bone metab and tooth movement

7/28/2019 bone metab and tooth movement

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Bone metabolism & Biological

Theories of Tooth movementPreceptors:

Dr. Pavan Kumar Chandra

Dr. Piush Kumar

Presented by:

Dr. Anuja Aggarwal


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Bone is a specialized mineralized connective tissue

made up of an organic matrix of collagen fibrils

embedded in an amorphous substance with mineralcrystals precipitated within the matrix.


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Matrices

organicinorganic

35 % of dry wt.

Type I collagen.

10 % non collagenousproteins.ex:BMP

Non collagenousproteins are PG orGAG

Modulate cellularattachment.

6070 % of dry wt.

99% Ca, 85 % P, 40

60 % Na & Mg


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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 boneEg., Bones of

cranial vault, maxilla, etc.

Intracartilagenous boneEg., Vertebra,

ribs, base of the skull, etc


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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 boneBundle bone is a functional adaptation of lamellar structure to

allow attachment ofSharpey's fibers

Mature Bone or Lamellar boneLamellar bone a strong, highly organized, well-mineralized

tissue. Adult human bone is almost entirely of the remodeled

variety: secondary osteons and spongiosa..


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W Woven Bone L Lamellar Bone


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HISTOLOGY OF BONE


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Periosteum

Compact Bone

Circumferential lamellae

Concentric lamellae

Interstitial lamellae

Bony trabeculae

Bone Marrow

HISTOLOGY OF BONE


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Bone consists of 4 microstructural components

1. Cells

2. Organic matrix

3. Inorganic matrix

4. Soluble signalling factors

Osteoblasts

Osteocytes

osteoclasts


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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.


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Osteoblasts

Round cells with an organelle rich cytoplasm. Form boneby 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 , interleukin1 & plateletderived growth factor & osteoid.

Expression of these factors by osteoblasts occurs during

bone embryogenesis, maintenance(ex: remodeling) &repair.


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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 forosteoblastdifferentiation

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.


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Osteocytes

Osteocytes are former osteoblasts that have becomeentrapped in bone matrix.

These are relatively inactive cells. Their subduedmetabolic activity is crucial to bone viability & tosustain homeostasis.

The complex processes of homeostasis are regulated byphysiologic interactions among cells, tissues, organs &signaling factors such as harmones & growth factorsthat meticulously titrate intra & extra cellular levels ofcationic & anionic moieties


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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 fromosteocytes & from osteocytes to osteoblasts.


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Osteocytes,osteoblasts & osteoclasts are the

cellular crafts men performing the

managerial roles of calcium regulation &

bone homeostasis, physiological processes

fundamental to modeling & remodeling.


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Osteoclasts

Granulocyticprecursors found in bone marrowenter the circulation as monocytes , and throughasynchronous fusion, produce a multinucleated cellwith an average of 1012 nuclei known asosteoclast. They represent the terminal stage ofdifferenciation of these cells.

Osteoclasts have a ruffled border, possess calcitonin

receptors.

They secrete a lysosomal enzyme, tartrate- resistantacid phosphatase (TRAP),which is also used as a

marker for osteoclast identification.


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Differentiation of osteoclasts

Osteoclasts differentiate from

hematopoietic cells. This pathway

of differentiation is also shared bymacrophages.

GM-CSF (granulocyte monocyte

colony stimulating factor) and M-

CSF (macrophage colony stimulatingfactor) are important in regulating

these shared stages of development.


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Another important discovery ofosteopotegerin

(OPG) or Osteoclastogenesis inhibiting factoe

(OCIF)secreted by osteoblasts and functions to

block the formation of osteoclasts and boneresorption.

SUDA et al isolated an osteoblast membrane bond

molecule called osteoclast differentiation factor

(ODF).ODF was able to induceosteoclastogenesis inbone organ cultures.


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Osteoblast regulates the differentiation of osteoclasts. TheTALK between an osteoblast and osteoclast isaccomplished through an osteoblast membrane bondRANK Ligand (RANKL) (receptor activator of nuclear

factor kB ligand)

In this situation OPG can develop to block RANKL in turnblocking the interaction between RANK and RANKL/ODF

Cytokines (TNF, interleukin-1), prostaglandins E andgrowth factors (TGF-, BMP) are upstream signals whichregulate the OPG/ODF ratio.


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How do osteoclasts work?

Osteoclasts contain large amounts of carbonic anhydrase tofacilitate the conversion of CO2 and H2O to H2CO3. Thedegradation of bone matrix is presumably the result of theactivity of a number of lysosomal enzymes which can degradebone at low pH.

There is a correlation between activation of bone resorptionand acid phosphatase release and oxygen derived free radicalslocalized in ruffled border..

A variety of cathepsins, superoxide dismutase and other lyticenzymes which are produced by the osteoclast are able todegrade collagen at low pH.


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Decreased blood Ca level

parathyroid kidney

parathormone Vitamin D

Bone

Increase in

resorption &release of Ca

Intestine

Increase in

absorption ofCa

Increased blood Ca level

thyroid

calcitonin

Bone

Inhibition of bone

resorption anddeposition of Ca

Normal calcium level


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Tooth Movement

2 types of tooth movements-

Physiologic

Under the effect of force.


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Theories explaining orthodontic

tooth movement-

Pressure tension theory

Biological electricity or bioelectrictheory

Fluid Dynamic Theory


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Why it was rejected?

Baumrind, pointed out a conceptual flaw in it.

He considered the PDL to be a continuous hydrostatic system andsuggested that any force delivered to it would be transmitted equally toall regions accoording to Pascals Law.

He further stated that the presence of fibers in the PDL does not modifythe operation of this law, because of the concomitant existence of acontinuous body of liquefied ground substance.

He recognized that only part of the periodontium where differentialpressures, as mentioned in the pressure-tension hypothesis, can bedeveloped, is solidbone, tooth, and discrete solid fractures of thePDL.


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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 inducemigration of electrons that generate local electric fields. This phenomenon is

calledpiezoelectricity.

Zengo et al concluded that the concave side of orthodontically treated bone is

electronegative and favors osteoblastic activity, whereas the areas of positivityor electrical neutralityconvex surfacesshowed elevated osteoclastic

activity.


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The 2 unusual properties of

piezoelectricity, which seem to notcorrelate well with orthodontic tooth

movement are(1) a quick decay rate

(2) production of an equivalent signal in the

opposite direction upon force removal


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Further, ions in the fluids surrounding the living bone interact withthese electrical fields. These currents of small voltages are called

streaming potentials.

Davidovitch et al suggested recently that piezoelectric potentialsresult 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 isdisplaced) predominate as the interstitial fluid moves.


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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 ananeurysm.


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How is ortho mvmt diff from

physiological TM

Orthodontic tooth movement is uniquelycharacterized by the abrupt creation of compressionand tension regions in the PDL.

Physiological tooth movement is a slow process thatoccurs mainly in the buccal direction into cancellousbone or because of growth into cortical bone. Incontrast, orthodontic tooth movement can occur

rapidly or slowly, depending on the physicalcharacteristics of the applied force, and the size andbiological response of the PDL.


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Biology of tooth movement due to

applied force: Current Concepts


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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 boneremodeling

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.


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Pathway II

Orthodontic forces trigger inflammatory processes inthe involved dental and paradental tissues.

Lymphocytes, monocytes, and macrophages invadethese tissues

The local elevation in prostaglandins and asubsequent increase in cellular cAMP concentrations

increase osteoclast activity. Secreted hydrolyticenzymes, such as collagenase, dissolve themechanically strained ECM.


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Recent model

Recent reports by Jones et al detailed events in bone cells immediately after the application of mechanicalstress.

Osteoblasts respond to physiologic levels of stress- increase in intracellular free calcium andmembrane 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 stressapplication by keeping the mechanosensitve ion channels open and by further activation of proteinkinase 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.


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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++


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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.


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Phospholipids

Mechanical,

hormonal,

pathological,

electrical

Phospholipase A

Arachidonic acid

Leucotrienes

Lipooxygenase pathway

Cyclic peroxide

Cyclooxygenase pathway

PG E PG F


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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 andinduce osteoclast proliferation are-

Interleukin 1

Interleukin-6

Tumor necrosis factor

Granulocyte-macrophage colony stimulating factor

Macrophage colony stimulating factor


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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-Icollagen and matrix synthesis by osteoblasts.

Transforming growth factor (BMP)- induce mesenchymalprogenitors to differentiate into both osteoblasts and chondrocytes

Platelet growth factors


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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 endothelialcells. 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 andgrowth factors, that stimulate PDL and alveolar bone

lining cells to remodel their ECM.


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The PDL is abundantly supplied with 2 kinds of nerve terminals:

Ruffini-like endings & nociceptive endings which change theirstructures in response to external stimuli, such as orthodonticforce.

Mechanoreceptors in the apical half of the dental root have a low

threshold and respond to even minor stretching of the PDL. Incontrast, nociceptors have a high threshold and are activated byheavy forces, tissue injury, and inflammatory mediators.

The mechanoreceptors are silent in physiological conditions but

contain various neuropeptides such as substance P, vasoactiveintestinal polypeptide, and calcitonin gene-related peptide(CGRP) released when strained.


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Increased immunoreactivity (increases PG) of substanceP has been demonstrated in the PDL in the early phasesof tooth movement.

Another neurotransmitter involved in orthodontic toothmovement is CGRP.

Kvinnsland and Kvinnsland localized CGRP in the PDLand the dental pulp after 3 days of molar movement infibroblasts at PDL tension sites.

Saito et al reported finding intense reactivity tovasoactive intestinal polypeptide, in the compressed PDLand in the pulp of moving teeth in cats.


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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 ofintracellular 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


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Pressure/tension-electrical-cell

After an orthodontic force is applied, the initialstep is the detection of a mechanical strain.

Application of small bending force to long bones

result in compression on one side and tension onthe opposite side.

This produces a flow of interstitial fluid throughthe canalicular network, generatingstreaming

potentials and/or fluid shear stress.


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Streaming potentials is the electric potential that developsbetween two components by an electrolyte flowing

between the solid surfaces.

Eg:bone is partially composed of proteoglycans, which areentrapped in a collagen network. Because of the negative

charge of proteoglycans, there is an excess of positive mobileions in the fluid. Such potentials could possibly arise invascular channels, Haversian systems, canaliculi,microporosities of the structure and as a result of the bloodflow and interstitial fluid movement.

Slow decay of signal due to relaxation of fluid flow in thestressed bone.


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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-cellattachment or cell attachment to ECM molecules such ascollagen, fibronectin, laminin etc.

The cytoskeleton (Microtubules, microfilaments,Intermediate filaments) presents a number of possibilitiesfor transducing mechanical forces acting on cells and/ortheir adjacent matrices.


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Many of the extracellular matrixproteins responsible for celladhesion contain a common peptidesequence Arg-Gly-Asp (RGD)

which is essential for the cell-binding properties of theseproteins.


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Classically, the second messengerassociated with mechanical forcetransduction isAdenosine 35 cyclicmonophosphate (cAMP).

It was first identified in 1960 bySUTHERLAND et al-

When liver slices were exposed toadrenalin, free glucose appeared underthese conditions and it was postulated that

adrenalin was acting as the firstmessenger, binding to a receptor andstimulating the production of a powerfulchemical second messenger.


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The G proteins act as intermediariesbetween receptors and intermediaryenzymes.

The three important G proteins

pertinent to orthodontic toothmovement are

Gs- the stimulatory regulator of adenylatecyclase

Gi- the inhibitory regulator of adenylatecyclase

Gp-the stimulatory regulator of the PIpathway.


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Early gene expression

In the nucleus different second

messengers account for the

differential pattern ofimmediate

early gene expression (I EG).

IEGs are among the earliest

responses that can be measured at

the transcription level.


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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


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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.


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Signal input-genetic output

Cytoplasmic signaling proteins such

as sonic hedgehog, TGF-

superfamily and many transcriptionfactors and ions reach the nuclear

matrix and then genome- resulting in

enhanced or suppressed gene

expression.


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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 andECM.

This process is continuous.


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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.

D i i


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Drug interaction

Pharmacological agents manipulate toothmovement in both directions.

Factors that enhance tooth movement are vitamin

D & direct injection of prostaglandin intoperiodontal ligament.

Drugs that inhibit tooth movement areBisphosphonates used in the treatment of

osteoporosis. Ex : alendronateProstaglandin inhibitors. Ex : NSAIDS,

Corticosteroids , Parathyroid, Thyroxin.

Osteoporosis is a problem particularlyd i l f l b i


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encountered in post menopausal females but isassociated with aging in both sexes.

Estrogen therapy , which is used frequently toprevent loss of bone in older women , has noimpact on orthodontic treatment.

Bisphosphonates are synthetic analogues of

pyrophosphates that bind to hydroxyapatite inbone & act as specific inhibitors of osteoclastmediated bone resorption.

If orthodontic treatment is necessary in olderpatients it is better to switch over to estrogen atleast temporarily Or use Raloxifene (estrogenrec modulator).

Bartzela et al Am J Orthod Dentofac Orthop 2009;135:16-26


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Dietary calcium : Adults require 1000 to 1300 mg ofcalcium in their daily diet.

The effect of dietary supplemental calcium on OTM wasstudied in dogs that were fed low- or high-calcium diets for 10weeks before orthodontic premolar movement was induced witha force of 100 N for 12 weeks.

From 8 weeks on, the low-calcium regimen led to asignificantly higher rate of OTM than did the high calcium diet.

These data support bone turnover studies showing increases inthe number of osteoclasts and osteoblasts in dogs with a low-

calcium diet. The final outcome was increased bone remodelingphenotype in which excessive bone resorption prevailed overdeposition.

Bartzela et al Am J Orthod Dentofac Orthop 2009;135:16-26

P l di E i hibi


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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.


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Kehoe MJ et al, 1996 suggested Misoprostol (producesanalgesia 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 ofPGe1.

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 minimuminhibition of PG, the treatment time can be reduced.


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bone metab and tooth movement

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