,

Dr. Pllnkaj Juneja

Dr. Prabhuraj B. Kambalya l

Abstract

Key Words

AN OVERVIEW OF THE ROLE OF DRUGS AND SYSTEMIC FACTORS ON ORTHODONTIC TOOTH MOVEMENT Authors: Dr. Pankaj Juneja B.D.S. (M.D.S.) Postgraduate student, Department of Orthodontics and Dentofacial Orthopedics, Co llege of Dental Sciences, Davangere, Karnataka. Email : drpankaL1 23dentist@yahoo.com Phone: +91- 9964143808

Dr. G. Shivaprakash B.D.S., M.D.S. Professor and Head, Department of Orthodonti cs and Dentofacial O rthopedics, College of Dental Sciences, Davangere, Karnataka. Email : drshiva64@gmail.com Phone: +91- 9844041 620

Dr. Prabhuraj B. Kambalyal B.D.S., M.D.S. Assoc iate Professor, Department of Orthodontics and Dentofacia l Orthopedics, College of Dental Sc iences, Davangere, Karnataka. Email : prabhurajkambalya l@yahoo.com Phone: +91- 944811 0394

The specialty of Orthodontics is based on the fact that it is poSSible, by applying appropriate forces, to move the teeth through the alveolar bone of the jaws. Orthodontic tooth movement and the concomitant bone remodeling process are dependent on various local and systemic factors like age, nutrition, consumption of drugs etc. Orthodontic patients may be affected by systemic diseases that might need treatment with drugs that could possibly affect bone metabolism. Patients undergOing orthodontic treatment can experience significant levels of pain. Analgesics are commonly recommended for the control of such orthodontic pain.

This article reviews all the existing published biomedical literature on the effects of some commonly used drugs by the patients for the relief of orthodontic pain and treatment of systemic conditions known to affect the bone tissue and thereby influencing the rate of orthodontic tooth movement. An attempt has been made to propose a complete picture and orient the reader for the better understanding of some commonly used pharmaceutical products.

This is considered essential in order for the orthodontist to take into account all factors related to the therapy and to select the best therapeutic strategy in every individual patient keeping the mechanics as simple as possible.

orthodontics, force, drugs, systemic, tooth movement.

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INTRODUCTION: The aim of orthodontic trea tment in the movement of teeth through bone is to obtain a more perfect dental occlusion. Orthodontic tooth movement has been defined by Proffit ' as the result of a biologi ca l response to interference in the physiologica l equilibrium in the dentofacial complex by an externally applied force.

Nowadays, attention is mainly focused on the relation of orthodontic tooth movement to the applied force. The contro l of pain during orthodontic treatment is of interest to both clinician and patients. Prescription and over th e co unter analges ics are common ly recommended for orthodonti c pain. Interestingly, despi te cli nica l evidence that patients experi ence pain after orthodontic procedures, there have been few controlled studies that address the use of analgesics to contro l post appointment orthodontic pain.

The objective of this review is to discuss current data concern ing the mechanism of action and effects of some common ly used pharmaceutica l products and systemic factors known to affect bone ti ssue and thereby influenc ing the rat e o f tooth movement. This is considered essentia l in order for the orthodontist to take into account all factors related to the therapy and to

,. _=!n~

select the best therapeutic strategy in every individual patient keeping the mechanics as simple as possible.

An Overview of biological basis of orthodontic tooth movement : In a recent review on the current concepts in the biology of orthodontic tooth movement Richard and Malcolm' said that five micro-environments are altered by O rthodonti c for ce - ex trace llul ar matri x, ce ll membrane, cytoskeleton, nuclear protein matri x and genome. Cel l membrane receptor li gand docking is an important initi ator of signal transdu cti on and a discovery target for new bone enhancing drugs. Despite progress is identifi cation of regulatory molecules, the genetic mechanism of "orchestrated synthesis" between different cell s, tissues and systems remain largely unknown.

Ei cosa noids/A utoco id s are bi o logical l y ac tive derivatives of 20 ca rbon atom Polyunsaturated fatty acids (PUFA) that are released from cell membrane phospholipids. There are two major lipid derived autocoids :

1) Prostaglandins (PG's), and 2) Leucotrienes (L T's)

Membrane phospholipid

~ Cyclo-oxygenase

Isomerase

PGE,

PGD,

PGF, ..

~ PGG,

PGH, I . ~

Thromboxane synthase

TXA, TXB,

Chemical or mechanical st imuli 1 Phospholipase A ~

Arachidonic Acid -------,~

~ Prostacycl i n

synthase

PGL

6 KetoPGF, ..

..

12 HPETE t

12 HPETE

Biosynthesis of PG 's and L T's'

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Lipo-oxygenase I

5 HPETE-5 HETE

..

L TB,

~ L TA,

I

LTC,

LTD, LTE, LTF,

Cyclooxygenase is known to exist in two isoforms Cox-I and Cox-2 . While both isoforms catalyses the same reactions, cox-1 is constitu tive enzyme in most cells. O n the other hand cox-2 is normall y present in insignifi cant amounts but is inducible by cytokines, grow th fa ctor s and o ther sti mul i during the inilammatory response. It is believed that eicosanoids produced by cox- 1, participate in physiological (house keeping) function such as secretion of mucous for protection of gastric mucosa etc. while those produced by cox-2 lead to inflammatory and other pathological changes.

Tooth movement during orthodontic treatment requires remodeling of periodontal ligament tissues, especia ll y

Table I

in the alveolar bone. Force application disrupts the equilibrium that ex ists between bone formation on the pressure side and more bone formation than resorption on tension side. Resorption of bone by osteoclasts is coupl ed with subsequ ent bone formation by osteoblasts. Loca l and systemic factors' (Table I ) including cytokines, hormones, growth factors and mechanica l st imulation activate osteoblasts to produce the receptor activator of NF-a~ ligand (RANKL) which is vital for osteoclasts differentiation and activit y. RANKL is expressed on the surface of osteoblastic cell s and bone marrow stromal cell s and binds to the RANK receptor on the surface of osteoclastic precursors, thereby stimulating the differentiation and activation of osteoclasts.

Faclors affecling bone remodeling process Hormones and systemic faclors

-

-

-

-

-

-

-

-

Growth factors -

-

-

-

Cytokines -

-

-

-

-

Colony stimulating factors -

-

-

Others -

-

-

Intracellular secondary messengers play an important role in the differentiation of osteoclasts from monocytes in bone resorption during force app li catio n. Davidovitch et ai' measured cGMP and cAMP levels in the alveolar bone of cats under orthodontic treatment and reported that Ca" , cGMP and cAMP acts as a key mediators or secondary messengers in the function of many drugs and hormones.

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PTH Ca lcitosin Insulin Growth hormone Vitamin 0 Glucocorti coids Sex steroids Thyroid hormones

Insulin like GF I and II TGF~ Fibroblast growth factor Platelet derived growth factor

IL-1,4,6, 11, 13, 18 TNF Osteoclast differentiating factor Interferon y Osteoprotegrin

M-CSF G-CSF GM-CSF

Prostaglandins Leukotri enes Nitric ox ide

It is now clear that OTM is influenced both by drug and the systemic factors. An attempt has been made to review the past and present literature published in various articles in different journals on the factors that tend to influence the OTM, and same wi ll be discussed as presented in Tab le II and Table III.

Table II Effects of drugs on tooth movement

Drug Effects on bone tissue Effects on tooth Mechanism of movement action

1) NSAIDS - Decreased bone - Decreased rate of - Inhibition of - Aspirin resorption tooth movement cyclooxygenase -

Aceta minophen enzyme. - Ibuprofen - Rofecox ib - Valdecoxib - Celecoxib

2) Ecosanoids I Autocoids - Increased bone - Increased rate of - Increases cAMP and - Prostaglandins resorption tooth movement cGMP levels.

- Leukotrienes - Activates osteoclasts.

3) Bishosphonates - Decreased bone - Decreased rate of - Inhibit bone resorption tooth movement turnover.

- Decreases root - Increases bone resorption mineral density

4) Fluorides - Increased bone mass - Decreased rate of - Increases bone and mineral denSity tooth movement. mass/density

- Decreased bone resorption

5) Corticosteroids - I ncreased bone - Increased rate of - Inhibit osteoblastic resorption tooth movement function.

- Decreased bone - Greater potentia l for - Decreases bone formation relapse as movement Formation.

is less stable.

6) Epidermal growth factor - Increased bone - Increased rate of - Enhances osteoclats (EGF) resorption tooth movement. recruitment.

7) Osteoprotegrin gene - Decreased bone - Decreased rate of - Inhibits RANKL transfer resorption tooth movement mediated

osteoclastogenesis.

8) Echistatin (RGD peptide) - Decresed bone - Decreased rate of - Inhibits Integrin resorption tooth movement receptors.

9) Tezosentan - Increased bone - Increased rate of - Enhances bone resorption tooth movement resorption via ETA

receptors.

Table III Effects of systemic factors on tooth movement

Hormone Effects on bone tissue Effects on tooth movement Mechanism of action 1) Estrogen - Decreased bone resorption - Decreased rate of tooth movement - Inhibits cy tokine involved in

bone resorpti on. 2) Androgen - Decreased bone resorption - Decreased rate of tooth movement. - Enhances DNA transcription. 3) Vitamin D - Increased bone resorption - Increased rate of tooth movement. - Activa tes DNA and RNA

- Enhances reestablishment of w ithin target cell s. supporting tissues

4) Thyroid - Increased rate of bone - Increased rate of tooth movement - Activates a spec ific DNA remodeling

- Decreases root resorption sequence ca lled Thyroid hormone response element.

5) Parathyroid - Increased rate of bone - Increased rate of tooth movement. - Increases cAMP formation and resorption intracellular Ca in ta rget cells

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1. EFFECT OF DRUGS ON TOOTH MOVEMENT; NSAID'S: All drugs grouped in this class have analgesic , antipyreti c and anti -i nflammatory actions in different measures. They are also ca lled non narcoti c, non opioid, or aspiri n like analgesics . They act primarily on peripheral pain mechanisms but also in CNS to raise pain threshold, by inhibition of cyclo-oxygenase, which modulates the transforma tion of PG's from arachidonic acid in the cellular plasma membrane.

They are the most common group of medicati ons used in orthodontics for relief of pain.b" . Numerous studi es eva luated the pain reducing effects of va rious NSAIO's. Then drugs have become the focus of recent research in orthodontics.

Amongst the earliest studies ca rried out Chumbley et ai" eva luated the effect of indomethacin (an aspirin like drug) and recommended that aspirin like drugs not to be admi nistered to patients undergoing orthodontic treatmen t as it may extend the treatment time. W alker et al '" eva luated the impairment of O.T.M. ca used by NSAIO's and results showed that they can impair O,T.M and until long term human data are obtain ed, acetaminophen remains an appropriate alternative to NSAIO's. Similar results were found by Arias et al" who compared aspirin, acetaminophen and ibuprofen and found that acetaminophen did not affect OTM, Even Roche et al" concluded that acetaminophen has no effect on rate of OTM, Kehoe et al" also suggested acetaminophen as the analgesic of cho ice for minor discomiort associated w ith orthodontic treatment. But in a recen t contrasting study Brad ley et al" compared Ibuprofen and paracetamol for the control of pain and iOlll1d that pre-operative and post-operative Ibuprofen to be more effective than paracetamol. In another study by Polat et al1 ' , Naproxem sodium was found to have lower levels of pa in than patients taking ibuprofen, Moreover the use of over the counter drugs have also shown aberrant remodeling of th e periodontal vasculature affecting the tooth movement, Kyrkanides et al '" investigated the effects of indomethac in on co ll agenase acti vity and proco ll agen synthesis. Cyclooxygenase inhibit ion resulted in exacerbation of IL-l beta mediated collagenase B (MMP-9l production and acti vity, as well as alterati on oftype IV procollagen synthesis levels by endothelial cells in vi tro. The studies mentioned above showed that NSAIO's effecti vely reduce the pain and discomfort caused by orthodontic tooth movement but these drugs may also aiiect the sequence of tooth movement by inhibiting or at least by reducing the associated inflammatory and

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bone resorption process. O ne approach to dea l with this is the use of selective cox-2 inh ibitors, also cal led as cox ibs, which are replacing conventiona l NSAIO's, In comparison to NSAIO's, Cox-2 inhibitors have longer dose interva ls, different side effect profile, similar onset of action and similar analgesic effect.

Sari et al" showed that the inhibition effect of aspirin on PGE, was more than that of Rofecoxib, In another study Young et al " concluded that va ldecoxib may be a better approach to prevent discomfort of initial archwire placement. In a previous study by Carlos et al " found no substantial advantage in using a selective cox-2 inhibitor compared wi th non specific cox inhibitors. But in a recent study Carlos et al' evaluated orthodontic tooth movement after different coxib therapies and concluded that celecoxib and parecox ib, but not rofecoxib, seem appropriate for discomfort and pain relief while avo iding interference during tooth movement.

Gameiro et al" eva lauted the effects of short and long term celecoxib on orthodontic tooth movement and concluded that although celecox ib administration did not affect the number of osteoclasts, the osteoclasts activity might be reduced, which could explain the inhibition of tooth movement observed,

However the effect of these drugs on orthodontic root resorption is not well understood. Gameiro et al" did histologica l analysis of orthodontic root resorption treated with celecoxib and found that short and long term celecox ib did not suppress the root resorption,

Therefore, it is recommended that patients undergoing orthodontic treatment should be advised not to take these over the counter drugs w ithout the dentist' s prior knowledge,

EICOSANOIDS / AUTOCOIDS : Prostaglandins: Arachidonic acid is metaboli zed by cyclooxygenase resulting in prostaglandin production ." Experiments have shown that PG's are an important mediators of mechanica l stress during OTM, Ngan et al" observed that PG 's cause hyperalgesia by facilitating pain stimulus and increasing the effects of hi stamine and bradykinin , Chao et al" observed that PGE, injection increased the number of osteoclasts in pdl membrane. Oavidovitch et ai' demonstrated in vitro direct effect of PG's on bone resorption along with increase in cAMP and cGMP levels. Sandy et al" fou nd that inhibition of PG synthes is by flurbiprofen, a PG inh ibitor, showed inhibition of osteoclast activity and bone resorption. In another study by Gurton et al" found that PGI, and TXA, analogs increase the number

of multinuclear osteoclasts, osteoclastic bone resorption and rate of OTM. Si milar results were also shown by Yamasaki et al. "

Studi es were also conducted in order to eva luate the effect of PG's on root resorption. Leiker et al" found that the amount of root resorption did increase w ith the use of PG injec tion s, specifi ca ll y PGE, . In a contrasting study by Boekenoogen et al '" conc luded that PGE, appeared to have no effect on the number or depth of resorption lacunae. In a simi lar study Brudvick et al " found no significant difference in root resorption but trend towards more root resorption was seen on teeth where PGE, injecti on had been performed. In a recent study Seifi et al" showed the importance of Ca" ions worki ng in association wi th PGE, in stabili zing root resorption while significantly increased OTM.

Leucotr ienes : They are also metabolites of arachido ni c ac id , produced by lipo-oxygenase enzymes" They are also important mediators of OTM. Their role in OTM is clearly demonstrated when inhibitors of leucotrienes are used in different experiments.

It is a well known observation that inhibition of one pathway of arachidonic ac id will shunt the effect into an increase in the conversion via the other pathway. Mohammed et al]) investigated role of a L T inhibitor AA861 in OTM and found that it caused signifi cant LTB, inhibition and simultaneous increase in PGE, production, suggesting L T role in mediating OTM. However inspite of - PG levels, a selective inhibition of L T synthes is caused a Significant reduction in tooth movement.

Consequ entl y leucot ri ene inhibitors ca n delay orthodont ic trea tment, whereas leuco tri enes and prostaglandins can have future appli ca tions that could result in enhanced tooth movement. 11

BISPHOSPHONA TES: The pharmaco logic agent bisphosphonates are analogues of pyrophosphate. Recentl y" they have received mu ch att enti o n in denta l l iterature. Bisphosphonates in oral or IV forms are used to that va ri ous diseases such as certain ca ncer, bone and cal c ium related disorders, osteoporosis etc. Bisphosphonate inhibit bone turnover and result in increased bone mineral densi ty. The most serious side effect of Bisphosphonate treatment is osteonecrosis of the mandib le or the maxilla represented by exposed non hea li ng bone. O ther related complications include dec reased bone hea ling and an inhibition of orthodontic tooth movement.

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Sato Y et al 15 did a study to clarify the effects of Bi sphosphonate administration on struc ture and function of osteoclasts in alveolar bone resorption during experimental tooth movement and found that BP Significant ly impair the osteoclast structure and reduces express ion of both vacuolar type H(+) ATPase and cathepsin K in osteoclasts during tooth movement. Liu et al'6 also suggested the inhibitory effect of clodronate on tooth movement and osteoclasts may be due to inhibition of cox-2 dependent PGE, production and RANKL expression in pdl cells.

Root resorption associated with tooth movement in an un so lved probl em in orthodontics. If such root resorption could be prevented, it would be an important co ntribution towa rd s reduci ng risk factors in orthodontic treatment. The use of BP to reduce the amount of inflammatory root resorption has been investigated and were found to be effecti ve in thi s regard.

Liu et al37 found that local clodronate inhibited root resorption incident to tooth movement and suggested it to be a usefu l therapeutic adjunct in orthodontic treatment. Igarashi et al " eva lu ated topi ca l administration of residronate on root resorption and found that it did not appear to inhibit the repair process of root resorption .

The clinical utility of Bisphosphonates resides in their ability to inhibit bone resorpti on. In Orthodontics, undes irable movement of anchor teeth during tooth movement and relapse of moved teeth after treatment are the main cause of unsuccessful results. If these tooth movements could be prevented with pharmacologica l agents, a less complex orthodontic force system and less extensive retention wou ld be required.

Igarash i et al" eva luated the anchorage and retentive effects of a BP (AHBuBP) on tooth movement in rats and concluded that it could be useful in enhancing anchorage or retaining teeth . Kim et al'" eva luated the effect of Bisphosphonate administration on osteoclastic bone resorpti on during relapse and found that it decrease the extent of initial relapse via mechanism involving impai rment of the structure and resorption functions of osteoclasts.

In another study by Adachi et al", found that the top ica l admini stration of residronate may be helpful in anchoring and retai ning teeth under orthodontic treatment.

Therefore it is imperative that Bisphosphonate medica l screening, pat ient counseling, informed con cent, and changes in treatment planning shou ld be considered for every patient by the orthodontist."

FLOURIDE: The effect of fluoride on bone metabolism has been well reported in the medica l field, because it has been used as a drug by itself or as an adjunct in the treatment of osteoporosis. Fluoride treatment results in an increase in bone mass beca use of the stimulati on of bone formation .

Hellsing et al" eva luated the effect of fluoride on OTM and found that the veloc ity of TM is influenced by hormones as well as trace elements. In another study use of F' as a variable was found to increase the mean osteocalcin concentration" (a bone protein that has been used to mark bone turnover). Foom et al" eva luated the effect of systemic F' in take on root resorpt ion and fo und that F' reduces the size of resorption craters, but the effect is va riable.

The clin ical util ity of F' agents includes caries preventive treatment protocols such as fo llowing oral prophylax is, proxima l strippi ng/sli c ing etc . may increase the orthodont ic treatment time due to its anabolic effects on bone, as fl uoride increase both bone mass and density.

CORTICOSTEROIDS: Orthodontic pat ients may be affected by systemic diseases that might need treatment w ith drugs that could po ss ibly affec t bo ne metabo li sm. Sy nth et i c corticosteroids have been used in therapeutic regimens for the treatment of a w ide variety of ailments ranging from arthri tis to renal, collagen, allergic and neoplastic diseases. Supra-phys iologic doses of these drugs when administered induce the same osteoporosis found in naturall y occurr ing status of hypercorti so li sm." Corti costero ids inh ib it osteobl as ti c fun cti on by mediating its effects on osteoblast and its precursors resulting in decreased bone formation. The latter may be due to elevated PTH leve ls caused by direct inhibition of Cal< absorption by the steroids. End result being increase in bone resorption. Aschroft et al" found th at rabbi ts subjected to cor ti costero ids induced os teoporosis underwent more rapid O .T.M and subsequent relapse. Mavragani et al" found that low dose doxycyl ine may have an inhibitory effect on orthodont ica lly induced resorptive activity.

In a recent study Verna et al" investigated the effect of ac ute and chron ic corti costero id trea tment on orthodont ica ll y induced root resorption and found more root resorption in acute group. When compared to chronic group and suggested that it may be due to lack of ba lance between blastic and clastic activiti es during initia l phase of drug administration.

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Because acute corticosteroid ingestion reduces bone turnover, in these patients orthodontic treatment might best be postponed until a time the patient is free of the drug.50Chronic stero id ingestion leads to an increased bio log ica l reac ti on to mechani ca l perturbat ion indicating that the Orthodontic force level should be reduced and controlled more frequently in patients on chronic steroid treatment. 50 Moreover specific attention must be paid to the retention protocol as the tooth movement is less stable. As a consequence, carefu l monitor ing of pati ents undergoi ng cort icostero id treatment is suggested.

MISCELLANEOUS: 1) Epidermal growth factor : Recently the use of epidermal growth factor (EGF) to develop a suitable environment and stimulate selective d ifferentiation and proli feration has been proposed. It has also been suggested that it may be involved in responses of osteoblasti c cell li ves to mechanica l stimuli. Saddi et al" found that loca l administration of EGF located w ith in liposomes had an additive effect on the rate of osteoclasts recruitment, producing faster bone resorption and tooth movement.

2) Biological agents - Relaxin: Using biologica l agents to modify the rate of tooth movement have been shown to be effective in animals. Relaxin main action is to increase the turnover of fibrous connecti ve ti ssue. Madan et al" eva luated effect of human relax in on OTM and found that it does not acce lerate OTM, it ca n reduce the leve l of Pdl organization and mechanica l strength and increase tooth mobility at ea rly t ime periods.

3) Osteoprotegrin gene transfer: It has been reported that osteocl astogenesis is primarily acti vated by the receptor activator of nuclear factor Ka ppa b li ga nd (RAN KL) and inhi bi ted by osteoprotegrin (OPG). Pdl cell s which ex ists between teeth and alveo lar bone, induce osteoclastogenes is in vitro th rough the up regulati on of RANKL expression via PGE, synthesis w hen subjected to mechan ical compress ive force.

Kanzaki et al" found significantly d imin ished tooth movement on loca l O PG gene transfer to pd l ti ssue as it inhibited RANKL mediated osteoclastogensis and inhibited experimental tooth movement.

4) Echistatin and RGD peptide : Recently a study done on effect of echistatin, an Arginine-glycine-aspartic acid peptide by Dolce C et al" showed that ELVAX loaded w ith RGD peptide which was surgica ll y implanted next to max illary

molars inhibited OTM. The RGD peptide also reduced molar drifts, therefore it shows the feas ibility of using them to deliver integrin inhibitors adjacent to teeth to limit loca l tooth movement in response to orthodontic force.

In another recent study Talic et al" evaluated the effect of echistatin on orthodontica lly induced root resorption and concluded that targeting av~3 integrin receptor expressed by odontocl asts can be effecti ve in reducing root resorption during tooth movement.

5) Endothelin Antagonist: Tezosentan Endothelin is a cytokine peptide present in the pdl in physio logica l condit ions. Its concentration in the pdl doubles after 3 hors of ax ial loading of a tooth .

In a recent study by Sprogar et al", eva luated the effects of TBC 32 14, a se lecti ve endothelin ETA receptor antagonist on OTM in rats and found that H , is involved in OTM probably by enhanci ng bone resorption via ETA receptors . In another study Drevensek M et al57 found that Tezosentan, an endothelin antagoni st, enhanced orthodontic tooth movement in rats.

EFFECT OF SYSTEMIC FACTORS ON ORTHODONTIC TOOTH MOVEMENT: THYROID AND PARATHYROID HORMONE: The movement of teeth during orthodontic trea tment requires bo ne rem odelin g. Th e ro le o f bo ne metabolism, however, in contro lling tooth movement have been considered secondary to the force applied. This is largely a result of the difficulty in altering bone metabolism systemica ll y, in addition to the fac t that the force is the most easil y manipul ated fac tor . Consequently, several papers have focused on the changes in bone remodeling in relation to the applied force. In addition to applied force, tooth movement seems to depend on ca lcium metaboli sm is alveolar bone. A study by Midgetts" et al indicated that animals w ith hyperparathyroidism had signifi cantl y decreased bone density, as well as increased bone remodeling changes. Engstrom et al" demonstrated that although the level of PTH in serum plays an important rol e in the regulation of the resorptive activ ity in bone, a change in serum ca lci um level is determining fac tor for root resorption . This indicates that force- induced root resorption is dependent on more than one endocrine system. In addition to parathyroid hormone, bone resorpti ve activity is also regulated by L thyroxine. Patient w ith untrea ted hyperth yro id ism show increased bone resorpti on.'" The administrati on of high dose o f

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thyroxine in rats has been shown to increase bone resorption, in contrast to low dose administrati on, which was found to reduce peri ostea l resorption."

Po umpros et a l " al so found th at th yrox ine administration seems to lower the frequency of root resorption in rats. Shi raz i et alb' eva luated the effect of th yrOid hormone on OTM in rats and found that administration o f 20/mym/kg i.p. I day L-thyrox ine Significantl y increased the amount of OTM and the ex tent of root resorption decreased w ith th yroxine administration.

PTH is secreted by parathyrOid glands, regulated by plasma Ca" concentration; there is no trophic hormone for it. The PTH receptor is a G protein coupled receptor which on acti vation increases cAMP formation and intracellular Ca" in target cells. In bone the target cells appears to be the osteoblasts because PTH receptors are not expressed on the surface of osteoclasts. It has been proposed that PTH-osteoblast complex some how inc reases the acti vity of osteoclasts as well as the birth rate of bone remodeling units in w hich osteoclasts precursors are recruited.

Experiments have shown that PTH can induce bone resorption that would increase the rate of OTM. Soma et al""" eva luated the effect of loca l and chronic appl ication of PTH on tooth movement and found that loca l injection of PTH in a slow release formulation is appli cable to orthodontic therapy.

It is suggested that thyroid and parathyro id function is an important clini ca l factor in patients undergoing orthodontic trea tment. Orthodonti st should take a thorough history of the patients to determine whether they are on any hormonal supplementati on drugs as it might adversely affect the treatment. Administration of th y rox ine ca n be considered in some pati ents, especiall y in those who show beginning root resorption, or those who have low thyroid function.

VITAMIN D: Vitamin D is the co llecti ve name given to anti rachitic substances synthes ized in the body and found in foods activa ted by UV radiation. The ro le of Vit. D in the maintenance of Ca homeostasis in human bei ngs has been well documented. It is a steroid hormone Ihat has spec ific receptors in many target organs and ti ssues. It exerts its actions by activating DNA and RNA w ithin the target cell to produce proteins and enzymes that can be used in bone resorption process. In particular, the acti ve form of Vi t. O, 1,25 dihydroxy choleca lciferol is the most potent stimulus of osteoclasti c acti vi ty known. It is also involved in the formati on of osteoclasts from precursor monocytes .

Calcitriol enhances resorption of calcium and phosphate from bone by promoting recru itment and differentiation of osteoclast precursors in bone remodeling un its. but mature osteoclasts lack Vit.D receptor. Though osteoblastic cells express ViI. 0 receptor and respond to it. calcitriol appears to help bone mineral ization indirect ly by maintai ning normal plasma calc ium and phosphate concentra tion. Its action is independent of but fac ilitated by PTH.

Collins et al"" found on histologic levels an increase in the number of mononuclear osteoclasts recruitment and activation result ing in bone resorption on pressure side upon injection of Vit.D metaboli te 1.2 50 into Pd!. Yamamoto et al' found that injections of 1,25fOH),D, did not change serum Ca, PO, and ALPase activity and there were no apparent clinica l or microscopic side-effects. Nevertheless Vit. 0 (1 ,2S(OH),D,l enhances the re-establ ishment of supporting tissues, especially alveolar bone of teeth, after orthodontic treatmenl.'"

ESTORGEN : It has become increasingly evident hat estrogen is the most important hormone to affect bone metabolism in women. The various cytokines invo lved in bone reso rpt ion are inhibited by est rogen. Since mechanically induced bone modeling and remodel ing are essential for orthodont ic tooth movement. the response to orthodontic force may vary depending upon the phase of menstrual cycle. ZhaoQ et al" explored the iniluence ofOTM on estrous cycle and estrogen and found that estrous was the appropria te time for orthodont ic force. In another study j in Z et al '" suggested that estrogen promoted the alveolar bone forming and inhibited bone resorption. Haruyaman et al " also concluded that cycl ic changes in the estrad iol level may be associated with the estrous cycle dependent va ri ation in tooth movement through its effect on bone resorption. Osteoporosis is commonly seen in the postmenopausal women due to the defi ciency of estrogen. In order to evalua te the two most commonly used drugs for osteoporosis Wagle et al " determined the effects of FOSAMAX and EVISTA on OTM. Fosamax (alendronate) and Evista (ralaxifenel showed evidence of preventing bone resorption. Alendronate inh ib its orthodontic activity but not osteoclast recrui tment. whi le ralox ifene regulates osteoclastic act ivity by binding and modulating estrogen receptors to affect osteoclast number and acti vity. The author concluded that orthodontic treatment may be contraindica ted when taking these drugs. Estrogens are co mmonl y recommended for contraception. Moreover in orthodontic clinics. there

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are more fema le patients than male patients. Also there is an increase in the number of adult female patients seeking orthodontic treatment worldwide. Orthodontist shou ld pay specia l attenti on and should take this factor into cons ideration as then drugs have shown to reduce the velocity of O.T.M by inh ibiting bone resorption.

ANDROGENS: Androgens are the sub stan ces which cause development of secondary sex characters in the castrated men. Anabol ic steroids are used by the athletes during the period of training w hich are supposed to have higher anabolic and lower androgenic activi ty. As then drugs also inhibit bone resorption, it may affect the duration of the orthodontic treatment. Therefore a thorough history regard ing the use of such drugs should be taken from the adult males.

CONCLUSION: Since orthodontist plays a pivotal role in cl inical pharmacology in the dental practice, they should have an understanding of the fundamentals of drug therapy. Orthodontist should be able to converse with patients about medica tions prescr ibed for them, includ ing rev iewing potentia l adverse effects, drug interact ions. and how to take the medication. A thorough medica l history should be reviewed with the patient, including any prescript ion, and over the counter products. as many patients use drugs on daily basis wh ich have therapeutic as well as adverse effects.

Drugs like NSAID 's, Bi sphosphona tes, vitam in 0 metabolites, fluor ides can decrease the velocity of tooth movement. On the contrary drugs and systemic factors l ike eicosano ids, cor ti costeroids. th yroid and parathyroid hormones can increase the veloci ty of tooth movemenl. Orthodontist should be aware of such medications so that treatment plan best suited for the individual patient could be made and keeping the mechan ics as simple as possible.

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REVIEWS (Compiled by Dr. Sridevi Padmanabhan)

Near-end of Treatment Panoromic Radiogrph in the Assessment of Mesiodistal Root Angulation Ann Marie Owens; Ama Johal, Angle Orthodontist, Vol. 78, No.3, 2008.

This study aimed to test the hypothes is that there is no difference between the mesiodistal root angulation and the mesiodistal root angulation as measured on the panoramic radiograph. Thi s was eva luated using a typodont dentition set into Class I occlusion.

Wire strust were placed on the bucca l surface of each tooth to represent their long axes and the each the denti tion was fixed into a natural skull for imaging. The radiographic and true mesio-distal angulati on of each tooth to the horizontal reference plane was measured. The measurements were repeated after alteri ng the mes iodistal root pos itions to a more mesia l and more distal position.

O nly 26.7% of the root angulations were w ithin the clinica lly acceptable angular vari ation range of 2.5. The greatest va ri ati on in the upper arch was in the canine premolar region where the roots were projected as being more divergent. The greatest vari ation in the lower arch occurred in the lateral incisor-canine region w here these roo ts appea red more convergent. Radiographic distortion was statistica ll y more in the lower than in the upper arch.

Concl usion: There is a cl inica lly signifi cant vari ation between the radiographic and the true root angulations recorded and caution is advi sed w hen interpreting mes io-d istal root angulati on using O PG.

Torque expression of self-ligating brackets Hisham M. Badawi, Roger W. Toogood, Jason P.R.Carey, Giseon Heo and Paul W. Major. Th is study measured the difference in third-order mo ments th at ca n be del ivered by engag ing 0.019xO.025 - in stainless steel archwires to 2 active self- l igating brackets (In-ovati on and Speed) and two passive self- ligating brackets (Damon 2 and Smart Clip) using a novel torque measurement device.

There was a signi ficant di fference in the engagement angle between the two types of brackets. For the active self- ligat ing brackets, torque started to be expressed at

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7.5 of torsion and at 15 for the passive self- ligating brackets. The torque expression was higher for the active self-li gating brackets at cl inica lly usable torsion angles (0-35). The pass ive self-ligating brackets started producing moments at high torsion that cannot be used clini ca lly.

Thus the cl inica lly applicable range of torque activation and torque control was greater for the active self- ligating brackets.

Botulinum toxin type A (Botox) for the neuromuscular correction of excessive gingival display on smiling (gummy smile) Introduction: Prev iously, botulinum tox in type A (BTX-A) (Botox; Allergan, Irvine, Ca li f) was shown to be effecti ve in reducing excess ive gingiva l display in 5 pati ents with gummy smiles. This study was conducted to determin e w hether the doses and the primary injection si tes used in the pilot study for the correcti on o f gummy smiles prov ide consistent, stati sti ca ll y significant, and esthetica lly pleasing results.

Methods: Thirty patients received BTX-A injections to reduce excessive gingiva l display. Gingiva l display was defined as the difference between the lower margin of the upper lip and the superior margin of the right incisor. Patients were fo llowed at 2,4,8,12,16,20, and 24 weeks pos t i nj ec ti on, w ith changes doc um ented by photographs and videos. At week 2, the patients rated the effects of BTX-A. A group of specia lity cl inicians also evaluated the effects of BTX-A.

Results: Prei nj ecti on gingival di spl ay averaged 5.2 1 .4mm in the 30 patients. At 2 weeks post injection, mea n gingiva l di spl ay had dec lined to 0.09mm (1.06mm) in 30 pati ents (1=26.01 , P