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Comparison of Clinical Efficacy of a Dentifrice Containing Calcium Sodium Phosphosilicate to a Dentifrice Containing Potassium Nitrate and to a Placebo on Dentinal Hypersensitivity: A Randomized Clinical Trial AR Pradeep* and Anuj Sharma* Background: A considerable number of agents are effective in the treatment of dentin hypersensitivity. This 6-week ran- domized clinical trial compares a dentifrice containing cal- cium sodium phosphosilicate to potassium nitrate and to a placebo. Methods: A total of 110 subjects (58 males and 52 females; aged 20 to 60 years) were entered into the study. The volun- teers selected at baseline had a history of dentin hypersensitiv- ity caused by gingival recession or cervical erosion. Patients were required to have at least two teeth with a visual analog scale score of 4 to be included in the study. After sensitivity scores for controlled air stimulus (evaporative stimulus) and cold water (thermal stimulus) at baseline were recorded, sub- jects were given toothpastes randomly, and sensitivity scores were measured again at 2- and 6-week follow-ups. Results: All three groups showed reduction in sensitivity scores at 2 weeks and 6 weeks for air stimulus and cold water. The calcium sodium phosphosilicate group, however, was found to be significantly better in reducing the visual analog scale score compared to the potassium nitrate group and the placebo group at any time point for both measures of sensitiv- ity. Conclusion: Under the conditions of a clinical trial, the cal- cium sodium phosphosilicate group showed comparable reduc- tion in the symptoms of dentin hypersensitivity. J Periodontol 2010;81:1167-1173. KEY WORDS Biocompatible materials; clinical trial; dentifrice; dentin; pain; pain measurement. D entinal hypersensitivity (DH) has been defined as a short, sharp pain arising from exposed dentin as a result of various stimuli, such as heat, cold, chemical, or osmotic, that cannot be ascribed to any other pathol- ogy. 1 DH is a painful clinical condition that affects 8% to 35% of the population. 2 The incidence of DH reportedly peaks during the third and fourth decades of life. 3 There are many and varied etiologic and predisposing factors related to DH. Removal of enamel, as a result of attri- tion, abrasion, and erosion, or denuda- tion of the root surface by overlying cementum and periodontal tissue loss, are commonly cited. 4 Because exposure of the root area may be multifactorial, chronic trauma from toothbrushing, tooth flexure caused by abnormal occlu- sal loading forces, parafunctional habits, acute and chronic inflammatory gingival and periodontal diseases, acute trauma, periodontal surgery, and acidic dietary components are commonly cited as ma- jor causes of cervical lesions and DH. 5 Pain caused by DH can be explained by the widely accepted ‘‘hydrodynamic theory’’ proposed by Braennstroem and * Department of Periodontics, Government Dental College and Research Institute, Bangalore, Karnataka, India. doi: 10.1902/jop.2010.100056 J Periodontol • August 2010 1167

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Comparison of Clinical Efficacyof a Dentifrice Containing CalciumSodium Phosphosilicate to a DentifriceContaining Potassium Nitrate and toa Placebo on Dentinal Hypersensitivity:A Randomized Clinical TrialAR Pradeep* and Anuj Sharma*

Background: A considerable number of agents are effectivein the treatment of dentin hypersensitivity. This 6-week ran-domized clinical trial compares a dentifrice containing cal-cium sodium phosphosilicate to potassium nitrate and toa placebo.

Methods: A total of 110 subjects (58 males and 52 females;aged 20 to 60 years) were entered into the study. The volun-teers selected at baseline had a history of dentin hypersensitiv-ity caused by gingival recession or cervical erosion. Patientswere required to have at least two teeth with a visual analogscale score of ‡4 to be included in the study. After sensitivityscores for controlled air stimulus (evaporative stimulus) andcold water (thermal stimulus) at baseline were recorded, sub-jects were given toothpastes randomly, and sensitivity scoreswere measured again at 2- and 6-week follow-ups.

Results: All three groups showed reduction in sensitivityscores at 2 weeks and 6 weeks for air stimulus and cold water.The calcium sodium phosphosilicate group, however, wasfound to be significantly better in reducing the visual analogscale score compared to the potassium nitrate group and theplacebo group at any time point for both measures of sensitiv-ity.

Conclusion: Under the conditions of a clinical trial, the cal-ciumsodiumphosphosilicategroupshowedcomparable reduc-tion in the symptoms of dentin hypersensitivity. J Periodontol2010;81:1167-1173.

KEY WORDS

Biocompatible materials; clinical trial; dentifrice; dentin;pain; pain measurement.

Dentinal hypersensitivity (DH) hasbeen defined as a short, sharppain arising from exposed dentin

as a result of various stimuli, such asheat, cold, chemical, or osmotic, thatcannot be ascribed to any other pathol-ogy.1 DH is a painful clinical conditionthat affects 8% to 35% of the population.2

The incidence of DH reportedly peaksduring the third and fourth decades oflife.3

There are many and varied etiologicand predisposing factors related to DH.Removal of enamel, as a result of attri-tion, abrasion, and erosion, or denuda-tion of the root surface by overlyingcementum and periodontal tissue loss,are commonly cited.4 Because exposureof the root area may be multifactorial,chronic trauma from toothbrushing,tooth flexure caused by abnormal occlu-sal loading forces, parafunctional habits,acute and chronic inflammatory gingivaland periodontal diseases, acute trauma,periodontal surgery, and acidic dietarycomponents are commonly cited as ma-jor causes of cervical lesions and DH.5

Pain caused by DH can be explainedby the widely accepted ‘‘hydrodynamictheory’’ proposed by Braennstroem and

* Department of Periodontics, Government Dental College and Research Institute,Bangalore, Karnataka, India.

doi: 10.1902/jop.2010.100056

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Astroem in 1964.6 According to this theory, the pres-ence of lesions involving enamel or cementum loss incervical areas and the consequent opening of dentinaltubules to the oral environment, under certain stimuli,allow the movement of dentinal fluid inside the tu-bules, indirectly stimulating the extremities of the pulpnerves, causing the pain sensation. It is also found thatopen dentinal tubules serve as pathways for diffusivetransport of bacterial elements in the oral cavity tothe pulp, which may cause a localized inflammatorypulpal response.7 Histologically, under transmissionelectron microscope, a sensitive tooth shows wideneddentinal tubules, two times larger than tubules of nor-mal dentin and in greater number per area comparedto a tooth without DH.8 Although macroscopically thedentin of a hypersensitive tooth does not differ fromthat of a normal tooth, the symptoms suggest minorinflammation of pulp.9

Various strategies have been implicated in thetreatment of DH, including lasers, ions and salts, fluo-ride iontophoresis, dentin sealers, periodontal softtissue grafting, and homeopathic medications.10 Itis still not possible, however, to reach a consensusabout which techniques represent the gold standardin the treatment of DH.

Currently, two main approaches are used in thetreatment and prevention of DH: tubular occlusionand blockage of nerve activity. In the tubular occlu-sion approach, the tooth is treated with a physicalor chemical agent that forms a layer that mechani-cally occludes the dentinal tubules and preventspulpal fluid flow, thereby leading to reduction inDH.11,12 Such treatment strategies as lasers, dentinsealers, and periodontal soft tissue grafting work onthe same principle. In blockage of nerve activity, po-tassium ion tends to concentrate in the interior of thedentinal tubules, causing a depolarization of thecellular membrane of the nerve terminal and a re-fractory period with decreased sensitivity.13 Variousclinical trials14-17 have been performed to test the ef-ficacy of such agents to reduce DH, and most of theseproved efficient but some failed to show beneficialeffects. Although both main approaches are effectivein reducing DH, the condition usually reappears be-cause of toothbrush abrasion, the presence of acidchallenges in the mouth, or degradation of the coatingmaterial. There is a need to develop new desensitizingagents that permit the relief of DH symptoms from thebeginning of their appearance.

Calcium sodium phosphosilicate, a bioactive glass,reacts when exposed to aqueous media and providescalcium and phosphate ions that form a hydroxy-carbonate-apatite, a mineral that is chemically similarto the mineral in enamel and dentin.18 The chemicalreaction initiated by calcium sodium phosphosilicateto promote the formation of a hydroxy-carbonate-

apatite layer for the treatment of DH may also be use-ful in treating demineralized tooth structure or in pre-venting further demineralization.

This study investigates the effect of a new tooth-paste containing 5% calcium sodium phosphosilicateon DH over a period of 6 weeks. The efficacy of thenew toothpaste was compared to that of a positivecontrol toothpaste containing 5% potassium nitrateand to a placebo.

MATERIALS AND METHODS

The study was a single-center, longitudinal, triple-masked (investigators, subjects, and statistician),randomized parallel-arm design. The study durationwas 6 weeks, in which sensitivity scores were mea-sured at baseline, at 2 weeks, and at 6 weeks. The re-search protocol was initially submitted to the EthicalCommittee of the Government Dental College andResearch Institute, Bangalore, India. After ethical ap-proval, subjects were selected from the outpatientsection of the Department of Periodontics, Govern-ment Dental College and Research Institute, Banga-lore. Duration of the study was from May 2009 toJuly 2009.

The three toothpastes studied were 1) a commer-cially available non-aqueous toothpaste containing5% calcium sodium phosphosilicate with fusedsilica;† 2) a commercially available toothpaste con-taining 5% potassium nitrate as positive control;‡

and 3) a toothpaste containing the same formulationas calcium sodium phosphosilicate toothpaste exceptfor the active ingredient (calcium sodium phosphosi-licate) as negative control.§

Investigators (ARP and AS) and patients weremasked to toothpaste content. The toothpastes weredispensed in tubes labeled A, B, and C, the contents ofwhich were disclosed to the investigators only aftercompletion of the statistical analyses.

Sample size calculations were based on detectinga difference of 30% reduction in visual analog scale(VAS) scores19 between test and control groups usinga two-tailed significance level of 5% with a 90% power.A total of 120 subjects were included in the study andcategorized into three groups, each containing 40subjects. A total of 110 subjects (58 males and 52 fe-males) were finally considered because 10 subjectsfailed to follow up or discontinued the treatment. Se-lected subjects were randomly assigned to one ofthree treatment groups by lottery method. There were36 subjects in the calcium sodium phosphosilicategroup, 37 in the potassium nitrate group, and 37 inthe placebo group. Subjects participating in the studywere 20 to 60 years of age. The mean age of the

† SHY-NM, Group Pharmaceuticals, Mumbai, India.‡ SHY, Group Pharmaceuticals.§ Group Pharmaceuticals.

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subjects was not statistically different among groupsand ranged from 41.9 years for the calcium sodiumphosphosilicate group, 36.9 years for the positivecontrol group, and 39.4 years for the negative controlgroup. Subjects who were in good general health,could fulfill the scheduled appointment, and gavewritten informed consent to participate were recruitedinto the 6-week trial. A flow chart of the study is pro-vided in Figure 1.

Inclusion–Exclusion CriteriaThe volunteers selected at baseline had ahistory of DHcaused by gingival recession or cervical erosion. Pa-tients were required to have at least two teeth witha VAS score of ‡4 to be included in the study. Teethincluded in the study had small or no occlusal resto-ration. Teeth with caries, defective restorations, andsubjects with orthodontic appliances or bridge workthat would interfere with evaluation were excluded.In addition, subjects were also excluded if they were al-lergic to ingredients used in the study or exhibited anygross oral pathology, eating disorders, chronic dis-ease, or any disease requiring repeated or regular an-algesia, anti-inflammatory drugs, or antihistamines.

Sensitivity AssessmentTo assess tooth sensitivity, a controlled air stimulus(evaporative stimulus) and cold water (thermal stim-ulus) were used. Sensitivity was measured using

a 10-cm VAS score, with thescore of zero being a pain-freeresponse and a score of 10 be-ing excruciating pain or dis-comfort. Scoring of toothsensitivity was done first by us-ing controlled air pressure, froma standard dental syringe at 40to 65 psi at ambient tempera-ture, directed perpendicularlyand at a distance of 1 to 3 mmfrom the exposed dentin sur-face while adjacent teeth wereprotected with gloved fingersto prevent false-positive results.This was followed by scoring oftooth sensitivity using 10 ml ofice cold water applied to the ex-posed dentin surface whileneighboring teeth were isolatedduring testing using the opera-tor’s fingers and cotton rolls. Aperiod of at least 5 minuteswas allowed between the twostimuli on each tooth. Types ofteeth included in the study areshown in Table 1.

After the recording of sensi-tivity scores at baseline, subjects were given respec-tive toothpastes randomly and advised to use thetoothpaste with a soft bristle toothbrushi twicea day. Subjects were also directed to refrain fromany other dentifrice or mouthrinse during the trialbut were allowed to continue their normal oral hygienepractice.

Statistical AnalysesMean VAS scores and mean – SE were calculatedfrom raw VAS scores from all the subjects in a treat-ment group. Mean VAS scores were compared amonggroups at different time points (baseline, and 2 and 6weeks) and among groups at each time point usingone-way analysis of variance. Post hoc pairwisemultiple comparisons were done using the Holm-Sidak method (P <0.05) when significance wasdetected. Data were statistically analyzed using asoftware program.¶

RESULTS

Mean VAS scores for air stimulus for the calcium so-dium phosphosilicate group, the potassium nitrategroup, and the placebo group at baseline, and 2and 6 weeks are shown in Table 2. VAS scores forair stimulus of all three groups were not statistically

Figure 1.Study flow chart.

i Colgate Sensitive, Colgate-Palmolive, Daman, India.¶ SPSS statistical package (Version 17.5), SPSS, Chicago, IL.

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different from each other at baseline. Although allthree groups showed reduction in sensitivity scoresat 2 and 6 weeks, the calcium sodium phosphosilicategroup was found to be significantly better in reducingVAS scores compared to the potassium nitrate groupat 2 and 6 weeks and the placebo group at 6 weeks.

Mean VAS scores for water stimulus for the calciumsodium phosphosilicate group, the potassium nitrategroup, and the placebo group at baseline, and 2 and6 weeks are shown in Table 3. VAS scores for waterstimulus were not statistically different amongthe groups at baseline. There was greater reductionin mean sensitivity score for the calcium sodium phos-phosilicate group compared to the placebo and potas-sium nitrate groups at 2 and 6 weeks. The calciumsodium phosphosilicate group showed significant re-duction at 6 weeks compared to the other groups.

Percentage change in mean sensitivity scores forall three groups at all time points for both measures

is shown in Table 4. Percentage change in sensitivityscore for the calcium sodium phosphosilicate groupwas 72% and 68.7% for air and water stimulus, respec-tively, at 6 weeks. This change in score was stati-stically significant compared to the other groups.Negative value in all percentage change in sensitivityscores showed that there was a reduction in sensitivityscore from baseline to 2 and 6 weeks.

Intergroup comparison of percentage change in airand water sensitivity scores at all time points is shownin Table 5 and Table 6, respectively. The calciumsodium phosphosilicate group showed a statisticallysignificant difference in percentage change for bothair and water sensitivity from both the potassiumnitrate and placebo groups at all time points, but thepercentage change difference was greater for air stim-ulus at all time points.

Table 1.

Types of Teeth Included in Study

Types of Teeth

Teeth Selected by

Investigators (%)

Upper central incisors 5.4

Upper lateral incisors 6.2

Upper canine 13.1

Lower central incisors 4.6

Lower lateral incisors 3.4

Lower canine 12.4

Upper premolars 18.4

Lower premolars 14.3

Upper molars 11.8

Lower molars 10.4

Table 2.

Sensitivity Scores to Air Stimulus for AllTreatment Groups at All Time Points

Sensitivity Scores (mean – SE)

Toothpaste Groups Baseline 2 Weeks 6 Weeks

Potassium nitrate 6.57 – 0.25 5.66 – 0.22 3.66 – 0.18

Calcium sodiumphosphosilicate

7.17 – 0.25 4.71 – 0.23 1.97 – 0.14

Placebo 6.40 – 0.18 5.20 – 0.18 3.83 – 0.12

Table 3.

Sensitivity Scores to Water Stimulus forAll Treatment Groups at All Time Points

Sensitivity Scores (mean – SE)

Toothpaste Groups Baseline 2 Weeks 6 Weeks

Potassium nitrate 7.66 – 0.25 6.51 – 0.25 3.94 – 0.21

Calcium sodiumphosphosilicate

8.43 – 0.21 6.37 – 0.17 2.57 – 0.14

Placebo 6.91 – 0.21 6.00 – 0.18 4.31 – 0.18

Table 4.

Analysis of Variance Test: PercentageChange in Mean Sensitivity Scores for AllThree Groups at All Time Points for BothMeasures of Sensitivity

Change in Mean

Sensitivity Score (%)

Measure of

Sensitivity

Toothpaste

Groups

Baseline to

2 Weeks

Baseline to

6 Weeks

Air stimulusPotassium nitrate -12.6 -42.7Calcium sodium

phosphosilicate-34.6 -72

Placebo -18.3 -39.2

Water stimulusPotassium nitrate -14.2 -47.4Calcium sodium

phosphosilicate-24 -68.7

Placebo -12.7 -36.8

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DISCUSSION

This study compared calcium sodium phosphosili-cate toothpaste to potassium nitrate and placebotoothpastes. The trial was designed and reported inaccordance with good clinical practice. The resultsof the present study demonstrate reduction in symp-toms for all treatment groups from baseline to 2 and 6weeks for both measures of sensitivity. There was a re-markable pattern toward reduction of DH with time forall the variables during the 6 weeks of active phase ofthe study independent of treatment groups. The cal-cium sodium phosphosilicate group showed a higherdegree of effectiveness at reducing DH than commer-cially available potassium nitrate and a placebo for

both sensitivity measures. Percentage reduction insensitivity scorewasgreater for air stimuluscomparedto water stimulus from baseline to 2 and 6 weeks, ex-cept for the potassium nitrate group, which showedgreater percentage reduction for water stimulus com-pared to air stimulus with a meager difference.

Researching the literature, well-designed clinicaltrials providing some evidence for the formulationcontaining all potential active ingredients used in thisstudy can be found. Calcium sodium phosphosilicate,originally developed as a bone regenerative mate-rial, has been shown to be effective at physically oc-cluding dentinal tubules through the development ofa hydroxyapatite-like mineral layer.18,20 Clinical eval-uations of calcium sodium phosphosilicate for thetreatment of DH have shown statistically significantandclinicallypositive results.21 Thesignificantclinicaltreatment of hypersensitivity through the formation ofcrystalline apatite led researchers to hypothesize thatcalcium sodium phosphosilicate could be useful in re-mineralization and the prevention of demineralizationof tooth structures, especially dentin. Moreover, it hasdemonstratedstrong antimicrobial behavior invitro,22

which reduces symptoms of DH by preventing bacte-ria to induce pulpal response.

The 5% potassium nitrate toothpaste was used asa positive control in our study because it has provedto be clinically efficient in the treatment of DH. Somestudies have reported the effectiveness of 5% potas-sium nitrate gel as an active ingredient.14,23,24 Inour study, the potassium nitrate group showed signif-icant percentage reduction in sensitivity scores forboth air and water stimuli but reduction comparedto the calcium sodium phosphosilicate group wasless, although reduction was equal or even better thanthe placebo group. Difference in sensitivity reductionbetween potassium nitrate and calcium sodium phos-phosilicate can be explained by their mechanism ofaction. Potassium nitrate blocks intradental nervesby raising extracellular potassium ion. Evidence fromexperiments on nerve excitability indicates that po-tassium-induced effects are transient and revers-ible.25 Calcium sodium phosphosilicate, however,directly blocks dentinal tubules and has better desen-sitizing effects than 5% potassium nitrate.

Although a suitable duration for most of the previ-ous clinical trials for evaluating the effectiveness ofdesensitizing toothpaste was considered 8 weeks,some studies have stated that the optimum timecourse for different agents differs based on their ac-tion. Duration of our study was 6 weeks with sensitivitymeasurement at baseline, and 2 and 6 weeks, basedon a previous clinical trial conducted for assessmentof calcium sodium phosphosilicate as a desensitizingagent.26 The duration of a trial may vary, dependingon whether it is evaluating short- or long-term effects

Table 5.

Holm-Sidak Method for IntergroupComparison of Percentage Change in AirSensitivity Scores

Difference in Percentage Change (SE)

Groups Compared

Baseline to

2 Weeks

Baseline to

6 Weeks

Potassium nitrateversus calciumsodium phosphosilicate

22.0 – 3.1* 29.3 – 3.6*

Calcium sodiumphosphosilicateversus placebo

-16.3 – 3.1* -32.7 – 3.6*

Potassium nitrateversus placebo

5.7 – 3.1 -3.4 – 3.6

* Statistically significant at P value <0.05.

Table 6.

Holm-Sidak Method for IntergroupComparison of Percentage Change in WaterSensitivity Scores

Difference in Percentage Change (SE)

Groups Compared

Baseline to

2 Weeks

Baseline to

6 Weeks

Potassium nitrateversus calciumsodium phosphosilicate

9.8 – 2.8* 21.3 – 3.6*

Calcium sodiumphosphosilicateversus placebo

-11.2 – 2.8* -31.9 – 3.6*

Potassium nitrateversus placebo

-1.4 – 2.8 -10.6 – 3.6

* Statistically significant at P value <0.05.

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of the product. The trial duration should be sufficientto allow expression of the maximum efficacy of the ac-tive agent, while minimizing the magnitude of any pla-cebo effects.

Dentin sensitivity may differ for different stimuli,27

and it is recommended that at least two hydrodynamicstimuli be used in the clinical trial. We used evapora-tive air stimulus and cold water in our study becausethese are both physiologic and controllable. Evapora-tive air stimulus was used first for sensitivity assess-ment followed by water stimuli in our study becausethe least severe stimulus should be applied first to pre-vent interpretation error. The interval of ‡5 minuteswas allowed between the two stimuli to minimize inter-actions between stimuli.

In the present study, the placebo group also re-ported greater reduction in mean sensitivity scoresover time. One probable factor may be the environ-ment under which this study was performed. The pa-tients knowingly participated in a clinical trial todetermine the efficacy of desensitizing products.Despite randomization and stratification effects to ho-mogenize sample characteristics, enrolled volunteersoften try to please the investigators. Furthermore,positive emotional and motivational behavioral re-sponses can activate the body’s central pain-inhibit-ing system, which can modulate painful stimuli fromthe periphery through the release of endorphins cen-trally.28 Many investigators have described patientsobtaining relief without any treatment because of pla-cebo effect, which varies from 20% to 60% in DH clin-ical trials.29,30 Yet another possible phenomenon,which could cause such change, is the Hawthorne ef-fect. This effect is a response to non-intervention pro-cedures, such as improved oral hygiene or frequentexaminations. Improved oral hygiene would decreasethe pain because this may allow greater saliva accessto patent dentinal tubules, which in turn may enhancetubule obliteration through the deposition of salivarycalcium, phosphate, and proteins. The influence ofthe Hawthorne effect is difficult to calculate. No at-tempt was made to give oral hygiene instructions,and the number of visits was kept to a minimum.

With the present state of knowledge and technicalskills, evaluation of compounds for the treatment ofDH is based on clinical trials.31 To date no standardtechnology has been developed to test products de-signed for treatment of DH. To prevent the placebo ef-fect, which can mask any treatment effects, clinicaltrial designs for DH should be modified.

CONCLUSIONS

After the 6 weeks of clinical evaluation, all treatmentsshowed lower VAS sensitivity values compared withbaseline, independent of their different modes of ac-tion. It can be concluded that under the conditions

of a clinical trial, the calcium sodium phosphosilicategroup will show comparable, tremendous reductionsin DH symptoms.

Because calcium sodium phosphosilicate showedgreater reduction in sensitivity compared to highly ef-ficacious potassium nitrate, it may provide a new di-rection for the treatment of DH. For future prospects,longer-term studies with scanning electron micro-scope evaluations should be undertaken to ascertainthe efficacy of calcium sodium phosphosilicate.

ACKNOWLEDGMENTS

The authors express their gratitude to Mr. R.Pacheiyappan, Manager-Sales and Marketing, GroupPharmaceuticals, Bangalore, India, and Group Phar-maceuticals, India, for their support in providingSHY-NM (calcium sodium phosphosilicate), SHY (po-tassium nitrate), and placebo pastes. The authors alsoexpress their thanks to Mr. P. S. Jagannatha, a statis-tician, Rajajinagar, Bangalore, for carrying out all re-quired statistics. The authors report no conflicts ofinterest related to this study.

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Correspondence: Professor Avani R. Pradeep, Departmentof Periodontics, Government Dental College and ResearchInstitute, Bangalore-560002, Karnataka, India. E-mail:[email protected].

Submitted January 30, 2010; accepted for publicationMarch 16, 2010.

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