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Dualeffectofstatinmedicationonthe periodontium

Saxlin T, Suominen-Taipale L, Knuuttila M, Alha P, Ylo stalo P. Dual effect of statinmedication on periodontium. J Clin Periodontol 2009; 36: 9971003. doi: 10.1111/j.1600-051X.2009.01484.x.

Abstract

Aim: The aim of this study was to investigate the association between statin

medication and periodontal infection in an adult population.

Material and Methods: The study was based on a subpopulation of the Health 2000Survey, which included dentate non-diabetic, non-rheumatic subjects who did notsmoke, aged 4069 years (n52032). The main outcome variable was the number ofteeth with periodontal pockets of 4 mm or more. Statin medication was categorized in

two ways: firstly, subjects with statin medication of some sort (n5134) versus thosewith none, and secondly, subjects taking either simvastatin (n558), atorvastatin(n538), some other statin (n538) or no statin medication. Relative risks (RR) were

estimated using negative binomial and Poisson regression models.

Results: We found a weak negative association between statin medication andperiodontal infection among subjects with dental plaque or gingival bleeding. Amongsubjects with no gingival bleeding, statin medication was found to be associated withan increased likelihood of having deepened periodontal pockets.

Conclusion: Statin medication appears to have an effect on the periodontium that is

dependent on the inflammatory condition of the periodontium. More evidence is

needed to achieve a comprehensive understanding of the effects of statins.

Key words: periodontal infection; statin

medication

Accepted for publication 3 September 2009

Statins, 3-hydroxy-3-methylglutarylcoen-zyme A reductase inhibitors, are widelyused medications to prevent cardiovascu-lar events and have been proven to behighly effective. According to conven-tional thinking, the effectiveness of sta-

tins was based on their capability toreduce serum cholesterol levels, primar-ily low-density lipoprotein cholesterol(LDL cholesterol). However, inflamma-tion is also known to play a role inatherosclerosis (Libby 2002), and it hasbeen suggested that statins also possessanti-inflammatory activity, independentof their lipid-lowering effects (Schon-beck & Libby 2004, Jain & Ridker

2005).Periodontitis is a continuous inflam-

matory process, which, if left untreated,may lead to irreversible destruction ofperiodontal tissues. Statins have beensuggested to have a protective effectagainst periodontal infection, too. Arecent study suggested that chronicperiodontitis patients taking statin med-ication had a lower number of patholo-gical periodontal pockets than thosewithout statin medication (Lindy et al.2008). A novel index, the PeriodontalInflammatory Burden Index, also

showed lower figures for periodontitispatients on statin medication thanpatients without statins (Lindy et al.2008). It has also been suggested thatstatin use was associated with decreasedtooth loss in chronic periodontitispatients (Cunha-Cruz et al. 2006). Inanimal models, statins have been sug-gested to prevent periodontal tissuebreakdown (Vaziri et al. 2007) and to

have beneficial effects on alveolar bonerecovery after ligature-induced alveolarbone resorption (Seto et al. 2008).

Despite the above-mentioned find-ings, the effects of statins on the period-ontium are quite poorly documented.Moreover, unlike in the case of cardio-vascular diseases, the mechanisms ofhow statins have an effect on the period-ontium are not well understood. The aimof this study was to examine the asso-ciation between statin medication andexisting periodontal infection in an adultpopulation.

Tuomas Saxlin1

, Liisa Suominen-Taipale2, Matti Knuuttila1,3,

Pirkko Alha2 and Pekka Ylostalo1

1Institute of Dentistry, University of Oulu,

Oulu, Finland; 2National Institute for Health

and Welfare (THL), Helsinki, Finland; 3Oral

and Maxillofacial Department, Oulu

University Hospital, Oulu, Finland

Conflict of interest and source of

funding statement

The authors declare that there are no

conflicts of interest in this study.

The present study is part of the Health2000 Survey, organized by the NationalInstitute for Health and Welfare (THL)

(former National Public Health Institute

(KTL) of Finland) (http://www.terveys2000.fi), and partly supported by the Fin-

nish Dental Society Apollonia and the

Finnish Dental Association. The personalgrant received from the Finnish Dental

Society Apollonia and the Finnish DentalAssociation is acknowledged by Tuomas

Saxlin.

J Clin Periodontol 2009; 36: 9971003 doi: 10.1111/j.1600-051X.2009.01484.x

997r 2009 John Wiley & Sons A/S
http://www.terveys2000.fi/http://www.terveys2000.fi/http://www.terveys2000.fi/http://www.terveys2000.fi/http://www.terveys2000.fi/http://www.terveys2000.fi/http://www.terveys2000.fi/http://www.terveys2000.fi/http://www.terveys2000.fi/http://www.terveys2000.fi/http://www.terveys2000.fi/http://www.terveys2000.fi/http://www.terveys2000.fi/http://www.terveys2000.fi/http://www.terveys2000.fi/http://www.terveys2000.fi/

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Material and Methods

The Health 2000 Survey was carried outin 2000 and 2001, conducted by theNational Institute for Health and Welfare(THL) [former National Public HealthInstitute (KTL) of Finland]. This surveycomprised 8028 subjects aged 30 years or

older living in continental Finland. Thedata for this survey were collected fromclinical oral and health examinations,from laboratory analyses, from self-admi-nistered questionnaires and by interviews.The study protocol was approved by theethical committee of the Helsinki Univer-sity Hospital. Informed consent wasobtained from the participants. Additionalinformation about the Health 2000 Surveyis available in a published report byAromaa & Koskinen (2004).

Our study was based on a subpopula-tion that included dentate non-diabetic,

non-rheumatic subjects who did notsmoke and were aged between 40 and69 years (n52032). Diabetes was deter-mined on the basis of informationobtained from a health interview andhealth examination. Only subjects whohad not been diagnosed with diabetesand had no indications of the diseasewere included in the study population.Rheumatoid arthritis was determined onthe basis of information obtained from thehealth interview. The question posed wasDo you have rheumatoid arthritis diag-nosed by a physician? with the answer

options being yes/no. Diabetic and rheu-matic subjects were excluded because ofthe complex association between perio-dontal infection and these diseases, whichwould have been difficult to control.

Outcome variables

Clinical oral examinations were per-formed by five calibrated dentists in adental chair using a headlamp, mouthmirror and a WHO periodontal probe inline with the WHO instructions. Theclinical oral examinations included the

assessment of the condition of the per-iodontium and teeth.

The main outcome variable was exist-ing periodontal infection, measured in twoways: number of teeth with deepenedperiodontal pockets (4 mm or more) andnumber of teeth with deep periodontalpockets (6mm or more). Periodontalpocket depth on probing was measuredon four surfaces of each tooth (distobuc-cal, mid-buccal, mid-oral and mesio-oral),and the deepest pocket depth on eachtooth was recorded. Third molars wereexcluded from the periodontal examina-

tion. The percentual agreement for dee-

pened periodontal pockets in the parallelmeasurements, where field examinerswere individually compared with thereference examiner under field circum-stances, was 77% (k50.41) (Vehkalahtiet al. 2008, p. 19). Intra-examiner relia-bility assessments concerning pathologi-cally deepened periodontal pocketsproduced a k value of 0.83 (Vehkalahtiet al. 2004, p. 29). The distributions of thenumber of teeth with deepened perio-dontal pockets are presented in Fig. 1.

We also used bleeding on probing as anoutcome variable. Bleeding on probing

was observed immediately after the mea-surement of periodontal pockets and theobservations were recorded by sextant.The percentual agreement in the parallelmeasurements between the field exami-ners and the reference examiner for thepresence of gingival bleeding under fieldcircumstances was 66% (k50.36) (Veh-kalahti et al. 2008, p. 19). Intra-examinerreliability assessments of the presence ofgingival bleeding produced a k value of0.66 (Vehkalahti et al. 2004, p. 29). In theregression analyses, the number of bleed-ing sextants was used as a continuous

variable. In the stratified analyses, gingi-val bleeding was divided into two cate-gories: subjects with no gingival bleedingversus subjects with gingival bleeding inone or more sextants.

Explanatory variables

Information about statin medication wasobtained from the health interview. Statinmedication was categorized in two ways:firstly, subjects with statin medication ofsome sort versus those with none, andsecondly, subjects who use either sim-

vastatin, atorvastatin, some other statin

or no statin medication. A total of 134subjects used statin medication, out ofwhich 58 subjects used simvastatin med-ication, 38 subjects used atorvastatinmedication and 38 subjects used someother statin medication.

Possible confounders and effect

modifiers

Age was included in the analyses as acontinuous variable. Education was cate-gorized into three categories. Basic educa-tion included those who had not graduated

from high school and did not have formalvocational qualifications. Intermediateeducation included those who had gradu-ated from high school. Higher educationcomprised subjects with a universitydegree or those who had graduated frompolytechnics. Oral health behavioural fac-tors included toothbrushing frequency anddental attendance pattern. Toothbrushingfrequency was categorized into three cate-gories as follows: twice a day or more,once daily or less frequently. Dentalattendance patterns were categorized asfollows: those who regularly had dental

check-ups versus those who used dentalservices in a symptom-based manner orhad never used them.

The presence of dental plaque wasmeasured using a modified version ofthe method described by Silness & Loe(1964). The presence of dental plaquewas measured from three teeth at onesurface each as follows: buccal surfacefrom the most posterior tooth on theupper right side, lingual surface fromthe most posterior tooth on the lower leftside and buccal surface from the leftlower canine. The presence of plaque

0

200

400

600

800

1000

1200

1400

1600

1800

0 2 4 6 8 10 12 14 16 18 20 22 24 26 28

n

Number of teeth with deepened (4 mm or more) anddeep (6 mm or more) periodontal pockets

4 mm or more

6 mm or more

Fig.1. Number of subjects with teeth with deepened (4 mm or more) and deep (6mm ormore) periodontal pockets.

998 Saxlin et al.

r 2009 John Wiley & Sons A/S

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was categorized into three categories asfollows: no visible plaque, visible pla-que at gingival margins only or visibleplaque also elsewhere. The highestvalue was recorded. The percentualagreement in the parallel measurements

between the field examiners and thereference examiner for the presence ofdental plaque under field circumstanceswas 58% (k50.36) (Vehkalahti et al.2008, p. 19). Intra-examiner reliabilityassessments of the presence of dentalplaque produced a k value of 0.79(Vehkalahti et al. 2004, p. 29). Bodyweight was assessed by using body massindex (BMI), which is a measure ofbody weight in relation to height (kg/m2).Information on weight and height wascollected from the health examination,or alternatively, when this was not pos-

sible, from the health interview andquestionnaires. BMI was included inthe analyses as a continuous variable.The basic characteristics of the studypopulation according to statin medica-tion are presented in Table 1.

Statistical methods

Because of the skewed distribution ofthe outcome variables among the totalpopulation, especially the number ofteeth with periodontal pockets of 6 mmdeep or deeper, we estimated relativerisks (RR) and 95% confidence intervals(95% CI) using negative binomial andPoisson regression models. In addition,we performed analyses where weexcluded subjects with no teeth withpathologically deepened periodontal

pockets (extent of infection among subjects with teeth with deepened perio-dontal pockets). The number of teeth (asa continuous variable) was treated as theoffset variable in the regression models.The selection of covariates was based oncurrent knowledge of the potential risk

factors of periodontal infection. We stu-died the possible interaction by addingthe interaction terms (product terms forstatin medication and the other covari-ates one by one) in the regression model.

A stratified two-stage cluster sam-pling design was used in the survey.Weighting of the sample was based onpost-stratification according to gender,age and region. The data analyses wereperformed using Stata 8.0 (negativebinomial regression) and the SUDAANstatistical package 10.0 (Poisson regres-sion) to take into account the two-stage

cluster sampling design.

Results

Among the total study population, statinmedication was weakly negatively asso-ciated with the number of teeth withdeepened periodontal pockets (4 mm ormore; RR 0.9, 95% CI 0.71.2) and thenumber of bleeding sextants (RR 0.8,95% CI 0.71.0) after adjusting forconfounding factors such as gender,age, education, dental attendance pat-

tern, toothbrushing frequency, presenceof dental plaque and BMI. The negativeassociation of statin medication with thenumber of teeth with deep periodontalpockets (6 mm or more) was strongerthan with the number of teeth withdeepened (4 mm or more) periodontalpockets, but did not reach statisticalsignificance at a 0.05 level (Table 2).Simvastatin medication was found to bemost strongly negatively associated withthe number of teeth with deepened anddeep periodontal pockets (Table 2).

We found an interaction between

statin medication and the presence ofdental plaque [statistically significantproduct term for the number of teethwith deepened periodontal pockets(4 mm or more) (p50.004)]. We there-fore stratified the data according to thepresence of plaque. We found that thenegative association between statinmedication and the number of teethwith deepened (4mm or more) anddeep (6 mm or more) periodontal pock-ets was stronger among subjects withplaque, whereas a weak and statisticallyinsignificant (at 0.05 level) positive

Table 1. Basic characteristics of the study population; proportions/means and their standard

errors (in parentheses) in the total population and in the categories of statin use (no statin

medication/statin medication)

Total(n5 2032)

No statinmedication

(n5 1898)

Statin medication(n5 134)

Age (n5 2032) [mean (SE)] 52.5 (0.2) 52.1 (0.2) 58.4 (0.7)

Gender (n5 2032) [% (SE)]

Males 43.4 (1.1) 42.8 (1.1) 53.0 (4.1)Females 56.6 (1.1) 57.2 (1.1) 47.0 (4.1)

Educational level (n5 2032) [% (SE)]

Basic 34.6 (1.1) 34.1 (1.1) 41.7 (4.3)

Intermediate 31.7 (1.0) 31.4 (1.0) 36.0 (4.3)High 33.7 (1.1) 34.5 (1.2) 22.3 (3.7)

Number of teeth, mean (n5 2032) (SE) 22.8 (0.2) 23.0 (0.2) 18.9 (0.7)

Number of teeth with periodontal pocketsX4mm (n5 2032) [mean (SE)]

3.7 (0.2) 3.7 (0.2) 3.3 (0.4)

Number of teeth with periodontal pockets

X6mm (n5 2032) [mean (SE)]

0.5 (0.0) 0.5 (0.0) 0.4 (0.1)

Presence of plaque (n5 2012) [% (SE)]

No plaque 42.0 (1.5) 41.7 (1.5) 45.8 (4.3)Plaque at gingival margins only 48.3 (1.4) 48.6 (1.5) 45.1 (4.4)

Plaque also elsewhere 9.7 (0.7) 9.7 (0.8) 9.1 (2.3)

Gingival bleeding in one or more

sextants (n5 2030) [% (SE)]No 25.8 (1.7) 25.6 (1.8) 29.2 (4.8)

Yes 74.2 (1.7) 74.4 (1.8) 70.8 (4.8)

Number of bleeding sextants,

mean (SE) (2030)

2.4 (0.1) 2.4 (0.1) 1.9 (0.2)

Dental attendance pattern

(n5 1970) [% (SE)]Regular check-ups 64.9 (1.4) 65.6 (1.4) 54.7 (4.5)

No regular check-ups 35.1 (1.4) 34.4 (1.4) 45.3 (4.5)

Toothbrushing frequency

(n5 1968) [% (SE)]Twice a day or more often 65.6 (1.2) 65.5 (1.3) 67.2 (4.3)

Once daily 28.9 (1.1) 29.0 (1.1) 27.3 (4.0)

Less frequently 5.5 (0.6) 5.5 (0.6) 5.5 (1.8)

Body mass index, mean(SE) (n5 2032)

27.1 (0.1) 27.1 (0.1) 27.4 (0.3)

Statins and periodontal infection 999


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association was found among subjectswith no plaque; statin medication wasfound to be associated with an increasedlikelihood of having teeth with deepenedand deep periodontal pockets (Table 3).

Based on the findings of the stratifi-cation according to dental plaque, wealso stratified the data according to thepresence of gingival bleeding. In theseanalyses, the association between statinmedication and the number of teeth withdeepened (4mm or more) and deep(6mm or more) periodontal pocketsfollowed a pattern similar to the onefor stratification according to dentalplaque. Among subjects with gingivalbleeding in one or more sextants, anegative association was found betweenstatin medication and the number of

teeth with deepened (RR 0.9, 95% CI0.71.1) and deep (RR 0.6, 95% CI 0.31.1) periodontal pockets. Among sub-

jects with no gingival bleeding, statinmedication was associated with anincreased likelihood of having teethwith deepened (RR 1.7, 95% CI 1.02.8) and deep (RR 3.1, 95% CI 1.19.0)periodontal pockets (Table 4).

The results of the analyses where theassociation between statin use and theextent of periodontal infection was stu-died (subjects with no teeth with dee-pened periodontal pockets excluded)

followed a pattern similar to the onefor the total population (Tables 24).

Discussion

The results of this study showed thatamong the total study population, statinmedication was weakly negatively asso-ciated with the presence and extent ofperiodontal infection. In stratified ana-lyses, this beneficial effect was seenonly in subjects with dental plaque orgingival bleeding. Among subjects withno gingival bleeding, and also to a lesserextent among subjects with no dentalplaque, statin medication was associatedwith an increased likelihood of havingteeth with deepened periodontal pockets.

Some recent studies have suggestedthat statins have protective effectsagainst periodontal infection. For exam-ple, a study by Lindy et al. (2008)showed that statin use was associatedwith fewer numbers of pathologicallydeepened periodontal pockets comparedwith subjects not taking statin medica-tion among chronic periodontitispatients. Statin use was also suggestedto be associated with decreased toothloss among subjects with chronic perio-dontitis (Cunha-Cruz et al. 2006). Ourresults partly concurred with these

results because our results also sug-gested that statin medication may havesome beneficial effects when subjectshave aetiological load (dental plaque) ora sign of periodontal infection (gingival

bleeding).

Anti-inflammatory effects of statins

Tissue destruction in periodontal diseaseresults from the interaction of the hostsimmune responses with microorganismsin dental plaque. Statins have been sug-gested to have several anti-inflammatoryqualities, which may also be important inthe case of periodontal infection. Forexample, it has been demonstrated thatstatins are able to inhibit leucocyte func-tion antigen-1 (LFA-1)intercellular adhe-

sion molecule-1 interaction in vitro bybinding to LFA-1 (Weitz-Schmidt et al.2001). This binding inhibition might pre-vent leucocyte adhesion and extravasationto sites of inflammation and antigen pre-sentation. In addition, Weitz-Schmidtet al. found that inhibition of LFA-1resulted in impaired T-cell costimulation.

Statins have also been suggested torepress T-cell functions. Major histo-compability complex class II (MHC-II)molecules are directly involved in theactivation of T-lymphocytes and in thecontrol of the immune response through

Table 2. Association between statin medication and the number of teeth with deepened periodontal pockets. Unadjusted and adjustedn relative risks

(RR) with 95% confidence intervals (CI)

Teeth with periodontal pockets X4 mm Teeth with periodontal pockets X6 mm

unadjusted RR (95% CI) adjusted RR (95% CI) unadjusted RR (95% CI) adjusted RR (95% CI)

Total population (n5 1949)w

Statin medication

No 1.0 1.0 1.0 1.0Yes 1.0 (0.81.3) 0.9 (0.71.2) 0.9 (0.51.5) 0.7 (0.41.1)

Subjects with the number of teeth with periodontal pockets 40 (n5 1248)z

Statin medication

No 1.0 1.0 1.0 1.0

Yes 1.0 (0.81.2) 0.9 (0.71.1) 0.8 (0.51.3) 0.6 (0.31.0)

Total population (n5 1949)w

Statin medicationNo statin 1.0 1.0 1.0 1.0

Simvastatin 1.0 (0.71.4) 0.8 (0.61.2) 0.6 (0.31.3) 0.4 (0.21.0)Atorvastatin 1.1 (0.81.6) 1.1 (0.71.6) 0.7 (0.31.8) 0.8 (0.31.8)

Other statin 1.0 (0.61.6) 0.8 (0.51.3) 1.5 (0.63.9) 1.1 (0.52.4)

Subjects with the number of teeth with periodontal pockets 40 (n5 1248)z

Statin medication

No statin 1.0 1.0 1.0 1.0Simvastatin 1.0 (0.81.3) 0.9 (0.71.1) 0.7 (0.31.5) 0.4 (0.20.9)

Atorvastatin 1.0 (0.71.4) 0.9 (0.61.3) 0.7 (0.31.7) 0.6 (0.21.4)

Other statin 1.0 (0.71.5) 0.9 (0.61.3) 1.1 (0.52.4) 0.9 (0.42.1)

nAdjusted for gender, age (continuous variable), education, presence of dental plaque, dental attendance pattern, toothbrushing frequency, body mass

index (continuous variable) and number of teeth (offset variable).wNegative binomial regression models used.zPoisson regression models used.

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antigen presentation. Kwak et al. (2000)

found that statins act in vitro as directinhibitors of MHC-II expression inductedby interferon g. They also found thatrepression of MHC-II was highly specificfor the inducible form of MHC-II andconcerned neither constitutive expressionof MHC-II, like for example in B-lymphocytes, nor MHC class I expression. Theysuggested that the effect is due to theinhibition of inducible promoter IV of aclass II transactivator.

It has also been proposed that statinsdecrease the production of many pro-inflammatory cytokines. Sakoda et al.

(2006) studied the effect of simvastatinon a human epithelial cell line KB andfound that simvastatin in vitro down-regulated interleukin-1a-induced inter-leukin-6 (IL-6) and IL-8 production inepithelial cells in a dose-dependentmanner. Ikeda & Shimada (1999) foundthat statins were associated withdecreased IL-6 production in vitro,whereas Rosenson et al. (1999) foundthat pravastatin was associated withdecreased blood concentrations oftumour necrosis factor a and IL-6among hypercholesterolaemic patients.

Matrix metalloproteinases (MMP) are

considered to be one of the main pro-teinases involved in periodontal tissuedestruction, as they degrade extracellu-lar matrix molecules. Statins have beenfound to decrease secretion of MMP-1,MMP-2, MMP-3 and MMP-9 in vitro(Luan et al. 2003). Also, reduced levelsof C-reactive protein have been sug-gested to be associated with statin medi-cation (Ridker et al. 1999).

Statins as immunomodulators in

periodontal tissues?

An interesting finding in this study wasthat among subjects with no dentalplaque or no gingival bleeding, statinmedication was associated with anincreased likelihood of having teethwith deepened periodontal pockets.One interpretation for this result isthat statins may dampen the fierceimmune response in a situation wherethe aetiological load of dental plaque issubstantial, thus protecting againstperiodontal tissue destruction, possiblyvia some of the above-mentioned anti-inflammatory mechanisms. However,

in situations where the magnitude ofthe aetiological load is small (no visibleplaque) and the visible inflammation isminimal (no gingival bleeding), thisdampening of immune responses maylead to disruption of the immune home-ostasis in periodontal tissues, which

could predispose to periodontal tissuebreakdown.In addition to the direct anti-inflam-

matory effects, some of the beneficialeffects of statins could be mediatedthrough lowered oxidized LDL choles-terol, which has been suggested to havepro-inflammatory properties (Matsuuraet al. 2006). This could be a comple-mentary/alternative explanation, espe-cially because elevated levels of serumlipids have, in some studies, been foundto associate with periodontal infection(Losche et al. 2000, Noack et al. 2000,

Nibali et al. 2007). However, this inter-pretation is not supported by the find-ings in our previous study using theseHealth 2000 data, in which we foundthat serum LDL cholesterol did notseem to associate with the number ofteeth with deepened periodontal pockets(Saxlin et al. 2008).

From the medications investigated inthis study, simvastatin was found to bemost strongly negatively associated withperiodontal infection. However, thenumber of subjects using different sta-tins was fairly small, meaning that no

definite conclusions on their effect canbe made. Therefore, no detailed ana-lyses on the effect of different statinswere carried out.

Validity issues

The presence of deepened periodontalpockets is a standardized method toassess periodontal infection and it iswidely used in research, in screeningand in clinical work. Probing depths of 4and 6 mm were used as cut-off values,which are commonly used boundary

values for pathologically deepenedperiodontal pockets. We measured thepresence and the extent of periodontalinfection in this study in terms of thenumber of teeth with deepened perio-dontal pockets, which produced countdata. This in turn means that we coulduse negative binomial or Poisson regres-sion models, which yield risk estimates,i.e. RR, which can be interpreted in aprobabilistic manner.

This study population had a relativelylarge number of subjects with no teethwith pathologically deepened periodontal

Table 3. Association between statin medication (no/yes) and the number of teeth with deepened

periodontal pockets, stratified according to the presence of dental plaque. Adjustedn relative risks

(RR) with 95% confidence intervals (CI)

No plaque Plaque in gingivalmargins

Plaque alsoelsewhere

RR 95% CI RR 95% CI RR 95% CI

Teeth with periodontal pockets X4 mmTotal populationw

n5 821 n5 944 n5 184

Statin medication

No 1.0 1.0 1.0

Yes 1.2 0.81.8 0.6 0.50.9 0.8 0.51.2

Subjects with the number of teeth with periodontal pockets 40z

n5 430 n5 666 n5 152

Statin medication

No 1.0 1.0 1.0Yes 1.2 0.91.7 0.7 0.60.9 0.8 0.61.1

Teeth with periodontal pocketsX6 mm

Total populationw

n5 821 n5 944 n5 184

Statin medicationNo 1.0 1.0 1.0

Yes 1.2 0.62.2 0.3 0.10.8 0.1 0.00.5


n5 430 n5 666 n5 152Statin medication

No 1.0 1.0 1.0

Yes 1.5 0.82.8 0.3 0.10.6 0.1 0.00.4

nAdjusted for gender, age (continuous variable), education, dental attendance pattern, toothbrushing

frequency, body mass index (continuous variable) and number of teeth (offset variable).wNegative binomial regression models used.zPoisson regression models used.



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pockets (periodontally healthy subjects).This excessive number of zeros causedoverdispersion, which meant that Poissonregression models did not fit properly.Therefore, we estimated RRs among thetotal population using negative binomialregression models. When the estimates ofnegative binomial regression models werecompared with the estimates of Poissonregression models, it could be noted thatthe difference in the estimates, if any, didnot exceed 0.1 in most cases (data notshown).

We also performed analyses usingPoisson regression models where weexcluded subjects with no teeth withdeepened periodontal pockets. Thissort of exclusion reduces overdispersionand is one suggested method to handle asituation where overdispersion is appar-ent (Lewsey et al. 2000). There was noessential difference in the results of theanalyses of the total population and thesubpopulation where periodontallyhealthy subjects were excluded, whichincreases the credibility of the resultsobtained in the main analyses.

The distribution of the number ofbleeding sextants did not follow thePoisson distribution completely. There-fore, we performed complementary ana-lyses using a cumulative logit model toassess the effect of this deviation fromPoisson distribution (data not shown).These results were in accordance withthe results obtained of the Poissonregression models.

We studied the possible interactionby adding the interaction terms (productterms for statin medication and the other

covariates one by one) in the regressionmodel. In theory, there is always a riskof finding spurious interactions if thenumber of such tests is large. However,in this study, the number of interactiontests totalled seven, meaning that in thecase of no association, the probability ofobtaining a statistically significant inter-action between statin medication anddental plaque is low. Our interpretationthat the effect of statin medication onperiodontium is dependent on the pre-sence of dental plaque is supported bythe fact that the p-value for the interac-

tion between statin medication and den-tal plaque was low (p50.004). It couldbe noted that because gingival bleedingis a sign of periodontal infection, we didnot consider gingival bleeding as apotential confounder and therefore theinteraction between statin medication

and the presence of gingival bleedingwas not tested.The strengths of this study include the

restriction of the study population tonon-smokers, because smoking isknown to be a strong risk factor forperiodontitis and can therefore preventdetection of weaker determinants.Moreover, it has been suggested thatadjusting for smoking may otherwisebe insufficient (Hujoel et al. 2002). Inthis study, restriction to non-smokers isalso important because smoking isknown to reduce gingival bleeding

(Bergstrom & Preber 1994), which wasused as one of the outcome variablesand as a variable for stratification.Restricting the study population tonon-rheumatic subjects is also an advan-tage because rheumatic patients oftenhave other medications, such as immu-nomodulatory and anti-inflammatorymedications, whose effect would havebeen difficult to take into account in theanalyses. However, we cannot totallyexclude the possibility that unreportedsmoking or undiagnosed diseases couldhave some effect on the association

between statin medication and perio-dontal infection.

This study had a cross-sectionaldesign, which is considered to be alimitation. It prevents us from makingany definite conclusions about the tem-poral sequence between expected causeand effect. We also acknowledge thatthe presence of dental plaque and gingi-val bleeding are crude markers of aetio-logical load and inflammation ingingival tissues, respectively, and arealso subject to biases in registration. Itis, however, noteworthy that despite this

crudeness, the associations between sta-tin medication and the number of teethwith pathologically deepened perio-dontal pockets, especially in stratifiedanalyses, were fairly strong.

Concluding remarks

Our assumption was that statin medica-tion has beneficial effects on the period-ontium, as has been suggested in earlierstudies. In line with this assumption,statin medication was weakly negatively

Table 4. Association between statin medication (no/yes) and the number of teeth with deepened

periodontal pockets, stratified according to the presence of gingival bleeding. Adjusted n relative

risks (RR) with 95% confidence intervals (CI)

Among subjects with nogingival bleeding in any

sextants

Among subjects with gingivalbleeding in one or more

sextants

RR 95% CI RR 95% CI

Teeth with periodontal pockets X4 mm

Total populationw

n5 494 n5 1453

Statin medication

No 1.0 1.0Yes 1.7 1.02.8 0.9 0.71.1


n5 175 n5 1071

Statin medicationNo 1.0 1.0

Yes 1.7 1.22.5 0.8 0.71.0

Teeth with periodontal pockets X6 mm

Total populationw

n5

494 n5

1453Statin medicationNo 1.0 1.0

Yes 3.1 1.19.0 0.6 0.31.1


n5 175 n5 1071

Statin medicationNo 1.0 1.0

Yes 3.5 1.67.6 0.5 0.30.9

nAdjusted for gender, age (continuous variable), education, presence of dental plaque, dental

attendance pattern, toothbrushing frequency, body mass index (continuous variable) and number of

teeth (offset variable).wNegative binomial regression models used.zPoisson regression models used.

1002 Saxlin et al.


8/8/2019 statins[1].

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associated with periodontal infection inthis low-risk adult population of non-diabetic and non-rheumatic subjectswho did not smoke. An interesting andimportant finding was that among sub-

jects with no dental plaque or no gingi-val bleeding, statin medication was

associated with an increased likelihoodof having pathologically deepenedperiodontal pockets.

The results of this study suggestedthat statins have an effect on the period-ontium that is dependent on the inflam-matory condition of the periodontium.This has not been suggested previously.We acknowledge that these findingsmay be due to chance, not at least dueto the low number of individuals whohad statin medication, and must there-fore be interpreted with caution. Wealso acknowledge that these results

may be affected by various forms ofbiases, such as errors in measurementsof clinical parameters, insufficient orincorrect information about medicationsor confounding by extraneous factors.Altogether, the results of this study callfor further studies to replicate and verifythese findings and to attain a compre-hensive understanding of the effects ofstatins.

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Address:

Tuomas Saxlin

Institute of Dentistry

University of Oulu

PO Box 5281

90014 University of Oulu

Oulu

Finland

E-mail: [email protected]

Clinical Relevance

Scientific rationale for the study:

Statins have been suggested to haveanti-inflammatory effects, indepen-dent of their lipid-lowering effects.Some recent studies have suggestedthat statin medication may also havebeneficial effects on the periodontium.

Principal findings: Among subjectswith dental plaque or gingival bleed-ing, statin medication was found tobe weakly and negatively associatedwith periodontal infection. Amongsubjects with no gingival bleeding,statin medication was associatedwith an increased likelihood of hav-

ing teeth with deepened periodontalpockets.Practical implications: Statins mayalso have therapeutic effects due totheir anti-inflammatory potential, butmore studies are needed to replicateand verify these effects of statins.


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