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Accelerated orthodontic toMolecular mechanisms

Hechang Huang,a Ray C. Williams,b and Stephanos KyrkanStony Brook, NY

antlyrminems rrentical as. Thcele

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bled the regional acceleratory phenomenon (RAP),

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local process, which starts with bone resorption, fol-

inammatory process, and the rate-limiting factor for

bProfessor, Department of Periodontology.cProfessor and chair, Department of Orthodontics and Pediatric Dentistry; asso-

0889-5406/$36.00Copyright 2014 by the American Association of Orthodontists.

SPECIAL ARTICLElowed by reversal and bone formation phases, resultingin the replacement of old bone with new bone.21,22

Both bone modeling and remodeling are determinantsfor the rate of orthodontic tooth movement. Bonemodeling during orthodontic tooth movement is an

ciate dean, Research and Faculty Development.All authors have completed and submitted the ICMJE Form for Disclosure of Po-tential Conicts of Interest, and none were reported.Address correspondence to: Stephanos Kyrkanides, 100 Nicolls Rd, Stony Brook,NY 11794; e-mail, [email protected], February 2014; revised and accepted, July 2014.tion-resorption (catabolic) or activation-formation(anabolic) on bone surfaces, resulting in changes ofthe shape, size, or position of the bone.20 Bone remod-eling or turnover, on the other hand, is a tightly coupled

From the School of Dental Medicine, State University of New York, StonyBrook, NY.aAssistant professor, Department of Orthodontics and Pediatric Dentistry.http:/

620omy, the surgical procedure that completely cutsthe cortex and the medulla of the alveolar bone.rationale for performing osteotomy was to reducehanical resistance during tooth movement. In the0s, Kole8 introduced corticotomy, the perforationhe cortex of the bone alone without intrusion intoedulla, to replace osteotomy except in the subapical

tent with this observation, other studies also showthat nonsurgical interventions stimulating bone remeling can accelerate orthodontic tooth movement.14-

BONE MODELING, REMODELING, ANDORTHODONTIC TOOTH MOVEMENT

Bone modeling is the uncoupled process of actiintervention to accelerate tooth movement involved os- indicating increased bone remodeling activity. Consis-Accelerating orthodontic tooth movement can signicThe rate of orthodontic tooth movement is chiey detethis in turn is under the control of molecular mechanisperiodontal ligament. This review summarizes the curaccelerated orthodontic tooth movement, and the clintooth movement with possible molecular mechanismdevelop more clinically applicable methods to acDentofacial Orthop 2014;146:620-32)

Orthodontic movement of teeth under mechanicalforce depends on the remodeling of tissues sur-rounding the roots. Accelerating orthodontictooth movement has long been desired for its multiplepotential benets, including shorter treatment duration,reduced side effects (such as oral-hygiene related prob-lems, root resorption, and open gingival embrasurespaces1-5), enhanced envelope of tooth movement,differential tooth movement, and improvedposttreatment stability.6 Attempts to accelerate toothmovement can be dated back to the 1890s, almostcontemporary with Angle's groundbreaking work inmodern orthodontics.7 For the next half century, the/dx.doi.org/10.1016/j.ajodo.2014.07.007oth movement:

idesc

reduce treatment duration and risks of side effects.d by the remodeling of tissues surrounding the roots;egulating cellular behaviors in the alveolar bone andknowledge on the molecular mechanisms underlyingnd experimental methods that accelerate orthodontice review also shows directions for future studies torate orthodontic tooth movement. (Am J Orthod

region, to reduce invasiveness. Since it was less destruc-tive, corticotomy completely replaced osteotomy as thepreferred surgical method to accelerate tooth move-ment.9 Despite the evolution of clinical methods, the sci-entic explanation of accelerated tooth movement wasstill believed to be reduced mechanical resistance afterosteotomy or corticotomy, enabling the teeth to bemoved en bloc with the tissues surrounding them.10-12

This view was challenged by Wilcko et al13 (including aperiodontist and an orthodontist) circa 2000. Theydescribed the demineralization and remineralization pro-cess of the alveolar bone after corticotomy that resem-tooth movement is bone resorption at the bone and

initiation of bone resorption.

Huang, Williams, and Kyrkanides 621OSTEOCLAST FORMATION AND BONERESORPTION

The rate-limiting step in orthodontic tooth move-ment is considered to be bone resorption at the leading(compression) side. Histologic studies show that the for-mation of osteoclasts is induced at the compression sideduring orthodontic tooth movement.32-35 Alveolarcorticotomy and nonsurgical interventions thataccelerate tooth movement signicantly increase thenumbers and functions of osteoclasts.14-17,32-45 Theformation of osteoclasts depends on the effects ofstromal and osteoblastic cell-derived factors on osteo-clast precursors. One of these factors is receptor activatorof nuclear factor kappa B ligand (RANKL), which binds toits receptor, RANK, on the surface of developing osteo-clastic cells. The RANKL/RANK binding is crucial for thedifferentiation, function, and survival of osteoclasts.On the other hand, osteoprotegerin (OPG), another oste-oblastic cell-derived factor, interrupts the RANKL/RANKbinding as a decoy receptor of RANKL, inhibiting osteo-clastogenesis. Therefore, the RANKL/OPG ratio expressedby osteoblastic cells and the RANK expression by osteo-clast precursor cells largely determine the formation offunctional osteoclasts and the activation of the initialperiodontal ligament (PDL) interface.23 Even thoughbone remodeling renews the internal content of thebone without changing the size or shape of the boneunder physiologic conditions, it also affects the rate oforthodontic tooth movement.24

Both bonemodeling and remodeling are controlled bythe cellular activities of osteoclasts, osteoblasts, and oste-ocytes. Apparently, osteoclasts carry out resorption,whereas osteoblasts carry out bone formation duringbone modeling. The resorption-formation sequence ofthe bone remodeling process is performed by basic multi-cellular units, which are organized osteoclasts and osteo-blasts.25 Both biochemical and mechanical factorsregulate the rates of bone modeling and remodel-ing.22,26,27 Previous studies have shown that orthodontictreatment stimulates alveolar bone modeling,23 as wellas bone remodeling that resembles RAP28 with increasednumber and function of osteoclasts and osteoblasts, andmore active bone resorption-formation cycles.29-31

Activation of osteoblasts by mechanical forces,inammatory stimuli, or hypoxia appears to be the rstand necessary step in orthodontic tooth movement.Activated osteoblasts are responsible for the expressionof specic mediators of osteoclast formation andstep of bone remodeling.46 RANKL level in the gingivalcrevicular uid becomes signicantly higher than in the

American Journal of Orthodontics and Dentofacial Orthopedcontralateral control side after 24 hours of continuouscompressive force in adolescent patients.47 RANKLexpression is increased in the osteoblasts, osteocytes,and broblasts in the PDL and the alveolar bone, espe-cially by the compressive force, as early as 3 hours afterorthodontic force application and remains elevated afterat least 5 days.48-55 Tensile strain, however, signicantlyreduces the mRNA level of RANKL in osteoblastic cellcultures.56 Local delivery of RANKL with gene therapysignicantly stimulates osteoclast formation and speedsup orthodontic tooth movement.57,58 Contrary toRANKL, OPG concentration in the gingival crevicularuid at the compression side is decreased comparedwith the basal level as early as 1 hour after orthodonticforce application in adolescent patients59 and becomessignicantly lower than at the contralateral side after24 hours in these patients.47 Other studies have shownthat OPG expression is decreased by the compressiveforce but increased by the tensile force during orthodon-tic tooth movement, opposite to the effects onRANKL.52-54,56,60 As expected, local delivery of OPGsignicantly inhibits bone remodeling and orthodontictooth movement.61,62 The reciprocal regulation ofRANKL and OPG expression by the compressive andtensile strains coordinates predominant boneresorption at the leading side and predominant boneformation at the trailing side, enabling normal toothmovement.

Macrophage colony-stimulating factor (M-CSF) isanother stromal and osteoblastic cell-derived factorthat is crucial for recruitment and differentiation of earlyprecursors of osteoclasts.63 M-CSF expression is de-tected in osteoblasts and broblasts in the PDL and inthe alveolar bone at early time points during orthodontictooth movement.55,64 Compressive force increases theexpression of M-CSF in osteoblastic MC3T3-E1 cell cul-tures.54 Local administration of an optimum dose ofM-CSF signicantly increases the number of osteoclastsand accelerates orthodontic tooth movement in rats.65

Daily local injections of an antibody to c-Fms, the recep-tor of M-CSF, signicantly inhibit tooth movementwith compromised osteoclast formation.66 Early up-regulation of M-CSF is evident and important for ortho-dontic tooth movement.

Therefore, the expression patterns of M-CSF, RANKL,and OPG by osteoblasts play key roles in tooth move-ment. Mechanical force induction of M-CSF and RANKLin osteoblastic cells is mediated by other factors.Compressive force signicantly stimulates the expres-sion of cyclooxygenase (COX)-2, the chief enzymeresponsible for the majority of prostaglandin (PG)

production, in the PDL and osteoblastic cells,54,67

and thus increases the production of prostaglandin

ics November 2014 Vol 146 Issue 5

procedures. Interestingly, full-thickness mucoper-

622 Huang, Williams, and KyrkanidesE2 (PGE2).67,68 Compressive force also signicantly

increases expression of PGE2 receptors EP2 and EP4 inosteoblasts.68 PGE2 is a well-known factor to increaseRANKL and decrease OPG expression in osteoblasticcells, stimulating osteoclast formation. On the otherhand, inhibitors of COX-1 and COX-2, or specic inhib-itors of COX-2, reduce the expression of RANKL by oste-oblastic cells54,67 and impair orthodontic toothmovement.69,70 It is apparent that COX-2 stimulationand PGE2 production mediate the induction of RANKLby compressive force. Compressive force also increasesthe expression of interleukin (IL)-17 and its receptorsin osteoblasts. In the absence of compressive force, theaddition of IL-17 in the cell cultures mimics the effectsof compressive force to increase the expression of M-CSF and RANKL and to decrease the expression ofOPG, strongly suggesting that IL-17 also mediates theeffects of compressive force.52 The expressions ofvascular endothelial growth factor (VEGF) and its recep-tor VEGFR-1 are intensied by mechanical forces duringorthodontic tooth movement.64,71-73 A neutralizingantibody to VEGF partially inhibits the induction ofRANKL and VEGFR-1 by mechanical stress, indicatingthat VEGFmediates the induction of RANKL by mechan-ical force in an autocrine pathway.73

The inammatory response to orthodontic toothmovement is associated with the production and releaseof a variety of cytokines. After 24 hours of orthodonticforce application, the protein levels of IL-1, IL-6, and tis-sue necrosis factor (TNF)-a are signicantly increased inthe gingival crevicular uid in humans.74 The number ofcells expressing interferon-g is signicantly increased bytooth movement.75 Differential expression of cytokinesbetween the compression and tension sides has alsobeen shown: the compression side has higher levels ofTNF-a and matrix metalloproteinase-1, whereas thetension side has higher levels of IL-10, tissue inhibitorof metalloproteinase-1, and collagen-1.53 Ren et al76 re-ported that TNF-a level is increased soon after toothmovement (24 hours), along with IL-1b, IL-6, andIL-8. Some of these cytokines, including TNF-a, IL-1b,and IL-6, can stimulate osteoclast differentiation, func-tion, and survival, contributing to the activation of thebone remodeling process and tooth movement.77-79

Furthermore, tooth movement is slower in micelacking TNF-a expression, conrming the role of thiscytokine in orthodontic tooth movement.80

Many approaches affect the expression of the abovefactors on osteoclast formation to activate bone remod-eling and accelerate orthodontic tooth movement. Se-lective alveolar corticotomy signicantly increases local

osteoclast number and activity, and causes dramaticallyreduced trabecular bone surfaces, with the most obvious

November 2014 Vol 146 Issue 5 Americaniosteal ap surgery without corticotomy can induceRAP.81 Later, it was discovered that the same procedurecan stimulate new vascular plexus formation in the PDL,and the PDL width is increased.82 The same researchgroup also found that bone resorption by osteoclastsand bone formation by osteoblasts are quite obvioussurrounding the newly formed blood vessels, possiblydue to increased VEGF expression as a result of full-thickness ap surgery.83 The surgical procedures,including corticotomy and full-thickness mucoperios-teal aps, disturb the local microcirculation and causeregional hypoxia, which will stabilize an intracellulartranscription factor called hypoxia inducible factor in os-teoblasts.84 Hypoxia inducible factor in turn activatesthe expression of VEGF84,85 and induces the expressionof RANKL in PDL broblasts.86 Increased hypoxia induc-ible factor expression in osteoblasts under hypoxic con-ditions increases the expression of VEGF and RANKL andinduces peripheral blood mononuclear cells into func-tional osteoclasts, whereas a hypoxia inducible factor in-hibitor reduces hypoxia-induced osteoclast formation.87

Corticotomy also signicantly enhances the expressionof more than 20 cytokines, including TNF, IL-1, andIL-6, compared with tooth movement or soft-tissueap surgery alone.88 Low-energy laser irradiation up-regulates the number of RANKL and RANK positive cells2 to 3 days later; this contributes to accelerated toothmovement.89 Resonance vibration also stimulates theexpression of RANKL and osteoclast formation in thePDL.14 Some pharmacologic agents, including parathy-roid hormone, 1,25 dihydroxy vitamin D3 (1,25[OH]2D3), and PGE2, can increase RANKL and decreaseOPG expression in osteoblasts, promoting osteoclastformation and enhancing bone remodeling activity,therefore increasing the speed of orthodontic toothmovement.

OSTEOBLAST FORMATIONANDBONEAPPOSITION

Osteoblast proliferation, differentiation, survival, andfunction are regulated by a number of extracellular fac-tors including growth factors, cytokines, and hormones,as well as by interactions with osteoclastic cells. Trans-forming growth factor (TGF)-b1 is a secreted proteineffects at 3 weeks postoperatively in a rat study.36 Eventhough both orthodontic tooth movement and cortico-tomy can increase bone remodeling by increasing theexpression of RANKL, RANK, and VEGF and decreasingOPG, the combined procedures show distinctive effectson the genes that are not simply the addition of the 2

34,55that enhances bone formation by chemotactic effectson osteoblastic cells, promoting osteoblast proliferation

Journal of Orthodontics and Dentofacial Orthopedics

Huang, Williams, and Kyrkanides 623and differentiation at early stages while inhibiting oste-oclast formation by reducing RANKL and increasing OPGexpression.90 TGF-b1 protein concentration in gingivalcrevicular uid is signicantly increased after 24 hoursof orthodontic tooth movement in human patients.91

In another human experiment observing TGF-b1 proteinconcentrations in gingival crevicular uid after 24 hoursof orthodontic force application, the compression sidehad a higher concentration than did the tension side.92

In the human PDL, the mRNA level of TGF-b1 is similarlyincreased at both the compression and tension sides af-ter 7 days of force application.53 However, anotherexperiment in rats demonstrated that the level of TGF-b1 protein in the PDL is much higher at the tensionside than at the compression side from 5 to 7 days afterforce application.93 The discrepancy might be due to adifferent species or experimental protocol. The inductionof TGF-b1 by orthodontic tooth movement suggeststhat the factor is involved in the more activated boneformation process as part of the stimulated bone remod-eling activity during tooth movement. As mentionedabove, VEGF expression is increased early during ortho-dontic tooth movement. Street and Lenehan94 discov-ered that VEGF strongly inhibits apoptosis of culturedprimary human osteoblasts and promotes nodule forma-tion and alkaline phosphatase release. Differentiation ofosteoblastic cells as assessed with the expression ofmarker molecules alkaline phosphatase and osteocalcinis signicantly increased with VEGF stimulation.95

Thus, VEGF may have anabolic effects in addition toits catabolic effects in reaction to mechanical force.Wnt signaling is important for the commitment ofmesenchymal stem cells to differentiate into osteo-blasts.96 The canonical Wnt signaling pathway regulatesgene expression through stabilization and nuclear trans-location of b-catenin, an intracellular signaling mole-cule. Compressive force on PDL cells causes a transientcytoplasmic accumulation and nuclear translocation ofb-catenin, suggesting the role of Wnt/b-cateninsignaling in mediating the effects of mechanical forceon bone formation.97 Bone morphogenetic proteins(BMPs) are also important in the commitment of mesen-chymal stem cells into osteoblasts and the differentia-tion and function of osteoblasts.98,99 Compressiveforces of optimum magnitude can induce theexpression of BMPs and transcription factors crucialfor osteoblast differentiation of Runx2 and Osterix, aswell as promoting mineralization in osteoblastic Saos-2 cell cultures. Noggin, an antagonist of BMP, inhibitsthe compressive force-induced osteoblast differentiationand mineralization, further supporting that BMPs

mediate osteoblast differentiation induced by compres-sive force.100 However, local injection of BMP-2 does

American Journal of Orthodontics and Dentofacial Orthopednot increase the speed of orthodontic tooth movement,suggesting that enhancing bone formation alone mightnot be as effective as promoting bone resorption inaccelerating orthodontic tooth movement.101

The multiplural stem cells in the alveolar bonemarrow, PDL, and periosteum play important rolesin the regulation of bone remodeling and tooth move-ment. Human mesenchymal stem cells (MSCs) aretranscriptionally controlled by mechanical strain todifferentiate into osteo-chondrogenic lineage withincreased expression of osteoblastic and chondrocyticmarkers.102 Tensile strain has osteogenic differentiationeffects on human MSCs with signicantly up-regulatedBMP-2 mRNA level in 3-dimensional collagen matrixcultures.103 Under hypoxic conditions, expression ofmultiple intracellular and extracellular molecules by theMSCs are stimulated, including VEGF, surviving p21, cy-tochrome c, caspases, phosphorylated Akt, andothers.104,105 Inammatory cytokines, such as TNF,IL-1b, and TGF-b1, stimulate MSCs to produceVEGF,105,106 which acts back on MSCs directly andstimulates the expression of neurohilin 1 and 2, thechemotactic factors promoting recruitment ofosteoprogenitor cells.107 Therefore, it is highly possiblethat MSCs, under mechanical, hypoxic, and inamma-tory stimuli during orthodontic tooth movement or afteralveolar corticotomy, are the source of a variety of factorsthat not only determine the fate of MSCs themselves, butalso regulate the recruitment and function of osteoblastsand osteoclasts, and determine the level of bone remod-eling and the rate of tooth movement. MSCs are alsoaffected by various other approaches that accelerate or-thodontic tooth movement. 1,25 Dihydroxy vitamin D3directly stimulates the differentiation of MSCs into oste-oblasts, and this effect is synergistically enhanced byTGF-b.108 Low-energy irradiation promotes MSCs' pro-liferation and differentiation into osteoblasts.109 Pulsedelectromagnetic elds110,111 and electric current112 alsoincrease differentiation of human MSCs into osteoblastsin cell cultures. Further studies in this area are needed tohelp us understand the role of MSCs in bone remodelingand orthodontic tooth movement.

Bone formation and osteoblast differentiation andfunction are inuenced by different approaches thatregulate the speed of orthodontic tooth movement.Alveolar corticotomy alone signicantly increases therate of new cortical bone apposition 1 to 4 weeks post-surgically, and stimulates new trabecular bone forma-tion by about 1.5 times compared with the controls at3 weeks.36 Bone volume fraction, bone mineral content,and bone mineral density are all increased 1 to 3 weeks

after corticotomy as measured by microcomputed to-mography.55 Molecular studies have shown that alveolar


contain RANKL to induce osteoclast formation. Oste-

624 Huang, Williams, and Kyrkanidesocyte damage induced in cell cultures also resulted inincreased production of M-CSF and RANKL, increasingosteoclast formation.117 Osteocyte apoptosis has beenshown to be acutely induced by orthodontic toothmovement in mice, before osteoclast formation.118

RANKL expression was increased in osteocytes locatedclose to the resorption lacunae.49 Targeted ablation ofosteocytes signicantly reduced osteoclast formationand bone resorption during orthodontic tooth move-ment.119 On the other hand, mechanical loading fromcorticotomy enhances the expression of the anabolicfactor TGF-b1, as well as the osteoblast differentiationmarkers osteocalcin, osteopontin, and bone sialopro-tein.34,55 The combination of orthodontic toothmovement and alveolar corticotomy is not simply theaddition of 2 separate procedures but, rather, a moresophisticated synergy on bone cell activities andsubsequently on bone remodeling that calls for furtherinvestigations.

ROLE OF OSTEOCYTES

Osteocytes are terminally differentiated osteoblaststhat are embedded in the bone matrix during boneformation. They are stellate cells that form a functionalnetwork with other osteocytes, bone surface cells, bonemarrow cells, and endothelial cells via long cytoplasmicextensions, or dendrites. This network of osteocytes oc-cupies the lacunae-canaliculi system within the bonematrix, where the cell bodies and dendrites reside,respectively. Cell-to-cell signaling and material ex-changes take place through the gaps between the den-drites of osteocytes and the interstitial uid-lledlacunae-canaliculi system. Mechanical loading on thebone can cause strain in the bone structure, resultingin interstitial uid ow in the lacunae-canaliculi system,which generates shear stress on the surface of osteo-cytes, activating mechanoreceptors on the cytoplasmicmembrane of osteocytes113 and triggering intracellularsignaling pathways, most notably the canonical Wntpathway and the protein kinase A pathway.114 Thesesignaling pathways lead to changes in the productionlevel of biochemical factors that are crucial for osteo-clasts, osteoblasts, and bone remodeling.

Osteocytes express M-CSF, RANKL, and OPG andregulate osteoclast formation and function.115 Theexpression of these factors by osteocytes is affected bymicrodamage in bone and mechanical loading duringorthodontic tooth movement. Microdamage in bonecauses osteocyte apoptosis, and the apoptotic bodies

116uid ow up to 12 hours signicantly reduced theRANKL/OPG ratio and the osteoclast formation potential

November 2014 Vol 146 Issue 5 Americanin cultured osteocytes.120,121 The inhibitory effect ofmechanical loading on osteoclast formation duringorthodontic tooth movement has not been clearlydemonstrated and demands further studies.

Sclerostin is a protein factor produced by osteocytes.It inhibits the function and survival of osteoblasts andbone formation by antagonizing the canonical Wntsignaling pathway in osteoblastic cells. It was reportedthat mechanical loading decreased the expression ofsclerostin, favoring bone formation.122 Matsudaet al123 found that sclerostin expression was signicantlydecreased at the supercial zone of the alveolar bone onthe tension side, where bone formation took place.Fibroblast growth factor-23 is another osteocyte-derived factor that inhibits osteoblast differentiationand matrix mineralization.124,125 Fibroblast growthfactor-23 expression was signicantly reduced at thebone formation site on the tension side of the root dur-ing orthodontic tooth movement, similar to sclero-stin.123 These studies strongly support that osteocytesplay a key role in site-specic bone formation during or-thodontic tooth movement.

Vibration of a certain frequency, intensity, and dura-tion can increase bone mass. Whole body vibration hasbeen shown to signicantly improve bone mineral den-sity and structure,126,127 which is largely attributedto osteocytes' reaction to vibration as the chiefmechanosensory cells in the bone.114 However, sincereduced bone density, not the contrary, at the early stageof tooth movement is crucial for accelerated orthodontictooth movement, the anabolic effects of vibration seemto be undesirable. Nevertheless, there have been somereports or assertions that vibration increased the rateof tooth movement. Resonant vibration once everyweek was shown to increase the rate of orthodontictooth movement, and the effect was attributed toenhanced RANKL expression and an increased numberof osteoclasts.14 AcceleDent (OrthoAccel Technologies,Inc, Bellaire, Tex) is a vibration appliance approved bythe Food and Drug Administration to accelerate ortho-dontic tooth movement with daily use. Currently, its ef-fects on bone cells, density, and structure are stillunknown. Modern piezotome appliances also havesome vibration properties and may affect bone cellsand tooth movement. Vibration parameters of differentappliances, including whole body vibration, resonant vi-bration, AcceleDent, and piezotomes, are distinct fromeach other; this might explain different bone reactions,anabolic or catabolic, to the appliances. Further studiesare required to investigate the effects of various vibrationsettings on bone cells and bone remodeling to identify

the optimum settings to enhance bone remodeling andaccelerate orthodontic tooth movement.


Alveolar corticotomy is the vital step to enable faster

Huang, Williams, and Kyrkanides 625tooth movement in the clinical procedure calledperiodontally accelerated osteogenic orthodontics,which currently is probably the most commonly usedclinical procedure to accelerate tooth movement.13,130

The techniques, clinical applications, indications andcontraindications, limitations, and complications havebeen well described and summarized.6,130,133,134 Eventhough the method has been shown to be quiteIt is clear that osteocytes are important in regulatingboth osteoclast formation and function, and osteoblastdifferentiation during orthodontic tooth movement.However, their role in accelerated orthodontic toothmovement induced by different methods has not beenwell investigated. Future studies should focus more onthis aspect.

CLINICAL AND EXPERIMENTAL METHODS TOACCELERATE ORTHODONTIC TOOTH MOVEMENT

Direct injury to the alveolar or basal bones of themaxilla and mandible accelerates orthodontic toothmovement by inducing RAP as a wound-healing process,which is the basis for clinical procedures such ascorticotomy-assisted orthodontics, piezocision-aidedorthodontics, and surgery-rst orthodontics.24,33 Thewound-healing process after trauma is similar, if notidentical, as reviewed above. Nonsurgical methods,such as various physical and pharmacologic approaches,also enhance bone remodeling and facilitate toothmovement, and have been shown to be effective in an-imal and human experiments.128

The intentional use of alveolar surgery to speed uptooth movement began with the employment of osteot-omy, the complete cutting of cortical and medulla of thebone, in the 1890s.7,129 Corticotomy, a surgicalprocedure to perforate the cortical bone without goinginto the medulla, was used in combination withosteotomy to accelerate tooth movement starting inthe 1950s.8 Later, it was found that corticotomy alonewas also effective in achieving faster tooth movementwith much less tissue destruction and lower risks to peri-odontal tissues and dental pulp. Studies in both humansand animals have shown that corticotomy speeds uptooth movement by about 2-fold,35,130 and theaccelerating effect takes place chiey during the rstfew weeks after the procedure.131 Although both corti-cotomy and osteotomy accelerate tooth movement,they achieve the goal with different mechanisms: corti-cotomy induces RAP, whereas osteotomy acts in amanner similar to distraction osteogenesis.34,132effective in case reports and animal experiments,several obstacles prevent its more widespread use.

American Journal of Orthodontics and Dentofacial OrthopedPain, swelling, hematoma, and morbidity arecomplications of the surgery and can negativelyimpact the patients' experiences and acceptance of theprocedure. The additional cost to orthodontictreatment to cover the surgical procedures can also bea concern.

Piezocision-aided orthodontics was developed toaddress the drawbacks of surgical corticotomy.135 Likeperiodontally accelerated osteogenic orthodontics, italso speeds up tooth movement by alveolar corticotomy,but instead of full-thickness aps, small vertical cutsthrough the gingival tissues and periosteum are madeto reach the cortex of the bone. Bone grafts areembedded in tunnels connecting the vertical cuts.According to case reports in the literature, it appearsthat piezocision is similarly effective in acceleratingtooth movement and augmenting periodontal tissueswith much less trauma.135-137 In addition to directbone injury by piezocision, vibration may also play arole in activating bone remodeling, since many moderncommercial piezotomes incorporate high-frequencyvibration. More studies are needed about the mecha-nisms of piezocision to accelerate tooth movementand to evaluate its effectiveness and long-term results.Piezocision is a surgical procedure and has someinherent potential risks.

Surgery-rst orthodontics is a strategy to signi-cantly shorten treatment duration for patients whoneed orthognathic surgery to correct a severe dentofacialdeformity.138-145 Traditional comprehensive orthodontic-orthognathic surgery treatment starts with orthodontictreatment to align the teeth and decompensate thedentition to prepare for optimum correction of skeletaldiscrepancies. After surgery, orthodontic treatment isneeded to settle the occlusion and rene the nishing.Typically, the total treatment time is about 24 to30 months. Studies have shown that tooth movementafter orthognathic surgery is much faster than withroutine orthodontic treatment, which can be attributedto RAP stimulated by the surgical wound to thebone.143 Careful patient selection is required to performsurgery-rst orthodontics and should follow certainguidelines and procedures.144

Resonance vibration is based on a frequency equal tothe natural frequency of an object, causing the largestamplitude of vibration of this object. When applied tothe rst molars in rats for 8 minutes once a week, reso-nance vibration (60 Hz) increased tooth movement by15% compared with the controls, stimulating moreexpression of RANKL and osteoclast formation in thePDL.14 Recently, a vibration appliance, AcceleDent, has

been marketed, with claims that it can increase therate of orthodontic movement. However, it provides


626 Huang, Williams, and Kyrkanidesvibration with only 1 xed frequency (4 Hz). There is stillno peer-reviewed study on the biologic or the clinical ef-fects of the appliance.

Low-energy laser irradiation can also speed up ortho-dontic tooth movement according to most studies in hu-mans and animals.15,37-39,89,146-148 However, somestudies show that low-energy laser irradiation does notaccelerate tooth movement149-151 and can even slowit.152 The discrepancies may be explained by thedifferent treatment protocols used in these studies,including the wavelengths of the lasers, irradiationdoses, locations, and frequencies. Several studies havereported that low-energy laser irradiation stimulatesalveolar bone remodeling activities as indicated by theincreased numbers and functions of osteoclasts and os-teoblasts,15,37,38,40,41 as well as by molecular markerssuch as matrix metalloproteinase-9, cathepsin K, a(v)b(3) integrin,39 the RANK/RANKL/OPG system,89 andbasic broblast growth factor.153 Because of its nonin-vasiveness and relative ease of operation, low-level laserirradiation seems to be promising for accelerating ortho-dontic tooth movement. But more research needs to bedone to discover the most efcient protocol to enhanceits effect and reduce the frequency of irradiation to makethe method more clinically applicable.

Magnetic elds, including static magnetic eld18,154

and pulsed electromagnetic eld,18,42,155 have increasedthe speed of orthodontic tooth movement in animalstudies. Histologic analyses have suggested thatalveolar bone remodeling is activated under theinuence of magnetic elds as activities of bone cellsare elevated and new bone deposition is increased onthe tension side.18,42,155 Hyalinization in the PDL wasreduced in the group treated with the static magneticeld, which also contributed to accelerated toothmovement.154 However, 1 study showed that the staticmagnetic eld did not increase the rate of tooth move-ment, but root resorption was increased, promptingconcerns about the effectiveness and safety of thismethod.156 Further studies are needed to determinethe effect of magnetic elds on tooth movement androot resorption.

Electric current, when applied constantly at 15 mA for14 days in cats, signicantly increased canine retractionby over 2-fold.19 Histologic studies have demonstratedthat bone remodeling was enhanced with more boneformation at the cathode side and more bone resorptionat the anode side, and osteoblast numbers increasedsignicantly in the PDL with increased cellular activ-ity.19,157 Alternatively, when applied in the form of a1-Hz square wave of 6 V with a current of about

10 mA, the micropulsed electric current accelerated or-thodontic tooth movement as well, with more osteoblast

November 2014 Vol 146 Issue 5 Americanand bone formation on the tension side, and moreosteoclast-like cell formation on the compressionside.43 The source of electricity, however, poses a prob-lem for the clinical use of this method. Microfabricatedbiocatalytic fuel cells (enzyme batteries) might resolvethis problem.158

Parathyroid hormone is the major hormone regu-lating bone remodeling and calcium homeostasis. It ele-vates serum calcium concentration by both stimulatingbone resorption and up-regulating calcium reabsorptionand the enzyme 25-hydroxy D3 1-alpha-hydroxylase inthe kidneys, which in turn form more 1,25 dihydroxyvitamin D3 that increases calcium absorption in the smallintestines. Animal studies have shown that continuousglobal infusion or chronic local injection of parathyroidhormone accelerated orthodontic tooth movement byabout 1.6- to 2-fold, and signicantly increased osteo-clast numbers.16,159 It is well-known that chronic eleva-tion of parathyroid hormone leads to pathologicchanges in multiple organs, especially kidneys andbones. These short-term studies did not determine thelong-term effects of this systemic hormone at the doseused to accelerate tooth movement, especially kidneyfunction and bone condition, so safety remains aconcern for its clinical application in orthodontic treat-ment. Even though local injection with control-releasesystems may increase the effectiveness and lower therisks, a more effective release system is still desired,and safety should be carefully studied.

1,25 Dihydroxy vitamin D3, as mentioned above, pro-motes calcium resorption in the small intestines. It alsoacts on bone cells to increase bone remodeling.160 Ani-mal studies have indicated that local injection of 1,25dihydroxy vitamin D3 accelerated orthodontic toothmovement by about 1.2- to 2.5-fold.17,45,161

Histologic examination shows that 1,25 dihydroxyvitamin D3 stimulates the formation of osteoclasts in adose-dependent manner, synergizing with the mechan-ical force,44 and causes signicantly more alveolar boneresorption.45 On the other hand, osteoblast formationand bone formation are also elevated under 1,25 dihy-droxy vitamin D3 stimulation, seemingly presenting amore balanced effect of 1,25 dihydroxy vitamin D3 onbone volume.17,162 Frequent injections of 1,25dihydroxy vitamin D3 were given to the animals,making the clinical practicality of this factor inhumans questionable. And like parathyroid hormone,the safe use of this systemic factor in orthodontictreatment should be investigated.

PGs are local autocrine/paracrine lipid inammatoryfactors that also regulate bone remodeling. Several ani-

mal experiments have shown that local application ofPGE1, PGE2, or analogs of PGE1, PGE2, or thromboxane


Huang, Williams, and Kyrkanides 627A2 increase the speed of orthodontic tooth move-ment.17,163-167 Local submucosal injection of PGE1 inhuman patients was also successful in acceleratingtooth movement by 1.6-fold.168 Alternatively, ortho-dontic tooth movement is impaired by nonsteroidalanti-inammatory drugs, the compounds that inhibitthe COX-1 and COX-2 enzymes that catalyze the rate-limiting step of prostaglandin formation.69,70 Oneconcern of using PGs clinically is the pain reactionfrom patients, since PGs are potent pain inducers.Another concern is increased root resorptionconcomitant with accelerated tooth movement, asindicated by several independent studies.163-165

CONCLUSIONS

The rate of orthodontic tooth movement depends onthe modeling and remodeling of the alveolar processwhile adapting to the new biomechanical environment.The rate of alveolar modeling and remodeling is deter-mined by the level of activity of bone cells (osteoclasts,osteoblasts, and osteocytes), which are under the controlof mechanical and biochemical factors, most notablyPGs and cytokines. Osteoclast activation is crucial for

Fig. Summary of cellular and molecular mechanismsment. Methods to accelerate orthodontic toothmovemblunted arrow, inhibition; MSC, mesenchymal stem cinducible factor; FGF, broblast growth factor.

American Journal of Orthodontics and Dentofacial Orthopedelevated bone modeling and remodeling required foraccelerated tooth movement. Osteoblastic cell-derivedcytokines M-CSF and the RANKL/OPG ratio determineosteoclast formation and function. Methods that accel-erate orthodontic tooth movement stimulate M-CSF andincrease the RANKL/OPG ratio directly or indirectlythrough changes in blood ow and hypoxia, and tissuedamage, promoting the production of cytokinesincluding VEGF, TNF-a, interferon-b, ILs, matrix metal-loproteinases, and others. Osteoblasts are important inmaintaining normal bone density and mass in the alve-olar process. Some methods that accelerate tooth move-ment also induce enhanced osteoblast function bystimulating mesenchymal stem cells to differentiateinto osteoblasts through cytokines including TGF-b,BMPs, VEGF, and others. Osteocytes, the most abundantbone cells, may also mediate the effects of methods thataccelerate tooth movement by inducing osteoclast for-mation through apoptosis. The role of osteocytes is stillnot clear. The cellular and molecular mechanisms ofaccelerated orthodontic tooth movement are illustratedin the Figure. There is an obvious need to investigatein more depth the molecular mechanisms underlyingaccelerated orthodontic tooth movement to elucidate

underlying accelerated orthodontic tooth move-ent are shown in red.Blue arrow, Stimulation; redell; HSC, hematopoietic stem cell; HIF, hypoxia


628 Huang, Williams, and Kyrkanidesbone remodeling during experimental tooth movement in rats.Lasers Surg Med 2000;26:282-91.

16. Soma S, Iwamoto M, Higuchi Y, Kurisu K. Effects of continuousinfusion of PTH on experimental tooth movement in rats. JBone Miner Res 1999;14:546-54.

17. Kale S, Kocadereli I, Atilla P, Asan E. Comparison of the effects of1,25 dihydroxycholecalciferol and prostaglandin E2 on ortho-the key factors that make the procedure most effectivewith the fewest side effects, shortest times, and lowestcosts to patients. New knowledge in this eld willempower us to revolutionize orthodontic therapy andits practice in the future.

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Accelerated orthodontic tooth movement: Molecular mechanismsBone modeling, remodeling, and orthodontic tooth movementOsteoclast formation and bone resorptionOsteoblast formation and bone appositionRole of osteocytesClinical and experimental methods to accelerate orthodontic tooth movementConclusionsReferences