Bone metabolism & Biological Theories of Tooth movement Preceptors: Dr. Pavan Kumar Chandra Dr.

Piush Kumar Presented by: Dr. Anuja Aggarwal 2 Bone is a specialized mineralized connective tissue made up of an organic matrix of collagen fibrils embedded in an amorphous substance with mineral crystals precipitated within the matrix. Matrices organic inorganic 35 % of dry wt. Type I collagen. 10 % non collagenous proteins.ex:BMP Non collagenous proteins are PG or GAG Modulate cellular attachment. 60 70 % of dry wt. 99% Ca, 85 % P, 40 60 % Na & Mg 5 Classification of bone Based on Structure Compact Bone or cortical bone - the dense outer shell of the skeleton. Cancellous Bone or trabecular bone - comprises of a system of plates, rods, arches and struts traversing the medullary cavity encased within the shell of compact bone. Based on development Intramembranous bone Eg., Bones of cranial vault, maxilla, etc. Intracartilagenous bone Eg., Vertebra, ribs, base of the skull, etc 6 Based on the arrangement of the collagenous matrix. Immature Bone : is subdivided into : Woven Bone : Relatively weak ,disorganized and poorly mineralized. The first bone formed in response to orthodontic loading usually is the woven type. Bundle bone Bundle bone is a functional adaptation of lamellar structure to allow attachment of Sharpey's fibers Mature Bone or Lamellar bone Lamellar bone a strong, highly organized, well-mineralized tissue. Adult human bone is almost entirely of the remodeled variety: secondary osteons and spongiosa.. 7 W Woven Bone L Lamellar Bone 8 HISTOLOGY OF BONE 9 Periosteum Compact Bone Circumferential lamellae Concentric lamellae Interstitial lamellae Bony trabeculae Bone Marrow HISTOLOGY OF BONE Bone consists of 4 microstructural components 1. Cells 2. Organic matrix 3. Inorganic matrix 4. Soluble signalling factors Osteoblasts Osteocytes osteoclasts According to Brighton following fracture with in 12 hrs polymorphic mesenchymal cells appear providing preosteoblastic cell resource. Depending on the presence of environmental cues such as nutrient supply, specific growth factors, blood vessels & mechanical stability , they can convert either to cartilage forming chondrocytes or bone forming osteoblasts. Osteoblasts Round cells with an organelle rich cytoplasm. Form bone by laying down osteoid first and then mineralizing it. Osteoblasts are metabolically active secretory cells that express soluble signaling factors ex: BMPs, TGF- beta, insulin like growth factor I & II , interleukin 1 & platelet derived growth factor

& osteoid. Expression of these factors by osteoblasts occurs during bone embryogenesis, maintenance(ex: remodeling) & repair. Osteoblasts are derived from paravascular connective tissue cells. Mesenchymal stem cells differentiate into osteoblasts when they are exposed to bone morphogenic proteins (BMP). Cbfa1 is a transcription factor that is expressed by the cells of osteoblastic lineage and is necessary for osteoblast differentiation During remodeling , osteoid is produced at the rate of 2 3 micrometers per day at a thickness of 20 micrometers. After a maturational period of 10 days, osteoid mineralises at a rate of 1- 2 micro meters per day. Osteocytes Osteocytes are former osteoblasts that have become entrapped in bone matrix. These are relatively inactive cells. Their subdued metabolic activity is crucial to bone viability & to sustain homeostasis. The complex processes of homeostasis are regulated by physiologic interactions among cells, tissues, organs & signaling factors such as harmones & growth factors that meticulously titrate intra & extra cellular levels of cationic & anionic moieties Vitality of bone is maintained through a network of osteocytic cytoplasmic processes that traverse canaliculi. This highway system enables osteocytes to interact through gap junctions & permits signal transmission to osteoblasts from osteocytes & from osteocytes to osteoblasts. Osteocytes,osteoblasts & osteoclasts are the cellular crafts men performing the managerial roles of calcium regulation & bone homeostasis, physiological processes fundamental to modeling & remodeling. Osteoclasts Granulocytic precursors found in bone marrow enter the circulation as monocytes , and through asynchronous fusion, produce a multinucleated cell with an average of 10 12 nuclei known as osteoclast. They represent the terminal stage of differenciation of these cells. Osteoclasts have a ruffled border, possess calcitonin receptors. They secrete a lysosomal enzyme, tartrate- resistant acid phosphatase (TRAP), which is also used as a marker for osteoclast identification. Differentiation of osteoclasts Osteoclasts differentiate from hematopoietic cells. This pathway of differentiation is also shared by macrophages. GM-CSF (granulocyte monocyte colony stimulating factor) and M- CSF (macrophage colony stimulating factor) are important in regulating these shared stages of development. Another important discovery of osteopotegerin (OPG) or Osteoclastogenesis inhibiting factoe (OCIF) secreted by osteoblasts and functions to block the formation of osteoclasts and bone resorption. SUDA et al isolated an osteoblast membrane bond molecule called osteoclast differentiation factor (ODF). ODF was able to induce osteoclastogenesis in bone organ cultures. When ODF was cloned, it was found identical to an already cloned member of the TNF ligand family, called TRANCE (TNF-related activation induced cytokine) or RANKL (receptor activator of nuclear factor kB ligand) Osteoblast membrane bond RANK ligand interact with developing monocytes to cause them to differentiate eventually into osteoclasts. Osteoblast regulates the differentiation of osteoclasts. The TALK between an osteoblast and osteoclast is accomplished through an osteoblast membrane bond RANK Ligand (RANKL) (receptor activator of nuclear factor kB ligand) In this situation OPG can develop to block RANKL in turn blocking the interaction between RANK and RANKL/ODF Cytokines (TNF, interleukin-1), prostaglandins E and growth factors (TGF-, BMP) are upstream signals which regulate the OPG/ODF ratio. How do osteoclasts work? Osteoclasts contain large amounts of carbonic anhydrase to facilitate the conversion of CO2 and

H2O to H2CO3. The degradation of bone matrix is presumably the result of the activity of a number of lysosomal enzymes which can degrade bone at low pH. There is a correlation between activation of bone resorption and acid phosphatase release and oxygen derived free radicals localized in ruffled border.. A variety of cathepsins, superoxide dismutase and other lytic enzymes which are produced by the osteoclast are able to degrade collagen at low pH. Decreased blood Ca level parathyroid kidney parathormone Vitamin D Bone Increase in resorption & release of Ca Intestine Increase in absorption of Ca Increased blood Ca level thyroid calcitonin Bone Inhibition of bone resorption and deposition of Ca Normal calcium level Factors affecting bone metabolism Stimulation Inhibition Bone formation GH Calcitonin Insulin Testosterone Estrogen Cortisol Mineralization Calcitonin Insulin Vit D Cortisol Bone resorption Parathormone Thyroxine Cortisol Testosterone Tooth Movement 2 types of tooth movements- Physiologic Under the effect of force. Theories explaining orthodontic tooth movement- Pressure tension theory Biological electricity or bioelectric theory Fluid Dynamic Theory Pressure tension theory (Schwartz 1932) Sandstedt (1904), Oppenheim (1911), and Schwarz (1932) hypothesized that a tooth moves in the periodontal space by generating a pressure side and a tension side. This hypothesis explained that on the pressure side: PDL displays disorganization and diminution of fiber production, cell replication decreases seemingly due to vascular constriction on the tension side: stimulation produced by stretching of PDL fiber bundles results in an increase in cell replication, fiber production. He concluded that the forces delivered as part of orthodontic treatment should not exceed the capillary bed blood pressure (20-25 g/cm2 of root surface). The third phase of bone remodeling consists of loss of bone mass at PDL pressure areas and apposition at tension areas. This succession of events formed the central theme of the pressuretension hypothesis. Why it was rejected? Baumrind, pointed out a conceptual flaw in it. He considered the PDL to be a continuous hydrostatic system and suggested that any force delivered to it would be transmitted equally to all regions accoording to Pascals Law. He further stated that the presence of fibers in the PDL does not modify the operation of this law, because of the concomitant existence of a continuous body of liquefied ground substance. He recognized that only part of the periodontium where differential pressures, as mentioned in the pressure-tension hypothesis, can be developed, is solidbone, tooth, and discrete solid fractures of the PDL. Bone Bending & Bioelectric Theory (Farrar 1876) Farrar was the first to suggest, that alveolar bone bending plays a pivotal role in orthodontic tooth movement. It has been hypothesized that mechanical deformation of the crystalline structure of the hydroxyapetite and the crystalline structure of collagen induce migration of electrons that generate local electric fields. This phenomenon is called piezoelectricity.

Zengo et al concluded that the concave side of orthodontically treated bone is electronegative and favors osteoblastic activity, whereas the areas of positivity or electrical neutralityconvex surfacesshowed elevated osteoclastic activity. The 2 unusual properties of piezoelectricity, which seem to not correlate well with orthodontic tooth movement are (1) a quick decay rate (2) production of an equivalent signal in the opposite direction upon force removal Further, ions in the fluids surrounding the living bone interact with these electrical fields. These currents of small voltages are called streaming potentials. Davidovitch et al suggested recently that piezoelectric potentials result from distortion of fixed structures of the periodontium collagen, hydroxyapatite, or bone cell surface. But in hydrated tissues, streaming potentials (the electrokinetic effects that arise when the electrical double layer overlying a charged surface is displaced) predominate as the interstitial fluid moves. Fluid Dynamic Theory (Bein 1966) Tooth movement occurs as a result alterations in fluid dynamics in the PDL. When PDL is compressed due to orthodontic force blood vessels of the PDL get trapped between the principal fibers and this results in stenosis. The vessel above the stenosis then balloons resulting in the formation of an aneurysm. The process of tooth movement under the effect of force is unique to humans. During the process of evolution PDL appeared between the tooth and the alveolar socket. Remodeling changes in paradental tissues are considered essential in effecting orthodontic tooth movement. The force-induced tissue strain produces local alterations in vascularity, cellular and extracellular matrix reorganization, leading to the synthesis and release of various neurotransmitters, cytokines, GFs, CSFs & metabolites of arachidonic acid. How is ortho mvmt diff from physiological TM Orthodontic tooth movement is uniquely characterized by the abrupt creation of compression and tension regions in the PDL. Physiological tooth movement is a slow process that occurs mainly in the buccal direction into cancellous bone or because of growth into cortical bone. In contrast, orthodontic tooth movement can occur rapidly or slowly, depending on the physical characteristics of the applied force, and the size and biological response of the PDL. Biology of tooth movement due to applied force: Current Concepts PATHWAYS OF TOOTH MOVEMENT On the basis of research in basic biology and clinical observations, Mostafa et al proposed an integrated hypothetical model for tooth movement. This model consists of 2 pathways I ----Physiological response II----Generation of local inflammatory response Pathway I Orthodontic force creates vectors of pressure and tension bone bending, generation of tissue bioelectric polarization, and subsequent bone remodeling act on the cell surface cyclic nucleotide pathway, generating changes in the levels of intracellular second messengers cAMP cell proliferation, differentiation, and activation electrically neutral or positive areas promote osteoclast activity, whereas electronegativity supporting osteoblastic activity. Pathway II Orthodontic forces trigger inflammatory processes in the involved dental and paradental tissues. Lymphocytes, monocytes, and macrophages invade these tissues The local elevation in prostaglandins and a subsequent increase in cellular cAMP concentrations increase osteoclast activity. Secreted hydrolytic enzymes, such as collagenase, dissolve the mechanically strained ECM. Recent model Recent reports by Jones et al detailed events in bone cells immediately after the application of mechanical stress. Osteoblasts respond to physiologic levels of stress- increase in intracellular free calcium and membrane potential through activation of K channels. activation of phospholipase C, which releases inositol triphosphate within 10 seconds. Elevated levels of phospholipase C maintain the high calcium concentration throughout stress application by keeping the mechanosensitve ion channels open and by further activation of protein kinase C

Phospholipase A is activated Arachidonic acid Prostaglandins (10 mins) Release of products of the lipooxygenase pathway (leucotriens and hydroxyeicosatetraenoic acids), followed by an elevation in the concentration of cAMP. Cellular synthetic and secretory activities. Primary stimulus Acts on Pdl and bone cells Interaction between these cells leads to Transient increase in the intracellular levels of second messengers CAMP IP3 Ca++ Secondary messenger Nucleus Takes signal to In the nucleus of each cell different second messengers account for the differential patterning, protein synthesis and Gene expression. Recently identified Immediate Early Gene expression include Cfos, Cjon mRNA, egr-I, SP1 growth differentiation factor 9B, extracellular GLA protein. These transcription factors can produce either cellular proliferation or cellular differentiation leading to osteoblastic bone formation or osteoclastic bone resorption. Phospholipids Mechanical, hormonal, pathological, electrical Phospholipase A Arachidonic acid Leucotrienes Lipooxygenase pathway Cyclic peroxide Cyclooxygenase pathway PG E PG F Role of Prostaglandins Are mediators of inflammation cause an increase in intracellular cAMP and calcium accumulation by monocytes. Increase the number of osteoclasts as well as stimulate osteoblastic cell differentiation and new bone formation. Klein and Riasz in 1970 reported for the first time the involvement of prostaglandins in orthodontic tooth movement. Yamasaki et al in a rat model of tooth movement, demonstrated that injection of PGs increased osteoclast numbers & local PG injection could also increase the rate of orthodontic tooth movement in primates In a study done by Anand K Patil et al- PGE in lesser dosage of 3gm along with lignocaine as a vehicle was injected distal to canine in 14 orthodontic patients and it was found to increase the rate of orthodontic tooth movement. Role of cytokines and growth factors Cytokines are the protein factors released from cells, which modulate the activity of other cells and have multiple actions like bone remodelling, bone resorption & deposition. Prominent cytokines which have been shown to stimulate bone resorption and induce osteoclast proliferation are- Interleukin 1 Interleukin-6 Tumor necrosis factor Granulocyte-macrophage colony stimulating factor Macrophage colony stimulating factor The early phase of orthodontic tooth movement involves an acute response causing release of inflammatory mediators such as prostaglandins and interleukins (IL-1) that interact with bone cells. Cytokines secreted by leucocytes may interact directly with bone cells or indirectly, via neighboring cells such as monocytes/macrophages, lymphocytes and fibroblasts. Osteoblasts regulate the activity of existing osteoclasts and the formation of new osteoclasts through release of cytokines. (TNF)

Growth factors are released during inflammation and repair by the cells of PDL and bone. These factors include Fibroblast growth factor Insulin like growth factor (IGF-I, IGF-II)increase type-I collagen and matrix synthesis by osteoblasts. Transforming growth factor (BMP)- induce mesenchymal progenitors to differentiate into both osteoblasts and chondrocytes Platelet growth factors Role of neurotransmitters In areas where tension or compression evolves under the influence of the orthodontic appliance, vasoactive neurotransmitters are released from distorted nerve terminals that interact first with capillary endothelial cells. In response, the endothelial cells express receptors that bind circulating leukocytes, promoting their migration by diapedesis out of the capillaries to secrete signal molecules, including cytokines and growth factors, that stimulate PDL and alveolar bone lining cells to remodel their ECM. The PDL is abundantly supplied with 2 kinds of nerve terminals: Ruffini-like endings & nociceptive endings which change their structures in response to external stimuli, such as orthodontic force. Mechanoreceptors in the apical half of the dental root have a low threshold and respond to even minor stretching of the PDL. In contrast, nociceptors have a high threshold and are activated by heavy forces, tissue injury, and inflammatory mediators. The mechanoreceptors are silent in physiological conditions but contain various neuropeptides such as substance P, vasoactive intestinal polypeptide, and calcitonin gene-related peptide (CGRP) released when strained. Increased immunoreactivity (increases PG) of substance P has been demonstrated in the PDL in the early phases of tooth movement. Another neurotransmitter involved in orthodontic tooth movement is CGRP. Kvinnsland and Kvinnsland localized CGRP in the PDL and the dental pulp after 3 days of molar movement in fibroblasts at PDL tension sites. Saito et al reported finding intense reactivity to vasoactive intestinal polypeptide, in the compressed PDL and in the pulp of moving teeth in cats. Role of neurotransmitters in orthodontic tooth movement Orthodontic force Movement of tissue fluids inside and out of PDL Distortion of nerve endings Release of stored neurotransmitters centrally and peripherally Pressure sensation, pain Interaction with PDL fibroblasts and alveolar bone cells Increased levels of intracellular 2nd messengers Synthesis and secretion of cell products- cell proliferation etc. Interaction with endothelial cells vasodilatation Extrusion of plasma (prostaglandins) and leukocytes Synthesis and secretion of cytokines Pressure/tension-electrical-cell After an orthodontic force is applied, the initial step is the detection of a mechanical strain. Application of small bending force to long bones result in compression on one side and tension on the opposite side. This produces a flow of interstitial fluid through the canalicular network, generating streaming potentials and/or fluid shear stress. Streaming potentials is the electric potential that develops between two components by an electrolyte flowing between the solid surfaces. Eg: bone is partially composed of proteoglycans, which are entrapped in a collagen network. Because of the negative charge of proteoglycans, there is an excess of positive mobile ions in the fluid. Such potentials could possibly arise in vascular channels, Haversian systems, canaliculi, microporosities of the structure and as a result of the blood flow and interstitial fluid movement. Slow decay of signal due to relaxation of fluid flow in the stressed bone. The cells responsible for sensing mechanical strains in bone have been considered to be osteoblasts, osteocytes or both.

 These cells sense mechanical strain by virtue of Mechanosensitive ion channels (Ca and K passage due to streaming potential) Extracellular matrix and cytoskeleton reorganization. Cell to Cell contact There are two types of cellular adhesions- Cell-to-cell adhesion Cell-to-extracellular matrix adhesion. Integrins are cell surface receptors that mediate cell-to-cell attachment or cell attachment to ECM molecules such as collagen, fibronectin, laminin etc. The cytoskeleton (Microtubules, microfilaments ,Intermediate filaments) presents a number of possibilities for transducing mechanical forces acting on cells and/or their adjacent matrices. Many of the extracellular matrix proteins responsible for cell adhesion contain a common peptide sequence Arg-Gly-Asp (RGD) which is essential for the cell- binding properties of these proteins. Osteoclasts also express integrin receptors including the vitronectin receptor, which plays an important role in the adhesion of osteoclasts to bone surface. Peptides containing the RGD motif has been shown to inhibit osteoclast mediated bone resorption in vitro and prevent osteoporosis in vivo. These peptides could potentially aid in the treatment of osteoporosis and possibly in modulating the orthodontic tooth movement. Second messengers The behavior of all cells is modulated by internal signaling systems, which translate a wide array of external stimuli such as hormones or mechanical forces into a narrow range of internal signals or second messengers. Classically, the second messenger associated with mechanical force transduction is Adenosine 35 cyclic monophosphate (cAMP). It was first identified in 1960 by SUTHERLAND et al- When liver slices were exposed to adrenalin, free glucose appeared under these conditions and it was postulated that adrenalin was acting as the first messenger, binding to a receptor and stimulating the production of a powerful chemical second messenger. Role of G proteins- Some cell membrane receptors operate by activating membrane bound transducing proteins which bind guanine nucleotides such as GTP or GDP. These are commonly referred to as G protiens. At the surface of the cell the external signal binds to the receptor and induces a conformational change in the receptor. This is transmitted through the cell membrane and renders the appropriate G proteins susceptible to GTP binding. The G protein-GTP complex then activates effector enzymes such as adenylate cyclase which generates cAMP. The activity of the complex is ended by hydrolysis of the GTP to GDP thus closing of the signaling reactions. The G proteins act as intermediaries between receptors and intermediary enzymes. The three important G proteins pertinent to orthodontic tooth movement are Gs- the stimulatory regulator of adenylate cyclase Gi- the inhibitory regulator of adenylate cyclase Gp-the stimulatory regulator of the PI pathway. 2 active second messengers are generated Water soluble phosphatidyl inositol triphosphate (IP3) and Hydrophobic diacylglycerol. In a signaling cascade process- receptor activation is followed by second messenger generation i.e. cAMP and inositol triphosphate. They advance signals to the nucleus through a series of kinases. Early gene expression In the nucleus different second messengers account for the differential pattern of immediate early gene expression (IEG). IEGs are among the earliest responses that can be measured at the transcription level. The transcription of the IEGs has been shown to increase when cells are exposed to cytokines, growth factors or mechanical stimulation. IEGs are- c-fos c-jun and egr-1 Protein products from the c-fos and c-jun genes form a hetrodimeric complex named activator protein-1 (AP-1). Depending on the state of the cell or in the presence of various stimuli Ap-1 can produce either cellular proliferation or differentiation. Signal input-genetic output Cytoplasmic signaling proteins such as sonic hedgehog, TGF- superfamily and many transcription factors and ions reach the nuclear matrix and then genomeresulting in enhanced or suppressed gene expression. Input becomes output as gene expressed proteins Protein synthesis inhibition Mobilize

mitosis Cell motility Secretion of other proteins Programmed cell death (apoptosis) all of which modify cytoskeleton, cell membrane and ECM. This process is continuous. Changes in cell environment (development, ageing, external conditions) might change the pattern of gene expression. This epigenetic regulation of gene expression involves heritable changes not from DNA base sequence changes but from chemical modification of bases ATCG or transcription factors bound with DNA. Such genomic changes can occur throughout life. Pain & Orthodontic Tooth Movement Tooth movement-associated tissue remodeling, an inflammatory process, might induce painful sensations, particularly after activation of the orthodontic appliance. After 24 hours of force application, C-fos (immunoreactive neurons known to be involved in transmission of nociceptive information) expression is noted ipsilaterally in the trigeminal nuclues modulated through serotonergic and dopaminergic systems. Drug interaction Pharmacological agents manipulate tooth movement in both directions. Factors that enhance tooth movement are vitamin D & direct injection of prostaglandin into periodontal ligament. Drugs that inhibit tooth movement are Bisphosphonates used in the treatment of osteoporosis. Ex : alendronate Prostaglandin inhibitors. Ex : NSAIDS, Corticosteroids , Parathyroid, Thyroxin. Osteoporosis is a problem particularly encountered in post menopausal females but is associated with aging in both sexes. Estrogen therapy , which is used frequently to prevent loss of bone in older women , has no impact on orthodontic treatment. Bisphosphonates are synthetic analogues of pyrophosphates that bind to hydroxyapatite in bone & act as specific inhibitors of osteoclast mediated bone resorption. If orthodontic treatment is necessary in older patients it is better to switch over to estrogen at least temporarily Or use Raloxifene (estrogen rec modulator). Bartzela et al Am J Orthod Dentofac Orthop 2009;135:16-26 Dietary calcium : Adults require 1000 to 1300 mg of calcium in their daily diet. The effect of dietary supplemental calcium on OTM was studied in dogs that were fed low- or high-calcium diets for 10 weeks before orthodontic premolar movement was induced with a force of 100 N for 12 weeks. From 8 weeks on, the low-calcium regimen led to a signicantly higher rate of OTM than did the high calcium diet. These data support bone turnover studies showing increases in the number of osteoclasts and osteoblasts in dogs with a low- calcium diet. The nal outcome was increased bone remodeling phenotype in which excessive bone resorption prevailed over deposition. Bartzela et al Am J Orthod Dentofac Orthop 2009;135:16-26 Prostaglandin E inhibitors: Prostaglandin E inhibitors are of two categories: Corticosteroids & NSAIDs. Prostaglandins are formed from arachidonic acid which in turn is derived from phospholipids. Corticosteroids reduce prostaglandin synthesis by inhibiting the formation of arachidonic acid. NSAIDs inhibit conversion of archidonic acid to prostaglandins by acting on Cox. There is evidence that PGs play an important role as balancing agents in bone remodeling induced by mechanical stress. PGs of the E and F series have been implicated in bone remodeling activities, particularly resorption; they decrease collagen synthesis and increase cyclic adenosine monophosphate (AMP). Animal studies showed that the tooth movement index significantly increases when PGs are injected. Arias OR ,Orozco MCM Am J Orthod Dentofac Orthop 2006;130:364-70 Other classes of drugs which reduce tooth movement are: Tricyclic antidepressants (doxepin, amitriptyline, imipramine.) Anti arrhythmatic agents( procaine) Anti malarial drugs ( quinine, quinidine, chloroquine.) Anticonvulsant drug (Phenytoin.) Tetracyclines ex: doxycycline (inhibit osteoclast recruitment) Indomethacin and flurbiprofenwhich are specific inhibitors of PGs reduce the amount of osteoclasts in the alveolar bones of cats and rabbits receiving orthodontic forces and also reduce the dental movement index by 50%. Acetaminophen is the DOC. Arias OR ,Orozco MCM Am J Orthod Dentofac Orthop 2006;130:364-70 John et al AO, 1996 , Acetaminophen (paraminophenol) is suggested as DOC for relieving the

discomfort associated with ortho treatment. It is a very weak PG inhibitor & no significant antiinflamatory effects. Exact mechanism by which it relieves fever & pain is not known, it is believed to act in the CNS. It has no effect on orthodontic tooth movement. Kehoe MJ et al, 1996 suggested Misoprostol (produces analgesia similar to morphine) has insignificant inhibitory effect on local PGe2 production. The degree & rate of tooth movement increased attributed to the enhanced bone resorbing activity of PGe1. It was found ibuprofen significantly decreases PG synthesis in pdl of guinea pigs. There is a marked decrease in degree & rate of tooth movement. Acetaminophen decreases peripheral PG production. But there is no significant effect on tooth movement. Thus by prescribing OTC analgesics with minimum inhibition of PG, the treatment time can be reduced. 89 CONCLUSION Tooth movement is a highly conserved physiological mechanism for continuous adaptation of the dentition. Orthodontic tooth movement is a biomechanical exploitation of the physiologic mechanisms for developing and maintaining optimal occlusal function. The tooth continues to move until it achieves equilibrium with natural and applied loads. ****************