Volume 85 • Number 6
Tooth Loss, Periodontitis, and Statins in a Population-Based Follow-Up Study Peter Meisel,*† Heyo K. Kroemer,† Matthias Nauck,‡ Birte Holtfreter,* and Thomas Kocher*
Background: Statins, frequently prescribed in lipid-lowering therapies, seem to have additional beneficial effects on periodontitis and tooth loss. If this is true, then chronic treatment with statins should also result in diminished tooth loss as a long-term response. Methods: A 5-year population-based follow-up study of tooth loss was performed comparing participants treated with statins (n = 134) with those not on the drugs (Study of Health in Pomerania). Negative binomial regression models were used to analyze the count variable of the outcome, including risk factors for tooth loss and measures of cholesterol metabolism. Results: When adjusted for age and sex, statins were associated with reduced tooth loss during the follow-up period (incidence risk ratio [IRR] = 0.70, 95% confidence interval [CI] = 0.50 to 0.99, P = 0.04). When additionally adjusted for risk factors of periodontal breakdown, IRR was 0.72 (95% CI = 0.52 to 1.01). There was significant interaction with low-density lipoprotein cholesterol (LDL-c) at baseline. After stratification by LDL-c, statins were associated with reduced tooth loss, resulting in IRR = 0.89 (95% CI = 0.44 to 1.83) and 0.64 (95% CI = 0.43 to 0.95), P = 0.03, at LDL-c concentrations £100 mg/dL and >100 mg/dL (2.58 mmol/L), respectively. The data also showed reduced tooth loss associated with the 5-year reduction in LDL-c levels on a mmol/L basis and independently of statins (IRR = 0.87, 95% CI = 0.80 to 0.96, P = 0.004). Conclusion: Long-term treatment with systemically administered statins may have the beneficial effect of protecting against tooth loss. J Periodontol 2014;85:e160-e168. KEY WORDS Anticholesteremic agents; C-reactive protein; cholesterol, LDL; hydroxymethylglutaryl-CoA reductase inhibitors; periodontitis; tooth loss. * Dental Clinics, Unit of Periodontology, Ernst Moritz Arndt University Greifswald, Greifswald, Germany. † Department of Pharmacology, University of Greifswald. ‡ Department of Clinical Chemistry and Laboratory Medicine, University of Greifswald.
I
n the last decade, various studies were conducted in an attempt to find beneficial effects of statins on tooth loss or periodontal diseases.1-15 The rationale behind these studies arose from different views regarding the pathogenesis of periodontitis. Periodontitis is associated with increased cholesterol levels, especially LDL cholesterol (LDL-c). Probably, periodontitis is also associated with cardiovascular diseases for which elevated LDL-c is a risk factor.16 Patients with elevated LDL-c concentrations and/or at risk for cardiovascular diseases are frequently treated with statins for long periods of time.17 Besides the LDL-c–lowering effect of statins, there are pleiotropic properties of the drugs influencing inflammatory and bone-modeling processes, both of which participate in the pathogenic course of periodontitis and tooth retention.18 Thus, there is the encouraging hypothesis that use of statins could attenuate periodontal inflammation and diminish bone loss with the consequence of improved tooth preservation.19 The question arises whether the long-term use of statins in cardiovascular settings may also affect the periodontal tissues. Periodontitis is an inflammatory disease caused by periodontal-pathogenic bacteria residing in dental plaque, i.e., the biofilm on the tooth surface. It is accompanied by pocket formation and leads to attachment loss (AL) and alveolar bone loss. Reduced bone heights around dental roots may be induced by progressive periodontal inflammation doi: 10.1902/jop.2013.130456
e160
J Periodontol • June 2014
and pose a high risk of early tooth loss. This risk may be even higher in individuals with periodontitis who are suffering from concurrent systemic diseases, especially osteoporosis. Various studies revealed that the local inflammation within the oral cavity is associated with increased levels of markers of systemic diseases. Special attention was given to the relationships among periodontal diseases and diabetes, cardiovascular disease, and osteoporosis, among others.20-23 Increased blood levels of hemoglobin A1c, cholesterol, C-reactive protein (CRP), and cytokines supported the idea that periodontitis may affect or worsen systemic metabolic status. However, only a few studies disputed the causal direction.21,22 A bidirectional relationship may exist between local periodontitis and systemic diseases, both of which are inflammatory in nature.24 Among the factors for which an association with the severity of periodontitis was reported are the phospholipids, cholesterol, and cholesterol subfractions LDL-c and high-density lipoprotein cholesterol (HDL-c).23 There is substantial evidence that periodontal diseases might be associated with elevated systemic cholesterol concentrations.20,21 Other reports conclude that an unfavorable lipid composition cannot be considered an important risk of periodontal diseases, at least below age 50.25 Presumably, the association between periodontitis and lipid levels is the consequence of systemic effects of inflammatory stimuli.23 Concentrations of CRP are elevated in both conditions.26 The 3-hydroxy-3-methyl-glutaryl-CoA (HMG CoA) reductase inhibitors, or statins, are the most effective agents currently available to lower LDL-c levels. Several clinical trials have demonstrated a considerable reduction of cardiovascular risk associated with statin intake. In addition, it was suggested that statins may have other effects beyond their lipid-reducing ability, especially with respect to inflammatory events.27,28 Thus, the question arises whether statins may have an influence on periodontal parameters by affecting either the inflammation or the association between the disease and cholesterol concentrations or both. Moreover, statins exert beneficial effects on bone mineral density, which is possibly also relevant to the alveolar bone crest.29,30 Some studies reported effects of statins in cell cultures or in animal experiments supporting the idea that these drugs could have some effects on periodontal diseases.31,32 Fifteen research papers were identified in the literature that engaged the question whether statins could affect gingivitis, periodontitis, or tooth loss in humans.1-15 Three types of research strategies were followed, namely: 1) assessment of periodontal measures in individuals treated conventionally by statins for their lipid profile;1,2,4,7,10 2)
Meisel, Kroemer, Nauck, Holtfreter, Kocher
application of fixed doses of statins and subsequently following the progression of periodontitis;3,5,6,8,9 and 3) similarly, local application of fixed doses of statins in the pockets of affected teeth only and subsequent follow-up.11-15 Notably, almost exclusively, the lipophilic simvastatin or atorvastatin was used. Although different in design, most studies reported a positive effect of statin intake on different periodontal measures. Reduced bone or tooth loss was reported.2,3,11,12 Besides their lipid-lowering effects, statins exert some pleiotropic actions influencing inflammatory processes and bone remodeling. Statin effects on probing depth (PD) and clinical attachment level (CAL) are quite consistent among the studies cited; associations with a healthier periodontium or improvements in periodontal conditions during followup were reported.7-9,11-14 Inconsistent results were reported for statin treatment on gingivitis symptoms: some studies reported improved gingival conditions,8,11 whereas others found worsened conditions.5,6 Alveolar bone loss was improved by systemic statin treatment.3 Likewise, topical administration promoted the formation of alveolar bone.11-15 If it is true that the severity of periodontal symptoms increases circulating cholesterol levels, then it might be expected that statins could prevent this association due to their cholesterol-decreasing effect.10 On the other hand, periodontal treatment was shown to add to the statin’s LDL-c–lowering effect in patients with hyperlipidemia and periodontitis outcome.4 Statins locally administered directly into the gingival pockets showed CAL gain and reduced bone loss in follow-up studies.11-15 As an adjunctive measure to mechanical debridement for the treatment of localized forms of periodontal breakdown, such a technique may have a potential role in periodontal regenerative therapy.33 The relationships among periodontitis and systemic inflammatory diseases are widely discussed and have been associated with elevated concentrations of CRP, LDL-c, and other inflammatory markers.34-36 Statins have anti-inflammatory and bone-stimulatory effects, which may offer benefits in treating periodontal sequelae in addition to their systemic benefits.24,37,38 From animal experiments with locally administered drugs, it was suggested that simvastatin with boneanabolic properties in combination with bisphosphonates as antiresorptive agents (e.g., alendronate) may increase and preserve alveolar bone thickness.39 Altogether, most of the findings were inconsistent regarding the association between statin use and reduced tooth loss or improved periodontitis symptoms. Different threshold criteria between periodontal cases and controls and different schedules of statin e161
Tooth Loss and Statins
Volume 85 • Number 6
from SHIP-0 were again invited to participate in SHIP-1, the 5-year follow-up. From October 2002 to 2006, 3,300 individuals were examined (follow-up response rate of 76.9%). Of these individuals, 2,969 (1,403 males and 1,566 females, mean age of final cohort: 46.7 – 14.5 years) had matching reports on statin use (Fig. 1). Dental Examination Dental examinations were conducted in rotation by seven trained, calibrated, and licensed dentists (TK, Florian Mack, Olaf Berhardt, Almut Wenetiadis, Antje Hartelt, Valentine Koerber, Christian Juengel, Dental Clinics University of Greifswald, Greifswald, Figure 1. Flowchart indicating the recruiting of the study groups. *Individuals reported intake of statins at Germany).43 Calibration exerbaseline and follow-up (ever) or neither at baseline nor at follow-up (never). cises were performed on dentists not connected to the study every 6 months, yielding an intraclass correlation of 0.82 to usage hamper the interpretation of the results. Thus, 0.91 per examiner and an interclass correlation of the use of statins in dental settings is still in an ex0.84, both for AL. Assessment of number of teeth perimental phase, raising future expectations for included all teeth except the third molars (28 teeth applications in practice.18,19,24,30 Presentations remaximum). Tooth loss was defined as the difference cently held at international symposia seem to conin the number of teeth at baseline minus the number firm statin-related improvements of periodontitis.40,41 of teeth at follow-up. Measurements of CAL and PD The findings require confirmation in further epiwere assessed with a periodontal probe§ at distodemiologic studies. The authors hypothesize that buccal, mid-buccal, mesio-buccal, and mid-lingual chronic treatment with statins should result in disites according to the half-mouth method, alternating minished tooth loss as a long-term response, preon the left or right side (maximum 14 teeth). If resumably related to its effect on LDL-c. cession was present at the examined site, CAL was directly measured as the distance between the ceMATERIALS AND METHODS mento-enamel junction (CEJ) and the pocket base Study Design and Sample rounded to the next whole millimeter.43 The Study of Health in Pomerania (SHIP) is a longitudinal population-based medical-dental health Independent Variables survey of a 20- to 79-year-old population in the Socio-demographic variables were taken from the northeast of Germany. Approved by the local ethics health-related interview (education, income) and the committee, SHIP-0 is based on a representative, agepersonal questionnaire (risk factors and resources for stratified cluster sample that was examined from health in living and working conditions, smoking). 1997 to 2001 in West Pomerania. From official resLevel of education was divided according to the final ident data files, 7,008 individuals were drawn at school grade (10 years). Monthly random in numbers proportional to the population household income per persons living in the household size of each community and were stratified by age was categorized into quartiles: 960 euros (third and fourth quarGerman citizenship were included. Of the 6,262 tiles). Approximately, the income median corresponds adults invited to participate in SHIP, 4,308 were exto the average income in Germany. Body mass index amined, corresponding to a response rate of 68.8%.42 (BMI) was used to define obesity according to World All participants gave their written informed consent. Health Organization criteria as BMI ‡30 kg/m2. Data collection and instruments comprised four Total cholesterol, LDL-c, HDL-c, and apolipoparts: oral health examination, medical examination, proteins were measured by standard laboratory health-related interview, and health- and risk factor– related questionnaire. After 5 years, individuals § PCP 11, Hu-Friedy, Chicago, IL. e162
J Periodontol • June 2014
Meisel, Kroemer, Nauck, Holtfreter, Kocher
database consisted of 134 participants undergoing statin treatment and 2,555 without statins (Fig. 1). Counts of tooth loss were overdispersed. Therefore, negative binomial regression was applied for the analysis of the incidence risk ratio (IRR) of tooth loss. In all regression analyses, the log-transformed follow-up time was included as an offset variable. Kruskal–Wallis test was used to assess differences in continuous variables. Significance levels were set at P
Tooth Loss, Periodontitis, and Statins in a Population-Based Follow-Up Study Peter Meisel,*† Heyo K. Kroemer,† Matthias Nauck,‡ Birte Holtfreter,* and Thomas Kocher*
Background: Statins, frequently prescribed in lipid-lowering therapies, seem to have additional beneficial effects on periodontitis and tooth loss. If this is true, then chronic treatment with statins should also result in diminished tooth loss as a long-term response. Methods: A 5-year population-based follow-up study of tooth loss was performed comparing participants treated with statins (n = 134) with those not on the drugs (Study of Health in Pomerania). Negative binomial regression models were used to analyze the count variable of the outcome, including risk factors for tooth loss and measures of cholesterol metabolism. Results: When adjusted for age and sex, statins were associated with reduced tooth loss during the follow-up period (incidence risk ratio [IRR] = 0.70, 95% confidence interval [CI] = 0.50 to 0.99, P = 0.04). When additionally adjusted for risk factors of periodontal breakdown, IRR was 0.72 (95% CI = 0.52 to 1.01). There was significant interaction with low-density lipoprotein cholesterol (LDL-c) at baseline. After stratification by LDL-c, statins were associated with reduced tooth loss, resulting in IRR = 0.89 (95% CI = 0.44 to 1.83) and 0.64 (95% CI = 0.43 to 0.95), P = 0.03, at LDL-c concentrations £100 mg/dL and >100 mg/dL (2.58 mmol/L), respectively. The data also showed reduced tooth loss associated with the 5-year reduction in LDL-c levels on a mmol/L basis and independently of statins (IRR = 0.87, 95% CI = 0.80 to 0.96, P = 0.004). Conclusion: Long-term treatment with systemically administered statins may have the beneficial effect of protecting against tooth loss. J Periodontol 2014;85:e160-e168. KEY WORDS Anticholesteremic agents; C-reactive protein; cholesterol, LDL; hydroxymethylglutaryl-CoA reductase inhibitors; periodontitis; tooth loss. * Dental Clinics, Unit of Periodontology, Ernst Moritz Arndt University Greifswald, Greifswald, Germany. † Department of Pharmacology, University of Greifswald. ‡ Department of Clinical Chemistry and Laboratory Medicine, University of Greifswald.
I
n the last decade, various studies were conducted in an attempt to find beneficial effects of statins on tooth loss or periodontal diseases.1-15 The rationale behind these studies arose from different views regarding the pathogenesis of periodontitis. Periodontitis is associated with increased cholesterol levels, especially LDL cholesterol (LDL-c). Probably, periodontitis is also associated with cardiovascular diseases for which elevated LDL-c is a risk factor.16 Patients with elevated LDL-c concentrations and/or at risk for cardiovascular diseases are frequently treated with statins for long periods of time.17 Besides the LDL-c–lowering effect of statins, there are pleiotropic properties of the drugs influencing inflammatory and bone-modeling processes, both of which participate in the pathogenic course of periodontitis and tooth retention.18 Thus, there is the encouraging hypothesis that use of statins could attenuate periodontal inflammation and diminish bone loss with the consequence of improved tooth preservation.19 The question arises whether the long-term use of statins in cardiovascular settings may also affect the periodontal tissues. Periodontitis is an inflammatory disease caused by periodontal-pathogenic bacteria residing in dental plaque, i.e., the biofilm on the tooth surface. It is accompanied by pocket formation and leads to attachment loss (AL) and alveolar bone loss. Reduced bone heights around dental roots may be induced by progressive periodontal inflammation doi: 10.1902/jop.2013.130456
e160
J Periodontol • June 2014
and pose a high risk of early tooth loss. This risk may be even higher in individuals with periodontitis who are suffering from concurrent systemic diseases, especially osteoporosis. Various studies revealed that the local inflammation within the oral cavity is associated with increased levels of markers of systemic diseases. Special attention was given to the relationships among periodontal diseases and diabetes, cardiovascular disease, and osteoporosis, among others.20-23 Increased blood levels of hemoglobin A1c, cholesterol, C-reactive protein (CRP), and cytokines supported the idea that periodontitis may affect or worsen systemic metabolic status. However, only a few studies disputed the causal direction.21,22 A bidirectional relationship may exist between local periodontitis and systemic diseases, both of which are inflammatory in nature.24 Among the factors for which an association with the severity of periodontitis was reported are the phospholipids, cholesterol, and cholesterol subfractions LDL-c and high-density lipoprotein cholesterol (HDL-c).23 There is substantial evidence that periodontal diseases might be associated with elevated systemic cholesterol concentrations.20,21 Other reports conclude that an unfavorable lipid composition cannot be considered an important risk of periodontal diseases, at least below age 50.25 Presumably, the association between periodontitis and lipid levels is the consequence of systemic effects of inflammatory stimuli.23 Concentrations of CRP are elevated in both conditions.26 The 3-hydroxy-3-methyl-glutaryl-CoA (HMG CoA) reductase inhibitors, or statins, are the most effective agents currently available to lower LDL-c levels. Several clinical trials have demonstrated a considerable reduction of cardiovascular risk associated with statin intake. In addition, it was suggested that statins may have other effects beyond their lipid-reducing ability, especially with respect to inflammatory events.27,28 Thus, the question arises whether statins may have an influence on periodontal parameters by affecting either the inflammation or the association between the disease and cholesterol concentrations or both. Moreover, statins exert beneficial effects on bone mineral density, which is possibly also relevant to the alveolar bone crest.29,30 Some studies reported effects of statins in cell cultures or in animal experiments supporting the idea that these drugs could have some effects on periodontal diseases.31,32 Fifteen research papers were identified in the literature that engaged the question whether statins could affect gingivitis, periodontitis, or tooth loss in humans.1-15 Three types of research strategies were followed, namely: 1) assessment of periodontal measures in individuals treated conventionally by statins for their lipid profile;1,2,4,7,10 2)
Meisel, Kroemer, Nauck, Holtfreter, Kocher
application of fixed doses of statins and subsequently following the progression of periodontitis;3,5,6,8,9 and 3) similarly, local application of fixed doses of statins in the pockets of affected teeth only and subsequent follow-up.11-15 Notably, almost exclusively, the lipophilic simvastatin or atorvastatin was used. Although different in design, most studies reported a positive effect of statin intake on different periodontal measures. Reduced bone or tooth loss was reported.2,3,11,12 Besides their lipid-lowering effects, statins exert some pleiotropic actions influencing inflammatory processes and bone remodeling. Statin effects on probing depth (PD) and clinical attachment level (CAL) are quite consistent among the studies cited; associations with a healthier periodontium or improvements in periodontal conditions during followup were reported.7-9,11-14 Inconsistent results were reported for statin treatment on gingivitis symptoms: some studies reported improved gingival conditions,8,11 whereas others found worsened conditions.5,6 Alveolar bone loss was improved by systemic statin treatment.3 Likewise, topical administration promoted the formation of alveolar bone.11-15 If it is true that the severity of periodontal symptoms increases circulating cholesterol levels, then it might be expected that statins could prevent this association due to their cholesterol-decreasing effect.10 On the other hand, periodontal treatment was shown to add to the statin’s LDL-c–lowering effect in patients with hyperlipidemia and periodontitis outcome.4 Statins locally administered directly into the gingival pockets showed CAL gain and reduced bone loss in follow-up studies.11-15 As an adjunctive measure to mechanical debridement for the treatment of localized forms of periodontal breakdown, such a technique may have a potential role in periodontal regenerative therapy.33 The relationships among periodontitis and systemic inflammatory diseases are widely discussed and have been associated with elevated concentrations of CRP, LDL-c, and other inflammatory markers.34-36 Statins have anti-inflammatory and bone-stimulatory effects, which may offer benefits in treating periodontal sequelae in addition to their systemic benefits.24,37,38 From animal experiments with locally administered drugs, it was suggested that simvastatin with boneanabolic properties in combination with bisphosphonates as antiresorptive agents (e.g., alendronate) may increase and preserve alveolar bone thickness.39 Altogether, most of the findings were inconsistent regarding the association between statin use and reduced tooth loss or improved periodontitis symptoms. Different threshold criteria between periodontal cases and controls and different schedules of statin e161
Tooth Loss and Statins
Volume 85 • Number 6
from SHIP-0 were again invited to participate in SHIP-1, the 5-year follow-up. From October 2002 to 2006, 3,300 individuals were examined (follow-up response rate of 76.9%). Of these individuals, 2,969 (1,403 males and 1,566 females, mean age of final cohort: 46.7 – 14.5 years) had matching reports on statin use (Fig. 1). Dental Examination Dental examinations were conducted in rotation by seven trained, calibrated, and licensed dentists (TK, Florian Mack, Olaf Berhardt, Almut Wenetiadis, Antje Hartelt, Valentine Koerber, Christian Juengel, Dental Clinics University of Greifswald, Greifswald, Figure 1. Flowchart indicating the recruiting of the study groups. *Individuals reported intake of statins at Germany).43 Calibration exerbaseline and follow-up (ever) or neither at baseline nor at follow-up (never). cises were performed on dentists not connected to the study every 6 months, yielding an intraclass correlation of 0.82 to usage hamper the interpretation of the results. Thus, 0.91 per examiner and an interclass correlation of the use of statins in dental settings is still in an ex0.84, both for AL. Assessment of number of teeth perimental phase, raising future expectations for included all teeth except the third molars (28 teeth applications in practice.18,19,24,30 Presentations remaximum). Tooth loss was defined as the difference cently held at international symposia seem to conin the number of teeth at baseline minus the number firm statin-related improvements of periodontitis.40,41 of teeth at follow-up. Measurements of CAL and PD The findings require confirmation in further epiwere assessed with a periodontal probe§ at distodemiologic studies. The authors hypothesize that buccal, mid-buccal, mesio-buccal, and mid-lingual chronic treatment with statins should result in disites according to the half-mouth method, alternating minished tooth loss as a long-term response, preon the left or right side (maximum 14 teeth). If resumably related to its effect on LDL-c. cession was present at the examined site, CAL was directly measured as the distance between the ceMATERIALS AND METHODS mento-enamel junction (CEJ) and the pocket base Study Design and Sample rounded to the next whole millimeter.43 The Study of Health in Pomerania (SHIP) is a longitudinal population-based medical-dental health Independent Variables survey of a 20- to 79-year-old population in the Socio-demographic variables were taken from the northeast of Germany. Approved by the local ethics health-related interview (education, income) and the committee, SHIP-0 is based on a representative, agepersonal questionnaire (risk factors and resources for stratified cluster sample that was examined from health in living and working conditions, smoking). 1997 to 2001 in West Pomerania. From official resLevel of education was divided according to the final ident data files, 7,008 individuals were drawn at school grade (10 years). Monthly random in numbers proportional to the population household income per persons living in the household size of each community and were stratified by age was categorized into quartiles: 960 euros (third and fourth quarGerman citizenship were included. Of the 6,262 tiles). Approximately, the income median corresponds adults invited to participate in SHIP, 4,308 were exto the average income in Germany. Body mass index amined, corresponding to a response rate of 68.8%.42 (BMI) was used to define obesity according to World All participants gave their written informed consent. Health Organization criteria as BMI ‡30 kg/m2. Data collection and instruments comprised four Total cholesterol, LDL-c, HDL-c, and apolipoparts: oral health examination, medical examination, proteins were measured by standard laboratory health-related interview, and health- and risk factor– related questionnaire. After 5 years, individuals § PCP 11, Hu-Friedy, Chicago, IL. e162
J Periodontol • June 2014
Meisel, Kroemer, Nauck, Holtfreter, Kocher
database consisted of 134 participants undergoing statin treatment and 2,555 without statins (Fig. 1). Counts of tooth loss were overdispersed. Therefore, negative binomial regression was applied for the analysis of the incidence risk ratio (IRR) of tooth loss. In all regression analyses, the log-transformed follow-up time was included as an offset variable. Kruskal–Wallis test was used to assess differences in continuous variables. Significance levels were set at P
