2) OTM 1 right hemi-maxilla: Mi 6 wk, 20 M 10 21 60% less OTM compared with No
2 mL intragingival SFN (Nrf2 activator) in DMF, controls (P \0.05)
left hemi-maxilla DMF only; G3) OTM 1 right
hemi-maxilla: 2 mL intragingival EGCG (Nrf2
activator) in DMF, left hemi-maxilla DMF only
Hakami et al,40 2015 CS 32 G1) CG: no OTM; G2) 1.5 mg/d intragingival Mi 10-12 wk, 32 M 10 12 Less OTM with 1.5 mg/d IL-4 No
IL-4 1 OTM; G3) intragingival PBS 1 OTM; G4) but not with the rest of the
0.015 mg/d intragingival IL-4 1 OTM; G5) doses (P \0.01)
0.15 mg/d intragingival IL-4 1 OTM
Fernandez-Gonzalez CS 42 G1) CG: OTM only; G2: OTM 1 twice/w subgingival SDR 6 mo, 42 M 50 21 52%, 31%, and 22% less OTM Yes
et al,31 2015 injections of 5 mg/kg OPG-Fc mesial and distal to at days 7, 14 (P \0.01), and
maxillary first molar 21 (P \0.05), respectively
Venkataramana CS 20 G1) CG: 1 mL IP saline solution 1 OTM; G2) 1.5 mg/ R 16 wk, 20 M 100 21 Less OTM with pamidronate Yes
et al,41 2014b kg IP pamidronate 1 OTM (P \0.05)
Venkataramana CS 20 G1) CG: 1 mL IP saline solution 1 OTM; G2) 0.3 mg/ R 16 wk, NM 100 21 Less OTM with ibandronate Yes
et al,42 2014a kg intragingival ibandronate 1 OTM (P \0.05)
Oliveira et al,29 2014 CS 20 G1) vehicle only; G2) OTM 1 vehicle; G3) WR 3 mo, 20 M 50 10 Low dose propranolol No
OTM 1 0.1 mg/kg/d oral propranolol; G4) (0.1 mg/kg) reduced OTM by
OTM 1 20 mg/kg/d oral propranolol 41%; a higher dose did not
(P \0.05)
Nagaie et al,43 2014 CS 20 G1) CG, OTM 1 oral administration of basal pure WR 13 wk, 20 M NM 10 28% less OTM with nicotine No
water; G2) OTM 1 13 mg/mL TSC water containing (P \0.01)
1 mg/mL nicotine
Toro et al,4 2013 CS 30 G1) 2-wk SC injection vehicle then OTM; G2) 2-wk SC SDR NM, 30 M 13 28 BE and alendronate reduced No
July 2016  Vol 150  Issue 1

injections 25 mg/kg BE, then OTM; G3) 2-wk SC OTM by 64% and 84%,
injections 1 mg/kg alendronate, then OTM respectively (P \0.05)
Kaipatur et al,16 CS 20 G1) OTM 1 SC injection 0.015 mg/kg alendronate; SDR 12 wk, 20 F 50 56 65% less OTM on G1/G2 No
2013 G2) OTM 1 vehicle; G3) 3-mo alendronate, then (P 5 0.05), 86% less OTM
OTM; G4) 3-mo vehicle, then OTM on G3/G4 (prior intake
bisphosphonates) (P \0.01)
Yabumoto et al,17 CS 80 G1) wild-type mice, OTM 1 saline solution; G2) wild- Mi 8 wk, 80 M NM 3 NSRD after 3 days between No
2013 type mice, OTM 1 injection of 15 mg/kg IP groups
reveromycin A; G3) OPG deficient KO mice,
OTM 1 saline solution; G4) OPG deficient KO mice,
OTM 1 15 mg/kg IP reveromycin A

39
July 2016  Vol 150  Issue 1

40
Table II. Continued

Human
clinical
Study Sample Force Time applicability
Authors, year design (n) Description of groups Species Age, sex (g) (d) Decrease in rate of OTM tested
Olyaee et al,18 2013 CS 48 G1) OTM 1 100 mg/kg/d ethinyl estradiol by WR 12 wk, 48 F 30 14 39% less OTM with estradiol No
gavage 1 1 mg/kg/d norgestrel by gavage; G2) CG and norgestrel (P \0.05)
OTM 1 saline solution
Sodagar et al,19 CS 28 G1) OTM only; G2) OTM 1 injection of 0.3 mg SDR 5 wk, 28 M 60 18 50% less OTM (P \0.01) No
2013 celecoxib
Kondo et al,20 CS NM G1) 7-d IP injections 20 mg/g propranolol (b- Mi 8 wk, M NM 5 b-antagonist decreased OTM No
2013 antagonist) then OTM; G2) 7-d IP injections 5 mg/g by 35.7%; b-agonist increased
isoproterenol (b-agonist) then OTM; G3) 7-d IP it by 14.3% (P \0.05)
injections 0.9% saline solution, then OTM
Esfahani et al,32 CS 32 G1) CG: OTM 1 saline solution; G2) OTM 1 2.5 mg/ WR 8-10 wk, 32 M 60 17 Significantly less OTM (P \0.024) No
2013 kg IP simvastatin
Yoshimatsu et al,33 CS 32 G1) no OTM or injection (CG); G2) OTM 1 0.015 mg/ Mi 8 wk, 32 M 10 12 1.5 mg/d IL-12 significantly No
2012 d IL-12; G3) OTM 1 0.15 mg/d IL-12; G4) decreases OTM (P \0.001);
OTM 1 1.5 mg/d IL-12 G5) OTM 1 PBS with lower doses, NSRD were
found
American Journal of Orthodontics and Dentofacial Orthopedics

Kohara et al,44 2012 CS NM G1) OTM 1 injections IFN-g (0.015-1.5 mg per Mi 8 wk, NM 10 12 61.4% less OTM in the group No
20 mL); G2) (CG) OTM 1 PBS treated with interferon
(P \0.05)
Hammad et al,45 CS 40 G1) CG: reverse osmosis water 1 OTM; G2) 10 mg/kg WR 12 wk, 40 M 50 60 celecoxib did not reduce OTM Yes
2012 celecoxib 1 OTM; G3) 3 mg/kg ketorolac 1 OTM; compared with ketorolac and
G4) 150 mg/kg paracetamol 1 OTM. paracetamol (P \0.01)
Meh et al,46 2011 CS 48 G1) oral saline solution; G2) OTM 1 oral saline SDR 13 wk, 48 M 25 42 cetirizine reduced OTM by 26.1% No
solution; G3) 3 mg/kg/d oral cetirizine 1 OTM (P \0.01)
Hao and Hua,34 2011 CS 72 G1) OTM 1 local injections of PBS (CG); G2, G3, G4) SDR 6 wk, 72 M 50 14 NSRD in the 0.04 mg/mL group, No
OTM and systemic injections of 0.16, 0.12, 0.08, but 40% decrease in OTM in the
and 0.04 mg/mL rhsTNF-RI. rest of the groups (P \0.01)
Gonzales et al,21 CS 50 G1) no OTM, no NaF; G2) OTM, no NaF; G3) WR NM, 50 M 50 84 74% decrease in OTM (P \0.01) Yes
2011 OTM 1 2-wk 45 ppm oral NaF; G4) OTM 1 4-wk
45 ppm oral NaF; G5) OTM 1 12-wk 45 ppm oral
NaF
Shoji et al,47 2010 CS 48 in OPG -/- mice (a model for juvenile Paget disease): Mi 8 wk, 48 M NM 3 administration of alendronate to No
G1) CG: IP saline solution 1 OTM; G2) 1.25 mg/kg/ OPG -/- mice decreased OTM

Cadenas-Perula et al
d IP alendronate 1 OTM in wild-type mice; G3) (P \0.01)
CG: IP saline solution 1 OTM; G4) 1.25 mg/kg/d IP
alendronate 1 OTM
Santos et al,10 2010 CS 120 G1) OTM 1 saline solution; G2) OTM 1 FK506; G3) WR 9 wk, 120 M 35 14 19% less OTM with tacrolimus No
FK506 only; G4) saline solution only immunosuppressant (FK506)
treatment (P \0.05)
Han et al,48 2010 CS 32 G1) 2.5 mg simvastatin per kg/d; G2) CG WR 7-8 wk, 32 M 50 49 45% less OTM (P \0.001) Yes
 American Journal of Orthodontics and Dentofacial Orthopedics

Cadenas-Perula et al
Table II. Continued

Human
clinical
Study Sample Force Time applicability
Authors, year design (n) Description of groups Species Age, sex (g) (d) Decrease in rate of OTM tested
Choi et al,3 2010 CS 54 G1) 2.5 mM/L clodronate; G2) 10 mM/L clodronate; WR 8 wk, 27 M/27 F 60 17 OTM reduced by 32% and 36.3%, Yes
G3) CG respectively (P \0.05)
Baysal et al,23 2010 CS 28 G1) no OTM; G2) OTM 1 thyroxine; G3) WR 7-8 wk, 28 M 50 14 NSRD Yes
OTM 1 doxycycline; G4) OTM only
Akhoundi et al,22 CS 40 G1) OTM; G2) OTM 1 injections 5 mg/d morphine; WR NM, 40 M 60 14 morphine reduced OTM by 52% No
2010 G3) OTM 1 5 mg/d morphine 1 20 mg/ (P \0.05)
d naltrexone; G4) OTM 1 20 mg/d naltrexone/
normal saline solution
Karras et al,11 2009 CS 50 G1) CG, OTM only; G2) OTM 1 injections of SDR NM, NM 50 35 42% less OTM in the alendronate No
alendronate sodium of 7 mg/kg body weight per group after 4 weeks (P \0.001)
week
Fujimur et al,49 2009 CS NM G1) OTM 1 local bisphosphonate; G2) OTM 1 PBS Mi 8 wk, M NM 12 50% less OTM (P \0.05) No
Sprogar et al,50 2008 CS 34 G1) no OTM 1 saline solution; G2) OTM 1 saline WR NM, 34 M 25 42 significantly less OTM (P \0.001) No
solution; G3) OTM 1 10 mg/kg IP famotidine
Kriznar et al,51 2008 CS 34 G1) no OTM 1 saline solution; G2) OTM 1 saline WR NM, 34 M 25 42 significantly less OTM (P \0.05) No
solution; G3) OTM 1 10 mg/kg IP cetirizine
Kitaura et al,52 2008 CS NM G1) OTM 1 daily injection 10 mg anti-CFms antibody; Mi 8 wk, NM 10 12 anti-CFms antibody reduces OTM No
G2) OTM 1 PBS by in 36.7% (P \0.05)
Hauber Gameiro CS 32 G1) OTM 1 IP injections celecoxib 3 d; G2) OTM 1 IP WR NM, 32 M 50 14 celecoxib decreases OTM by 30% No
et al,24 2008 injections saline 3 d; G3) OTM 1 IP injections with short-term dosage, and
celecoxib 14 d; G4) OTM 1 IP injections control 46% with long-term dosage
14 d (P \0.05)
Sprogar et al,53 2007 CS 30 G1) OTM 1 TBC3214; G2) OTM 1 placebo; G3) WR 11-12 wk, 30 M 25 40 daily TBC3214, treatment reduces No
placebo OTM by 33.3% (P \0.001)
Keles et al,15 2007 CS 51 G1) OTM; G2) Pamidronate 1 OTM; G3) OPG 1 OTM Mo 8 wk, 51 M 22,4 12 pamidronate inhibited OTM by Yes
34%, OPG by 77% (P \0.01)
Dunn et al,28 2007 CS 30 G1) OTM 1 injection PBS; G2) OTM 1 0.5 mg/kg WR NM, 30 M 54 21 OTM was inhibited by 70.6% after No
local injections recombinant OPG; G3) 14 days in higher-dose group
July 2016  Vol 150  Issue 1

OTM 1 50 mg/kg local injections recombinant (P \0.001) and by 31.8% in

OPG lower-dose group (P \0.05)
de Carlos et al,36 CS 28 G1) OTM 1 rofecoxib; G2) OTM 1 celecoxib; G3) WR 12 wk, 28 M 50 5 rofecoxib inhibits OTM (P \0.05); Yes
2007 OTM 1 Ppecoxib; G4) control NSRD between parecoxib and
celecoxib and controls
Bildt et al,54 2007 CS 18 G1) OTM 1 PBS injection; G2) OTM 1 injection 6 mg WR NM, 18 M 10 14 CMT reduced OTM by 15.7% in No
CMT-3/kg body weight; G3) OTM 1 injection 6-mg group and 34.3% in
30 mg CMT-3/kg body weight 30-mg group, respectively
(P \0.05)

41
July 2016  Vol 150  Issue 1

42
Table II. Continued

Human
clinical
Study Sample Force Time applicability
Authors, year design (n) Description of groups Species Age, sex (g) (d) Decrease in rate of OTM tested
de Carlos et al,35 CS 42 G1) OTM (50 g) 1 rofecoxib; G2) OTM WR NM, 42 M 50-100 10 Diclofenac inhibits OTM under 50 Yes
200635 (50 g) 1 diclofenac; G3) control and 100 g forces (P \0.01);
G4) G5) G6) OTM (100 g) 1 same pharmacologic rofecoxib inhibits OTM under
treatment as 1, 2, and 3 50 g force (P \0.01) and
reduces it by 73.6% under
100 g force (P \0.05)
Arias and CS 36 G1) OTM 1 100 mg/kg/d ASA; G2) OTM 1 30 mg/kg/ WR NM, 36 M 30 10 aspirin reduced OTM by 38.75% Yes
Marquez-Orozco,1 d ibuprofen; G3) OTM 1 200 mg/kg/ (P \0.05), ibuprofen by 41.52%
2006 d acetaminophen; G4) CG: OTM 1 vehicle (P \0.01); acetaminophen
did not affect OTM
J€ager et al,37 2005 CS 80 G1) OTM 1 PBS; G2) OTM 1 sIL-1-R; G3) WR 12 wk, 80 M 50 12 60% less OTM (P \0.05) No
OTM 1 sTNF-a-RI; G4) OTM 1 both
Liu et al,55 2004 CS 26 G1) OTM; G2) OTM 1 2.5 mM clodronate; G3) WR 7 wk, 26 M 12 21 56%, 65%, and 81% less OTM, No
OTM 1 10 mM clodronate; G4) OTM 1 40 mM respectively (P \0.001)
clodronate
American Journal of Orthodontics and Dentofacial Orthopedics

Gurton et al,25 2004 CS 150 G1) OTM 1 iloprost; G2) OTM 1 indomethacin; G3) SDR NM 150 M 20 5 Pg analogs increase OTM by Yes
OTM 1 U 46619; G4) OTM 1 imidazole; G5) 31.28%
OTM 1 0.9% NaCl; G6) no OTM 1 NaCl; G7) no Pg antagonists reduce OTM by
OTM or solution 20.26% (P \0.01)
Shirazi et al,26 2002 CS 48 G1) CG, no injections; G2) saline solution group; G3) SDR NM, M 60 13 50% less OTM with the L-NAME No
200 mg/kg injections of L-arg; G4) 10 mg/kg L- group (reduced nitric oxide
NAME group production led to a decrease in
OTM) (P \0.001)
Zhou et al,12 1997 CS 96 G1) OTM 1 subcutaneous indomethacin; G2) SDR 5-6 wk, 96 M 40 10 40% less OTM with indomethacin No
OTM 1 saline solution (P \0.05)
Karsten and CS 20 G1) OTM 1 phenytoin; G2) control SDR 3-5 mo, 20 F 15 42 not conclusive. No
Hellsing,27 1997
Kehoe et al,2 1996 CS 40 G1) CG: OTM 1 placebo; G2) 100 mg/kg/12-h GP 6-8 wk, 40 M 25 11 acetaminophen showed NSRD with No
misoprostol 1 OTM; G3) 200 mg/kg/12-h controls; ibuprofen reduced OTM
acetaminophen 1 OTM; G4) 30 mg/kg/12-h by approximately 22% (P \0.001)
ibuprofen 1 OTM
Igarashi et al,13 1994 CS 77 G1) systemic AHBuBP (bisphosphonate) every WR 9-10 wk, 77 M 16.8 21 40% less OTM with systemic No

Cadenas-Perula et al
24 h 1 OTM; G2) OTM only; G3) topical application, 70% less OTM with
AHBuBP 1 OTM topical administration (P \0.001)
Wong et al,56 1992 CS 11 G1) CG: OTM 1 sodium bicarbonate; G2) OTM 1 oral GP NM, NM 8 28 NSRD No
administration of 65 mg/kg/d ASA
Hellsing and CS 16 G1) OTM in pregnant rats; G2) OTM in nonpregnant SDR 3-5 mo, 16 F 15 21 52% less OTM with NaF; 39% No
Hammarstrom,57 rats; G3) nonpregnant rats 1 NaF more OTM in pregnant rats
1991 (P \0.01)
 American Journal of Orthodontics and Dentofacial Orthopedics

Cadenas-Perula et al
Table II. Continued

Human
clinical
Study Sample Force Time applicability
Authors, year design (n) Description of groups Species Age, sex (g) (d) Decrease in rate of OTM tested
Mohammed et al,14 CS 132 G1) OTM 1 leukotriene synthesis inhibitor; G2) SDR NM, NM 60 14 29.8% less OTM with AA861 No
1989 OTM 1 indomethacin; G3) OTM; G4) OTM 1 both combined with indomethacin;
groups 36.2% less OTM with
indomethacin only (P \0.05)
Chumbley and CS 12 G1) OTM (CG); G2) OTM 1 oral administration of C 12-18 mo, NM 250 21 indomethacin group achieved No
Tuncay,30 1986 5 mg/kg/d indomethacin approximately 50% less than
the CG (P \0.01)
Sandy and Harris,58 CS 14 G1) CG (OTM 1 vehicle of MC; G2) R NM 7 F/7 M 100 14 NSRD No
1984 OTM 1 flurbiprofen
Gene therapy
Kanzaki et al,7 2004 CS 20 G1) CG, no OTM CG; G2) OTM 1 PBS; G3) WR 6 wk, 20 M 17 20 92.8% less OTM (P \0.001) Yes
OTM 1 injections of OPG gene transfer
Low-level laser therapy
Kim et al,59 2015 CS 10 G1) CG: OTM alone; G2) OTM into the grafted D 18-24 mo, 10 M 100 42 LLLT decreased OTM into the Yes
defects; G3) OTM into the grafted defects 1 LLLT. bone-grafted surgical defects
(P \0.01)
Kim et al,5 2009 CS 12 G1) CG OTM only; G2) OTM 1 CO; G3) OTM 1 LLLT; D 84 wk, 12 M 150 56 LLLT after CO decreases OTM No
G4) OTM 1 CO 1 LLLT 48.4% (P \0.001)
Seifi et al,6 2007 CS 18 G1) CG; G2) LLLT (850 nm); G3) LLLT (630 nm) R 16 wk, 18 M 10-120 16 Pulsed and continuous LLLT No
reduced OTM by 40.6% and
50.6% (P \0.001)

AHBuBP, 4-amino-l-hydroxybutylidene-1,1 bisphosphonate; anti-CFms, anti-mouse c-Fms antibody; ASA, acetylsalicylic acid; BE, Bis-enoxacin; CG, control group; CMT, chemically modified
tetracycline; CO, corticotomy; CS, comparative study; D, dogs; DMF, dimethylformamide; F, female; FK506, immunosuppressant FK506 (tacrolimus); EGCG, epigallocatechin gallate; G, group;
GP, guinea pigs; IFN-g, recombinant mouse interferon; IL-12, interleukin 12; IP, intraperitoneal; KO, knockout; L-arg, L-arginine: LLLT, low-level laser therapy; M, male; MC, methylcellulose;
Mi, mice; Mo, monkeys; NaF, sodium fluoride; NM, not mentioned; Nrf2, nuclear factor E2-related factor 2; NSRD, no statistically relevant differences; OPG, osteoprotegerin; PBS, phosphate buff-
ered saline solution; rhsTNF-RI, recombinant human soluble tumor necrosis factor receptor type I; R, rabbits; sIL-1-R, soluble interleukin 1 receptor; s-TNF-a RI, soluble tumor necrosis factor-alpha
receptor; SC, subcutaneous, SDR, Sprague-Dawley rats; SFN, sulforaphane; TBC3214, a selective endothelin ETA receptor antagonist; U46619, thromboxane A2 analog; WR, Wistar rats.
July 2016  Vol 150  Issue 1

43
44
in 70% less OTM when it was applied topically and 40%
less after systemic use (P \0.001).13
Fluoride intake reduced OTM by 74% (P \0.01)21
and 52% (P \0.01)57 (from medium-quality and high-
quality studies, respectively). The effect of hormone
therapy on OTM was studied in 2 high-quality
studies.18,23 The first reported 39% less OTM
(P \0.05) using estradiol and norgestrel,18 whereas
the second found no significant differences using L-
thyroxine and doxycycline in rats.23 As described in a
high-quality study, a low dose of the beta blocker pro-
pranolol (0.1 mg/kg) reduced OTM by 41%, but a higher
dose did not (P \0.05) (Table II).29
Han et al48 and Esfahani et al32 found, in studies as-
sessed as medium quality, that simvastatin significantly
reduced OTM, by 45% in the study of Han et al
(P \0.001). In a similar medium-quality study,
Akhoundi et al22 (P \0.05) studied the effect of
morphine on OTM in rats and found a 52% reduction,
which did not occur when another opioid, naltrexone,
was used. In orthodontically treated animals, chronic
use of antihistamines, especially cetirizine (P \0.05)
(P \0.01)46,51 and famotidine (P \0.001),50 was re-
ported in a medium-quality study as having the poten-
tial to reduce tooth movement by decreasing
inflammation, whereas in a high-quality study the
immunosuppressant FK506 reduced OTM by 19%
(P\0.05).10 Chemically modified tetracycline was found
to decrease OTM by 15.7% (in the 6-mg group) and by
34.3% (in the 30-mg group) (P \0.05), as described in
a high-quality study.54 In their high-quality study, Shir-
azi et al26 reported that a 50% decrease in OTM
(P \0.001) could be produced using an inhibitor of ni-
tric oxide synthase.
A different set of methods for inhibiting OTM, the use
of gene therapy in orthodontics, was successfully tested
on rat models by Kanzaki et al,7 who observed, in their
high-quality study, an inhibitory effect on OTM
(98.2% less OTM; P \0.001) when OPG was overex-
pressed locally in the paradental region (Table II).
With respect to low-level laser therapy, Seifi et al6
found 40.6% and 50.6% (P \0.001) reductions in
OTM in rabbits using pulsed (850 nm) laser and contin-
uous (630 nm) wave low-level laser therapy, respec-
tively, and Kim et al5 discovered that although
separate use of laser and corticision stimulated an in-
crease in the rate of OTM, the 2 procedures in combi-
nation significantly reduced it because of the reparative
effect of low-level laser therapy on the tissues, produc-
ing a 48.4% decrease in OTM after corticotomy
(P \0.001) (Table II); both studies had medium meth-
odologic quality. In a more recent high-quality study,
Kim et al59 found a decrease of OTM when low-level
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Cadenas-Perula et al
laser therapy was applied to bone-grafted surgical de-
fects (P \0.01) (Table I)
DISCUSSION
Changes in OTM rates
When the experimental objective was to slow down
or inhibit OTM completely, pharmacologic modulation
was the most frequently described method in the scien-
tific literature that we selected (53 of 57 articles).
Changes in the rate of decrease of OTM varied from
86% (P \0.01)16 to 15.7% (P \0.05)54 in studies of
high methodologic quality. The observed differences
may not have derived exclusively from the substance
evaluated, even when the same animals or similar types
of force were used. At the same time, the observational
periods—ranging from 3 days17 to 12 weeks in studies
of medium methodologic quality21—also varied (Table
II). The different kinds of substances tested, even when
they were chemically similar or tested on the same spe-
cies, were also administered in quite different dosages.
Magnitude and type of force
Other factors that could affect differences in the
tooth movement rate are the type of appliance chosen
to exert the orthodontic force and the amount of force
used. Although these are key features of tooth move-
ment studies, there is little reflection of them in the or-
thodontic literature.61 In the study of biologic reactions
to OTM, molecular or tissue responses vary considerably
depending on the method used to move the teeth.
Because orthodontic devices apply forces of quite
different magnitudes, both constant and intermittent,
and in a mesiodistal or buccopalatal direction, experi-
ments performed with different force application proto-
cols would not be expected to show the same tissue
reactions.
The most commonly used appliance in the studies
included in this review was the nickel-titanium closed-
coil spring, although other springs of different materials
were also used, as well as elastics, whose force decay was
rarely quantified or taken into account. With coil springs,
the direction and magnitude of the force cannot always
be controlled because, owing to force decay, it may not
remain constant during the experiment. In water, elastics
show force decay from about 45 N to almost 0 N within
the first 0.2 mm of decompression.61 Another critical
point is that the direction of the force can also vary.
As shown in Table II, the range of forces used in the
studies varied considerably. A low force is suggested as
optimal in orthodontics,61 although even in the same
species (rats), the forces ranged from 10 g33,44,52,54 to
100 g35,58 in the included studies. In this species, the
Cadenas-Perula et al
preferred magnitude for moving 3 ferulized molars has
been suggested as a force of 10 g62; even forces less
than 20 g per molar might be considered excessive for
evaluating alveolar bone reactions to tooth movement
because different behaviors are observed under different
degrees of force.63
Furthermore, at least 2 main physiologic characteris-
tics of the rat model prejudice some findings in the
studies. The continuous eruption of the incisors makes
the incisor a variable anchorage point, and so the force
direction systematically varies during the experiment.62
The second point is that when the force is applied in a
mesial direction, the physiologic distal drift in rat molars
may lead to misinterpretation of the histologic, immu-
nohistochemical, radiologic, and even clinical results of
tooth movement, since physiologic bone resorption
can interfere with tissue changes observed on the so-
called tension side.62
Biologic mechanisms for inhibiting tooth movement
and cellular reactions
Most of the methods of inhibiting OTM, especially
chemical substances, were investigated for creating dif-
ferential anchorage, preventing relapses, or solving
orthodontically induced root resorption, as well as ex-
tending the knowledge of which drugs commonly taken
by patients can slow or influence OTM, so that the prac-
titioner is aware of them.
With respect to pharmacologic administration,
several substances, from hormones to cytokines, have
been associated with inhibiting or reducing OTM in a
way that depends on the bone-remodeling rate. Inhibi-
tors such as bisphosphonates, for example, are thought
to affect bone physiology directly by reducing both oste-
oclast numbers and their activity, as described in high
methodologic quality studies.16,64
Bisphosphonates are nonhydrolysable analogs of
inorganic pyrophosphate widely used to treat osteopo-
rosis and other bone diseases; they act by selective
adherence to bone mineral surfaces, inhibiting the activ-
ity of osteoclasts and so preventing bone resorption.65
Non–nitrogen-containing bisphosphonates (eg, clodro-
nate) form a nonfunctional molecule that competes
with adenosine triphosphate in cellular energy meta-
bolism, leading to osteoclast apoptosis. Independently
of their composition, bisphosphonates have been
reported in the literature as provoking a general dose-
dependent decrease in the rate of OTM. Nitrogen-
containing bisphosphonates (eg, alendronate) show
greater antiresorptive potency because of their ability
to interrupt the prenylation of guanidine triphospha-
tases in the cell, thus interfering with osteoclast survival
and function.66
American Journal of Orthodontics and Dentofacial Orthopedics
45
NSAIDs and COX-2 inhibitors were another large
group studied.1,2,12,19,24,25,30,35,36,38,45,58,67 These are
commonly used analgesics, whose anti-inflammatory
effect is due to the inhibition of prostaglandin (PG) syn-
thesis that acts on the cyclooxygenase involved in the
catabolism of arachidonic acid stored in the cell mem-
brane.68 It has been suggested in studies rated as me-
dium methodologic quality that prostaglandins may
mediate the osteoclastic response during bone resorp-
tion, therefore having an effect on OTM.30,58 In the
studies included, acetaminophen showed no effect on
OTM,1,2 which can be attributed to the fact that it
belongs to the family of paraminophenols, weak
suppressors of PG1 and COX-2 in studies with similar
medium quality.2 The rest of the NSAIDs studied (indo-
methacin,12,25,30 acetylsalicylic acid,1,38,56 and
1,2,58
ibuprofen ) seem to have a dose-dependent effect
on OTM, except for diclofenac, which inhibited it
completely, as shown in a high-quality study.35
de Carlos et al36 proposed COX-2 inhibitors as a
better alternative than NSAIDs for chronic inflamma-
tory conditions. However, in all the substances tested,
only parecoxib seemed not to affect OTM. Celecoxib
and rofecoxib significantly decreased the rate of
OTM in 3 studies,19,24,36 although 1 article reported
a greater OTM decrease with paracetamol and
ketorolac.45 The authors of 2 studies looked for
diminished numbers of osteoclasts,19,24 although
significant differences were found in only 1 study
(P \0.05).19
Studies testing the expression of biologic proteins in
key molecular factors linked to the involvement and acti-
vation of osteoclasts show the decisive role of biologic
modulation in OTM. Gene therapy illustrates this fact
once more: OPG gene transfer carried out by Kanzaki
et al7 led to the inhibition of OTM (P \0.001). This
was achieved by injecting a hemagglutinating virus of
Japan (HVJ)-envelope vector containing a mouse OPG
plasmid into the gingiva. Previous studies along the
same lines achieved significant acceleration of OTM by
RANKL gene transfer with the same method.69,70 When
it comes to the biologic substrate of low-level laser ther-
apy, it has been suggested in the literature that, far from
decreasing OTM, low-level laser therapy could accelerate
it by stimulating alveolar bone remodeling via RANKL
and the c-fms/macrophage colony-stimulating factor
system.71 However, there is a lack of solid clinical evi-
dence,72 and the results are sometimes contradictory
when compared with those in this review.5,6,59
Derived side effects
Derived side effects should be a required field of in-
terest when evaluating experimental therapies directed
July 2016  Vol 150  Issue 1
46
at the clinical setting from the laboratory bench. There is
no clear overview of which side effects might be evalu-
ated to analyze the viability of such experimental thera-
pies. Most selected studies included a more or less
exhaustive analysis of indirect observed findings
(Table II). In these studies and the general literature,
experimental laser techniques are described as having a
beneficial effect on pain relief,73 soft tissue repair,74
and pulp healing,75 although there have been no long-
term evaluations that allow us to conclude that these
are the side effects of a maintained treatment. Pharma-
cologic or chemical acceleration of OTM has been asso-
ciated with undesirable secondary effects that should be
particularly considered with substances used systemi-
cally, such as hormones.
Slowing down tooth movement by administering
chemicals such as sodium fluoride, clodronate, simva-
statin, or NSAIDS has been described as causing a reduc-
tion in the parameters of root resorption in the rat
model,1,3,21,48 independent of the range of forces
used—from 10 g33,34,52,54 to 100 g35,58—and even over
substantially different periods of observation, from 317
to 84 days.21
Pain relief is one of the most important effects of
using substances such as ibuprofen,2 acetylsalicylic
acid,1 or diclofenac,35 whose inhibitory action on
OTM has been confirmed. In this respect, after the
studies on animals, acetaminophen has been proposed
as the most effective painkiller when it comes to its ef-
fect on OTM.
CONCLUDING REMARKS AND FUTURE
PERSPECTIVES
Although individual conclusions can be inferred from
every study, few strictly evidence-based conclusions
about the inhibition of OTM can be extrapolated from
experimental animal-based studies to the clinical field.
There is a need for evidence-based orthodontics with
greater translational potential, conducted in well-
designed experimental studies. Even though some excel-
lent hypotheses can be tested in the laboratory, there are
few high-quality studies whose intention is anything
more than the first step of the translational purpose.
No homogeneity was found on essential topics, such
as the observation time required, the type and magni-
tude of force required for different animal models, the
types of appliance used, the battery of laboratory probes,
and the side effects needed to evaluate them, among
others. There is an urgent need for international
consensus and for standards laid down by a panel of
the many highly regarded experts in the field to create
guidelines that will serve as points of reference for all
researchers.
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Cadenas-Perula et al
Experiments regarding chemical methods have
tended to focus more on preventing analgesic interfer-
ence during OTM, although this should be studied in
greater depth. Since orthodontic treatment is increas-
ingly reaching the middle-aged group of patients, we
should be cautious about pharmacologic interference,
and bearing in mind the results of the studies, patients
should be warned of the possibility of slower OTM or
even inhibition, as with bisphosphonate-treated pa-
tients. There were fewer side effects with these therapies;
in the short term, more clinical bench applications
should be obtained. Biologic therapies concentrating
on the inhibition of OTM should be directed toward
the major regulators of OTM, as was recently proposed
for gene therapy, to modulate OTM selectively and
effectively.
SUPPLEMENTARY DATA
Supplementary data related to this article can be
found at http://dx.doi.org/10.1016/j.ajodo.2016.01.
015.
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