SPECIAL ARTICLE

Accelerated orthodontic tooth movement:

Molecular mechanisms
Hechang Huang,a Ray C. Williams,b and Stephanos Kyrkanidesc
Stony Brook, NY

Accelerating orthodontic tooth movement can significantly reduce treatment duration and risks of side effects.
The rate of orthodontic tooth movement is chiefly determined by the remodeling of tissues surrounding the roots;
this in turn is under the control of molecular mechanisms regulating cellular behaviors in the alveolar bone and
periodontal ligament. This review summarizes the current knowledge on the molecular mechanisms underlying
accelerated orthodontic tooth movement, and the clinical and experimental methods that accelerate orthodontic
tooth movement with possible molecular mechanisms. The review also shows directions for future studies to
develop more clinically applicable methods to accelerate orthodontic tooth movement. (Am J Orthod
Dentofacial Orthop 2014;146:620-32)

O
rthodontic movement of teeth under mechanical
force depends on the remodeling of tissues sur-
rounding the roots. Accelerating orthodontic
tooth movement has long been desired for its multiple
potential benefits, including shorter treatment duration,
reduced side effects (such as oral-hygiene related prob-
lems, root resorption, and open gingival embrasure
spaces1-5), enhanced envelope of tooth movement,
differential tooth movement, and improved
posttreatment stability.6 Attempts to accelerate tooth
movement can be dated back to the 1890s, almost
contemporary with Angle's groundbreaking work in
modern orthodontics.7 For the next half century, the
intervention to accelerate tooth movement involved os-
teotomy, the surgical procedure that completely cuts
both the cortex and the medulla of the alveolar bone.
The rationale for performing osteotomy was to reduce
mechanical resistance during tooth movement. In the
1950s, K€ ole8 introduced corticotomy, the perforation
of the cortex of the bone alone without intrusion into
the medulla, to replace osteotomy except in the subapical
From the School of Dental Medicine, State University of New York, Stony
Brook, NY.
a
Assistant professor, Department of Orthodontics and Pediatric Dentistry.
b
Professor, Department of Periodontology.
c
Professor and chair, Department of Orthodontics and Pediatric Dentistry; asso-
ciate dean, Research and Faculty Development.
All authors have completed and submitted the ICMJE Form for Disclosure of Po-
tential Conflicts of Interest, and none were reported.
Address correspondence to: Stephanos Kyrkanides, 100 Nicolls Rd, Stony Brook,
NY 11794; e-mail, Stephanos.Kyrkanides@stonybrookmedicine.edu.
Submitted, February 2014; revised and accepted, July 2014.
0889-5406/$36.00
Copyright Ó 2014 by the American Association of Orthodontists.
http://dx.doi.org/10.1016/j.ajodo.2014.07.007
620
region, to reduce invasiveness. Since it was less destruc-
tive, corticotomy completely replaced osteotomy as the
preferred surgical method to accelerate tooth move-
ment.9 Despite the evolution of clinical methods, the sci-
entific explanation of accelerated tooth movement was
still believed to be reduced mechanical resistance after
osteotomy or corticotomy, enabling the teeth to be
moved en bloc with the tissues surrounding them.10-12
This view was challenged by Wilcko et al13 (including a
periodontist and an orthodontist) circa 2000. They
described the demineralization and remineralization pro-
cess of the alveolar bone after corticotomy that resem-
bled the regional acceleratory phenomenon (RAP),
indicating increased bone remodeling activity. Consis-
tent with this observation, other studies also showed
that nonsurgical interventions stimulating bone remod-
eling can accelerate orthodontic tooth movement.14-19
BONE MODELING, REMODELING, AND
ORTHODONTIC TOOTH MOVEMENT
Bone modeling is the uncoupled process of activa-
tion-resorption (catabolic) or activation-formation
(anabolic) on bone surfaces, resulting in changes of
the shape, size, or position of the bone.20 Bone remod-
eling or turnover, on the other hand, is a tightly coupled
local process, which starts with bone resorption, fol-
lowed by reversal and bone formation phases, resulting
in the replacement of old bone with new bone.21,22
Both bone modeling and remodeling are determinants
for the rate of orthodontic tooth movement. Bone
modeling during orthodontic tooth movement is an
inflammatory process, and the rate-limiting factor for
tooth movement is bone resorption at the bone and
Huang, Williams, and Kyrkanides
periodontal ligament (PDL) interface.23 Even though
bone remodeling renews the internal content of the
bone without changing the size or shape of the bone
under physiologic conditions, it also affects the rate of
orthodontic tooth movement.24
Both bone modeling and remodeling are controlled by
the cellular activities of osteoclasts, osteoblasts, and oste-
ocytes. Apparently, osteoclasts carry out resorption,
whereas osteoblasts carry out bone formation during
bone modeling. The resorption-formation sequence of
the bone remodeling process is performed by basic multi-
cellular units, which are organized osteoclasts and osteo-
blasts.25 Both biochemical and mechanical factors
regulate the rates of bone modeling and remodel-
ing.22,26,27 Previous studies have shown that orthodontic
treatment stimulates alveolar bone modeling,23 as well
as bone remodeling that resembles RAP28 with increased
number and function of osteoclasts and osteoblasts, and
more active bone resorption-formation cycles.29-31
Activation of osteoblasts by mechanical forces,
inflammatory stimuli, or hypoxia appears to be the first
and necessary step in orthodontic tooth movement.
Activated osteoblasts are responsible for the expression
of specific mediators of osteoclast formation and
initiation of bone resorption.
OSTEOCLAST FORMATION AND BONE
RESORPTION
The rate-limiting step in orthodontic tooth move-
ment is considered to be bone resorption at the leading
(compression) side. Histologic studies show that the for-
mation of osteoclasts is induced at the compression side
during orthodontic tooth movement.32-35 Alveolar
corticotomy and nonsurgical interventions that
accelerate tooth movement significantly increase the
numbers and functions of osteoclasts.14-17,32-45 The
formation of osteoclasts depends on the effects of
stromal and osteoblastic cell-derived factors on osteo-
clast precursors. One of these factors is receptor activator
of nuclear factor kappa B ligand (RANKL), which binds to
its receptor, RANK, on the surface of developing osteo-
clastic cells. The RANKL/RANK binding is crucial for the
differentiation, function, and survival of osteoclasts.
On the other hand, osteoprotegerin (OPG), another oste-
oblastic cell-derived factor, interrupts the RANKL/RANK
binding as a decoy receptor of RANKL, inhibiting osteo-
clastogenesis. Therefore, the RANKL/OPG ratio expressed
by osteoblastic cells and the RANK expression by osteo-
clast precursor cells largely determine the formation of
functional osteoclasts and the activation of the initial
step of bone remodeling.46 RANKL level in the gingival
crevicular fluid becomes significantly higher than in the
American Journal of Orthodontics and Dentofacial Orthopedics
621
contralateral control side after 24 hours of continuous
compressive force in adolescent patients.47 RANKL
expression is increased in the osteoblasts, osteocytes,
and fibroblasts in the PDL and the alveolar bone, espe-
cially by the compressive force, as early as 3 hours after
orthodontic force application and remains elevated after
at least 5 days.48-55 Tensile strain, however, significantly
reduces the mRNA level of RANKL in osteoblastic cell
cultures.56 Local delivery of RANKL with gene therapy
significantly stimulates osteoclast formation and speeds
up orthodontic tooth movement.57,58 Contrary to
RANKL, OPG concentration in the gingival crevicular
fluid at the compression side is decreased compared
with the basal level as early as 1 hour after orthodontic
force application in adolescent patients59 and becomes
significantly lower than at the contralateral side after
24 hours in these patients.47 Other studies have shown
that OPG expression is decreased by the compressive
force but increased by the tensile force during orthodon-
tic tooth movement, opposite to the effects on
RANKL.52-54,56,60 As expected, local delivery of OPG
significantly inhibits bone remodeling and orthodontic
tooth movement.61,62 The reciprocal regulation of
RANKL and OPG expression by the compressive and
tensile strains coordinates predominant bone
resorption at the leading side and predominant bone
formation at the trailing side, enabling normal tooth
movement.
Macrophage colony-stimulating factor (M-CSF) is
another stromal and osteoblastic cell-derived factor
that is crucial for recruitment and differentiation of early
precursors of osteoclasts.63 M-CSF expression is de-
tected in osteoblasts and fibroblasts in the PDL and in
the alveolar bone at early time points during orthodontic
tooth movement.55,64 Compressive force increases the
expression of M-CSF in osteoblastic MC3T3-E1 cell cul-
tures.54 Local administration of an optimum dose of
M-CSF significantly increases the number of osteoclasts
and accelerates orthodontic tooth movement in rats.65
Daily local injections of an antibody to c-Fms, the recep-
tor of M-CSF, significantly inhibit tooth movement
with compromised osteoclast formation.66 Early up-
regulation of M-CSF is evident and important for ortho-
dontic tooth movement.
Therefore, the expression patterns of M-CSF, RANKL,
and OPG by osteoblasts play key roles in tooth move-
ment. Mechanical force induction of M-CSF and RANKL
in osteoblastic cells is mediated by other factors.
Compressive force significantly stimulates the expres-
sion of cyclooxygenase (COX)-2, the chief enzyme
responsible for the majority of prostaglandin (PG)
production, in the PDL and osteoblastic cells,54,67
and thus increases the production of prostaglandin
November 2014  Vol 146  Issue 5
622
E2 (PGE2).67,68 Compressive force also significantly
increases expression of PGE2 receptors EP2 and EP4 in
osteoblasts.68 PGE2 is a well-known factor to increase
RANKL and decrease OPG expression in osteoblastic
cells, stimulating osteoclast formation. On the other
hand, inhibitors of COX-1 and COX-2, or specific inhib-
itors of COX-2, reduce the expression of RANKL by oste-
oblastic cells54,67 and impair orthodontic tooth
movement.69,70 It is apparent that COX-2 stimulation
and PGE2 production mediate the induction of RANKL
by compressive force. Compressive force also increases
the expression of interleukin (IL)-17 and its receptors
in osteoblasts. In the absence of compressive force, the
addition of IL-17 in the cell cultures mimics the effects
of compressive force to increase the expression of M-
CSF and RANKL and to decrease the expression of
OPG, strongly suggesting that IL-17 also mediates the
effects of compressive force.52 The expressions of
vascular endothelial growth factor (VEGF) and its recep-
tor VEGFR-1 are intensified by mechanical forces during
orthodontic tooth movement.64,71-73 A neutralizing
antibody to VEGF partially inhibits the induction of
RANKL and VEGFR-1 by mechanical stress, indicating
that VEGF mediates the induction of RANKL by mechan-
ical force in an autocrine pathway.73
The inflammatory response to orthodontic tooth
movement is associated with the production and release
of a variety of cytokines. After 24 hours of orthodontic
force application, the protein levels of IL-1, IL-6, and tis-
sue necrosis factor (TNF)-a are significantly increased in
the gingival crevicular fluid in humans.74 The number of
cells expressing interferon-g is significantly increased by
tooth movement.75 Differential expression of cytokines
between the compression and tension sides has also
been shown: the compression side has higher levels of
TNF-a and matrix metalloproteinase-1, whereas the
tension side has higher levels of IL-10, tissue inhibitor
of metalloproteinase-1, and collagen-1.53 Ren et al76 re-
ported that TNF-a level is increased soon after tooth
movement (24 hours), along with IL-1b, IL-6, and
IL-8. Some of these cytokines, including TNF-a, IL-1b,
and IL-6, can stimulate osteoclast differentiation, func-
tion, and survival, contributing to the activation of the
bone remodeling process and tooth movement.77-79
Furthermore, tooth movement is slower in mice
lacking TNF-a expression, confirming the role of this
cytokine in orthodontic tooth movement.80
Many approaches affect the expression of the above
factors on osteoclast formation to activate bone remod-
eling and accelerate orthodontic tooth movement. Se-
lective alveolar corticotomy significantly increases local
osteoclast number and activity, and causes dramatically
reduced trabecular bone surfaces, with the most obvious
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Huang, Williams, and Kyrkanides
effects at 3 weeks postoperatively in a rat study.36 Even
though both orthodontic tooth movement and cortico-
tomy can increase bone remodeling by increasing the
expression of RANKL, RANK, and VEGF and decreasing
OPG, the combined procedures show distinctive effects
on the genes that are not simply the addition of the 2
procedures.34,55 Interestingly, full-thickness mucoper-
iosteal flap surgery without corticotomy can induce
RAP.81 Later, it was discovered that the same procedure
can stimulate new vascular plexus formation in the PDL,
and the PDL width is increased.82 The same research
group also found that bone resorption by osteoclasts
and bone formation by osteoblasts are quite obvious
surrounding the newly formed blood vessels, possibly
due to increased VEGF expression as a result of full-
thickness flap surgery.83 The surgical procedures,
including corticotomy and full-thickness mucoperios-
teal flaps, disturb the local microcirculation and cause
regional hypoxia, which will stabilize an intracellular
transcription factor called hypoxia inducible factor in os-
teoblasts.84 Hypoxia inducible factor in turn activates
the expression of VEGF84,85 and induces the expression
of RANKL in PDL fibroblasts.86 Increased hypoxia induc-
ible factor expression in osteoblasts under hypoxic con-
ditions increases the expression of VEGF and RANKL and
induces peripheral blood mononuclear cells into func-
tional osteoclasts, whereas a hypoxia inducible factor in-
hibitor reduces hypoxia-induced osteoclast formation.87
Corticotomy also significantly enhances the expression
of more than 20 cytokines, including TNF, IL-1, and
IL-6, compared with tooth movement or soft-tissue
flap surgery alone.88 Low-energy laser irradiation up-
regulates the number of RANKL and RANK positive cells
2 to 3 days later; this contributes to accelerated tooth
movement.89 Resonance vibration also stimulates the
expression of RANKL and osteoclast formation in the
PDL.14 Some pharmacologic agents, including parathy-
roid hormone, 1,25 dihydroxy vitamin D3 (1,25
[OH]2D3), and PGE2, can increase RANKL and decrease
OPG expression in osteoblasts, promoting osteoclast
formation and enhancing bone remodeling activity,
therefore increasing the speed of orthodontic tooth
movement.
OSTEOBLAST FORMATION AND BONE APPOSITION
Osteoblast proliferation, differentiation, survival, and
function are regulated by a number of extracellular fac-
tors including growth factors, cytokines, and hormones,
as well as by interactions with osteoclastic cells. Trans-
forming growth factor (TGF)-b1 is a secreted protein
that enhances bone formation by chemotactic effects
on osteoblastic cells, promoting osteoblast proliferation
Huang, Williams, and Kyrkanides
and differentiation at early stages while inhibiting oste-
oclast formation by reducing RANKL and increasing OPG
expression.90 TGF-b1 protein concentration in gingival
crevicular fluid is significantly increased after 24 hours
of orthodontic tooth movement in human patients.91
In another human experiment observing TGF-b1 protein
concentrations in gingival crevicular fluid after 24 hours
of orthodontic force application, the compression side
had a higher concentration than did the tension side.92
In the human PDL, the mRNA level of TGF-b1 is similarly
increased at both the compression and tension sides af-
ter 7 days of force application.53 However, another
experiment in rats demonstrated that the level of TGF-
b1 protein in the PDL is much higher at the tension
side than at the compression side from 5 to 7 days after
force application.93 The discrepancy might be due to a
different species or experimental protocol. The induction
of TGF-b1 by orthodontic tooth movement suggests
that the factor is involved in the more activated bone
formation process as part of the stimulated bone remod-
eling activity during tooth movement. As mentioned
above, VEGF expression is increased early during ortho-
dontic tooth movement. Street and Lenehan94 discov-
ered that VEGF strongly inhibits apoptosis of cultured
primary human osteoblasts and promotes nodule forma-
tion and alkaline phosphatase release. Differentiation of
osteoblastic cells as assessed with the expression of
marker molecules alkaline phosphatase and osteocalcin
is significantly increased with VEGF stimulation.95
Thus, VEGF may have anabolic effects in addition to
its catabolic effects in reaction to mechanical force.
Wnt signaling is important for the commitment of
mesenchymal stem cells to differentiate into osteo-
blasts.96 The canonical Wnt signaling pathway regulates
gene expression through stabilization and nuclear trans-
location of b-catenin, an intracellular signaling mole-
cule. Compressive force on PDL cells causes a transient
cytoplasmic accumulation and nuclear translocation of
b-catenin, suggesting the role of Wnt/b-catenin
signaling in mediating the effects of mechanical force
on bone formation.97 Bone morphogenetic proteins
(BMPs) are also important in the commitment of mesen-
chymal stem cells into osteoblasts and the differentia-
tion and function of osteoblasts.98,99 Compressive
forces of optimum magnitude can induce the
expression of BMPs and transcription factors crucial
for osteoblast differentiation of Runx2 and Osterix, as
well as promoting mineralization in osteoblastic Saos-
2 cell cultures. Noggin, an antagonist of BMP, inhibits
the compressive force-induced osteoblast differentiation
and mineralization, further supporting that BMPs
mediate osteoblast differentiation induced by compres-
sive force.100 However, local injection of BMP-2 does
American Journal of Orthodontics and Dentofacial Orthopedics
623
not increase the speed of orthodontic tooth movement,
suggesting that enhancing bone formation alone might
not be as effective as promoting bone resorption in
accelerating orthodontic tooth movement.101
The multiplural stem cells in the alveolar bone
marrow, PDL, and periosteum play important roles
in the regulation of bone remodeling and tooth move-
ment. Human mesenchymal stem cells (MSCs) are
transcriptionally controlled by mechanical strain to
differentiate into osteo-chondrogenic lineage with
increased expression of osteoblastic and chondrocytic
markers.102 Tensile strain has osteogenic differentiation
effects on human MSCs with significantly up-regulated
BMP-2 mRNA level in 3-dimensional collagen matrix
cultures.103 Under hypoxic conditions, expression of
multiple intracellular and extracellular molecules by the
MSCs are stimulated, including VEGF, surviving p21, cy-
tochrome c, caspases, phosphorylated Akt, and
others.104,105 Inflammatory cytokines, such as TNF,
IL-1b, and TGF-b1, stimulate MSCs to produce
VEGF,105,106 which acts back on MSCs directly and
stimulates the expression of neurohilin 1 and 2, the
chemotactic factors promoting recruitment of
osteoprogenitor cells.107 Therefore, it is highly possible
that MSCs, under mechanical, hypoxic, and inflamma-
tory stimuli during orthodontic tooth movement or after
alveolar corticotomy, are the source of a variety of factors
that not only determine the fate of MSCs themselves, but
also regulate the recruitment and function of osteoblasts
and osteoclasts, and determine the level of bone remod-
eling and the rate of tooth movement. MSCs are also
affected by various other approaches that accelerate or-
thodontic tooth movement. 1,25 Dihydroxy vitamin D3
directly stimulates the differentiation of MSCs into oste-
oblasts, and this effect is synergistically enhanced by
TGF-b.108 Low-energy irradiation promotes MSCs' pro-
liferation and differentiation into osteoblasts.109 Pulsed
electromagnetic fields110,111 and electric current112 also
increase differentiation of human MSCs into osteoblasts
in cell cultures. Further studies in this area are needed to
help us understand the role of MSCs in bone remodeling
and orthodontic tooth movement.
Bone formation and osteoblast differentiation and
function are influenced by different approaches that
regulate the speed of orthodontic tooth movement.
Alveolar corticotomy alone significantly increases the
rate of new cortical bone apposition 1 to 4 weeks post-
surgically, and stimulates new trabecular bone forma-
tion by about 1.5 times compared with the controls at
3 weeks.36 Bone volume fraction, bone mineral content,
and bone mineral density are all increased 1 to 3 weeks
after corticotomy as measured by microcomputed to-
mography.55 Molecular studies have shown that alveolar
November 2014  Vol 146  Issue 5
624
corticotomy enhances the expression of the anabolic
factor TGF-b1, as well as the osteoblast differentiation
markers osteocalcin, osteopontin, and bone sialopro-
tein.34,55 The combination of orthodontic tooth
movement and alveolar corticotomy is not simply the
addition of 2 separate procedures but, rather, a more
sophisticated synergy on bone cell activities and
subsequently on bone remodeling that calls for further
investigations.
ROLE OF OSTEOCYTES
Osteocytes are terminally differentiated osteoblasts
that are embedded in the bone matrix during bone
formation. They are stellate cells that form a functional
network with other osteocytes, bone surface cells, bone
marrow cells, and endothelial cells via long cytoplasmic
extensions, or dendrites. This network of osteocytes oc-
cupies the lacunae-canaliculi system within the bone
matrix, where the cell bodies and dendrites reside,
respectively. Cell-to-cell signaling and material ex-
changes take place through the gaps between the den-
drites of osteocytes and the interstitial fluid-filled
lacunae-canaliculi system. Mechanical loading on the
bone can cause strain in the bone structure, resulting
in interstitial fluid flow in the lacunae-canaliculi system,
which generates shear stress on the surface of osteo-
cytes, activating mechanoreceptors on the cytoplasmic
membrane of osteocytes113 and triggering intracellular
signaling pathways, most notably the canonical Wnt
pathway and the protein kinase A pathway.114 These
signaling pathways lead to changes in the production
level of biochemical factors that are crucial for osteo-
clasts, osteoblasts, and bone remodeling.
Osteocytes express M-CSF, RANKL, and OPG and
regulate osteoclast formation and function.115 The
expression of these factors by osteocytes is affected by
microdamage in bone and mechanical loading during
orthodontic tooth movement. Microdamage in bone
causes osteocyte apoptosis, and the apoptotic bodies
contain RANKL to induce osteoclast formation.116 Oste-
ocyte damage induced in cell cultures also resulted in
increased production of M-CSF and RANKL, increasing
osteoclast formation.117 Osteocyte apoptosis has been
shown to be acutely induced by orthodontic tooth
movement in mice, before osteoclast formation.118
RANKL expression was increased in osteocytes located
close to the resorption lacunae.49 Targeted ablation of
osteocytes significantly reduced osteoclast formation
and bone resorption during orthodontic tooth move-
ment.119 On the other hand, mechanical loading from
fluid flow up to 12 hours significantly reduced the
RANKL/OPG ratio and the osteoclast formation potential
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Huang, Williams, and Kyrkanides
in cultured osteocytes.120,121 The inhibitory effect of
mechanical loading on osteoclast formation during
orthodontic tooth movement has not been clearly
demonstrated and demands further studies.
Sclerostin is a protein factor produced by osteocytes.
It inhibits the function and survival of osteoblasts and
bone formation by antagonizing the canonical Wnt
signaling pathway in osteoblastic cells. It was reported
that mechanical loading decreased the expression of
sclerostin, favoring bone formation.122 Matsuda
et al123 found that sclerostin expression was significantly
decreased at the superficial zone of the alveolar bone on
the tension side, where bone formation took place.
Fibroblast growth factor-23 is another osteocyte-
derived factor that inhibits osteoblast differentiation
and matrix mineralization.124,125 Fibroblast growth
factor-23 expression was significantly reduced at the
bone formation site on the tension side of the root dur-
ing orthodontic tooth movement, similar to sclero-
stin.123 These studies strongly support that osteocytes
play a key role in site-specific bone formation during or-
thodontic tooth movement.
Vibration of a certain frequency, intensity, and dura-
tion can increase bone mass. Whole body vibration has
been shown to significantly improve bone mineral den-
sity and structure,126,127 which is largely attributed
to osteocytes' reaction to vibration as the chief
mechanosensory cells in the bone.114 However, since
reduced bone density, not the contrary, at the early stage
of tooth movement is crucial for accelerated orthodontic
tooth movement, the anabolic effects of vibration seem
to be undesirable. Nevertheless, there have been some
reports or assertions that vibration increased the rate
of tooth movement. Resonant vibration once every
week was shown to increase the rate of orthodontic
tooth movement, and the effect was attributed to
enhanced RANKL expression and an increased number
of osteoclasts.14 AcceleDent (OrthoAccel Technologies,
Inc, Bellaire, Tex) is a vibration appliance approved by
the Food and Drug Administration to accelerate ortho-
dontic tooth movement with daily use. Currently, its ef-
fects on bone cells, density, and structure are still
unknown. Modern piezotome appliances also have
some vibration properties and may affect bone cells
and tooth movement. Vibration parameters of different
appliances, including whole body vibration, resonant vi-
bration, AcceleDent, and piezotomes, are distinct from
each other; this might explain different bone reactions,
anabolic or catabolic, to the appliances. Further studies
are required to investigate the effects of various vibration
settings on bone cells and bone remodeling to identify
the optimum settings to enhance bone remodeling and
accelerate orthodontic tooth movement.
Huang, Williams, and Kyrkanides
It is clear that osteocytes are important in regulating
both osteoclast formation and function, and osteoblast
differentiation during orthodontic tooth movement.
However, their role in accelerated orthodontic tooth
movement induced by different methods has not been
well investigated. Future studies should focus more on
this aspect.
CLINICAL AND EXPERIMENTAL METHODS TO
ACCELERATE ORTHODONTIC TOOTH MOVEMENT
Direct injury to the alveolar or basal bones of the
maxilla and mandible accelerates orthodontic tooth
movement by inducing RAP as a wound-healing process,
which is the basis for clinical procedures such as
corticotomy-assisted orthodontics, piezocision-aided
orthodontics, and surgery-first orthodontics.24,33 The
wound-healing process after trauma is similar, if not
identical, as reviewed above. Nonsurgical methods,
such as various physical and pharmacologic approaches,
also enhance bone remodeling and facilitate tooth
movement, and have been shown to be effective in an-
imal and human experiments.128
The intentional use of alveolar surgery to speed up
tooth movement began with the employment of osteot-
omy, the complete cutting of cortical and medulla of the
bone, in the 1890s.7,129 Corticotomy, a surgical
procedure to perforate the cortical bone without going
into the medulla, was used in combination with
osteotomy to accelerate tooth movement starting in
the 1950s.8 Later, it was found that corticotomy alone
was also effective in achieving faster tooth movement
with much less tissue destruction and lower risks to peri-
odontal tissues and dental pulp. Studies in both humans
and animals have shown that corticotomy speeds up
tooth movement by about 2-fold,35,130 and the
accelerating effect takes place chiefly during the first
few weeks after the procedure.131 Although both corti-
cotomy and osteotomy accelerate tooth movement,
they achieve the goal with different mechanisms: corti-
cotomy induces RAP, whereas osteotomy acts in a
manner similar to distraction osteogenesis.34,132
Alveolar corticotomy is the vital step to enable faster
tooth movement in the clinical procedure called
periodontally accelerated osteogenic orthodontics,
which currently is probably the most commonly used
clinical procedure to accelerate tooth movement.13,130
The techniques, clinical applications, indications and
contraindications, limitations, and complications have
been well described and summarized.6,130,133,134 Even
though the method has been shown to be quite
effective in case reports and animal experiments,
several obstacles prevent its more widespread use.
American Journal of Orthodontics and Dentofacial Orthopedics
625
Pain, swelling, hematoma, and morbidity are
complications of the surgery and can negatively
impact the patients' experiences and acceptance of the
procedure. The additional cost to orthodontic
treatment to cover the surgical procedures can also be
a concern.
Piezocision-aided orthodontics was developed to
address the drawbacks of surgical corticotomy.135 Like
periodontally accelerated osteogenic orthodontics, it
also speeds up tooth movement by alveolar corticotomy,
but instead of full-thickness flaps, small vertical cuts
through the gingival tissues and periosteum are made
to reach the cortex of the bone. Bone grafts are
embedded in tunnels connecting the vertical cuts.
According to case reports in the literature, it appears
that piezocision is similarly effective in accelerating
tooth movement and augmenting periodontal tissues
with much less trauma.135-137 In addition to direct
bone injury by piezocision, vibration may also play a
role in activating bone remodeling, since many modern
commercial piezotomes incorporate high-frequency
vibration. More studies are needed about the mecha-
nisms of piezocision to accelerate tooth movement
and to evaluate its effectiveness and long-term results.
Piezocision is a surgical procedure and has some
inherent potential risks.
Surgery-first orthodontics is a strategy to signifi-
cantly shorten treatment duration for patients who
need orthognathic surgery to correct a severe dentofacial
deformity.138-145 Traditional comprehensive orthodontic-
orthognathic surgery treatment starts with orthodontic
treatment to align the teeth and decompensate the
dentition to prepare for optimum correction of skeletal
discrepancies. After surgery, orthodontic treatment is
needed to settle the occlusion and refine the finishing.
Typically, the total treatment time is about 24 to
30 months. Studies have shown that tooth movement
after orthognathic surgery is much faster than with
routine orthodontic treatment, which can be attributed
to RAP stimulated by the surgical wound to the
bone.143 Careful patient selection is required to perform
surgery-first orthodontics and should follow certain
guidelines and procedures.144
Resonance vibration is based on a frequency equal to
the natural frequency of an object, causing the largest
amplitude of vibration of this object. When applied to
the first molars in rats for 8 minutes once a week, reso-
nance vibration (60 Hz) increased tooth movement by
15% compared with the controls, stimulating more
expression of RANKL and osteoclast formation in the
PDL.14 Recently, a vibration appliance, AcceleDent, has
been marketed, with claims that it can increase the
rate of orthodontic movement. However, it provides
November 2014  Vol 146  Issue 5
626
vibration with only 1 fixed frequency (4 Hz). There is still
no peer-reviewed study on the biologic or the clinical ef-
fects of the appliance.
Low-energy laser irradiation can also speed up ortho-
dontic tooth movement according to most studies in hu-
mans and animals.15,37-39,89,146-148 However, some
studies show that low-energy laser irradiation does not
accelerate tooth movement149-151 and can even slow
it.152 The discrepancies may be explained by the
different treatment protocols used in these studies,
including the wavelengths of the lasers, irradiation
doses, locations, and frequencies. Several studies have
reported that low-energy laser irradiation stimulates
alveolar bone remodeling activities as indicated by the
increased numbers and functions of osteoclasts and os-
teoblasts,15,37,38,40,41 as well as by molecular markers
such as matrix metalloproteinase-9, cathepsin K, a(v)
b(3) integrin,39 the RANK/RANKL/OPG system,89 and
basic fibroblast growth factor.153 Because of its nonin-
vasiveness and relative ease of operation, low-level laser
irradiation seems to be promising for accelerating ortho-
dontic tooth movement. But more research needs to be
done to discover the most efficient protocol to enhance
its effect and reduce the frequency of irradiation to make
the method more clinically applicable.
Magnetic fields, including static magnetic field18,154
and pulsed electromagnetic field,18,42,155 have increased
the speed of orthodontic tooth movement in animal
studies. Histologic analyses have suggested that
alveolar bone remodeling is activated under the
influence of magnetic fields as activities of bone cells
are elevated and new bone deposition is increased on
the tension side.18,42,155 Hyalinization in the PDL was
reduced in the group treated with the static magnetic
field, which also contributed to accelerated tooth
movement.154 However, 1 study showed that the static
magnetic field did not increase the rate of tooth move-
ment, but root resorption was increased, prompting
concerns about the effectiveness and safety of this
method.156 Further studies are needed to determine
the effect of magnetic fields on tooth movement and
root resorption.
Electric current, when applied constantly at 15 mA for
14 days in cats, significantly increased canine retraction
by over 2-fold.19 Histologic studies have demonstrated
that bone remodeling was enhanced with more bone
formation at the cathode side and more bone resorption
at the anode side, and osteoblast numbers increased
significantly in the PDL with increased cellular activ-
ity.19,157 Alternatively, when applied in the form of a
1-Hz square wave of 6 V with a current of about
10 mA, the micropulsed electric current accelerated or-
thodontic tooth movement as well, with more osteoblast
November 2014  Vol 146  Issue 5 American Journal of Orthodontics and Dentofacial Orthopedics
Huang, Williams, and Kyrkanides
and bone formation on the tension side, and more
osteoclast-like cell formation on the compression
side.43 The source of electricity, however, poses a prob-
lem for the clinical use of this method. Microfabricated
biocatalytic fuel cells (enzyme batteries) might resolve
this problem.158
Parathyroid hormone is the major hormone regu-
lating bone remodeling and calcium homeostasis. It ele-
vates serum calcium concentration by both stimulating
bone resorption and up-regulating calcium reabsorption
and the enzyme 25-hydroxy D3 1-alpha-hydroxylase in
the kidneys, which in turn form more 1,25 dihydroxy
vitamin D3 that increases calcium absorption in the small
intestines. Animal studies have shown that continuous
global infusion or chronic local injection of parathyroid
hormone accelerated orthodontic tooth movement by
about 1.6- to 2-fold, and significantly increased osteo-
clast numbers.16,159 It is well-known that chronic eleva-
tion of parathyroid hormone leads to pathologic
changes in multiple organs, especially kidneys and
bones. These short-term studies did not determine the
long-term effects of this systemic hormone at the dose
used to accelerate tooth movement, especially kidney
function and bone condition, so safety remains a
concern for its clinical application in orthodontic treat-
ment. Even though local injection with control-release
systems may increase the effectiveness and lower the
risks, a more effective release system is still desired,
and safety should be carefully studied.
1,25 Dihydroxy vitamin D3, as mentioned above, pro-
motes calcium resorption in the small intestines. It also
acts on bone cells to increase bone remodeling.160 Ani-
mal studies have indicated that local injection of 1,25
dihydroxy vitamin D3 accelerated orthodontic tooth
movement by about 1.2- to 2.5-fold.17,45,161
Histologic examination shows that 1,25 dihydroxy
vitamin D3 stimulates the formation of osteoclasts in a
dose-dependent manner, synergizing with the mechan-
ical force,44 and causes significantly more alveolar bone
resorption.45 On the other hand, osteoblast formation
and bone formation are also elevated under 1,25 dihy-
droxy vitamin D3 stimulation, seemingly presenting a
more balanced effect of 1,25 dihydroxy vitamin D3 on
bone volume.17,162 Frequent injections of 1,25
dihydroxy vitamin D3 were given to the animals,
making the clinical practicality of this factor in
humans questionable. And like parathyroid hormone,
the safe use of this systemic factor in orthodontic
treatment should be investigated.
PGs are local autocrine/paracrine lipid inflammatory
factors that also regulate bone remodeling. Several ani-
mal experiments have shown that local application of
PGE1, PGE2, or analogs of PGE1, PGE2, or thromboxane
Huang, Williams, and Kyrkanides
Fig. Summary of cellular and molecular mechanisms underlying accelerated orthodontic tooth move-
ment. Methods to accelerate orthodontic tooth movement are shown in red. Blue arrow, Stimulation; red
blunted arrow, inhibition; MSC, mesenchymal stem cell; HSC, hematopoietic stem cell; HIF, hypoxia
inducible factor; FGF, fibroblast growth factor.
A2 increase the speed of orthodontic tooth move-
ment.17,163-167 Local submucosal injection of PGE1 in
human patients was also successful in accelerating
tooth movement by 1.6-fold.168 Alternatively, ortho-
dontic tooth movement is impaired by nonsteroidal
anti-inflammatory drugs, the compounds that inhibit
the COX-1 and COX-2 enzymes that catalyze the rate-
limiting step of prostaglandin formation.69,70 One
concern of using PGs clinically is the pain reaction
from patients, since PGs are potent pain inducers.
Another concern is increased root resorption
concomitant with accelerated tooth movement, as
indicated by several independent studies.163-165
CONCLUSIONS
The rate of orthodontic tooth movement depends on
the modeling and remodeling of the alveolar process
while adapting to the new biomechanical environment.
The rate of alveolar modeling and remodeling is deter-
mined by the level of activity of bone cells (osteoclasts,
osteoblasts, and osteocytes), which are under the control
of mechanical and biochemical factors, most notably
PGs and cytokines. Osteoclast activation is crucial for
American Journal of Orthodontics and Dentofacial Orthopedics
627
elevated bone modeling and remodeling required for
accelerated tooth movement. Osteoblastic cell-derived
cytokines M-CSF and the RANKL/OPG ratio determine
osteoclast formation and function. Methods that accel-
erate orthodontic tooth movement stimulate M-CSF and
increase the RANKL/OPG ratio directly or indirectly
through changes in blood flow and hypoxia, and tissue
damage, promoting the production of cytokines
including VEGF, TNF-a, interferon-b, ILs, matrix metal-
loproteinases, and others. Osteoblasts are important in
maintaining normal bone density and mass in the alve-
olar process. Some methods that accelerate tooth move-
ment also induce enhanced osteoblast function by
stimulating mesenchymal stem cells to differentiate
into osteoblasts through cytokines including TGF-b,
BMPs, VEGF, and others. Osteocytes, the most abundant
bone cells, may also mediate the effects of methods that
accelerate tooth movement by inducing osteoclast for-
mation through apoptosis. The role of osteocytes is still
not clear. The cellular and molecular mechanisms of
accelerated orthodontic tooth movement are illustrated
in the Figure. There is an obvious need to investigate
in more depth the molecular mechanisms underlying
accelerated orthodontic tooth movement to elucidate
November 2014  Vol 146  Issue 5
628
the key factors that make the procedure most effective
with the fewest side effects, shortest times, and lowest
costs to patients. New knowledge in this field will
empower us to revolutionize orthodontic therapy and
its practice in the future.
REFERENCES
1. Brin I, Tulloch JF, Koroluk L, Philips C. External apical root
resorption in Class II malocclusion: a retrospective review of 1-
versus 2-phase treatment. Am J Orthod Dentofacial Orthop
2003;124:151-6.
2. Sunku R, Roopesh R, Kancherla P, Perumalla KK, Yudhistar PV,
Reddy VS. Quantitative digital subtraction radiography in the
assessment of external apical root resorption induced by ortho-
dontic therapy: a retrospective study. J Contemp Dent Pract
2011;12:422-8.
3. Jiang RP, McDonald JP, Fu MK. Root resorption before and after
orthodontic treatment: a clinical study of contributory factors.
Eur J Orthod 2010;32:693-7.
4. Richter AE, Arruda AO, Peters MC, Sohn W. Incidence of
caries lesions among patients treated with comprehensive
orthodontics. Am J Orthod Dentofacial Orthop 2011;139:
657-64.
5. Ikeda T, Yamaguchi M, Meguro D, Kasai K. Prediction and causes
of open gingival embrasure spaces between the mandibular cen-
tral incisors following orthodontic treatment. Aust Orthod J
2004;20:87-92.
6. Hassan AH, Al-Fraidi AA, Al-Saeed SH. Corticotomy-assisted or-
thodontic treatment: review. Open Dent J 2010;4:159-64.
7. Fitzpatrick BN. Corticotomy. Aust Dent J 1980;25:255-8.
8. Kole H. Surgical operations on the alveolar ridge to correct
occlusal abnormalities. Oral Surg Oral Med Oral Pathol 1959;
12:515-29.
9. Generson RM, Porter JM, Zell A, Stratigos GT. Combined surgical
and orthodontic management of anterior open bite using corti-
cotomy. J Oral Surg 1978;36:216-9.
10. Anholm JM, Crites DA, Hoff R, Rathbun WE. Corticotomy-facili-
tated orthodontics. CDA J 1986;14:7-11.
11. Gantes B, Rathbun E, Anholm M. Effects on the periodontium
following corticotomy-facilitated orthodontics. Case reports. J
Periodontol 1990;61:234-8.
12. Duker J. Experimental animal research into segmental alveolar
movement after corticotomy. J Maxillofac Surg 1975;3:81-4.
13. Wilcko WM, Wilcko T, Bouquot JE, Ferguson DJ. Rapid ortho-
dontics with alveolar reshaping: two case reports of decrowding.
Int J Periodontics Restorative Dent 2001;21:9-19.
14. Nishimura M, Chiba M, Ohashi T, Sato M, Shimizu Y, Igarashi K,
et al. Periodontal tissue activation by vibration: intermittent
stimulation by resonance vibration accelerates experimental
tooth movement in rats. Am J Orthod Dentofacial Orthop
2008;133:572-83.
15. Kawasaki K, Shimizu N. Effects of low-energy laser irradiation on
bone remodeling during experimental tooth movement in rats.
Lasers Surg Med 2000;26:282-91.
16. Soma S, Iwamoto M, Higuchi Y, Kurisu K. Effects of continuous
infusion of PTH on experimental tooth movement in rats. J
Bone Miner Res 1999;14:546-54.
17. Kale S, Kocadereli I, Atilla P, Asan E. Comparison of the effects of
1,25 dihydroxycholecalciferol and prostaglandin E2 on ortho-
dontic tooth movement. Am J Orthod Dentofacial Orthop
2004;125:607-14.
November 2014  Vol 146  Issue 5 American Journal of Orthodontics and Dentofacial Orthopedics
Huang, Williams, and Kyrkanides
18. Darendeliler MA, Sinclair PM, Kusy RP. The effects of samarium-
cobalt magnets and pulsed electromagnetic fields on tooth
movement. Am J Orthod Dentofacial Orthop 1995;107:578-88.
19. Davidovitch Z, Finkelson MD, Steigman S, Shanfeld JL,
Montgomery PC, Korostoff E. Electric currents, bone remodeling,
and orthodontic tooth movement. II. Increase in rate of tooth
movement and periodontal cyclic nucleotide levels by combined
force and electric current. Am J Orthod 1980;77:33-47.
20. Frost HM. Skeletal structural adaptations to mechanical usage
(SATMU): 1. Redefining Wolff's law: the bone modeling problem.
Anat Rec 1990;226:403-13.
21. Hattner R, Epker BN, Frost HM. Suggested sequential mode of
control of changes in cell behaviour in adult bone remodelling.
Nature 1965;206:489-90.
22. Hadjidakis DJ, Androulakis II. Bone remodeling. Ann N Y Acad Sci
2006;1092:385-96.
23. Roberts WE, Huja S, Roberts JA. Bone modeling: biomechanics,
molecular mechanisms, and clinical perspectives. Semin Orthod
2004;10:123-61.
24. Verna C, Dalstra M, Melsen B. The rate and the type of orthodon-
tic tooth movement is influenced by bone turnover in a rat model.
Eur J Orthod 2000;22:343-52.
25. Frost HM. Skeletal structural adaptations to mechanical usage
(SATMU): 2. Redefining Wolff's law: the remodeling problem.
Anat Rec 1990;226:414-22.
26. Kim CH, You L, Yellowley CE, Jacobs CR. Oscillatory fluid flow-
induced shear stress decreases osteoclastogenesis through
RANKL and OPG signaling. Bone 2006;39:1043-7.
27. Seeman E. Bone modeling and remodeling. Crit Rev Eukaryot
Gene Expr 2009;19:219-33.
28. Frost HM. The regional acceleratory phenomenon: a review. Hen-
ry Ford Hosp Med J 1983;31:3-9.
29. King GJ, Keeling SD, Wronski TJ. Histomorphometric study of
alveolar bone turnover in orthodontic tooth movement. Bone
1991;12:401-9.
30. Melsen B. Biological reaction of alveolar bone to orthodontic
tooth movement. Angle Orthod 1999;69:151-8.
31. Verna C, Zaffe D, Siciliani G. Histomorphometric study of bone
reactions during orthodontic tooth movement in rats. Bone
1999;24:371-9.
32. Cho KW, Cho SW, Oh CO, Ryu YK, Ohshima H, Jung HS. The effect
of cortical activation on orthodontic tooth movement. Oral Dis
2007;13:314-9.
33. Mostafa YA, Fayed MMS, Mehanni S, ElBokle NN, Heider AM.
Comparison of corticotomy-facilitated vs standard tooth-
movement techniques in dogs with miniscrews as anchor units.
Am J Orthod Dentofacial Orthop 2009;136:570-7.
34. Wang L, Lee W, Lei DL, Liu YP, Yamashita DD, Yen SL. Tisssue re-
sponses in corticotomy- and osteotomy-assisted tooth move-
ments in rats: histology and immunostaining. Am J Orthod
Dentofacial Orthop 2009;136:770.e1-11;discussion 70-1.
35. Iino S, Sakoda S, Ito G, Nishimori T, Ikeda T, Miyawaki S. Accel-
eration of orthodontic tooth movement by alveolar corticotomy
in the dog. Am J Orthod Dentofacial Orthop 2007;131:448.e1-8.
36. Sebaoun JD, Kantarci A, Turner JW, Carvalho RS, Van Dyke TE,
Ferguson DJ. Modeling of trabecular bone and lamina dura
following selective alveolar decortication in rats. J Periodontol
2008;79:1679-88.
37. Sun X, Zhu X, Xu C, Ye N, Zhu H. Effects of low energy laser on
tooth movement and remodeling of alveolar bone in rabbits.
Hua Xi Kou Qiang Yi Xue Za Zhi 2001;19:290-3.
38. Yoshida T, Yamaguchi M, Utsunomiya T, Kato M, Arai Y,
Kaneda T, et al. Low-energy laser irradiation accelerates the
Huang, Williams, and Kyrkanides
velocity of tooth movement via stimulation of the alveolar bone
remodeling. Orthod Craniofac Res 2009;12:289-98.
39. Yamaguchi M, Hayashi M, Fujita S, Yoshida T, Utsunomiya T,
Yamamoto H, et al. Low-energy laser irradiation facilitates the ve-
locity of tooth movement and the expressions of matrix
metalloproteinase-9, cathepsin K, and alpha(v) beta(3) integrin
in rats. Eur J Orthod 2010;32:131-9.
40. Habib FA, Gama SK, Ramalho LM, Cangussu MC, Santos Neto FP,
Lacerda JA, et al. Laser-induced alveolar bone changes during or-
thodontic movement: a histological study on rodents. Photomed
Laser Surg 2010;28:823-30.
41. Altan BA, Sokucu O, Ozkut MM, Inan S. Metrical and histological
investigation of the effects of low-level laser therapy on ortho-
dontic tooth movement. Lasers Med Sci 2012;27:131-40.
42. Stark TM, Sinclair PM. Effect of pulsed electromagnetic fields on
orthodontic tooth movement. Am J Orthod Dentofacial Orthop
1987;91:91-104.
43. Hashimoto H. Effect of micro-pulsed electricity on experimental
tooth movement. Nihon Kyosei Shika Gakkai Zasshi 1990;49:
352-61.
44. Takano-Yamamoto T, Kawakami M, Kobayashi Y, Yamashiro T,
Sakuda M. The effect of local application of 1,25-
dihydroxycholecalciferol on osteoclast numbers in orthodonti-
cally treated rats. J Dent Res 1992;71:53-9.
45. Collins MK, Sinclair PM. The local use of vitamin D to increase the
rate of orthodontic tooth movement. Am J Orthod Dentofacial
Orthop 1988;94:278-84.
46. Theoleyre S, Wittrant Y, Tat SK, Fortun Y, Redini F, Heymann D.
The molecular triad OPG/RANK/RANKL: involvement in the
orchestration of pathophysiological bone remodeling. Cytokine
Growth Factor Rev 2004;15:457-75.
47. Nishijima Y, Yamaguchi M, Kojima T, Aihara N, Nakajima R,
Kasai K. Levels of RANKL and OPG in gingival crevicular fluid dur-
ing orthodontic tooth movement and effect of compression force
on releases from periodontal ligament cells in vitro. Orthod Cra-
niofac Res 2006;9:63-70.
48. Kook SH, Jang YS, Lee JC. Human periodontal ligament fibro-
blasts stimulate osteoclastogenesis in response to compression
force through TNF-alpha-mediated activation of CD41 T cells.
J Cell Biochem 2011;112:2891-901.
49. Shiotani A, Shibasaki Y, Sasaki T. Localization of receptor acti-
vator of NFkappaB ligand, RANKL, in periodontal tissues during
experimental movement of rat molars. J Electron Microsc (Tokyo)
2001;50:365-9.
50. Oshiro T, Shiotani A, Shibasaki Y, Sasaki T. Osteoclast induc-
tion in periodontal tissue during experimental movement of
incisors in osteoprotegerin-deficient mice. Anat Rec 2002;
266:218-25.
51. Brooks PJ, Nilforoushan D, Manolson MF, Simmons CA,
Gong SG. Molecular markers of early orthodontic tooth move-
ment. Angle Orthod 2009;79:1108-13.
52. Zhang F, Wang CL, Koyama Y, Mitsui N, Shionome C, Sanuki R,
et al. Compressive force stimulates the gene expression of IL-
17s and their receptors in MC3T3-E1 cells. Connect Tissue Res
2010;51:359-69.
53. Garlet TP, Coelho U, Silva JS, Garlet GP. Cytokine expression
pattern in compression and tension sides of the periodontal lig-
ament during orthodontic tooth movement in humans. Eur J Oral
Sci 2007;115:355-62.
54. Sanuki R, Shionome C, Kuwabara A, Mitsui N, Koyama Y,
Suzuki N, et al. Compressive force induces osteoclast differentia-
tion via prostaglandin E(2) production in MC3T3-E1 cells. Con-
nect Tissue Res 2010;51:150-8.
American Journal of Orthodontics and Dentofacial Orthopedics
629
55. Baloul SS, Gerstenfeld LC, Morgan EF, Carvalho RS, Van Dyke TE,
Kantarci A. Mechanism of action and morphologic changes in the
alveolar bone in response to selective alveolar decortication-
facilitated tooth movement. Am J Orthod Dentofacial Orthop
2011;139(4 Suppl):S83-101.
56. Tang L, Lin Z, Li YM. Effects of different magnitudes of mechan-
ical strain on osteoblasts in vitro. Biochem Biophys Res Commun
2006;344:122-8.
57. Kanzaki H, Chiba M, Arai K, Takahashi I, Haruyama N,
Nishimura M, et al. Local RANKL gene transfer to the periodontal
tissue accelerates orthodontic tooth movement. Gene Ther 2006;
13:678-85.
58. Iglesias-Linares A, Moreno-Fernandez AM, Yanez-Vico R, Men-
doza-Mendoza A, Gonzalez-Moles M, Solano-Reina E. The use
of gene therapy vs. corticotomy surgery in accelerating orthodon-
tic tooth movement. Orthod Craniofac Res 2011;14:138-48.
59. Toygar HU, Kircelli BH, Bulut S, Sezgin N, Tasdelen B. Osteopro-
tegerin in gingival crevicular fluid under long-term continuous
orthodontic force application. Angle Orthod 2008;78:988-93.
60. Kobayashi Y, Hashimoto F, Miyamoto H, Kanaoka K, Miyazaki-
Kawashita Y, Nakashima T, et al. Force-induced osteoclast
apoptosis in vivo is accompanied by elevation in transforming
growth factor beta and osteoprotegerin expression. J Bone Miner
Res 2000;15:1924-34.
61. Kanzaki H, Chiba M, Takahashi I, Haruyama N, Nishimura M,
Mitani H. Local OPG gene transfer to periodontal tissue inhibits
orthodontic tooth movement. J Dent Res 2004;83:920-5.
62. Dunn MD, Park CH, Kostenuik PJ, Kapila S, Giannobile WV. Local
delivery of osteoprotegerin inhibits mechanically mediated bone
modeling in orthodontic tooth movement. Bone 2007;41:
446-55.
63. Udagawa N, Takahashi N, Akatsu T, Tanaka H, Sasaki T,
Nishihara T, et al. Origin of osteoclasts: mature monocytes and
macrophages are capable of differentiating into osteoclasts under
a suitable microenvironment prepared by bone marrow-derived
stromal cells. Proc Natl Acad Sci U S A 1990;87:7260-4.
64. Kaku M, Motokawa M, Tohma Y, Tsuka N, Koseki H, Sunagawa H,
et al. VEGF and M-CSF levels in periodontal tissue during tooth
movement. Biomed Res 2008;29:181-7.
65. Brooks PJ, Heckler AF, Wei K, Gong SG. M-CSF accelerates ortho-
dontic tooth movement by targeting preosteoclasts in mice.
Angle Orthod 2011;81:277-83.
66. Kitaura H, Yoshimatsu M, Fujimura Y, Eguchi T, Kohara H,
Yamaguchi A, et al. An anti-c-Fms antibody inhibits orthodontic
tooth movement. J Dent Res 2008;87:396-400.
67. Kanzaki H, Chiba M, Shimizu Y, Mitani H. Periodontal ligament
cells under mechanical stress induce osteoclastogenesis by recep-
tor activator of nuclear factor kappaB ligand up-regulation via
prostaglandin E2 synthesis. J Bone Miner Res 2002;17:210-20.
68. Sanuki R, Mitsui N, Suzuki N, Koyama Y, Yamaguchi A,
Isokawa K, et al. Effect of compressive force on the production
of prostaglandin E(2) and its receptors in osteoblastic Saos-2
cells. Connect Tissue Res 2007;48:246-53.
69. Walker JB, Buring SM. NSAID impairment of orthodontic tooth
movement. Ann Pharmacother 2001;35:113-5.
70. Arias OR, Marquez-Orozco MC. Aspirin, acetaminophen, and
ibuprofen: their effects on orthodontic tooth movement. Am J
Orthod Dentofacial Orthop 2006;130:364-70.
71. Miyagawa A, Chiba M, Hayashi H, Igarashi K. Compressive force
induces VEGF production in periodontal tissues. J Dent Res
2009;88:752-6.
72. Kohno T, Matsumoto Y, Kanno Z, Warita H, Soma K. Experi-
mental tooth movement under light orthodontic forces: rates
November 2014  Vol 146  Issue 5
630
of tooth movement and changes of the periodontium. J Orthod
2002;29:129-35.
73. Nakai T, Yoshimura Y, Deyama Y, Suzuki K, Iida J. Mechanical
stress up-regulates RANKL expression via the VEGF autocrine
pathway in osteoblastic MC3T3-E1 cells. Mol Med Report
2009;2:229-34.
74. Uematsu S, Mogi M, Deguchi T. Interleukin (IL)-1 beta, IL-6,
tumor necrosis factor-alpha, epidermal growth factor, and beta
2-microglobulin levels are elevated in gingival crevicular fluid
during human orthodontic tooth movement. J Dent Res 1996;
75:562-7.
75. Alhashimi N, Frithiof L, Brudvik P, Bakhiet M. Orthodontic move-
ment induces high numbers of cells expressing IFN-gamma at
mRNA and protein levels. J Interferon Cytokine Res 2000;20:
7-12.
76. 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;78:453-8.
77. Glantschnig H, Fisher JE, Wesolowski G, Rodan GA, Reszka AA.
M-CSF, TNFalpha and RANK ligand promote osteoclast survival
by signaling through mTOR/S6 kinase. Cell Death Differ 2003;
10:1165-77.
78. Yao Z, Xing L, Qin C, Schwarz EM, Boyce BF. Osteoclast precursor
interaction with bone matrix induces osteoclast formation
directly by an interleukin-1-mediated autocrine mechanism. J
Biol Chem 2008;283:9917-24.
79. Kayamori K, Sakamoto K, Nakashima T, Takayanagi H, Morita K,
Omura K, et al. Roles of interleukin-6 and parathyroid hormone-
related peptide in osteoclast formation associated with oral can-
cers: significance of interleukin-6 synthesized by stromal cells in
response to cancer cells. Am J Pathol 2010;176:968-80.
80. Yoshimatsu M, Shibata Y, Kitaura H, Chang X, Moriishi T,
Hashimoto F, et al. Experimental model of tooth movement by
orthodontic force in mice and its application to tumor necrosis
factor receptor-deficient mice. J Bone Miner Metab 2006;24:
20-7.
81. Yaffe A, Fine N, Binderman I. Regional accelerated phenomenon
in the mandible following mucoperiosteal flap surgery. J Perio-
dontol 1994;65:79-83.
82. Nobuto T, Imai H, Suwa F, Kono T, Suga H, Jyoshi K, et al. Micro-
vascular response in the periodontal ligament following muco-
periosteal flap surgery. J Periodontol 2003;74:521-8.
83. Nobuto T, Suwa F, Kono T, Hatakeyama Y, Honjou N, Shirai T,
et al. Microvascular response in the periosteum following muco-
periosteal flap surgery in dogs: 3-dimensional observation of an
angiogenic process. J Periodontol 2005;76:1339-45.
84. Kim HH, Lee SE, Chung WJ, Choi Y, Kwack K, Kim SW, et al. Sta-
bilization of hypoxia-inducible factor-1 alpha is involved in the
hypoxic stimuli-induced expression of vascular endothelial
growth factor in osteoblastic cells. Cytokine 2002;17:14-27.
85. Akeno N, Robins J, Zhang M, Czyzyk-Krzeska MF, Clemens TL.
Induction of vascular endothelial growth factor by IGF-I in
osteoblast-like cells is mediated by the PI3K signaling pathway
through the hypoxia-inducible factor-2alpha. Endocrinology
2002;143:420-5.
86. Park HJ, Baek KH, Lee HL, Kwon A, Hwang HR, Qadir AS, et al.
Hypoxia inducible factor-1alpha directly induces the expression
of receptor activator of nuclear factor-kappaB ligand in peri-
odontal ligament fibroblasts. Mol Cells 2011;31:573-8.
87. Dandajena TC, Ihnat MA, Disch B, Thorpe J, Currier GF. Hypoxia
triggers a HIF-mediated differentiation of peripheral blood
mononuclear cells into osteoclasts. Orthod Craniofac Res 2012;
15:1-9.
November 2014  Vol 146  Issue 5 American Journal of Orthodontics and Dentofacial Orthopedics
Huang, Williams, and Kyrkanides
88. Teixeira CC, Khoo E, Tran J, Chartres I, Liu Y, Thant LM, et al.
Cytokine expression and accelerated tooth movement. J Dent
Res 2010;89:1135-41.
89. Fujita S, Yamaguchi M, Utsunomiya T, Yamamoto H, Kasai K.
Low-energy laser stimulates tooth movement velocity via expres-
sion of RANK and RANKL. Orthod Craniofac Res 2008;11:
143-55.
90. Janssens K, ten Dijke P, Janssens S, Van Hul W. Transforming
growth factor-beta 1 to the bone. Endocr Rev 2005;26:743-74.
91. Uematsu S, Mogi M, Deguchi T. Increase of transforming growth
factor-beta 1 in gingival crevicular fluid during human orthodon-
tic tooth movement. Arch Oral Biol 1996;41:1091-5.
92. Barbieri G, Solano P, Alarcon JA, Vernal R, Rios-Lugo J, Sanz M,
et al. Biochemical markers of bone metabolism in gingival crev-
icular fluid during early orthodontic tooth movement. Angle
Orthod 2013;83:63-9.
93. Wang LL, Zhu H, Liang T. Changes of transforming growth factor
beta 1 in rat periodontal tissue during orthodontic tooth move-
ment. Chin J Dent Res 2000;3:19-22.
94. Street J, Lenehan B. Vascular endothelial growth factor regulates
osteoblast survival—evidence for an autocrine feedback mecha-
nism. J Orthop Surg Res 2009;4:19.
95. Tan YY, Yang YQ, Chai L, Wong RW, Rabie AB. Effects of vascular
endothelial growth factor (VEGF) on MC3T3-E1. Orthod Cranio-
fac Res 2010;13:223-8.
96. Bennett CN, Longo KA, Wright WS, Suva LJ, Lane TF,
Hankenson KD, et al. Regulation of osteoblastogenesis and
bone mass by Wnt10b. Proc Natl Acad Sci U S A 2005;102:
3324-9.
97. Premaraj S, Souza I, Premaraj T. Mechanical loading activates
beta-catenin signaling in periodontal ligament cells. Angle Or-
thod 2011;81:592-9.
98. Wozney JM, Rosen V, Celeste AJ, Mitsock LM, Whitters MJ,
Kriz RW, et al. Novel regulators of bone formation: molecular
clones and activities. Science 1988;242:1528-34.
99. Katagiri T, Takahashi N. Regulatory mechanisms of osteoblast
and osteoclast differentiation. Oral Dis 2002;8:147-59.
100. Mitsui N, Suzuki N, Maeno M, Yanagisawa M, Koyama Y,
Otsuka K, et al. Optimal compressive force induces bone forma-
tion via increasing bone morphogenetic proteins production
and decreasing their antagonists production by Saos-2 cells.
Life Sci 2006;78:2697-706.
101. Iglesias-Linares A, Yanez-Vico RM, Moreno-Fernandez AM,
Mendoza-Mendoza A, Solano-Reina E. Corticotomy-assisted or-
thodontic enhancement by bone morphogenetic protein-2
administration. J Oral Maxillofac Surg 2012;70:e124-32.
102. Friedl G, Schmidt H, Rehak I, Kostner G, Schauenstein K,
Windhager R. Undifferentiated human mesenchymal stem cells
(hMSCs) are highly sensitive to mechanical strain: transcription-
ally controlled early osteo-chondrogenic response in vitro. Oste-
oarthritis Cartilage 2007;15:1293-300.
103. Sumanasinghe RD, Bernacki SH, Loboa EG. Osteogenic differen-
tiation of human mesenchymal stem cells in collagen matrices:
effect of uniaxial cyclic tensile strain on bone morphogenetic
protein (BMP-2) mRNA expression. Tissue Eng 2006;12:
3459-65.
104. Chacko SM, Ahmed S, Selvendiran K, Kuppusamy ML, Khan M,
Kuppusamy P. Hypoxic preconditioning induces the expression
of prosurvival and proangiogenic markers in mesenchymal stem
cells. Am J Physiol Cell Physiol 2010;299:C1562-70.
105. Wang M, Zhang W, Crisostomo P, Markel T, Meldrum KK, Fu XY,
et al. STAT3 mediates bone marrow mesenchymal stem cell VEGF
production. J Mol Cell Cardiol 2007;42:1009-15.
Huang, Williams, and Kyrkanides
106. Luo Y, Wang Y, Poynter JA, Manukyan MC, Herrmann JL,
Abarbanell AM, et al. Pretreating mesenchymal stem cells with
interleukin-1beta and transforming growth factor-beta synergis-
tically increases vascular endothelial growth factor production
and improves mesenchymal stem cell-mediated myocardial pro-
tection after acute ischemia. Surgery 2012;151:353-63.
107. Fiedler J, Leucht F, Waltenberger J, Dehio C, Brenner RE. VEGF-A
and PlGF-1 stimulate chemotactic migration of human mesen-
chymal progenitor cells. Biochem Biophys Res Commun 2005;
334:561-8.
108. Liu P, Oyajobi BO, Russell RG, Scutt A. Regulation of osteogenic
differentiation of human bone marrow stromal cells: interaction
between transforming growth factor-beta and 1,25(OH)(2)
vitamin D(3) In vitro. Calcif Tissue Int 1999;65:173-80.
109. Soleimani M, Abbasnia E, Fathi M, Sahraei H, Fathi Y, Kaka G. The
effects of low-level laser irradiation on differentiation and prolif-
eration of human bone marrow mesenchymal stem cells into
neurons and osteoblasts—an in vitro study. Lasers Med Sci
2012;27:423-30.
110. Esposito M, Lucariello A, Riccio I, Riccio V, Esposito V, Riccardi G.
Differentiation of human osteoprogenitor cells increases after
treatment with pulsed electromagnetic fields. In Vivo 2012;26:
299-304.
111. Jansen JH, van der Jagt OP, Punt BJ, Verhaar JA, van
Leeuwen JP, Weinans H, et al. Stimulation of osteogenic differ-
entiation in human osteoprogenitor cells by pulsed electromag-
netic fields: an in vitro study. BMC Musculoskelet Disord 2010;
11:188.
112. Kim IS, Song JK, Song YM, Cho TH, Lee TH, Lim SS, et al. Novel
effect of biphasic electric current on in vitro osteogenesis and
cytokine production in human mesenchymal stromal cells. Tissue
Eng Part A 2009;15:2411-22.
113. Weinbaum S, Cowin SC, Zeng Y. A model for the excitation of os-
teocytes by mechanical loading-induced bone fluid shear
stresses. J Biomech 1994;27:339-60.
114. Bonewald LF. The amazing osteocyte. J Bone Miner Res 2011;26:
229-38.
115. Zhao S, Zhang YK, Harris S, Ahuja SS, Bonewald LF. MLO-Y4
osteocyte-like cells support osteoclast formation and activation.
J Bone Miner Res 2002;17:2068-79.
116. Kogianni G, Mann V, Noble BS. Apoptotic bodies convey activity
capable of initiating osteoclastogenesis and localized bone
destruction. J Bone Miner Res 2008;23:915-27.
117. Kurata K, Heino TJ, Higaki H, Vaananen HK. Bone marrow cell
differentiation induced by mechanically damaged osteocytes in
3D gel-embedded culture. J Bone Miner Res 2006;21:616-25.
118. Moin S, Kalajzic Z, Utreja A, Nihara J, Wadhwa S, Uribe F, et al.
Osteocyte death during orthodontic tooth movement in mice.
Angle Orthod 2014 Apr 2 [Epub ahead of print].
119. Matsumoto T, Iimura T, Ogura K, Moriyama K, Yamaguchi A. The
role of osteocytes in bone resorption during orthodontic tooth
movement. J Dent Res 2013;92:340-5.
120. You L, Temiyasathit S, Lee P, Kim CH, Tummala P, Yao W, et al.
Osteocytes as mechanosensors in the inhibition of bone resorp-
tion due to mechanical loading. Bone 2008;42:172-9.
121. Cui L, Li XT, Zhang D. Effect of fluid flow-induced shear stress on
osteoclast formation induced by osteocyte. Zhongguo Yi Xue Ke
Xue Yuan Xue Bao 2012;34:207-11.
122. Robling AG, Niziolek PJ, Baldridge LA, Condon KW, Allen MR,
Alam I, et al. Mechanical stimulation of bone in vivo reduces oste-
ocyte expression of Sost/sclerostin. J Biol Chem 2008;283:
5866-75.
American Journal of Orthodontics and Dentofacial Orthopedics
631
123. Matsuda K, Haga-Tsujimura M, Yoshie S, Shimomura-Kuroki J.
Characteristics of alveolar bone associated with physiological
movement of molar in mice: a histological and histochemical
study. Odontology 2014;102:98-104.
124. Yoshiko Y, Wang H, Minamizaki T, Ijuin C, Yamamoto R,
Suemune S, et al. Mineralized tissue cells are a principal source
of FGF23. Bone 2007;40:1565-73.
125. Wang H, Yoshiko Y, Yamamoto R, Minamizaki T, Kozai K,
Tanne K, et al. Overexpression of fibroblast growth factor 23 sup-
presses osteoblast differentiation and matrix mineralization
in vitro. J Bone Miner Res 2008;23:939-48.
126. Rubin C, Turner AS, Bain S, Mallinckrodt C, McLeod K. Anabo-
lism. Low mechanical signals strengthen long bones. Nature
2001;412:603-4.
127. Prisby RD, Lafage-Proust MH, Malaval L, Belli A, Vico L. Effects of
whole body vibration on the skeleton and other organ systems in
man and animal models: what we know and what we need to
know. Ageing Res Rev 2008;7:319-29.
128. Nimeri G, Kau CH, Abou-Kheir NS, Corona R. Acceleration of
tooth movement during orthodontic treatment—a frontier in
orthodontics. Prog Orthod 2013;14:42.
129. Merrill RG, Pedersen GW. Interdental osteotomy for immediate
repositioning of dental-osseous elements. J Oral Surg 1976;34:
118-25.
130. Wilcko MT, Wilcko WM, Pulver JJ, Bissada NF, Bouquot JE.
Accelerated osteogenic orthodontics technique: a 1-stage surgi-
cally facilitated rapid orthodontic technique with alveolar
augmentation. J Oral Maxillofac Surg 2009;67:2149-59.
131. Sanjideh PA, Rossouw PE, Campbell PM, Opperman LA,
Buschang PH. Tooth movements in foxhounds after one or two
alveolar corticotomies. Eur J Orthod 2010;32:106-13.
132. Lee W, Karapetyan G, Moats R, Yamashita DD, Moon HB,
Ferguson DJ, et al. Corticotomy-/osteotomy-assisted tooth
movement microCTs differ. J Dent Res 2008;87:861-7.
133. Cano J, Campo J, Bonilla E, Colmenero C. Corticotomy-assisted
orthodontics. J Clin Exp Dent 2012;4:e54-9.
134. Oliveira DD, de Oliveira BF, Soares RV. Alveolar corticotomies in
orthodontics: indications and effects on tooth movement. Dent
Press J Orthod 2010;15:144-57.
135. Dibart S, Sebaoun JD, Surmenian J. Piezocision: a minimally
invasive, periodontally accelerated orthodontic tooth movement
procedure. Compend Contin Educ Dent 2009;30:342-4, 46,
48-50.
136. Dibart S, Surmenian J, Sebaoun JD, Montesani L. Rapid treat-
ment of Class II malocclusion with piezocision: two case reports.
Int J Periodontics Restorative Dent 2010;30:487-93.
137. Keser EI, Dibart S. Piezocision-assisted Invisalign treatment.
Compend Contin Educ Dent 2011;32:46-8:50-1.
138. Nagasaka H, Sugawara J, Kawamura H, Nanda R. “Surgery first”
skeletal Class III correction using the skeletal anchorage system.
J Clin Orthod 2009;43:97-105.
139. Baek SH, Ahn HW, Kwon YH, Choi JY. Surgery-first approach in
skeletal Class III malocclusion treated with 2-jaw surgery: evalu-
ation of surgical movement and postoperative orthodontic treat-
ment. J Craniofac Surg 2010;21:332-8.
140. Villegas C, Uribe F, Sugawara J, Nanda R. Expedited correction of
significant dentofacial asymmetry using a “surgery first”
approach. J Clin Orthod 2010;44:97-103.
141. Sugawara J, Aymach Z, Nagasaka DH, Kawamura H, Nanda R.
“Surgery first” orthognathics to correct a skeletal Class II
malocclusion with an impinging bite. J Clin Orthod 2010;44:
429-38.
November 2014  Vol 146  Issue 5
632
142. Yu CC, Chen PH, Liou EJ, Huang CS, Chen YR. A surgery-first
approach in surgical-orthodontic treatment of mandibular prog-
nathism—a case report. Chang Gung Med J 2010;33:699-705.
143. Liou EJ, Chen PH, Wang YC, Yu CC, Huang CS, Chen YR. Surgery-
first accelerated orthognathic surgery: postoperative rapid ortho-
dontic tooth movement. J Oral Maxillofac Surg 2011;69:781-5.
144. Liou EJ, Chen PH, Wang YC, Yu CC, Huang CS, Chen YR. Surgery-
first accelerated orthognathic surgery: orthodontic guidelines
and setup for model surgery. J Oral Maxillofac Surg 2011;69:
771-80.
145. Hernandez-Alfaro F, Guijarro-Martinez R, Molina-Coral A,
Badia-Escriche C. “Surgery first” in bimaxillary orthognathic sur-
gery. J Oral Maxillofac Surg 2011;69:e201-7.
146. Cruz DR, Kohara EK, Ribeiro MS, Wetter NU. Effects of low-
intensity laser therapy on the orthodontic movement velocity of
human teeth: a preliminary study. Lasers Surg Med 2004;35:
117-20.
147. Sousa MV, Scanavini MA, Sannomiya EK, Velasco LG, Angelieri F.
Influence of low-level laser on the speed of orthodontic move-
ment. Photomed Laser Surg 2011;29:191-6.
148. Genc G, Kocadereli I, Tasar F, Kilinc K, El S, Sarkarati B. Effect of
low-level laser therapy (LLLT) on orthodontic tooth movement.
Lasers Med Sci 2013;28:41-7.
149. Gama SK, Habib FA, Monteiro JS, Paraguassu GM, Araujo TM,
Cangussu MC, et al. Tooth movement after infrared laser photo-
therapy: clinical study in rodents. Photomed Laser Surg 2010;
28(Suppl 2):S79-83.
150. Marquezan M, Bolognese AM, Araujo MT. Effects of two low-
intensity laser therapy protocols on experimental tooth move-
ment. Photomed Laser Surg 2010;28:757-62.
151. Kim YD, Kim SS, Kim SJ, Kwon DW, Jeon ES, Son WS. Low-level
laser irradiation facilitates fibronectin and collagen type I turn-
over during tooth movement in rats. Lasers Med Sci 2010;25:
25-31.
152. Seifi M, Shafeei HA, Daneshdoost S, Mir M. Effects of two types of
low-level laser wave lengths (850 and 630 nm) on the orthodon-
tic tooth movements in rabbits. Lasers Med Sci 2007;22:261-4.
153. Zhu X, Chen Y, Sun X. A study on expression of basic fibroblast
growth factors in periodontal tissue following orthodontic tooth
movement associated with low power laser irradiation. Hua Xi
Kou Qiang Yi Xue Za Zhi 2002;20:166-8.
154. Sakata M, Yamamoto Y, Imamura N, Nakata S, Nakasima A. The
effects of a static magnetic field on orthodontic tooth movement.
J Orthod 2008;35:249-54.
November 2014  Vol 146  Issue 5 American Journal of Orthodontics and Dentofacial Orthopedics
Huang, Williams, and Kyrkanides
155. Chen Q. Effect of pulsed electromagnetic field on orthodontic
tooth movement through transmission electromicroscopy.
Zhonghua Kou Qiang Yi Xue Za Zhi 1991;26:7-10:61.
156. Tengku BS, Joseph BK, Harbrow D, Taverne AA, Symons AL. Ef-
fect of a static magnetic field on orthodontic tooth movement in
the rat. Eur J Orthod 2000;22:475-87.
157. Davidovitch Z, Finkelson MD, Steigman S, Shanfeld JL,
Montgomery PC, Korostoff E. Electric currents, bone remodeling,
and orthodontic tooth movement. I. The effect of electric currents
on periodontal cyclic nucleotides. Am J Orthod 1980;77:14-32.
158. Kolahi J, Abrishami M, Davidovitch Z. Microfabricated bio-
catalytic fuel cells: a new approach to accelerating the orthodon-
tic tooth movement. Med Hypotheses 2009;73:340-1.
159. Soma S, Matsumoto S, Higuchi Y, Takano-Yamamoto T,
Yamashita K, Kurisu K, et al. Local and chronic application of PTH
accelerates tooth movement in rats. J Dent Res 2000;79:1717-24.
160. Suda T, Ueno Y, Fujii K, Shinki T. Vitamin D and bone. J Cell Bio-
chem 2003;88:259-66.
161. Takano-Yamamoto T, Kawakami M, Yamashiro T. Effect of age
on the rate of tooth movement in combination with local use
of 1,25(OH)2D3 and mechanical force in the rat. J Dent Res
1992;71:1487-92.
162. Kawakami M, Takano-Yamamoto T. Local injection of 1,25-dihy-
droxyvitamin D3 enhanced bone formation for tooth stabiliza-
tion after experimental tooth movement in rats. J Bone Miner
Metab 2004;22:541-6.
163. Leiker BJ, Nanda RS, Currier GF, Howes RI, Sinha PK. The effects
of exogenous prostaglandins on orthodontic tooth movement in
rats. Am J Orthod Dentofacial Orthop 1995;108:380-8.
164. Seifi M, Eslami B, Saffar AS. The effect of prostaglandin E2 and
calcium gluconate on orthodontic tooth movement and root
resorption in rats. Eur J Orthod 2003;25:199-204.
165. Sekhavat AR, Mousavizadeh K, Pakshir HR, Aslani FS. Effect of mi-
soprostol, a prostaglandin E1 analog, on orthodontic tooth move-
ment in rats. Am J Orthod Dentofacial Orthop 2002;122:542-7.
166. Yamasaki K, Shibata Y, Fukuhara T. The effect of prostaglandins
on experimental tooth movement in monkeys (Macaca fuscata).
J Dent Res 1982;61:1444-6.
167. Gurton AU, Akin E, Sagdic D, Olmez H. Effects of PGI2 and TxA2
analogs and inhibitors in orthodontic tooth movement. Angle Or-
thod 2004;74:526-32.
168. Yamasaki K, Shibata Y, Imai S, Tani Y, Shibasaki Y, Fukuhara T.
Clinical application of prostaglandin E1 (PGE1) upon orthodontic
tooth movement. Am J Orthod 1984;85:508-18.