Orthodontics

Effects of drugs and systemic factorson orthodontic treatment

Joanna B. Tyrovola, DDSVMeropi N. Spyropoulos, DDS, Dr Odont, MS^

Orthodontic tooth movement and bone remodeling activity are dependent on systemio lactors such asnutritional factors, metabolic bone diseases, age, and use ot drugs. Therefore, a comprehensive review olthe effects ot these factors on orthodontic tootii movement is attempted in this article. Systemic hormonessuch as estrogen, androgen, and calcitonin are associated with an increase in bone mineral content, bonemass, and a decrease in the rate of bone résorption. Consequently, they could delay orthodontic toothmovement. On the contrary, thyroid hormones and corticosteroids might be involved in a more rapid ortho-dontic tooth movement during orthodontic therapy and have a less stable orthodontic result. Drugs suchas bisphcsphonates, vitamin D metabolites, and fluorides can probabiy cause a reduction of tooth move-ment atter the orthodontic torce is applied. Nonsteroidal anti-infiammatory drugs have aiso been shown toreduce bone résorption. Long-term administration of these drugs may therefore delay the necessary boneresponse to respective tooth-borne pressure and should not be administered for long periods of time topatients undergoing orthodontic tooth movement. Attention has also been focused on the effects ofprosfaglandins and leukofrienes in orthodontic tooth movement. It seems that fhey might have future clini-cal appiieations that could result in enhanced tocth movement. The use of the above drugs should be con-sidered by every dentist in evaiuating fhe treatment time and in planning treatment when tooth movementis attempted. (Quintessence int 2001:32:365-371)

Key words: bone metabolism, bone résorption, corti ce steroids, hormones, systemic factcrs, toofhmovement

III orthodontic therapy, tnechanical forces exerted ontooth roots initiate complex cellular interactions re-

lated to bone remodeling activity. These interactions areregulated by local factors such as cytokines and growthfactors, as well as by systemic factors such as para-tiijToid hormone, vitamin D, estrogen, or caicitonin.'-^

Today, attention is mainly focused on the relationof orthodontic tooth movement to the applied force.Very little is known about the efiects of systemic fac-tors on orthodontic tooth movement, although itseems possible and reasonable to assume that thevelocity of tooth movement is also influenced by fac-tors such as hormones, pharmacological agents, traceelements, or metabolic bone diseases that affect thehard tissue metabolism in general.

The purpose of this review is to discuss current dataconcerning the role of pharmaceutical products knownto aäect bone tissue and to influence the velocity oforthodontic tooth movement. Moreover, information

'Priuate Practice, Athens, Greece.

^Professer and Head, Department of Ort lio don lies, University of Athens,School of Dentistry. Attiens, Greece.

Rsprlnt requests; Or Joanna Tyrovola, 72A Phokionos Negri Street, 11361 Athens, Greece. Fax: +301-8B16445.

will be presented regarding other systemic factors thatcan affect tooth movement through involvement of thealveolar bone. This information is considered essentialin order for the dentist to take into account all factorsrelated to orthodontic therapy and to select the besttherapeutic strategy in every individual case.

EFFECTS OF SYSTEMIC FACTORSON TOOTH MOVEMENT

In addition to applied force, bone metabolism plays animportant role in regulating the rate of tooth move-ment. Bone remodeling changes induced by systemicfactors such as nutritional factors, metabolic bone dis-eases, age, or the use of drugs, affect tooth movementthrough involvement of the alveolar bone.

Tootb movement depends on the state of calciummetabolism in the alveolar bone. Nutritional hyper-parathyroidism, induced in experimental animals byadministering a diet with decreased calcium to phos-phorus ratio, has been shown to increase the rate oforthodontic tooth movement. The difference in therate of movement was attributed to the increased rateof bone turnover and decreased bone density.'

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In rabbits subjected to corticosteroid-induced osteo-porosis, the velocity of orthodontic tooth movementand the stability of this movement were significantlyinfluenced. The tooth movement was more rapid butthe orthodontic results were less stable. In this case,elevation of osteoclastic activity, increased skeletalrésorption, and suppressed bone deposition resulted inaccelerated tooth movement and subsequent relapse.**

Generally, osteoporosis is suggested to be ciassifiedinto postmenopausal and senile osteoporosis. Thepostmenopausal type is considered to induce rapidturnover of bone, whereas the senile type is reportedas the low turnover type. This may well be an exampleof an age-related bone remodeling change. Since moreadults are continuously seeking orthodontic treatment,more studies are essential to demonstrate the type ofage-related bone metabolistn changes and how thesedifferences can affect the orthodontic treatment's

Other factors affecting bone metabolism may betrace elements, hormones, or drugs that the patient istaking during the orthodontic therapy. Very little ¡sknown about the effect of these systemic factors onthe metabolism of osseous tissue and, consequently,on orthodontic tooth movement. Therefore, a reviewregarding this issue was considered essential.According to the data found in the literature, and pre-sented in Tables 1 and 2, drugs that can influence therate of tooth movement can be divided into 6 maincategories:

1. Hormones2. Bisphosphonates3. Vitamin D metabolites4. Fluoride5. Nonsteroidal anti-inflammatory drugs6. Eicosanoids

HORMONES

Estrogens and androgens

Estrogen is considered to be the most important hor-mone to affect hone metabolism in women.' It con-trols bone remodeling during reproductive life, and itseems crucial to acquisition and maintenance of maxi-mum bone mass after menarche.^

The beneficial effect of estrogens on bone tissueresults from the decrease of the rate of bone résorp-tion. There are indications that estrogens inhibit theproduction of various cytokines, mainly interleukin-1(IL-l), tumour necrosis factor-a (TNF-a), and inter-leukin-6 (IL-6}. These cytokines appear to be involvedin bone résorption by stimulating ostcoclast formationand osteoclastic bone résorption.''^-'^

In addition, estrogens may be related to the parathy-roid hormone levels; according to a population-basedstudy, deficiency in estrogens seems to be responsiblefor the secondary hyperparathyroidism found in latepostmenopausal women.'' They also inhibit osteoblasts'responsiveness to parathyroid hormone (PTH).'''"

Estrogens do not appear to have any anaboliceffects on bone tissue.^ However, there are also studiesindicating that they directly stimulate the bone-formingactivity of osteoblasts.'^"^'

As Pharmaceuticals, estrogens are recommendedfor contraception, for the regulation of menorrhea,and for the treatment of amenorrhea. They are alsoused in the treatment of post-menopausal syndromeand osteoporosis.^^

In all the above circumstances, it is reasonable toexpect a decrease of the velocity of orthodontic toothmovement. Oral contraceptives, which are taken byyounger women for long periods of time, can influencethe rate of tooth movement, and therefore, it is recom-mended that the dentist pays special attention duringorthodontic treatment^ and takes this factor into con-sideration while selecting the best therapeutic strategy.

Androgens also inhibit bone résorption and modu-late the growth of the muscular system,̂ ^ Thus, theexcessive use of these drugs by athletes, in an attemptto achieve better athletic scores, may affect the lengthand the results of orthodontic treatment.

Thyroid hormones

Thyroid hormones are recommended for the treatmentof hypothyroidism and are also used after thyroidec-tomy in substitutive therapy.^' Thyroxine administrationseems to lead to increased hone remodeling, increasedhone resorptive activity, and reduced bone density.̂ ''̂ ^̂

These effects on bone tissue may he related to theaugmentation of interleukin l(IL-lB) production thatthyroid hormones induce at low concentrations,' acytokine that appears to stimulate osteoclast forma-tion, and osteoclastic bone résorption.^' It has alsobeen found that thyroid hormones increase osteoclas-tic bone résorption in neonatal mouse calvarla bystimulation of prostaglandin synthesis and thus mayalso work via this mechanism.̂ » Taking into consider-ation the skeletal actions of thyroid hormones, itseems possible for the speed of orthodontic toothmovement to be increased in patients undergoingsuch medication.

Low-dosage and short-term thyroxine administra-tions are also reported to lower the frequency anddimensions of "force-induced" root résorption le-sions.̂ '̂̂ ° This decrease of resorptive lesions may becorrelated to a change in the bone remodelingprocess^" and a reinforcement of the protection of the

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TABLE 1 Effects of drugs on orthodontic treatment

Hormones

Bisphosphonates

Vitamin D

Fluoride

Nonsteroidalanti-inflammatoryagents

Eicosanoids

Drugs

EstrogenAndrogen

Thyroidhormones

Calcitonin

Corticosteroids

Salicylates

ProstaglandihsLeukotrienes

Possibie effects

Decreased velocity of tooth movement

increased veiocity of tooth movementLower frequency and dimensions ofresorpiion lesions

Decreased veiocity of tooth movement

Increased veiocity of tooth movementGreater possibility of relapse

Decreased velocity of tooth movement

Decreased velocity of tooth movement

Decreased velocity of tooth movement

Decreased velocity of tooth movement

Increased velocity of tooth movementIncreased velocity of tooth movement

TABLE 2 Effects of drugs on bone tissue

Hormones

Bisphosphonates

Vitamin D

Fluoride

Nonsteroidalanti-inflammatoryagents

Eicosanoids

Drugs

EstrogenAndrogen

Thyroidhormones

Calcitonin

Corticosteroids

Saiicylates

ProstagiandinsLeukotrienes

Possible effects

Reguiation of bone remodelingDecreased rate of bone résorption

Increased rate of bone remodelingIncreased bone résorption

Decreased bone résorptionIncreased bone formation

Increased bane résorptionDecreased bone formation

Decreased bone résorption

Increased bone massPossibie decrease of bone résorption

Increased bone mass and mineral densityDecreased bone résorption

Decreased bone résorption

Increased bone résorptionIncreased bone résorption

cementum and dentin to "force-induced" osteoclasticrésorption." Low-dose tberapy seems to be effectivewithout reducing bone density.̂ ^

Furtber studies are essential to determine the exacteffects of this hormone regarding root résorption, thecircumstances under which it could he used, and theeffective dosage."

Caicitonin

Calcitonin is a peptide hormone secreted by the thy-roid in response to hypocalcemia; it targets the kidneysand bones. In bones, calcitonin inactivates osteoclastsand thus inhibits bone résorption. It also sfimulates thebone forming activity of osteoblasts.^^'"

Calcitonin is used in the treatment of hypercal-cemia and in osteoporosis; because of its pbysioiogicalrole, it is considered to inhibit tootb movement.Consequently, a delay in orthodontic treatment can heexpected and, as with estrogens, special attentionshould be taken by tbe dentist.'

Corticosteroids

Synthefic corticosteroids are used in the treatment of awide variety of medical conditions sucb as arthritic,allergic, blood, renal, collagen, or neoplastic diseases.̂ ̂ 't

Evidence indicates that the main effect of corticos-teroids on bone tissue is tbe direct inbibition of theosteoblastic function and thus the decrease of total bone

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formation. They are also associated with increased bonerésorption. Tbe latter may be due to elevated parathy-roid hormone levels caused by the inhibition of intesti-nal calcium absorption that the corticosteroids in-duce.*""" Therefore, it may he reasonable to assumethat corticosteroids increase the rate of tooth movementand, since new bone formation can be difficult in treatedpatients, they decrease the stability of tooth movementand the stability of orthodontic results in general.

When they are used for long periods of time, themain side effect of these drugs is osteoporosis.'"' Ithas been demonstrated in animal models with thistype of osteoporosis that the rate of active tooth move-ment is greater, but the tooth movement is less stablesince little bone is present and no indication of newbone formation appears."

A more extensive retention may be helpful inretaining tbese teetb if the dentist decides to proceedwith the orthodontic treatment.

BISPHOSPHONATES

This class of pharmacological agents is characterizedby their high affinity for calcified tissues.'"* Bisphos-phonates are potent blockers of bone résorption. Theyhave been used successfully in the treatment of hyper-calcemia, osteoporosis,̂ *'*" and generally in the treat-ment of metabolic bone diseases that involve in-creased bone résorption.""'"

Their impact on the resorptive process is reported tobe a consequence of the inhibition of osteoclasticmetabolism"^ and the marked decrease of the numberof osteoclasts'" they cause. It is also suggested that tbeyaffect the structure and function of osteoclasts."'"'''^"^The above findings are considered as indications thatbisphosphonates can inhibit ortbodontic tootb move-ment and delay the orthodontic treatment, an effectthat is also supported by other authors.^

These indications are confirmed by studies thatdemonstrate that orthodontic tooth movement isinhibited by the topical application of a bisphospho-nate. Furthermore, it seems that topical application ofbisphosphonates could be helpful in anchoring andretaining teeth under orthodontic treatment. However,further studies of drug application methods arerequired before clinical application of these drugs inorthodontics can he attempted with the assurance thatthere are no systemic effects."̂

VITAMIN D3

Vitamin D and especially its most active metabolite,which is 1, 25 2(OH)D3, together with parathyroid hor-

mone and calcitonin, regulates the amount of calciumand phosphorus in the human organism. It promotesintestinal calcium and phosphorus absorption. It alsopromotes calcium's release from the skeletal system toblood circulation."' Results of the latest clinical trials ofvitamin D indicate that it can be effective in the treat-ment of osteoporosis. According to these results, vita-min D3 increases bone mass and tbus reduces fracturesin osteoporotic patients."""^ Because of these beneficialeffects on bone tissue, we can assume this pharmaco-logical agent can inhibit orthodontic tooth movement,as supported by other authors.' However, it is interest-ing to mention that some authors consider vitamin D3to be a résorption-promoting agent because it has stim-ulatory effects on osteoclasts.'"'' In addition, vitamin Dreceptors have been demonstrated not only inosteoblasts but also in osteoclast precursors as well as

FLUORIDE

One of the severai trace elements that affect hard tis-sue metabolism is fluoride. On the cellular level, fluo-ride stimulates the growth and synthetic activity ofosteoblasts and bone formation and influences thechemistry of the bone mineral.^'' In the form of sodiumfluoride, it has been shown to inhibit the osteoclasticactivity and to reduce the number of active osteo-clasts.̂ ^ Tberefore, fluoride increases bone mass andmineral density'^ and, because of these skeletalactions, it has been used in the treatment of metabolicbone diseases tbat involve increased bone résorptionsucb as osteoporosis.

On tbe clinical level, the mentioned findings sug-gest that the use of ñuoride can influence tbe velocityof orthodontic tooth movement. Even a very activecaries preventive treatment with sodium fluorideduring orthodontic treatment may delay orthodontictooth movement and affect the time of the orthodontictherapy.'^

NONSTEROIDAL ANTI-INFLAMMATORYDRUGS (SALICYLATES)

Acetylsalicylic acid and the related compounds areused clinically as anti-inflammatory drugs. Their phar-macological action is considered to result from theirinhibition of cyclooxygenase activity, which convertsunsaturated fatty acids in the cell membrane toprostaglandins."

Researeb on tbe effects of sodium salicylate onbone in growing rats has suggested that it inhibits therésorption process of bone.'^-^" Clinical experience

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shows that orthodontic tooth movement is very slowin patients undergoing long-term acetylsalicylic acidtherapy, whereas when these patients are taken offthis anti-inflammatory medication, a striking differ-ence in orthodontic tooth movement occurs.^'

The salicylate's action can be attributed to their inhi-bition of prostaglandin synthesis, which seems to play asignificant role in bone résorption during orthodontictherapy." In addition, salicylates may affect the differen-tiation of osteoclasts from their precursors, and thus theinhibition of bone résorption by them may be in partdue to the action of these drugs on osteoclastogenesis,"

Therefore, it is recommended that patients under-going orthodontic treatment should not take aspirin orrelated compounds for long periods of time during thetime of orthodontic treatment, because there is a greatpossibility of extension of tbe treatment time.̂ ^

lized by lipoxygenase enzymes,' Leukotrienes may alsobe important mediators of orthodontic tooth move-ment. It has been demonstrated that they stimulatebone résorption. It seems that both these inflamma-tory modulators-prostaglandins and leukotrienes-play an important role in bone remodeling.'"

This role is clearly demonstrated when inhibitorsoí leukotriene synthesis are used in experimentalmodels. It results in a significant reduction of ortho-dontic tootb movement. Moreover, researcb continueson the syntbesis and clinical use of leukotrieneinhibitors for tbe control of allergic and inflammatoryconditions.'^"''

Consequently, tbe use of leukotriene inbibitors candelay orthodontic treatment, whereas leukotrienes andprostaglandins can bave future clinical applicationstbat could result in enhanced tooth movement.'̂

EICOSANOIDS

Prostaglandins

The precursor for prostaglandins is arachidonic acid.Arachidonic acid is metabolized by eyelooxygenaseenzymes, resulting in prostaglandin production.'Experiments bave sbown that prostaglandins may beimportant mediators of mechanical stress duringorthodontic tooth movement. They stimulate bonerésorption"-^' by increasing the number of osteoclastsand activating already existing osteoclasts.̂ '̂̂ "̂̂ ^

Their pbarmacological action drew the attention ofscientists to the effects of prostaglandin administrationin shortening the treatment time m orthodontic patients.Indeed, it was found that administration of Prosta-glandin 1 (PGEi) or Prostaglandin 2 (PGEj) in experi-mental models or in orthodontie patients acceleratedbone résorption and orthodontic tooth movement.̂ ''•̂ ^

Systemic administration is reported to have a bettereffect than local administration. However, rapid inac-tivation of prostaglandins in the lung, local irritation,and phlebitis are among tbe side effects of intravenousadministration. Generally, prostaglandins can increasethe sensitivity of pain receptors, hut when the dosesare within the clinical safety range, no other sideeffects are observed. However, further research isneeded in order to improve application methods ofthese drugs and to overcome certain technical prob-lems. Only tben can dentists endorse the use of pros-taglandins as an adjunct to orthodontic treatment,^'

Leukotrienes

Leukotrienes are also metabolites of arachidonic acid.They are produced when arachidonic acid is metabo-

CONCLUSION

In addition to applied force, bone remodeling changesinduced by systemic factors such as nutritional factors,metabohc bone diseases, age, or tbe use of drugs, piayan important role in regulating the rate of tooth move-ment. Certain pharmacological agents that affect bonetissue metabolism can influence the velocity of toothmovement. Estrogen, androgen, calcitonin, bisphos-pbonates, vitamin D, fluoride, and salicylates maydecrease tbe velocity of tooth movement. In contra-distinction, thjToid hormones, corticosteroids, prosta-glandins, and leukotrienes can enhance orthodontictootb movement. The dentist should always discuss thepatient's current drug therapy in order to accuratelyevaluate the treatment time and to select the best thera-peutic strategy in everj' individual case. Moreover, stud-ies related to the intake of thyroid hormones, bisphos-phonates, prostaglandins, and leukotrienes are requiredin order to have future and beneflcial clinical applica-tions of these drugs for orthodontic tooth movement.

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