Objectives: This pilot retrospective case-control study questioned whether systemic statin use causes pulp calcification using cone-beam computed tomography (CBCT) images from the patients prescribed oral statins and comparing those of healthy individuals. Subjects and Methods: CBCT scans of 54 patients, including 27 age- and sex-matched patients for the study and control groups, were analysed using Mimics Innovation Suite software. The study included patients using statins regularly for at least 1 year. Only intact teeth with opposing teeth were selected for the study group and matched with the control group. Dental crown and pulp chamber volumes were calculated and proportioned. The data were analysed with chi-square and Shapiro-Wilk tests to assess normal distribution, followed by Mann-Whitney U test if necessary. Results: Statistical analysis showed no difference between the study and control groups (p = 0.505). Statin use duration did not cause statistically significant difference in terms of the reduction of pulp chamber volume (p = 0.141). Conclusion: Within the limitations of the study, systemic statin use did not cause dental pulp calcification. The results suggest, oral administration of the statin drugs is not an unfavourable condition for dental practice. Further studies with larger numbers of patients are needed to support this conclusion.

Highlights of the Study

  • Cone-beam computed tomography images were used to analyse volumetric alterations of the pulp chamber.

  • Systemic use of statin type drugs does not necessarily cause calcification in the pulp chamber of the teeth.

  • Duration of systemic statin use does not cause significant alterations on the pulp chamber volume.

Statins are the first-line pharmaceuticals used in the treatment and prevention of dyslipidaemia. The drug acts as 3-hydroxy-3-methylglutaryl-coenzyme A inhibitor that limits the cholesterol biosynthesis, resulting reduced intracellular cholesterol levels [1]. The reduction in cholesterol levels achieved with statin therapy has been shown to reduce all-cause mortality by 10% and cardiovascular events by 25% by delaying the development of atherosclerosis and reducing the incidence of vascular disorders [2]. According to one report [3], 25% of adults over the age of 40 in the USA, which equates to approximately 25 million people, use statins. Another study [4], reported that the global prevalence of statin use was 40% as of 2013, and this rate is predicted to increase by 20% in the coming years. On the other hand, there are regions where statin use is limited due to reasons such as low income, living in rural areas, and old age [5]. Lovastatin, the first type of statin to be introduced, was approved in the USA in 1987, followed by simvastatin and pravastatin in 1991, fluvastatin in 1994, atorvastatin in 1997, rosuvastatin in 2003, and pitavastatin in 2009 [3]. Atorvastatin and rosuvastatin appear to be the most used statins as they are reported to be the most effective ones, while atorvastatin was also to be the safest [6]. Beyond lipid lowering feature, statins have many pleiotropic effects such as improvement of endothelial dysfunction, increased nitric oxide bioavailability, antioxidant effects, anti-inflammatory properties, and stabilization of atherosclerotic plagues. The action of statins in the regulation of bone metabolism is also studied and it was shown that statins stimulate the release of bone anabolic factors [7]. To take advantage of this effect, it was thought that anabolic and anti-inflammatory effects of statins on bone metabolism could be used in dental treatments [8, 9]. The aims of the previous clinical and animal studies investigating the pleiotropic effects of statins in the field of dentistry were to increase the fracture healing rate, heal critical bone defects, make bone augmentation, maintain the height of the alveolar crest after tooth extraction, accelerate bone formation in the distraction osteogenesis procedure, increase the success of dental implants, and treat periodontal diseases [8‒10]. In the case of endodontics, some studies showed that statins can increase odontoblastic differentiation and mineralization of dental pulp cells or stem cells in vivo and in vitro [11, 12]. While an enhanced dentine formation could be beneficial for certain dental treatments like pulp capping [11], odontoblastic activation could lead to an adverse effect like calcification of the pulp chamber [13]. Pulp calcifications can be observed in both physiological and pathological forms, manifesting as either diffuse or discrete. Moreover, these calcifications are distinguished by their location, being classified as either pulp chamber or radicular calcifications [14]. The aetiology of these calcifications is multifactorial, involving systemic conditions, local irritants, and age-related changes [14‒17]. In a clinical setting, if a root canal treatment is required, calcifications restricting or entirely obliterating the root canal space can make the procedure extremely difficult and may potentially be the primary cause of mishaps like missing canals, perforation, instrument separation, or a reason for undesired tooth extraction [14].

The effect of statin use on pulp chamber calcification was only studied by Pettiette et al. [13] and they concluded that systemic statin use may result in increased tertiary dentine formation and pulp chamber calcification; also, they reported that mineralization within the pulp chamber of mandibular molars increased significantly in patients using statins. However, the study’s conclusion was reached by analysing digital bite-wing X-rays, in which only linear measurements could be made. To our knowledge, no other study has been performed on volumetric change of the pulp chamber to demonstrate a possible adverse effect of systemic statin use. Therefore, the present study aimed to examine the relationship between the systematic use of statins and the alteration of pulp chamber size using cone-beam computed tomography (CBCT) images, allowing volumetric calculation. It was hypothesized that the systematic use of statins causes pulp chamber calcification and volume reduction in pulp chamber.

Study Design

The Institutional Review Board and Ethical Committee of Baskent University approved this retrospective case-control study (Project Number: D-KA22/37) and the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) guidelines were followed [18] (Table 1: STROBE flowchart). In this study, the electronic patient archive of Dr. Turgut Noyan Application and Research Centre, Adana, Baskent University was used to select both study and control subjects. To determine the study group, patients who applied to the endocrinology or cardiology unit of the relevant centre between 2012 and 2022 and were diagnosed with hyperlipidaemia, as well as those who had CBCT for any reason in the dental clinic, was documented for selecting the study group samples. The prescriptions of these patients were examined and those who have been prescribed a statin group drug at least 1 year before the CBCT application and whose information is available in the clinical course of their regular use were selected [19]. CBCT scans of healthy patients with no history of systemic disease were also documented for selecting the control group samples. All CBCT scans were performed with a Pax-i3D apparatus (Vatech, Hwaseong, Republic of Korea) with the manufacturer’s recommended exposure conditions (24 s, 90 kVp, 5.7 mA) and a voxel size of 0.200 mm. All the datasets were acquired and saved using the Digital Imaging and Communications in Medicine (DICOM) format.

Table 1.

STROBE flowchart

Table 1.

STROBE flowchart

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Inclusion Criteria

In the CBCT images of the statin user patients, the intact teeth without caries, without severe damage to the periodontal tissues, without crown or bridge prosthesis, without orthodontic brackets and who have not undergone any dental procedure were recorded with their numbers; those with opposing teeth were included in the study group. The study group was determined by classifying these teeth as upper incisors, upper canines, upper premolars, upper molars, lower canines, lower premolars, and lower molars. The intact teeth (same as described for the study group) selected from the list of healthy patients who underwent CBCT were matched according to the age, sex, and tooth type of the statin user patients, and the control group samples were formed.

Exclusion Criteria

CBCT images with insufficient quality or artefacts were excluded from the study. Also, the study did not include mandibular incisors since smaller sizes of such single-rooted teeth may lead to less clear images and inaccurate measurements [20]. Taking any medication known to alter bone metabolism was an exclusion criterion from the study group. The presence of a systemic disease or regular drug intake was an exclusion criterion for the control group. In both groups, if the relevant tooth did not have an antagonist tooth, the patient was excluded from the study. Patients with a history of dental trauma were also excluded from the study as it may cause pulpal calcification [14].

Sample Size

Power analysis carried out using the G-Power package program (version 3.1.9.2), showed that a total of 54 patients, at least 27 patients in each group (without considering subgroups), should be included to achieve 95% power and to control type 1 error <0.05 based on the vertical ratio values of Pettiette et al. [13]. Since the teeth in the study and control groups had to be matched exactly according to the method of our study, the distribution of the teeth that could be evaluated was not homogeneous.

Procedures

After applying inclusion/exclusion criteria, 54 teeth of 54 patients (27 for the study group, and 27 for the control group) were selected and the tooth type distribution was as follows; 20 mandibular first premolars, 8 maxillary second molars, 6 mandibular canines, 4 mandibular second molars, 4 maxillary central incisors, 4 maxillary first premolars, 4 maxillary canines, 2 mandibular second premolars, 2 maxillary first molars. Mimics Innovation Suite 25.0 (Materialise, Belgium, Leuven) software was used in the study. CBCT images were opened in axial, coronal, and sagittal image projections. The threshold screen was used to detect the voxel density values and boundaries of the examined teeth, set to the “teeth” mode. The same function was used in “soft tissue” mode to identify the voxel density values and boundaries of the pulp chamber. The software allowed adjusting the threshold limits to recognize the grey-level intensities and boundaries of the pulp chamber and crown.

Segmentation was performed by following the crown and pulp tissue boundaries from radiological sections from the cementoenamel junction line for the multi-rooted teeth, and 3 mm below from the cementoenamel junction line for the single-rooted teeth, as described by Lo Giudice et al. [21] (shown in Fig. 1, 2) using the Segmentation module. Separate and modify commands, which are multiple edit mask and split mask commands, were used in the segmentation phase. The determined segmentation steps were used in the modelling of other loaded CBCT data. The same model and design process were applied to each CBCT data. The segmented tissues on the 2-dimensional sections are masked in different colours. 3-dimensional models were obtained from the 2-dimensional radiological sections shown in different colours using the calculate part command. The 3-dimensional crown and pulp models obtained by segmentation are transferred to the design module 3-matic 17.0 (Materialise, Belgium, Leuven). Finish-trim command operations were performed on the tissue model structures taken into 3-matic and data editing operations were performed. Surface properties of 3D models were improved and optimized with Fix wizard commands. Geometric measurement and volume values of crown and pulp models were automatically obtained from part properties in the object area. Pulp chamber/crown volume ratios were used for comparisons. A single researcher carried out the volumetric measurements. The same researcher, blinded to the previous measurements, randomly selected 10 CBCT scans, and repeated the entire process to assess intra-observer reliability and repeatability.

Fig. 1.

a–d Getting 3D model of a multi-rooted tooth from CBCT images. e Segmentation of a multi-rooted tooth from cementoenamel junction. f Isolated pulp chamber of a multi-rooted tooth.

Fig. 1.

a–d Getting 3D model of a multi-rooted tooth from CBCT images. e Segmentation of a multi-rooted tooth from cementoenamel junction. f Isolated pulp chamber of a multi-rooted tooth.

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Fig. 2.

a–d Getting 3D model of a single-rooted tooth from CBCT images. e Segmentation of a single-rooted tooth 3 mm below from cementoenamel junction. f Isolated pulp chamber of a single-rooted tooth.

Fig. 2.

a–d Getting 3D model of a single-rooted tooth from CBCT images. e Segmentation of a single-rooted tooth 3 mm below from cementoenamel junction. f Isolated pulp chamber of a single-rooted tooth.

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Statistical Analysis

SPSS (Statistical Package for the Social Sciences) 26.0 package program was used for statistical data analysis. Categorical measurements were summarized as numbers and percentages, continuous measurements as mean and standard deviation, and as median with minimum-maximum where appropriate. The chi-square test was used to compare categorical variables. Shapiro-Wilk test was used to determine whether the parameters in the study showed a normal distribution. Mann-Whitney U test was used for the parameters that did not show normal distribution. The level of statistical significance was taken as 0.05 in all tests.

The study was carried out with 54 patients, 27 of whom used statin drugs formed the study group and 27 healthy patients formed the control group. The mean age of the patients was 57.7 ± 9.2 years, and sex distribution of study and control groups was equal, with 10 male and 17 female patients. The most frequently used statin drugs by the patients in the study group were atorvastatin 20 mg in 11 patients (40.7%), rosuvastatin 10 mg in 7 patients (25.9%), atorvastatin 10 mg in 3 patients (11.1%), atorvastatin 40 mg in 3 patients (11.1%), rosuvastatin 20 mg in 2 patients (7.4%), and rosuvastatin 40 mg in 1 patient (3.7%), and the most common systemic diseases were hypertension (48.1%), diabetes (48.1%), atherosclerotic cardiovascular disorders (25.9%). Table 2 shows the type, dose, and duration of statin medication used by each patient in the study group. Since at least 1 year of statin use was an inclusion criterion, the minimum period of use was monitored as 1 year, the longest period of use observed in 1 patient was 9 years. The average duration of statin intake of patients in the statin group was 4.63 ± 2.3 years (median 5 years, IQR 4 years), and no statistically significant relationship was observed between the duration of statin intake and pulp chamber/crown volume in the study group (r = 0.291, p = 0.0141).

Table 2.

Type, dose, and duration of statin medication used by each patient in the study group

Patient numberStatin typeDuration of use in years
Rosuvastatin 10 mg 
Atorvastatin 40 mg 
Atorvastatin 20 mg 
Rosuvastatin 10 mg 
Rosuvastatin 20 mg 
Atorvastatin 20 mg 
Atorvastatin 40 mg 
Atorvastatin 40 mg 
Rosuvastatin 10 mg 
10 Rosuvastatin 10 mg 
11 Atorvastatin 20 mg 
12 Rosuvastatin 10 mg 
13 Atorvastatin 20 mg 
14 Rosuvastatin 10 mg 
15 Atorvastatin 20 mg 
16 Atorvastatin 20 mg 
17 Atorvastatin 20 mg 
18 Atorvastatin 10 mg 
19 Atorvastatin 10 mg 
20 Atorvastatin 20 mg 
21 Rosuvastatin 20 mg 
22 Rosuvastatin 40 mg 
23 Rosuvastatin 10 mg 
24 Atorvastatin 20 mg 
25 Atorvastatin 20 mg 
26 Atorvastatin 20 mg 
27 Atorvastatin 10 mg 
Patient numberStatin typeDuration of use in years
Rosuvastatin 10 mg 
Atorvastatin 40 mg 
Atorvastatin 20 mg 
Rosuvastatin 10 mg 
Rosuvastatin 20 mg 
Atorvastatin 20 mg 
Atorvastatin 40 mg 
Atorvastatin 40 mg 
Rosuvastatin 10 mg 
10 Rosuvastatin 10 mg 
11 Atorvastatin 20 mg 
12 Rosuvastatin 10 mg 
13 Atorvastatin 20 mg 
14 Rosuvastatin 10 mg 
15 Atorvastatin 20 mg 
16 Atorvastatin 20 mg 
17 Atorvastatin 20 mg 
18 Atorvastatin 10 mg 
19 Atorvastatin 10 mg 
20 Atorvastatin 20 mg 
21 Rosuvastatin 20 mg 
22 Rosuvastatin 40 mg 
23 Rosuvastatin 10 mg 
24 Atorvastatin 20 mg 
25 Atorvastatin 20 mg 
26 Atorvastatin 20 mg 
27 Atorvastatin 10 mg 

Tables 3 and 4 summarize both groups’ sex, tooth type, age distributions, and pulp chamber/crown ratio comparisons. According to the results, our null hypothesis was rejected. Contrary to expectations, the pulp volume/crown ratio was found to be higher in the study group, although it was not statistically significant (p = 0.505).

Table 3.

Sex and tooth type percentages of the study and control groups

Study group (n = 27), n (%)Control group (n = 27), n (%)p valuea
Sex 
 Male 10 (37.0) 10 (37.0) 1.00 
 Female 17 (63.0) 17 (63.0) 
Tooth type 
 Lower first premolar 10 (37.0) 10 (37.0)  
 Lower second molar 2 (7.4) 2 (7.4)  
 Lower second premolar 1 (3.7) 1 (3.7)  
 Lower canine 3 (11.8) 3 (11.8)  
 Upper first molar 1 (3.7) 1 (3.7)  
 Upper central incisor 2 (7.4) 2 (7.4)  
 Upper first premolar 2 (7.4) 2 (7.4)  
 Upper second molar 4 (14.8) 4 (14.8)  
 Upper canine 2 (7.4) 2 (7.4)  
Study group (n = 27), n (%)Control group (n = 27), n (%)p valuea
Sex 
 Male 10 (37.0) 10 (37.0) 1.00 
 Female 17 (63.0) 17 (63.0) 
Tooth type 
 Lower first premolar 10 (37.0) 10 (37.0)  
 Lower second molar 2 (7.4) 2 (7.4)  
 Lower second premolar 1 (3.7) 1 (3.7)  
 Lower canine 3 (11.8) 3 (11.8)  
 Upper first molar 1 (3.7) 1 (3.7)  
 Upper central incisor 2 (7.4) 2 (7.4)  
 Upper first premolar 2 (7.4) 2 (7.4)  
 Upper second molar 4 (14.8) 4 (14.8)  
 Upper canine 2 (7.4) 2 (7.4)  

aChi-square test.

Table 4.

Age and pulp chamber/crown ratio comparison of test and control groups

Study groupControl groupp valuea
mean±SDmean±SD
median (IQR)median (IQR)
Age, years 57.7±9.3 57.7±9.3 1.00 
60 (17) 60 (17) 
Pulp chamber/crown volume ratio 0.0428±0.026 0.0409±0.028 0.505 
0.04 (0.028) 0.031 (0.037) 
Study groupControl groupp valuea
mean±SDmean±SD
median (IQR)median (IQR)
Age, years 57.7±9.3 57.7±9.3 1.00 
60 (17) 60 (17) 
Pulp chamber/crown volume ratio 0.0428±0.026 0.0409±0.028 0.505 
0.04 (0.028) 0.031 (0.037) 

aMann-Whitney U test.

This retrospective case-control study was designed on whether there is a relationship between systemic statin use and pulp chamber calcification. According to the results of the present study, no significant difference between the pulp chamber/crown volume ratio among statin users and healthy non-statin users was observed. So, the hypothesis that the systematic use of statins causes pulp chamber calcification and reduced pulp chamber volume was rejected, contrary to the findings of Pettiette et al. [13].

One of the reasons for this discrepancy between Pettiette et al. [13] and the present study’s results may be the difference in the methodology used to analyse the pulp chamber dimensions. Pettitte et al. [13] used bite-wing radiographs of mandibular molars, performed linear measurements of the pulp chamber and the crown with a standardized method for height and mesiodistal distances and calculated the dimensions of the pulp chamber as ratios that determine the proportional degree of reduction in the size of the pulp chamber. Although they observed a significant reduction in the pulp chamber height ratio shown in the statin group compared with the control group, in terms of the mesiodistal width, they found no significant difference between the two groups. Considering the anatomy of the teeth and pulp chamber, CBCT images were used in the present study, which allowed volumetric measurements 3-dimensionally to be more precise. In a recent study [22], pulp volume measurements made with CBCT have been reported to be as reliable as micro-CT measurements, which are considered the gold standard technique to study the pulp chamber and other anatomic structures. Maddalone et al. [23] compared the measurements of pulp chamber size in single-rooted and multi-rooted teeth using CBCT and optical microscopy and suggested that the use of CBCT may be used as an alternative in cases where conventional imaging systems are inadequate in the treatment of endodontic problems. Xiang et al. [24] found that pulpal calcification was related to periodontal status and that the prevalence of pulpal calcification was higher in patients with periodontitis using CBCT. Although the aim and method of our study are different, the findings of Xiang et al. showed that the CBCT technique is a suitable tool for determining pulp chamber size and morphology. The present study focused on measuring and evaluating pulp chamber volume change within the confines of the pulp chamber wall. If diffuse calcification occurred in the teeth, it could be detected by this method because of the changes in the boundaries of the pulp chamber wall. On the other hand, discrete calcifications in the pulp chamber may or may not be in contact with the pulp chamber wall; hence, they do not necessarily cause volume reduction in pulp chamber.

The type of medicine used could be another factor for conflicting results. The previous study [13] did not investigate which type of statin the patients used. In the present study, the patients used two types of statin drugs at different doses. Atorvastatin is a second-generation lipophilic statin, whereas rosuvastatin is third generation and hydrophilic [25]. The solubility of statins plays a key factor in their transportation and metabolism. Lipophilic statins such as atorvastatin can easily cross cell membranes by passive diffusion, allowing their distribution in many tissues; rosuvastatin, a hydrophilic statin, requires active, transporter-mediated mechanisms that may inhibit their capacity to act outside the liver [26]. Due to these pharmacokinetic differences, it is estimated that the effect of statins may be different, considering that they can pass the liver filter by 5–30 per cent in the oral administration [7, 25].

Statins are drugs that not only regulate blood cholesterol levels but also promote bone formation [7‒10]. Administered either systematically or locally, the drug has been shown to be effective in improving varying degrees of alveolar bone mass in rats [9]. Dental pulp, which is metabolically active, such as bone tissue, and has a significant amount of blood vessels and peripheral nerves, may be affected by systematic statin use, as local application of simvastatin has been reported to induce the formation of mineralized tissue through odontogenic differentiation [11]. Formation of reparative dentine tissue could be efficacious for vital pulp therapies, which are becoming popular and the first-choice approaches for inflamed pulp cases [27]. However, there has yet to be any statin-supplemented material in dental practice. The benefits of the drug may be the subject of future studies in dentistry, but the side effects, if any, should be determined in advance.

Considering the possible dentine regeneration capacity of statins and their ability to heal inflamed pulp, local applications such as pulp capping have been suggested [11]. But, in animal studies resulting in enhanced bone structure, the amount of statin used was almost 10 times higher than the human tolerated daily dose or was given subcutaneously [9]. Although not all have been proven yet, high doses of statins can have adverse effects such as statin-associated muscle syndrome, diabetes mellitus, neurological disorders, and renal dysfunction [25]. The safe use dose of statins should be considered in the local application of statin enhanced pulp capping agents and similar materials used in dental practice.

Calcification of the root canal system is a phenomenon that may occur in different forms and different locations for various local reasons such as trauma, age-related changes, orthodontic treatment, caries, periodontal disease, restorative procedures, pulp inflammation, bruxism or systemic, and genetic conditions [14‒17]. In the present study, to minimize the effect of variables on the results, most of these local factors except for bruxism were excluded with the selecting intact teeth without severe periodontitis, history of trauma, and orthodontic brackets. The inclusion of matching control group patients with the same age, sex, and teeth type was to eliminate the possible effect of age-related local factors. Although the selection of control group patients from a completely healthy population was intended to eliminate the impact of systemic diseases, the same criterion was not applicable to the study group since statin users had at least one systemic disease.

According to the current literature, several systemic conditions, such as type 2 diabetes [28] and inflammatory diseases [29], have been linked to an increased risk of pulp calcification. Additionally, a recent meta-analysis [17] concluded that there is a low level of evidence for an association between pulp calcification and cardiovascular diseases. It is well-established that mechanical forces during orthodontic treatment can lead to pulpal calcifications [16]. Similarly, it is reasonable to hypothesize that bruxism, a parafunctional habit, may also cause pulpal calcification through a comparable mechanism. However, the literature on this topic presents conflicting findings. One study examining the relationship between sleep bruxism and pulpal calcifications in young women found no statistically significant association between the two [30]. Conversely, another study reported an increased incidence of pulp sclerosis in the bruxist group [15].

In this retrospective study, the ability to eliminate all potential local factors that could influence pulp calcification was limited, due to the study’s design. The retrospective study design is a limitation since the strength of the evidence is undoubtedly weaker than that of the prospective ones. Another limitation was that conditions like malocclusion and bruxism, which may contribute to pulp calcification, could not be reliably detected without clinical examination. While the age and sex matching of the study and control group patients, as well as matching the tooth numbers had strengthen the reliability of the findings, the complex health conditions and medications of the study group pose an additional limitation. By the way, the limited sample size is one of the key limitations of this study. Since the study data were collected from patients in a single health-care centre, only a minimum sample size could be reached; subgroups could not be formed depending on the drug type. Further research with larger sample sizes, including multi-centred records, can be planned to overcome these issues and limitations, where more generalizable findings can be obtained.

Within the limitations of this pilot study, systemic statin use did not cause dental pulp calcification. The results suggest, oral administration of the statin drugs is not an unfavourable condition for dental practice. Further studies with larger numbers of patients are needed to support this conclusion.

This project (D-KA22/37) was reviewed and approved by Non-invasive Clinical Research Ethics Committee of Baskent University. Formal consent is not required for this type of study.

The authors have no conflicts of interest to declare.

This study was supported by Baskent University Research Fund.

Selen Nihal Sisli designed the study and analysed the data; Tufan Ozasir wrote the main manuscript text; Birgul Ozasir and Derin Bugu Yuzer prepared the figures and tables; Kamran Gulsahi conducted and supervised the study. All authors approved the final manuscript.

The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions.

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