J Orofac Orthop

https://doi.org/10.1007/s00056-019-00206-5

SYSTEMATIC REVIEWS AND META-ANALYSES

Age effect on orthodontic tooth movement rate and the composition

of gingival crevicular fluid

A literature review

Anne Schubert1 · Fabian Jäger1 · Jaap C. Maltha2 · Theodosia N. Bartzela3

Received: 2 November 2018 / Accepted: 20 October 2019

© Springer Medizin Verlag GmbH, ein Teil von Springer Nature 2019

Abstract
Purpose To evaluate and form a comprehensive understanding of the effect of patient age on bone remodeling and
consequently on the rate of orthodontic tooth movement (OTM).
Methods A systematic search in PubMed and Embase from 1990 to December 2017 was performed and completed by
a hand search. Prospective clinical trials which investigated the rate of OTM and/or studies assessing age-related changes
in the composition of gingival crevicular fluid (GCF) in older compared to younger study groups were included. Study
selection, data extraction and risk of bias were assessed by two authors.
Results Eight studies fulfilled the inclusion criteria. Among them, four evaluated the rate of OTM and six investigated
mediators in the GCF (prostaglandin E2, interleukin [IL]-1β, IL-6, IL-1 receptor antagonist, receptor activator of nuclear
factor kappa-Β ligand, osteoprotegerin, granulocyte–macrophage colony-stimulating factor, pentraxin 3). Patient age ranged
between 16 and 43 years for older and <16 years for younger groups. In most of the studies, the younger patients showed
faster OTM in the first phase of treatment and more pronounced cytokine levels. Older patients had a delayed reaction to
orthodontic forces.
Conclusion The small number of included studies and large heterogeneity in study design give limited clinical evidence
that the older patients are less responsive to orthodontic force in comparison to younger patients. The initial cellular
response to orthodontic force is expected to be delayed in older patients. Control intervals during orthodontic treatment
should be adjusted to the individual’s treatment response.

Keywords Adults · Humans · Orthodontic force · Periodontal ligament · Interleukin · Cytokines

Einfluss des Alters auf die Geschwindigkeit der kieferorthopädischen Zahnbewegung und die
Zusammensetzung des gingivalen Sulkusfluids
Ein Literaturreview

Zusammenfassung
Ziel Das Ziel dieses Reviews war die Einschätzung und Entwicklung eines umfassenden Verständnisses des Einflusses
des Patientenalters auf den Knochenumbau und folglich auf die Geschwindigkeit der kieferorthopädischen Zahnbewegung
(OTM).

 Dr. med. dent. Theodosia N. Bartzela, MSc, PhD

theodosia.bartzela@charite.de

1
Private practice, Berlin, Germany
2
Department of Orthodontics and Craniofacial Biology,
Radboud University Medical Center Nijmegen,
6500 HB Nijmegen, The Netherlands
3
Department of Orthodontics, Dentofacial Orthopedics
and Pedodontics, Charité Centrum 3, Charité –
Universitätsmedizin Berlin, Aßmannshauser
Str. 4–6, 14197 Berlin, Germany

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 A. Schubert et al.

Methoden Es wurde eine systematische Suche in PubMed und Embase im Zeitraum von 1990 bis Dezember 2017
durchgeführt, ergänzt durch eine Handsuche. Prospektive klinische Studien zum Vergleich der Geschwindigkeit der OTM
und/oder Studien zu altersabhängigen Veränderungen in der Zusammensetzung des gingivalen Sulkusfluids (GCF) bei
älteren und jüngeren Probandengruppen wurden inkludiert. Die Studienauswahl, Datenextraktion und Bewertung des
Risikos für Bias erfolgte durch 2 der Studienautoren.
Ergebnisse Acht Studien erfüllten die Einschlusskriterien. Vier von ihnen ermittelten die Geschwindigkeit der kiefer-
orthopädischen Zahnbewegung und 6 untersuchten Mediatoren im GCF (Prostaglandin E2, Interleukin [IL]-1β, IL-6,
IL-1-Rezeptorantagonist, „receptor activator of nuclear factor κ-Β ligand“, Osteoprotegerin, „granulocyte-macrophage co-
lony-stimulating factor“, Pentraxin 3). Die ältere Probandengruppe war 16–43 Jahre alt, die jüngeren Patienten wiesen ein
Alter von <16 Jahren auf. Bei den jüngeren Patienten wurden in der Mehrzahl der Studien eine initial schnellere Zahnbe-
wegung und höhere Zytokinspiegel festgestellt. Die älteren Probanden zeigten eine verzögerte Reaktion auf orthodontische
Kräfte.
Schlussfolgerung Aufgrund der geringen Studienzahl und der Heterogenität der Studiendesigns ist die klinische Evidenz
für eine verminderte Reaktion auf kieferorthopädische Kräfte bei älteren im Vergleich zu jüngeren Patienten eingeschränkt.
Die initialen zellulären Reaktionen scheinen bei älteren Patienten verzögert abzulaufen. Kontrollintervalle während der
kieferorthopädischen Behandlung sollten an das individuelle Reaktionsverhalten angepasst werden.

Schlüsselwörter Erwachsene · Menschen · Kieferorthopädische Kraft · Periodontalligament · Interleukin · Zytokine

Introduction
Increased esthetic awareness [1] and barely visible treat-
ment options are contributing to the increasing number of
adult patients seeking orthodontic treatment during the last
few decades [2]. Patients seek optimal esthetic outcome in
the shortest treatment period possible.
Adult patients showed decreased bone turnover rates,
which was related to limited numbers of progenitor cells [3,
4], reduced blood vessel forming capacity [5, 6], and fibrob-
last density [7]. The alveolar walls are mainly covered by
inactive osteoblasts, the so-called lining cells, whereas the
number of active osteoblasts and osteoclasts are markedly
reduced [4, 8] and structural changes of osteoblasts have
been described [4]. The bone is becoming gradually denser
[9], while the cortical bone is diminished [10] and the How-
ship’s lacunae are increased [4].
In the periodontal ligament (PDL), a comparable decline
in cellular and metabolic activity with increasing age has
been described [7, 8, 11–18]. Sharpey’s fibers are decreased
with irregular insertion into bone [17], while other principal
fibers might become thicker with increasing age [19].
All abovementioned findings suggest a decreased respon-
siveness of the aged dentoalveolar complex, compromis-
ing bone formation and resorption during orthodontic tooth
movement (OTM) [4, 20].
Since orthodontically induced bone remodeling is related
to the expression of various inflammatory mediators, extra-
cellular matrix components and tissue-degrading enzymes,
their presence in gingival crevicular fluid (GCF) is supposed
to be related to the rate of OTM [21, 22]. Some proinflam-
matory cytokines show a higher expression in aged PDL
subsequent to mechanical stress [23–25]. The knowledge
we have with respect to the effect of age on the rate of OTM
is based mainly on animal studies [9, 26–32]. However, it
is still unclear which molecules can specifically predict the
rate of OTM [3].
To the best of our knowledge, up to now, no attempt has
been made to systematically evaluate the existing prospec-
tive clinical trials (PCT) on the effect of age on the rate of
OTM. Hence, the objective of this literature review was to
form a comprehensive understanding of (1) The effect of
age on the rate of OTM, and (2) the age-dependent changes
in the composition of GCF going along with alveolar bone
remodeling.
Methods
Protocol and registration
This systematic review was performed according to the Pre-
ferred Reporting Items for Systematic Reviews and Meta-
Analysis (PRISMA) statement [33]. The investigation was
registered with the number CRD42016037469 in the PROS-
PERO database (http://www.crd.york.ac.uk/PROSPERO).
Eligibility criteria
The Population Intervention Comparison Outcome (PI-
COS) framework was used to define the inclusion criteria
and the search strategy:
 Population: Healthy children or adolescents, adults and
elderly, who underwent orthodontic treatment. Included

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Age effect on orthodontic tooth movement rate and the composition of gingival crevicular fluid

Table 1 Embase Clas-

sic + Embase search strategy
Tab. 1 Suchstrategie für Em-
base Classic + Embase
Database searched: Embase Classic + Embase
Data Coverage: 1990–December 2017
1 Orthodontics/ or (orthodontic*).tw
2 (age* or aging or matur* or adult* or juvenil* or adolescen* or child* or
grow* or young* or elder*).tw
3 Orthodontic tooth movement/ or (movement* or move or moving or
velocity or orthodontic force*).ti
4 (cytokin* or receptor* or matrix metallop* or crevicular fluid*).ti
5 #1 and #2 and (#3 or #4)
6 Limit #5 to (human and yr=00 1990 -201700 )

studies compared the two different age groups of interest
and not reporting on young or old individuals only.
 Intervention: OTM induced by fixed appliances.
 Comparison: Split-mouth design or baseline characteris-
tics versus posttreatment characteristics.
 Outcome:
– The rate of tooth movement, measured by caliper or
digital superimposition and/or
– Changes in the composition of the GCF, especially in
the level of cytokines.
 Study types: Prospective randomized or nonrandomized
clinical trials.
Studies that concomitantly investigated the effect of any
medication on the rate of OTM were excluded. Use of anti-
inflammatory drugs or antibiotic therapy within the last
6 months of study initiation, systemic or congenital dis-
eases, smoking habit, and any form of gingival inflamma-
tion and/or periodontal disease were the exclusion criteria.
Databases and search strategy
A systematic search from 1990 to December 2017 was per-
formed in two main databases: PubMed, Embase Classic
and Embase with the assistance of a senior librarian. No
language restrictions criteria were considered. The search
strategy covers terms focusing on:
 The population of interest, meaning younger and older
individuals. Included studies compared the two different
age groups of interest and did not report on young or old
individuals only
 OTM induced by fixed appliances, force application and
rate of OTM
 Biochemical mediators of the GCF and
 Humans and clinical trials.
The literature search strategies are presented in Table 1
for Embase Classic and Embase data search and in Table 2
for PubMed. References of the retrieved articles were pe-
rused in order to identify additional relevant publications.
Selection process
First, two authors (AS, TB) searched the databases inde-
pendently and reviewed titles and available abstracts after
duplicates removal and hand search. Full text reading ver-
ified the eligibility of the included articles. In case of dis-
agreement, consensus was reached through discussion. All
included articles were based on findings in younger and
older groups of humans and were separated into studies
that evaluated the rate of OTM and studies that evaluated
the composition of GCF.

Table 2 PubMed search strat-

Database searched: PubMed
egy
Data Coverage: 1990–December 2017
Tab. 2 Suchstrategie für
PubMed 1 Orthodontic*[tiab]
2 ((age[tiab] OR aging[tiab] OR matur*[tiab] OR adult*[tiab] OR juvenil*[tiab] OR
adolescen*[tiab] OR child[tiab] OR children[tiab] OR grow*[tiab] OR young*[tiab]
OR elder*[tiab])
3 (movement*[ti] OR move[ti] OR moving[ti] OR velocity[ti] OR orthodontic
force*[ti])
4 (cytokin*[ti] OR receptor*[ti] OR matrix metallop*[ti] OR crevicular fluid*[ti])
5 #1 AND #2 AND (#3 OR #4)
6 #5 AND (00 1990/01/0100 [PDAT] : 00 2016/12/3100 [PDAT]) AND 00 humans00 [MeSH
Terms])

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 A. Schubert et al.

Fig. 1 Flow diagram illustrating

the systematic selection process Records identified through database

Identification
according to the Preferred Re- searching Additional records identified
porting Items for Systematic Embase Classic + Embase=468, through hand search
PubMed=313(n = 781) (n = 2)
Reviews and Meta-Analysis
(PRISMA) statement [33]
Abb. 1 Flussdiagramm zum
Prozess der systematischen Lite-
raturauswahl entsprechend den Records after duplicates removed
PRISMA(Preferred Reporting (n = 568+2)
Items for Systematic Reviews
and Meta-Analysis)-Vorgaben
Screening
[33]
Records excluded (n = 555)
Records screened Reason: Did not evaluate the
(n = 570) effect of age on OTM

Full-text articles assessed Full-text articles excluded (n = 7)

Reasons:
Eligibility

for eligibility
(n = 15) 1. Did not evaluate the rate of
OTM (n = 6);
2. The same study group was used
twice (n = 1)

Studies included in
qualitative synthesis
(n = 8)
Included

Studies included in
quantitative synthesis
(meta-analysis)
(n = 0)

Data collection process and data items Assessment of risk of bias

Two authors (AS, TB) extracted the data independently fol- The selected studies were screened for bias according to
lowing a piloted form. The variables of data sought were the Cochrane Collaboration’s tool for assessing risk of bias
the following: [34]. Two authors (AS, TB) independently rated the quality
of the selected studies. Differences in decisions of the two
 Participant characteristics: Number of patients in the
examiners were discussed until consensus was reached.
younger and older study groups, sex distribution, age of
included patients (mean age ± standard deviation or age
range), patient’s inclusion criteria and health status, oral
Results
hygiene regime, periodontal screening, tooth selection
for the OTM evaluation, type of control.
Study selection
 Study characteristics: Mode of investigation, mechanics
and nature of force application, force level, force reac-
The database search (Tables 1 and 2) provided 781 citations.
tivation, type of tooth movement, observation intervals,
After duplicates removal and hand search (n = 2), titles and
and total duration of force application, side of GCF col-
abstracts of 555 articles were reviewed. A flow chart illus-
lection and process, rate of tooth movement and evalua-
trating the selection process according to PRISMA state-
tion of level of studied mediators.
ment [33] is presented in Fig. 1. Fifteen studies were scru-
tinized for eligibility. Eight studies fulfilled the inclusion
criteria. The studies excluded and the reason for exclusion
are presented in Fig. 1 and in Table 3. The interexaminer
reliability of the two authors AS and TB for eligibility as-

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Age effect on orthodontic tooth movement rate and the composition of gingival crevicular fluid

Table 3 Articles excluded from this review and reason for exclusion
Tab. 3 In das Literaturreview nicht aufgenommene Artikel und Begründung für den Ausschluss
Study Reason for exclusion
Dyer et al. (1991) [3] Force application: Class II elastics
Outcome: increased mandibular molar eruption, increased maxillary molar intrusion, increased maxillary
incisor eruption
Giannopoulou et al. (2016) [56] The same study group was used in the study by Dudic et al. [39]
Grzibovskis et al. (2011) [57] The signaling molecules were evaluated in the interradicular septum in 3 age groups. Pilot study
Grzibovskis et al. (2011) [58] The signaling molecules were evaluated in the interradicular septum in 3 age groups. Preliminary study
Krieger et al. (2013) [59] The buccal segment of the periodontal ligament of the mesiobuccal root of the first maxillary molar was
evaluated for fibroblast density. No orthodontic force was applied
Tanne et al. (1998) [60] Outcome: Tooth mobility and differences in the biomechanical response of periodontium and tooth after
orthodontic tooth application in adolescence and adults
Zhang and Ren (2001) [61] Outcome: PGE2, IL-6 and GM-CSF in GCF of upper lateral incisor before activation and 24 h after labial
orthodontic force application in both child group and adult group
PGE2 prostaglandin E2, IL-6 interleukin-6, GM-CSF granulocyte–macrophage colony-stimulating factor, CSF colony-stimulating factor

sessment of the included publications was measured (Co-
hen’s kappa coefficient 0.8543), indicating a high degree
of agreement [35]. Studies investigating the effect of age
on the rate of OTM and those that are focusing on age-
dependent changes of the level of mediators in GCF only
(GCF group) are listed in Tables 4 and 5 respectively, and
were analyzed separately (authors are listed in alphabetical
order).
Study characteristics
All studies included were identified as clinical controlled
trials. Data on these studies are provided in Tables 4 and 5.
Within the eight included studies, two studies evaluated the
rate of OTM and changes in the level of mediators in GCF
[36, 37]. Two studies reported on the rate of OTM only
[38, 39] and four of them investigated mediators just on the
GCF during OTM [21, 40–42].
Within the eight included studies (Tables 4 and 5), the
sample size of the age groups varied markedly between 4
[36] and 43 subjects [21]. Two studies showed distinct dif-
ferences in the number of participants among their two age
groups [38, 39]. The age was presented as a range or as
a mean with standard deviation (Tables 4 and 5). In two
studies [36, 38], the comparison groups were selected based
on patients’ serial body height and cephalometric measure-
ments. Within the included studies the younger study group
comprised adolescents with an age ranging from 105 [39]
to 16 years [39]. The older study group considered a larger
age interval ranging from 151 [36] to 43 years [39]. In one
of the studies the cutoff age between the groups was justi-
fied by the group distribution [39]. Based on growth obser-
vations from data on body height and cephalometric mea-
surements previously mentioned, the study by Nickel et al.
divided the observation groups into growers (10.1–17 years)
and nongrowers (14.2–30.9 years) and consequently a bi-
ological age overlap was observed [38]. From the selected
studies, some used nontreated contralateral(s) [21, 36, 37]
or/and opposing teeth [37, 41, 42] and some other studies
used baseline data as control [37, 39, 40, 42]. Blinding of
participants and personnel was not feasible in any of the
included studies. Selection bias and performance bias were
not assessed due to inconsistencies in the study methods.
Randomization and allocation concealment were not feasi-
ble or influenced by the clinician’s judgment.
Mechanics and force application
Three studies of the OTM group (Table 4) considered max-
illary canine retraction either by vertical loops, which were
activated by NiTi coil-springs [36, 38] or by an elastomeric
chain applied on a 0.018 inch stainless steel wire after level-
ing [37]. In one study, sectional TMA wires were used for
buccal movement of maxillary and mandibular premolars
[39]. Among the studies that reported on changes in GCF,
two of them investigated the mediators in GCF (Table 5)
after tipping labially the maxillary lateral incisors with off-
set bends on a 0.012 inch NiTi archwire [21, 40]. One other
retracted canines with a laceback on a 0.012 inch NiTi arch-
wire [42] and one more aligned the maxillary incisors with
a sequence of ascending NiTi archwires [41].
A great diversity of force magnitude was applied, rang-
ing from 18 [36, 38] to 360 cN [38]. Two studies [41, 42]
did not mention the force magnitude at all. In two studies,
continuous forces were applied by NiTi coil-springs [36,
38] whereas all other studies applied descending [21, 37,
40, 42] or interrupted forces [39, 41]. Two studies reported
reactivation of the appliance after 4 [39] and 6 weeks [41].
The duration of force application exhibited large variations
from as low as 7 days [37] to 8 weeks [39] in the OTM
group and 24 h [21] to 20 weeks [41] in the GCF group
(Table 2). The frequency of GCF collection ranged from 2

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 Table 4 Overview of studies evaluating the rate of tooth movement
Tab. 4 Studienübersicht zur Geschwindigkeit kieferorthopädischer Zahnbewegung

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Study Design Younger group Older group Inclusion criteria Oral hygiene Type of force Force Observation Rate OTM Additional
Size Size and health status regimes application level period considera-
[age range] [age range] OH and perio tions on study
(year(s)) (year(s)) screening design
(M/F) (M/F)
Dudic CT 19 11 Good general Good dental and Buccal move- 100 cN 8w OTM Y > O Intra- and
et al. (11/19)a (11/19)a health perio health ment of max- No sig. differ- interarch in-
[39] (36 teeth) (21 teeth) illary and ences in sex and terferences,
[<16] [≥16–43 y] mandibular pre- location sex and loca-
molars with sec- Sig. less tion (maxilla
tional archwire OTM with or mandible)
(0.019 × 0.025 obstacle: in-
TMA) ter-arch < intra-arch
Iwasaki CT 6 4 NA Mouth rinse day Maxillary canine 60 cN –28, –14, 0 d Velocity Y > O, Sex, side,
et al. (3/7)a (3/7)a –28 (anchorage retraction by (one (baseline) varied between stress
[36] [10.5–14.3] [15.1–30.11] in situ) vertical loop and side), 1, 3, 14, 28, subjects Force appli-
Chlorhexidine coil spring 18, 120 42, 56, 70, Correlation cation
mouth or 240 cN 84 d of OTM with was deter-
rinse (other 3, 14, 28 d force level up to mined
2 × daily + routine side) (lag phase) 120 cN by tooth size
oral hygiene Lag phase asso- and
Each visit (day 0 ciated with force target stress
on) of 240 cN
oral prophylaxis
Kawasaki CT 15 15 Good health Healthy perio Canine retrac- 250 cN 0, 1, 24, Y > O after 168 h NA
et al. (7/8) (6/9) No antibiotics tissues tion on 0.018 SS 168 h
[37] [15.1 ± 2.8] [31 ± 3.6] the last 6 months Bone loss by elastomeric
No anti-inflam- Ä3 mm chain
matory 1 month
before the study
Nickel CT 32 9 NA Chlorhexidine Maxillary canine 18, 60, 1, 3, 14, 28, Velocity 1.6 OTM in re-
et al. (15/17) (2/7) gluconate mouth retraction by 120, 42, 56, 70, times higher lation to ap-
[38] (64 teeth) (18 teeth) rinse 2 x daily closing loop and 240 and 84 d in Y than O plied load
[13.4 ± 1.7] [19.6 ± 5.4] Day of registra- coil spring 360 cN Velocity higher Individualized
tion: supragingi- in force levels of OTM re-
val oral prophy- 60, 120, 240 cN; sponse
laxis increased loga-
rithmically with
force level
M/F male, female distribution, OH oral hygiene, OTM orthodontic tooth movement, CT prospective clinical trial, TMA titanium molybdenum alloy, cN centinewton(s), w week(s), Y younger study
group, O older study group, NA not applicable, d day(s), SS stainless steel, h hour(s), sig significant, perio periodontal
a
M/F distribution was only provided for the total sample and not for each group separately
A. Schubert et al.
 Table 5 Studies reporting on age-related composition changes in gingival crevicular fluid in humans
Tab. 5 Studien zu altersabhängigen Veränderungen der Zusammensetzung des gingivalen Sulkusfluids (GCF)
Study Design Younger Older group Inclusion crite- Oral hy- Side of GCF collec- Control Type of Force level Observation Data on GCF analy-
group Size [age ria and health giene tion and process force ap- period sis
Size [age range] status regimes plication
range] (y) and OH
(y)
(M/F) (M/F) Evaluation
Chibebe CT 25 23 Good health Good perio Mesiobuccally Baseline Labial 0.7 N 2, 21 PGE2 level at base-
et al. (10/15) (7/16) No antibiotics health Area was isolated level movement and 28 d line and end: O > Y
[40] [13.6 ± 2.1 y] [24.1 ± 2.1 y] the last 6 m OH instruc- with cotton rolls, of one Increase of PGE2
No anti-inflam- tion during gently dried maxillary level to day 21,
matory the last the study Paper strip inserted right then decrease to
2m and kept for 30 s lateral baseline in O + Y
incisors Sig. changes in PGE2
by 0.012 levels only in Y
NiTi (baseline compared
to day 21)
Iwasaki CT 6 4 NA Chlorhexidine Distally Opposing Maxillary 60 cN (one 1, 3, 14, Correlation of veloc-
et al. (3/7)a (3/7)a mouth rinse Washed with water, teeth canine side), 18, 28, 42, ity and level of IL-1β
[36] [10.5–14.3 y] [15.1–30.11 y] 2 x daily isolated with cotton retraction 120 or 56, in GCF
Strict OH and dried by verti- 240 cN 70, 84 d Correlation of
In each Sterile strips in GC cal loop (opposing) changes in cytokine
appointment for 30 s and a 2nd and coil Lag phase levels in SWB and
modified GI strip 1 min later, spring associated velocity/IL-1 activity
+ OP then strips sealed with force index
Age effect on orthodontic tooth movement rate and the composition of gingival crevicular fluid

in polypropylene of 240 cN
containers
KawasakiCT 15 15 Good health Color of Distally Contra- Canine 250 cN 0, 1, 24, Mean volume of
et al. (7/8) (6/9) No antibiotics gingiva was Plaque was re- lateral retrac- 168 h GCF Y > O
[37] [15.1 ± 2.8 y] [31 ± 3.6 y] the last 6 m recorded moved with perio and tion on Level of RANKL
No anti-inflam- Plaque as- probe opposing 0.018 SS raised at 24 h, Y > O
matory 1 m sessment Teeth were washed teeth by elas- Level of OPG de-
preceding the Silness and with water and tomeric creased at 24 h, Y > O
study Loe index isolated with cotton chain RANKL-OPG ratio
Strip was remained at 24 h, Y > O
in GC for 1 min
and then a 2nd strip
was used

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 Table 5 (Continued)
Tab. 5 (Fortsetzung)
Study Design Younger Older group Inclusion crite- Oral hy- Side of GCF collec- Control Type of Force level Observation Data on GCF analy-

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group Size [age ria and health giene tion and process force ap- period sis
Size [age range] status regimes plication
range] (y) and OH
(y)
(M/F) (M/F) Evaluation
Ren CT 43 41 Good health OH Distobuccally Contra- Labially 70 cN 24 h GCF volume Y > O
et al. (all males) (all males) No antibiotics instructions Plaque was re- lateral tipped Baseline cytokine
[21] [11 ± 0.7 y] [24 ± 1.6 y] the last 6 m before study moved tooth maxillary level O > Y
No anti-inflam- Area was isolated lateral Sign. increase
matory 1 m with cotton Sterile incisors of PGE2, IL-6,
preceding the strip on GC for 30 s by 0.012 GM-CSF in Y
study NiTi Sign. increase of
PGE2 in O
Rody CT 10 10 Good health 2 weeks be- Labially Opposing Alignment NA 3, 6, 18, No differences in
et al. (3/7) (4/6) Nonsmokers and fore fixed Dried and isolated teeth of max- 20 w IL-1 level in control
[41] [14.4 ± 1.4 y] [28.5 ± 7.8 y] drug users appliance with cotton illary vs. experimental side
professional Strip inserted for incisors Sig. increase in
tooth-clean- 60 s with NiTi IL-1RA in O after
ing and wires 3w
assessment RANKL-OPG ratio
for perio increased
health at w 3 in Y + O; high-
est at w 20 in Y
No sig. changes in
MMP-9
Surlin CT 16 13 Good health sta- OH instruc- Distally Baseline Maxillary NA 4, 8, 24, PTX3 baseline level
et al. (9/7) (5/8) tus, nonsmoking tions and Supragingival level, canine 72 h, not influenced by age
[42] [13.81 ± 0.98 y] [28.23 ± 3.4 y] No antibiotic the motivated plaque removal con- retrac- 1 and 2 w Increase in PTX3
last 3 m during the with curette tralateral tion by earlier in Y than O
No anti-inflam- study Air syringe and tooth laceback Maximum level at
matory PI was mea- saliva ejector for 24 h
the last 30 d sured isolation PTX3 decrease to
Paper strips in GC baseline level faster
for 30 s in O than Y
GCF measure in
precalibrated device
and stored in
polypropylene tubes
M/F male/female distribution, OH oral hygiene, GCF gingival crevicular fluid, CT prospective controlled trial, y year(s), m month(s), s seconds, NiTi nickel–titanium, N Newton, d day(s),
PGE2 prostaglandin E2, O older study group, Y younger study group, sig. significant, NA not applicable, GI gingival index, OP oral prophylaxis, GC gingival crevice, min minute(s),
cN centinewton(s), IL-1ß Interleukin-1ß, SWB stimulated whole blood, SS stainless steel, h hour(s), RANKL receptor activator of NF-κB ligand, OPG osteoprotegerin, IL-6 interleukin-6,
GM-CSF granulocyte–macrophage colony-stimulating factor, w week(s), IL-1RA interleukin-1 receptor antagonist, MMP-9 matrix metalloproteinase 9, PI plaque index, PTX3 pentraxin 3,
perio periodontal
a
M/F distribution was only provided for the total sample and not for the two groups separately
A. Schubert et al.
Age effect on orthodontic tooth movement rate and the composition of gingival crevicular fluid
Table 6 The mediators in gin-
Parameter categories
gival crevicular fluid (GCF)
composition that were exam- Cytokines
ined during orthodontic tooth
movement
Tab. 6 Mediatoren des während
der kieferorthopädischen Zahn-
bewegung untersuchten gingi-
valen Sulkusfluids (GCF) Receptors and their antago-
nists
Enzymes for matrix degrada-
tion
[21] to 9 times [36] over the experimental period. Proper
oral hygiene regimen and gingival health assessment was
considered in 6 studies ([21, 36–38, 40, 42]; Tables 4 and 5).
Assessment strategies for the rate of OTM
The rate of OTM was assessed by measurements on plaster
casts either by a caliper [36, 37], a measuring microscope
[38] or by digital superimposition of the digitalized plaster
models [39]. Results associated with the rate of OTM are
listed in Table 4.
GCF collection and level of mediators
Within the included studies (Table 5), the mediators in GCF
that were evaluated during the OTM are presented in Ta-
ble 6. All studies (Table 5) used periodontal paper strips
for the collection of the GCF. The strips were inserted into
the gingival crevice for either 30 [21, 36, 40, 42] or 60 s
[37, 41]. In one study, additional GCF samples were taken
at the tension side [36], but the data were not followed fur-
ther. Repeated measurements were considered in one study
only [37].
Three studies measured changes in GCF volume using
a Periotron [21, 37, 42]. Quantitative GCF analysis was
performed with radioimmunoassay (RIA) [21] or enzyme-
linked immunosorbent assay (ELISA) [36, 37, 40–42]. Me-
diators were presented either by their weight [21], or by the
concentration of total GCF volume [21, 37, 41, 42] or as
activity index [36].
Two studies observed higher mean baseline volumes of
GCF in the younger than the older group [30, 37]. Baseline
concentration of mediators (PGE2, IL-6, GM-CSF) in GCF
was higher in the older than in the younger group [30, 40].
PTX-3 [42] and RANKL baseline level [37] did not differ
significantly in GCF between the age groups [42].
Individual mediators
Interleukin-1 beta (IL-1β) [16]
Interleukin-1 (IL-1) without differentiation [48]
Receptor activator of NF-κB ligand (RANKL) [21, 48]
Prostaglandin E2 (PGE2) [8, 46]
Interleukin 6 (IL-6) [46]
Granulocyte macrophage colony-stimulating factor (GM-CSF) [46]
Interleukin-1 receptor antagonist (IL1-RA) [16, 48]
Osteoprotegerin (OPG) [21, 48]
Pentraxin 3 (PTX-3) [50]
Matrix metalloproteinase 9 (MMP-9) [48]
Regulation pattern
Prostaglandin E2
One of the studies showed that at baseline, the younger pa-
tients had a lower PGE2 concentration in the GCF than the
older group. After 24 h, the concentration was increased
in both the younger and the older groups, but no differ-
ences between the two groups were present anymore [21].
The other study showed no differences between the groups,
although after 3 weeks of force application a significant
increase of PGE2 concentration was found in the younger
group [40].
Interleukin-1
The concentration of IL-1 in GCF did not differ signifi-
cantly between the experimental and control teeth through-
out the time of force application in any of the age groups
involved [41]. The ratio of IL-1 to IL-1RA, however, de-
creased significantly in the older group after 3 weeks of
force application, indicating an increase in IL-1RA levels.
The average IL-1 activity index was significantly higher
in the younger group, showing a positive correlation with
the velocity of OTM [36]. The mean activity index was
further significantly influenced by the force magnitude and
the presence of a lag phase. In comparison to a force ap-
plication lower than 120 cN, a significantly higher activity
index was observed in the post-lag phase for canines where
the applied force was 240 cN [36].
Receptor activator of NF-κB ligand/osteoprotegerin
In the short term, 24 h after force application, RANKL
showed significantly elevated levels in the GCF in both age
groups, whereas OPG decreased simultaneously [37]. The
level of RANKL and OPG was significantly lower in the
older compared to the younger groups. The ratio of RANKL
to OPG significantly increased after 3 weeks of force ap-
plication in both age groups [41] and reached a peak in the
K
 A. Schubert et al.

18th observational week in the younger group. This was

related to a decrease in OPG. The level of OPG in the older
group did not differ significantly between the experimental
and control group at any time point.

Matrix metalloproteinase 9

The level of MMP-9 in GCF did differ neither between the

control and experimental teeth nor between the age groups
[41].

Pentraxin 3

The PTX-3 level increased after force application with

a peak at 24 h (2.5-fold in the younger group; 2-fold in
the older group) followed by a decline to baseline after
2 weeks in the younger and after 1 week in the adult group
[42]. Significant differences compared to the baseline level
were detected at 4, 8, 24 and 72 h in younger patients and
at 8, 24 and 72 h in older patients, indicating an increased
rate of OTM in the younger group.

Risk of bias within studies

A summary of the risk of bias for the included studies is

presented in Fig. 2. Serious risk of bias was found in 6
of the 8 studies for one domain [41, 42] or two domains
[36–39]. The most problematic issues were lack of blinding
for the OTM outcome assessor [37, 38] and the existence
of other potential bias [36–39, 41, 42]. Two studies did not
report complete outcome data [38, 39].

Risk of bias across studies

Significant signs of selection bias, attrition bias and other

bias were seen for the assessment of OTM in all four in-
cluded studies [36–38], which indicate weakness of the
study design and the potential of unreliable data for this
outcome. Three of the studies that investigated the GCF
showed similar weaknesses in study design, creating bias
in the analysis of the GCF [37, 41, 42].
Fig. 2 Risk of bias across the included studies. The signs indicate:
low risk of bias (+), high risk of bias (–) and unclear risk of bias (?).
OTM orthodontic tooth movement, GCF gingival crevicular fluid
Abb. 2 Risiko für das Auftreten eines Bias für die inkludierten Studi-
en. Bedeutung der Symbole: geringes Risiko für Bias (+), hohes Risi-
ko für Bias (–), unklares Risiko für Bias (?). OTM kieferorthopädische
Zahnbewegung, GCF gingivales Sulkusfluid

Discussion
Quality of evidence
This systematic review included eight prospective clinical
trials, which investigated the rate of OTM and/or changes
in the GCF of juvenile and adult individuals subsequent to
orthodontic force application. In the literature, most trials
reporting on age-related differences in the rate of OTM are
small observational studies or case series showing slower
tooth movement in adults in comparison to juvenile sub-
jects. Little evidence exists regarding higher levels of in-
flammatory mediators in aged PDL.
This systematic review revealed a large heterogeneity
in the included clinical trials (study group size and wide
age intervals, mode of force application, level of force and
reactivation, observation period, GCF collection method,
oral hygiene regimen).

K
Age effect on orthodontic tooth movement rate and the composition of gingival crevicular fluid
The mediators were evaluated either by their weight [21],
or by their concentration in total GCF [21, 37, 41, 42] or as
activity index [36]. There is no scientific evidence whether
the amount of or the concentration of a mediator is a better
indicator for the evaluation of the rate of OTM. The study by
Ren et al. showed that the concentration of a mediator in the
CGF is more sensitive in the detection of OTM responses
for the comparison between younger and older individuals
[21]. Their threshold is higher in older than younger study
probands [21] indicating more responsive cytokine levels in
juveniles than in adults [21].
The response to force application is site-specific, depend-
ing on the bone deformation and the distortion of the pe-
riodontal ligament (stress/strain). The data of the collected
mediators were provided mainly from the distal side [36,
37, 42] or the distobuccal side [21], but also from the labial
[42] or the mesiobuccal side ([40]; Table 5).
The optimal mechanical stimulus for OTM response may
differ between younger and older individuals and among
individuals of the same age [43]. Adults also may have
a later initial response [21] leading to a delay in the overall
orthodontic treatment time. The force application of con-
tinuous or interrupted forces also has an impact on the rate
of OTM, altering the cytokine levels in the GCF [32]. Light
continuous forces induce longer lasting levels of cytokines
during OTM [32] and heavy, decreasing forces create fluc-
tuating cytokine levels and increase the risk for root re-
sorption and hyalinization [44]. In retraction OTM with
laceback [42] or elastomeric chain [37] smaller forces are
applied, while retraction with vertical loops or coil spring
[36] or alignment [41] and labial movement [40] with NiTi
wires, continuous forces are delivered (Table 2). Some cy-
tokines, showing an upregulation subsequent to orthodontic
stresses, should not be overrated, since these studies de-
tected large fluctuations in cytokine level and the size of
the study groups were small [32].
Irrespective of the serious bias found in the included
OTM studies, juveniles appear to present a higher rate of
OTM than adults [36–39]. However, accurate prediction of
the rate of OTM is difficult due to the high interindivid-
ual variability [36], the genetic background and complexity
of bone remodeling induced by OTM [45]. Many different
intrinsic factors including sex and possibly the ethnicity
[9], root length, bone level, bone density [9, 46] affected
by weight and bone turnover rates [47] have an impact
on the rate of OTM. These factors were not considered
in any of the included studies. A genetic predisposition to
a high bone turnover rate was associated with increased
rate of OTM compared to normal or low turnover rates
when applying the same force in different subjects [47].
Pharmacologic agents for prevention or treatment of dis-
eases, including painkillers and dietary supplements altered
the rate of OTM [48]. General health [21, 37, 39–42] and
the intake of medication (antibiotics and anti-inflammatory
drugs only) were considered for the participants in most of
the studies. The last use of antibiotics was settled to more
than 3 [42] or 6 months [21] and the last anti-inflammatory
medication intake to more than 1 [21] or 2 months [40].
Estrogen fluctuation (sex hormones/estradiol and estrone)
during menopause or the reproductive female period or vi-
tamin D3 supplementation (for prevention or treatment of
osteoporosis) or even dietary calcium intake (low- vs. high-
calcium diet) [49] play an important role in the RANK/
RANKL/OPG signaling pathway affecting the rate of OTM
[50]. Also osteopenia, a condition in which bone mineral
density is reduced as a sign of normal aging, is often ob-
served before estrogen decline or menopause [51], or eat-
ing disorders, or suppressed estrogen balance seen often in
young female athletes may affect the rate of OTM [52]. The
selection of exclusively male individuals, like in the study
by Ren et al. [21] eliminates sex-related bone turnover bias.
The high heterogeneity in study design and outcome param-
eters of all included studies preclude clear evidence-based
conclusions.
Limitations of the study set-up
None of the included studies reported on any randomization
method. The experimental sides are likely to be selected
and allocated by judgement of the clinician. Opposing or
neighboring teeth may prevent the experimental tooth to
move or decrease the effective force level applied, thus,
leading to bias in the outcome measurement.
The velocity of OTM at crown level is influenced by the
type of OTM [53] and varies among the included studies.
Tipping [37, 39] will be accomplished faster than bodily
tooth movement [38]. The amount of tipping is related to the
patient’s bone level. Decreased bone levels result in more
tipping when the same line of force is applied. Since the
bone level will decrease with age due to periodontal prob-
lems, more tipping and apparently faster tooth movement
can be expected in the adult group. Furthermore, if OTM
is defined by space closure without a proper anchorage de-
vice, the results may be biased by the undefined movement
of the adjacent teeth [36].
Proper control of oral hygiene throughout the study is
important, since the outcome is likely to change with the
presence of gingival inflammation. Gingivitis has an influ-
ence on the expression of IL-1β [22] and the level of IL-1
may be increased in patients with poor or moderate oral
hygiene [41].
Most of the studies included in this review present re-
sults of short observational periods. Since the biological
response to orthodontic stimuli varies among and within
the patient and throughout the stages of OTM, short obser-
K

vational periods are not representative and might provide
misleading conclusions [54].
The above-mentioned problems may be avoided in an-
imal studies, for example in rodents. Such studies allow
a design with more homogenous study groups, proper ran-
domization procedures, and the availability of more analyt-
ical tools for the analysis of cellular and molecular events
during OTM. The results of such studies can serve as a basis
for properly designed hypothesis-driven clinical studies.
The increased interest of adult patients for high esthetic
and short-lasting orthodontic treatment outcome has turned
the experimental and clinical orthodontic interest on cus-
tomized appliances, surgical procedures [55] or pharmaco-
logical and dietary agents that may accelerate the OTM
[48]. Whether aging is a factor that influences the rate
of OTM is rather unclear. It is a fact that interindividual
variations seem to play a role in the biological responses
triggered by the orthodontic forces. The three-dimensional
computer-simulated OTM with accurate stress–strain dis-
tribution and biological profiles of each patient may be
valuable for optimizing the treatment time and eliminating
complications on the involved soft and hard tissues.
Conclusions
The small number of studies and large heterogeneity in
study design preclude a meta-analysis. There is limited clin-
ical evidence that older patients are less responsive to or-
thodontic stress than younger ones. Future animal studies
and well-designed prospective clinical studies should focus
on multiple variables involved in the rate of OTM.
Compliance with ethical guidelines
Conflict of interest A. Schubert, F. Jäger, J.C. Maltha and T.N. Bartzela
declare that they have no competing interests.
Ethical standards For this article no studies with human participants
or animals were performed by any of the authors. All studies performed
were in accordance with the ethical standards indicated in each case.
For this type of study informed consent is not required.
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