Author's Accepted Manuscript

Biological Principles Behind Accelerated Tooth

Movement
Sarah Alansari DDS, Chinapa Sangsuwon DDS,
Thapanee Vongthongleur DDS, Rachel Kwal
DDS, Miang chneh Teo DDS, Yoo B. Lee DDS,
Jeanne Nervina DDS, MS, PhD, Cristina Teixeira
DDS, MS, PhD, Mani Alikhani DDS, MS, PhD

www.elsevier.com/locate/ysodo

PII: S1073-8746(15)00032-8
DOI: http://dx.doi.org/10.1053/j.sodo.2015.06.001
Reference: YSODO416

To appear in: Semin Orthod

Cite this article as: Sarah Alansari DDS, Chinapa Sangsuwon DDS, Thapanee
Vongthongleur DDS, Rachel Kwal DDS, Miang chneh Teo DDS, Yoo B. Lee DDS,
Jeanne Nervina DDS, MS, PhD, Cristina Teixeira DDS, MS, PhD, Mani Alikhani
DDS, MS, PhD, Biological Principles Behind Accelerated Tooth Movement, Semin
Orthod, http://dx.doi.org/10.1053/j.sodo.2015.06.001

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 Biological principles behind accelerated tooth movement

Sarah Alansari, Chinapa Sangsuwon, Thapanee Vongthongleur, Rachel Kwal, Miang chneh

Teo, Yoo B. Lee, Jeanne Nervina , Cristina Teixeira, Mani Alikhani

Sarah Alansari, DDS

Orthodontic Resident, Consortium for Translational Orthodontic Research, New York University

College of Dentistry, New York, NY

Chinapa Sangsuwon, DDS

Junior Research Scientist, Consortium for Translational Orthodontic Research

New York University College of Dentistry, New York, NY, USA

Thapanee Vongthongleur, DDS

Junior Research Scientist, Consortium for Translational Orthodontic Research

New York University College of Dentistry, New York, NY, USA

Rachel Kwal, DDS

Orthodontic Resident, Department of Orthodontics, New York University College of Dentistry,

New York, NY
Miang chneh Teo, DDS

Orthodontic Resident, Consortium for Translational Orthodontic Research, New York University

College of Dentistry, New York, NY

Yoo B. Lee, DDS

Orthodontic Resident, Department of Orthodontics, New York University College of Dentistry,

New York, NY

Jeanne Nervina, DDS, MS, PhD

Assistant Professor, Department of Orthodontics

New York University College of Dentistry, New York, NY, USA

Cristina Teixeira, DDS, MS, PhD

Associate Professor, Chairperson, Department of Orthodontics

New York University College of Dentistry, New York, NY, USA

Mani Alikhani, DDS, MS, PhD

Associate Professor and Director, Consortium for Translational Orthodontic Research

New York University College of Dentistry, New York, NY, USA

Associate Professor, Department of Developmental Biology

Harvard School of Dental Medicine, Boston, Massachusetts, USA

Corresponding Author:

Mani Alikhani, DDS, MS, PhD

345 East 24th Street

New York, NY 10010

Tel (212) 998-9958

Fax (212) 995 4087

 Biological principles of accelerated tooth movement

Sarah Alansari, Chinapa Sangsuwon, Thapanee Vongthongleur, Rachel Kwal,

Miang chneh Teo, Yoo B. Lee, Jeanne Nervina , Cristina Teixeira, Mani Alikhani

Abstract

Understanding the biology of tooth movement has great importance for

developing techniques that increase the rate of tooth movement. Based on

interpretations of data on the biology of tooth movement, the resulting

accelerating techniques can be divided to two main groups: one group

stimulates upstream events to indirectly activate downstream target cells, while

the other group bypasses the upstream events and directly stimulates

downstream target cells. In both approaches there is a general consensus that

the rate of tooth movement is controlled by the rate of bone resorption, which in

turn is controlled by osteoclast activity. Therefore, to increase the rate of tooth

movement, osteoclasts should be the target of treatment. In this article both

approaches will be reviewed and the biological limitations of each group will be

discussed.
Introduction

Orthodontic tooth movement is possible because the complex anatomy of the

teeth, their alveolar housing and the soft tissues covering and coursing through

the mineralized tissues are capable of remodeling. Without this remarkable

normal biological phenomenon, the practice – indeed, the very concept – of

orthodontics would not be possible. Yet, orthodontic appliances are not

intentionally built to activate or inhibit specific remodeling pathways in specific

cells. Rather, they are built to generate biomechanical force systems that

produce the desired tooth and jaw movements needed to establish an ideal

occlusion – regardless of the cellular mediators of the response. This begs the

question, should we be designing orthodontic appliances to target specific

remodeling pathways to move teeth and jaws into an ideal occlusion faster?

The biology of tooth movement is not a new field of inquiry. What is new is that

we are now designing innovative appliances and treatments that optimize

skeletal and dental target cell responses that produce controlled, safe

accelerated tooth movement. By identifying and harnessing reactions of the

target cells we can develop two different approaches to accelerate the rate of

tooth movement: directly stimulate the target cells by artificial, physical, or

chemical means to increase their numbers and their activity, or indirectly

stimulate the body to recruit and activate more target cells. In either scenario,

identifying the target cells and understanding how they are activated is crucial.
Bone cells and their role in biology of tooth movement

Bone is a surprisingly dynamic tissue that remodels in response to mechanical force.

The cells that perform this remarkable response are distributed throughout the bone and

each is specialized to perform specific functions needed to detect force (both its

magnitude and direction), recruit cells that resorb bone at specific sites and activate

cells to deposit new bone matrix and promote mineralization that will withstand

mechanical force. The mechanosensors are osteocytes, which are by far the most

numerous bone cells in the body, but are also the least well studied because they are

embedded entirely within the bony matrix. The bone resorbing cells are giant

multinucleated osteoclasts, which are found on the bone surface at resorption sites. The

bone forming cells are osteoblasts, which spend their lives attached to the bone

surface. Finally, inflammatory cells (specifically, T lymphocytes and macrophages) that

reside in the bone marrow are important regulators of osteoclasts and osteoblasts.

Osteoblasts are mononuclear cells found along the surface of bones. They are derived

from mesenchymal stem cells in the bone marrow and synthesize collagenous and non-

collagenous proteins that form the organic bone matrix called osteoid. Inactive

osteoblasts that cover bone surfaces, particularly in the adult skeleton, are called bone-

lining cells. These cells are quiescent until growth factors or other anabolic stimuli

induce them to proliferate and differentiate into cuboidal osteoblasts. While osteoblasts

play an important role in maintaining the integrity of alveolar bone during tooth

movement, they are not the cells that control the rate of tooth movement.
The osteocyte is a mature osteoblast embedded in lacunae within the bone matrix.

Although immobile, osteocytes possess exquisitely fine processes, which traverse the

mineralized matrix in tunnels called canaliculi, to make contact with other osteocytes, as

well as with osteoblasts residing on the bone surface. Given their preponderance in

bone, and their intricate three-dimensional network, osteocytes are key

mechanosensors. Loading of bone results in strain, or deformation, in the matrix,

including the lacuanae and canaliculi. This deformation evokes osteocytic responses via

fluid shear stress (produced by increased fluid flow in the lacuno-canalicular system) or

electrical strain potential. Osteocytes orchestrate the overall remodeling response by

secreting key factors, such as prostaglandins, nitric oxide, insulin-like growth factors

(IGFs), which activate osteoblasts and osteoclasts and the bone remodeling system.

Under the influence of orthodontic forces, osteocytes play a critical role in detecting

force and activating osteoclast-osteoblast coupling, but they are not the cells that

regulate the rate of tooth movement.

In fact, it is the osteoclast that determines the rate of bone resorption and, therefore, the

rate of tooth movement. These cells are the major bone resorbing cells. They are

specialized monocyte/macrophage family members that differentiate from

haematopoietic stem cells in the bone marrow. Mature osteoclasts are giant

multinucleated cells that form from the fusion of monocytic precursors. Terminal

differentiation in this lineage is characterized by the acquisition of mature phenotypic

markers, such as the calcitonin receptor and tartrate-resistant acid phosphatase

(TRAP), and the appearance of an astounding ruffled border rich in proton pumps that

acidify the bone surface to which the cells are attached, resulting in resorption pits.
When viewed physiologically, normal healthy bone remodeling is a tightly

choreographed sequence of cellular activity. Mechanical force distorts osteocytes

housed in lacunae and canaliculi, often producing micro-fractures, which are cleared out

by osteoclasts. Osteoblasts follow to fill in the newly excavated site. Some of those

osteoblasts become embedded in the new bone to form new osteocytes to replace

those lost at the remodeling site. Thus, healthy strong bone that can withstand

mechanical force applications is formed due to signaling between osteocytes,

osteoclasts and osteoblasts. As we will discuss below, a variation of this response,

which incorporates immune cells and inflammatory cytokines, is key to understanding

the biology of tooth movement and developing approaches to accelerate tooth

movement.

Theories on biology of tooth movement

During recent years many theories have been developed to explain the mechanism of

tooth movement. In general these theories split into two camps: one camp proposes

that bone is the direct target of mechanical force (direct view), while the other camp

proposes that it is the periodontal ligament (PDL) that is the key target (indirect view).

According to the direct view model, compression stress generated in the direction of

tooth movement directly stimulates osteoclasts and tension stress in the opposite

direction of tooth movement directly stimulates osteoblasts. Under this assumption

osteocytes may play a significant role by coordinating osteoclast and osteoblast activity.

There is significant evidence against this proposal. First, bone does not recognize static

forces such as orthodontic forces (1). Second, the lack of movement of implants and

ankylosed teeth in response to orthodontic forces argues against the claim that bone is
the target of orthodontic forces. Third, in experiments where bone is loaded directly,

without interference of the PDL, compression stresses stimulate bone formation, not

bone resorption.

Supporters of the indirect view of tooth movement propose that the PDL is the primary

target of orthodontic forces. Consider the impossibility of moving an ankylosed tooth,

which lacks a PDL. Based on this proposal the PDL will exhibit areas of compression

and tension in response to the application of orthodontic forces. Distribution of these

areas varies depending on the different types of tooth movement, which in turn are

controlled by the magnitude of the force and the moment applied to the tooth.

Regardless of the type of tooth movement, if the duration of force application is limited

to a few seconds, the incompressible tissue fluid prevents quick displacement of the

tooth within the PDL space. However, if the force on a tooth is maintained, the fluid is

rapidly squeezed out and the tooth displaces within the PDL space, leading to the

compression of the PDL. The immediate result of this displacement is the constriction of

blood vessels in the compression site. Alteration in blood flow would cause a decrease

in nutrition and oxygen levels (hypoxia). Depending on the magnitude of pressure and

level of blood flow reduction, some of the cells will go through apoptosis, while some

cells will die non-specifically, resulting in areas of necrosis (cell-free zone). It should be

emphasized that apoptotic or necrotic changes are not limited to PDL cells and some of

the osteoblasts and osteocytes in adjacent alveolar bone also die in response to

orthodontic forces. These sequences of events lead to an aseptic, acute inflammatory

response with the early release of chemokines from local cells (Figure 1). Chemokines

are small proteins released by local cells that can attract other cells into the area. The
release of chemokines in response to orthodontic forces facilitates expression of

adhesion molecules in blood vessels and stimulates further recruitment of inflammatory

and precursor cells from the microvasculature into the extravascular space.

One of the chemokines that is released during tooth movement is monocyte

chemoatractant protein-1 (MCP-1 or CCL2) (2), which plays an important role in

recruiting monocytes. These cells leave the bloodstream and enter the surrounding

tissue to become tissue macrophages or osteoclasts. Similarly, the release of CCL3 (3)

and CCL5 (RANTES) (4) during orthodontic tooth movement leads to osteoclast

recruitment and activation. Within the first few hours of orthodontic treatment there is

further release of a broader spectrum of inflammatory mediators. In addition to

chemokines, cytokines are released during orthodontic treatment. These extracellular

proteins play an important role in regulating the inflammatory process. Many cytokines

are pro-inflammatory. They amplify or maintain the inflammatory response and

activation of bone resorption. Importantly, other cytokines are anti-inflammatory and

prevent an unrestrained inflammatory response. The main pro-inflammatory cytokines

that are released during orthodontic tooth movement are IL- - - -6

(5). These cytokines are produced by inflammatory cells such as macrophages, and by

local cells such as osteoblasts, fibroblasts and endothelial cells.

Another series of inflammatory mediators that are released during orthodontic tooth

movement are prostaglandins (PGs) and neuropeptides. PGs are derived from the

metabolism of arachidonic acid and can mediate virtually every step of inflammation

such as vasodilation, increase vascular permeability, and adhesion of inflammatory

cells. During orthodontic tooth movement, these mediators can be directly produced by
local cells or by inflammatory cells in response to mechanical stimulation, or indirectly

by cytokines. For example, TNF- is a potent stimulator of PGE2 formation (6).

Prostaglandins act locally at the site of generation and then decay spontaneously or are

enzymatically destroyed (7, 8). Similar to PGs, neuropeptides can participate in many

stages of the inflammatory response to orthodontic forces. Neuropeptides are small

proteins, such as substance P, that transmit pain signals, regulate vessel tone and

modulate vascular permeability (9).The importance of all these inflammatory makers

can be appreciated in the role that they play in osteoclastogenesis.

Osteoclastogenesis

As previously discussed, osteoclasts are multinucleated giant cells that resorb bone and

are derived from hematopoietic stem cells of the monocyte-macrophage lineage. After

recruitment to the compression sites, osteoclast precursors begin to differentiate into

osteoclasts (Figure 2). Cytokines are important mediators of this process. For example,

TNF- and IL-1 bind to their receptors, TNFRII (10) and IL-1R (11), respectively, and

directly stimulate osteoclast formation from precursor cells and osteoclast activation

(Figure 3). Additionally, IL-1 and IL-6 (12) can indirectly stimulate local cells or

inflammatory cells to express M-CSF (macrophage colony-stimulating factor) and

RANKL (receptor activator of nuclear factor B ligand). These ligands, through cell-to-

cell interactions bind to their respective receptors, c-Fms and RANK, which are both

expressed on the surface of osteoclast precursors (Figure 3).

Other inflammatory mediators that enhance osteoclast formation through enhancing

RANKL expression by stromal cells are PGs, especially PGE2 (13). As mentioned

before, PGs can be produced by local cells directly in response to orthodontic forces or

indirectly as down-stream of cytokines such as TNF-

It should be emphasized that local cells normally try to down regulate

osteoclastogenesis by producing a RANKL decoy receptor, osteoprotegerin (OPG),

(14). Therefore, OPG levels in compression sites should decrease to enable tooth

movement.

Different approaches to accelerate the rate of tooth movement

The approach that a researcher selects to accelerate the rate of tooth movement

depends on his or her interpretation of the data on the biology of tooth movement. A

researcher who chooses to amplify body reactions to orthodontic forces may either try

to increase the release of cytokines (if they believe inflammatory responses of the PDL

and bone are the key factor in controlling the rate of tooth movement), or optimize the

mechanical stimulation (if they believe orthodontic tooth movement is a direct

physiologic response to mechanical stimulation). On the other hand, another researcher

who does not propose mimicking the body’s response to orthodontic forces may choose

instead to increase the rate of tooth movement by artificially increasing the number of

osteoclasts. These approaches include local or systemic induction of different chemical

factors or application of physical stimuli that can increase the number of osteoclasts

independent of orthodontic forces. It should be emphasized that, in spite of some

disagreement about initial trigger that start the cascade of events leading to bone
resorption and tooth movement, all theories agree that osteoclast activation is the main

rate-controlling factor in orthodontic tooth movement.

Stimulation of cytokines to increase the rate of tooth movement

As previously discussed, orthodontic force induces an aseptic inflammatory response

(15), during which many cytokines and chemokines are activated and play a significant

role in osteoclastogenesis. The importance of these molecules in controlling the rate of

tooth movement can be appreciated through the dramatic results obtained from studies

that block their effects. For example, injections of IL-1 receptor antagonist (IL-1Ra) or

TNF- receptor antagonist (sTNF--RI) result in a 50% reduction in the rate of tooth

movement (16). Similarly, tooth movement in TNF type II receptor-deficient mice is

reduced compared to wild type mice (17). Animals that are deficient in CC chemokine

receptor 2 (CCR2), which is a receptor for CCL2, or animals that are deficient in CCL3,

demonstrate a significant reduction in orthodontic tooth movement and number of

osteoclasts (2). Likewise, non-steroidal anti-inflammatory drugs (NSAIDs) reduce the

rate of tooth movement by inhibiting PG synthesis (18). Inhibiting other derivatives of

arachidonic acid, such as leukotrienes, also significantly decreases the rate of tooth

movement (19).

If inhibiting inflammatory markers decreases the rate of tooth movement, it is logical to

assume that increasing their activity should significantly increase the rate of tooth

movement. Indeed, injecting PGs into the PDL in rodents increases the number of

osteoclasts and the rate of tooth movement (20). Systemic application of misoprostol, a

PGE1 analog, to rats undergoing tooth movement for 2 weeks, significantly increases
the rate of tooth movement (21). Similarly, local injection of other arachidonic acid

derivatives, such as thromboxane and prostacyclin (22), increases the rate of tooth

movement.

Unfortunately injection of PGs to increase the rate of tooth movement has limitations.

First, due to their very short half-life, PGs must be delivered repeatedly. Second, local

PGs injections can cause hyperalgesia due to release of histamine, bradykinin,

serotonin, acetylcholine and substance P from nerve endings (23).

Another approach to increasing inflammatory mediators that will increase the rate of

tooth movement is to stimulate the body to produce these factors at a higher level. The

advantage of this approach is a coordinated increase in the level of all inflammatory

mediators. As discussed before, many cytokines participate in response to orthodontic

forces. Injecting one cytokine does not mimic the normal inflammatory response, which

is a balance of pro- and anti-inflammatory mediators. However, the approach that safely

triggers the body to produce higher levels of inflammatory mediators is not clear.

One may suggest that increasing the level of orthodontic force should increase the level

of cytokine expression, since a higher magnitude of force produces greater trauma to

the PDL and bone leading to higher levels of inflammation. In fact, increasing the force

magnitude is accompanied by higher levels of cytokine and chemokine expression, but

only to certain point. Increasing the magnitude of force beyond that point does not

produce higher levels of inflammatory mediators or accelerated tooth movement (24).

This observation led to the conclusion that there is a “biological saturation point” in

response to orthodontic forces. However, It should be emphasized that extremely high

levels of forces may lead to the appearance of micro-fractures in bone that can

stimulate further cytokine expression and bone resorption. While these forces are

beyond the magnitude of orthodontic forces applied during orthodontic treatment, the

observation highlights the possibility of stimulating a similar reaction in bone via another

method, thus facilitating orthodontic tooth movement by increasing the rate of bone

resorption.

Animal studies have shown that introducing small perforations in the alveolar bone

(micro-osteoperforations; MOPs) during orthodontic tooth movement can significantly

stimulate the expression of inflammatory mediators. While application of orthodontic

force beyond the saturation point does not elevate the expression and activation of

inflammatory mediators beyond certain levels, adding MOPs to the area of tooth

movement increase the level of inflammatory mediators (25). This response is

accompanied by a significant increase in osteoclast number, bone resorption and

localized osteopenia around all adjacent teeth, which could explain the increase in the

rate and magnitude of tooth movement. One may argue that the effects of the shallow

perforations on tooth movement are not a response to increased cytokine expression,

but rather due to weakening of the bone structure. While the effects that perforations

can have on the physical properties of the bone cannot be ignored, the number and

diameter of these perforations is too small to have significant impact (38). Similarly, a

human clinical trial using a canine retraction model, demonstrates that MOPs can

amplify the catabolic response to orthodontic forces. Canine retraction in the presence

of MOPs results in twice as much distalization in comparison with patients receiving

similar orthodontic forces without MOPs. This increase in tooth movement is

accompanied by an increase in the level of inflammatory mediators (26).

Clinical studies demonstrate that increasing the number of MOP’s significantly

increases expression of inflammatory mediators and the magnitude of tooth movement

(Alikhani et al, Seminars in Orthodontics , current issue). Therefore, one should expect

procedures such as orthognathic surgery, corticotomies , or piezocision would

significantly increase the levels of inflammatory cytokines beyond those induced by

MOPs. While increase in cytokine release is accompanied with higher rate of tooth

movement, unfortunately, the increase in the expression of inflammatory mediators is

not sustained for a long time. A significant decrease in cytokine activity is observed 2-3

months after any of these treatments. As a result, each of these procedures would need

to be repeated during the course of orthodontic treatment, which renders some of the

above-mentioned modalities impractical.

Recently a modification of these techniques has been introduced where, after selective

decortication in the form of lines and points, a resorbable bone graft is placed over the

surgical sites. Falsely, the accelerating effect of these techniques has been attributed to

the shape of the cuts made into the bone (block concept) and to the bone grafts (27,

28). As previously discussed in this article, the rate of tooth movement is controlled by

osteoclast recruitment and activation which is controlled by cytokine release in response

to trauma. While magnitude of trauma ( number and depth of the cuts) can affect the

magnitude of cytokine release, shape of trauma does not affect inflammatory response.

Moreover, bone grafts do not increase osteoclast activation and as a result do not

contribute to the increase in the rate of tooth movement. Therefore, while the application

of bone grafts can help in increasing the boundary of tooth movement toward cortical
bone, during routine orthodontic treatment where teeth are moved in trabecular bone,

they are unnecessary.

Mechanical stimulation to increase the rate of tooth movement

Another methodology that has been suggested to increase the rate of tooth movement

is the application of high frequency low magnitude forces (52). The main assumption in

this hypothesis is that bone is a direct target of orthodontic forces and therefore by

optimizing mechanical stimulation it is possible to increase the rate of tooth movement.

There are many flaws in this theory. As we discussed before, the assumption that tooth

movement is the result of direct response of bone cells to mechanical stimulation is

incorrect, which means that optimizing the mechanical stimulation based on bone cell

activity, especially osteocytes, is not a correct approach. Based on this biological

principle, application of vibration and orthodontic forces will never be able to move an

ankylosed tooth. In addition, all studies in long bone and alveolar bone (24)

demonstrate an osteogenic effects of these stimulants with increases in bone density

without any resorptive effect, which logically should delay, rather than accelerate, the

rate of tooth movement. It is possible that application of high frequency low magnitude

forces during orthodontic movement stimulates a pathway far different from its effect on

bone. If that is true, the frequency-dependence of the stimulant is questionable and

literature in this field should not be used to justify applying vibration during tooth

movement.
Heat, light, electric currents and laser to increase the rate of tooth movement

Early studies on the application of heat and light during orthodontic tooth movement

(29) have demonstrated faster tooth movement. Similarly, animals exposed to longer

hours of light also show an increase in the rate of tooth movement (30). However, the

magnitude of this acceleration was either small or could be explained more by systemic

effect of the stimulant and not necessarily local effects.

Minute electric currents have been suggested to increase the rate of tooth movement. In

this regard, some studies did not report any changes in the rate of tooth movement (31)

while others report significant increase (32). Similarly, studies on static magnetic fields

produce inconsistent results on the rate of tooth movement with some showing an

increase (33), and others demonstrating no change in the rate of tooth movement (34).

Based on the piezoelectric theory, some researchers suggest using a pulsed

electromagnetic field to accelerate tooth movement (35). Indeed, animals that received

this type of stimulation during orthodontic tooth movement demonstrate a faster rate of

tooth movement.

Recently more attention has been given to possible effect of low-level laser therapy

(LLLT) on the rate of tooth movement. LLLT is a treatment that uses low-level lasers or

light-emitting diodes to alter cellular function. LLLT is controversial in mainstream

medicine with ongoing research to determine whether there is a demonstrable effect.

Also disputed are the dose, wavelength, timing, pulsing and duration (36). The effects of

LLLT appear to be limited to a specified set of wavelengths (37) and administering LLLT

below a dose range does not appear to be effective (38).

In general the mechanism of action of LLLT is not clear and sometimes opposite to what

is required for orthodontic tooth movement. For example, LLLT may reduce pain related

to inflammation by dose-dependently lowering levels of PGE2, IL-1, and TNF-,

decreasing the influx of inflammatory cells such as neutrophils, oxidative stress and

edema (39). Another mechanism may be related to stimulating mitochondria to increase

the production of adenosine triphosphate (ATP) resulting in an increase in reactive

oxygen species, which influences redox signaling, which then affects intracellular

homeostasis or cellular proliferation (40). The final enzyme in the production of ATP by

mitochondria, cytochrome-c oxidase, appears to directly respond to lasers, making it a

possible candidate for mediating the properties of laser therapy (41). Due to anti-

inflammatory and osteogenic effects of LLLT, application of LLLT to increase the rate of

tooth movement is controversial. While some studies demonstrate increased rates of

tooth movement (42) other studies did not see any effect (43). The anti- inflammatory

effect of LLLT should delay the tooth movement, while the proliferative effect may help

increase the number of osteoblasts. On the other hand, some studies show an increase

in number of osteoclasts during LLLT application with orthodontic tooth movement (44),

which cannot be explained by a proliferative effect of lasers since osteoclasts arise from

precursor cells and not proliferation of mature osteoclasts, as some have suggested.

Further studies in this subject are clearly necessary.

Unfortunately, applying any of these physical stimuli to increase the rate of tooth

movement at present suffers from a lack of evidence, an unknown mechanism and

general impracticality. In addition, the magnitude of increase in the rate of tooth

movement is not significantly high to justify their application. Nevertheless, this field has

great potential for growth.

Chemical agents to increase the rate of tooth movement

If bone resorption is the key factor in controlling the rate of tooth movement, application

of any agent that increases the rate of bone turnover should increase the rate of tooth

movement. With this in mind, the application of parathyroid hormone (PTH), Vitamin D3,

corticosteroids, thyroxin and osteocalcin have been examined. It should be noted that

other factors, such as calcitonin or estrogens, can prevent bone resorption and

decrease the rate of tooth movement (45).

PTH is secreted by the parathyroid glands and increases the concentration of serum

calcium in by stimulating bone resorption. A significant stimulation of the rate of tooth

movement by exogenous PTH appears to occur in a dose-dependent manner, but only

when it is continuously applied by either systemic infusion (46) or local delivery every

other day in a slow-release formulation (47). It should be noticed that although

continuous elevation of PTH leads to bone loss, intermittent short elevations of the

hormone level are anabolic for bone (48) and perhaps cannot increase the rate of tooth

movement.

Vitamin D3 (1,25 dihydroxycholecalciferol) is another factor that can affect the rate of

bone remodeling and therefore its possible effect on the rate of tooth movement has

been studied. Vitamin D3 regulates calcium and phosphate serum levels by promoting

their intestinal absorption and reabsorption in the kidneys. Furthermore, it promotes

bone deposition and inhibits PTH release. Based on these mechanisms one would
expect that vitamin D3 should decrease the rate of tooth movement. To the contrary, it

has been shown that Vitamin D3 can increase the rate of tooth movement if injected

locally (49). This effect can be related to the effect of Vitamin D3 on increasing the

expression of RANKL by local cells and therefore activation of osteoclasts (50).

Similarly, local injection of osteocalcin (a bone matrix component) caused rapid tooth

movement due to attraction of numerous osteoclasts into the area (51)

Corticosteroids are another group of chemical agents that have been suggested for

accelerating the rate of tooth movement. While the anti-inflammatory effect of

corticosteroids can decrease the rate of tooth movement, in the presence of cytokines

such as IL-6 they may help stimulate osteoclastogenesis and cause osteoporosis (52).

Therefore, the effect of corticosteroids on tooth movement can vary depending on the

dosage and whether they are administered before the expression of cytokines

(induction period) or after their presence. While some studies demonstrate an increase

in rate of tooth movement following corticosteroid treatment (53), others did not report

any changes (54, 55).

Another factor that may increase the rate of tooth movement is the thyroid hormone

(thyroxin). Thyroxin affects intestinal calcium absorption, thus it is indirectly involved in

bone turnover and induction of osteoporosis. It has been shown that exogenous

thyroxin increases the rate of tooth movement (56), which can be related to increase in

bone resorption.

Recently, the hormone Relaxin has been used in rats to increase the rate of tooth

movement. Relaxin is capable of reducing the organization level of connective tissues,

facilitating rapid separation between adjoining bones. Unfortunately, no significant

increase in rate of tooth movement was observed (57).

The application of chemicals to accelerate tooth movement suffers from many

problems. First, all the chemical factors have systemic effects that raises questions

about their safety during clinical application. Second, the majority of the factors have a

short half-life; therefore multiple applications of the chemical are required, which is not

practical. In addition, administration of a factor in a manner that allows an even

distribution along the alveolar bone surface in the compression site is still a challenge.

Uneven distribution can change the pattern of resorption and therefore the

biomechanics of tooth movement.

Summary and future directions

While many seemingly random approaches have been taken to increase the rate of

tooth movement, a successful approach should be based on solid biological principles

where the target cells and mechanism to stimulate those cells are well defined. This

would be possible only if theories on biology of tooth movement are revisited. A good

accelerating technique should be affordable, repeatable, practical, efficient, and have no

side effects on the periodontium, including roots and alveolar bone. At this moment all

the current approaches are suffering form one or more deficiencies, but it is not far from

reality to claim that we are on the right track.

References:

1. Lanyon LE, Rubin CT. Static vs dynamic loads as an influence on bone

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 Legends for the Alansari et al (#1)

FIGURE 1 Schematic representation of increase in permeability of vessels, release of

chemokines, expression of adhesion molecules, and recruitment of inflammatory and precursor

cells during early events of orthodontic tooth movement.

FIGURE 2 Schematic representation of interaction between RANKL expressed by local cells

and inflammatory cells, and RANK expressed by precursor cells resulting in osteoclast

differentiation.

FIGURE 3 Diagram of the effect of cytokines on skeletogenesis. Cytokines can directly help in

the differentiation or activation of osteoclasts from osteoclast precursor cells. Also, cytokines

can stimulate local cells to express RANKL that interacts with its receptor (RANK) on precursor

cells and help the development of osteoclasts.

 Figure  orientation  of  Alansari  et  al  article  
 
 
 

Figure  1  
 
 
 

Figure  2  
 

Figure  3