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Medicationandtoothmovement

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American Journal of Pharmacy and Pharmacology 2014; x(x): xx-xx

Published online MM DD 2014 (http://www.aascit.org/journal/ajpp)

Keywords

Drugs,

Orthodontic Tooth Movement,

Systematic Review

Received: September 24, 2014

Revised: October 09, 2014

Accepted: October 10, 2014

Medication and tooth movement

Nezar Watted1, *

, Peter Proff2, Borbély Péter

3,

Abu-Hussein Muhamad4

1Department of Orthodontics, Arab American University, Jenin, Palestine 2Department of Orthodontics, University of Regensburg, Regensburg, Germany 3Fogszabályozási Stúdió, Budapest, Hungary 4Department of Pediatric Dentistry, University of Athens, Athens, Greece

Email address

Prof.watted@gmx.net (N. Watted)

Citation

Nezar Watted, Peter Proff, Borbély Péter, Abu-Hussein Muhamad. Medication and Tooth

Movement. American Journal of Pharmacy and Pharmacology. Vol. x, No. x, 2014, pp. x-x.

Abstract

Orthodontic tooth movement is basically a biologic response towards a mechanical force.

Osteoclast and osteoblast cells mediate bone resorption and apposition, which eventually

produces tooth movement. Researches showed that the rate of orthodontic tooth

movement can be altered by certain drugs locally or systemically. The Objective of this

article is to discuss the current data concerning the effect of drugs on orthodontic tooth

movement.

1. Introduction

Orthodontics is a specialty, using biomechanical principles of physiological

mechanisms that can correct dental malposition and malformations of the jaws to restore

a functional and aesthetic dentition. Orthodontic treatments are limited to dental

displacements, using either fixed or removable systems. Only the alveolar bone needs to

be remodeled. Dentofacial orthopedics treatments also include the control and

modification of jaw positions and facial growth by controlling the growth sites in the

maxilla and mandible.{1,2}

When a force is applied to the crown of a tooth, it is transmitted through the root of

the tooth to the periodontal ligament and alveolar bone. According to the direction of the

force, there will be areas of pressure and areas of tension on these supporting

structures{1}. For the tooth to move, there must be resorption of alveolar bone in

response to this stress, and if the tooth is to remain firmly attached there must also be

deposition of bone to maintain the integrity of the attachmentmechanism. In effect, the

socket of the tooth must move, concomitant with movement of the tooth through the

alveolar bone. Although the general nature of the cellular reactions to force on the teeth,

which result in bone resorption and deposition, are not in dispute, the intermediary

causes of these reactions have been the subject of morerecent investigation. The classical

theory of tooth movement suggests that the cellular reactions are simply the result of

differential pressuresinduced in the periodontal ligament, and that the response to force

is confined to the cellular elements of the ligament and the endosteal marrow spaces. {1,

2, 3}(Fig. 1, Fig. 2)

This concept has been challenged by several investigators; Baumrind has suggested

that the ligament should be considered as a continuous hydrostatic system, in which

differential pressures cannot exist. If this is so, the pressure-tension concept of the

classical theory must be questioned. {4.5, 6}

The effects of physical distortion of the alveolar bone by the forces from orthodontic

appliances may be responsible for the cellular reactions observed. Picton, Cochran et al.,

Baumrind and Grimm, among others, have shown that even relatively light forces on the

2 Nezar Watted et al.: Medication and Tooth Movement

teeth, such as are used in orthodontic treatment, cause

bending of the alveolar bone. It has also been shown that

bone which is deformed by stress becomes electrically

charged, concave surfaces taking a negative polarity and

convex surfaces a positive polarity.[6,7,8,9,10,11}

Fig. 1. Orthodontic tooth movement

Fig. 2. The biology of tooth movement17

As a result of these bioelectric potential differences, bone

is added to the concave surfaces and resorbed from the

convex surfaces. In the dento-alveolar complex this would

result in tooth movement.

Justus and Luft have put forward a mechano-chemical

hypothesis for the remodelling of bone under stress. Their

experiments have suggested that altered physical stress in the

bone changes the solubility of the hydroxyapatite crystals,

which in turn induces the osteoblastic and osteoclastic

activity which results in bone remodelling.{12,13}

Davidovitch et al. have also shown a biochemical process

resulting from mechanically stressed alveolar bone to be an

intermediate stage in bone resorption and tooth

movement.{14}

Gianelli confirmed, from experimental work, the previous

findings of several investigators that an intact vascular

perfusion system in the periodontal ligament seems to be

necessary for frontal resorption of the bone, and that when

American Journal of Pharmacy and Pharmacology 2014; x(x): xx-xx 3

the vessels are occluded by the force, undermining resorption

occurs. He put forward the suggestion that the vasculature

may act as a hydraulic pressure system, transmitting the

applied force to the attachment apparatus, the resultant

pressures distorting the crystal structure of the bone.{15}

Mostafa et al. have postulated that force applied to a tooth

produces two main effects, the periodontal tissue injury

causing vascular responses and the bending of the alveolar

bone causing piezoelectric responses and the local production

of prostaglandins, all of which mediate tooth movement.{16}

Schwarz , the ideal force is one which induces a pressure

in the periodontal ligament not exceeding capillary blood

pressure, i.e. not more than 32 mmHg. The force to be

applied by artificial means to the crown of a tooth in order to

produce such a pressure on the periodontal ligament vessels

has not been accurately assessed It is likely to depend on the

size and shape of the tooth, and particularly the size and

number of the roots. It will also be influenced by other

factors, such as the natural forces acting on the teeth and the

exact nature and direction of the force applied.{17}

The forces used in successful orthodontic treatment have

usually been determined empirically, and no doubt

sometimes cause pressures greater than capillary blood

pressure.{1,2,3,4,5,6}

In considering these forces it is necessary to review the

different types of tooth movement which are commonly

required.Table.1

Table 1. tooth movements

Several different types of tooth movement occur during

orthodontic treatment. Because of the nature of the

attachment of the teeth to the alveolar bone all these

movements are likely to be complex, but they can be

considered in simplified form as follows;

1 Tipping movements.

2 Rotational movements.

3 Bodily movements.

4 Torque movements.

5 Vertical movements

2. Force and Center of Resistance

Orthodontic appliances are used to produce force systems

that will displace teeth and initiate a biologic cascade,

allowing teeth to move. Although many treatment modalities

and philosophies advocate different appliances, the force

system they produce can be dissected into the same basic

physical components: forces and moments. Force alone can

be used to move teeth and will often produce moment

causing the teeth to also rotate, tip, and torque. By using

appliances to control rotation, practitioners gain more control

over how teeth move. Varying the ratio of moment to force

applied allows the orthodontist to vary the type of tooth

movement effected. {1}

Forces are vectors having both direction and magnitude.

To move a tooth predictably, a force needs to be applied in

the desired direction, with the desired magnitude, and at the

correct position on the tooth. Changing the direction,

magnitude, or point of force application will affect the

quality of the tooth displacement that will occur.in other

words, if mesial movement of a tooth is indicated, a force to

push or pull the tooth in a mesial direction must be

applied.{1.2}

Intuitively, the point of force application also has an

influence on the quality of the tooth movement. There is only

one point on a tooth through which a force can be applied

that will move the tooth in the direction of the force without

tipping or rotating it. This point is the center of resistence and

a force acting through it will cause pure translation of the

tooth.{1,2,5} (Fig.3, Fig. 4)

Fig. 3. Center of resistance, shown throughout as a solid black dot. A force

acting through the center of resistance results in pure translation of the tooth

Fig. 4. Center of resistance, shown throughout as a solid black dot. Center

of rotation, shown throughout as a solid red dot. A force acting not through

the center of resistance results in tipping of the tooth

4 Nezar Watted et al.: Medication and Tooth Movement

The location of center of resistance, therefore, depends on

the size and shape of the tooth as will as on the quality and

level of the supporting structures. In a healthy tooth with an

intact PDL, the center of resistance is presumed to bi

somewhere 1/3 and ½ the distance from the alveolar crest to

the root apex. For a maxillary central incisor, this is

approximately 10 mm apical to the level of placement of an

orthodontic bracket. The center of resistance is located mor

apically for a priodontally compromised tooth with loss of

attachment. {1.2.3.4} (Fig. 5, Fig. 6, Fig. 7)

Fig. 5. Center of resistance, shown throughout as a solid black dot.

Fig. 6. The center of resistance in a tooth with full periodontal support

(right). The center of resistance is more apical in periodontally compromised

tooth (left)

Fig. 7. Clinical situation, The center of resistance of the central incisor (red

dot) is different because of bone height.

3. Forces and Moment

When a force is applied at any point other than through the

center of resistence, in addition to moving the center of

resistance in the direction of the force, a moment is created.

A moment is defined as a tendency to rotate and may refer to

rotaion, tipping, or torque in orthodontic terminology (Fig. 8).

If a distal force is applied buccal to the center of resistence,

the center of resistence of the tooth will move distaly and the

tooth will rotate mesiobuccally {1}

Fig. 8. Center of resistance, shown throughout as a solid black dot. The

center of resistance of the central incisor (red dot)

4. Tipping Movements

The centre of rotation of the tooth will depend on the exact

point at which the force is applied, becoming nearer to the

apex of the root as the point of application becomes nearer to

the incisal or occlusal tip of the crown (Fig. 9, Fig. 10).

Christiansen and Burstone have shown that the amount of

force applied does not affect the position of the centre of

rotation {18}. In practice, Stephens has found that with

single rooted teeth the centre of rotation is most frequently

located in the middle third of the root {19}.

Fig. 9. Tipping-uncontrolled movement : The applied force system (A). The

equivalent force system at the Center of resistance (B). The predicted tooth

movement with a center of rotation, shown throughout as a red dot, just

apical to the center of resistance (black dots) (C).

Fig. 10. Tipping-controlled movement : The applied force system (A). The

equivalent force system at the Center of resistance (B). The predicted tooth

movement with a center of rotation at the crown (C)

American Journal of Pharmacy and Pharmacology 2014; x(x): xx-xx 5

Crabb and Wilson found that forces of 0.3 N, 0.4 N and 0.5

N would produce satisfactory distal tipping movement on

permanent upper canine teeth, the degree of force not having

any material effect on the speed of movement, but the 0.5 N

force tended to give rise to more discomfort and difficulty

with the appliance {20}. Reitan found that intermittent forces

of 70-100 g (c. 0.7-1.0 N) may produce cell-free areas in the

periodontal ligament of an upper canine [21}.

Buck and Church showed that a tipping force of

approximately 0.7 N produced undermining resorption on

upper premolars {22}.

5. Rotational Movements

Rotational movements do not normally require any greater

force than tipping movements, but there is a much greater

tendency for rotational movements to relapse. This appears to

be due to the fact that although the fibres which attach the

tooth to the bone become reorganized fairly quickly during

and after tooth movement, the fibres joining the tooth to the

gingival tissue remain intact for a long time, simply

becoming distorted during tooth movement. In rotational

movements most of these gingival fibres are compressed on

one side and on the other side stretched, and this produces the

tendency for relapse{1,2} (Fig. 11a-c).

a

b

c

Fig. 11a-c. Rotational movement (a, b) and the arregement of free gingival

fibers after rotation (c).

6. Bodily Movements –Pure

Translation

The term 'bodily movement' is taken to mean the complete

translation of a tooth to a new position, all parts of the tooth

moving an equal distance.

As force can only be applied directly to the crown of the

tooth, it must be applied over a wide area of the crown, and

any tilting movements must be restricted, if bodily movement

is to be achieved. Furthermore, for bodily movement to occur,

a restraining force must be applied to prevent tilting of the

tooth. When a force to move a tooth is applied at bracket that

is 10 mm away from the center of resistance, a tendency for

the tooth to tip is created that is 10 times the magnitude of

the force. To counteract the tendency for tipping, a couple

can be applied intentionally to produce a moment of equal

magnitude in the opposite direction. The force alone would

cause the tooth to move in the direction of the force and the

crown to tip in the same direction. The couple completely

negates this tendency to tip, but the tooth still moves in the

direction of the force. When the applied moment forces

greater than the tip forces, the tooth will translate in the

direction of the force without tipping. In pure translation, the

center of rotation is considered to be at infinity because no

rotation occurs.{1,2,3,4} ( Fig 12)

Fig. 12. Translation movement : The applied force system (A). The

equivalent force system at the Center of resistance (B). The predicted tooth

movement (C). The pure translation, the center of rotation at infinity.

For these reasons the actual force applied to the crown is

usually greater for bodily movements than for tipping

movements.

Forces of up to approximately 3.0 N have been reported as

being successful for bodily movement of upper and lower

canines, the actual amount of force depending, of course, on

the size of the root.{1}

Nikolai has found that bodily movement of a tooth

requires two to three times the force needed for simple

tipping of the same tooth, and Quinn and Yoshikawa have

reported that forces of 1.0 N-2.0 N give satisfactory bodily

movement of upper canine teeth.{23,24}

7. Torque Movements

The term 'torque' in orthodontic practice is taken to mean

6 Nezar Watted et al.: Medication and Tooth Movement

the differential movement of one part of a tooth, physically

restraining any movement of other parts.

In this sense it is the opposite of the tipping movement, in

which the crown is moved, with little movement of the root.

However, as it is not possible to apply direct force to the root

of the tooth, root torque is more difficult to achieve than

crown movement (Fig. 13, Fig 14).

Fig. 13

Fig. 14

Fig. 13, 14. Controlled root movement- torque, : The applied force system

(A). The equivalent force system at the Center of resistance (B). The

predicted tooth movement with a center of rotation at the crown (C)

At the same time, it is easier to restrain movement of the

crown than of the root, and therefore it is theoretically

possible to achieve greater differential root movement. The

main limitations to root torque lie in the size and form of the

bone of the jaw, as the root movement must be confined to

the available supporting bone.

For practical purposes the forces are generally applied over

an area of the crown rather than at single points, this giving

greater control over the movements. Shows that the pressure

on the supporting structures is greatest in the apical area, and

the apex of the root moves further than any other part of the

tooth. There is a greater risk of apical resorption with this

type of movement than with any other type if the forces are

not carefully controlled, and the forces required should not be

as great as for bodily movement, though they will be greater

than for tipping movements because of the necessity of

applying an opposing force to restrict movement of the

crown. Reitan reported that a force of approximately 0.5 N is

favourable for to rquing movement of upper first premolars.

{1, 2, 3, 4, 22, 23|

8. Vertical Movements

Vertical movements are essentially bodily movements, but

are considered separately because they are easier to produce

and involve different types of pressure on the supporting

structures.

Extrusion of the tooth from its socket can be achieved

without much resorption of bone, bone deposition being

required to re-form the supporting mechanism of the tooth

(Fig. 15a, b) Generally speaking, tension is induced on the

whole of the supporting structures, rather than pressure

Intrusion of the tooth involves resorption of bone,

particularly around the apex of the tooth.{1,2,3,4,9,17,22,23}

(Fig. 16a-d).

a

b

Fig. 15a, b. Extrusion of an intruded tooth

a

b

American Journal of Pharmacy and Pharmacology 2014; x(x): xx-xx 7

c

d

Fig. 16a-d. Intrusion of an extruded tooth (a, b, c). Bone Remodeling (d)

In this movement the whole of the supporting structures

are under pressure, with virtually no areas of tension.

Vertical movements of teeth need the application of force

over a wide area of the crown, being difficult to bring about

with force applied only to one point. As no counteracting

forces are required, forces of the same order as, or less than,

those used for tipping movements are sufficient, and, because

of the direction of tooth movement, excessive forces are

likely to damage the blood vessels entering the dental pulp at

the apex, with subsequent death of the tooth. Resorption of

the root apices is another potential hazard, particularly with

intrusive forces. Dermaut and De Munck have reported

considerable root shortening after intrusion of upper

incisors{25}. Reitan found that a force of approximately 0.25

N was sufficient for the extrusion of an individual tooth{26},

and Burstone found a similar force suitable for intrusion of

an incisor{27}.

9. Multiple Tooth Movement

Orthodontic treatment frequently involves the application

of force to move a number of teeth simultaneously. In these

circumstances, the total force applied will often exceed the

figures previously quoted for individual tooth movement,

because the force will be spread over several teeth (Fig 11b).

Orthodontists often prescribe drugs to manage pain from

force application to biological tissues, manage

temporomandibular joint problems and tackle fungal and

viral infections throughout the course of treatment. A recent

review of pharmaceuticals commonly used in orthodontic

practice, provided an insight into the dosage,

pharmacological actions and side effects of these agents.

A part from these drugs, patients who consume vitamins,

minerals, and other compounds, for the prevention or

treatment of various diseases, can also be found in every

orthodontic practice. Some of these drugs may have profound

effects on the short and long term outcomes of orthodontic

treatment. However, in manycases little is known on the

nature of this interaction between specific drugs and

orthodontic tissue remodeling, thereby increasing the risk of

negative effects.{1,2,3,4,17}

Orthodontic treatment is based on the biologic principle

that prolonged pressure on teeth results in remodelling of

periodontal structures, allowing for tooth movement[1]. The

bony response is mediated by the periodontal ligament.

Within a few hours after force application, a change in the

chemical environment produces a cascade of cellular events.

There is an increased level of cAMP, prostaglandin E and

interleukin-1 beta levels. Other chemical messengers like

cytokines, nitric oxide and other regulators of cellular

activity are also involved. Since drugs of various types can

affect both prostaglandin levels and other potential chemical

messengers, pharmacologic interventions may modify the

response to orthodontic force.{1,2,3,4}

This information is important for clinicians in

communications with patients, because many patients use

prescription and over-the counter medications, as well as

dietary supplements daily. Consequently, these substances

can affect both the rate of orthodontics teeth movement and

the expected duration of treatment.{1,4}Table.2

Table 2. Bone Remodeling with orthodontics forces

It is possible to categories drugs that would affect

orthodontic tooth movement into the four broad categories:

non-steroidal anti-inflammatory drugs (NSAID),

8 Nezar Watted et al.: Medication and Tooth Movement

corticosteroids, other analgesics and bisphosphonates. There

are a number of systemic factors and mediators however that

could influence the rate of orthodontic tooth movement.{1,5}

10. Effect of Individual Drugs on the

Orthodontic Tooth Movement can

be summarized as

10.1. Analgesics

Analgesic is a drug that selectively relieves pain by acting

on the CNS or peripheral pain mechanisms, without

significantly altering consciousness. The analgesic action is

mainly due to obtunding of peripheral pain receptors and

prevention of PG mediated sensitization of nerve endings.

NSAIDs are a relatively weak inhibitor of PG synthesis.{3,5}

NSAID’s are the most commonly used medications in

orthodontics, for control of pain following mechanical force

application to tooth.

Recent research demonstrated the molecular mechanisms

behind the inhibition of tooth movement by NSAID’s. The

levels of Matrix Mettallo-proteinases(MMPs)-9 and

(MMPs)-2 were found to be increased, along with elevated

collagenase activity, followed by a reduction in procollagen

synthesis which are essential for bone and periodontal

remodelling. The whole process is controlled by inhibition of

COX activity, leading to altered vascular and extra vascular

matrix remodelling, causing a reduction in the pace of the

tooth movement.{5,6,7}

Acetylsalicylic acid and the related compounds: Their

action results from inhibition of cyclooxygenase activity,

which converts unsaturated fattyacids in cell membrane to

prostaglandins. Clinical experience shows that orthodontic

tooth movement is very slow in patients undergoing long-

term acetylsalicylic therapy. Salicylate therapy decreases

bone resorption by inhibition of PG synthesis and may affect

differentiation of osteoclasts from their precursors.

Therefore, it is recommended that patients undergoing

orthodontic treatment should not be advised to take aspirin &

related compounds for longer periods during orthodontic

treatment.

A recent study reported that nabumetone,a drug belonging

to NSAID group, reduces the amount of root resoption along

with control of pain from intrusive orthodontic forces without

affecting the pace of tooth movement.{1.5}Table.3

Table 3. Effects of NSAIDs on orthodontic tooth movement

Kyrkanides et al investigated the effect of indomethacin on

orthodontic tooth movement. Their results indicated loss of

prostaglandin mediated cellular effects subsequent to

cyclooxygenase inhibition by this drug.{28}

The cyclooxygenase inhibition resulted in exacerbation of

IL-1β-mediated collagenase B (MMP-9) synthesis and

activity, as well as attenuation of type IV procollagen

synthesis levels by endothelial cells. Furthermore, Ito et al(38)

reported that the induction of MMP-9 synthesis caused

cyclooxygenase inhibition in rabbit articular

chondrocytes.{29}

Chan et al reported that new COX-2 specific inhibitors

decreased serious gastrointestinal perforations, obstructions

and bleeding when compared with conventional NSAID.{30}

De Carlos et al studied orthodontic tooth movement that

resulted from the effect of rofecoxib (COX-2 inhibitor) and

compared with diclofenac (a traditional NSAID). The results

showed both rofecoxib and diclofenac can inhibit COX-2

action that means that the orthodontic tooth movement was

inhibitedby these drugs.{31}

Kyrkanides et al stated that the use of anti-inflammatory

drugs may

Influence orthodontic tooth movement by altering

biochemical pathways that mediate extracellular matrix

remodeling. At the present, the use of cyclooxygenase-2

(COX-2) inhibitor for relief orthodontic pain is increasing,

and replacing conventional NSAIDs because its anti-

inflammatory effect is less injurious to gastrointestinal

mucosa than the nonselective NSAID.{28}

Chumbley and Tuncay recommended that orthodontic

patient should avoid to using aspirin and other nonsteroidal

anti-inflammatory analgesics to relieve pain because these

drugs can prolong orthodontic treatment time{32}.

Gameiro et al reported the short- and long-term effects of

celecoxib (COX-2 inhibitor) on orthodontic tooth movement

in rats. The short-term treatment was simulated the

preoperative administration of analgesics to decrease post-

operative pain whereas the long-term effect treatment was

simulated the situation that patients receive celecoxib in

treatment of chronic

American Journal of Pharmacy and Pharmacology 2014; x(x): xx-xx 9

disease all time of tooth movement. The results showed

that tooth movement was inhibited by celecoxib action in

both situations. Moreover, they stated that celecoxib not only

affected COX-2 level but also affected IL-1 and IL-6 that had

the result of bone resorption and toothmovement.{33}

Mohammed et al foundthat orthodontic tooth movement is

inhibited by indomethacin in rats. Furthermore, Arias’s study

showed the effect of aspirin and ibuprofen on orthodontic

tooth movement in the rats. Fewer osteoclasts were observed

in the pressure side of the teeth because these drugs inhibited

the production of PGs. Because the bone resorption was

reduced, the teeth moved less than average.{34}

Sari et al suggested that the one drug, rofecoxib, can be

used to relieve pain or patient discomfort during orthodontic

treatment because the inhibitory effect on PGs synthesis with

rofecoxib was less than the inhibition effect of aspirin during

the first 24 hours.{35}

Wong et al stated that aspirin does not change the

orthodontic tooth movement in guinea pigs. However, they

found that the dose of the analgesic used was lower than the

dose that can reduce the secretion of PGs because the

metabolic rate of these animals is faster than humans. For

this reason, they require higher doses than the does to

produce the same orthodontic effect in humans.{36}

Williams etal studied the effect of ibuprofen on alveolar

bone in dogs. Their result showed that ibuprofen can inhibit

alveolar bone loss when the dogs were treated with 4 mg/kg

of ibuprofen daily for 13 months. {37}

Kehoe et al confirmed that ibuprofen inhibits PGE2

synthesis in the PDL of guinea pig significantly by

decreasing the degree and rate of orthodontic tooth

movement.{38}

10.2. Acetaminophen

Paracetamol (acetaminophen) was first identified in the

late nineteenth century and it was available in the UK on

prescription in 1956, and over-the-counter in 1963. Since

then, it has become one of the most popular antipyretic and

analgesic drugs worldwide, and it is often also used in

combination with other drugs. The lack of a significant anti-

inflammatory activity of paracetamol implies a mode of

action which is distinct from that of the non-steroidal anti-

inflammatory drugs. Yet, the Cochrane Systematic Review,

2004 concluded that paracetamol was effective against the

postoperative pain in adults.{1.5,28}

Acetominophen (paracetamol) a weak COX-1 and COX-2

inhibitor that also reduces urinary prostaglandin levels after

systemic administration, has shown no effect on orthodontic

tooth movement in quinea pigs and rabbits. Comparative

studies and our clinical experience have demonstrated that

acetaminophen is effective for controlling pain and

discomfort associated with orthodontic treatment.{5,28,38}

Kehoe et al found that at the level of PDL, acetaminophen

inhibited the peripheral PGs synthesis but the degree and rate

of orthodontic tooth movement were not significantly

different when compared with control group.{38}

Arias et al showed the presence of osteoclasts in the

pressure side of the orthodontically moved incisors in rats

treated with acetaminophen. The bone resorption lacunae and

dental movement are the same as the control group.

Furthermore, the bone is actively regenerated because of

orthodontic treatment that activates the secretion of PGs and

the osteoclasts that act in bone resorption. These results did

not happen in the groups treated with aspirin and

ibuprofen.{39}

Roche claimed that acetaminophen has no effect on

orthodontic tooth movement in rabbits because

acetaminophen is a weak inhibitor of cyclooxygenase-1 and

cyclooxygenase-2, and analgesic action lacks the anti-

inflammatory properties.{40}

Piroxicam is an oxicam derivative (enolic acid) that

inhibits COX-1 and COX-2 and it has antiinflammatory,

analgesic, and antipyretic activities. It is a nonselective COX

inhibitor. Approximately 20% of the patients experience side

effects with piroxicam, and about 5% of the patients

discontinue its use because of these effects {41}

Tenoxicam, a long acting analgesic has been in use for a

long time, with good patient compliance, as it only needs to

be used once a day because of its long elimination half-life. It

has shown good results in controlling acute pain of mild or

moderate intensity, such as the pain which is triggered by an

orthodontic activation, without the presentation of any

significant adverse effects.{42}

In 1997, Roche JJ et al reported that acetaminophen

showed no effect on tooth movement when tested on rats.

Generally, studies suggests that paracetamol does not affect

orthodontic tooth movement, so it’s safe to use as a choice of

pain management in orthodontic treatment.{40}

As orthodontic tooth movement is considered to involve an

inflammation process, many studies regarding the effect of

anti-inflammatory drugs on tooth movement and root

resorption have been reported. However, controversy still

exists. The purpose of the present investigation is to provide

a quantitative assessment of the effect of steroidal and

nonsteroidal anti-inflammatory drugs on tooth movement and

root resorption by using scanning electron and laser

microscopes.{5,7,40,41,42}

10.3. Vitamin D

Vitamin D and its active metabolite, 1,25,2(OH)D3,

together with parathyroid hormone (PTH) and calcitonin,

regulate the amount of calcium and phosphorus levels.

Vitamin D receptors have been demonstrated not only in

osteoblasts but also in osteoclast precursors and in active

osteoclasts{43}. In 1988, Collins and Sinclair demonstrated

that intraligamentary injections of vitamin D metabolite,

1,25-dihydroxy cholecalciferol, caused increase in the

number of osteoclasts and amount of tooth movement during

canine retraction with light forces{44}. In 2004, Kale and

colleagues observed that local applications of vitamins

enhanced the rate of tooth movement in rats due to the well-

balanced bone turnover induced by vitamin D.{45} Brandi

and colleagues reported that rats treated with vitamin D

showed increased bone formation on the pressure side of the

10 Nezar Watted et al.: Medication and Tooth Movement

periodontal ligament after application of orthodontic forces.

In 2004, Kawakami observed an increase in the mineral

appositional rate on alveolar bone after orthodontic force

application; they suggested that local application of vitamin

D could intensify the re-establishment of supporting alveolar

bone, after orthodontic treatment.{46} The effect of vitamin

D may be the same as PTH. The rate of bone resorption will

increase when vitamin D is in excess.

10.4. Bisphosphonates

Bisphosphonates (BPNs) have strong chemical affinity to

the solid-phase surface of calcium phosphate; this causes

inhibition of hydroxyapatite aggregation, dissolution, and

crystal formation. Bisphosphonates cause a rise in

intracellular calcium levels in osteoclastic-like cell line,

reduction of osteoclastic activity, prevention of osteoclastic

development from hematopoietic precursors, and production

of an osteoclast inhibitory factor. Studies have shown that

BPNs can inhibit orthodontic tooth movement and delay the

orthodontic treatment {47}. Topical application of BPNs

could be helpful in anchoring and retaining teeth under

orthodontic treatment..{4,5,6}

The study of Igarashi et al showed that after giving of

subcutaneousbisphosphonates for 3 weeks in rats, tooth

movement was decreased by 40%. In addition, the alveolar

bone adjacent to the periodontal ligament showed the

reducing of osteoclasts after giving a single dose of

intravenous bisphosphonate (pamidronate) during tooth

movement.{47,48} Marx et al stated that bisphosphonate

osteonecrosis showed the decrease of microcirculation of

bone until the stage of necrosis happened. Because the

osteoclast cannot absorb the mineral matrix of bone, and the

capillary formation in new bone cannot be stimulated

completely, acellular and avascular bone will occur.) The

typical osteonecrosis in patients who received intravenous

bisphosphonate appeared as painful abscess teeth. When they

are extracted, the underlying necrosis bone will be exposed,

and abnormal healing causes bone loss in the future. {49}

At the present, there should be concerned about

orthodontic treatment in the patients who received

bisphosphonates High intravenous doses of bisphosphonates

can inhibit tooth movement more than lower oral doses.

Orthodontic tooth movement may increase the uptake of

bisphosphonates locally, so it decreases osteoclastic activity.

The result of this process shows as slower

toothmovement.{5,7,18.47,48,49}

10.5. Fluorides

Fluoride is one of the trace elements having an effect on

tissue metabolism. Fluoride increases bone mass and mineral

density, and because of these skeletal actions, it has been

used in the treatment of metabolic bone disease, osteoporosis.

Even a very active caries treatment with sodium fluoride

during orthodontic treatment may delay orthodontic tooth

movement and increase the time of orthodontic treatment.

Sodium fluoride has been shown to inhibit the osteoclastic

activity and reduce the number of active osteoclasts. {50}

10.6. Corticosteroids

These drugs are used as anti inflammatory and

immunosuppressive agent in treatment of a wide range of

chronic medical conditions. a low dose(1mg/kg body

weight)decreases orthodontic tooth movement by

suppressing osteoclastic activity. At high dose (15mg/kg

body weight)it increases osteoclastic activity thus produces

more rapid orthodontic tooth movement and subsequent

relapse.[51]

The main effect of corticosteroid on bone tissue is direct

inhibition of osteoblastic function and thus the decrease of

total bone formation.{51} Decrease in bone formation is due

to elevated parathyroid hormone levels caused by inhibition

of intestinal calcium absorption which are induced by

corticosteroids. Corticosteroids increase the rate of tooth

movement, and since new bone formation can be difficult in

treated patient, they decrease the stability of tooth movement

and stability of orthodontic treatment in general.{51,52}

When they are used for longer periods of time, the main

side effect is osteoporosis. It has been demonstrated in

animals with this type of osteoporosis that the rate of active

tooth movement is greater, but tooth movement is less stable

since little bone is present and no indication of bone

formation. A more extensive retention may be required.{52}

Corticosteroids acts by preventing the formation of

prostaglandins by influencing the arachidonic acid pathway.

An endogenous protein, lipocortin formed by steroids acts by

blocking the activity of phospholipase A2, thus inhibits the

release of arachidonic acid which in return influences the

synthesis of prostaglandin, leukotrienes or thromboxanes.

Corticosteroids also act by reducing the release of

lymphokines, serotonin and bradykinin at the injured site[25].

They play a vital role in inhibiting the intestinal calcium

absorption, which leads to direct inhibition of osteoblastic

function, and increase in bone resorption.{51,52,53}

Kalia and colleagues[26] evaluated the rate of tooth

movement in rats during short and long term corticosteroid

therapy. They concluded that bone remodeling seemed to

slow down in acute administrations, whereas the rate of tooth

movement increased in chronic treatment. This suggest that

orthodontic treatment should be postponed in patient

undergoing short term corticosteroids whereas, patient with

long term corticosteroid therapy treatment can be continued

with minimal adverse effect and more extensive retention

may be helpful in retaining these teeth if the dentist decides

to proceed with the orthodontic treatment.{54}

When they are used for longer periods of time, the main

side effect is osteoporosis. It has been demonstrated in

animal models with this type of osteoporosis that the rate of

active tooth movement is greater, but tooth movement is less

stable since little bone is present and there is no indication of

bone formation. A more extensive retention may be

required.{52,53,54}

American Journal of Pharmacy and Pharmacology 2014; x(x): xx-xx 11

10.7. Thyroid Hormones

Thyroid hormones are recommended for the treatment of

hypothyroidism and used after thyroidectomy in substitutive

therapy. Thyroxin administration lead to increased bone

remodeling, increased bone resorptive activity, and reduced

bone density. Effects on bone tissue may be related to the

augmentation of interleukin-1 (IL-1B) production that

thyroid hormones induce at low concentrations, cytokine

stimulate osteoclast formation and osteoclastic bone

resorption.

The speed of orthodontic tooth movement increased in

patients undergoing such medication. Low-dosage and short-

term thyroxin administrations are reported to lower the

frequency of “force induced” root resorption. Decrease in

resorption may be correlated to a change in bone remodeling

process and a reinforcement of the protection of the

cementum and dentin to “force induced” osteoclastic

resorption {55}

Calcitonin has the opposite effects. It is a peptide hormone

secreted by the thyroid, which decreses the intestinal calcium

and renal calcium reabsorption. In bones, calcitonin

inactivates osteoclasts and hence inhibits bone résorption. It

also stimulates the bone forming activity of

osteoblasts.{5,7,55} The thyroid hormone increases the speed of orthodontic

tooth movement in patients undergoing such medication. Low

dosage and short-term thyroxine administration are reported

to lower the frequency of "force-induced" root resorption.

Decrease in resorption may be correlated to a change in bone

remodeling process and a reinforcement of the protection of

the cementum and dentin to "force-induced" osteoclastic

resorption{55}

10.8. Sex Hormones

Sex hormones play a role of bone metabolism. Estrogen

has a direct effect on bone. It preserves calcium in bone by

suppressing the activation frequency of bone remodeling.

The remodeling activation will increase when menopause

starts and the result is rapid bone loss leading to symptomatic

osteoporosis.

Estrogen directly stimulates the bone-forming activity of

osteoblasts, so it is reasonably to expect a slower rate of

orthodontic tooth movement.[56]

Androgens also inhibit bone resorption and modulate the

growth of the muscular system. Thus, the excessive use of

these drugs by athletes, in an attempt to achieve better

athletic scores, may affect the duration and results of the

orthodontic treatment[,57,56].

10.9. Parathyroid Hormone

The function of parathyroid is to maintain a normal level

of diffuse calcium and phosphorus in the blood plasma and to

keep constant the ratio of these minerals to each other. The

act as a check on the thyroid gland parathyroids are important

organs in ca metabolism and play a leading role in

calcification of teeth. However, once the teeth are formed,

there is no evidence found of calcium withdrawal from teeth

due to parathyroid disturbances. The parathyroids are

important in regulating blood ca level, but have little or no

direct effect on growth or tooth eruption.{5,7}

PTH affects osteoblasts’ cellular metabolic activity, gene

transcriptional activity, and multiple protease secretion. Its

effects on osteoclasts occur through the production of

RANK-L Recepor activator of nuclear factor kappa -B

ligand), a protein playing a crucial role in osteoclasts’

formation and activity. In 1970s, animal studies demonstrated

that PTH could induce an increase in bone turnover that

would accelerate orthodontic tooth movement. More recently,

an increased rate of tooth movements has been observed in

rats treated with PTH, whether administered systemically or

locally. These results indicate that orthodontists should take

note of patients being treated with PTH, as for example, in

cases of severe osteoporosis.{57}

Parathyroid hormone affects both bone resorption and

formation process. If PTH appears around bone cells, the

effect of bone will be resorption. By contrast, low level of

PTH results in bone formation. When the calcium level in

blood decreases, PTH will stimulate osteoclastic activity to

increase calcium and phosphate absorption in the gut, and

decrease calcium excretion and tubular phosphate

reabsorption in the kidney. This plays a role as regulator of

calcium homeostasis by PTH.{57,58}

10.10. Anti Convulsants

Valporic acid has a potential to induce gingival bleeding

even with minor trauma making orthodontic maneuvers

difficult. Phenytoin induces gingival hyperplasia due

overgrowth of gingival collagen fibers, which involves the

interdental papilla, making application of orthodontic

mechanics difficult and difficulty in maintaining oral hygiene.

Gabapentin produce xerostomia, making oral hygiene

maintenance difficult during orthodontic treatment. In these

cases, clinician should be aware of possible difficulties

during treatment period, and discuss it with the patients and

or parents and educate them so that adequate measures to

maintain oral hygiene are followed.{59}

10.11. Alcohol

Chronic ingestion of large amounts on daily basis may

have devastating effects on a number of tissue systems,

including skeletal system. Alcoholism may lead to severe

complications, such as liver cirrhosis, neuropathies,

osteoporosis, and spontaneous bone fractures. Circulating

ethanol inhibits the hydroxylation of vitamin D3 in liver, thus

impending calcium homeostasis. In such cases the synthesis

of PTH is increased, tipping the balance of cellular function

towards the enhanced resorption of mineralized tissues,

including root resorption in order to maintain normal levels

of calcium in blood. It was found that chronic alcoholics

receiving orthodontic treatment are high risk of developing

severe root resorption during course of orthodontic

treatment.{60}

12 Nezar Watted et al.: Medication and Tooth Movement

Davidovitch et al. have found that chronic alcoholics

receiving orthodontic treatment are at high risk of developing

severe root resorption during course of orthodontic

treatment.{60,61}

10.12. Prostaglandins and Analogs

Experiments have shown that PGs may be mediators of

mechanical stress during orthodontic tooth movement. They

stimulate bone resorption, root resorption, decrease collagen

synthesis, and increase cAMP. They stimulate bone

resorption by increasing the number of osteoclasts and

activating already existing osteoclasts. A lower concentration

of PGE2 (0.1 μg) appears to be effective in enhancing tooth

movement. Higher concentration leads to root resorption.

Systemic administration is reported to have better effect than

local administration. Researchers have injected PGs locally at

the site of orthodontic tooth movement to enhance the bone

remodeling process and the pace of tooth movement. The

main side effect associated with local injection of PGs is

hyperalgesia due to the release of noxious agents.{61}

Yamasaki et al found an increased number of osteoclasts in

rats alveolar bone after local injection of PGEI. A similar

regimen in human subjects increased significantly the rate of

canine and premolar movement.{62}

PGs act by increasing the number of osteoclasts, and by

promoting the formation of ruffled borders, thereby

stimulating bone resorption. Among the PGs that had been

found to affect bone metabolism (E1, E2, A1, and F2-alpha),

PGE2 stimulated osteoblastic cell differentiation and new

bone formation, coupling bone resorption in vitro.This

indicates that although they enhance the tooth movement

process, their side effects are very serious to consider its

clinical use. Recent trends are directed toward combining

local anesthetics with PGs, in order to reduce pain while

injected locally. Research in this regard is still in its

preliminary phase.{63,64}

For prostaglandin mediated bone resorption process,

intracellular calcium is essential. Furthermore, IL-1 can

stimulate prostaglandins as a potent stimulator of bone

resorption.PGE1 and PGE2 are found to increase bone

resorption. But PGI2 inhibits osteoclastic activity and

stimulates bone formation.{63,64,65}

11. Insulin

Insulin is a polypeptide hormone secreted by the beta cells

of the Langerhans islets of the pancreas. A normal non-obese

man secretes approximately 50U/day, with a basal plasma

insulin concentration of 10-50 microns/ml. Its main function

is to maintain the blood glucose level. Insulin deficiency

produces a clinical state called diabetes mellitus, while its

excess leads to hypoglycemia. Diabetes mellitus is diagnosed

in 3-4% of the population treated in our day-to-day

orthodontic practice. The orthodontic practitioner should

have a basic knowledge and understanding of this disease

and of its impact on the oral cavity, as well as of its

consequences upon the dental treatment.{66}

Informed on the oral complications induced by diabetes

mellitus, the dental practitioner should consider them when

treating a DM patient; the key to any orthodontic treatment is

a good medical control. No orthodontic treatment should be

performed in a patient with uncontrolled diabetes. There is no

treatment reference with regard to fixed or removable

appliances.{67}

A good oral hygiene is especially important when fixed

appliances are used, as they may increase plaque retention,

which could more easily cause tooth decay and periodontal

breakdown. Daily rinses with fluoride-rich mouthwash can

provide further preventive benefits. Candida infections may

also occur in the oral cavity, so that they should be well

monitored. Diabetes related microangiopathy can

occasionally appear in the periapical vascular supply,

resulting in unexplained odontalgia, percussion sensitivity,

pulpitis, or even loss of vitality in sound teeth. Especially in

orthodontic treatments involving force application for

moving teeth over a considerable distance, the practitioner

should regularly check the vitality of the teeth involved. It

isadvisable to apply light forces and not to overload the

teeth .{66}

Holtgrave and Donath, who studied the periodontal

reaction to orthodontic forces, evidenced retarded osseous

regeneration, weakening of the periodontal fibers and

microangiopathies in the gingival areas. In adults, before

starting the orthodontic treatment, the orthodontist should

obtain a full-mouth (periodontal) examination and evaluation

of the need for periodontal treatment.

The periodontal condition should be improved before

staring the treatment and should be monitored regularly.

Maintaining a strict oral hygiene is important, by a proper

use of toothbrush, interdental toothbrush and chlorhexidine

mouthwash.{67,68}

To minimize the neutralizing effect of toothpaste on the

chlorhexidine molecule, an at least 30-min interval should be

left between tooth brushing and chlorhexidine rinse As no

upper age limit for orthodontic treatments is any longer valid

today, the practitioner will see both type1 and type2 DM

patients. Type2 patients can be considered more stable than

type1 ones, as hypoglycemic reactions are more frequent in

these patients. If a patient is scheduled for a long treatment

session, he or she should be advised to eat a usual meal and

take the medication as usual.{66.67} At each appointment,

the orthodontist should confirm the meal and medication, to

avoid a hypoglycemic reaction in the office. DM patients

with good metabolic control, without local factors, such as

calculus, and with a good oral hygiene, have a similar

gingival status as the healthy ones, consequently they can be

treated orthodontically.{66,67,68}

11.1. Anaesthetic Gels

Anaesthetic gels are safer alternatives to analgesics in

reducing the pain which results from orthodontic procedures.

Keim et al., in their study, stated that they may be of use

when orthodontic procedures are performed, such as band

placement and cementation, archwire ligation, and

American Journal of Pharmacy and Pharmacology 2014; x(x): xx-xx 13

band/bracket removal. The advantage of this system is its

delivery method, which simply introduces the gel into the

gingival crevice and makes it entirely painless.{69}

11.2. Cytokines

Cytokines are small proteins that are identified as

mediators of bone resorption. One cytokine, Interferon

(IFN)-γ, acts as a bone resorption inhibitor that is opposite to

other cytokines.

Leukotrienes are a type of eicosanoid which is a product of

arachidonic acid conversion and are the only eicosanoids that

are formed independently from cyclooxygenase (COX). They

are produced when arachidonic acid is metabolised by

lipoxygenase enzymes[19].Leukotrienes also play an

important role in Inflammation, allergies, and diseases such

as asthma. These conditions can be cured by using

leukotriene inhibitors which block leukotriene receptors

hence counteracts their effects. Examples of medication are

montelukast and zafirlukast. According to Mohammed AH et

al. , leukotrienes causes increase in orthodontic tooth

movement, through bone remodeling whereas, leukotrine

inhibitors work the other way round. Therefore, the use of

leukotriene inhibitors can delay orthodontic treatment,

leukotrienes can be used in future clinical applications that

could result in increasing tooth movement.{34}

Interleukin (IL)-1 has potential as a bone resorption

stimulator by stimulation of prostaglandins. From

experimental studies, applying tensile stress to periosteal

fibroblasts will increase the level of IL-1 inhibitor. IL-1 has

two molecular forms, alpha (IL-1∝)and beta (IL-1β), and is

secreted by many kinds of cells such as macrophages, B cells,

neutrophils, fibroblasts, and epithelial cells. IL-1 and

prostaglandins are synergistic.{70}

Interleukin (IL)-2 shows in the attraction and proliferation

of osteoclast progenitors as well as the stimulation of acid

production by osteoclasts.{70,71)

Interleukin (IL)-6 is produced by lymphocytes,monocytes

and fibroblasts.(11) It is one of an inflammatory cytokines

that stimulates plasma cell proliferation and antibody

production. Furthermore, this cytokine stimulates osteoclast

and bone resorption.{5,.72,73}

Interleukin (IL)-11 stimulates osteoclast formation and

bone resorption. The effect of osteoclast formation may be

prostaglandins mediated.{72,73}

Tumor necrosis factor (TNF) and lymphotoxin are

cytokines that are implicated in the stimulation of

osteoclastic bone resorption. This effect is produced by

prostaglandins mediation.{71,72,73}

Interferon (IFN)-γ is produced by activated T lymphocytes.

It can inhibit bone resorption by inhibiting the differentiation

of precursors into mature cells.{71}

Leukotriene B4 (LTB4) has a highly potential as a

chemotactic agent. It induces the accumulation of

inflammatory cells especially neutrophils and stimulates bone

resorption.{72,73}

11.3. Cyclosporine

It increases gingival hyperplasia. In most patients the

greatest changes in the gingival occurs in first six months of

cyclosporine therapy. Severe gingival hyperplasia, make

orthodontic treatment, and maintenance of oral hygiene

difficult. Treatment should be started or resumed after

surgical removal of excessive gingival tissues once there is

good oral hygiene. Whenever possible, fixed appliances

should be kept to a minimum period with brackets, and

avoiding the user of cemented bands. Removable appliances

in these cases are not recommended, due to improper fit.{5,7}

11.4. Anti-Histamines

Histamine (H(1)) receptor antagonists are widely used

drugs for treatment of allergic conditions. Although

histamine was shown drugs may have varying effects on

orthodontic tooth movement.{66,67,72}

11.5. Growth Factors

Bone morphogenetic proteins (BMPS) are stored in the

osteoblasts and bone. They are the important factors that can

initiate osteoblastogenesis.

Fibroblast growth factor (FGF) is secreted by macrophages,

osteoblasts and stored in bone. It has a direct effect to

stimulate osteoblast proliferation.{72}

Transforming growth factor (TGF)-β is stored in bone and

secreted by osteoblasts, macrophages and PDL cells. It can

stimulate formation of bone by involving the cartilaginous

intermediate and induce granulation tissue formation. TGF-β

was found on the tension side of tooth movement and plays a

negative role for osteoclastogenesis.{72}

Platelet-derived growth factor (PDGF) is secreted by PDL

cells, macrophages, endothelial cells, and osteoblasts, and

stored in bone. It has biologic effects of mitogenesis and

chemotaxis on osteoblasts and fibroblasts. PDGF can

promote skin healing, bone formation and periodontal

regeneration,

Insulin-like growth factor (IGF) is secreted by PDL cells,

macrophages, osteoblasts, plasma cells and stored in bone as

well as TGF- β. It is an important mediator of postnatal

longitudinal growth. Normally, IGF alone can not

significantly stimulate bone healing, but it can work together

with platelet-derived growth factor (PDGF) for enhancing

bone healing process. So, IGF is synergistic with PDGF and

stimulates extracellular matrix.

11.6. Relaxin

Relaxin has been known for decades as a pregnancy

hormone. It is released just before child birth to loosen the

pubic symphysis, so that the relaxed suture will allow

widening of the birth canal for parturition. It has also been

shown to have effects on a multitude of other physiological

processes, including the regulation of vasotonus, plasma

osmolality, angiogenesis, collagen turnover, and renal

function.{77}

14 Nezar Watted et al.: Medication and Tooth Movement

Relaxin’s influence on soft tissue remodeling and on

several mediators that stimulate osteoclast formation have

attracted attention from orthodontics researchers.{77,78}

11.7. EP4 Agonist

Bone anabolic responses to external loading areinduced by

stimulation of prostaglandin receptor EP4.

Chung et al claimed that the activation of the EP4 receptor

of the paradental region might induce osteoblasts and

stimulate new bone formation in vivo. Their study reported

that the local administration of EP4 agonist can induce tooth

movement and increase bone volume at least in the tension

side. Furthermore, PGE stimulates bone resorption through

the EP4 receptor via a mechanism involving an increase of

cAMP and RANKL in osteoblasts. So, there is a high

possibility of increased bone resorption.{77,79}

Chung et al stated that the role of EP4 agonists not only

enhances bone formation during tooth movement but also

stimulate osteoblasts to produce increased amounts of

RANKL that increase osteoclastogenesis and bone

resorption.{79}

12. Discussion

This systematic review of literature summarizes the effects

of medications, such as anti-inflammatory and anti-asthmatic ,

anti-arthritics, analgesics, corticosteroids, estrogens and other

hormones, and calcium regulators in orthodontic tooth

movement. As described by Krishnan V and Davidovitch Z,

these groups of drug have an effect on OTM. Some of these

drugs are promoter drugs where it promotes orthodontic tooth

movement, but others have an inhibitory effect{70,71}.

Orthodontic tooth movement is accompanied by bone

remodeling (alveolar bone turnover). The remodeling of bone

is a cycle that starts with activation followed by resorption,

reversal and formation phases.

The activation period is about 10 days. There are cells

recruitment, differentiation, proliferation and migration in

this period followed by resorption. The resorption period

takes 21 days that occurs by osteoclast activity.{70}

The next stage is reversal stage when inactive osteoblasts

become activated and begin to form bone. Bone formation is

determined by rate and duration of osteoblast activity.

The new bone formation is completed over a period of 6

months with mineralization. The remodeling cycle from

activation through to the start of the formation phase requires

about 4 months in humans. The amount of bone remodeling

is related to the amount of tooth movement at that site.{70,71}

Davidovitch et al.and Yamasaki et al.[concluded in their

study that the rate of orthodontic tooth movement can be

altered by administrating certain drugs locally or systemically.

The drugs used in orthodontics can be broadly classified into

two major groups, promoter drugs and suppressor agents.

Promoter drugs are agents that act with the secondary and

primary inflammatory mediators and enhance the tooth

movement, examples being; Prostaglandin, Leukotrienes,

Cytokines, Vitamin D, Osteocalcin, and Corticosteroids.

Suppressor agents are drugs which reduces bone resorption

examples are; Nonsteroidal anti-inflammatory agents and

bisphosphonates.{62,63,64,70,71}

As a clinician, this information is very important because

orthodontic treatment does involve postoperative pain and

the form of pain management is very important because not

all drugs favours tooth movement. Many patients use over

the counter medications for immediate pain relief, which may

interfere with the treatment plan. Therefore, practitioners

should have a proper knowledge of the drugs being

prescribed and the patient should be well

informed.{5,6,7,62,70}

During orthodontic tooth movement, bone remodeling

process is related to the expression of mediators. Acute

inflammatory response is presented in the early phase of

orthodontic tooth movement. Inflammatory mediators may

stimulate the biological processes that associated with

alveolar bone resorption and deposition. Furthermore,

orthodontic forces can induce the bone remodeling process

by the local mediators, such as prostaglandins, cytokines and

growth factors, that play an important role in bone

remodeling. PGE2 has been involved in bone remodeling and

especially recognized as a potent stimulator of bone

resorption.{62,63,64}

There are several studies showing the usage of

pharmacologic agents to induce bone resorption and

deposition for control of tooth movement. For example, the

study of Yamasaki shows the usage of local injection of

prostaglandin to stimulate tooth movement.Other

pharmacologic agents such as calcitonin, and

1,25(OH)2D3can also induce tooth movement. The daily

injection of osteocalcininto the palatal subperiosteum in rat

showed it can stimulate tooth movement significantly in the

early period but not significantly after day 5th.One injection

of 1,25(OH)2D3 per 7 days into the PDL of cats increased

tooth movement 60% as well as in the human that received

PGE1 submucosal injection. Although the pharmacologic

agents can induce the tooth movement in both human and

animal study but they have side effects during the injection

procedure such as local pain and discomfort, so these

techniques are not practical to use for the patient.{5}

Role of vitamin D3 and Corticosteroids in still orthodontic

tooth movement{5,61,62,63} remains unclear. Some author

have reported that it promotes tooth movement but there are

also studies that demonstrate bone formation after application

of these drugs. So, it is important to have more clinical trials

on determining the exact role of Vitamin D3 and

Corticosteroids in orthodontic tooth movement.{61.62,63}

Bisphosphonates are drugs which also effect the calcium

homeostasis. It is known for its role in inhibiting tooth

movement. They are used in cases of prevention of

orthodontic relapse but it should be used with great caution

because of its severe side effects on long term use.{47.48}

Eicosanoids such as prostaglandins and leukotrienes are

group of drugs, which increases the rate of orthodontic tooth

movement.

They act by stimulating bone resorption. Eicosanoid

American Journal of Pharmacy and Pharmacology 2014; x(x): xx-xx 15

inhibitors on the other hand acts in preventing OTM.

Example of eicosanoid inhibitors are NSAIDs where it

inhibits the synthesis of prostanoids which is an important

mediator of bone resorption. So, it is important that the

patient does not take NSAIDs such as aspirin or other related

compounds for long periods of time during orthodontic

treatment[55]. The alternative that can be suggested to

patients is paracetamols. Paracetamol also known as

acetaminophen is a type of analgesic, which does not have

any deleterious effect on orthodontic tooth movement.

Hormones also play an important role in tooth movement.

Hormones such as thyroxin is known to increase the rate of

tooth movement by directly stimulating the actionof

osteoclast.Calcitonin and estrogen have the opposite effect on

tooth movement. It is very important to know if the patient is

under any oral contraceptive pills. It contains estrogens,

which inhibits tooth movement.{5,7,8,23}

NSAIDs such as Ibuprofen and aspirin can inhibit

orthodontic tooth movement. They reduce the synthesis of PGs

that results in decreasing osteoclasts in the pressure sides.

Because they have potential for slowing tooth movement, it is

not recommended to use them for relief of orthodontic pain.

Nowadays, the numbers of adult orthodontic patients are

increased, so orthodontists for long-term treatment for chronic

diseases such as arthritis, tricyclic antidepressants, and

antiarrhythmics that can experience reduced rate of tooth

movement. COX-2 inhibitor reduce the osteoclast activity and

inhibit tooth movement as well as NSAIDs.{28,30}

Orthodontists should be aware of the patients who under

short- and long- term therapy with COX-2 inhibitors because

these drugs can decrease the rate of orthodontic tooth

movement. Acetaminophen acts at the central nervous system

and does not stimulate PGs synthesis, so it does not interfere

with the orthodontic tooth movement. The numbers of

osteoclasts in the pressure areas are not decreased, and the

bone regeneration does not change by acetaminophen.So, it is

a drug of choice that orthodontists should recommend to their

patients for relieving the discomfort during orthodontic

treatment.{5,7,33,36,61,62,63}

Bisphosphonate is used in patients who have bone

metabolism disorders. It can inhibit tooth movement.

Furthermore, it impairs bone healing and induces

osteonecrosis in alveolar bones of maxilla and mandible.

Medication screening and patient counseling are essential in

these patients.{47,48,49}

13. Conclusion

As more and more chemical analogues are being used in

the form of new drugs to avoid resistance, today’s clinicians

should mandatorily update his knowledge on the clinical

efficacy of the new drugs as well as the beneficial and

harmful effects on human tissues . It is always advisable for a

dentist to confirm with the family physician or the concerned

physician for fitness of the patients who under go

orthodontics involving tooth movement.

Orthodontists should assume that many patients are taking

prescription or over-the counter medications regularly. The

orthodontist must identify these patients by carefully

questioning them about their medication history and their

consumption of food supplements and it should consider a

part of every orthodontic diagnosis.

References

[1] Proffit WR. The biological basis of orthodontic therapy. Contemporary orthodontics. 3rd ed. St. Loius: Mosby Year Book; 2000:296-325.

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