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1
UNIVERSITA’DEGLISTUDIDIPARMA
Dottoratodiricercain
SCIENZEMEDICHECicloXXXI
Coordinatore:Chiar.moProf.CARLOFERRARITutor:Chiar.moProf.GIOVANNIPASSERI
OSTEOPOROSISANDJAWBONES:
DENTALPANORAMICRADIOGRAPHSTOSCREENFORPOST-
MENOPAUSALOSTEOPOROSISANDCORRELATIONBETWEEN
PERIODONTALSTATUSANDBMD
OSTEOPOROSIEOSSAMASCELLARI:
UTILIZZODIRADIOGRAFIEPANORAMICHEPERESEGUIRESCREENINGDI
OSTEOPOROSIPOSTMENOPAUSALEECORRELAZIONETRASTATUS
PARODONTALEEBMD
Dottorando:FEDERICORIVARA
ANNI2015-2018
2
Aimieigenitori,
MarioeElena
“Generapiùspessoconfidenzal'ignoranzadi
quantononfaccialaconoscenza”
-CharlesRobertDarwin-
3
ABSTRACT
Osteoporosis is themostcommonchronicbonediseasethatmay interferewithbone
metabolism. This PhD thesis aimed to investigate the effect of osteoporosis on the
jawbones, in particular the relationship between the systemic bone density and the
jawboneconditions.
Firstly, a literature reviewon the effect of osteoporosis on the jawbones and on the
accuracyofpanoramicmorphometricindicestoscreenforreducedbonemineraldensity
werepresented.Despitethepoorqualityoftheavailablestudies,ourdatashowedthat
acorrelationbetween jawboneandskeletaldensity inosteoporoticpatientsmightbe
expected. A second critical review on the correlation between osteoporosis and
periodontalconditionofthepatientsweredone.Similarlytotheaforementionedreview,
despitethequalityofthepapers,acorrelationhasbeensuggested.
Secondly, a clinical trial to compare BMD and jawbones condition in terms of bone
densityandperiodontalstatuswerepresented.Seventypatients,thatweredoneaDxa
scan to investigate the BMD in the previous year, were enrolled and a complete
periodontaldatacollectionaswellasastandardizedortopantomographyweredone.T-
scoresfromtheDxascanwereusedtoclassifypatientsinhealthyorosteoporoticand
specificmorphometricindicesweremeasuredontheOPG.
Finally, a statistical analysis was performed and a significant correlation was found
betweenBMDandacombinationoftwoindices:thequalitative“Klemettiindex”andthe
quantitative“mandibularcorticalwidth”.Theaccuracyofthese indiceswascalculated
andthecombinationshowedahighpredictivevalueindetectinghealthypatients.The
statisticalanalysisappliedtotheperiodontalindicesshowedthatpocketprobingdepth
³ 5 mm and attachment level 3-4 mm were correlated to healthy condition. These
controversial results may be related to the limitations of the study that include the
reducedsamplesizeandtherecruitmentcentre.
4
RIASSUNTO
L’osteoporosi è la più comune patologia cronica che influenza il metabolismo osseo.
Questatesididottoratomiraainvestigareglieffettidell’osteoporosisulleossamascellari
einparticolarelarelazionecheintercorretradensitàosseasistemicaelecondizionidel
cavoorale.
Inizialmente, è stata effettuata una revisione della letteratura circa gli effetti
dell’osteoporosi sulle ossa mascellari e riguardo all’accuratezza di specifici indici
morfometricipereffettuarescreeningdiridottadensitàosseaminerale.Nonostantela
modestaqualitàdeglistudiadisposizione,idatidimostranounacorrelazionetradensità
osseasistemicaemascellareneipazientiosteoporotici.Allostessomodo,èstataeseguita
unasecondarevisionecriticasullacorrelazionetraosteoporosiemalattiaparodontale.
Ancheinquestocasounacorrelazioneèstatasuggerita.
Secondariamente,èstatoeseguitountrialclinicopercomparareBMDecondizionidelle
ossamascellariinterminididensitàosseaestatusparodontale.Sonostatireclutati70
pazienticheavevanoeseguitounadensitometriaDxanell’ultimoannoesonostativisitati
per ottenere le informazioni relative allo stato parodontale oltre ad una
ortopantomografiastandardizzata.Specificiindicimorfometricisonostatimisuratisulla
radiografiapanoramica.
Inultimo,unacorrelazionestatisticamentesignificativaèstatadimostratatrailBMDe
unacombinazionedidueindicipanoramici:ilqualitativo“Klemettiindex”eilquantitativo
“mandibular cortical widht”. È stata calcolata l’accuratezza di questi indici e la
combinazionedeiduehamostratounaltovalorepredittivonell’identificarepazientisani.
L’analisi statistica applicata agli indici parodontali ha mostrato una correlazione di
profonditàdisondaggiomaggioredi5mmeunaperditadiattaccoclinicodi3-4mmcon
lacondizionedipazientesano.Questirisultaticontroversipossonoesserecollegatialle
limitazioni dello studio come la numerosità del campioneo il bias legato al centro di
reclutamento.
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TABLEOFCONTENTS
ABSTRACT
RIASSUNTO
TABLEOFTABLES
TABLEOFFIGURES
1 INTRODUCTION............................................................................................................12
1.1 OSTEOPOROSIS.........................................................................................................13
1.1.1 DEFINITION.......................................................................................................13
1.1.2 DIAGNOSIS........................................................................................................13
1.1.3 CLASSIFICATION................................................................................................15
1.1.4 EPIDEMIOLOGY................................................................................................17
1.1.4.1 EUROPE...................................................................................................................................17
1.1.4.2 ITALY........................................................................................................................................18
1.1.5 PATHOGENESIS.................................................................................................19
1.1.6 RISKFACTORS...................................................................................................22
1.2 PERIODONTALDISEASE.............................................................................................23
1.2.1 DEFINITION.......................................................................................................23
1.2.1.1 ANATOMYOFTHEPERIODONTALTISSUES.............................................................................23
1.2.1.1.1 Gingiva–macroscopicanatomy..........................................................................24
1.2.1.1.2 Gingiva–microscopicanatomy...........................................................................25
1.2.1.1.3 Periodontalligament...........................................................................................27
1.2.1.1.4 Rootcementum...................................................................................................28
1.2.1.1.5 Alveolarbone......................................................................................................29
1.2.1.1.6 Bloodsupplyoftheperiodontium.......................................................................30
1.2.1.1.7 Lymphaticsystemoftheperiodontium..............................................................31
1.2.1.1.8 Nervesoftheperiodontium................................................................................33
1.2.1.2 FEATURESOFPERIODONTALDISEASE....................................................................................34
1.2.1.3 EXAMINATIONMETHODS.......................................................................................................35
1.2.1.3.1 Inflammationassessment....................................................................................36
1.2.1.3.2 Periodontalsupportassessment.........................................................................37
1.2.1.3.3 Radiographicevaluation......................................................................................40
1.2.2 DIAGNOSISOFPERIODONTALDISEASE............................................................40
1.2.3 CLASSIFICATIONOFPERIODONTALDISEASE....................................................41
6
1.2.3.1 GINGIVALDISEASE...................................................................................................................42
1.2.3.2 CHRONICPERIODONTITIS........................................................................................................43
1.2.3.3 AGGRESSIVEPERIODONTITIS..................................................................................................44
1.2.3.4 PERIODONTALDISEASEASARISKFORSYSTEMICDISEASE.....................................................45
1.2.3.5 NECROTIZINGPERIODONTALDISEASE....................................................................................46
1.2.3.6 ABSCESSESOFTHEPERIODONTIUM.......................................................................................47
1.2.3.7 PERIODONTITISASSOCIATEDWITHENDODONTICLESIONS...................................................47
1.2.4 EPIDEMIOLOGYOFPERIODONTALDISEASE.....................................................48
1.2.4.1 Prevalenceofperiodontaldisease..........................................................................................48
1.2.5 ETIOPATHOGENESISOFPERIODONTALDISEASE..............................................50
1.2.5.1 MICROBIALETIOLOGY.............................................................................................................50
1.2.5.1.1 Dentalplaqueandthebiofilmconcept...............................................................50
1.2.5.1.2 Plaque-formationmechanism.............................................................................51
1.2.5.1.3 Dentalcalculus....................................................................................................53
1.2.5.1.4 Periodontalpathogens........................................................................................53
1.2.5.1.5 Themicrobialcomplexes.....................................................................................55
1.2.5.2 PATHOGENESISOFPERIODONTALDISEASE............................................................................57
1.2.6 RISKFACTORSFORPERIODONTITIS.................................................................61
1.2.6.1 NON-MODIFIABLERISKFACTORS............................................................................................62
1.2.6.1.1 Age.......................................................................................................................62
1.2.6.1.2 GenePolymorphisms...........................................................................................62
1.2.6.2 MODIFIABLEENVIRONMENTAL,AQUIREDANDBEHAVIORALFACTORS................................63
1.2.6.2.1 Specificmicrobiota..............................................................................................63
1.2.6.2.2 Smoking...............................................................................................................63
1.2.6.2.3 DiabetesMellitus.................................................................................................64
1.2.6.2.4 Obesity................................................................................................................65
1.2.7 PERIODONTITISANDOSTEOPOROSIS..............................................................65
1.3 OSTEOPOROSISANDJAWBONES..............................................................................67
1.3.1 SYSTEMICANDJAWBONELOSS......................................................................67
2 HYPOTHESISANDAIMOFTHERESEARCH….................................................................70
2.1 BACKGROUNDANDHYPOTHESIS..............................................................................71
2.2 AIMOFTHESTUDY....................................................................................................72
2.2.1 PRELIMINARYLITERATUREREVIEWS................................................................72
2.2.2 PRIMARYOUTCOMES.......................................................................................72
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2.2.3 SECONDARYOUTCOMES..................................................................................73
3 LITERATUREREVIEWS…………………………………...............................................................74
3.1 SYSTEMICMINERALBONEDENSITYANDJAWBONES...............................................75
3.2 PERIODONTITISANDOSTEOPOROSIS.......................................................................82
4 CLINICALSTUDYDESIGN…………………………………………………………………………………………….86
4.1 OVERALLSTUDYPLAN...............................................................................................87
4.2 INCLUSIONCRITERIA.................................................................................................88
4.3 EXCLUSIONCRITERIA.................................................................................................88
4.4 STUDYVISITS.............................................................................................................89
4.5 STUDYMEASUREMENTS...........................................................................................89
4.5.1 Dentalpanoramicradiographs.........................................................................89
4.5.2 PeriodontalExaminations................................................................................90
4.6 STATISTICALPROCEDURES........................................................................................91
4.6.1 Samplesizeestimation.....................................................................................91
4.6.2 Statisticalmethod............................................................................................91
5 RESULTS…………………………………………………….................................................................92
5.1 GENERALANDDEMOGRAPHICDATA........................................................................93
5.2 OPGINDICESANDOSTEOPOROSISDATA..................................................................93
5.3 PERIODONTALDATA.................................................................................................98
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6 DISCUSSION…………………………………………….................................................................116
6.1 PANORAMICMORPHOMETRICINDICESFORDETECTINGREDUCEDBMD..............117
6.2 PERIODONTALEXAMINATIONDATAANDBMD......................................................120
6.3 SAMPLESIZEANDRECRUITMENTPATTERN............................................................123
6.4 CONFUNDINGFACTORS..........................................................................................124
6.4.1 Age.................................................................................................................124
6.4.2 Smoke.............................................................................................................124
6.4.3 Medications....................................................................................................125
7 CONCLUSIONS………………………………………………………………………………………………………….126
8 REFERENCES…………………………………………….................................................................129
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TABLEOFTABLES
Tab.1WHOOperationalDefinitionofOsteoporosisbasedonBMDmeasurement....................13
Tab.2Conditions,diseasesandmedicationsthatcauseorcontributetoosteoporosisand
fractures(from(Clinician’sguidetopreventionandtreatmentofosteoporosis2014).....16
Tab.3Searchstrategy....................................................................................................................76
Tab.4Papersincludedinthereview(2014-2018)........................................................................81
Tab.5Searchstrategy....................................................................................................................82
Tab.6Papersincludedinthereview.............................................................................................85
Tab.7Klemettiindexaccuracy.......................................................................................................95
Tab.8MCWROC-areaunderthecurvedata...............................................................................95
Tab.9Mandibularcorticalwidthindexaccuracy..........................................................................95
Tab.10AccuracyofKIinassociationwithMCWwhenrelatedtot-scores..................................97
Tab.11Accuracyofpanoramicmandibularindex,Mentalratio,antegonialindexandgonial
index.......................................................................................................................................98
Tab.12Pocketprobingdepth(PPD)statisticalanalysis:medianand1stquartile.......................99
Tab.13Clinicalattachmentloss(CAL)statisticalanalysis:averageandstandarddeviation.....101
Tab.14Toothlossstatisticalanalysis:medianand1stquartile..................................................102
Tab.15Recession(REC)andtoothmobility:medianand1stquartile.......................................102
Tab.16Demographicdatacollection.Age,etnicity,smoke,height,weight,bmiandmedications
havebeenrecorded.............................................................................................................105
Tab.17T-scoresanddiagnosticclassificationinhealty,osteopenicandosteoporotic.Healthy
andosteopenicpatientshavebeenclassifiedas"0"andosteoporoticas"1"..................108
Tab.18Panoramicmorphometricindices:Klemettiindex,mandibularcorticalwidth(MCW),
panoramicmandibularindex(PMI),mentalratio(M/M),antegonialindex(AI),gonialindex
(GI)........................................................................................................................................111
Tab.19Periodontaldatacollection:Number/percentageofteethloss,percentageofteethwith
augmentedmobility,furcationinvolvement,percentageofsiteswithpockedprobing
depth(PPD),recession(REC)andclinicalattachmentlevel(AL)........................................115
10
TABLEOFFIGURES
Fig.1Bonemassmodificationandbehaviorovertime................................................................20
Fig.2Bonemassresorptionrateinwomen(left)andmen(right)...............................................21
Fig.3Theperiodontium:gingiva(G),peridontalligament(PL),rootcementum(RC),alveolarbone
proper(APB),alveolarprocess(AP)......................................................................................23
Fig.4Threepartsofthegigngiva:freegingiva(FG)thatfinishesatthecemento-enameljunction
(CEJ),interdentalgingiva,attachedgingiva(AG).Thedemarcationlineisthemuco-gingival
junction(MCJ)........................................................................................................................25
Fig.5Theschematicdrawingofthehistologicsectiondescribingthecompositionofthegingiva
andthecontactareabetweenthegingivaandtheenamel.................................................27
Fig.6Schematicdrawofperiodontalligamentwithfibersorientation:alveolarboneproper(ABP),
rootcementum(RC),alveolarcrestfibers(ACF),horizontalfibers(HF),obliquefibers(OF)
andapicalfibers(APF)...........................................................................................................28
Fig.7Vertical sections throughvarious regionsofmandibulardentition.Thebonewall at the
buccal(B)andlingual(L)aspect............................................................................................30
Fig. 8 The schematic draw of the blood supply to the teeth and the periodontal tissues: the
intraseptalartery(B),periodontalligamentartery(A)andsupraperiostealvessels(C).....31
Fig.9Schematicdrawof the lymphaticsystem: Jagulodigastricnode (JD),deepcervicalnodes
(CP),sub-mandibularnodes(SMA)andsubmentalnodes(SME)........................................32
Fig.9Schematicdrawoftheinnervationofthejaws...................................................................34
Fig.11Probingdepthinacompromised(left)andhealty(right)peridontalpocket...................35
Fig.12Differentdegreesofinflammationinaperiodontaltissue................................................37
Fig.12Furcationsounding:TheNabersprobeentersthefurcationaccordingtohorizontalthe
bonedestruction(F1,F2,F3,left).Thegradingofverticalboneresorption:AifF<3mm,Bif
3mm<F<6mm,CifF>6mm(right)..........................................................................................39
Fig.14Toothmobilityassessment.................................................................................................39
Fig.15Completeapico-periapicalstatus.......................................................................................40
Fig.16Schematicrepresentationofthedifferentstagesintheformationofdentalbiofilms.a)
Pellicleformsonacleantoothsurface.Bacteriaaretransportedpassivelytothesurface.b)
attachment becomes more permanent through specific stereochimical molecular
11
interactionsbetweenbacteriumandpellicleandsecondarycolonizersattachtothealready
attachedprimarycolonizers.C)growthresultsinbiofilmmaturation................................52
Fig.17a)Associationamongsubgingivalspecies.Thedifferentcolorsinthepyramidrepresent
different bacterial complexes which are frequently detected in association with one
another. The base of the pyramid represents the early stage of plaque development,
whereas the apex contains those organisms thought to be the last species to become
establishedinthemicrobiota.b)PiechartsofthemeanpercentageDNAcountofmicrobial
groupsinsupragingivalplaque..............................................................................................57
Fig. 18 Classical model of Page & Kornman, showing host–microbeinteractions in the
pathogenesisofperiodontitis.LPS, lipopolysaccharide;MMPs,matrixmetalloproteinases;
PMNs,polymorphonuclearneutrophils................................................................................58
Fig.19Contemporarymodelofhost–microbeinteractionsinthepathogenesisofperiodontitis,
inwhich the host response drives an incipient dysbiosis (gingivitis). If the biofilm is not
disrupted/removed, frank dysbiosis results and perpetuates a chronic nonresolving and
destructive inflammation. DAMPs, damage-associated molecular patterns; fMLP, N-
formylmethionyl-leucyl-phenylalanine; GCF, gingival crevicular fluid; LPS,
lipopolysaccharide; MMPs, matrix metalloproteinases; PMNs, polymorphonuclear
neutrophils.............................................................................................................................60
Fig.20A)Quantitativeindices:MCW=b;PMI=b/a;GI=d;AI=e;M/M=c/a...............................69
Fig.21Numberofarticleperyearfrom1949to2018..................................................................83
Fig.22MandibularcorticalwidthROCcurve.................................................................................96
Fig.23PMI,M/M,AI,GIROCcurve...............................................................................................97
Fig.24ScatterplotrepresentingthedistributionofthesiteswithaPPD³5mminrespectoft-
scoresasacontinuousvariable...........................................................................................100
Fig.25ScatterplotrepresentingthedistributionofthesiteswithaAL3-4mminrespectoft-
scoresasacontinuousvariable...........................................................................................101
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1 INTRODUCTION
13
1.1 OSTEOPOROSIS
1.1.1 DEFINITIONOsteoporosis is a “systemic skeletal disease characterized by low bone mass and
microarchitectural deterioration of bone tissue, with a consequent increase in bone
fragilityandsusceptibilitytofracture”(1).Itisconsideredasa“silent”disease,whichis
often diagnosed belatedly, since most of the times it is not associated with clinical
manifestations until a fracture occurs (2). Osteoporotic fractures normally involve
weight-bearing portions of the skeleton such as spine, proximal femur andwrist and
developasaconsequenceoffallsorlow-impacttraumaorevenspontaneously.(3).
1.1.2 DIAGNOSIS
The diagnosis of densitometric osteoporosis is related to the measurement of bone
mineraldensity(BMD),whichiscommonlydefinedinrelationtoaT-orZ-score,bothof
whichareunitsofstandarddeviation(SD).TheT-scoredescribesthenumberofSDsby
whichtheBMDrecordedinthesinglepatientdiffersfromthemeanvalueexpectedin
youngwhitehealthyfemales,whilsttheZ-scoredefinesthenumberofSDsbywhichthe
BMDrecordeddiffersfromthemeanvalueexpectedforpeopleofthesameageandsex.
TheWorldHealthOrganization (WHO)definesosteoporosis as a T score2.5ormore
belowtheyoung femaleadultmean (4-6),whileosteopeniacorresponds toaTscore
between-1and-2.5.Tab.1
Classification Tscore
Normal ≥-1
Osteopenia -1<T>2.5
Osteoporosis ≤-2.5
Severeorestablishedosteoporosis ≤-2.5+oneormorefractures
Tab.1WHOOperationalDefinitionofOsteoporosisbasedonBMDmeasurement
14
TheNationalHealthandNutritionExaminationSurvey(NHANES)IIIdatabaseoffemoral
neckBMDmeasurementsinwhitewomenaged20-29years(7)hasbeenrecommended
byWHO, IOF, ISCD and NOF as the reference database for calculating T-scores and,
therefore,thefemoralneckhasbecomethereferencesiteforosteoporosisdiagnosis(8).
Some guidelines promoted the evaluation of BMD at both hip and lumbar spine and
suggestedtoconsiderthelowerofthetwovaluestoplaceadiagnosisofosteoporosis
(9), although the use of multiple sites does not seem to improve the prediction of
fractures(10,11)
SeveraltechniqueshavebeenadoptedforBMDmeasurement(singleanddualphoton
absorptiometry,quantitativecomputedtomography,quantitativeultrasound,etc),but
themostvalidatedoneisdualenergyX-rayabsorptiometry(DXA),owingtothesensitivity
ofX-raysabsorptionto thebonecalciumcontentandthe trivialamountof radiations
delivered (12).When it is impossible tomeasure/interpretBMDat thehipor lumbar
spine, it is advisable to consider the 33% distal radius (one third of the radius) as
referencesite(13).
Althoughthehipandlumbarspinearebyfarthemostwidelyusedsitesforthediagnosis
of osteoporosis, other sites are sometimes evaluated to measure BMD, such as the
calcaneus, the phalanx and the radius. Several studies have also tried to measure
jawbonemineraldensityandtocorrelateitwiththedensityatotherskeletalsites(see
chapter1.3).
ScreeningprogramsforosteoporosisdifferbetweenCountries.TheWHOreports that
thereisindirectevidencesupportingscreeningprogramsinwomenaged65orolder,but
nodirectevidencesupportswidespreadscreeningprograms(14)andoverallthisideais
not feasible incountry like Italydueto the largenumberofpotentialpatientandthe
limitsofnationalhealthcaresystem.TheNationalOsteoporosisFoundation(NOF)and
International Society for Clinical Densitometry (ISCD) (15) recommend bone
densitometryfor:
- womenaged65andolderandmenaged70andolder
15
- post-menopausalwomenandmenolderthan50yearsbasedontheriskfactor
profile
- post-menopausalwomen andmenolder than 50 yearswhohad an adult age
fracture,withtheaimtodiagnoseanddeterminethedegreeofosteoporosis.
Adifferent approach is suggestedby theUKNational Institute forHealth andClinical
Excellence (NICE) (https://www.nice.org.uk/guidance/cg146), which recommends the
following:
- donotroutinelymeasureBMDtoassessfractureriskwithoutpriorassessingit
withFracturedRiskAssessment(FRAX)toolorQFracture
- considerfractureriskassessmentinallwomenaged65andolderandmenaged
75andolder
- considerfractureriskassessmentinwomenagedunder65yearsandmenaged
under75yearsinthepresenceofriskfactors
- donotroutinelyassesstheriskinpeopleyoungerthan50years,unlesstheyhave
majorriskfactors
- followingriskassessmentwithFRAX(withoutaBMDvalue)orQFracture,consider
measuringBMDwithDXA in peoplewhose fracture risk is in the regionof an
intervention threshold foraproposed treatment,and recalculateabsolute risk
usingFRAXwiththeBMDvalue.
InItaly,theapproachconsiderstheBMDevaluationforwomenandmenaged6570and
olderorinwomenandmenagedunder65inthepresenceofriskfactors
1.1.3 CLASSIFICATION
Traditionally,twotypesofosteoporosishavebeendistinguished:primaryandsecondary
osteoporosis:
- Primaryosteoporosis isaconditionthatdoesnotdevelopasaconsequenceof
concomitantdiseases and includespost-menopausal osteoporosis (type1) and
senileosteoporosis(type2).
16
Secondaryosteoporosis iscausedbycertainconcomitantdiseasesormedicationsthat
affectbonemetabolismandbonemineraldensity.Tab.2
Tab.2Conditions,diseasesandmedicationsthatcauseorcontributetoosteoporosisandfractures(from(Clinician’s
guidetopreventionandtreatmentofosteoporosis2014).
However,thisdistinctionwasmeaningfulwhenlittlewasknownaboutosteoporosisand
mostofthecasesweredefinedas“primary”simplybecausetheunderlyingcauseswere
unknown.Nowadays,thisdistinctionisconsideredsimplisticandnolongersatisfactory
HypogonadalstatesAndrogeninsensitivity Anorexianervosa AthleticamenorrheaHyperprolactinemia Panhypopituitarism Prematuremenopause(<40yrs)EndocrinedisordersCentralobesity Cushing’ssyndrome Diabetesmellitus(type1&2)Hyperparathyroidism Thyrotoxicosis Gastrointestinaldisorders
Celiacdisease Gastricbypass GastrointestinalsurgeryInflammatoryboweldisease Malabsorption PancreaticdiseasePrimarybiliarycirrhosis HematologicdisordersHaemophilia Leukaemiaandlymphomas MonoclonalgammopathiesMultiplemyeloma Sicklecelldisease SystemicmastocytosisThalassemia RheumatologicandimmunediseasesAnkylosingspondylitis OtherrheumaticandautoimmunediseasesRheumatoidarthritis Systemiclupus NeurologicalandmusculoskeletalriskfactorsEpilepsy Multiplesclerosis MusculardystrophyParkinson’sdisease Spinalcordinjury StrokeMiscellaneousconditionsanddiseasesAIDS/HIV Alcoholism AmyloidosisChronicmetabolicacidosis Chronicobstructivelungdisease CongestiveheartfailureDepression Endstagerenaldisease HypercalciuriaIdiopathicscoliosis Post-transplantbonedisease SarcoidosisWeightloss MedicationsAluminium(inantacids) Anticoagulants(heparin) AnticonvulsantsAromataseinhibitors Barbiturates CancerchemotherapeuticdrugsDepo-medroxyprogesterone(premenopausalcontraception)
Glucocorticoids (≥5 mg/dprednisoneorequivalentfor≥3months)
GnRH (Gonodotropin releasinghormone)agonists
Lithium Cyclosporine A andtacrolimus
Methotrexate Parentalnutrition
Protonpumpsinhibitors Selective serotonin reuptakeinhibitors
Tamoxifen(premenopausaluse)
Thiazolidinediones (such asActos®andAvandia®)
Thyroidhormones(inexcess)
17
(16).Asignificativeamountofthecasesofosteoporosis,especiallyinmales,cannowbe
ascribedtodifferentriskfactors(suchasoestrogendeficiency,corticosteroidtherapyor
hypogonadism)actingatdifferentlevelsincausingboneloss(16).Moreover,in1998the
type1and2ofprimaryosteoporosiswerereviewedandsincethenthe“unitarymodel
of osteoporosis in postmenopausal women and ageing men” has been applied (17).
Accordingtothismodel,oestrogendeficiencyistheleadingcauseofbonelossinwomen
butgivesalsoamajorcontributionintheslowandcontinuousbonelossexperiencedalso
byelderlymen(18).
1.1.4 EPIDEMIOLOGY
1.1.4.1 EUROPE
In2010,itwasestimatedthatosteoporosishadaprevalenceof27.6millioninEurope
(22millionwomenand5.6millionmen),with3.5millionnewfragilityfracturesrecorded
and related to osteoporosis. These data are expected to significantly increase in the
future,owingtopopulationgrowthandageing(19).Theprevalenceofosteoporosisis
the highest in Whites (or Caucasians) and the lowest in US Blacks, while Mexican-
Americans fall in between the two groups (16). Approximately one in two Caucasian
womenandoneinfivemenareexpectedtoexperienceanosteoporosis-relatedfracture
withintheirlifetime(20).
Thesitesmosttypicallyaffectedbyosteoporoticfracturesarevertebralbodies,proximal
femur, proximal homerus and distal radius (19). The hip (proximal femur) fracture is
consideredthemostseriousone,sinceitalmostalwaysrequireshospitalizationanditis
associatedwithahighmorbidity(60%ofpatientsshowdifficultiesinatleastoneessential
dailylifeactivityafteroneyear(21)andhighmortality(24%ofpatientsdiewithinthe
first year (22). Osteoporosis-related fractures have been related to more disability-
adjustedlife-years(DALYs)lostthananytypeofcancer,withtheexceptionoflungcancer
and account for 0.83% of the worldwide burden associated with non-communicable
diseases (23). In 2010 estimated the economic cost related to osteoporotic fracture
18
treatment,long-termcareandpharmaceuticalpreventioninEuropeequivalentto€26
billions,€11billionsand€2billions,respectively.
1.1.4.2 ITALY
In a 2013 country-specific report of the ministry of health on epidemiology of the
osteoporosis,theItalianpopulationatriskofosteoporosiswasconsideredtoincludemen
andwomen≥50years.Thenumberofmenandwomen≥50yearsofageamountedto
10,791,000and12,997,000respectivelyinItalyin2010.
Inthepopulationatrisk,thenumberofindividualswithosteoporosis—asdefinedbythe
WHOdiagnosticcriteria—wasestimatedat3,790,000.Thenumberofincidentfractures
in 2010 was estimated at 465,000. Incident hip, clinical spine, forearm and “other”
fractureswereestimatedat91,000,71,000,72,000and232,000respectively.69%of
fracturesoccurred inwomen. In thepopulationover 50 years of age, thenumberof
individualswithhipandvertebralfracturesthatoccurredbefore2010wasestimatedat
517,000and539,000respectively.Moreover,thenumberofcausallyrelateddeathsin
2010was estimated at 5,476 and, overall, approximately 53%of deaths occurred in
women,confirmingtherelativemoreelevatedriskinosteoporoticmales.Regardingthe
economicincidenceinItaly,thecostofosteoporosisin2010wasconsideredtoconsist
ofthreecomponents:
- costoffracturesthatoccurredin2010(“firstyearcosts”)
- costoffracturessustainedpriortoyear2010butwhichstillincurredcostsin2010
(“long-termdisabilitycost”)
- cost of pharmacological fracture prevention including administration and
monitoringcosts(“pharmacologicalfracturepreventioncosts”).
The cost of osteoporosis in 2010 was estimated at € 7,032 million. First year costs,
subsequent year costs and pharmacological fracture prevention costs amounted to €
4,269million,€2,402millionand€361millionrespectively.
19
Accordingtothisreport,thepopulationabove50yearsofageisexpectedtoincrease
from23.8millionin2010to29.2millionin2025,correspondingtoanincreaseof23%.
Thetotalnumberoffractureswasestimatedtorisefrom465,000in2010to598,000in
2025,correspondingtoanincreaseof28%.
1.1.5 PATHOGENESIS
Itisintuitivetounderstandthatwheneveradiseasecausesboneloss,thismustbedue
toanimbalanceinbonemetabolism,betweentheanabolicprocessofboneformation
and the catabolic process of bone resorption. Following an increase throughout the
puberty,bonemasspeaksclosetotheendofthethirddecadeoflife,afterwhichaslow
and progressive phase of bone loss begins. Studies utilising quantitative computed
tomography(QCT)havedemonstratedadifferentbehaviourofcorticalandtrabecular
bonedensityacrosstime(Fig.1).ThecorticalBMDtendstoremainstableuntilmid-life
andstartsdecreasingsignificantlywithageing(inassociationwithsexsteroiddeficiency).
Onthecontrary,trabecularBMDbeginstoslowlydecreasealreadyduringadulthoodand
continues throughout life, thus suggestinganoestrogen-independentcomponent (24,
25).
20
Fig.1Bonemassmodificationandbehaviorovertime
Themostcriticaleventforwomen’sbonemassisundoubtedlythecessationofovarian
functionatmenopause.Typically,atmenopausethereisaninitialrapidphaseofbone
loss(2-4%ofBMDratedeclineayear)thatlastsforthefirst7-10years.Duringthistime,
BMDmayreduceinsomewomenupto25-33%,ifnotpreventedbyaspecifictherapy
abletoreducebone loss, (ie,bisphosphonates,anti rank-LAb,oestrogenorhormone
replacementtherapy).Afterwards,bonelosscontinuesataslowerpace(approximately
1-2%BMDdeclineayear)fortheremaininglifetime(17,26-29).Intheearlyphase,BMD
loss involves mainly the cancellous bone and it seems to be triggered by oestrogen
withdrawaland itssubsequenteffectsonboneturnoverandcalciumlevels. Inelderly
people,bonelosscontinuesataslowerrateandaffectsboththetrabecularandcortical
bone(30)(Fig.2). It isworthtorememberthatthecancellousbone is thefirstoneto
respond to anymetabolic alteration, owing to its higher surface-to-volume ratio and
denservascularization(31).
21
Fig.2Bonemassresorptionrateinwomen(left)andmen(right)
Oestrogen deficiency has a multiple effect on bone metabolism. Oestrogens act by
bindingtohighaffinityreceptors(ERαandERβ)andareabletodirectlymodulatethe
activityofosteoblastsandosteoclasts(32,33),buttheycanalsoindirectlyinfluencebone
physiology,owingtothepresenceofoestrogenreceptorsonothercells(suchasstromal
cellsandcellsoftheimmunesystem)(30).However,theriseinboneformingcellsdoes
notcompensatetheriseinboneresorptioncellsandthisimbalanceresultsinboneloss
(34).
Another important function of oestrogen is to modulate the production of pro-
inflammatorycytokines,suchasinterleukin1and6(IL-1,IL-6)andtumornecrosisfactor
(TNF)-alpha (35, 36). Oestrogen withdrawal is therefore associated with a pro-
inflammatory status that stimulates bone resorption (37). There is some evidence,
however,thatthismechanismofincreasedbonelosscouldbelimitedonlytothefirst
earlystageaftermenopause(38).Ithasbeenarguedthatoestrogenwithdrawalcanalso
increase the sensitivity of bone to parathyroid hormone (PTH), intensifying the bone
resorptioneffect(39). Thisphenomenonofsecondaryhyperparathyroidismiscommon
tobothelderlymenandwomenandseemsoneofthekeymechanismsofthesecondary
slowphaseofboneloss(17).
Another key element in the establishment of secondary hyperparathyroidism in aged
peopleisvitaminDdeficiency,sinceVitaminDplaysanpivotalroleinmaintainingthe
22
appropriate calcium and phosphorus serum levels by stimulating intestinal calcium
absorption (calcemic action), thus indirectly regulating bone mineralization. The
biologically active form of Vitamin D, 1,25(OH)2D3, was demonstrated to be a key
modulatorofosteoblastandosteoclastactivity(40,41).
Moreover,numerousstudieshaveshownthatageing isassociatedwithasignificantly
reduceddifferentiation, activationand functionof osteogenic cells (42).Mesenchymal
stem cells of bone marrow tend to differentiate more into adipocytes rather than
osteoblastlineage,andthisimpairedosteoblastdevelopment/activationcontributesto
bonelossespeciallyintheelderly(43,44).
1.1.6 RISKFACTORS
Severalmodifiableandnon-modifiableriskfactorshavebeenrelatedtoosteoporosisand
arearelevantpartofthepathophysiologicalmechanismsofthesediseases.Amongthe
modifiableones themost importantandmoredefinedare: lowbodymass indexand
anorexia(BMI),alcoholconsumption,poornutrition(notonlyinsufficientdietarycalcium
intake), smoking, vitamin D deficiency, and a sedentary lifestyle. Among the non-
modifiablethemostrelevantare:riskfactors,femalegender,age,Caucasianethnicity,
earlymenopauseanddiseasesaffectingbonemetabolismarethemostlargelystudied
(45,46).
23
1.2 PERIODONTALDISEASE
1.2.1 DEFINITION
1.2.1.1 ANATOMYOFTHEPERIODONTALTISSUES
Theperiodontium(peri=around,odontos=tooth) includesthe followingtissues: the
gingiva, the periodontal ligament, the root cementum and the alveolar bone that is
continuouswiththealveolarprocess.
Theprimaryfunctionoftheperiodontiumistocreatetheattachmentbetweenthetooth
andthesurroundingbonetissueandforthisreasonisconsidered“thesupportingtissue
oftheteeth”.Thisapparatuscreatesadevelopmental,biologicandfunctionalunitthat
canchangeduetoage,functionalmodificationsandoralenvironmentalterations.Fig.3
Fig.3Theperiodontium:gingiva(G),peridontalligament(PL),root
cementum(RC),alveolarboneproper(APB),alveolarprocess(AP)
24
1.2.1.1.1 Gingiva–macroscopicanatomy
The oral mucosa consists of the masticatory mucosa (gingiva and hard palate), the
specializedmucosa(dorsumofthetongue)andtheliningmucosa(theremainingparts).
Thegingivacoversthealveolarprocessoftheboneandthecervicalportionoftheteeth.
It can be subdivided in two different layers: the epithelial layer and the underlining
connectivetissue(laminapropria).Coronallythegingivaterminateswiththefreegingival
margin, and in apical direction is continuous with the alveolar mucosa. The clearly
recognizablelinesthatseparatesthetwotypesofmucosaiscalledmucogingivaljunction.
Duringanoralexaminationtwotypesofgingivacanbedifferentiated:thefreeandthe
attachedgingiva.
Thefreegingivaisboundedbythegingivalmargincoronallyandthefreegingivalgroove
(correspondingtothecemento-enameljunction,CEJ)apically.Asmallinvaginationcalled
sulcusisformedbythefreegingivaallaroundthetoothand,whentheperiodontalprobe
isinsertedinthissulcustowardstheCEJ,alittlepocketiscreatedseparatingthetissue
fromthetoothsurface.Thissocketiscalled“periodontalpocket”or“gingivalpocket”.
Aftercomplete/physiologicaltootheruptionandinconditionofperiodontalhealththis
pocket is very thin and the soft tissues are in strictly contact to the enamel. In the
interdental area, the shape of the gingiva is determined by the contact areas of the
adjacentteeth,theCEJ,thetoothshape.Thisportionofgingivaiscalled“interdental
papilla”andcanbepyramidal, i.e. intheanteriorareawheretherearecontactpoints
betweenteeth,ormoreflattenedintheposteriorregionwherecontactareasaremore
frequent.
Theattachedgingivaisboundedbythefreegingivalgrovecoronallyandextendtothe
muco-gingivaljunctionapically.AftertheMGJtheattachedgingivabecomescontinuous
withtheliningmucosathatcoversalltheoralcavity.Themainfeaturethatcharacterized
theattachedgingivaisthefirmbondingwiththeunderliningalveolarbonebyconnective
tissue.Forthisreason,thistypeofgingivaltissueisconsiderednotmovable,contrariwise,
thealveolarmucosaisloosyboundedtothealveolarbone.Fig.4
25
Fig.4Threepartsofthegigngiva:freegingiva(FG)thatfinishesatthecemento-enameljunction(CEJ),interdental
gingiva,attachedgingiva(AG).Thedemarcationlineisthemuco-gingivaljunction(MCJ)
1.2.1.1.2 Gingiva–microscopicanatomy
Thegingivacomprisestwotypesofstructures,theepithelialtissueandtheconnective
tissue.Theepitheliumcoversallthegingivaandcanbedifferentiatedindifferentlayers:
oralepithelium(facestheoralcavity),oralsulcularepithelium(facesthetoothwithout
contact)andthejunctionalepithelium(createsthecontactgingiva-tooth).Thecontact
betweenoralepitheliumandtheunderliningconnectivetissuehasashapeofdigits.The
areasofconnectivetissuethatinvadetheepiteliumarecalledconnectivetissuepapillae,
interspersedwithepithelialridgescalledretepegs.
OralEpitheliumiskeratinized,stratified,squamousepitheliumthatcanbesubdividedin
basal layer (str. Basale), prickle cell layer (str. Spinosum), granular cell layer (str.
Granulosum)andkeratinizedcelllayer(str.Corneum).Oralepitheliumismainlymadeby
keratine-producing cells (90%) and the remaining part is made by clear cells
(malanocytes,langheranscells,merkel’scells,inflammatorycells).
Themaintissuecomponentofthegingivaistheconnectivetissue(laminapropria),made
by connective tissue fibers, fibroblasts, vessels and nerves. All these structures are
26
embeddedinanamorphousmatrixthatworksasanenvironmentforthecells.Different
typesofcellsarepresentinthe
connectivetissue:fibroblaststhatrepresentthe65%oftheentirepopulationandare
involvedinthecreationofthecollagentissueandthematrix;mastcellsthatareinvolved
intheproductionofseveralcomponentsofthematrixandinthecontroloftheblood
circulationthroughthetissues;macrophageshavealotofsynteticfunctionsandtheyare
particularly numerous in the inflamed tissue. Neutrophilic granulocytes
(polimorphonuclear leukocytes), lymphocytes and plasma cells are also present in
connectivetissue.
Connective tissue fibers, created by the fibroblasts, can be distinguished in 4 main
categoiries: collagen fibers (the most essential components of the periodontium),
reticulinfibers(presentattheinterfacesepithelium-connectivetissueandendothelium
- connective tissue), oxytalan fibers (scarse in gingiva but present in periodontal
ligament), and elastic fibers (present in associacionwith blood vessels in gingiva and
without blood vessels in liningmucosa). Although, other collagen fibers are present,
randomlyorregularlydistributed,andaccordingtotheirdirectionandtheirinsertionare
distinguished in:circular fibersCF(present inthefreegingivawithacircularshapeall
aroundthetooth),Dento-gingivalfibersDGF(embeddedinthecementumofthesupra-
alveolarportionoftherootandconnectedtothefreegingiva),dento-periostealfibers
DPF(embeddedinthecementumbutinconnectionwiththeattachedgingiva.Inthearea
betweenDGFandDPFcanbepresentalineofdepressioncalledgingivalgroove),Trans-
septalfibersTF(connectingsupraalveolarcementumofadjacentteeth).
Theconnectivetissuematrixismainlyproducedbythefibroblasts,andisamediumin
whichthefibroblastsandothercellsareembedded.Withinthematrixthereoccuranon-
stopexchangeofnutrients,metabolites,water,electrolytesandothersubstances.The
maincomponentsofthematrixareproteoglycansandglycoproteins.
27
1.2.1.1.3 Periodontalligament
Theperiodontalligament(PDL)islocatedintheslightspacebetweenrootandalveolar
boneanditisthestructureresponsibleoftheconnectionbetweenthelaminaduraand
thetoothcementum.Theligamentisarichlyvascular,softtissuethatcompletelyencircle
therootandisincontinuouswiththelaminapropriaofthegingivacoronally.Thewidth
ofperiodontalligamentisabout0,25mm(0.2-0.4mmrange)andhismainfunctionisto
adsorbanddistribute themasticatory loadaswellas theocclusal forcesduringother
toothcontacts.AccordingtothePDLcharacteristics(width,height,quality)themobility
patternofteethcanbedifferent.
DifferentbundlesofcollagenfibersconstitutetheperiodontalligamentandItispossible
todistinguish4differenttypesdependingontheirorientation:alveolarfiberscrestAFC,
horizontalfibresHF,obliquefibresOF,apicalfibersAF(Fig.6).TheprincipalcollagenI
fibers of the PDL are located between the cementum and the alveolar bone, and
penetrateboththecementumandthebonesurface.ThistypeoffiberiscalledSharpey’s
Fig.5Theschematicdrawingofthehistologicsectiondescribingthecompositionofthegingivaand
thecontactareabetweenthegingivaandtheenamel.
28
fiber.Inaddition,thePDLcontainsoxytalanefibersthatrunaroundbloodvesselswithan
apico-occlusalorientationandtheyarealsoinsertedinthecementum.
The ligament is colonized by several cells as fibroblasts (along principal fibers),
osteoblasts (on the bone surface), cementoblasts (on the cementum surface),
osteoclasts, epithelial cells as well as nerve fibers. Epithelial cells are called Rest of
Mallassezandareorganizedinclustersonrootsurface.Thesecellsarearemnantofthe
Hertwig’sepithelialrootsheath.Thesecellsarestillvitalbutwithapoormetabolism.
1.2.1.1.4 Rootcementum
The cementum is a tissue covering the tooth root characterized by several bone-like
features. It is a mineralized highly specialized structure without blood vessels and
innervation. Cementum undergoes a continue reposition during life increasing in
thicknessbytheadditionofnewlayersbut,asopposedtothebone,doesnotpresent
alternated periods of resorption and apposition. It is formed by collagen fibred
embeddedinanorganicmatrixlikeothermineralizedtissuesandcontainsmoreorless
Fig.6Schematicdrawofperiodontalligamentwithfibersorientation:
alveolarboneproper(ABP),rootcementum(RC),alveolarcrestfibers(ACF),
horizontalfibers(HF),obliquefibers(OF)andapicalfibers(APF)
29
asmuchhydroxyapatiteasthebone(65%vs60%) in itsmineralizedcomposition.The
two functionsof the cementumare: linking theperiodontal ligament to the rootand
contributetotherepairingprocessesoftherootincaseofdamage.Rootcementumcan
bedivided in threedifferent types: Acellular extrinsic fiber cementumAEFC (situated
coronallyandinthemiddleportionoftherootandcontainstheSharpay’sfibers),Cellular
mixed stratified cementum CMSC (in the apical third and in the furcations), Cellular
intrinsicfibercementumCIFC(foundinresorptionlacunae).Sharpey’sfibersconstitute
theextrinsicfibersystemofthecementumandareprovidebyfibroblasts,contrarywise,
theintrinsicfibersystemismadebybundlesorientatedmainlyparalleltothelongaxisof
thetoothandisproducedbycementoblasts.Sharpey’sfibersareconstitutedbyanon-
mineralized central part and two mineralized termination that are embedded into
cementumandbone.
Cementum,throughoutthelife,becomeswiderintheapicalportionthatcanreachthe
widthof150-250microns,incomparisontothecoronalareawherethethicknessisabout
20-50microns.
1.2.1.1.5 Alveolarbone
Thealveolarprocess is theportionof jawbonesthat includeandsupport theteeth. It
developsatthesametimeofthedevelopmentanderuptionoftheteeth.Thealveolar
bone composes the attachment structure of tooth in combination with periodontal
ligamentandrootcementum.Themainfunctionoftheapparatusistoadsorb,distribute
andmodulatethemasticatoryandocclusalload.Thewallsofthesocketthatcontainsthe
teetharecoveredbycorticalbone,whiletheareasbetweenwallsandbetweensockets
ofadjacentteethareconstitutedbycancellousbone,fulloftrabeculae(Fig.7).Inmaxilla,
bonewallsof the socketsare thinnerat thebuccal aspect if compared to thepalatal
aspectandthethicknesscanvaryindifferentareasofthemouth.Inposteriorareaofthe
mandiblethebonewallinthebuccalaspectisthickerthantheboneinlingualarea,this
isemphasizedbythepresenceofthelineaobliquaatlevelofsecondandthirdmolars.In
general,socketswallsbecomethinnerfrommolarregiontoanteriorarea.Thelayerof
30
boneinthesocketinwhichSharpey’sfibresareinsertediscalledbundlebone,atypeof
bonewithsomecementum-likefeaturesandahighturnoverrate.Thealveolarboneis
constantly renewed as response to functional stimuli with a non-stop resorption-
repositionpattern.Thesephysiologicalfunctionaldemandsincludemasticatoryloading,
occlusalforcesorteethmovements.Thecellsinvolvedinthisprocessofresorptionare
osteoclasts,agiantcelltypespecializedinmineralizationmatrixbrakeagebytherelease
ofacids.Thecontinuousremodelingpatternaffectscorticalaswellascancellousbone,
after bone resorption acted by osteoclast, the newly formed bone is deposed by
osteoblastsandanewBoneMulticellularUnitBMU(the“structure”composedbyallthe
cellsandvascularsupplynecessaryforboneremodeling)iscreated.
1.2.1.1.6 Bloodsupplyoftheperiodontium
Hardandsofttissuesofthemaxillaandthemandiblearesuppliedbyacomplexsystem
ofbloodvesselsratherthansinglegroupsofvessels.Infact,oralcavityischaracterized
by a packednetwork of anastomoses. Periodontal tissue and teeth is vascularizedby
vesselsfromtheinternalmaxillaryartery(IMA),thatdismissestheinternalalveolarartery
(IAA) in themaxilla and in themandible. In correspondenceofeach tooth thedental
artery(DA)originatesfromtheIAAandcarriesontowardsthedentalapexand,before
Fig.7Verticalsectionsthroughvariousregionsofmandibulardentition.Thebonewallatthebuccal(B)
andlingual(L)aspect
31
entering thedental socket,dismisses the intraseptalartery (AI)with ramiperforantes
(RRP)thatcompenetratestheperiodontalligament.Beneaththejunctionalepithelium
thereisafinemeshnetworkofsmallvesselswithoutloopscalleddento-ginigivalplexus
(DGP).
Gingiva,contrarywise,receivesthebloodsupplymainlythroughsupraperiostealvessels
asterminalbranchesofagroupofarteries:thesublingualartery,thementalartery,the
buccalartery,thefacialartery,thegreaterpalatineartery,theinfraorbitarialarteryand
theposteriorsuperiordentalartery.Thisnetworkcreatesthesubepithelialplexus(SP)in
correspondence of free and attached gingiva. The plexus is characterized by several
capillary loops projected from connective rete pegs to the epithelium. Free gingiva
vascularization in completed and integrated by terminal branches coming from the
periodontalligamentinanastomoseswithsupraperiostealandbonevessels.Fig.8
1.2.1.1.7 Lymphaticsystemoftheperiodontium
The lymphatic structures in periodontium are not easily identified because of the
dimension. Infact,the lymphcapillariesthatformanextensivenetwork inconnective
Fig.8Theschematicdrawofthebloodsupplytotheteethandtheperiodontaltissues:theintraseptal
artery(B),periodontalligamentartery(A)andsupraperiostealvessels(C)
32
tissuearecharacterizedbyawallformbyasinglelayerofendothelialcells.Beforethe
entranceinthebloodstream,thelymphpassesthroughagroupoflymphnodesinwhich
isfilteredandsuppliedwithlymphocytes.Allperiodontallymphaticdrainageiscollected
inheadandnecknodes.Forthemandible,thedrainagefromtheanteriorgingivaandlips
is collected in the submental nodes and for buccal/lingual gingiva of premolar/molar
areastothesubmandibularnodes.Regardingthemaxilla,thepalatalgingivaisdrained
tothedeepcervicalnodesandthebuccalgingivaisdrainedtothesubmandibularnodes.
Exceptforthethirdmolars,thatdraintothejagulogastricnode,andforthemandibular
incisors,thatdrainstothesubmentalnodes,alltheteethandtherelativeperiodontium
aredrainedtothesubmandibularlymphnodes.Fig.10
Fig.9Schematicdrawofthelymphaticsystem:Jagulodigastricnode(JD),deepcervicalnodes
(CP),sub-mandibularnodes(SMA)andsubmentalnodes(SME)
33
1.2.1.1.8 Nervesoftheperiodontium
Periodontium contains nociceptors and mechanoreceptors that can transfer the
informationaboutpain,touchandpressure.Thesenerveshavethetrophiccenterinthe
semilunarganglionandcomestotheperiodontiumwithtrigeminalnerveanditsthree
branches.Thepresenceofaverythinmetalfoilcanbeidentifiedbytheperiodontium
(10-30microns).Periodontalreceptorstogetherwiththeproprioceptorsinmusclesand
tendons can be considered themasticatory system of the jaws playing a key role in
regulationofchewingandocclusionmovements.
Theteethof theupper jaware innervatedby thesuperioralveolarplexus,and in the
lowerjawbytheinferioralveolarnerve.Fortheperiodontiumthenervoussystemisthe
same of the dental systembut the small nerves that go from themain nerve to the
periodontalspacefollowthesamecourseofthecorrespondingbloodvessel.
Inthemaxilla,thegingivaofbuccalaspectofincisors/canines/premolarsisinnervatedby
superior labial branches from the infraorbital branch,while themolar gingiva on the
buccalaspect issuppliedbytheposteriorsuperiordentalnerve.Thepalatalgingiva is
innervatedbythegreaterpalatalnerveexceptfortheincisorsarea,servedbythelong
sphenopalatinenerve.Regardingthemandible,thelingualgingivaisinnervatedbythe
sublingualnerve(terminalbranchofthelingualnerve).Inthelabialaspectoftheincisors
andcanines thegingiva is suppliedby thementalnerve,while themolarareaby the
buccalnervebut,inthepremolarregionthetwonervesfrequentlyoverlap.Fig.10
34
1.2.1.2 FEATURESOFPERIODONTALDISEASE
Periodontal diseases are a class of infections characterized by the presence of
microorganismsthatcolonizethetoothsurfaceatorbelowthegingivalmargin.While
billionsofmicroorganismscolonizecontinuallythetooth,mostsitesinmostpatientsdo
notshowlossofsupportingtissuesatanytime.Therelationshipbetweenperiodontal
microbiota and the host is in balance normally, but sometimes, a specific group of
bacteria takes over the balance and lead to periodontal damage. Like other human
infection,periodontaldiseaseischaracterizedbythepresenceofperiodontalpathogens,
butisofprimaryimportancetoconsiderthatthisconditionisnecessarybutnotsufficient
toatissuedestruction.Inalargenumberofindividualsinwhichtheteetharecolonized
byperiodontalpathogensatbothlevels(supraorsubgingiva),thesignsofperiodontal
sufferingareabsentandthisisnotananomaly.Inthesamewayofalltheotherinfection
inthehumanbody,wheredifferentbacterialspecieshavedifferenttissuesspecificities
and targets, periodontal disease appear to be caused by a restricted number of
pathogens acting alone or in combination. These species include: Aggregatibacter
actinomycetemcomitans, Tannerella forsythia, Campylobacter rectus, Eubacterium
Fig.10Schematicdrawoftheinnervationofthejaws
35
nodatum, Fusobacterium nucleatum, Peptostreptococcus micros, Porphyromonas
gingivalis,Prevotella intermedia,Prevotellanigrescens,Streptococcus intermediusand
Treponema(47).
The peculiar feature of periodontal infection is the presence of a “unusual anatomic
featurethatamineralizedstructure,thetooth,passesthroughtheintegument,sothat
partofitisexposedtotheexternalenvironmentwhilepartofiswithintheconnective
tissue”.Themicroorganismsthatcausethediseaseresideinabiofilmthatexistontooth
or on the epithelial surface. Themajor characteristic of the diseases is that they are
causedbybacteriathatresideinabiofilmoutsidethebodyandtheirtreatment,aswell
asthediagnosisandtheprognosis,iscomplex.
Ingeneral,periodontaldiseasesareaclassofparaphysiologicconditionsorpathologies
characterizedbybacterial colonization, soft tissue inflammationand/or soft andhard
tissuedestruction.
1.2.1.3 EXAMINATIONMETHODS
Examinationofperiodontalconditionsconsistsofclinicalassessmentofinflammationin
periodontaltissues,recordingofprobingdepthandclinicalattachmentlevels,besidesa
radiographicassessmentofalveolarbone.Fig.11
Fig.11Probingdepthinacompromised(left)andhealty(right)
peridontalpocket
36
1.2.1.3.1 Inflammationassessment
Presenceofinflammationatgingivalmargininevaluatedinsertingametalprobetothe
bottomofagingivalpocketaccordingtotheprinciplesoftheGingivalIndexpublishedby
Loein1967wherethecompleteabsenceofinflammationatthemarginwasrecordedas
0, the light tendency to inflammation with a change in color and appearance was
recordedas1,aslightbleedingafterprobingwasrecordedas2andthespontaneous
bleedingwas3(48).Asimilarscorewassettorecordthepresenceofplaquewhere0
was recorded in absence of deposits, 1 in presence of plaque visible moving the
periodontalprobealongthemargin,2whentheplaquewasclearlyvisibleand3ifthe
plaquewasabundant(49).
Later,simplifiedvariantsofthesetypesofscoringhavebeenproposedandused(50).
These “new” scores are based on the dichotomy between presence or absence of
bleedingandplaque.Inthisway,0recordstheabsenceand1recordsthepresenceof
bleeding/plaque (“dichotomous scores”). Thebleedinghas to startwithin 15 seconds
after theprobingandthis iscalledbleedingonprobing (BOP). Incaseofa fullmouth
assessment six sites per tooth are probed and a Bleeding on Probing index can be
recorded.ThemeanBoPscoreisgivenasapercentage,andthisindexcanbeusedasa
negativepredictorofperiodontaldisease(51).Likewise,ifthePlaqueisassessedinafull
mouthexamination,aPlaque Indexcanbeeasilyrecorded.Thesetwo indexescanbe
easily used in order to analyse and compare the periodontal inflammation status at
differentobservationperiods.Fig.12
37
1.2.1.3.2 Periodontalsupportassessment
Avarietyofexaminationindexhasbeenproposedovertheyears.Inordertoevaluate
theamountoftissuelostandtoidentifytheapicalextensionoftheinflammatorylesion,
thefollowingparametersshouldberecorded:
- Probingpocketdepth(PPD)
- Clinicalattachmentlevel(CAL)
- Furcationinvolvement(FI)
- Toothmobility(TM)
Nowadays,lossofperiodontalsupportisassessedbyrecordingofperiodontalprobing
depth(PPD),definedasthedistancebetweenthegingivalmargintothelocationofthe
tipofaperiodontalprobe,withastandardizedtipdiameterof0,4/0,5mm,insertedin
thepocketwithmoderateforce.InaperiodontalchartPPD<4mmaremarkedinblack
whiledeepersoundingwithPPD>4mmarered.Redfiguresrepresentthediseasedsites
bothfromaseverityandextensionpointofview.Severalstudieshavedemonstratedthat
PPD is themost valuable tool in clinical attachment loss prediction. In particular PPD
associatedtoBOP+hasthehigherlevelofpredictabilityat42months(52),moreover,
Fig.12Differentdegreesofinflammationinaperiodontaltissue
38
residual pockets of 7mm have a predictability of 50% at 5 years and an increase of
PPD>1mmhasapredictabilityof80%at5years(53).
Instead, clinical attachment level (CAL) is defined as the distance from the cemento-
enameljunction(CEJ)andthetipoftheprobe.Inafullmouthexamination,anumberof
six points per tooth of the entire dentition aremeasured by probing (buccal, lingual,
interproximal).Incaseofrecession,thedistancebetweenfreegingivalmarginandthe
CEJ turns negative and the height of the recession has to be added to the PPD to
determinetheCAL.
Intheprogressionofperiodontaldiseaseonmulti-rootedteeth,thedestructiveprocess
caninvolvethestructuresaroundthefurcationarea.Furcationinvolvementisassessed
fromalltheentrancesofpossibleperiodontallesionsofmulti-rootedteethwithacurved
periodontalprobegraduatedat3mmcalled“NabersFurcationProbe”,anddepending
onthepenetratingdepth,FIareclassifiedas(54):
- F1:horizontalPD<3mmfromoneortwoentrances
- F2:horizontalPD>3mminatthemostonefurcationentranceorincombination
withadegreeF1
- F3: horizontal PD > 3 mm in two or more furcation entrances (through-and-
through)
Afterwards,in1984theclassificationhasbeenintegratedtakingintoaccountthevertical
distructionofperiodontalsupportandthreeclassescanbedefinedbesidesthehorizontal
penetrationdeegres(55)(Fig.13):
- ClassA:1-3mmofPD
- ClassB:4-6mmofPD
- ClassC:>7mmofPD
39
Thecontinuouslossofperiodontalsupportingtissueovertimemayresultinincreased
tooth mobility, as well as the occlusal trauma. Increased tooth mobility has been
classifiedin1950byMiller(56):
- Degree0:Physiologicalmobilityof0,2-0,1mminahorizontaldirection
- Degree1:increasedmobilityatleast1mminahorizontaldirection
- Degree2:visuallyincreasedmobilityexceeding1mminahorizontaldirection
- Degree3:severemobilityofthecrowninbothhorizontalandverticaldirection
(nofunction)
Iscrucialto identifythecauseofthemobility, inordertoplanthepropertherapeutic
approach,infactseveralfactorscouldleadtoanincreasetoothmobilitylikeoverloading,
periapicallesions,periodontalsurgery,periodontaldisease.Fig.14
Fig.13Furcationsounding:TheNabersprobeentersthefurcationaccordingtohorizontalthebonedestruction
(F1,F2,F3,left).Thegradingofverticalboneresorption:AifF<3mm,Bif3mm<F<6mm,CifF>6mm(right)
Fig.14Toothmobilityassessment
40
1.2.1.3.3 Radiographicevaluation
Radiologyiswidelyusedinperiodontologybutthelimitationsinsupportingtissueloss
evaluationarewellknown(57).Assessmentofbonelossinradiographscanbeusedto
evaluate: the presence of lamina dura, the width of periodontal ligament, the
morphologyofbonecrest,thedistancebetweenCEJandbonecrest,theshape/distance
of the roots. In general, radiological assessment is consideredauseful toolmainly to
perform epidemiological studies, rather than in clinical examination, where the
periodontalproberemainsthemostreliableappliance.Fig.15
1.2.2 DIAGNOSISOFPERIODONTALDISEASE
Basedontheinformationregardingtheconditionofthevariousperiodontalstructures
(gingiva, periodontal ligament, alveolar bone) which has been obtained through the
comprehensiveexaminationlistedabove,aclassificationaswellasadiagnosisforeach
tooth regarding the periodontal conditionsmay be given. Four different tooth-based
diagnosismaybeused:
Fig.15Completeapico-periapicalstatus
41
- Gingivitis:teeththatshowbleedingonprobingbutthesulcusdepthremainsata
physiologicallevelof1-3mmirrespectiveofthelevelofclinicalattachment.The
diagnoseofgingivitischaracterizedlesionsconfinedtothegingivalmargin.
- Periodontitis“mild-moderate”:gingivitisincombinationwithattachmentlossis
termed “periodontitis”. If the PPD do not exceed 6mm, a diagnosis of mild-
moderate periodontitis is given irrespective of themorphology of periodontal
lesion. This diagnosis can be applied to teeth with horizontal bone loss,
representing suprabony lesions and/or vertical or angular bone loss with
infrabonydefects(one/two/threewallsdefectsorcraters).
- Periodontitis “advanced”: If PPD exceeds 6 mm, a diagnosis of advanced
periodontitis isgiven irrespectiveofthemorphologyofperiodontal lesion.The
distinctionwiththemild-moderateisonlybasedonthePPD,infacthorizontalas
wellasverticaldefectscanbepresent.
- Periodontitis interradicularis: This is the periodontitis characterized by the
involvementofthefurcationarea.IfafurcationisinvolvedwithaPPD<4mmitis
consideredmildmoderate,ifPPD>4isconsideredadvancedperiodontitis.
1.2.3 CLASSIFICATIONOFPERIODONTALDISEASE
The currently use d classification of periodontal diseasewas introduced by the 1999
InternationalWorkshop foraClassificationofPeriodontalDiseaseandConditionsand
encompasseseightmaincategories,namely:
1. Gingivaldisease
2. Chronicperiodontitis
3. Aggressiveperiodontitis
4. Periodontitisamanifestationofsystemicdisease
5. Necrotizingperiodontaldisease
42
6. Abscessesoftheperiodontium
7. Periodontitisassociatedwithendodonticlesions
8. Developmentaloracquireddeformitiesandconditions
1.2.3.1 GINGIVALDISEASE
It is demonstrated that inflammation of the gingiva induced by bacteria is themost
commonformofgingivitis(58),andthecategorizationofdiseasesaffectingthegingiva
requiresevaluationofpatientsignsandsymptoms,medicalanddentalhistories,aclinical
examinationthatincludestheextend,distribution,durationandthephysicaldescription
oflesions.Theuniversalfeaturesofgingivaldiseaseincludeclinicalsignsofinflammation,
signs and symptoms that are confined to the gingiva, reversibility of the disease by
removalofetiology,thepresenceofbacteria-ladenplaquetoinitiateand/orexacerbate
theseverityofthelesion,andapossibleroleasaprecursortoattachmentlossaround
teeth. The intensity of the clinical signs and symptomsof gingivitiswill vary between
individuals(59),aswellasbetweensiteswithinadentition.Thecommonclinicalfindings
ofplaque-inducedgingivitisincludeerythema,edema,bleeding,sensitivity,tenderness
andenlargement(58).Veryspecificfeaturesofgingivitisaretheabsenceofsupporting
structure lossand the reversibility.According toLöe, it is important tounderline that
gingivitisbecomesmanifestonlyafterdaysorweeksofplaqueaccumulation.
Gingival inflammation, clinically presenting as gingivitis, is not always due to
accumulationofplaqueonthetoothsurface,thisspecificcategoryofgingivitisiscalled
“non-plaqueinducedinflammatorygingivallesions”(60).Theymayoccurduetoseveral
causes,suchasspecificbacterial,viralorfungalinfectionwithoutanassociatedplaque-
related gingival inflammatory reaction. Gingival lesions of genetic origin are seen in
hereditary gingival fibromatosis, and severalmucocutaneousdisorders (lichenplanus,
pemphigus,pemphigoidsanderythemamultiforme).Allergicandtraumaticlesionsare
otherexamplesofgingivaldiseasenon-plaquerelated.
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1.2.3.2 CHRONICPERIODONTITIS
Chronicperiodontitisisconsideredtostartasplaque-inducedgingivitis,areversible
conditionleftuntreated.TheclinicalfeaturesofCPincludesymptomssuchas
color/texture/volumealterationsofthemarginalgingiva,bleedingonprobingfrom
gingivalpockets,increasingprobingdepth,lossofclinicalattachment,recessionofthe
gingivalmargin,lossofalveolarbone,rootfurcationexposure,increasedtoothmobility,
driftingand,eventually,exfoliationofteeth.
Chronicperiodontitishassomepeculiaritiesthatcanhelptheclinicianindiagnose:
- CPisprevalentinadultsbutmayoccuralsoinchildren
- Thedestructionoftheperiodontaltissuesseeiscommiseratedwithoral
hygienelevel,localpredisposingfactors,smoking,stressandsystemicrisk
factors.
- Subgingivalbiofilmharborsavarietyofbacterialspecies(biofilmcomposition
variesbetweenindividualsandsites)
- CPisclassifiedaslocalizedwhenlessthan30%ofsitesareaffected,contrariwise
isdefinedgeneralized
- Severityofchronicperiodontitisatthesitelevelcanbeclassifiedbasedonthe
degreeofclinicalattachmentlossasmild(1-2mm),moderate(3-4mm),severe
(>5mm)
- AlthoughCPisinitiatedbyplaque,hostfactorsdeterminethepathogenesisand
progressionrateofthedisease
- Therateofprogressioninmainlyslowormoderate(butafasterprogressioncan
occur)
Ifgingivitisbecomesmanifestonlyafterweeksofplaqueaccumulation,chronic
periodontitisrequiresfarlongerperiodsofplaqueandcalculusexposuretodevelop
(61,62).TissuedestructioninCPdoesnotaffectallteethevenly,buthasasite
predilection.Asresultsinthesamedentition,someteethmaybeseverelyaffected
whileotherteethcanbealmostfreefromtheperiodontaldestruction.Regardingthe
44
progressionofthedisease,acontinuousslowprocesswithperiodsofexacerbation
(burst)seemsthemostconcertedpattern.Ingeneral,itisimportanttoknowthat
factorsassociatedtothediseasecaninfluencethediseaseprogression.Furthermore,
theextensionandtheseverityofthediseasearegoodpredictorsoffuturedisease
occurrence.
1.2.3.3 AGGRESSIVEPERIODONTITIS
Aggressiveperiodontitis(AgP)comprisesagroupofrare,oftensevere,rapidly
progressiveformsofperiodontitisoftencharacterizedbyanearlyageofclinical
manifestation.Intheabsenceofanetiologicalclassification,aggressiveformsof
periodontaldiseasehavebeendefinedbasedonthefollowingprimary,universally
present,features:
- non-contributorymedicalhistory
- rapidattachmentlossandbonedestruction
- familialaggregationofcases
Andsecondary,generallybutnotuniversallypresent,features:
- Amountsofmicrobialdepositsinconsistentwiththeperiodontaldestruction
- ElevatedpresenceofAggregatibacterActinomicetemcomitansand
PorphiromonasGingivalis
- Phagocyteabnormalities
- Hyperresponsivemacrophagephenotype,includingelevatedproductionof
ProstaglandinE2andinterleukin-1B
- Progressionofattachmentlossandbonelossmaybeself-arresting
- Iflocalizedaggressiveperiodontitis:
o Circumpubertalonset
o Localizedfirstmolar/incisorwithinterproximallossofattachmentonat
least2permanentteeth,oneofwhichisafirstmolar,andinvolvingnon
morethantwoteethotherfirstmolarandincisors
45
o Robustserumantibodyresponsetoinfectingagent
- Ifgeneralizedaggressiveperiodontitis:
o Usuallyaffectingpersonsunder30yearsofagebutsometimescanbe
older
o Generalizedinterproximallossaffectingatleast3teethotherthanfirst
molarsandincisors
o Pronouncedepisodicnatureofthedestructionofattachmentanalveolar
bone
o Poorserumantibodyresponsetoinfectingagent
Diagnosisofoneoftheseformsrequirestheabsenceofsystemicdiseasesthatmay
impairhostdefensesandleadtoprematureexfoliationofteeth.Theearly
manifestationofclinicallydetectablelesionsisgenerallyinterpretedasbeingthe
expressionofhighlyvirulentcausativeagentsorhighlevelsofsusceptibilityofthe
individualpatient,oracombinationoftwo(63).
1.2.3.4 PERIODONTALDISEASEASARISKFORSYSTEMICDISEASE
Theevidenceabouttheimplicationofperiodontaldiseaseasariskfactorforseveral
systemicconditionssuchascardiovasculardisease,adversepregnancyoutcome,
diabetes,andpulmonarydisease,hasemergedsince1990s(64).Thefindingsgathered
fromtheinvestigatorsworldwideinthelast60yearsareverycompelling,anditwould
certainlyappearthatperiodontaldiseaseisstronglyassociatedwithsystemic
conditions.Forthisreason,dentistrymustfocusoninterventionstudiestodetermine
whethertreatingperiodontitiswillhaveabeneficialeffectonsystemicdisease.
Regardingcardiovasculardisease,evidencedemonstratingthebeneficialeffectsof
periotreatmentsonthediseaseoutcomeislimitedandindirect(65).Inconsidering
adversepregnancyoutcomes,fewstudiesprovideevidencethatpreventivetreatments
aimedtoreducedmaternalperiodontalinfectionmayreducethelikelihoodofpreterm
lowbirthweightinfants(66).
46
Numerousepidemiologicsurveysdemonstrateanincreasedprevalenceofperiodontitis
amongpatientswithuncontrolledorpoorlycontrolleddiabetesmellitus.Moreover,
diagnosingDiabetestype2,investigatorsfoundahigherprevalenceofclinicaland
radiologicalattachmentlossfordiabeticsversusnon-diabeticpatients.Hence,itisclear
thatdiabetesisamodifierorriskfactorforperiodontaldisease(67).Itisalso
demonstratedthatperiodontalinfectionreductioncanimproveglycemiccontrol(68,
69).
Thereareanumberofstudieswhichexaminetheeffectoftreatingoralinfectionin
reducingtheriskofpneumoniainhigh-riskpopulations(69).Recentreviewsclearly
indicatethatwhenbacterialplaqueisreducedinmouthofat-riskpatients,theriskof
pneumoniaisreduced.
1.2.3.5 NECROTIZINGPERIODONTALDISEASE
Necrotizinggingivitis(NG)andnecrotizingperiodontitis(NP)arethemostsevere
inflammatorydisorderscausedbyplaquebacteria.Theselesions,usually,runanacute
courseandarerapidlydestructiveanddebilitating(70).Necrotizingdiseaseisan
inflammatorydestructiveperiodontalconditioncharacterizedbyulceratedandnecrotic
papillaeandgingivalmarginresultinginapunched-outappearance.Theulcersare
coveredbyayellowishwithorgrayishslough,termed“pseudomembrane”.Removalof
thematerialresultsinaulcerativelesionwithmassivebleeding.Thelesionsappear
rapidlyandarepainfull,evenifintheearlystagepaincouldbemoderate.Thelesions
areseldomassociatedwithdeeppocketsbecausegingivalnecrosisiscommonly
associatedtoacrater-likeinterproximalbonedestruction.
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1.2.3.6 ABSCESSESOFTHEPERIODONTIUM
Odontogenicabscessesincludeabroadgroupofacuteinfectionsthatoriginatefrom
thetoothand/ortheperiodontium.Suchabscessesareassociatedwithanarrayof
symptomsincludinglocalizedpurulentinflammationintheperiodontaltissuesthat
causespainandswelling.Dependingontheoriginoftheinfectionlesionscanbe
classifiedasperiapical,periodontalandpericoronayabscesses.Aclassificationhasbeen
proposedandincludedgingivalabscesses,causedbyimpactationofforeignbodies,
periodontalabscesses,eitheracuteorchronicdependingonaperiodontalpocket,and
pericoronalabscesses,fortheincompleteeruptionofatooth.Periodontalabscesses
classificationisbasedontheetiology:
- periodontitis-relatedabscess:ifanacuteinfectionoccursfrombacteriapresent
inadeepperiodontalpocket
- non-periodontitis-relatedabscess:whentheinfectionoriginatesfromadifferent
source,suchasforeignbodyimpactionoranalteredrootintegrity.
1.2.3.7 PERIODONTITISASSOCIATEDWITHENDODONTICLESIONS
Lesionofendodonticoriginaresignificantastheyfrequentlyextendandmanifest
themselvesintheattachmentapparatus.Notonlydotheselesionsproducesignsand
symptomsofinflammationinapicalareabutalsoalongthelateralaspectofrootsand
infurcationareas.Thefactthattheperiodontiumandthedentalpulpareanatomically
interconnectedalsoimpliesthatexchangeofnoxiousagentsmayoccurinboth
directions(71).Ingeneral,periodontal-endodonticlesionsareusuallyatooth-related
andnotpatient-relateddiseaseand,forthisreasoncanoccureitherinperiodontalor
non-periodontalpatients.Hence,thistypeofperiodontallesionisnotconsidereda
diseasethatcanaffectthepatientbutonlythesite.
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1.2.4 EPIDEMIOLOGYOFPERIODONTALDISEASE
Epidemiologyisdefinedas“thestudyofthedistributionofadiseaseoraphysiological
conditioninhumanpopulationandthefactorsthataffectthisdistribution”(72).Based
on this definition and previous epidemiological research in the medical field, in
periodontal research, is it of primary importance the study of the prevalence of the
diseaseindifferentpopulations(frequency,severity,changes).
1.2.4.1 PREVALENCEOFPERIODONTALDISEASE
Since the last classification has been introduced in June 2018, a substantial part of
existing literature on the prevalence and extend of periodontal disease in various
populationsisstillbasedonanearlyclassificationofthedisease.Currently,twoprincipal
forms of destructive periodontal disease are recognized – chronic periodontitis and
aggressive periodontitis (73). It is relevant to attempt to appraise some key features
relevanttotheepidemiologyofhumanperiodontitisthatunderlieitscore‘identity’asa
bacterial biofilm-induced inflammatory disease. There is consensus that the
epidemiologic hallmark of periodontitis is destruction of the tooth-supporting tissues
manifestedbyclinicalattachmentlossandradiographicboneloss.Aspecialfeatureof
periodontitisisitssitespecificity,andanimportantconsequenceofthissitespecificityis
thatanymeasureofperiodontitisasapathologicconditionwhichaffectsanindividual
ratherthanatooth/toothsitemustincorporateameasureofextentandalsoameasure
ofseverity.Toconfusetheissuefurther,allbiologicmeasurements,includingattachment
loss andbone loss, are subject toboth temporalbiologic variationandmeasurement
errors(74).Auniversallyaccepteddefinitionoftheappropriatecombinationofextent
andseverityvaluestodenotea‘caseofperiodontitis’hasnotbeenestablishedandisone
of the reasons why prevalence estimates of periodontitis vary considerably across
studies.Indevelopedcountries,thereisgrowingconsensusthatavalidexaminationof
periodontal status should include full-mouth assessments of gingival/periodontal
inflammation,probingdepthandattachmentloss,inotherwordsmeasurementsatsix
sites per tooth at all teeth present in the dentition and continuous, rather than
49
dichotomous, measures of extent and severity. According to the World Health
Organizationpublication,‘TowardsaCommonLanguageforFunctioning,Disabilityand
Health: The International Classification of Functioning, Disability andHealth’, appears
reasonabletoassumethatformsofhighextentandseverityarethosemostlikelytobe
capableofnegativelyaffectingthefunctionandwell-beingofanindividual.Butifwetry
to understand why it has not been feasible to establish a universal definition of
periodontitis forepidemiologicuse, it is important toconsider that the sameseverity
level of periodontitis signifies vastly different prognosis at different ages: 6 mm of
attachmentlossatage80maybeperfectlycompatiblewiththeretentionofafunctional
dentitionforlife;however,thesamemagnitudeofattachmentlossaffectingateenager
suggestsasignificantlyworseprognosiswithrespecttotoothfunctionandsurvival(75).
Althoughperiodontitisisoftencalleda‘silent’diseasebecauseitisrarelyassociatedwith
obvioussignsandsymptomsunlessthediseasehasprogressedtoitsterminalstages.A
keyissueinthepresentdiscussionisthecurrentprevalenceestimatesofperiodontitis.A
systematicreviewincluding72studiesanddatafrom291,170individuals≥15yearsof
age from37countriesestimated that theglobalprevalenceof severeperiodontitis in
2010amountedto10.8%(95%confidenceinterval:10.1–11.6%),affecting743million
people worldwide and representing the sixth most prevalent condition (76). The
prevalencevariedaccordingtoworldregions,withsouthernLatinAmericaandeastSub-
Saharan regions scoring the highest prevalence, of 20%.We argue that the currently
adopted epidemiologicmethodologies/definitions that result in an almost ubiquitous
prevalenceofperiodontitisindeedoverestimatetheoccurrenceofthediseasethatmay
actuallyput individualsatatruebiologic, functionalorpsychosocialdisadvantage.For
thisreason,nowadays,amultidimensionalapproachtotheassessmentofperiodontitis
wouldfacilitateanimprovedunderstandingofitsepidemiologyanditsconsequences.
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1.2.5 ETIOPATHOGENESISOFPERIODONTALDISEASE
1.2.5.1 MICROBIALETIOLOGY
Periodontitisisacomplexdiseasewithmultiplecomponentcauses,somewiththeirbasis
ingenetics,somecausedbyepigeneticinfluencesandothersthataremodifiablebecause
they relate to patient behaviors, medications or environmental factors, all of which
conspiretoestablishandpropagatetheperiodontitislesion(77).
1.2.5.1.1 Dentalplaqueandthebiofilmconcept
Ingeneral,alltheinterfacesurfacesofthebodyareexposedtocolonizationbyawide
rangeofmicro-organismandtheestablishmicrobiotaliveinharmonywiththehost.The
accumulationandmetabolismofbacteriaonhardoraltissueisconsideredtheprimary
causeofdentaldiseasesuchas:caries,gingivitis,periodontitis,peri-implant infections
andstomatitis.Plaqueremoval,infact,leadstothedisappearanceoftheclinicalsignsof
inflammation(58).Theterm“infection”referstothepresenceandmultiplicationofa
micro-organisminbodytissue.Dentalplaquemayaccumulatesupragingivallybutalso
below the gingivalmargin,with a different composition ofmicrobiota, that has been
attributedtothelocalavailabilityofbloodproducts,pocketdepth,redoxpotentialand
O2(78).Theabilitytoadheretosurfacesisageneralpropertyofalmostallbacteria.The
term“biofilm”describesthemicrobialcommunityassociatedwithatoothsurface,Inthe
lower levels of most biofilms a dense layer of microbes is bound together in a
polysaccharidematrixwithorganicandinorganicmaterials.Biofilmprotectbacteriafrom
antimicrobicagents,and,forthisreason,treatmentswithantimicrobicagentswithouta
mechanical plaque removal are unsuccessful. Literature data indicate that our host-
associatedpolymicrobialcommunities,suchasthosefoundintheoralcavity,co-evolved
withusandhavebecomean integralpartofwhoweare. Indeed,Roberts&Darveau
arguethatweshouldconsiderthemicrobiomeasahumanorgan.(79)
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1.2.5.1.2 Plaque-formationmechanism
Immediatelyuponimmersionofasolidsubstratumintothefluidmediaoftheoralcavity,
oruponcleaningofasolidsurfaceinthemouth,hydrophobicandmacromoleculesbegin
toadsorbtothesurfacetoformaaconditioningfilm,termed“theacquiredpellicle”.The
filmiscomposedofavarietyofglycoproteins(mucins)andantibodies.Bacteriaadhere
variablytothiscoatedsurface.Behaviorsofbacteriachangeoncetheybecomeattached
tothesurfacesandthebacteriamassincreasesduetocontinuedgrowthandadhering
organisms,newadhesionandsynthesisofpolymers.Completelyanaerobicconditions
emergeinthedeeperlayer.Primarycolonizationisdominatedbyfacultativeanaerobic
Gram-positivecocciandplaquecollectedwithin24hoursmainlyconsistsofstreptococci
(S. sanguis). In the next phase, Gram-positive filaments (Actynomices) are the
predominant species. Veillonella, fusobacteria and other anaerobic gram-negative
bacteria can attach due to the surface receptors despite of the poor ability to bind
themselves to the first layer. Due to the difference of local environmental factors,
structurally different types of plaque evolve at different locations. In summary,
immediately following the immersion of hard, non-shedding surfaces into the fluid
environmentoftheoralcavity,adsorptionofmacromoleculeswillleadtoformationofa
biofilm.Fig.16
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Fig.16Schematicrepresentationofthedifferentstagesintheformationofdentalbiofilms.a)Pellicle
formsonacleantoothsurface.Bacteriaaretransportedpassivelytothesurface.b)attachment
becomesmorepermanentthroughspecificstereochimicalmolecularinteractionsbetweenbacterium
andpellicleandsecondarycolonizersattachtothealreadyattachedprimarycolonizers.C)growth
resultsinbiofilmmaturation.
53
1.2.5.1.3 Dentalcalculus
Dentalcalculusconsistsofmineralizedbacterialplaque.
Thedegreeofcalculusformationisnotonlydependentontheamountofpacterialplaque
presentbutalsoonthesecretionofthesalivaryglands(80).Supragingivally,calculuscan
berecognizedasacreamy-withishtodarkyellow/brownishmassofmoderatehardness.
Subgingivally,instead,maybefoundbytactileexplorationonly,sinceitsformationoccurs
apical to thegingivalmargin.Plaquemineralizationvariesgreatlybetweenandwithin
individualsalsowithindifferentregionsoftheoralcavity,andevidenceofmineralization
mayalreadybepresentafterfewdays(81).Supragingivalplaquebecomesmineralized
salivaandsubgingivalplaqueinthepresenceofinflammatoryexudateinthepocket.Itis
evidentthatcalculusrepresentsasecondaryproductofinfectionandnotaprimarycause
of periodontitis but it has to be realized that calculus is always covered by an
unmineralized layer of viable bacterial plaque. It has been established that calculus
roughness alone do not initiate gingivitis but can provide an ideal surface to further
plaqueaccumulationandsubsequentmineralization(82).
1.2.5.1.4 Periodontalpathogens
Thecriteriafordefiningpathogensofdestructiveperiodontaldiseaseinitiallywerebased
onfirstandsecondKoch’spostulate:
1. theagentmustbeisolatedfromeverycaseofthedisease
2. it must not be recovered from cases of other forms of disease or non-
pathogenically
Thesecriteriaincludeassociation,elimination,hostresponse,virulencefactors,animal
studiesandriskassessment.However,microbiologistsdonotexpecttofindthepathogen
in“allcasesofthedisease”becausetheycannotcurrencydistinguish“allcasesofagiven
disease”.Thecriterionofeliminationisbasedontheconceptthateliminationofaspecies
shouldbeaccompaniedbyaparallelremissionofdisease.Ifaspeciesiseliminatedby
treatment and the disease progresses, or if the level of a species remains high or
54
increases ina siteand thedisease stops,doubtwouldbecaston the species’ role in
pathogenesis.
The World Workshop in Periodontology (1996 Consensus Report) designated A.
actinomycetemcomitans, P. gingivalis and T. forsythia as periodontal pathogens. The
consensus summary, nowadays, is by no means exhaustive but does indicate that a
growingliteraturesuggestssomereasonablecandidatesasetiologicagentsofdestructive
periodontaldisease.
Thevirulenceofamicrobialpathogenisgenerallydefinedasthedegreeofpathogenicity
orabilityoftheorganismtocausediseaseasmeasuredbyanexperimentalprocedure.It
represents a combination of highly complex parameters and depends upon both the
relativeinfectivityoftheorganismandtheseverityofthediseaseproduced.However,
thesetwoparametersofinfectivityanddiseaseseverityareprofoundlyinfluencedbythe
natureandstatusofthehostorganismorthesiteofcolonizationinthathost.Forthis
reason, a breach in the normal defensive barriers of the host such as, trauma,
immunosuppression, coinfection can increase the virulence of a given organism. The
virulencedeterminantofapathogencansimplybedefinedasthosegeneproductswhich
facilitatecolonization,growth,andsurvivalwithinthediseasedhostorganismandspread
toanewhost.Anemergingkeypropertyofthesepathogens istheabilitynotonlyto
overcomehostdefensebutalsotomanipulatethesesystemstotheirownadvantage.
Oneexampleofthisuniquefeatureistheabilityofbothgram-negativeandgram-positive
bacteriaA.actinomycetemcomitansandP.gingivalistoinfluencethepatternofcytokines
expressionsbyhostcells(83).
Aggregatibacter actinomycetemcomitans: one of the clearest associations between a
suspected pathogen and destructive periodontal disease is provided by A.
actinomycetemcomitans.Aaisasmall,non-motileGram-negativerodthatformssmall
colonies(84).Itwasdemonstratedthatthemajorityofsubjectswithlocalizedaggressive
periodontitishadanenormouslyelevatedserumantibodyresponsetothisspecies(85).
Aa has been shown, in vitro, to have the ability to invade cultured human gingival
epithelialcells,humanvascularendothelialcells,andbuccalendothelialcellsinvivo(86).
Aahasalsobeenimplicatedinadultformsofdestructiveperiodontaldisease,butitsrole
55
islessclear.Thisspecieshasbeenisolatedinchronicperiodontitisbutlessfrequentlyand
inlowernumbersthenfromthelesioninAggressiveperiodontallesionssubjects(87).
Porphiromonasgingivalis:isasecondconsensusperiodontalpathogenthatcontinuesto
be investigated. Pg is a non-motile Gram-negative anaerobic rod that forms black to
browncolonies.Membersofthisspeciesproducecollagenase,gingivalpain,anarrayof
protease thatdestroy immunoglobulins,hemolysins, endotoxin, fattyacids, ammonia,
hydrogensulfideetc.StudieshavestrengthenedtheassociationofPgwithdiseaseand
demonstratedthatthespeciesisuncommonandinlownumbersinhealthorgingivitis
butmorefrequentlydetectedindestructiveformofdisease.Pghasbeenalsoshownto
induceelevatedsystemicandlocalimmuneresponsesinsubjectswithvariousformsof
periodontitis (88). LikeAa, Pg has beendemonstrated, in vitro, to have the ability to
invade cultured human gingival epithelial cells, human vascular endothelial cells, and
buccalendothelialcellsinvivo(86).
Tannerellaforsythia:Tfwasdescribedasthethirdperiodontalpathogeninlate70’s(89).
TheorganismisaGram-negative,anaerobic,spindle-shapedrod.Frequentlyisassociated
withF.nucleatuminsubgingivalsites(90).AfeatureofTfisthepresenceofaserratedS-
layerthathasshowntomediateepithelialcells invasionandto inducecellsapoptosis
(86).Thispathogenwasthoughttobeuncommonbutfurtherstudieswithmonoclonal
antibodieshavedemonstratedthatismorecommonthanpreviouslyfoundanditslevels
were strongly related to increasing pocket depth. In addiction Tf was found more
frequently and in higher numbers in actively progressing periodontal lesions than in
activelesions(91).
1.2.5.1.5 Themicrobialcomplexes
Theassociationofbacteriawithinmixedbiofilmisnotrandom,ratherthereare
aspecificassociationsamongbacterialspecies.Thepresenceofspecificmicrobial
groupswithindentalplaquehasbeendemonstrated(90).
Sixcloselyassociatedgroupsofbacterialspecieswererecognized(4earlycolonizers
and2predominantlyGram-negativeperiodontalpathogenscomplexes):
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- SpecificspeciesofActinomyces
- Yellowcomplex,consistingofmembersofthegenusStreptococcus
- Greencomplex,consistingofCapnocytophagaspecies,A.
actinomycetemcomitansserotypea,E.corrodensandCampylobacterconcisus
- Purplecomplex,consistingofV.parvulaandActinomycesodontolyticus.
- Orangecomplex,consistsofCampylobactergracilis,C.rectus,C.showae,E.
nodatum,F.nucleatum,F.periodonticum,Pe.Micros,Pr.Intermedia,Pr.
nigriscensandS.costellatus.
- RedComplex,consistingofT.forsythia,P.gingivalisandTreponemadenticola.
Thelasttwocomplexesarecomprisedofthespeciesthoughttobethemajoretiologic
agents of periodontal diseases. It is of primary importance to know that the
microorganismshaveaneffectontheirhabitat,theperiodontaltissues,andthehabitat
hasamajoreffectonthecomposition,metabolicactivities,andvirulencepropertiesof
the colonizing microorganisms. Thus, modifications of the supra- and sub-gingival
microbiota certainly affect the outcome, periodontal health or disease. Moreover,
changesinthehostor localhabitatalsoaffectthecompositionandtheactivityofthe
microbiota.
Perhapsthemostinfluentialfactoronthecompositionofthesubgingivalmicrobiotais
theperiodontaldiseasestatusofthehost(92).Themajordifferencebetweenhealthand
disease, on average, was the increase counts, proportion and prevalence of the red
complexspecies,T.forsythia,P.gingivalisandT.denticolainsubjectswithperiodontal
disease.Fig.17
Inaddition,otherputativeperiodontalpathogensoftheorangecomplexwerealsomore
prevalent and in higher levels in periodontitis subjects. However, individuals with
differentformofthediseasehavedifferentsubgingivalmicrobialprofiles.Evensubjects
withthe“same”periodontaldiseaseintermofbothclinicalappearanceandseveritycan
exhibitquitedifferentsubgingivalmicrobiotas.
Inconclusion,ifthebiofilmisnotdisruptedfrequentlyandisallowedtoaccumulate,the
conditionswithin itstarttofavorbacterialspecies,suchasFusobacteriumnucleatum,
57
thatare capableof sensingand influencing theirenvironmentbyemploying chemical
cues. Such ‘quorum-sensing’ organisms start to emerge and elicit a stronger host
response, which, in turn, can lead to the development of gingival inflammation and
increasethesupplyofcertainnutrients thatencouragetheproliferationof traditional
pathogenssuchasPorphyromonasgingivalis.
1.2.5.2 PATHOGENESISOFPERIODONTALDISEASE
Theclassicalmodelofperiodontaldiseasepathogenesis,developedbyPageeKornman
in1997(Fig.18)providesakeyframeworktounderpinstudiesaimedatunravelingthe
complex interdependent relationships that exist both within the plaque biofilm and
betweenthebiofilmandthehostresponse.Wenowrecognizethatapathogenicbiofilm
isanecessaryprerequisiteforperiodontitistodevelopbutinitselfisinsufficienttocause
Fig.17a)Associationamongsubgingivalspecies.Thedifferentcolorsinthepyramidrepresentdifferent
bacterialcomplexeswhicharefrequentlydetectedinassociationwithoneanother.Thebaseofthepyramid
representstheearlystageofplaquedevelopment,whereastheapexcontainsthoseorganismsthoughtto
bethelastspeciestobecomeestablishedinthemicrobiota.b)PiechartsofthemeanpercentageDNAcount
ofmicrobialgroupsinsupragingivalplaque.
58
thedisease(93).Diseaseresultsfromcomplexinteractionsbetweenthebiofilmandthe
inflammatoryimmuneresponse,anditisthelatterthatisestimatedtoaccountfor
almost80%oftheriskofperiodontaltissuedamage(94).
Theperiodontitisphenotypeischaracterizedbyanexaggerated,yetpoorlyeffectiveand
non-resolving,inflammationoftheconnectivetissuessupportingtheteeththatleadsto
tissue destruction, rather than a specifically targeted, effective and self-resolving
inflammatoryimmuneresponse.Oneofthekeychangesinresearcherperceptionsofthe
infectiousimmunecondition,whichitiscallperiodontitis,istherealizationthatretaining
orattainingclinicalhealth requiresahealth-promotingbiofilmwithinwhichsymbiotic
relationshipsexistbetweenmicroorganismsandwiththehostresponse.
Moreover,insusceptiblepatients,incipientdysbiosiscantriggeraninappropriate,and
frequentlyexcessive,hostresponse,inwhichexcesscytokines,reactiveoxygenspecies
(oxidative stress) and matrix metalloproteinases are generated and overwhelm their
respective antagonists, resulting in collateral periodontal tissue damage. the chronic
inflammatory state is characterizedbyattemptsathealing (angiogenesis and fibrosis)
Fig.18ClassicalmodelofPage&Kornman,showinghost–microbeinteractionsinthe
pathogenesisofperiodontitis.LPS,lipopolysaccharide;MMPs,matrixmetalloproteinases;
PMNs,polymorphonuclearneutrophils.
59
arising at the same time as inflammation, creating a rich nutritional environment for
sustainingthedysbiosisandthusthepathogenicbiofilm.
The colonizing microbes on mucosal surfaces, together with dangerous endogenous
signaling molecules, such as extracellular ATP or extracellular DNA, activate the
inflammasome,resultinginthesubsequentsecretionoftheproinflammatorycytokines
interleukin-1betaandinterleukin-18.Inflammasomeactivationismediatedbycaspase-1
activity,whichalsohasanimportantroleintheactivationofcellularapoptosis.Reactive
oxygenspeciesarealsorequired,andindeedperiodontitisischaracterizedbyoxidative
stress,providingfurtheropportunitiesforinflammasomeactivation,whichmayresultin
positivefeedback,impactinguponthehostresponseaswellasonthechronicityofthe
inflammation (95). The release and secretion of proinflammatory cytokines activates
polymorphonuclear leukocytes (neutrophils), which express various cell-surface
receptorsthatbindtochemotacticstimuliandinitiatedownstreamsignalingsequences
thatleadtocomplexreactionsandevents,includingcytosolicactinreorganization,shape
changesanddevelopmentofcellularpolarity.Thereleaseofhistamineandtheactivation
of complement components C3a and C5a leads to vasodilatation, increased vascular
permeability and slowing of blood flow within the respective capillary beds. The
neutrophilsthenfalloutofmildstreambloodflowandcontactthevascularendothelium,
wheretheymarginateandrollontheendothelialsurfaceofthecapillariesbeforebinding
firmly,viaintergrinreceptors,andmovingoutofthebloodvessels intothetissuesvia
diapedesis.Neutrophilsbelongtothefastest-movingmammaliancells,andonceinthe
tissuestheymigratealongachemotacticgradientthatenablesthemtolocatethesiteof
infectionandrespondviareceptormediatedphagocytosisandsubsequentintracellular
killingoftheingestedbacteria(96).
A major role in this process is played by the lectin site of the leukocyte b2-integrin
receptor (also knownasCR3,Mac-1 andCD11b/CD18). Reports suggest that another
potentiallyimportantreceptor(delineatedfromothermyeloidcells),lipopolysaccharide
receptor (CD14), is only found in an inactive form. Eventually stored within the
neutrophil,CD14becomesexpressedontheoutercell-membranesurfaceunderextreme
conditions.Togetherwithneutrophildiapedesisandchemotacticmigrationtowardthe
60
siteofbacterialinfection,localcapillariesalsoreleaseanenhancedamountofserumas
a result of the effects of histamine and complement C3a and C5a upon vascular
permeability.Theincreasedtissuefluidcausesthetissuestoswellandalsoincreasesthe
exudationofgingivalcrevicular fluid.Somepathogensareabletoextendandprolong
theseinflammatoryreactionsinordertoguaranteeacontinuoussupplyofhost-derived
nutrients.
Neutrophilactivationleadstophagocytosisandintracellularkillingofmicroorganisms,as
well as to the release of enzymes, whichmay contribute to local tissue destruction.
Enhancedreleaseofelastaseandotherproteinases,suchascollagenase,resultsinthe
depolymerizationoftissuecollagenfibers,thusincreasinglocaltissuepermeability.Fig.
19
Fig.19Contemporarymodelofhost–microbeinteractionsinthepathogenesisofperiodontitis,inwhichthehost
responsedrivesanincipientdysbiosis(gingivitis).Ifthebiofilmisnotdisrupted/removed,frankdysbiosisresults
andperpetuatesachronicnonresolvinganddestructiveinflammation.DAMPs,damage-associatedmolecular
patterns;fMLP,N-formylmethionyl-leucyl-phenylalanine;GCF,gingivalcrevicularfluid;LPS,lipopolysaccharide;
MMPs,matrixmetalloproteinases;PMNs,polymorphonuclearneutrophils.
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1.2.6 RISKFACTORSFORPERIODONTITIS
Thereisanabundanceofbothempiricalevidenceandsubstantialtheoreticaljustification
foracceptingthewidespreadbeliefthanmanydiseaseshavemorethanacause,inother
wordstheyhaveamultifactorialetiology(97).Consequently,inanyparticularinstance
when a causal relationship is investigated, the specificity of the relation between
exposure to an etiological agent and effect (the necessity or the sufficiency of the
condition)maybechallenged.Inthecaseofperiodontaldiseases,itisknownthatthe
presenceofthemicrobialagent(whichisdefinedasanecessarycondition)isnotalways
accompaniedbysignsorsymptomscharacteristicofthatdisorder.Thecausalinference,
theprocessofdrawing conclusions related to the causeof adisease, is aparticularly
complexissueinepidemiologicresearch.Hillin1971formalizedthecriteriathathaveto
befulfilledinordertoacceptacausalrelation(98):
- Strengthofassociation:thestrongertheassociationbetweenputativeriskfactor
andthedisease,themorelikelyitisthattheanticipatedcausalrelationisvalid.
- Dose-responseeffect:theobservationofthefrequencyofthediseaseincrease
withthedoseofexposuretoafactor
- Temporal consistency: to establish if the exposure to the causative factor
occurredpriortothedisease
- Consistencyoffindings:ifseveralstudiesaboutthesamerelationshipshowthe
sameresults.
- Biologicplausibility:iftherelationshipshouldmakesenseinthecontestofcurrent
biologicknowledge.
- Specificityoftheassociation:iftheinvestigatedfactorisfoundtobeassociated
withonlyonediseaseandviceversa.
Inthecontestofperiodontitis,numerouscross-sectionalstudiesidentifyingpotentialrisk
factors are available, but a relatively limited number of longitudinal studies involve a
multivariateapproachtotheidentificationofexposuresofinterestwhilesimultaneously
controllingfortheeffectofpossibleconfounders.AreviewbyBorrellandPapapanou,
62
hasmadeadistinctionbetweenputativefactorsthatarenotamenabletointervention
(non-modifiablebackgroundfactors)andmodiafiablefactors(environmental,acquired,
andbehavioral)(99).
1.2.6.1 NON-MODIFIABLERISKFACTORS
1.2.6.1.1 Age
The relationshipbetweenperiodontitisandage is complex,even if it is clear that the
prevalenceofperiodontaldiseaseincreaseswithage(100).Someauthorschallengethe
relationship considering the “age effect” as the cumulative effect of the prolonged
exposure to true risk factors (101). The association between periodontitis and age
appearstobedifferentforpocketdepthandamountofclinicalattachmentloss.While
thereisapronouncedeffectofincreasingattachmentlosswithage,theeffectonpocket
depth is minimal (102). Since periodontitis is a microbially-induced inflammatory
disorder, an age-dependent alteration in innate immunity likely contribute to more
pronouncedperiodontalpathologyinelderlyindividuals.Inconclusion,anage-related,
ratherthananage-dependent,increasedsusceptibilitytoperiodontitisinolderpeopleis
biologicallyplausible.
1.2.6.1.2 GenePolymorphisms
Evidence of genetic predispositions of certain individuals has been documented in
classicaltwinandfamilystudies.Anassociationbetweenacompositegenotypebasedon
specificpolymorphismsintheinterleukin1(IL-1)geneclusterandsevereperiodontitisin
non-smokers has been reported (). Similar work has investigated polymorphism in
additionalinflammatorygenes,includingthetumornecrosisfactor(TNF)gene,theIL-6
gene,TheIL-4andtheIL-10gene.(103,104)
The majority of cross-sectional studies report positive associations between the
investigatedpolymorphismsandtheextendandtheseverityofperiodontitis.However,
theseresultsarenotconsistentacrosspopulationsandbetweenethnicgroups(105).The
resultsoffewlongitudinalstudiesarealsoconflicting.Nevertheless,Langhasconcluded
63
thatIL-1genotype-positivepatientshaveageneticallydeterminedhyper-inflammatory
responsethat isexpressedclinically intheperiodontaltissuesas increasedprevalence
andincidenceofBOPduringmaintenance(51).
Inconclusion,thereisinsufficientepidemiologicevidencetoestablishapolymorphismas
trueriskfactorforperiodontitis(106)
1.2.6.2 MODIFIABLEENVIRONMENTAL,AQUIREDANDBEHAVIORALFACTORS
1.2.6.2.1 Specificmicrobiota
Theassociationbetweenhigh levelsof colonizationby specificperiodontalpathogens
andtheprogressionofperiodontaldiseasehasbeencorroboratedbylongitudinaldata
in untreated population (see Etiopathogenesis of periodontal disease chapter).
Collectively,Datageneratedinthepastdecadeshaveenhancedourknowledgeofthe
roleofspecificperiodontalbacteriaasriskfactorforperiodontitisandhaveclarifiedthat
theintensityoftheexposuretothespecificmicrobiotaratherthanthepresenceofthe
pathogenisanimportantdeterminantoftheclinicalphenotype.Moreover,thevirulence
ofthepathogen,anditsabilitytocauseperiodontaltissuedamageandconferriskfor
diseaseprogressionmaybeentirelydifferentamongvariousclonaltypeswithinasingle
species.Ontheotherhand,pathogeneliminationfromthesubgingivalmicrobiotaresults
inimprovementsinclinicalperiodontalstatus.Aswidelydemonstrated,anantimicrobial
approach, including removal of subgingival plaque with or without the adjunct of
antibioticsorantiseptics,followedbyanadequatemaintenanceprotocol, isthesingle
mostsuccessfulandconsistentstrategyinthetreatmentofperiodontitis(107).
1.2.6.2.2 Smoking
Theassociationbetweentobaccosmokingandperiodontitiswasfoundedonthebroad
effects of multiple tobacco-related substances on cellular structure and function.
Smokinghasbeen shown toaffect thevasculature, thehumoral andcellular immune
64
responses, cell signaling processes, and tissue homeostasis (108). It is important to
underlinethattheinferiorperiodontalstatusofsmokerscannotbeattributedtopoorer
plaquecontrolormoreseveregingivitis.Infact,smokingcontributestotheformationof
adysbioticbiofilm,differentfromthenon-smokerbiofilm,characterizedbyahigherlevel
ofcolonizationbyperiodontalpathogens.Studiesexaminingtheeffectsofsmokingon
theoutcomeofperiodontaltreatmenthavedemonstratesthattreatmentresponsesare
modifiedbycigaretteconsumption,withcurrentsmokersexhibitingpoorer responses
thanformerorneversmokers(109).Thesestudieshaveconfirmedthenegativeeffectof
smokingon theoutcomeof severalperiodontal treatmentsmodalities, includingnon-
surgical, surgical, and regenerative periodontal therapy (110). In contrast, smoking
cessationwasshowntohavebeneficialeffectonperiodontalstatus.
Inconclusion,cigarettesmokingappearstofulfillthemajorityoftherequiredstepsof
theriskassessmentprocessstipulatedbyBeckandisconsideredoneofthemajorrisk
factorsforperiodontitis.
1.2.6.2.3 DiabetesMellitus
Theroleofdiabetesmellitus(DM)asariskfactorforperiodontitishasbeendebatedfor
decades(111).TheadverseeffectofDMonperiodontalstatusappeartobeparticularly
pronounced in subjectwith a longdurationofDMandpoormetabolic control (112).
Studieshaveprovidedevidenceofadose-responserelationshipbetweenpoormetabolic
controlandtheseverityofperiodontitis.Theoutcomeofperiodontaltreatmentinwell-
controlleddiabeticpatientsissimilartothatofnon-diabeticsubjects,whilepatientwith
poorlycontrolledDMdisplayaninferiortreatmentoutcome(113).
Severalstudiessuggestatwo-wayrelationshipbetweenDMandperiodontitis.Beyond
theobservedincreasedseverityofperiodontaltissuedestructioninsubjectswithDM,
studiesindicateahigherincidenceofDMcomplicationsandpoorermetaboliccontrolof
diabetesinperiodontitispatients.
65
1.2.6.2.4 Obesity
Theplausibilityofapotentiallinkbetweenobesityandperiodontitishasbeensuggested
to involve a hyper-inflammatory state and an aberrant lipidmetabolism prevalent in
obesity,aswellasthepathwayofinsulinresistanceallofwhichmaycollectivelyresultin
anacceleratedbreakdownoftheperiodontaltissues(114)
Anumberofstudieshaveindicatedapositiveassociationbetweenobesity,definedas
bodymassindex(BMI)>30kg/m2,andperiodontitis.It is importanttoknowthatthe
majorityofthepublicationiscross-sectional,andthusdonotfacilitateinterferenceson
temporalityormechanisms, and theavailableeoidemiologicdata are limitedandnot
universally consistent, additional research on the role of obesity in periodontitis is
warranted.
1.2.7 PERIODONTITISANDOSTEOPOROSIS
Likewiseosteoporosis,periodontitisisasilentdisease,whichoftenremainsundiagnosed
untillate,whenteethbecomelooseoranabscessdevelops.Interestingly,bothdiseases
alsosharesomeriskfactors,suchasoldage,smoking,anddiseases/medicationsthatmay
interferewithosseoushealing (115). As a consequence, several studies have tried to
investigate if these two diseases are linked and if osteoporosis can be considered a
predisposingfactorforthedestructionofperiodontalsupport.
Early cross-sectional studies of limited sample size and largely confined to post-
menopausalwomen, have suggested thatwomenwith low bonemineral density are
more likely to have gingival recession and/or pronounced gingival inflammation and
clinicalattachmentloss(116).
A radiographic study by Pearson in 2002 reported a positive association between
osteoporosisandperiodontitiswithasignificantORof1,8(95%CI1,2–2,5).However,
studiesthathavefailedtodemonstratethecorrelationhavealsobeenpublished(117).
66
Basedon theseobservation, it hasbeenhypothesized that the systemic loss of bone
densityinosteoporoticpatientsmay,incombinationwithotherfactors,provideahost
system that is increasingly susceptible to inflammation-associated destruction of the
periodontaltissues(118).Overallthedatafromlongitudinalstudiesareconflicting,infact
somestudiesreportapositiveassociationbetweenosteoporosisandclinicalattachment
lossinwomenwithsubgingivalcalculusbutnotifthecalculusweresupra-gingival(119).
Intheseavailablestudies,osteoporosiswasdiagnosedbyapplyingdifferenttechniques,
goingfromtheoldsingleanddualphotonabsorptiometry,tosingleordualX-rayenergy
absorptiometry tha is the actual WHO gold standard, to ultrasound or quantitative
computerized tomography. On the other side, periodontitis was assessed either
radiographically, by measuring alveolar bone resorption, or clinically, by measuring
clinical attachment loss or tooth loss. It is therefore intuitive to understand how
heterogeneous the publications are and how difficult it is to draw meaningful
conclusions.Morerecentsystematicreviewsoftheavailablestudiesonosteoporosisand
periodontitisconcludedthattherelationshipbetweentwoconditionscouldbeplausible
butisstillunclear(118).
67
1.3 OSTEOPOROSISANDJAWBONES
1.3.1 SYSTEMICANDJAWBONELOSS
It is plausible to hypothesize that osteoporotic-induced systemic bone loss may also
includebonelossatthejaws.Pre-clinicalstudiesinovariectomizedanimalsreportedthat
oestrogendeficiencycoulddetermineadecreaseinbonevolumeandalterationsinthe
trabecularstructureofthemandibularcondyle(120,121),intheinter-radicularseptaof
molaralveolarbone(122,123),anincreaseinmandibularcorticalporosity(124)anda
reduction inmineralizationdensity,osteocyte lacunae,andosteocytenuclearnumber
(125).
Someclinical studies suggested that there isan increasedalveolarbone resorption in
osteoporotic versus non-osteoporotic edentulous patients (126, 127), and that
medications affecting systemic bone density (like hormone replacement therapy and
bisphosphonates) are associatedwith a slower loss of alveolar bone (128). However,
otherclinicalevidencesdidnotconfirmtheinfluenceofsystemicbonemineraldensity
ontheresorptionofedentulousjaws(129-131).Severalclinicalstudiesinvestigatedthe
relationshipbetweenbonedensitymeasuredindifferentsystemicskeletalsitesandin
thejawbonesinsubjectswithdifferentTscores.Althoughmanyofthesestudiesfounda
positive correlation (132-139), others reported that jawbone density is only partially
correlatedtothedensityinotheranatomicsites(140-142).Therearealsosomelimited
evidencesthatdidnotfoundanydifferences in jawbonedensitybetweennormaland
osteopenic/osteoporoticsubjects(143,144).Theheterogeneitybetweentheavailable
studiesmayhavecontributedtotheseconflictingresults.Infact,differenttechniquesto
measurebonedensitywereadopted,dentateandedentulousareaswereoftenpulled
together and populations with different demographic characteristics were evaluated
withoutaccountingfortheseimportantconfoundingvariables.
Despite the contrasting results, during the past two decades, several studies have
evaluated the accuracy of different quantitative and qualitative indices calculated on
68
dentalradiographs(OPG) in identifyingpatientswithreducedskeletalBMD(145-150).
Amongstthelinearindices,thefollowingarethemostpopularones:
1) Mandibular corticalwidth (MCW) ormental index (MI) ormandibular cortical
thickness(MCT):Itisusuallymeasuredinthementalforamenregion,alongaline
passingthroughthemiddleoftheforamenandperpendiculartothetangentto
thelowerborderofthemandible(151).
2) Panoramicmandibular index (PMI): It is the ratio between theMCW and the
distancefromthelowerbordertotheinferioredgeofthementalforamen(152)
3) Antegonial index (AI): It is themandibular thicknessmeasured at the anterior
borderoftheramus(153)
4) Gonialindex(GI):Itisthemandibularthicknessmeasuredattheposteriorborder
oftheramus(154).
5) Mandibularratio(M/M):Itistheratiobetweenthetotalheightofthemandibular
bodyandtheheightfromthelowerborderofthemandibletothelowerborder
ofthementalforamen(155)
Amongstthequalitativemorphometricparameters,theKlemettiindex(KI)isbyfarthe
mostwidelyadoptedindex.TheKI,alsoknownasmandibularcorticalindex,classifiesthe
mandibularcortexdistaltothementalforameninthreecategories:
• C1,whentheendostealmarginisevenandsharp;
• C2,whentheendostealmarginpresentslacunarresorptionorcorticalresidues
ononeorbothsides;
• C3,whenthere isaclearlyporouscortical layer,withheavyendostealcortical
residues(156)
69
Fig.20A)Quantitativeindices:MCW=b;PMI=b/a;GI=d;AI=e;M/M=c/a
(B)Klemettiindex(orMCI)
70
2 HYPOTHESISANDAIMOFTHERESEARCH
71
2.1 BACKGROUNDANDHYPOTHESIS
Osteoporosisisoftenreferredtoasa“silentdisease,”sincequiteoftenitisnotdiagnosed
until a fragility fracture occurs. Osteoporotic fractures are expected to occur in
approximatelyone intwoCaucasianwomenandone infivemen,thusrepresentinga
worldwideburdenwithanassociatedhighmorbidityandmortality.Themeasurementof
bonemineraldensity(BMD)atthefemurneckandlumbarspinewithdual-energyX-ray
absorptiometry(DXA)isthegoldstandardforosteoporosisdiagnosis.Althoughthereis
indirectevidencethatsupportsthescreeningofpopulationgroups(mainlywomen>65
yearsold)toreducetheriskoffracturesbyidentifyingandtreatingpeoplewithreduced
BMD,inmostcountriesthecostofageneralscreeningprogrammeisnotaffordableor
cost effective. As a consequence, osteoporotic patients are often undiagnosed or
untreatedforlongperiodsoftime.Remarkably,only23%ofwomen>67yearsoldwho
have experienced an osteoporosis-related fracture receive either a BMD test or an
osteoporoticmedicationinthesixmonthsafterthefracture,asreportedbytheNational
CommitteeforQualityAssurance(NationalCommitteeforQualityAssurance2014).
Considering that dental panoramic radiographs (OPGs) are frequently performed for
diagnostic purposes during dental check-ups or before several dental procedures
(Tugnait, Clerehugh et al. 2003), it would be of great value if they could be used in
identifyingpatientsatriskofosteoporosis.Theideaisthatdentistscouldpotentiallyspot
previouslyundiagnosedosteoporoticpatients and refer them to the specialist,where
theycouldbetreatedbeforedevelopingafracture.
Periodontitisisachronicinflammatorydiseasethataffectsthesupportingtissuesofteeth
(periodontalligament,gumandbone)and,ifuntreated,caneventuallyleadtotoothloss.
AccordingtotheNationalHealthandNutritionExaminationSurvey (NHANES),46%of
adultspresentedwithperiodontitisinUSin2009to2012,thusaccountingfor64.7million
people, with 8.9% of them presenting severe periodontitis. The demonstration of a
relationship between osteoporosis and periodontitis is difficult, especially in
considerationofthefactthattheyaremultifactorialdiseasesandthatthecommonrisk
72
factorsmay introduceadditionalbiases.Although several cross-sectional studieshave
reportedanassociation.
2.2 AIMOFTHESTUDY
2.2.1 PRELIMINARYLITERATUREREVIEWS
1. Todoanarrativereviewontheavailableevidenceonthecorrelationbetween
skeletalandjawbonedensityinosteoporoticsubjects
2. Todoanarrativereviewontheavailableevidenceonthecorrelationbetween
periodontitisandosteoporosis
2.2.2 PRIMARYOUTCOMES
3. To assess the feasibility of using dental panoramic indices to screen for post-
menopausalosteoporosis
4. To assess the sensitivity and specificity of Klemetti Index (KI) to screen for
osteoporosisinpostmenopausalwomen
5. To assess the sensitivity and specificity of quantitative panoramic indices
(Mandibular Cortical Width and Panoramic Mandibular Index) to screen for
osteoporosisinpostmenopausalwomen
6. To assess the precision and reproducibility of panoramic indices to screen for
osteoporosisinpostmenopausalwomen
73
2.2.3 SECONDARYOUTCOMES
7. To assess a statistical significant correlation between periodontitis and
osteoporosis
74
3 LITERATUREREVIEWS
75
3.1 SYSTEMICMINERALBONEDENSITYANDJAWBONES
Recently,Calciolarietal(Calciolari,Donosetal.2015)conductedasystematicreviewof
theliteratureandmeta-analysisontheaccuracyofpanoramicmorphometricindicesin
detecting reduced BMD. 50 studies meeting the inclusion/exclusion criteria were
includedinthequalitativeevaluation,buttheriskofbiasassessment(performedwith
theQUADAS-2tool)revealedthatagreatpartofthestudieswasnotofhighquality.In
particular, methodological concerns were associated to the index test and patient
selection domains, as several studies did not report clearly the patients’
inclusion/exclusion criteria, they did not state if the examiners were blinded to the
patients’ skeletal BMD or they did not measure intra/inter observer agreement. 19
studieswereeventuallyincludedinthemeta-analysis,whichcouldbeperformedonlyfor
three indices: MCW, PMI and KI. Within the limitations of this review, the authors
concludedthatPMIwithacut-offvalueof0.3seemedthemostaccuratelinearindexto
screenforreducedBMD(sensitivityandspecificityabove70%).Lessstrongconclusions
couldbedrawnforMCW,butthisindexseemedmoreusefultoexcludetheriskoflow
BMD,since in90%ofthecasespatientswithacorticalwidthwiderthan4mmhada
normalskeletalBMD.Thequalitativeevaluationofmandibularcorticalerosions(KI)was
also found to be a useful and reliable indicator of reduced skeletal BMD, since in
approximately80%ofthecasesitwasassociatedwithatleastosteopenia.
Asnopanoramicindexwith100%sensitivityandspecificityhasbeenidentifiedyet, in
some studies it has also been proposed to combine different indices between them
(Klemetti,Kolmakovetal.1994,Miranda,Aritaetal.2012)orwithwell-knownclinical
riskfactorsforosteoporosis(suchasBMI)(Horner,Devlinetal.2002).
SincethesystematicreviewbyCalciolarietalhasincludedstudiestillMarch2014,the
samesearchstrategyhasbeenusedinOctober2018toupdatetherecentreviewwith
theliteratureofthelastfouryears.
The applied research strategy included terms related to the population and the
interventioninvestigatedandhasbeenperformedintwodatabases,MEDLINEviaOVID
andEMBASE,updateinOctober2013.
76
No language restrictions have been applied. The search strategy for MEDLINE and
EMBASE have used a combination of MeSH terms and text words which have been
combinedasPopulationANDIntervention.Tab.3
MEDLINEviaOVID Meshterms Free-textsearch LimitsPopulation bonedisease,
metabolic/orexpbonedemineralization,pathologic/orexposteoporosis
osteoporo$ ORosteopeni$
NOT (animals NOThumans)
Intervention/Exposure BoneDensityORexpDensitometryexpJawORexpJawEdentulous
(bone adj2 densit$) OR(bone adj2 content) ORbmd OR bmc ORdensitometr$jaw$ OR mandib$ ORmaxill$oredentul$
EMBASE Emtreeterms Free-textsearch LimitsPopulation exp.osteoporosis
ORosteopeniaosteoporo$ ORosteopeni$
NOT (animals NOThumans)
Intervention/Exposure BoneDensityORBonedensitometryJawOREdentulousness
(bone adj2 densit$) OR(bone adj2 content) ORbmd OR bmc ORdensitometr$jaw$ OR mandib$ ORmaxill$oredentul$
Tab.3Searchstrategy
Due to the large volumeof literatureon this topic, a three-stage screeninghasbeen
appliedto increasetheprecisionofscreening.All stages (titles,abstract, full-text)has
beencarriedoutbythereviewer.Atthestageoffull-textscreening,adataextraction
formwascompletedtocheckeligibilityofthestudiesand,ifeligible,tocollectdetailed
informationaboutpopulation,interventionandoutcomes.
Sevenarticleshavebeenincludedinthe2018update,accordingtotheinclusioncriteria
ofthe2015reviewbyCalciolarietal.Alltheselectedpapershavedescribed:
- Totalnumberofpatientandthepartitioninhealthy,osteopenicandosteoporotic
- Almostonepanoramicindexusedforthepredictionofthebonemasscondition
77
- Thegroupsconsideredtobematchedforthecomparison
- At leastoneof these information: sensitivity, specificity,numberof false/true
negative/positive,ROCcurve.
TheindicesthathavebeenusedmostfrequentlytoscreenforreducedBMDhavebeen:
Mandibular cortical width (MCW): In the original revision, 34 studies reported
measurements of the width of themandibular cortex, which was referred to as the
mandibularcorticalwidth(MCW)ormentalindex(MI)ormandibularcorticalthickness
(MCT).Inmostofthestudies,MCWwasmeasuredinthementalforamenregion,along
a line passing through the middle of the mental foramen and perpendicular to the
tangent to the lower border of themandible eithermanually or digitally,with image
analysissystems.ThecutoffvalueswerechosenafterdrawingtheROCcurveinorderto
findthehighestsensitivity/specificityandtheyrangedfrom2.69mmto5mm.Thelevels
ofsensitivityandspecificityassociatedwiththis indexwereheterogeneousandhada
reciprocal relationship that varied in relation to the threshold chosen. A few studies
reporteda sensitivity>95% (157,158),while inother studies, thisparameterdidnot
reach20%(157,159).Thesamevariabilityappliedtothespecificitylevels.Theupdate,
hasshownthatinthearticlespublishedinthelastfouryears,theanalysisofthewidthof
themandibularcortexhasbeenreportedinallthearticles.Thecutoffvalueswerechosen
afterdrawingtheROCandranged from1.5mmto4mm.Similarly to the2015data,
sensitivity and specificity were heterogeneous. Carmo et al. (160) have reported a
sensitivity/specificity>95%,butotherstudies(161-164)haveshownlevels<70%.
Panoramicmandibular index (PMI): In the original revision, 9 studies considered the
panoramic mandibular index (PMI). This index represents the ratio between the
mandibularcorticalwidthatthementalforamenregionandthedistancefromthelower
bordertotheinferioredgeofthementalforamen(152).Mostofthestudiesreporteda
cutoffvalueof0.3,withlevelsofsensitivityandspecificityindetectingindividualswith
reducedbonedensity(Tscore<–1)rangingfrom40.8%to100%andfrom47%to88%,
78
respectively.Only1studyconsidered4differentcutoffs(159).OnlyonestudibyBaltoet
al.hasconsideredthePMIaspredictorofosteoporosis,reportingaAUCof0,591(161).
Klemettiindex(KI):Twenty-sevenstudiesconsideredtheKlemettiindex(KI)asatoolfor
predictionofreducedBMDaccordingtoCalciolarietal.(165)Thisindex,alsoknownas
themandibularcorticalindex,qualitativelyclassifiesthemandibularcortexdistallytothe
mentalforameninthefollowingcategories:C1,whentheendostealmarginisevenand
sharp;C2,whentheendostealmarginpresentslacunarresorptionorcorticalresidueson
oneorbothsides;andC3,whenthecorticallayerisclearlyporous,withheavyendosteal
corticalresidues.Intheincludedstudies,thepresenceofcorticalerosions(eitherC2or
C3 type)produceda sensitivity indetecting reducedBMD (T score<–1) ranging from
48.7% to 100% and a specificity ranging from 31% to 88.89%. The sensitivity in the
diagnosisofosteoporosis(Tscore≤–2.5)variedfrom35.9%to90.9%andthespecificity
from 7.8% to 93.9%. The wide range of outcomes reported is a sign of the high
heterogeneitybetweenthestudies.Onlyafewstudiesevaluatedtheaccuracyofclearly
erodedcortex(C3)indetectingosteoporosis(151,166,167).Onlyoneoftherecently
publishedarticleshasreporteddataonklemettiindex.InthepaperbyCarmoetal.the
presenceofcorticalerosions(eitherC2orC3type)producedasensitivity indetecting
reducedBMD (T score<–1)of 100%anda specificity of 90,1%. The sensitivity in the
diagnosis of osteoporosis (T score ≤–2.5) was 95% and the specificity was 98,9%
(160).Tab.4
79
Author(year)
TotalN.pts
N.Ost
N.Osp
N.Healthy
Age(y±SD)
Panoramicindex
Typemeasurement
Cutoff Groupsmatching
Sensitivity,%(95%CI)
Specificity,%(95%CI)
PPV,%(95%CI)
NPV,%(95%CI)
AUC(SE,95%CI)
Baltoetal.(2018)
431 75 124 232 57.78±6.24
MCW
Manualannotation
4.6mm Healthyvs.osp+ost
58.4 60.2 0.620(0.031,0.550-0.690)
4.1mm Healthy+ospvs.ost
69.4 68.4
PMI
Manualannotation
0.591(0.036,0.521-0.662)
M/M Manualannotation
0.592(0.041,0.512-0.672)
Carmoetal.(2017)
198W 20(lumbarspine)
101(lumbarspine)
77(lumbarspine)
53.1±5.0
KI
Visual C1vs.C2+C3
Healthyvs.osp+ost
100% 90.1% 94.5% 100%
C1+C2vs.C3
Healthy+ospvs.ost
95% 98.9% 90.5% 99.4%
MCW
Manualannotation
3mm Abnormavs.normal*
100% 67.5% 82.9% 100%
11(femoralneck)
77(femoralneck)
110(femoralneck)
KI
Visual C1vs.C2+C3
Healthyvs.osp+ost
100% 63.6% 68.8% 100%
C1+C2vs.C3
Healthy+ospvs.ost
100% 94.7% 52.4% 100%
80
MCW
Manualannotation
3mm Abnormalvs.normal*
100% 47.3% 60.3% 100%
Kathirveluetal.(2014)
64W 36 28 52.5±12.7
MCW Manualannotation
unclear Healthy+ospvs.ost
0.856(0.05,0.759-0.953)
Papamanthosetal.(2014)
315w
106 103 106 59.64±8.19
MCW Manualannotation
Osteopenic</=3.69
Healthyvsosteopenic
66.99 62.26 0.656
Osteoporotic</=3.24
Healthyvsosteoporotic
80.19 81.13 0.872
Osteoporotic</=3.24
Osteopenicvsosteoporotic
80.19 72.82 0.809
Anburajan(2014)
141W 21(spine)/20(femoralneck)
120(spine)/121(femoralneck)
49.07±3.06
MCW Computer-aidedsystem
unclear Healthyvs.ost
0.886(0.03,0.840-0.941)
Nagietal.(2014)
120w 60 0 60 60.17±5.5
MCW Manualannotation
3.35
Healthyvsosteoporotic
55 93.3 0.778(0.693–0.849)
81
Kimetal.(2014)
194W Unclear
Unclean
Unclear
65.6±8.6
MCW
Computer-aidedsystem
1.5mm
Healthy+ospvs.ost
14.3 96.2 0.737
2mm 35.7 91.8 2,22mm
67.9 78.5
2.5mm
67.9 69.6
3mm
85.7 43.7
3.5mm 67.9 78.5
Tab.4Papersincludedinthereview(2014-2018)
3.2 PERIODONTITISANDOSTEOPOROSISDespitetheinvestigationontherelationshipbetweentheincidenceofperiodontitisin
osteoporoticpatientshasbeenconsideredasecondaryoutcome,anarrativereviewhas
beencarriedouttosummarizethecontroversialavailableliteratureaboutthecorrelation
andtobetterunderstandthepositionoftheinternationalscientificcommunity.
The question addressed was the following: “Is periodontitis correlated with
osteoporosis?” and the applied research strategy included terms related to the
populationandtheinterventioninvestigatedandhasbeenperformedintwodatabases,
MEDLINEviaOVIDandEMBASE,updatein2018.
No language restrictions have been applied. The search strategy for MEDLINE and
EMBASE have used a combination of MeSH terms and text words which have been
combinedasPopulationANDIntervention.Tab.5
MEDLINEviaOVID/EMBASE MeSHterms Freetext LimitsPopulation
Bonedisease,metabolic/orexpbonedemineralization,pathologic/orexposteoporosis
Osteoporo$ORosteopeni$OR(bonelossadj2agerelated)
NOT(animalsNOThumans)
Intervention/Exposure ExpPeriodontalDiseases/
Periodont$orparodontos$orpyorrheaorfurcation
Tab.5Searchstrategy
Thestudiesassessingthecorrelationbetweenperiodontitisandosteoporosishavebeen
considered.Onlystudieswithatleastfivepatientswereselectedtoexcludeindividual
casereports.Studiescarriedoutascase-controlorcohortorcross-sectionalhavebeen
included.Studieshavebeenincludediftheydirectlycomparedtheassociationbetween
osteoporosisandchronicperiodontitis,measured intermsofclinicalattachment level
83
(CAL)and/orpocketprobingdepth(PPD).Theconsidereddiagnosisofosteoporosishas
beentheDXAtestateitherhiporspine.
Articlespublishedfrom1949to2018havebeenconsidered.Interestingly,thenumberof
articlesrelatedtothistopichasprogressivelyincreasedinthepastyears.Fig.21
Fig.21Numberofarticleperyearfrom1949to2018
Athree-stagescreening(titles,abstract,full-text)wasappliedtoincreasetheprecision
ofthereview.Atthestageoffulltextscreening,adataextractionformwascompleted
tochecktheeligibilityofthestudiesandtocollectdetailedinformationaboutpopulation,
interventionandoutcomes.Tab.6
Fifteenstudieshavematchedwiththeinclusioncriteriafortheliteraryreview.
Pilgrametal.havefoundaweakpositivecorrelationbetweentheperiodontalstatusand
BMD in longitudinal follow-up of 3 years though no correlation could be seen at
cross-sectionallevelin135participants(168).Brennanhasfoundasignificantcorrelation
betweenCALandBMDoftotalforearm,worstsiteT-score,anteroposteriorspine,and
whole body (119) while Tejal has reported a weak correlation between the CAL and
systemicosteoporosis(r=0.10–0.17),whichhasnotreachedastatisticalsignificance.
AlthoughWeyanthasfoundnostatisticallysignificantassociationbetweenperiodontal
indicators and BMD in 292 participants, a trend toward a more severe periodontal
diseasewasseeninalltheirmeasurementswithdecreasingBMD,indicationofapossible
0
20
40
60
801949
1963
1968
1972
1976
1980
1985
1989
1993
1997
2001
2005
2009
2013
2017
Num
bero
farticles
Years
84
association (117).Moeintaghavi andMarjanovic also have not found any statistically
significantassociationbetweenosteoporosisandperiodontitis,butthesamplesizehas
beenverysmall(169,170)
Ten out of 15 studies included have reported a significant association between
periodontitis and osteoporosis. Most of the included studies have been either cross
sectionalorprospectivestudiesandincludedpost-menopausalwomen.Themajorityof
the studies have reported values of CAL and have used the correlation or regression
coefficientsoroddratios.
Inconclusion,theliteraturepointsoutthatcouldbeacorrelationbetweenoralboneloss
and skeletal osteoporosis but the topic is still controversial. Several studieshave also
reported a correlation between systemic osteoporosis and number ofmissing teeth,
reducedalveolarcrestalheight,ortoothmobility.Whentoothlossoccurs,thereisno
mechanical stress in its antagonistic and in the alveolar bone supporting. The
consequenceistheexpansionofthebonemarrowcavitytogetherwitha loss inbone
volume.
Forallthesereasons,theassociationbetweenthesetwodiseasesisbiologicallyplausible
andseveralmechanismshavebeenproposedtolinkthem.Itcanbespeculatedthatthe
reducedBMDassociatedwithosteoporosismightalsoaffect the jawbonesandmight
acceleratealveolarbonelossfollowinginsultbyperiodontalbacteria(118).
Author(year)TotalN.pts
Age(y±SD))
Periodontaldiseasecut-off
BoneMineralDensity
Numberofpatientswithosteoporosis
Numberofpatientswithperiodontitis
AssociationbetweenCAL
andosteoporosis
Brennanetal.(2007)
1329 66.6±7.0 CALDEXAspine,hip,forearm,wholebody
Normal508(44.8%)Osteopenia469(41.4%)Osteoporosis157
yes
Passosetal.(2013)
521 60.8PPD>5mmCAL>6mm
DEXAproximalFemurandlumbarspine
Osteoporosis380Osteopenia141
94 yes
Habashnehetal.(2010)
400 62.5±6.4PPD,CAL5
mmPD/6mmCAL
DEXAlumbarspine(L1-L4)andfemoralneck
Normal94(23.5%)Osteopenia170(42.5%)
yes
85
Osteoporosis136(34.0%)
Iwasakietal.(2013)
39768.2
(60-80)
CAL,PPD≥4mm
DEXAlumbarspine(L2-L4),felneck
Normal161(44.8%)Osteopenia136(41.4%)Osteoporosis100
142(35.8%)
Yes
Marjanovicetal.(2013)
380 45-65PPD>5.5mmCAL>7mm
DEXAproximalFemurandlumbarspine
Osteoporotic98Nonosteoporotic282
150 No
Weyantetal.(1999)
29275.5±4.38
PPD,CALDEXAproximalFemurandlumbarspine
142 No
Gondim(2013)
148 58.93±4.7
CAL,PPDModerate:CAL≤5mmSevere:CAL>5mm
DEXAlumbarspine(L1-L4),femoralneck,andtotalfemur
Yes
Gomes-Filhoetal.(2007)
139 58.8±6.4
PPD>4mmCAL>3mm
DEXAfemur/spine
40cases60controls
48 Yes
Pilgrametal.(2002)
135 59PPDCAL
DEXAproximalFemurandlumbarspine
No
Penonietal.(2015)
13469.84
PPD>5mmCAL>6mm
DEXAproximalFemur,totalfemurandlumbarspine
Normal48Osteoporosis86 51 Yes
Julurietal.(2015)
100 60.12 CALPPD
DEXAlumbarspine
50cases50controls
Yes
Singhetal.(2014)
78 PPD,CALDEXAlumbarspine(L1-L4)
Normal22Osteopenia25Osteoporosis31
Yes
Tejaletal.(2000)
70 62.10±7.1 CAL,ABLDEXAproximalFemurandlumbarspine
No
Moeintaghavietal.(2013)
60 53.05 PPD,CALDEXAproximalFemurandlumbarspine
Normal20Osteopenia20Osteoporosis20
No
Grocholewiczetal.(2012)
37 59.4±5.6
PDIof6indicatesanattachmentlossof≥6mm
DEXAlumbarspine(L2-L4),femoralneck,anddistalradius
Yes
Tab.6Papersincludedinthereview
86
4 CLINICALSTUDYDESIGN
87
Inthepastyears,specificquantitativeandqualitativeindices/parameters,whichcanbe
calculated on dental panoramic radiographs, have been proposed as tools to detect
osteoporosis,withdifferentlevelsofaccuracy.
Amongst thequantitative indices, themostadoptedonesare themandibular cortical
width(MCW)andthepanoramicmandibularindex(PMI).
Regardingthequalitativeindices,theKlemettiindex(KI)isbyfarthemostappliedone.
A recent systematic review andmeta-analysis fromour group (165) showed that the
presence of any kind of cortical porosity (C2+C3) is associatedwith a sensitivity and
specificityindetectingosteoporosisof80.6%and64.3%,respectively.Theadvantageof
usingthisindex,comparedtoothersavailable,isthatitisstraightforwardandrelatively
easytomeasureanditdoesnotrequirespecificsoftwares.
ItisclearthatthepanoramicindicescannotreplacethediagnosisofosteoporosisbyBMD
measurementwithDXAscan.However,wheneverapanoramicradiographisavailable,
they might be opportunistically used to detect previously undiagnosed osteoporotic
patientsandreferthemtoaspecialist.
Whileseveralstudiessupporttheuseofpanoramicindices,theyhaveneverbeentested
inanItalianUniversityHospitalsettingandinastudyadequatelypoweredandcontrolled
forconfoundingvariablesandthereforeabletoputtogethertheinformationoftheKI
withDXA.
4.1 OVERALLSTUDYPLAN
Thisiscross-sectionalobservationalstudyaimingtorecruitacohortof124consecutive
post-menopausalwomen.Theonlystudyvisittookplaceatthe“CentroUniversitariodi
Odontoiatria,DipartimentodiMedicinaeChirurgia,UniversitàdiParma”.
All post-menopausal women ≥ 65 years old attending the Centro Universitario di
Odontoiatriainthenewpatients’orfollow-ups’clinicswereapproachedtocheckforthe
inclusion/exclusioncriteriaandtheirwillingnesstotakepartinthestudy.Furthermore,
doctors (general practitioners or osteoporosis specialists)were contacted andwill be
kindlyaskedtoinformtheirpatientthathaddoneaDXAscanwithinthepast12months
88
aboutthestudy.Potentiallyeligiblepatientswerebookedanappointmentatthe“Centro
UniversitariodiOdontoiatria,DipartimentodiMedicinaeChirurgia,UniversitàdiParma”
tocheckforinclusion/exclusioncriteriaandfortherecruitment.Aspartofthestudy,they
receivedafull-mouthexaminationofthehardandsofttissuesandanOPGatnocost.
Beforeenrolment,writtenandverbalinformationwasgiventothepatientsandwritten
informedconsentwasobtained.
4.2 INCLUSIONCRITERIAEachparticipanthadtomeetthefollowinginclusioncriteriatobeenrolledinthestudy:
• ≥65yearsold
• Inself-reportedmenopause,definedasthepermanentcessationofovulation,for
atleastoneyearbeforethevisit(171).
• ADXAexaminationatthehipandlumbarspineperformedwithintheprevious12
months
4.3 EXCLUSIONCRITERIAParticipantswerenoteligibleforparticipationinthestudyif:
• Affectedbysystemicdiseases(withtheexceptionofosteoporosis)recognizedto
severely affect bonemetabolism (e.g. Cushing's syndrome, Addison's disease,
diabetes mellitus type 1, leukaemia, pernicious anaemia, malabsorption
syndromes,chronicliverdisease,rheumatoidarthritis).
• KnowinglyaffectedbyHIVorviralhepatitis.
• Historyoflocalradiationtherapyinthelastfiveyears.
• Affectedbylimitedmentalcapacityorlanguageskillssuchthatstudyinformation
cannot be understood, informed consent cannot be obtained, or simple
instructionscannotbefollowed.
89
• Other severe acute or chronic medical or psychiatric condition or laboratory
abnormalitywhichmayincreasetheriskassociatedwithtrialparticipationormay
interferewith the interpretation of study results and, in the judgment of the
investigator,wouldmaketheparticipantinappropriateforentryintothistrial.
4.4 STUDYVISITSOnly1studyvisitwasperformedwithdatacollection:
• Signingofinformedconsent;
• Recordingofanyconcomitantmedication;
• Confirmation of participant eligibility in relation to the inclusion/exclusion
criteria;
• Examinationofhardandsofttissues;
• Full-mouth six-points periodontal chart, with recording of probing pocket
depth(PPD),recession(REC),furcationinvolvementandmobility.
• Dental panoramic radiograph (OPG) if not performed at the Centro
UniversitariodiOdontoiatriawithintheprevious12months
4.5 STUDYMEASUREMENTS4.5.1 Dentalpanoramicradiographs
If not performed within the previous 12 months at the Centro Universitario di
Odontoiatria,anOPGwasperformedduringenrolmentvisit.
OPGsareroutine low-dosex-raysthatareperformedduringdentalcheck-ups,follow-
upsorbeforedentaltreatments(e.g.extractions,implantplacement,etc.),astheyallow
the evaluation of bone and dental structures of both jaws, the sinus and temporo-
90
mandibular joints. Theyare routinelydone toeachnewpatient attending theCentro
UniversitariodiOdontoiatria.
AnORTHOPHOSXG3D(SironaDental)machinewillbeusedandthestandardsettings
recommendedbythedeveloperwillbeapplied.
Two examiners blinded to the DXA results (provided by the patients) independently
measured the panoramic indices on the OPGs. In particular, for the KI, the level of
mandibular cortical erosion in themental foramen regionwasqualitatively evaluated
afterzoomingtheOPGandoptimizationoftheimagecontrastandwhitebalance.
TheMCWandPMIweremeasuredwiththedigitalsoftwareprovidedbyORTHOPHOSXG
3D.
Afteratleast1week,theexaminerswillrepeatthemeasurementsin20%oftheOPGs,
inordertoevaluateintra-examinerreproducibility.
4.5.2 PeriodontalExaminationsA complete medical and dental history were obtained during enrolment visit. The
histories included demographic background information, systemic and dental status
information.
During the enrolment visit, a detailed examination of the hard and soft tissues was
performed and a trained examiner also registered the probing pocket depth (PPD),
gingivalrecession(REC),atsixsites(mid-buccal,buccal,disto-buccal,lingual,mid-lingual
anddisto-lingual)aroundeachtoothwithaUNC-15probe.Furcationinvolvementwas
assessedwithaNabersprobeandmobilitywasassessedwiththehelpofamirror.
Theresultsofthedentalandperiodontalexaminationwereexplainedtothepatients.
Itisimportanttohighlightthattheperiodontalanddentalexaminationwereperformed
aspartofthestandardexaminationthateachpatientreceiveswhenattendingtheCentro
UniversitariodiOdontoiatriaoranyotherdentalcentre.
91
4.6 STATISTICALPROCEDURES4.6.1 SamplesizeestimationThesamplesizewasbasedontheresultsofsensitivityandspecificityoftheKI(primary
outcome)obtainedfromasystematicreviewandmeta-analysisrecentlypublishedbyour
group(Calciolarietal.2015)andonthelevelofsensitivityofapanoramicindexthatboth
osteoporosisexpertsandpatientswouldconsiderasmeaningful.Infact,duringaPatient
andPublicInvolvement(PPI)group,boththepatientsandtheconsultantsinterviewed
agreedthatatestthatcorrectlyscreenforosteoporosisin80%ofthecaseswouldbe
worth, provided that the lower confidence limit is at least 55%. By taking into
considerationthesetargetvalues,andspeculatingaprevalenceofosteoporosisof30%
amongstpost-menopausalwomenattendingadentalhospital,124participantsneeded
toberecruitedforthisstudy.
4.6.2 StatisticalmethodThefollowingdatawererecorded:
- Sensitivity, specificity, false positive rate, negative positive rate of Klemetti Index
(primaryoutcome)indetectingosteoporosis.Thepresenceofahighlevelofmandibular
corticalerosion(C3)wereconsideredasasignofosteoporosis,whileasharpandeven
endostealmargin(C1,C2)wasconsideredasignofnormalbonemineraldensity.
- Sensitivity, specificity, false positive rate, negative positive rate and ROC curve of
MandibularCorticalWidthandPanoramicMandibularIndexindetectingosteoporosis
-Statisticalsignificantcorrelationbetweenperiodontalstatusandreducedsystemicbone
density(Periodontalprobingdepth(PPD),FullMouthBleedingScore(FMBS),FullMouth
Plaque Score (FMPS), Clinical attachment loss (CAL), Recession (REC), tooth mobility
(MOB),furcationinvolvement(FURC),toothloss).
SPSSsoftwarepackagehasbeenused.
92
5 RESULTS
93
5.1 GENERALANDDEMOGRAPHICDATAAtthemomentofthedrawingupofthisthesis,patient’senrolmentisstillinprogress.
70patientshavebeenenrolledtotakeparttotheclinicalstudy.All thepatientshave
satisfiedinclusioncriteria:
• ≥65yearsoldfemale
• Inself-reportedmenopause
• With a DXA examination at the hip and lumbar spine performed within the
previous12months
During the study visit, age, ethnicity, smoke habits, body mass index, height and
medicationshavebeenrecordedintheClinicalReportForm(CRF).Tab.16
5.2 OPGINDICESANDOSTEOPOROSISDATA
DxascanresultshavebeenregisteredintheClinicalReportForm(CRF)andpatientshave
beenclassifiedinhealthy,osteopenicandosteoporoticaccordingtotheT-scoreofeither
lumbarspineorfemurneck.Theworstvaluehasbeenusedtoclassifythebonedensity
status.Tab.17
Thedistributionofthet-scorevaluesbetweenthesamplehasbeen:
- Healthypatients: 2 (3%)
- Osteopenicpatients: 31 (44,2%)
- Osteoporoticpatients: 37 (52,8)
Accordingtotheliterature,patientshavebeenclassifiedintotwomaingroups:
- healthy+osteopenic(0): 33 (47%)
94
- Osteoporoticpatients(1): 37 (53%)
OPGshavebeenanalysedtoobtainmorphometricindicesvaluessuchasKlemettiindex
(KI),MandibularCorticalWidth(MCW),Mentalindex(MI),Panoramicmandibularindex
(PMI),Antegonialindex(AI),Gonialindex(GI)andMandibularratio(M/M).Tab.18
AllthepatientshavebeenanalysedfortheKlemettiindexandthedistributionbetween
thesamplehasbeen:
- C1: 13 (18%)
- C2: 28 (40,5%)
- C3: 29 (41,5%)
Accordingtotheliterature,KIhasbeenclassifiedintotwomaingroups:
- C1+C2(consideredhealthy): 46 (58,5%)
- C3(consideredosteoporotic): 29 (41,5%)
SincetheKlemetticlusterscanbeusedtoquantitativelyclassifyhealthy,osteopenicand
osteoporoticpatients, sensitivity and specificityhavebeencalculated considering�the
KlemettiindexasatoolforpredictionofreducedBMD(T-score</=-2,5).Thepresenceof
corticalerosion(C3vs.C1-C2)hasproducedasensitivityof61,1%andaspecificityof
79,4%withapositivepredictivevalueof75,9%andanegativepredictivevalueof65,9
%.�
�
�
�
�
�
95
KI
Truepositive(TP) 22
Truenegative(TN) 27
Falsepositive(FP) 7
Falsenegative(FN) 14
Sensitivity 61,1%
Specificity 79,4%
Positivepredictivevalue 75,9%
Negativepredictivevalue 65,9%
Tab.7Klemettiindexaccuracy
Mandibular corticalwidth (MCW) indexhasbeenanalysedon51patientsbecauseof
some technical issues in detecting the required measurements with accuracy in the
remaining19patients.ThecutoffvaluehasbeenchosenafterdrawingtheROCcurvein
ordertofindthehighestsensitivity/specificityandithasbeensetat3,33mm.Thelevels
of sensitivity and specificity associatedwith this index have been 72,2% and 64,7%
respectively.Tab.8-Tab.9-Fig.22
MCW
Area StandarderrorAsintotic
significance
AsintoticConfidenceInterval95%
Inferiorlimit Upperlimit
0,676 0,081 0,038 0,517 0,836
Tab.8MCWROC-areaunderthecurvedata
MCW
Sensitivity 72,2%
Specificity 64,7%
Tab.9Mandibularcorticalwidthindexaccuracy
96
A correlation between Klemetti Index and Mandibular Cortical Width has been
investigatedforthegroupof51patients.AMann-Whitneytesthasbeenappliedonthe
resultsobtainedbythesamepopulationandastatisticalsignificativecorrelationbetween
MCWandtheKlemettiC1+C2vs.C3hasbeenfound(p=0,001).
Accordingtothisfinding,theKIvalueforhealthypatientshasbeencorrelatedtopatients
withaMCWhigherthanthecut-offvalueasacombinedtooltopredictosteoporosis.
After this analysis, sensitivity and specificity have been calculated for the combined
indicesandtheresulthasbeen88,8%and58,8%respectively,withanegativepredictive
valueof90,9%.Tab.10
ROCCURVE
1-Specificity
Sensitivity
Fig.22MandibularcorticalwidthROCcurve
97
MCW/KI
Sensitivity 88,8%
Specificity 58,8%
Negativepredictivevalue 90,9%
Tab.10AccuracyofKIinassociationwithMCWwhenrelatedtot-scores
Any other combination of MCW and KI (KI=C3 and/or MCW<3,33 mm) have been
statisticallytestedbutnoimprovementinsensibility,specificityorpredictivevalueshave
beenobserved.
PanoramicMandibularIndex(PMI),Mentalratio(M/M),antegonialindex(AI)andgonial
index(GI),havebeenalsotestedaspredictortoolsindetectingosteoporosis.AROCcurve
hasbeendrawnandtheareaunderthecurvehasbeenidentified.Lowlevelofsensitivity
andspecificityhavebeenreportedforalltheseindices.Tab.11-Fig.23
ROCCURVE
1-Specificity
Sensitivity
Fig.23PMI,M/M,AI,GIROCcurve
98
SECONDARYINDICES
index Area StandarderrorAsintotic
significance
AsintoticConfidenceInterval95%
Inferiorlimit Upperlimit
PMI 0,552 0,088 0,538 0,380 0,725
M/M 0,456 0,085 0,604 0,290 0,622
AI 0,444 0,087 0,513 0,273 0,616
GI 0,512 0,085 0,885 0,346 0,678
Tab.11Accuracyofpanoramicmandibularindex,Mentalratio,antegonialindexandgonialindex
5.3 PERIODONTALDATAPeriodontaldata suchasPeriodontalprobingdepth (PPD), FullMouthBleedingScore
(FMBS),FullMouthPlaqueScore(FMPS),Clinicalattachmentloss(CAL),Recession(REC),
toothmobility(MOB),furcationinvolvement(FURC)havebeenregisteredinacomplete
periodontalchart(Tab.19).Bothcompleteedentulouspatientsordentatepatientshave
beenenrolledforthestudyandthenumberandpercentageofmissingteethhavebeen
takenintoaccount.Accordingtotheliterature,onlypatientswithatleast8teethhave
beenconsidereddentatepatientsandincludedinperiodontaldataanalysis.Fifty-eight
dentatepatientshavebeenclassifiedaccordingtot-scorecut-off.Thedistributionwithin
the sample has been 24 patients for the healthy group and 34 patients for the
osteoporoticgroup.Astatisticalsignificancehasbeeninvestigatedbetweenperiodontal
indicesanddiagnosisofosteoporosisaccordingtotheT-score(0=healthy/osteopenic;
1=osteoporotic).AKolmogorov-Smirnovtesthasbeenperformedtoassessthenormality
ofthedistributionoftheperiodontaldatasamples.TheK-Stesthasidentifiedtheclinical
attachmentlevelasanormaldistributionvariable.Inthiscaseat-testhasbeenapplied
to investigate the statistically significant correlation in case of normal distribution
99
(averageandstandarddeviation).IncaseofPPD,REC,MOBandFURCaMann-Whitney
testhasbeenusedtotestthecorrelation(medianandquartile).
Periodontalprobingdepth (PPD):58patientshavebeenconsidered for the statistical
analysis. A six-sites periodontal probing has been performed on each tooth and the
probingdepthhasbeenclassifiedintwoclustersaccordingtoacut-offof5mm.
Sincethepocketprobingdepthhasbeendefinedasanon-normaldistributedvariable
(Kolmogorov-Smirnovtest),medianand25%quartilehavebeencalculated.Astatistically
significant correlation between PPD and BMD has been found for the patients with
PPD>/=5mm(p=0,006).ThemedianofthepatientwithPPD>/=5mmgrouphasbeen
9,75%(25quartile:2,7%)inthehealthygroup,and3,45%(25quartile:0,6%).Tab.12
Sample N Median(%) 25quartile(%)
Healthy 24 9,75 2,7
Osteoporotic 34 3,45 0,6
Tab.12Pocketprobingdepth(PPD)statisticalanalysis:medianand1stquartile
TheaforementionedcorrelationhasbeentestedbetweenPPDandBMD,consideredas
adichotomicvaluedefinedonthet-scorecut-offs.Thecorrelationhasbeenalsotested
considering t-score as a continuous variable and a Spearman’s rank correlation
coefficient has been applied. Spearman’s rho has shown a statistical significance
(p=0,005).Fig.24
100
Fig.24ScatterplotrepresentingthedistributionofthesiteswithaPPD³5mminrespectoft-scoresasacontinuous
variable
Clinicalattachmentloss(CAL):ClinicalattachmentlosshasbeendefinedastheRECin
additiontoPPDvalues.Averageandstandarddeviationhavebeencalculatedandt-test
hasbeenperformedtodemonstrateacorrelationbetweenCALandt-scores.Siteshave
beenclassifiedinthreeclusters,withCALof1-2mm,CALof3-4mmandCAL>5mm.
Onlytheclusterof3-4mmofCALhasshownastatisticallysignificantcorrelationwitht-
scoresclassification(healthyandosteoporotic)withap=0,21.Theaverageofsiteswith
CALof3-4mmhasbeen49,4%(SD11,05%)forthehealthygroupand56,9%(SD12,6
%)fortheosteoporoticgroup.Tab.13
%ofsite
swith
PPD³5
mm
t-score
101
Sample N CALgroups Average(%)Standard
deviation(%)
Healthy 24
%siteswithCAL1-2mm 22,429 14,8368
%siteswithCAL3-4mm 49,417 11,0525
%siteswithCAL>5mm 28,563 20,2506
Osteoporotic 34
%siteswithCAL1-2mm 22,615 13,6314
%siteswithCAL3-4mm 56,982 12,6118
%siteswithCAL>5mm 20,388 15,1708
Tab.13Clinicalattachmentloss(CAL)statisticalanalysis:averageandstandarddeviation
TheSpearman’srankcorrelationcoefficienthasbeenalsoappliedtotheCALinorderto
investigate the correlation between attachment level and t-score as a continuous
variable.Similarlytothet-test,Spearman’srhohasidentifiedacorrelationtothegroup
withCALof3-4mm(p=0,13).Fig.25
Fig.25ScatterplotrepresentingthedistributionofthesiteswithaAL3-4mminrespectoft-scoresasacontinuous
variable
%ofsite
swith
AL3-4mm
t-score
102
Toothloss:Thenumberofteethlosshasbeenanalysedonthewholesample.AMann-
Whitneytestforthenon-parametricvariableshasbeenappliedtoinvestigateastatistical
significanceinrelationtothet-score(dichotomicvalue)andapvalueof0,007hasbeen
found.Themedianofthepercentageofteethloss(considered28teethas100%)has
been25%(25quartileof17,8%)forhealthygroup(33patients),and14,3%(25quartile
of7,1%)fortheosteoporoticgroup(37patients).Tab.14
The Spearman’s rank correlation coefficient has been also applied and no statistical
differenceshavebeendemonstratedconsideringt-scoreasacontinuousvariable
Sample N Median(%) 25quartile(%)
Healthy 33 25 17,8
Osteoporotic 37 14,3 7,1
Tab.14Toothlossstatisticalanalysis:medianand1stquartile
Recession, Furcation, Mobility: All the remaining periodontal indices that have been
statistically tested, have shown no significance between groups. For the furcation
involvement, the frequency has been analysed but the chi-square test has shownno
significance.Tab.15
Indices Median(%) 25quartile(%)
REC>3mm(%sites) 0,25 0
REC≤3mm(%sites) 99,4 95,35
Mobility(%teeth) 6,3 0
Tab.15Recession(REC)andtoothmobility:medianand1stquartile
103
PatientsIDAGE ETHNICITY SMOKE HEIGHT WEIGHT BMI Vit.D BISPHOSPHONATES
(0=no;1=yes)
L-Z001 73 caucasian 0 154,5 49 20,53 1 1
G-P002 72 caucasian 0 165 101 37,1 0 0
M-M003 79 caucasian 1 158,1 50 20 0 1
A-B004 73 caucasian 1 162,5 65 24,62 0 0
R-L005 81 caucasian 0 161 56 21,6 0 0
C-G006 79 caucasian 0 158 74 29,64 1 0
L-M007 68 caucasian 0 154 59 24,88 0 0
T-C008 67 caucasian 1 157,4 59 23,81 0 0
M-G009 68 caucasian 0 165 83 30,49 0 0
S-M010 76 caucasian 0 157 61 24,75 0 0
O-C011 73 caucasian 0 160,4 49 19,05 1 0
M-P012 73 caucasian 0 156,3 53 21,69 0 0
O-C013 74 caucasian 0 160 59 23,05 1 0
T-C014 70 caucasian 0 160,2 60 23,38 0 0
L-B015 67 caucasian 0 156 61 25,07 0 0
G-M016 77 caucasian 0 153 56 23,92 1 0(2y)
N-G017 81 caucasian 0 144,4 57 27,34 0 0
A-B018 66 caucasian 1 153,6 55 23,31 1 0
G-P019 73 caucasian 0 164 56 20,82 0 0
R-G020 80 caucasian 0 167 66 23,67 1 0
D-N021 69 caucasian 0 153,2 48 20,45 0 0
A-C022 72 caucasian 1 154,5 54 22,62 0 0
M-M023 67 caucasian 0 153 62 26,49 0 0
M-S024 69 caucasian 0 154,8 55 22,95 1 0
S-G025 72 caucasian 0 151,2 66 28,87 0 0
L-T026 71 caucasian 1 155,2 50 20,76 1 0
M-C027 74 caucasian 1 162,7 57 21,53 0 0
E-S028 76 caucasian 0 160 46 17,97 1 0
M-G029 79 caucasian 0 152 54 23,37 0 0
A-C030 67 caucasian 1 154 53 22,35 0 0
M-F031 65 caucasian 162 75 28,6 1 0(3m)
104
M-M032 65 caucasian 0 166 51 18,5 1 0
M-P033 67 caucasian 0 148 53 24,2 1 0(7y)
MR-B034 65 caucasian 0 162 60 23 0 0
G-C035 65 caucasian 0 161 57 22 1 0
A-G036 66 caucasian 0 164 58 21,6 1 0(5y)
G-S037 66 caucasian 0 159 56 22,2 0 0
R-S038 66 caucasian 0 158 89 35,9 1 1
G-S039 66 caucasian 0 155 47 19,7 0 0
G-C040 66 caucasian 0 146 60 27,9 1 1
MN-T041 67 caucasian 0 160 69 27 1 0
F-D042 66 caucasian 1 152,7 54 23,16 0 0
M-A043 75 caucasian 0 154,7 55 22,98 0 0
MP-G044 84 caucasian 0 159,5 66 25,94 0 0
A-D045 67 caucasian 0 148 72 32,9 1 0
R-C046 65 caucasian 1 156 55 22,6 1 0
L-R047 65 caucasian 0 163 60 22,6 1 0
D-B048 67 caucasian 0 158 54 21,6 1 0
C-P049 67 caucasian 0 153 66 28,2 1 1
A-P050 78 caucasian 0 160,3 63 24,52 0 0
M-B051 74 caucasian 0 160,5 64 24,84 0 0
M-M052 66 caucasian 0 167 103 36,9 1 0
PKS053 60 caucasian 0 149,5 57,2 1 1
AMF054 63 caucasian 0 152,3 65 1 0(6m)
K-D055 63 caucasian 0 157,6 56 1 0
C-M056 66 caucasian 0 160 108 1 1
PFF057 59 caucasian 0 156 60 0 0
G-G058 75 caucasian 0 158,2 92 0 0
NMF059 66 caucasian 0 166 62 0 1
DJG060 69 caucasian 0 153 51 1 1
DIG061 72 caucasian 0 155 52 0 0
LMK062 60 caucasian 0 166 48,3 17,5 1 1
J-W063 55 caucasian 0 162 63 1 0
J-B064 68 caucasian 0 153 48,3 1 0
MBM065 61 caucasian 0 165 68 1 0(4y)
105
V-F066 63 caucasian 0 161,5 52,1 1 1
SAR067 53 caucasian 0 159 71 0 0
JAL068 60 caucasian 0 155 52 1 0(2y)
A-S069 60 caucasian 0 160 58 0 no
A-L070 70 caucasian 0 152 51,3 0 1
E-M071 66 caucasian 1 175 85 27,8 0 0
Tab.16Demographicdatacollection.Age,etnicity,smoke,height,weight,bmiandmedicationshavebeenrecorded
106
PatientsID DxascanT-score diagnosis classification
lumbarspine femurneck worstvalue
L-Z001 -1,9 -3,4 -3,4 Osteoporotic 1
G-P002 4,2 -0,2 -0,2 Healty 0
M-M003 -1,6 -1,8 -1,8 Osteopenic 0
A-B004 0,2 -2,4 -2,4 Osteopenic 0
R-L005 -2,4 -1,4 -2,4 Osteopenic 0
C-G006 -2,4 -2,2 -2,4 Osteopenic 0
L-M007 -1,2 -0,7 -1,2 Osteopenic 0
T-C008 -3,2 -3,2 -3,2 Osteoporotic 1
M-G009 -1,2 -1,1 -1,2 Osteopenic 0
S-M010 -3,1 -2,5 -3,1 Osteoporotic 1
O-C011 -1 -2,7 -2,7 Osteoporotic 1
M-P012 -1,3 -2,5 -2,5 Osteoporotic 1
O-C013 -3 -2,8 -3 Osteoporotic 1
T-C014 -2 -2 -2 Osteopenic 0
L-B015 -1,8 -1,5 -1,8 Osteopenic 0
G-M016 -1,2 -2,5 -2,5 Osteoporotic 1
N-G017 -2,7 -1,8 -2,7 Osteoporotic 1
A-B018 -2,6 -2 -2,6 Osteoporotic 1
G-P019 -3,2 -1,7 -3,2 Osteoporotic 1
R-G020 -1,2 -1,6 -1,6 Osteopenic 0
D-N021 -3,6 -2,2 -3,6 Osteoporotic 1
A-C022 -1,8 -1,6 -1,8 Osteopenic 0
M-M023 -1,4 -1 -1,4 Osteopenic 0
M-S024 -2,1 -2,1 -2,1 Osteopenic 0
S-G025 0,6 -1,3 -1,3 Osteopenic 0
L-T026 -2,1 -1,1 -2,1 Osteopenic 0
M-C027 -2,4 -1,3 -2,4 Osteopenic 0
E-S028 -2,7 -2,6 -2,7 Osteoporotic 1
M-G029 -2,2 -1,8 -2,2 Osteopenic 0
A-C030 0,8 -1,9 -1,9 Osteopenic 0
M-F031 -1,3 -1,3 Osteopenic 0
M-M032 -2,1 -2,4 -2,4 Osteopenic 0
M-P033 -3,3 -1,4 -3,3 Osteoporotic 1
107
MR-B034 -1,6 -1,7 -1,7 Osteopenic 0
G-C035 -2,8 -2,7 -2,8 Osteoporotic 1
A-G036 -3,6 -3,8 -3,8 Osteoporotic 1
G-S037 -1,9 -2,1 -2,1 Osteopenic 0
R-S038 -2,6 -1,5 -2,6 Osteoporotic 1
G-S039 -2 -1,4 -2 Osteopenic 0
G-C040 -3,3 -1,9 -3,3 Osteoporotic 1
MN-T041 -1,9 -1,9 Osteopenic 0
F-D042 -1,6 -1,8 -1,8 Osteopenic 0
M-A043 -2,1 -3 -3 Osteoporotic 1
MP-G044 -1,6 -2,2 -2,2 Osteopenic 0
A-D045 -1 -1,5 -1,5 Osteopenic 0
R-C046 -1,1 -2,1 -2,1 Osteopenic 0
L-R047 -1,9 -1,9 -1,9 Osteopenic 0
D-B048 -1,6 -0,9 -1,6 Osteopenic 0
C-P049 -2,2 -2 -2,2 Osteopenic 0
A-P050 0,1 -0,7 -0,7 Healty 0
M-B051 -1,9 -1,4 -1,9 Osteopenic 0
M-M052 -0,9 -1,6 -1,6 Osteopenic 0
PKS053 -2,5 -2,5 Osteoporotic 1
AMF054 -3,1 -3,1 Osteoporotic 1
K-D055 -2,7 -2,7 Osteoporotic 1
C-M056 -2,5 -2,5 Osteoporotic 1
PFF057 -3,3 -3,3 Osteoporotic 1
G-G058 -2,7 -2,7 Osteoporotic 1
NMF059 -3,7 -3,7 Osteoporotic 1
DJG060 -2,6 -2,6 Osteoporotic 1
DIG061 -3,8 -3,8 Osteoporotic 1
LMK062 -3,2 -3,2 Osteoporotic 1
J-W063 -2,5 -2,5 Osteoporotic 1
J-B064 -3,5 -3,5 Osteoporotic 1
MBM065 -2,5 -2,5 Osteoporotic 1
V-F066 -3,6 -3,6 Osteoporotic 1
SAR067 -2,7 -2,7 Osteoporotic 1
JAL068 -2,9 -2,9 Osteoporotic 1
108
A-S069 -3,6 -3,6 Osteoporotic 1
A-L070 -2,5 -2,5 Osteoporotic 1
Tab.17T-scoresanddiagnosticclassificationinhealty,osteopenicandosteoporotic.Healthyandosteopenicpatientshavebeenclassifiedas"0"andosteoporoticas"1".
109
Patients MorphometricIndices Diagnosis
KLEMETTI
INDEX
MCW
mm
PMI
mm
M/M
mm
AI
mm
GI
mm
0=healthy/osteopenic;
1=osteoporotic
L-Z001 C2 4,57 0,40 3,15 3,27 1,96 1
G-P002 C2 3,62 0,26 2,56 2,48 1,22 0
M-M003 C2 3,14 0,22 1,70 3,26 1,52 0
A-B004 C2 1,97 0,15 1,65 2,56 1,61 0
R-L005 C2 2,55 0,19 1,69 2,88 1,41 0
C-G006 C3 1,95 0,17 1,79 2,02 1,15 0
L-M007 C2 3,73 0,34 1,88 2,58 1,58 0
T-C008 C2 3,21 0,30 1,88 3,09 1,91 1
M-G009 C1 3,84 0,30 2,24 2,80 1,37 0
S-M010 C3 4,27 0,33 2,05 3,43 1,26 1
O-C011 C3 2,33 0,29 2,48 3,15 1,35 1
M-P012 C3 2,92 0,24 2,62 3,15 1,69 1
O-C013 C3 0,97 0,08 2,15 2,19 1,50 1
T-C014 C2 4,20 0,62 3,54 2,42 2,08 0
L-B015 C2 3,83 0,33 2,64 3,49 4,49 0
G-M016 C2 3,03 0,24 2,67 2,11 1,71 1
N-G017 C3 2,73 0,20 2,03 2,35 1,61 1
A-B018 C1 3,36 0,25 2,41 3,34 1,98 1
G-P019 C3 1,93 0,15 2,01 2,06 0,97 1
R-G020 C2 1,96 0,15 1,57 1,50 1,48 0
D-N021 C2 2,44 2,33 2,50 2,16 1,12 1
A-C022 C3 3,02 0,34 3,23 2,24 1,91 0
M-M023 C1 3,73 0,27 1,85 1,57 1,51 0
M-S024 C1 4,65 0,36 2,12 3,10 1,28 0
S-G025 C1 3,80 0,26 2,08 2,83 1,51 0
L-T026 C1 4,37 0,37 2,99 2,99 1,59 0
M-C027 C2 3,14 0,22 2,02 2,53 1,80 0
E-S028 C1 4,20 0,39 1,41 3,30 1,99 1
M-G029 C2 4,13 0,23 1,28 1,69 1,07 0
A-C030 C1 5,39 0,42 2,28 3,86 1,33 0
110
M-F031 C1 4,55 0,32 2,09 2,55 1,69 0
M-M032 C2 3,89 0,31 2,27 3,10 1,13 0
M-P033 C3 4,20 0,31 2,37 3,36 1,42 1
MR-B034 C1 4,34 0,31 1,90 3,31 1,80 0
G-C035 C3 1,23 0,10 1,81 1,99 0,84 1
A-G036 C2 3,32 0,26 1,86 2,39 1,41 1
G-S037 C2 3,78 0,35 2,23 2,73 1,00 0
R-S038 C2 3,28 0,34 2,44 3,00 1,45 1
G-S039 C2 5,02 0,40 1,95 4,72 2,94 0
G-C040 C3 2,33 0,17 1,95 3,42 2,01 1
MN-T041 C3 3,53 0,25 2,35 4,11 2,10 0
F-D042 C1 4,23 0,41 3,45 3,17 1,76 0
M-A043 C2 2,09 0,13 1,27 2,41 1,62 1
MP-G044 C3 3,39 0,20 1,46 1,99 0,84 0
A-D045 C2 3,48 0,21 1,89 2,51 1,28 0
R-C046 C2 3,12 0,20 1,99 1,53 1,14 0
L-R047 C3 2,67 0,20 1,94 2,76 1,47 0
D-B048 C2 4,19 0,31 2,06 2,93 2,01 0
C-P049 C2 3,43 0,31 2,18 1,61 1,85 0
A-P050 C3 3,31 0,21 1,21 2,60 1,75 0
M-B051 C3 2,13 0,16 2,34 2,17 1,47 0
M-M052 C2 2,06 0,18 2,75 3,15 75,37 0
PKS053 C2 n/d n/d n/d n/d n/d 1
AMF054 C3 n/d n/d n/d n/d n/d 1
K-D055 C3 n/d n/d n/d n/d n/d 1
C-M056 C2 n/d n/d n/d n/d n/d 1
PFF057 C3 n/d n/d n/d n/d n/d 1
G-G058 C3 n/d n/d n/d n/d n/d 1
NMF059 C3 n/d n/d n/d n/d n/d 1
DJG060 C3 n/d n/d n/d n/d n/d 1
DIG061 C3 n/d n/d n/d n/d n/d 1
LMK062 C3 n/d n/d n/d n/d n/d 1
J-W063 C1 n/d n/d n/d n/d n/d 1
111
J-B064 C3 n/d n/d n/d n/d n/d 1
MBM065 C3 n/d n/d n/d n/d n/d 1
V-F066 C3 n/d n/d n/d n/d n/d 1
SAR067 C2 n/d n/d n/d n/d n/d 1
JAL068 C1 n/d n/d n/d n/d n/d 1
A-S069 C3 n/d n/d n/d n/d n/d 1
A-L070 C2 n/d n/d n/d n/d n/d 1
Tab.18Panoramicmorphometricindices:Klemettiindex,mandibularcorticalwidth(MCW),panoramicmandibularindex(PMI),mentalratio(M/M),antegonialindex(AI),gonialindex(GI).
112
PatientNofteeth
loss
%teeth
loss
%teethwith
mobiiltyfurcations T-score
%siteswith
PPD≥5mm
%siteswith
PPD<5mm
%siteswith
REC>3mm
%siteswith
REC≤3mm
%siteswith
AL1-2mm
%siteswith
AL3-4mm
%siteswith
AL≥5mm
(28=100%)(no/gradeI=0;
gradeII/III=1)
(0=healthy/osteopenic
1=osteoporotic)
L-Z001 3 10,7 8 0 1 0 100 0 100 11,3 83,4 5,3
G-P002 7 25 62,5 0 0 13,9 86,1 0 100 15,9 54,9 29,2
M-M003 22 78,6 0 0 0 13,9 86,1 18 82 6 36,4 57,6
A-B004 28 100 0 0 0 0 100 0 100 16,7 83,3 0
R-L005 28 100 0 0 0 16,7 83,3 6 94 3 41 56
C-G006 28 100 0 0 0 33,3 66,7 0 100 36,7 30 33,3
L-M007 4 14 4 0 0 1,3 98,7 7,7 92,3 24,3 48,1 27,6
T-C008 26 92,8 0 0 1 0 100 83,3 16,7 0 0 100
M-G009 16 57,1 0 0 0 5,3 94,7 1,7 98,3 19,4 40,3 40,3
S-M010 6 21,4 56,5 1 1 5,8 94,2 14,5 85,5 3,6 25,4 71
O-C011 14 50 0 0 1 3,6 96,4 4,7 95,3 13,1 53,6 33,3
M-P012 3 10,7 23,1 0 1 7 93 1,9 98,1 31,4 50 18,6
O-C013 5 17,9 26,9 0 1 3,8 96,2 0 100 26,5 57,6 15,9
T-C014 28 100 0 0 0 0 0 0 0 0 0 0
L-B015 3 10,7 48 1 0 27,3 72,7 1,3 98,7 8,6 44,7 46,7
G-M016 3 10,7 46,1 1 1 12,8 87,2 0,6 99,4 20,5 47,4 32,1
N-G017 22 78,6 0 0 1 19,4 80,6 8,3 91,7 2,8 22,2 75
A-B018 1 3,6 0 0 1 0,6 99,4 0,6 99,4 25,6 63,5 10,9
113
G-P019 10 35,7 33,3 0 1 18,7 81,3 0 100 17,7 35,4 46,9
R-G020 21 75 0 0 0 8,3 91,7 0 100 10 78,3 11,7
D-N021 2 7,1 51,8 1 1 9,8 90,2 6,2 93,8 19,1 46,9 34
A-C022 6 21,4 0 0 0 6,7 93,3 0 100 29,3 63,3 7,4
M-M023 11 39,3 4,7 0 0 21,7 78,3 0 100 22,5 54,2 23,3
M-S024 5 17,9 17,2 0 0 5,7 94,3 1,1 98,9 25,3 53,4 21,3
S-G025 5 17,9 0 0 0 4,2 95,8 0 100 38,2 56,9 4,9
L-T026 3 10,7 20 1 0 15,3 84,7 0 100 4,6 50,7 44,7
M-C027 14 50 40,9 0 0 44,7 55,3 2,3 97,7 3 28 69
E-S028 12 42,8 0 0 1 0 100 4,2 95,8 22,9 42,7 34,4
M-G029 8 28,6 31,8 0 0 3 97 5,3 94,7 22,7 58,3 19
A-C030 17 60,7 50 0 0 52,6 47,4 0 100 2,6 26,9 70,5
M-F031 0 0 0 0 0 1,6 98,4 0 100 57,5 40,9 1,6
M-M032 6 21,4 10 0 0 0,5 99,5 0,5 99,5 57,8 37,2 5
M-P033 1 3,6 0 0 1 0,6 99,4 0 100 46,3 51,8 1,9
MR-B034 4 14,3 0 0 0 5,3 94,7 3,3 96,7 20 63,3 16,7
G-C035 18 64,3 50 0 1 6,7 93,3 3,3 96,7 16,7 70 13,3
A-G036 0 0 3,6 0 1 2,9 97,1 0 100 22,1 69,6 8,3
G-S037 5 17,9 18,5 1 0 22,2 77,8 0,6 99,4 17,9 58,6 23,5
R-S038 13 46,4 18,7 0 1 7,3 92,7 0 100 8,4 70,8 20,8
G-S039 13 46,4 0 0 0 2,6 97,4 0 100 20,2 71,9 7,9
G-C040 8 28,6 0 0 1 0 100 0 100 24,2 71,2 4,6
114
MN-T041 0 0 0 0 0 2,4 97,6 0 100 35,7 60,7 3,6
F-D042 4 14,3 34,6 0 0 16,7 83,3 0 100 12,3 50 37,7
M-A043 26 92,8 33,3 0 1 58,3 41,7 5,5 94,5 2,8 30,5 66,7
MP-G044 28 100 0 0 0 0 0 0 0 0 0 0
A-D045 3 10,7 4 1 0 6,7 93,3 0 100 20 73,3 6,7
R-C046 22 78,5 0 0 0 25 75 5 95 2 55 43
L-R047 6 25 41,6 1 0 30,5 69,5 0 100 18 38,1 43,8
D-B048 8 28,6 7,6 0 0 0,6 99,4 0 0 41,6 51,2 7,1
C-P049 6 21,4 76,9 1 0 12,8 87,2 7 93 16,6 42,9 50,5
A-P050 28 100 0 0 0 14 86 1,2 98,8 21,7 56,4 21,8
M-B051 5 17,8 55,5 0 0 14,8 85,2 1,8 98,2 12,3 47,5 40,2
M-M052 5 17,9 24 1 0 14,7 85,3 0,7 9,3 12 44 44
PKS053 1 3,6 0 1 1 27,5 72,5 1,5 98,5 8 49 43
AMF054 2 7,1 0 1 1 5,7 94,3 0 100 60,9 30,1 9
K-D055 1 3,6 0 0 1 5,2 94,8 0 100 32,8 60,3 6,9
C-M056 2 7,1 18,5 0 1 9,3 90,7 0 100 21 61,7 17,3
PFF057 4 14,3 60,7 0 1 4,2 95,8 0 100 27,4 56,5 16,1
G-G058 9 32,1 52,6 0 1 0,9 99,1 2,6 97,4 9,6 59,6 30,8
NMF059 8 28,6 30 0 1 8,3 91,7 0 100 12,5 64,2 23,3
DJG060 5 17,8 45,8 0 1 1,4 98,6 4,8 95,2 19,4 54,9 25,7
DIG061 9 32,1 21 0 1 1,7 98,3 0,9 99,1 25,5 59,6 14,9
LMK062 2 7,1 38,5 0 1 1,3 98,7 0 100 33,3 53,4 12,8
115
J-W063 2 7,1 17,2 0 1 0,6 99,4 0 100 35,6 59,8 4,6
J-B064 4 14,3 0 0 1 0 100 0 100 42 52 6
MBM065 6 21,4 54,5 1 1 5,5 94,5 4,5 95,5 18,2 52,3 29,5
V-F066 5 17,8 4 0 1 0 100 0 100 27,3 68,7 4
SAR067 1 3,6 0 0 1 2,7 97,3 0 100 51,6 43 5,4
JAL068 2 7,1 34,6 0 1 0 100 1,3 98,7 7 64,7 28,3
A-S069 4 14,3 3,6 1 1 2,4 97,6 0,6 99,4 2,4 66,7 30,9
A-L070 8 28,6 5 1 1 3,3 96,7 5 95 5 68,3 26,7
Tab.19Periodontaldatacollection:Number/percentageofteethloss,percentageofteethwithaugmentedmobility,furcationinvolvement,percentageofsiteswithpockedprobingdepth(PPD),recession(REC)andclinicalattachmentlevel(AL)
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6 DISCUSSION
117
Accordingtotherevisionoftheliteraturethatithasbeenperformed,fouroutofthefive
studiesincludedreportedasignificantcorrelationbetweenBMDmeasuredatdifferent
systemicskeletalsitesandmandibleBMD.Cakuretal(172)reportedin2009noevidence
ofanyrelationshipbetweensystemicandmandibularBMD.However,weneedtobevery
cautious on drawing conclusions, since these studies are not easily and satisfactory
comparable due to several confounding factors such as different techniques used to
measureBMDandthedifferentanatomicsitesconsidered.
Since the heterogeneity of the studies and considering that the meta-analysis was
performedtakingintoaccountonlytwo-studies,itispossibletostatethatthesignificance
ofthesedatacanbequestionable.
Forthesereasons,aclinicaltrialhasbeendesignedinordertoinvestigatethecorrelation
betweensystemicbonemineraldensity(BMD)andjawbonescondition,usingasetof
specific radiographic morphometric indices proposed in the last decades. Moreover,
since the enrolment has been performed in a Dental Hospital, it was decided to
investigate the relationship between BMD and periodontal status in this group of
selectedpatients.Thecorrelationbetweent-scoresandperiodontalindiceshasalready
beenproposedinscientificliteraturebut,similarlytothecorrelationbetweenBMDand
jawbonedensity,theevidenceispoorandcharacterizedbyalargeheterogeneityofthe
studies.TheavailableliteratureonapossiblecorrelationhasbeenreviewedinChapter
3.
6.1 PANORAMICMORPHOMETRICINDICESFORDETECTINGREDUCEDBMD
Severalclinicalstudiesinvestigatedtherelationshipbetweenbonedensitymeasuredin
differentsystemicskeletalsitesandinthejawbonesinsubjectswithdifferentTscores.
Althoughmanyofthesestudieshavefoundapositivecorrelation(132-139),othershave
reportedthatjawbonedensityisnot,oronlytoalimiteddegree,correlatedtothedensity
inothersystemicsites(140-142).Ithasalsobeendemonstratedthatthatthereareno
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differences in jawbonedensitybetweennormalandosteopenic/osteoporotic subjects
(143,144).
Theavailableliteratureontheaccuracyofpanoramicmorphometricindicesindetecting
reducedBMDhasbeensystematicallyreviewedinChapter3.Inthepast20yearsseveral
evidenceshavebeenpublishedon theaccuracyofqualitative/quantitativepanoramic
indices in screening for reduced skeletal density (either osteopenia or osteoporosis)
(173).Consideringthehighpercentageofpeopleattendingregulardentalvisitsandthe
fact thatpanoramic radiographsof the jawbonesarenowadaysacommonprocedure
duringroutinedentalcheck-upsorbeforeseveraldentaltreatments(174-176),itwould
be of great clinical value if dentists could opportunistically use panoramic X-rays to
identifypatientsathighriskofosteoporosisandatleastreferthemtometabolicbone
diseasesclinic.
Inthestudypresented,theKlemettiindex(KI),thequalitativeindex,hasbeenevaluated
onthewholesampleof70patients,whilepanoramicmorphometricquantitativeindices
such as mandibular cortical width (MCW), panoramic mandibular index (PMI),
mandibularratio(M/M),antegonialindex(AI)andgonialindex(GI)havebeenmeasured
on51patientsduetotechnicalradiologicalissues.
Inlinewithseveralresearchersinthefield,weagreethatthebasalareaofthemandible
posteriortothementalforamenisprobablytheonlypartofthejawswithreasonably
suitablecharacteristicstobeastandardsiteforBMDmeasurements,sinceithassmall
inter- and intra-individual variations in anatomical size, shape, bone structure and
function(177),althoughithastoberememberedthatthemandibularforamencannot
bedetectableinallconditions.
Mandibular cortical width represents the thickness of the mandibular cortex and is
usuallymeasuredinthementalforamenregion.Regardlessthelimitationsofthisstudy
duetothesamplesize,thestatisticalanalysishasshownasignificantcorrelationbetween
MCWandastatusofosteoporosisandacut-offvaluehasbeensetat3,3mmwitha
sensitivityandspecificityof72,2%and64,7%,respectively.Accordingtotheliterature,
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MCWhas showed a better specificity rather than sensitivity in detecting peoplewith
reducedBMD,since90%ofpeoplewithMCW≥4mmcouldbecorrectlyidentifiedas
havinganormalBMD(157).
Regarding the qualitative measurement, Klemetti index has been evaluated by two
differentblindedexaminersandcorrelatedtothestatusofbonehealthorosteoporosis
of the patient. KI qualitatively classifies themandibular cortex distally to themental
foramenin3categoriesaccordingtothepresenceoferosions.Thepresenceofcortical
erosion(C3vs.C1-C2)hasproducedasensitivityof61,1%andaspecificityof79,4%with
apositivepredictivevalueof75,9%andanegativepredictivevalueof65,9%. In the
revisionoftheliterature,thepresenceofanykindofcorticalerosion(C2+C3categories,
asassessedwithKI)hasseemedasensitive tool todetect reducedBMD,since itwas
associatedwithatleastosteopeniainapproximately80%ofthecases(160).
ExaminingtheclinicaltrialresultsofMCWandKI,apossiblecorrelationbetweenthetwo
mainindiceshasbeentestedandastrongcorrelationhasbeenfound(pvalue=0,001).
According to this finding,a correlationbetween the twocut-off values that identifya
healthypatient (MCW>3,3mmandKI=C1/C2)and t-scoreshasbeen investigated.The
correlationhasshownanincreaseinsensibilityandspecificitytillthevaluesof88,8%
and58,8%,respectively,but,mostimportant,demostratedanegativepredictivevalue
of91%.Theseindicescanbeconsideredpotentiallyusefultoscreenforreducedskeletal
BMDifusedincombinationandinparticulartoidentifyahealthypatientinmorethan
90%ofcases.
Even if scientific literature has demonstrated that panoramicmandibular index (PMI)
seem themost accurate and consistent quantitative tool to screen for reducedBMD
(sensitivity and specificity >70%) (161), this work PMI has reached no significance if
relatedtothet-scoresvaluestoscreenforhealthyorosteoporoticpatients. Mostofthe
studiesreportedacutoffvalueof0,3,withlevelsofsensitivityandspecificityindetecting
individualswith reducedbonedensity (T score<–1) ranging from40.8%to100%and
from47%to88%,respectively.
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In the sameway, antegonial index, gonial indexandmandibular ratiohave shownan
insufficientsignificanceaspredictortools.Literaturedataonthese“secondary”indices
ispoor,becausealltheavailablemeta-analysishavebeenperformedonMCW,PMIand
KI. Moreover, several studies reporting a positive correlation between skeletal and
jawboneBMDhavenotdistinguishedbetweenosteoporoticandhealthypatientswhen
reporting the correlation coefficients, thus further limiting the possibility of drawing
robustconclusions.
Anotherlimitationwefoundduringtheliteraturereviewwasrelatedtothefactthatall
studieshaveconsideredonlymandibulardata,withouttakingintoaccountthemaxilla.It
is well known that in osteoporotic subjects bone loss is not uniform and that the
trabecularboneisearlierandmoredeeplyaffectedthanthecorticalbone(29,178).The
mandiblehasabetterresemblancewiththefemurneck(179,180),wherefracturesare
primarilycausedbyalossincorticalratherthantrabecularbone(181,182).Considering
thatthemaxillaismainlymadeoftrabecularbone,itislikelythatbonedensitymeasured
atthissitewouldhavebeenbetterrelatedtovertebralosteoporosis.However,thelack
ofstablereferralpoints(likethementalforameninthemandible)makesitchallenging
toevaluatestandardizedsitesinthemaxilla.
When dealingwith jawbones it should also be kept inmind that they display unique
anatomic characteristics in comparison with other bones of the skeleton, owing for
exampletotheirspecialrelationshipwithteethandthedistinctionbetweenthemore
stablebasalboneandthealveolarbone,whichatrophiesafterteetharelost(183,184).
Itmaybehypothesizedthattheseandotheranatomical/physiologicalpeculiaritiesofthe
jawscansomehowaccountfordifferencesinbonemetabolismresponse(185).
�
6.2 PERIODONTALEXAMINATIONDATAANDBMD
Periodontitis is an infection-induced inflammationof the structures around the tooth
resultinginlossofitssofttissueattachmentandsurroundingbonemass,finallyresulting
intoothloss.Arelationbetweenosteoporosisandperiodontitishasalsobeenpostulated
in literaturesincemanyyears.Osteoporosisbeingasystemicdisease, leads to lossof
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bone stocknotonly fromspineandappendicular skeletonbut also from thealveolar
bone. Thus, osteoporosis is expected to hasten the process of bone loss in chronic
periodontitis(186).
Osteoporosisiswellknowninpostmenopausalwomenwithprevalenceashighas50%
(187) and the postmenopausal status is also associated with increased severity of
periodontitis with prevalence as high as 30% (102, 188). Periodontitis is clinically
measuredintermsofCAL,PPD,andalveolarboneloss.Otherperiodontalindicesthat
researchers have to take into account are recession, tooth mobility, furcations
involvementandtoothloss.
Inthepresentstudy,all theaforementionedparametershavebeenrecordedfrom70
patientsinordertoanalyzetheprevalenceofperiodontaldiseaseinapopulationofpost-
menopausal women. The correlation between periodontal status and BMD has been
statisticallyinvestigatedcomparingperiodontalindicesandtheworstt-scorevalue.
Pocket probing depth has been recordedwith a 6-point sounding and a group of 51
patientshasbeenanalyzed.Astatisticalsignificantcorrelationhasbeendemonstrated
betweenperiodontalprobingdepth>5mmandBMDt-scores.Itisofprimaryimportance
tounderlinethatthedirectionofthecorrelationhasbeentowardsthehealthygroup.
These data show that osteoporotic patients exhibit a better periodontal condition in
termsofperiodontalsoundinginrespectofthepatientswithat-score>-2,5.
Similarly, clinical attachment loss, considered as PPD added to REC value, has been
correlatedtothediagnosisofosteoporosis.Siteshavebeenclassifiedinthreeclusters
accordingtheprogressiveclinicalattachment loss.ThegroupwithCALof1-2mmhas
beenconsideredasperiodontalhealthandthecorrelationhasshownnosignificance,
similarly, thegroupwithCAL>5mm, representativeof thepopulationwitha severe
periodontaldestructionhasshownapoorcorrelation.
Interestingly, the groupwithCALof 3-4mm, representative of the larger part of the
populationhasshownastatisticallysignificanceifcorrelatedtoBMD.Accordinglytothe
PPDvalue,thecorrelationistowardsthepatientsdiagnosedashealthy.
These two parameters are considered, in the scientific literature, two of the most
predictabletoolstoidentifyacorrelationbetweenosteoporosisandperiodontitis(189).
122
Several studies have demonstrated that postmenopausal women, with lower bone
mineraldensity,haveahighernumberofDecayed-Missing-Filled-Teethand,astheage
of the postmenopausal subject increases, the number of teeth decreases and the
Decayed-Missing-Filled-Teethscoreincreases(189).Oldosteoporoticwomenmostlikely
haveperiodontaldiseasecomparedtothosewithoutosteoporosis.Anincreasinginage
andadecreasinginfemalesexualhormonesarerelatedtoanincreasinginboneloss.
Oralsigns,BodyMassIndexandagecanbeusedascriteriaindicatingosteoporosis’risk.
ArecentsystematicreviewbyGoyaletal.hasfavoredastrongassociationbetweenthe
centralBMDandCAL.
Findingsfromthisresearchareindisagreementwithdataoftheliterature,andPPD³5
andCAL3-4mmhavebeendemonstratedassociatedtoaconditionofhealthysystemic
bonedensity,andconsequently,osteoporoticpatientshaveshownbetterperiodontal
conditions(190).Theseresultscouldseemcontroversialbutitiscrucialtoanalyzetwo
key-factors: the recruiting pattern and the sample size. All the patients have been
enrolledinaDentalhospital,anditisplausiblethattheyhavebeenusedtoattendthe
dentalhospitaltoreceivedentaltreatments.Inaddition,itisplausiblethatpatientsthat
have receivedadiagnoseofosteoporosisand, in severalcases,a treatmentplan that
provides the assumption of medications such as bisphosphonates, have a particular
attentionandcaretotheirhealth.Theoralhealthofthistypeofpatientsisperiodically
controlledand theperiodontal status isusuallymaintainedwithaproperperiodontal
recallscheme.
Thesecondaspecttotakeintoaccountisthepowerofthestudy.Thesamplesizeofthe
researchhasbeensettoobtainastatisticalpoweraccordingtothefindings fromthe
reviewofCalciolarietal.andithasbeenbasedontheprimaryoutcomes:toassessthe
feasibilityofusingdentalpanoramicindicestoscreenforpost-menopausalosteoporosis
and to assess the sensitivity and specificity of quantitative and qualitative panoramic
indices (165). For this reason, the study is underpowered in assessing if periodontal
indices are correlated to BMD. Moreover, at the moment of the data analysis, the
recruitment has been still ongoing and only data from 70 patients were available.
Accordingtotheseconsiderations,alltheresultsfromtheperiodontaldataexamination
123
havetobeconfirmedwithfurtherstudieswitha largersampleofpatientsandwitha
strictrecruitmentoutline.
Regardingtheothersperiodontalindices,onlythenumberandthepercentageoftooth
losshavedemonstratedacorrelationthathasbeenconfirmedstatistically.Inthiscase
thetendencyofmissingteethhasbeentowardstheosteoporoticgroups.Thesedataare
in contrast to the aforementioned periodontal findings, and this strengthen the
hypothesisthatthesampleistoosmalltodrawmeaningfulconclusions.
6.3 SAMPLESIZEANDRECRUITMENTPATTERN
Aspreviouslydescribed,therecruitmentofthepatienthasbeendonewithinapoolof
post-menopausal women attending the Centre of Dentistry at Parma University.
Accordingtothe findingshereshown, it isplausiblethatarecruitment-centrerelated
bias could be present and of some importance. A large portion of the patients, that
regularlyattendsthedentalhospital,followsapersonalizedrecallprograminorderto
controltheperiodontalstatusovertime.Inparticular,periodontalcompromisedpatients
undergoasupportiveperiodontaltherapyaccordingtotheperiodontalriskassessment
tool.
Furthermore, the study has been designed to reach a statistical power of 80 % in
identifyingmorphometricpanoramicindicesastoolstodiagnoseosteoporosis,according
tothedatafromthereviewbyCalciolariet.al(2015),andthesamplenumberhasbeen
setat124(165).Asevidencedbythecriticalreviewoftheliterature,thepropersample
sizetoinvestigatetheprevalenceofperiodontaldiseaseinosteoporoticpatientshasto
bewider.Moreover,sincethestudyisstillgoing,only70patientshavebeenincludedin
thestudy,makingthesamplesizeevenlesspowered.Forthesereasons,furtherstudies
withapropersamplesizecalculationandwithoutpopulationselectionbiasesareneeded
andarealreadyongoing,inordertoobtainsignificativeresults.
124
6.4 CONFUNDINGFACTORS
Someconfoundingfactorscouldbeconsideredtobetterunderstandtheresultsandto
drawsensibleconclusions.
6.4.1 AgeTheinclusioncriteriaofthestudyhavesetat65yearsoldtheminimumagetobeeligible
forthestudy.ThishasbeendecidedaccordingtoItaliannationalhealthsystemguidelines
that considers above 65 years, the cut-off age from which consider the risk of
osteoporosisashigh.Itisimportanttoknowthat50yearsoldpost-menopausalwomen
couldbeeasilyfindwithinanormalpopulationand,withtheseinclusioncriteria,acluster
ofpatientfrom50to65yearsoldarenotinvolved.Furthermore,olderpatientsshow
different interfering medical conditions such as, bone metabolism, medications,
concomitantpathologies,dentalstatus,toothloss,etc.andthisaspectcouldbecrucial
in a statistical analysis. In fact, according to the literature a 30% prevalence of
osteoporosisamongstpost-menopausalwomenattendingadentalhospital,hasbeen
speculated. Anyhow, considering the age of the eligible patients, the prevalence of
osteoporosisinthepopulationcouldbehigherthanthe30%.Thisconsiderationhasbeen
confirmedbyourdatathathaveshownaprevalenceofosteoporoticpatientswithinthe
sampleof50%.
Attheendofthestudy,aFishertestcouldbenecessaryinordertoexcludetheageasa
confoundingvariable.
6.4.2 Smoke
Theavailableliteratureaboutpanoramicindicesdoesnottakeintoaccountthecondition
ofsmoker/non-smokerofthepatients.However,smokeisconsideredasariskfactorfor
theprogressionof theperiodontitisandhasbeendemonstratedstrictly correlated to
periodontal conditions. For this reason, smoke couldbe considered as a confounding
variableintheanalysisofthecorrelationbetweenperiodontalstatusandBMDbutthe
125
Fishertesthasshownnocorrelation.Nevertheless,thesmallsamplesizesuggeststhata
secondtestexecutedonalargerpopulationcouldbemoreeffective.
6.4.3 MedicationsDuringthepastdecade, increasingconcernhasdevelopedtowardsasevere,although
rare,complicationofanti-osteoporoticdrugsnamedosteonecrosisofthejaw(ONJ).
It is usually associated to bisphosphonates, in particular nitrogenous-based and
intravenousoneandthe firstdocumentedONJsdateback to2003andsince thenan
increasingnumberofpublicationshasfocusedonthisproblem.Sincethen,otherdrugs,
allable to inhibitbone resorption, suchasdenosumaborThor’s inhibitorshavebeen
consideredinvolvedinthepathogenesisofONJs(191).Recentlypubblishedpapershave
demonstratedacorrelationbetweenBP’sandbetterperiodontalconditions.
Theexactmechanism leading toONJ is still unknown, aswell as the reasonwhy this
conditiondevelopsonlyinthemaxilla-mandibularcomplex.Microdamageaccumulation,
infectionandsofttissuetoxicity(atleastforBPs)haveallbeensuggestedtoplayarole
inthedevelopmentofONJs(192).Itisalsoimportanttothinkthattheoralcavitypresents
withuniquecharacteristics compared tootherbonesof thebody,as thepresenceof
teethallowsadirectconnectionbetweentheboneandtheexterior.Moreover,dental
and periodontal infections and dento-alveolar trauma may be able to trigger this
condition(193).Itisimportanttonoticethatrecentlypubblishedpapershavesuggested
apossiblecorrelationbetweenBFsandbetterperiodontalconditions(194).Forallthese
reasons, apossible roleofBPs in influencing the correlationbetweenbodymassand
jawbonescouldbemoreinvestigatedbut,tostatisticallydemonstrateanyconnection,
thesampleneedtobeincreased.
126
7 CONCLUSIONS
127
According to our findings, although it is not indicated to prescribe an OPG with the
primary aim to screen for osteopenia/osteoporosis, whenever a pantomograph is
available,MCW,andKIcanbeahelpfulandeasilyusabletoolforthedentisttointercept
patientsatriskofreducedBMD,sincethisdiseasecanseverelyinterferewithanydental
treatment.Moreover,consideringthehighnegativepredictivevalueofthecombination
oftwoindices,thedentistcaneasilyexcludehealthypatientsandguidethepatientat
riskinaspecialisticdiagnosticpathway.
Thepossibilitytousedentalpanoramicradiographstoidentifypreviouslyundiagnosed
osteoporoticpatientsissuggestiveandseemstobesupportedbythesystematicreview
presentedinChapter3,althoughtheaveragequalityoftheavailablestudiesisnothigh.
Future studies should therefore account for confounding variables (e.g.medications,
concomitantdiseasesaffectingbonemetabolism,demographics),ensurethatexaminers
are blind to the skeletal BMD of the patients, and accurately evaluate the kappa of
agreement for intra- and inter-examiner reliability. The optimal cut-off has been
investigatedinthisstudy,byapplyingROCcurvesandtakingintoconsiderationnotonly
the sensitivity/specificity of the index, but also the positive and negative predictive
values,whichvarywiththeprevalenceofthediseaseandmayhaveamoremeaningful
clinical impact. Furthermore, the possibility to combine panoramic indices with well-
knownrisk factors forosteoporosisshouldbeaddressedby futurestudies inorder to
increasetheiraccuracyandthestrengthofthesesuggestions.Finally,thepossibilityto
measureindicesintheupperjawneedstobeinvestigated,althoughthelackofstable
anatomicreferencepointsinthemaxillamightbedifficulttoovercome.
Thewillingnessofgeneraldentiststotakepartintrainingsessionsandthewillingnessof
patientstobereferredtotheirGPortoaspecialistfollowingadentalappointment,as
wellasareferralpathwayfromgeneraldentistsdirectlytoGPsorosteoporoticspecialists
shouldbealsoevaluatedbyfutureclinicalprojects.Inthelongrun,aprospectivestudy
correlating panoramic indices to the risk of developing fractures, which are the real
burdenofosteoporosis,wouldaddadditionalstrengthtotheuseofthesetools,which
128
mightpotentiallybeaddedtoexistingfractureriskassessmenttools,suchasFRAXorthe
ItalianversionDeFRA.
RegardingthecorrelationbetweenperiodontalstatusandBMDitisclearthatthepresent
study is at the moment still unpowered. Further ongoing studies setting a proper
statisticalpowerandtakingintoaccounttheconfoundingvariablessuchassmoke,age
and enrolment facility are needed. In particular, PPD and CAL need to be more
investigatedconsideringthedifferencebetweenliteraturedataandthefindingsfromthis
study.Moreover,numberandpercentageoftoothlossareperiodontaldatathatcould
be related to the t-scorevalue. In conclusion,all theseperiodontal indices couldgive
meaningful informationbuttheenrolmentbiascouldbeavoidedandtherecruitment
hastobemorerepresentativeoftherealpopulation.
129
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RINGRAZIAMENTI
Moltesonostatelepersonechehannopartecipatoallarealizzazionediquestolavoroe,piùingenerale,chehannocontribuitoallamiacrescitaumanaeprofessionaledurantequestitreannidilavoro.IlprimosentitoringraziamentovaalmiotutoreeresponsabileProf.GiovanniPasseri,unaguidaespertachemihaaccompagnatoeinstradatodurantelarealizzazionedelprogettodi ricerca come anche della stesura della tesi. La possibilità di realizzare un lavoro diquesta portata, con i mezzi tecnici e umani a disposizione, è certamente legata allagenerositàealladisponibilitàchehasempremessoafavoredellacausa,edèancheperquesto che in questi anni il rapporto non si è limitato ad una mera collaborazionelavorativa.InsecondoluogoungrazievaalDirettoredelCentrodiOdontoiatria,Prof.GuidoMariaMacaluso, non un tutore ufficiale ma certamente un mentore che ha sempre datosostegnoallamiaattivitàclinicaedi ricercamediandocon intelligenza tracontrolloecollaborazionelasciandomisemprequelladosedilibertàeindipendenzanecessariaipiùgiovanipercrescere.Unruolofondamentalenellagestionedellamiaattivitàdiricercal’hannoavutaidirettoridirepartodelCentrodiOdontoiatria,Prof.SimoneLumettieProf.EdoardoManfrediperlafiduciacheognigiornomidannogarantendomilalibertàdigestireleattivitànecessariaadunaclinicaeunaricercadisuccessoeperquestoliringrazio.Insiemealoroungranderingraziamento va al Prof. Matteo Goldoni per l’indispensabile supportonell’interpretazionedell’analisistatistica.RingrazioinoltreperladisponibilitàelapazienzailpersonaletecnicoamministrativodelCentroOsteoporosiedelCentroUniversitariodiOdontoiatria:Dr.ssaGraiani,Alessandra,Annalisa,Celesta,Chiara,Deborah,Francesca,Romina,StefaniaeTina.Un ringraziamento va ai colleghi del Centro Universitario di Odontoiatria Alberto,Beatrice, Francesco e Lorenzo che mi hanno aiutato a superare i momenti difficiliriuscendoaportareunpo’dileggerezzainunambienteavolteosticodagestire.DesideroringraziareancheglistudentidelcorsodilaureaEliana,FernandoeAndreachehannopartecipatoattivamenteall’attivitàclinicalegataalprogetto.Unpensieroapartevaall’amicoecollegaDr.AndreaToffoli,avoltespallaavoltesparringpartner.Lasuapresenzacostantecomecompagnodiufficio,diavventureedisventureèstata,edètuttorafondamentale,percontinuareacrescereamigliorarecomeclinicoecomeamico.NonpossoinfinenoncitarelaDr.ssaLudovicaParisi,inseparabilecompagna
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diviaggionellenostreavventureinternazionali,èstataunsupportosemprepresenteinquestiannididuravitaalCentro.Terminati i ringraziamenti di natura professionale desidero spendere poche righeperringraziarelamiafamiglia.MiopadreMarioemiamadreElena,aiqualièdedicatoquestomanoscrittodicograzieperl’impagabilesupportoepazienza.Cometuttiifiglinonsaròmairiconoscenteasufficienzapertuttoquellocheavetefatto,fateefaretepermemasperodirendervifierisempredipiùognigiornochepassaesappiatechecercodifaredelmiomeglio.RingrazioanchemiofratelloRiccardochemihadatol’insegnamentopiùgrande che una persona possa dare, non arrendersi mai e prendere il meglio dallesituazioni.Seilapersonapiùfortecheconosco.Comespessofaccioholasciatoilmeglioallafine.IlringraziamentopiùgrandevaallamiafidanzataElena,mihaiinsegnatopiùdiquellocheunapersonacomemepossaimpararecredendoinmeanchequandoiostessoavevodeidubbi.Lastimacheelafiduciachemiinfondiognigiornomentrecondividiamolevicissitudinidellavitaedellavoromidannola spintaa cercarediessere sempremigliore. Sappi che senzadi te tuttoquestononsarebbe potuto realizzarsi, e sei l’artefice di ciò che di buono sono diventato e delsuccessochehoavuto.