The impact of simvastatin intervention on the healing of bone, soft tissue, and TMJ cartilage in dentistry: a systematic review and meta-analysis

Search strategy

This systematic review was reported following the Preferred Reporting Items for Systematic Review and Meta-Analyses statement (PRISMA) [10]. An electronic search was performed on the following databases: MEDLINE, Scopus, and Cochrane Central Register of Controlled Trials (CENTRAL). The last search was performed on December 31, 2017. The search terms used were “simvastatin,” “statin,” “bone healing,” “bone density,” “osseointegration,” “dental implants,” “bone graft,” “grafting,” “periodontal surgery,” “oral surgery,” “extraction socket,” “tooth extraction.” These terms were combined using Boolean operators OR and AND. Furthermore, a hand search of issues from 2000 up to the last issue available on December 15, 2017, including the “Early view” (or equivalent) section was undertaken in the following journals: British Journal of Oral and Maxillofacial Surgery, International Journal of Oral and Maxillofacial Surgery, Journal of Oral and Maxillofacial Surgery, Journal of Periodontology, Journal of Clinical Periodontology, Journal of Periodontal Research, Oral Surgery, Oral Medicine, Oral Pathology, Oral Radiology and Endodontology. The reference list of the retrieved reviews and the included studies was also searched for possible additional eligible studies not identified by the electronic search.

Inclusion criteria

1. The studies report the results of dental procedures (such as oral surgery, tooth extractions, periodontal treatment, orthodontic treatment, TMJ arthritis therapy, etc.) performed in human and animals, in which simvastatin was topically or systemically used as an adjunct to the standard surgical procedure.

2. The studies provide details on the method of randomization, type and dosage of simvastatin used, the duration of observation, and the report of any adverse effects.

3. The studies compared a test group in which statins were used, versus a control group without using the statins. The use of statins had to be the only difference between the test and control group.

The search was limited to oral surgical procedures in animal and human studies published in the English language only. Restrictions were not placed regarding the publication year. Only prospective studies were included. No limitation on sample size was placed.

Exclusion criteria

Publications that did not meet the above inclusion criteria and those that were not dealing with original clinical cases (e.g., reviews, technical reports) were excluded. In case of multiple publications relative to subsequent phases of the same study or to enlargements of the original sample size, only the most recent data (those with the longer follow-up and the larger sample size) were considered.

Selection of the studies

Two reviewers (JC and SG) independently screened the titles and the abstracts of the articles initially retrieved through the electronic search. The concordance between reviewers was assessed using Cohen’s Kappa coefficient. In the case of disagreement, a third reviewer (MDF) was consulted. The full texts of all studies of possible relevance were independently assessed by the same two reviewers to check if they met all inclusion criteria. For articles excluded at this stage, the reason for exclusion was recorded.

Data extraction

Data were extracted by two reviewers independently (MDF and SG). Cases of disagreement were subject to joint evaluation until an agreement was reached.

The studies were initially categorized on the type of animals used for the research as well as in the kind of procedure performed. The primary variables extracted further from each included study include study design, sample size, type, dosage and administration route of simvastatin, type of oral procedure, associated use of grafting (yes/no), type of graft material, control treatment, jaw (maxilla or mandible), follow-up duration, any outcome variable used to evaluate treatment success, outcomes used to assess radiographic, histological, and histomorphometric bone healing.

The following methodological parameters were also recorded such as the randomization method in randomized studies, the precise definition of outcomes assessment, and the length of the follow-up period for all studies.

Assessment of the quality of the trial

The methodological quality of the selected studies was evaluated independently and in duplicate by two reviewers (MDF and SG) according to the above methodological parameters. In the case of disagreement, a third reviewer (JC) was consulted. The risk of bias is assessed based on criteria such as randomization, allocation concealment, blinding of the examiner, completeness of follow-up, and the similarity of groups at the start of the study using modified Cochrane Collaboration’s tool for assessment of bias. When all criteria were met, and no more than one criterion was judged unclear, the risk of bias was estimated as low; if two or more criteria were judged unclear and other criteria were met, moderate risk of bias was assigned; when one or more criteria were not met, high risk was assigned. Besides, the assessment parameters like completion and duration of the study, dropouts, and statistical analysis methods appropriateness were determined to declare the study as adequate or inadequate. The authors of the included studies were contacted for providing clarifications or missing information as needed.

Outcome variables

The primary outcome variables included changes in hard tissue parameters, such as bone/alveolar ridge width and height, probing depth (PD), clinical attachment level (CAL), radiographic defect fill, and bone mineral density. The secondary outcome variables included the assessment of levels of soft tissue inflammatory parameters at the surgical sites.

Statistical analysis

If two or more comparative studies presented results regarding a similar outcome variable, they were aggregated in a meta-analysis. The weighted mean difference between statin-treated and control group was estimated using a random effect model with the software RevMan (Version 5.3, The Nordic Cochrane Centre, The Cochrane Collaboration, Copenhagen, 2014). Forest plots were produced to graphically represent the difference in outcomes of statin-treated groups and placebo groups for all included studies using defect site as the analysis unit.

Characteristics of the included studies

Wu et al. 2008 and Sherif et al. 2016 assessed the extraction and site preservation effect of 1 mg/ml of simvastatin in PLGA gel and 2.5% simvastatin in 1 ml chitosan gel respectively [13, 14]. Both studies concluded that simvastatin is potential to preserve bone height and bone mineral density (BMD). Increase in bone density was reported at the periods between 1 and 4 weeks, while the increase in bone height was only evident at 8 weeks [13]. Killeen et al. in 2012 conducted a study comparing the effects of 0.5 mg of simvastatin with 0.5 mg simvastatin in alendronate-cyclodextrin conjugate on fenestration defects created on molar roots in a rat model [15]. The study highlighted the osteopromotive impact of local simvastatin when used in conjunction with systemically administered alendronate. Rutledge et al. in 2011 compared simvastatin (10 mg) with porous hydroxyapatite collagen sponges applied locally as well as injected in dehiscence defects in dogs. The study demonstrated the ability of simvastatin to induce bone growth at sites of thin bone and edentulous sites [16]. Another study by Ozec et al. in 2007 compared simvastatin (2.5 mg/ml) with gelatin sponges for bone density in critical-sized defects in rats [17]. Healing in closed defects like distraction osteogenesis was determined by Kilic et al. in 2008 in rabbits. The experimental group included simvastatin administered locally in the dose of 2.5 mg/0.2 g of gelatin and 10 mg administered systemically [18].

The human studies included in this analysis showed greater homogeneity in the methodology than the animal studies [19–24]. Therefore, we performed a meta-analysis on these six selected human clinical studies. Of all these six human studies, only one study investigated soft tissue healing potential of simvastatin. All these clinical trials aimed to determine if simvastatin intervention could benefit surgical approaches and improve clinical and radiological parameters. The dosage of simvastatin used in all studies was 1.2 mg except in the study by Gouda et al. in 2017 [23]. In this study, the researchers conducted a split-mouth study comparing 0.1 mg of simvastatin/14 mg of beta-TCP to beta-TCP in maxillary sinus lifts. Although this study included the least number of patients among all the selected studies in this review, it exhibited the strength in extending the follow-up to 9 months after the surgeries.

The parameters of all selected studies included the changes in probing depth and clinical attachment levels. Some studies evaluated bone density (gray levels) and bone fill. One study investigated soft tissue parameters. Among them, Kinra et al. in 2010 compared simvastatin (10⁻⁸ M/mg of DFDBA) to DFDBA in bilateral two-walled and three-walled defects [19]. Ranjan et al. in 2017 assessed bone formation in intrabony defects by comparing open flap debridement (OFD) and a placebo to OFD with 1.25% simvastatin in the defects [20]. Pradeep et al. in 2012 performed a 6-month prospective study on 72 patients and compared scaling root planning (SRP) to SRP in combination with 1.2 mg simvastatin in class II furcation defects. This study included the highest patient number and the longest follow-up period [21]. Chauhan et al. in 2015 determined the site healing pattern in extraction sockets with 10 mg simvastatin. It also assessed the effects of simvastatin on patients’ comfort, post-op swelling, and pain [22]. Impact of statins on cartilage healing has also been studied in intra-articular-induced arthritis models in rats [37, 38]. The studies suggested that 0.5 mg of simvastatin has the potential to reduce sub-synovial inflammation and inducing new bone formation in steroid-induced bone resorption sites.

Results of analysis for bone height in animal studies and meta-analysis for CAL in human studies

Two animal studies assessed the effect of simvastatin on the bone height in extraction sockets [11, 13], and one evaluated the changes of bone height in the ligature-induced periodontitis with simvastatin treatment [14]. Even though all these studies suggested that simvastatin may have a beneficial effect, due to consistent differences in the protocols, outcome variables, and evaluation methods among these studies, it was not feasible to estimate an overall effect with meta-analysis.

Three human studies assessed the changes in CAL (Fig. 2a) and PD (Fig. 2b) in periodontal defects [19–21]. There was evidence of a significant benefit of simvastatin for both CAL gain (mean difference 1.50 mm, p < 0.001, 95% CI = 1.19, 1.82 mm) and PD reduction (mean difference 2.01 mm, p < 0.001, 95% CI = 1.41, 2.61 mm). All the studies favored the statin-treated group. The study by Gouda et al. [23] also showed a significant positive effect of statin on bone height improvement in the maxillary sinus augmentation. But we did not perform a meta-analysis on these topics because it is the only study on such procedure.

Results of analysis for bone width in animal studies and meta-analysis for defect bone fill in human studies

Four animal studies investigated the changes in bone fill after dental treatment with the use of simvastatin [14–16, 18]. Among these studies, one study was conducted on dehiscence [16], one on fenestration defects [15], one study was on tooth extraction defects [14], and one on distraction osteogenesis [18]. Except for the study on fenestration, all the other studies showed a positive effect of simvastatin, although no statistical significance was reached in two studies [16, 18]. Due to heterogeneity in the protocols and outcome measures, no meta-analysis could be performed to summarize the results of these studies.

Three human studies assessed the changes in the width of alveolar ridge evaluating bone fill radiographically [19–21]; we found the significant improvement of alveolar ridge width in the simvastatin group than its control group (mean difference = 1.40 mm, p < 0.001, CI = 0.99, 1.81 mm) (Fig. 3).

Results for analysis for bone mineral density in animal studies

Five animal studies investigated whether simvastatin application alters bone mineral density (BMD) [11–13, 17, 18]. Vaziri et al. in 2007 measured bone matrix resorption in ovariectomized rats using a dental X-ray unit, and giving densitometric measurement values in mm [11]. Anbinder et al. in 2007 measured BMD in ovariectomized rats with a digital dental X-ray unit, giving optical density values in gray levels [12]. Wu et al. in 2008 measured BMD with dual-energy X-ray absorptiometry (DXA) and provided the results in the unit of mg/cm² [13]. Kilic et al. in 2008 measured BMD changes in rabbits by peripheral quantitative computed tomography (pQCT) and represented the results in a Hounsfield scale [18]. Ozec et al. in 2007 were excluded from the final analysis because this study did not provide sufficient data [17]. These four studies all showed the mild positive effect of simvastatin on BMD, but without the statistical difference. Due to the methodological differences, it was not feasible for us to aggregate the results of BMD changes using a meta-analysis.