This systematic review was reported following the Preferred Reporting Items for Systematic Review and Meta-Analyses statement (PRISMA) . 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.
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.
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 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.
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.
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.