archives of oral biology 60 (2015) 347356

Available online at www.sciencedirect.com

ScienceDirect

journal homepage: http://www.elsevier.com/locate/aob

Review

Influence of orthodontic forces on human dental

pulp: A systematic review

Fawad Javed a, AbdulAziz A. Al-Kheraif b, Enisa B. Romanos a,

Georgios E. Romanos c,*
a
Division of General Dentistry, Eastman Institute for Oral Health, University of Rochester, Rochester, NY, USA.
b
Research Chair for Dental Biomaterials, Dental Health Department, College of Applied Medical Sciences, King Saud
University, Riyadh 11541, Saudi Arabia
c
Department of Periodontology, School of Dental Medicine, Stony Brook University, Stony Brook, NY, USA

article info abstract

Article history: Aim: The aim of the present study was to systematically review the influence of orthodontic
Accepted 17 November 2014 force on human dental pulp.
Methods and results: The addressed focused question was Do orthodontic forces affect the
Keywords: human dental pulp? which was based on the Preferred Reporting Items for Systematic
Dental pulp Reviews and Meta-Analyses (PRISMA) guidelines, a specific question was constructed
Growth factors according to the PICO (Participants, Interventions, Control, Outcomes) principle. Databases
Orthodontic force were explored from 1952 up to and including August 2014 using different combinations of
Pulpal blood flow the following keywords: orthodontic force; dental pulp; reaction and tooth move-
ment. Literature reviews, letters to the editor, commentaries and case-reports were
excluded. Thirty studies were included. Six studies assessed the effect of orthodontic forces
on pulpal blood flow and 20 studies investigated the pulpal cellular responses to orthodontic
forces. In 4 studies, pulpal responses to orthodontic forces were compared between
previously traumatized- and non-traumatized teeth.
Conclusions: There is insufficient scientific validation regarding the association between
orthodontic forces and human dental pulp. However, a history of dental trauma maybe
considered a risk factor for loss of pulp vitality during orthodontic treatment.
# 2014 Elsevier Ltd. All rights reserved.

Contents

1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 348
2. Materials and methods . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 348
2.1. Focused question. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 348
2.2. Search protocol . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 348

* Corresponding author. Tel.: +1 631 632 8755.

E-mail address: Georgios.Romanos@stonybrookmedicine.edu (G.E. Romanos).
http://dx.doi.org/10.1016/j.archoralbio.2014.11.011
00039969/# 2014 Elsevier Ltd. All rights reserved.
348 archives of oral biology 60 (2015) 347356

2.3. Quality assessment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 349

2.4. Level of evidence . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 349
3. Results . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 350
3.1. Effect of orthodontic forces on pulpal blood flow. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 350
3.2. Influence of orthodontic forces on the cellular responses of the human dental pulp . . . . . . . . . . . . . . . . . . . . 350
3.3. Influence of orthodontic forces on the pulpal response in traumatized teeth. . . . . . . . . . . . . . . . . . . . . . . . . . 350
3.4. Quality assessment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 350
4. Discussion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 350
5. Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 355
Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 355
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 355

1. Introduction 2. Materials and methods

Application of orthodontic forces to teeth for specific time
periods has been reported to induce molecular changes in the
cells of the periodontal ligament, alveolar bone and the pulp
dentine complex.17 Histologic studies have reported depres-
sion of pulp tissue respiration, vacuolization, circulatory
disturbances, haemorrhage, fibro-hyalinosis and even necro-
sis as the major pulpal changes that may be encountered
following the application of orthodontic forces to teeth.1,2,4
Hamersky et al.7 suggested that excessive and prolonged
orthodontic forces when applied to teeth may result in loss of
pulp vitality.
Laser Doppler flowmetry (LDF) by McDonald and Pitt Ford8
have reported a temporary decrease in pulpal blood flow (PBF).
The decrease in PBF has been associated with a drop in the
oxygen tension thereby increasing the possibility of cellular
injury and apoptosis as determined by alterations in the
expression of pulpal markers such as Aspartate Aminotrans-
ferase (AST) and alkaline phosphatase (ALP).911 However,
results by Barwick and Ramsay12 and Brodin et al.13 reported
no significant effect of a orthodontic forces (intrusive and/or
extrusive) on PBF. Studies5,1416 have also reported that
application of orthodontic forces on teeth for certain periods
of time increase the expression of various growth factors (GFs),
such as epidermal growth factor (EGF), platelet derived growth
factor (PDGF), vascular endothelial growth factor (VEGF),
fibroblast growth factor-2 (FGF-2) and transforming growth
factor beta (TGF-b) in pulpal tissues, which in turn contribute
to angiogenesis.
High levels of inflammatory mediators, such as interleu-
kin (IL)-6, IL-1b tumour necrosis factor alpha and receptor
activator of nuclear factor kappa B have been identified in
pulpal tissues of teeth exposed to orthodontic forces.17,18
Levels of inflammatory mediators in the gingival crevicular
fluid have also been reported to be significantly elevated
during orthodontic therapy.19,20 Therefore, from a clinical
perspective, it is hypothesized that long-term application of
orthodontic forces jeopardizes pulp vitality. Furthermore,
pulpal necrosis (PN) has also been reported after the
induction of orthodontic forces such as intrusion, extrusion
and retraction.8,21 It is tempting to speculate that the
magnitude of pulpal inflammation or injury is directly
proportional to the degree of orthodontic force applied on
the teeth.
The aim of the present study was to systematically review
the influence of orthodontic force on human dental pulp.
2.1. Focused question
Based on the Preferred Reporting Items for Systematic Reviews
and Meta-Analyses (PRISMA) guidelines, a specific question
was constructed according to the PICO (Participants, Inter-
ventions, Control, Outcomes) principle.22 The addressed
focused question was Do orthodontic forces affect human
dental pulp?
(P) Participants: It was essential for participants to have
undergone orthodontic treatment.
(I) Types of interventions: The interventions of interest
were orthodontic forces (such as intrusion, extrusion, tipping,
arch expansion and retraction).
(C) Control intervention: Teeth, which were either not
subjected to orthodontic forces or pulp tissues which treated
with antibodies other than those used in the test-groups, were
considered as controls.
(O) Outcome measures: Human pulpal response to ortho-
dontic forces.
2.2. Search protocol
In order to identify studies relevant to the PICO question, the
MEDLINE (OVID) database, the EMBASE database, the
Cochrane Central Register of Controlled Trials (CENTRAL),
Scopus, Web of Knowledge, The Cumulative Index to Nursing
and Allied Health Literature and Google-Scholar databases
were electronically searched for available data. Databases
were searched from 1954 up to and including August 2014
using different combinations of the following key words:
orthodontic force; human dental pulp; reaction and
tooth movement. Titles and abstracts of studies identified
using the above-described protocol were screened by two
authors (FJ AAK and GER) and checked for agreement. Full-
texts of studies judged by title and abstract to be relevant were
read by authors (FJ AAK and GER) and independently evaluated
in accordance with the following eligibility criteria: clinical
studies, application of orthodontic force on teeth and
assessment of pulp tissues. Kappa scores (Cohens kappa
coefficient) were employed to determine the level of agree-
ment between the two reviewers.23,24 Letters to the Editor,
historic reviews, commentaries, experimental (animal) stud-
ies and case-reports were excluded. Hand-searching of
potentially relevant original and review articles was also
performed. This was done to identify any studies that could
 archives of oral biology 60 (2015) 347356 349

Records identified Records Records Records Records identified Records identified

Identification
through identified identified identified through Cochrane through Google-
MEDLINE through PubMed through through Web of Central Register Scholar
(OVID) CENTRAL CINAHL Knowledge
(n=44) (n=78) (n=0) (n=98) (n=2) (n=79)

Total number of records

(n = 301)
Screening

Records screened Records excluded

(n = 105 ) (n = 60 )
Eligibility

Full-text articles assessed Full-text articles excluded,

for eligibility with reasons
(n = 45 ) (n = 15 )
Included

Studies included in
qualitative synthesis
(n = 30 )

Fig. 1 Literature search strategy according to the PRISMA guidelines (www.prisma-statement.org).

have remained unidentified in the previous step and checked
for disagreement via discussion among the authors. Articles
available online in electronic form ahead of print were
considered eligible for inclusion. Fig. 1 summarizes the
literature search strategy according to the PRISMA guidelines.
The pattern of the present systematic review was customized
to mainly summarize the relevant data.
end points; and diagnostic reliability tests and reproducibil-
ity tests described (all criteria should be met; otherwise,
grade C).
 Grade C (Low)One or more of the following settings are
encountered: poorly defined patient material, unclear
diagnosis and end points and large attrition of the
samples.

2.3. Quality assessment 2.4. Level of evidence

Three authors (FJ, AAK and GER) independently assessed the
methodological quality of the included studies according to a
grading system developed by the Swedish Council on
Technology Assessment in Health Care.25 The following
criteria were used for assessing the methodological quality
of the studies included in the present review:
 Grade A (High)A randomized controlled trial or prospec-
tive study, composed of a well-defined control group;
defined diagnosis and end points; diagnostic reliability tests
and reproducibility tests described; and blinded outcome
measurements (all criteria should be met).
 Grade B (Moderate)A cohort study or retrospective study,
composed of a defined control group; defined diagnosis and
For each study included in the present review, level of
evidence was judged in accordance with the following scale26:
 Strong Scientific Support (Evidence Grade 1)Conclusion is
based on at least 2 studies with level A-evidence. Studies
with opposite conclusions may lower the evidence grade.
 Moderately Strong Support (Evidence Grade 2)Conclusion
is based on 1 study with strong evidence (A) and at least 2
with moderately strong evidence (B). Studies with opposite
conclusions may lower the evidence grade.
 Limited Scientific Support (Evidence Grade 3)Conclusion is
based on at least 2 studies with moderately strong evidence
(B). If studies contradicting the conclusion exist, the
scientific basis is judged as contradictory or insufficient.
350 archives of oral biology 60 (2015) 347356
 Inconclusive Scientific Support (Evidence Grade 4)If
studies fulfilling the evidence criteria are lacking, the
scientific basis for conclusion is considered insufficient.
3. Results
3.1. Effect of orthodontic forces on pulpal blood flow
4,8,12,13,27,28
Six studies addressed the effect of orthodontic
forces on PBF (Table 1). The numbers of study participants
ranged between 6 and 21 patients. In 5 studies,4,8,12,13,28
orthodontic forces were applied to achieve extrusion, intru-
sion and retraction of premolar teeth; whereas in the study by
Babacan et al.,27 rapid maxillary expansion (RME) was
performed. Five studies4,8,12,13,28 reported the orthodontic
force applied to teeth which ranged between 0.5 Newton (N)
and 44 N. In one study27 the amount of orthodontic force
applied to perform RME was not reported. In these stud-
ies,4,8,12,13,27,28 the duration for which orthodontic forces were
applied ranged between 20 s and 152 days. Three studies4,13,28
reported that intrusive orthodontic forces temporarily reduce
PBF; and in the study by Barwick and Ramsay12 PBF remained
unaltered during all orthodontic treatment sessions. In the
study by Babacan et al.,27 PBF increased in the first week of
RME and decreased significantly by the third week of RME.
3.2. Influence of orthodontic forces on the cellular
responses of the human dental pulp
Twenty studies1,5,7,9,11,1416,21,2937 reported the influence of
orthodontic forces on human pulpal cellular responses
(Table 2). In 18 studies,13,5,7,9,11,1416,21,2932,34,36,37 orthodontic
forces were applied on premolars and in 2 studies33,35 teeth
exposed to orthodontic forces were not reported. The
magnitude of orthodontic force ranged between 0.3 N and
6 N for durations ranging between 21 min and 84 days.
Intrusion, extrusion and tipping movements were performed
in 8,1,11,30,31,3437 83,5,7,14,16,21,29,33 and 39,15,32 studies, respec-
tively. In one study,2 both intrusion and extrusion forces were
applied on premolars. Results by Lazzaretti et al.37 showed
that intrusive orthodontic forces caused vascular changes in
the pulpal tissue and also increased the presence of fibrosis
and the number of pulp calcifications. Four studies1,2,21,36
reported orthodontic forces to cause vacuolization and
disruption of osteoblasts in pulpal tissues but without
necrosis. Results by Caviedes-Bucheli et al.3 reported ortho-
dontic forces of 0.56 N and 2.24 N to increase the pulpal
expression of calcitonin gene-related peptide (CGRP) as
compared to the control group. Three studies5,14,16 reported
orthodontic forces to increase the expression of GFs in pulpal
tissues. Perinetti et al.9 and Veberiene et al.11 reported
orthodontic forces to increase pulpal AST activity. In one
study,34 pulpal AST levels were comparable with and without
mechanical load application. Kucukkeles and Okar31 showed
vascular degeneration in the pulps of orthodontically treated
teeth; Derringer et al.15 reported angiogenesis to be signifi-
cantly higher in orthodontically-treated teeth and control
teeth. In 4 studies,30,33,35,36 orthodontic forces were reported to
cause minor disturbances in pulpal circulation. Concentration
of substance P was negatively correlated with the magnitude
of orthodontic force in the study by Parris et al.32 and Subay
et al.29 reported no evidence of inflammatory reactions in the
pulps of orthodontically-moved teeth (Table 2).
3.3. Influence of orthodontic forces on the pulpal response
in traumatized teeth
Four studies3841 investigated the pulpal reaction of orthodon-
tic forces on traumatized teeth. Two studies38,40 reported the
magnitude of orthodontic force applied on traumatized teeth,
which were 0.2 N and 0.15 N. In these studies,3841 duration of
orthodontic treatment in previously traumatized teeth ranged
between 22.4 and 54 months. All studies3841 reported PN to be
more frequent when orthodontic treatment was performed in
previously traumatized teeth as compared to non-trauma-
tized teeth (Table 3).
3.4. Quality assessment
Most of the studies were graded as moderate to low mainly
because of their methodological quality (Tables 13). Low
grading was mainly based on no randomized assignment to
experimental and control treatment groups and no descrip-
tion of reliability tests.
4. Discussion
Since grading evidence is a complicated issue, we avoided
using a scale that allocates points to individual quality items
because this approach has proved to be inadequate.42 To our
knowledge from indexed literature, a gold standard quality
assessment tool is still missing.43,44 Lack of randomized
controlled trials and a disharmony in the study protocols
are limitations of the studies included in this review. These
factors may be held responsible for the moderate to low
grading of most studies included in this review.
In a systematic review published in the year 2012, von Bohl
et al.,45 reported that there is no conclusive scientific evidence
for a relation between force level and dental pulp tissue
reaction in humans. Authors of this systematic review
emphasized that there is a scarcity of long-term results
regarding pulpal injury occurring as a result of orthodontic
treatment.45 Since there is a debate among clinicians regard-
ing the optimal orthodontic forces that teeth can endure
without experiencing massive pulpal inflammation and/or
necrosis, we were tempted to re-search indexed literature to
identify additional studies (published after the year 2012) that
assessed the association between orthodontic force and its
effects on human dental pulp tissues. Moreover, in the
systematic review by von Bohl et al.45 the effect of orthodontic
forces on human dental pulp were assessed in non-trauma-
tized teeth only; however, in the present systematic review,
we reviewed pertinent literature regarding the influence of
orthodontic forces on human dental pulp tissues of non-
traumatized and traumatized teeth.
In the present study, a systematic review of pertinent
literature was performed in an attempt to assess the effect of
orthodontic forces on dental pulp tissues. It was hypothesized
that long-term application of orthodontic forces jeopardizes
Table 1 Studies on the effect of orthodontic forces on pulpal blood flow.
Authors et al. Design Study Type of Control Force Duration Pulpal blood flow Results Quality grade
subjects treatment group applied (N) of force measured by
Sano et al.4,*

archives of oral biology 60 (2015) 347356

Prospective 13 Intrusion 13 vital teeth 0.5, 1, 2 14 days LDF Intrusive forces temporarily B
without reduced PBF. PBF changes
orthodontic force returned to normal at the
application end of force application
McDonald and Prospective 10 Canine 10 vital teeth 0.5 Up to 4 days LDF PBF increased up to 48 h of B
Pitt Ford8,* retraction without load application but returned
orthodontic force to preload values within 72 h
application
Barwick and Prospective 8 Intrusion None 0.75, 1.25, 112 days LDF Baseline PBF remained A
Ramsay12,y 5, 44 unchanged during all
treatment sessions
Brodin et al.13,y Prospective 6 Intrusion and None 0.5 152 days LDF Extrusion had no significant C
extrusion effect on PBF. Intrusion
reduced the pulpal blood flow
by 20% during the first minute
only
Babacan et al.27,y Prospective 21 RME None NR Up to LDF PBF increased in the 1st week B
84 days and decreased significantly by
the 3rd week of RME
Ikawa et al.28,* Prospective 17 Intrusion None 0.5, 1, 5 20 s LDF Brief intrusive forces B
temporarily reduced PBF
LDF, laser Doppler flowmetry; NR, not reported; OT, orthodontic treatment; PBF, pulpal blood flow; RME, rapid maxillary expansion.
*
High risk of bias.
y
Low risk of bias.

351
 352
Table 2 Studies on the influence of orthodontic forces on the cellular responses of the dental pulp.
Authors et al. Design Subjects Number Type of Force Control Duration Pulpal response Conclusion Quality
of teeth movement applied group of force grade
(N)
Lazzaretti Prospective 17 34 Intrusion 0.58 No orthodontic 21 days There was a significant Intrusive orthodontic forces B
et al.37,y force applied increase in the number of caused vascular changes in
pulpal nodules in the the pulpal tissue and also
elements with no difference in increased the presence of
the number of blood vessels fibrosis and the number of
between the groups pulp calcifications
Han et al.1,y Prospective 27 54 Intrusion 0.5, 3 No orthodontic Up to In both force groups, Intrusive orthodontic forces C
force applied 84 days odontoblasts disruption, do not jeopardize pulp
vacuolization and moderate vitality
vascular congestion

archives of oral biology 60 (2015) 347356

occurred but without PN
Ramazanza-deh Prospective 26 52 Intrusion and 0.25, 0.74 No orthodontic Up to In both force groups, Histologic pulpal changes C
et al.2,* extrusion force applied 21 days odontoblasts disruption, between baseline and 21 days
vacuolization and moderate showed no statistically
vascular congestion significant difference
occurred but without PN
Caviedes-Bucheli Prospective NR 30 Extrusion 0.56, 2.24 No orthodontic 1 day In both force groups, pulpal Orthodontic forces increase C
et al.3,* force applied CGRP expression was CGRP expression in human
increased compared to the dental pulp
control group
Derringer and Prospective 20 80 Extrusion 0.51 Use of antibodies 14 days VEGF, FGF-2, PDGF and Growth factors are C
Linden5,* (In vitro) other than those TGF-b are released expressed in the pulp of
for VEGF, FGF2 following orthodontic force teeth exposed to
and TGFbeta application mechanical load
Hamersky et al.7,* Prospective 17 68 Extrusion At least No orthodontic 3 days Short-term orthodontic forces Orthodontic forces cause C
0.6 N force applied caused pulpal tissue hypoxia biochemical and biologic
pulpal tissue alterations
Perinetti et al.9,* Prospective 17 17 Tipping 0.30.9 No orthodontic 7 days Mean AST activity and EPT Application of mechanical B
force applied values were significantly load to teeth can cause
higher in teeth exposed to metabolic changes in the
mechanical load compared to pulp
controls
Veberiene Prospective 21 42 Intrusion 0.61 No orthodontic 7 days Mean AST activity and EPT Application of mechanical A
et al.11,* force applied values were significantly load to teeth can cause
higher in teeth exposed to metabolic changes in the
mechanical load compared pulp
to controls
Derringer and Prospective 10 10 Extrusion 0.51 Co-cultures 14 days Orthodontic forces EGF released following B
Linden14,y (In vitro) without anti-h stimulate the release of EGF orthodontic force
EGF in pulp tissues application plays a role in
pulpal angiogenic response
Derringer et al.15,* Prospective NR 30 Tipping 0.51 No orthodontic 5 days There were significantly Growth factors are expressed B
force applied greater numbers of micro- in the pulp of teeth exposed
vessels in orthodontically to mechanical load
treated teeth than control teeth
Derringer and Prospective 18 18 Extrusion 0.51 No orthodontic 14 days VEGF, FGF-2, PDGF and TGF-b Growth factors play a role in B
Linden16,y force applied are released following pulpal angiogenesis
orthodontic force application
Mostafa et al.21,y Prospective 18 36 Extrusion 0.5 No orthodontic Up to 28 Dilated and constricted blood Orthodontic forces can cause B
force applied days vessels, odontoblastic temporary inflammation and
degeneration, vacuolization fibrosis in pulpal tissues
and oedema of the pulp tissues,
and fibrotic changes occurred
in pulpal tissues
Subay et al.29,y Prospective 15 40 Extrusion 0.75 No control group 10 days, There was no evidence of in- Extrusive forces do not cause C
(All teeth were ex- 40 days flammatory reactions and/or significant pathological
truded) reparative dentine formation changes in pulp tissues

archives of oral biology 60 (2015) 347356

in all teeth
Raiden et al.30,y Prospective 20 40 Intrusion 1.5 No orthodontic 1520 Histologic results showed Intrusive forces can cause C
force applied days alterations in predentine, congestion, haemorrhage and
calcium deposition, fibrohyalinosis in the pulp
fibrohyalinosis, congestion, tissues
inflammation and
haemorrhage
Kucukkeles Prospective 2 4 Intrusion 1.5 No orthodontic 90 days Vascular degeneration Intrusive forces jeopardize C
and Okar31,y force applied occurred in the pulps of pulp vitality by causing
orthodontically-treated teeth. vascular degeneration.
Parris et al.32,* Prospective 20 80 Tipping 1.2, 1.4, 1.5, No orthodontic 2178 min Concentrations of ir-ME and Orthodontic forces and B
1.8, 2, 2.1, force applied ir-SP each correlated negatively pulpal ir-ME and ir-SP
2.15, 2.3, 2.45 with the magnitude of the concentrations are
and 6 orthodontic force interlinked

Stenvik33,y Prospective NR NR Extrusion 12 No orthodontic 714 days Minor reactions related to the Orthodontic forces cause C
force applied pulpal circulatory system can biochemical and biologic
occur pulpal tissue alterations
Veberiene Prospective 13 26 Intrusion 0.65 No orthodontic 14 days Mean pulpal AST levels and Orthodontic forces do not A
et al.34,y force applied EPT values similar with and influence pulpal AST activity
without mechanical load and EPT values
application
Stenvik and Prospective NR 25 Intrusion 0.52.5 No orthodontic 528 days Minor reactions related to the Orthodontic forces cause C
Mjor35,y force applied pulpal circulatory system can biochemical and biologic
occur pulpal tissue alterations
Stenvik a n d Prospective NR NR Intrusion 0.352.5 No orthodontic 435 days Vacuolization of the pulp tissue Orthodontic forces cause C
Mjor36,y force applied and circulatory disturbances biochemical and biologic
occurred pulpal tissue alterations
ALP, alkaline phosphatase; AST, aspartate aminotransferase; Control, mechanical load not applied; CGRP, calcitonin gene-related peptide; EGF, epidermal growth factor; EPT, electric pulp testing; ir-
ME, immunoreactive methionine enkephalin; ir-SP, immunoreactive substance P; NR, not reported; PM, premolars.
*
High risk of bias.
y
Low risk of bias.

353
354 archives of oral biology 60 (2015) 347356

pulp vitality; however, due to a variation in the magnitude and

Quality
grade
duration of orthodontic forces exerted on teeth in the studies
included, it is exigent to scientifically validate the aforemen-

C
tioned hypothesis. Amongst the studies4,8,12,13,27,28 which

Loss of pulp vitality was more

Group-1 than groups 2 and 3

assessed the influence of orthodontic forces of PBF, magnitude
and duration of orthodontic force applied varied considerably

PN was more frequent in

PN was more frequent in

PN was more frequent in

frequent among teeth in

Group-1 than Group-2

Group-1 than Group-2

Group-1 than Group-2

(0.5 N44 N and 20 s152 days, respectively). It is allured that a
Results

low orthodontic force (for instance 0.5 N) exerted on teeth for a

few minutes causes minor or no change in PBF than the same
force being applied for longer durations. However, scientific
or Group-3

or Group-3
evidence in this regard is still missing. Likewise, it may also be
argued that long-term application of intense orthodontic
forces to teeth influences PBF to a significantly greater extent
than when the same forces are applied for a short duration.
OT (months)
Duration of

23.8

23.7
23.7

22.4

39.6 Therefore, it is difficult to contemplate a direct association

24

54

between PBF and magnitude of orthodontic force. It has also

Group-1:
Group-2:
Group-3:
Group-1:
Group-2:
Group-3:
Group-1:
Group-2:
Group-1:
Group-2:
Group-3:
been reported that the effects of orthodontic forces on PBF are
associated with various factors including patientsage, size of
apical foramen, dentinogenic activity and not merely on the
magnitude and duration of the force applied.7,12 None of the
Group-3 (Control group)

studies4,8,12,13,27,28 that fulfilled the eligibility criteria assessed

dental trauma and OT
193 traumatized teeth

193 traumatized teeth

193 traumatized teeth

the influence of size of apical foramen on PBF in the study

26 patients* without

groups. It is however pertinent to mention that in these

studies4,8,12,13,27,28 age of the study participants was also
Table 3 Studies on the influence of orthodontic forces on the pulpal response in traumatized teeth.

without OT

without OT

without OT

markedly incoherent. For example, in the study by Sano et al.,4

individuals with age ranging between 27 and 31 years were
included; whereas Babacan et al.,27 assessed the effect of
orthodontic forces on PBF among 1015 year old patients.
Further clinical trials with standardized parameters (particu-
OT in 400 non-traumatized

800 teeth non-traumatized

Study groups

larly magnitude and duration of force application) are needed

OT in 29 patients* with
non-traumatized teeth

to clarify the effect of orthodontic forces on PBF.

Group-2

CGRP is a potent vaso-dilatory peptide that is found in

approximately 50% of the neurons of the trigeminal system.46,47
Substance P (SP) is mediator of neurogenic inflammation and
during OT

causes vasodilatation by direct action over endothelial cells and

teeth

indirect mast cell stimulation for histamine release, a dual

effect shared with CGRP.48 These molecules are capable of

provoking a tolerable discomfort among patients following the
59 teeth traumatized

OT in 269 previously
OT in 77 previously

OT in 54 previously

activation of orthodontic intrusive forces.49 In the study by

traumatized teeth

traumatized teeth

traumatized teeth

Caviedes-Bucheli et al.,3 orthodontic extrusion was associated

Group-1

with an increased expression of CGRP in the pulp. However, in

during OT

this study,3 CGRP levels were measured after 24 h of force

application. Likewise, Parris et al.,32 measured pulpal SP levels
after 0.31.3 h after force application. To assess the significance
of the results reported by Caviedes-Bucheli et al.,3 and Parris
applied (N)

et al.,32 further studies with long-term application of orthodon-

Force

tic force are warranted.

Angiogenesis is defined as the process of development of
0.15
NR

NR
0.2

new blood vessels from preexisting microvasculature. GFs

may act either directly or indirectly to regulate the endothelial
Retrospective

Retrospective

Retrospective

Retrospective

cell function and expression of other GFs by different cell

Design

types.50 Studies5,1416 have used neutralizing antibodies (anti-

h VEGF, FGF2, PDGF, TGF-b and EGF) to investigate the
presence of a combination of GFs in the human dental pulp
during orthodontic force application. The neutralizing anti-
Authors et al.

bodies significantly reduced the number of microvessels in the

Bauss et al.38

Bauss et al.39

Bauss et al.40

Brin et al.41

evaluated in vitro cultures thereby confirming the presence of

GFs in the pulp during orthodontic movement. This is an
explanation for the study by Derringer et al.,15 in which the
authors showed the presence of significantly greater numbers
 archives of oral biology 60 (2015) 347356
of micro-vessels in orthodontically treated teeth than control
teeth. Furthermore, in an experimental study on mice, Kaku
et al.,51 investigated the effect of recombinant human VEGF
(rhVEGF) on the differentiation of osteoclasts during experi-
mental tooth movement. The results suggested that local
administration of rhVEGF enhances the number of osteoclasts
and may increase the rate of orthodontic tooth movement.
It is known that pulpal fibroblasts and odontoblasts
synthesize and release ALP.52,53 Therefore, it is hypothesized
that application of orthodontic force on these cells reduces their
ALP expression. AST is an essential mediator of inflammatory
processes and is expressed in high concentrations in pulpal
inflammatory conditions.54 Raiden et al.,30 Perinetti et al.,9
Veberiene et al.,11 reported raised pulpal AST levels following
the application of intrusive orthodontic forces, which reflect a
state of inflammation in the pulp. However, due to a limited
number of studies that have assessed pulpal AST and ALP levels
during orthodontic force application, the significance of these
enzymes affecting pulpal tissues remains veiled.
A critical factor that could have biased the outcome of the
studies included in the present review is their design and
methodology. For example, in the studies4,8,12,13,27,28 which
assessed the influence of orthodontic forces on human dental
pulp, magnitude of force applied to teeth varied dramatically
among as well as between the studies (0.544 N). Similarly,
among studies that assessed the cellular response of dental
pulp cells to orthodontic forces1,5,7,9,11,1416,21,2936; the amount
of forces used in these studies also varied (0.36 N). It is
therefore tempting to speculate that an intense orthodontic
force (such as 44 N) when applied to teeth for prolonged
durations cause pulpal damage to a greater extent as
compared to when a low magnitude force is applied to teeth
or the same time frame or even longer. Furthermore, regarding
the 4 studies3841 in which pulpal response to orthodontic
treatment in previously traumatized teeth was assessed; the
results showed loss of pulp vitality following the application of
orthodontic force. It is possible that the traumatic insult (such
as periodontal trauma) itself may have damaged the dental pulp
tissues even before the application of orthodontic force.
Therefore, an in-depth assessment involving parameters such
as expression of GFs, AST and ALP may yield pertinent
information regarding the pulpal response to orthodontic forces
in previously traumatized teeth. It is therefore exigent to depict a
relationship between force level and the variables investigated
in the studies include in the present systematic review.
5. Conclusion
There is insufficient scientific evidence to prove that orthodon-
tic forces jeopardize the human dental pulp in terms of reducing
PBF and irreversible alterations in pulpal cellular response.
However, a history of dental trauma maybe considered a risk
factor for loss of pulp vitality during orthodontic treatment.
Funding
The authors declare that there was no external source of
funding for the present study.
355
Competing interest
The authors declare that they have no conflict of interest.
Ethical approval
Not required.
Acknowledgement
The authors extend their appreciation to the Research Center,
College of Applied Medical Sciences and Deanship of Scientific
Research at King Saud University for funding this research. The
authors also thank the Visiting Professor Program at King Saud
University, Saudi Arabia for supporting this research project.
references
1. Han G, Hu M, Zhang Y, Jiang H. Pulp vitality and histologic
changes in human dental pulp after the application of
moderate and severe intrusive orthodontic forces. Am J
Orthod Dentofacial Orthop 2013;144(4):51822.
2. Ramazanzadeh BA, Sahhafian AA, Mohtasham N,
Hassanzadeh N, Jahanbin A, Shakeri MT. Histological
changes in human dental pulp following application of
intrusive and extrusive orthodontic forces. J Oral Sci
2009;51(1):10915.
3. Caviedes-Bucheli J, Moreno JO, Ardila-Pinto J, Del Toro-
Carreno HR, Saltarn-Quintero H, Sierra-Tapias CL, et al. The
effect of orthodontic forces on calcitonin gene-related
peptide expression in human dental pulp. J Endod
2011;37(7):9347.
4. Sano Y, Ikawa M, Sugawara J, Horiuchi H, Mitani H. The
effect of continuous intrusive force on human pulpal blood
flow. Eur J Orthod 2002;24(2):15966.
5. Derringer KA, Linden RW. Vascular endothelial growth factor,
fibroblast growth factor 2, platelet derived growth factor and
transforming growth factor beta released in human dental pulp
following orthodontic force. Arch Oral Biol 2004;49(8):63141.
6. Romanyk DL, Melenka GW, Carey JP. Modeling stress-
relaxation behavior of the periodontal ligament during the
initial phase of orthodontic treatment. J Biomech Eng
2013;135(9):91007.
7. Hamersky PA, Weimer AD, Taintor JF. The effect of
orthodontic force application on the pulpal tissue
respiration rate in the human premolar. Am J Orthod
1980;77(4):36878.
8. McDonald F, Pitt Ford TR. Blood flow changes in permanent
maxillary canines during retraction. Eur J Orthod 1994;16(1):19.
9. Perinetti G, Varvara G, Festa F, Esposito P. Aspartate
aminotransferase activity in pulp of orthodontically treated
teeth. Am J Orthod Dentofacial Orthop 2004;125(1):8892.
10. Perinetti G, Varvara G, Salini L, Tete S. Alkaline phosphatase
activity in dental pulp of orthodontically treated teeth. Am J
Orthod Dentofacial Orthop 2005;128(4):4926.
11. Veberiene R, Smailiene D, Danielyte J, Toleikis A, Dagys A,
Machiulskiene V. Effects of intrusive force on selected
determinants of pulp vitality. Angle Orthod 2009;79(6):11148.
12. Barwick PJ, Ramsay DS. Effect of brief intrusive force on
human pulpal blood flow. Am J Orthod Dentofacial Orthop
1996;110(3):2739.
356 archives of oral biology 60 (2015) 347356
13. Brodin P, Linge L, Aars H. Instant assessment of pulpal blood
flow after orthodontic force application. J Orofac Orthop
1996;57(5):3069.
14. Derringer K, Linden R. Epidermal growth factor released in
human dental pulp following orthodontic force. Eur J Orthod
2007;29(1):6771.
15. Derringer KA, Jaggers DC, Linden RW. Angiogenesis in
human dental pulp following orthodontic tooth movement.
J Dent Res 1996;75(10):17616.
16. Derringer KA, Linden RW. Angiogenic growth factors
released in human dental pulp following orthodontic force.
Arch Oral Biol 2003;48(4):28591.
17. Yamaguchi M, Kasai K. Inflammation in periodontal tissues
in response to mechanical forces. Arch Immunol Ther Exp
(Warsz) 2005;53(5):38898.
18. Basaran G, Ozer T, Kaya FA, Kaplan A, Hamamci O.
Interleukine-1beta and tumor necrosis factor-alpha levels in
the human gingival sulcus during orthodontic treatment.
Angle Orthod 2006;76(5):8306.
19. van Gastel J, Teughels W, Quirynen M, Struyf S, Van Damme J,
Coucke W, et al. Longitudinal changes in gingival crevicular
fluid after placement of fixed orthodontic appliances. Am J
Orthod Dentofacial Orthop 2011;139(6):73544.
20. Ren Y, Hazemeijer H, de Haan B, Qu N, de Vos P. Cytokine
profiles in crevicular fluid during orthodontic tooth
movement of short and long durations. J Periodontol
2007;78(3):4538.
21. Mostafa YA, Iskander KG, El-Mangoury NH. Iatrogenic
pulpal reactions to orthodontic extrusion. Am J Orthod
Dentofacial Orthop 1991;99(1):304.
22. Boudin F, Nie JY, Bartlett JC, Grad R, Pluye P, Dawes M.
Combining classifiers for robust PICO element detection.
BMC Med Inform Decis Mak 2010;10:29.
23. Roberts C. Modelling patterns of agreement for nominal
scales. Stat Med 2008;27(6):81030.
24. Chang CH. Cohens kappa for capturing discrimination. Int
Health 2014;6(2):1259.
25. Bondemark L, Holm AK, Hansen K, Axelsson S, Mohlin B,
Brattstrom V, et al. Long-term stability of orthodontic
treatment and patient satisfaction. A systematic review.
Angle Orthod 2007;77(1):18191.
26. Mohlin B, Axelsson S, Paulin G, Pietila T, Bondemark L,
Brattstrom V, et al. TMD in relation to malocclusion and
orthodontic treatment. Angle Orthod 2007;77(3):5428.
27. Babacan H, Doruk C, Bicakci AA. Pulpal blood flow changes
due to rapid maxillary expansion. Angle Orthod
2010;80(6):113640.
28. Ikawa M, Fujiwara M, Horiuchi H, Shimauchi H. The effect of
short-term tooth intrusion on human pulpal blood flow
measured by laser Doppler flowmetry. Arch Oral Biol
2001;46(9):7817.
29. Subay RK, Kaya H, Tarim B, Subay A, Cox CF. Response of
human pulpal tissue to orthodontic extrusive applications. J
Endod 2001;27(8):50811.
30. Raiden G, Missana L, Santamaria de Torres E, Kozuszko S,
Pedroso R. Pulpal response to intrusive orthodontic forces.
Acta Odontol Latinoam 1998;11(1):4954.
31. Kucukkeles N, Okar I. Root resorption and pulpal changes due
to intrusive force. J Marmara Univ Dent Fac 1994;2(1):4048.
32. Parris WG, Tanzer FS, Fridland GH, Harris EF, Killmar J,
Desiderio DM. Effects of orthodontic force on methionine
enkephalin and substance P concentrations in human pulpal
tissue. Am J Orthod Dentofacial Orthop 1989;95(6):47989.
33. Stenvik A. The effect of extrusive orthodontic forces on
human pulp and dentin. Scand J Dent Res 1971;79(6):4305.
34. Veberiene R, Smailiene D, Baseviciene N, Toleikis A,
Machiulskiene V. Change in dental pulp parameters in
response to different modes of orthodontic force
application. Angle Orthod 2010;80(6):101822.
35. Stenvik A, Mjor IA. The effect of experimental tooth
intrusion on pulp and dentine. Oral Surg Oral Med Oral Pathol
1971;32(4):63948.
36. Stenvik A, Mjor IA. Pulp and dentine reactions to
experimental tooth intrusion. A histologic study of the
initial changes. Am J Orthod 1970;57(4):37085.
37. Lazzaretti DN, Bortoluzzi GS, Torres Fernandes LF,
Rodriguez R, Grehs RA, Martins Hartmann MS. Histologic
evaluation of human pulp tissue after orthodontic
intrusion. J Endod 2013;9. http://dx.doi.org/10.1016/
j.joen.2013.10.039.
38. Bauss O, Schafer W, Sadat-Khonsari R, Knosel M. Influence
of orthodontic extrusion on pulpal vitality of traumatized
maxillary incisors. J Endod 2010;36(2):2037.
39. Bauss O, Rohling J, Meyer K, Kiliaridis S. Pulp vitality in teeth
suffering trauma during orthodontic therapy. Angle Orthod
2009;79(1):16671.
40. Bauss O, Rohling J, Rahman A, Kiliaridis S. The effect of pulp
obliteration on pulpal vitality of orthodontically intruded
traumatized teeth. J Endod 2008;34(4):41720.
41. Brin I, Ben-Bassat Y, Heling I, Engelberg A. The influence of
orthodontic treatment on previously traumatized
permanent incisors. Eur J Orthod 1991;13(5):3727.
42. Juni P, Witschi A, Bloch R, Egger M. The hazards of scoring
the quality of clinical trials for meta-analysis. JAMA
1999;282(11):105460.
43. Katrak P, Bialocerkowski AE, Massy-Westropp N, Kumar S,
Grimmer KA. A systematic review of the content of critical
appraisal tools. BMC Med Res Methodol 2004;4:22.
44. Sanderson S, Tatt ID, Higgins JP. Tools for assessing quality
and susceptibility to bias in observational studies in
epidemiology: a systematic review and annotated
bibliography. Int J Epidemiol 2007;36(3):66676.
45. von Bohl M, Ren Y, Fudalej PS, Kuijpers-Jagtman AM. Pulpal
reactions to orthodontic force application in humans: a
systematic review. J Endod 2012;38(11):14639.
46. Raddant AC, Russo AF. Calcitonin gene-related peptide in
migraine: intersection of peripheral inflammation and
central modulation. Expert Rev Mol Med 2011;13:e36.
47. Cady RJ, Glenn JR, Smith KM, Durham PL. Calcitonin gene-
related peptide promotes cellular changes in trigeminal
neurons and glia implicated in peripheral and central
sensitization. Mol Pain 2011;7:94.
48. Fewtrell CM, Foreman JC, Jordan CC, Oehme P, Renner H,
Stewart JM. The effects of substance P on histamine and 5-
hydroxytryptamine release in the rat. J Physiol 1982;330:393411.
49. Chavarria-Bolanos D, Martinez-Zumaran A, Lombana N,
Flores-Reyes H, Pozos-Guillen A. Expression of substance P,
calcitonin gene-related peptide, beta-endorphin and
methionine-enkephalin in human dental pulp tissue after
orthodontic intrusion. Angle Orthod 2013;29. http://
dx.doi.org/10.2319/060313-423.1.
50. Folkman J, Klagsbrun M. Angiogenic factors. Science
1987;235(4787):4427.
51. Kaku M, Kohno S, Kawata T, Fujita I, Tokimasa C, Tsutsui K,
et al. Effects of vascular endothelial growth factor on
osteoclast induction during tooth movement in mice. J Dent
Res 2001;80(10):18803.
52. Kim YS, Min KS, Jeong DH, Jang JH, Kim HW, Kim EC. Effects
of fibroblast growth factor-2 on the expression and
regulation of chemokines in human dental pulp cells. J
Endod 2010;36(11):182430.
53. Qin W, Liu P, Zhang R, Huang S, Gao X, Song Z, et al. JNK
MAPK is involved in BMP-2-induced odontoblastic
differentiation of human dental pulp cells. Connect Tissue Res
2014. http://dx.doi.org/10.3109/03008207.2014.882331.
54. Spoto G, Fioroni M, Rubini C, Tripodi D, Perinetti G, Piattelli
A. Aspartate aminotransferase activity in human healthy
and inflamed dental pulps. J Endod 2001;27(6):3945.