Statins are class of drugs that inhibit 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, statins are widely used for lowering plasma cholesterol levels due to their high efficacy and good tolerability [1]. Beyond their role in cardiovascular health, statins have also been found to positively impact bone metabolism. In 1999, simvastatin (SMV) was shown to promote bone formation by increasing bone morphogenetic protein-2 (BMP-2) expression, making it a potential therapeutic agent for bone regeneration [2]. One of the most common clinical scenarios of bone loss occurs after tooth extraction, where the natural resorption process leads to a gradual decrease in alveolar bone height and width [3]. The severity of this bone loss varies depending on systemic health, mechanical loading, and individual healing responses [4]. Loss of bone structure not only affects soft tissue support but also leads to functional and aesthetic concerns, which can complicate future prosthetic or restorative treatments, to prevent bone loss. Various techniques for preserving the alveolar ridge have been developed, including guided bone regeneration [5,6]. Recent research has shown that statins have direct effects on bone formation and can be administered locally to stimulate osteoblast activity and increase BMP-2 expression. Unlike systemic statins, which primarily target cholesterol metabolism, locally applied statins may offer benefits for bone regeneration by enhancing bone formation, reducing inflammation, and inhibiting bone resorption. Experimental studies suggest that localized statin application could be a promising approach for improving bone healing and regeneration [6]. Statin role in improving post-extraction socket healing has been the subject of increasing research interest [7]. Successful bone regeneration depends not only on osteogenic stimulation but also on adequate vascularization. When blood supply and progenitor cells are insufficient, the natural healing process is compromised, increasing the likelihood of poor bone regeneration outcomes [8]. Because tooth loss has a significant impact on quality of life, affecting chewing function, speech clarity, and even social confidence, it is crucial to develop effective post-extraction bone preservation strategies that would allow teeth to be restored with dental implants [9]. Over the past two decades, multiple studies have assessed the efficacy of various socket-filling materials, including bioactive agents (such as growth factors and statins), autologous bone grafts, bone substitutes (allografts, xenografts, alloplasts), and autologous blood-derived products like platelet-rich plasma and platelet-rich fibrin [10]. Therefore, it is important to determine the effect of simvastatin on alveolar bone regeneration compared with other materials and methods.

The primary aim of this systematic review was to assess the effect of local simvastatin on alveolar bone regeneration, by measuring bone density and bone height loss on patients after tooth extraction with conditions requiring bone regeneration. The secondary aim was to evaluate the impact of local simvastatin application into extraction socket on pain and swelling.

Protocol and registration

The review followed the guidelines outlined in the Preferred Reporting Items for Systematic Reviews (PRISMA) statement to ensure comprehensive and transparent reporting [11].

Focus question

The focus question was formulated using the Patient, Intervention, Comparison, and Outcome (PICO) framework, as outlined in Table 1.

The focus question was: “There is any improvement of bone regeneration, pain and swelling after tooth extraction with application of local statins?”.

Information sources

The information source was the MEDLINE (PubMed) electronic database.

Search

The search was restricted to English language and articles published from January 1, 2015 to January 1, 2025. According to the PRISMA guidelines for the search, the following keywords were used in combination:

Selection of studies

The selection process of articles of this review was carried out in multiple steps by two reviewers (A.A. and L.P.) First, articles were searched using the previously mentioned keywords. Subsequently, duplicates across databases were eliminated. The selected publications were then carefully assessed to determine whether they were eligible and met the inclusion criteria. After a thorough review of the articles, only those that met the requirements were included in this review.

The reviewers independently checked the results, and disagreements were resolved by discussion with the senior investigator (G.J.). Reviewers were calibrated by calculating Cohen’s kappa coefficient (κ) values to ensure inter-rater reliability of abstracts and titles on a sample of 10% of publications.

Types of publications

The review included human studies published in English. Literature reviews, systematic reviews, and abstracts lacking full text were excluded.

Types of studies

This review included a prospective studies, a randomized clinical trial, pilot studies, and evaluation studies, published between January 1, 2015 and January 1, 2025. Grey literature, letters, editorials, doctoral dissertations, abstracts, case series, case reports, cross-sectional studies, reviews, unpublished literature were not included in this systematic review.

Population

Healthy adult patients (> 18 years) with conditions requiring bone regeneration after tooth extraction.

Inclusion and exclusion criteria

The article selection was based on the inclusion and exclusion criteria, using appropriate keyword combinations.

Inclusion criteria

Exclusion criteria

Sequential search strategy

The selection of articles was carried out in two stages by two reviewers (A.A. and L.P.). The first stage reviewed the titles of the articles, and the second stage reviewed the abstracts. Articles that were duplicated or did not meet the selection criteria were excluded. After selecting suitable publications, the texts were checked for compliance with the inclusion criteria to confirm the eligibility of each study. Title and abstract screenings were performed using an online screening tool Rayyan^® (Qatar Computing Research Institute; HBKU, Doha, Qatar [www.rayyan.ai]).

Data extraction

Data extracted from the articles were according to the aim and tasks of the review.

Data items

The following parameters were extracted when available: first author and publication year, study design, total number of sockets, use of local statin, type of statin, tooth extraction, dental socket, last follow-up period, regenerated bone morphology, pain evaluation, swelling evaluation.

Risk of bias assessment

Risk of bias was assessed using the Joanna Briggs Institute (JBI) Critical Appraisal Tools which were selected for each type of study: randomized controlled trials [12] (Table 2), quasi-experimental studies [13] (Table 3). JBI Critical Appraisal checklists include the specific questions that were reviewed. Each checklist item was rated as “Yes,” “No,” “Unclear,” or “Not applicable”.

The JBI Critical Appraisal Checklist categorizes bias risk as: “low risk” (≥ 70%) for high-quality studies, “moderate risk” (50 to 69%) for studies with some flaws but still valuable, and “high risk” (< 49%) for studies that are difficult to trust.

Synthesis of the results

Relevant data were collected and organized into tables. The first table provides an overview of each study, detailing the author, year, last follow-up period, research type, population, total number of patients, number of sockets, mean age, and gender distribution. The second table summarizing the filling material, filling method, and key results in both test and control groups, specifically analysing regenerated bone morphology, pain and swelling.

Statistical analysis

Article management was conducted using Mendeley^® Reference Manager version 2.110.2 (Elsevier; London, UK [www.mendeley.com]). The level of agreement between the two raters in selecting abstracts to be read in full text was assessed using Cohen‘s kappa coefficient (κ). A meta-analysis was not performed due to substantial heterogeneity among the included studies in terms of design, control groups, outcome measures, and follow-up durations.

Study selection and exclusion

The search initially revealed 628 results, of which 548 records were excluded because they were more than ten years old, not in English, or related to animal studies (Figure 1). After this initial screening, 80 records were assessed, and 69 were excluded based on title and abstract relevance. Full-text examination was conducted on 11 articles, of which 5 [14-18] were excluded for not meeting the inclusion criteria. Eventually, 6 studies [19-24] were included in this review. The level of agreement between two authors (A.A. and L.P.) in the selection of abstracts was measured at κ = 0.89.

Quality assessment of the included studies

The methodological quality of the included studies was evaluated using the JBI critical appraisal checklists for randomized controlled trials [12] and quasi-experimental studies [13]. The assessment results are summarized in Tables 4 and 5. Overall, the majority of the studies demonstrated good methodological quality [19-24].

Study characteristics

Four studies [19-22] were randomized controlled trials, one was prospective study [23] and one was pilot study [24] (Tables 4 and 5). The pooled sample across all studies included 154 patients. A total of 326 sockets with different types were evaluated, the effect of local simvastatin on regenerated bone morphology. Two studies [19,23] did not report how many males and females were treated. Among the remaining studies [20-22,24], a total of 38 males and 36 females were reported (Table 6).

Type of filling material

Several types of filling materials were applied (Table 7). Harsha et al. [19] used simvastatin (10 mg) powder with gelfoam moistened with saline, while the control group received gelfoam with saline alone. Cruz et al. [20] used 1.2% simvastatin gel covered with a polypropylene membrane (PPPM), while the control group received a placebo gel with PPPM. Sezavar et al. [21] combined powdered simvastatin (20 mg Sivastol^® - Tehran Chemie; Tehran, Iran) with collagen, with the control group receiving collagen alone. Degala et al. [22] used a 10 mg simvastatin tablet, crushed and dissolved in 0.9% saline, applied with gelfoam, while the control group received gelfoam with saline alone. Saifi et al. [24] used simvastatin (10 mg) powder along with gelfoam as carrier moistened with 2 ml normal saline solution, while control group received gelatin sponge. Chauhan et al. [23] used simvastatin (10 mg) powder in combination with gelfoam as carrier moistened with 2 ml normal saline solution, but did not specify a control group.

Socket filling method

Regarding the filling method all articles used direct application (Table 7).

Regenerated bone morphology

All included articles present regenerated bone morphology (Table 7). Harsha et al. [19] reported that in the first week, the test group had a bone density measured by mean gray value (MGV) of 68.99 (SD 13.28), while the control group had a value of 58.45 (SD 11.48) (P < 0.001). Bone density gradually increased and after 12 weeks the MGV value in the test group was 106.37 (SD 14.39) and in the control group it was 92.77 (SD 12.92). The difference between the groups was statistically significant (P < 0.001). Cruz et al. [20] evaluated bone dimensions, and in the test group, horizontal bone width was measured as 1.02 mm in section A at 1 mm from the crest, 1.01 mm in section B at 3 mm and 1.01 mm in section C at 5 mm, while vertical bone loss was 0.95 mm. In the control group, the horizontal measurements were statistically significantly larger, with 1.27 mm (P = 0.044) in section A (1 mm), 1.26 mm (P = 0.036) in section, B (3 mm), 1.25 mm (P = 0.048) in section C (5 mm) and vertical bone loss was greater - 1.46 mm (P < 0.0001). Sezavar et al. [21] analysed bone composition without reporting statistically significant changes over time. In the test group, the amount of vital bone was 20.3 (SD 12.9)%, non-vital bone 33.7 (SD 21.57)%, trabecular bone 10.3 (SD 9.83)%, amorphous bone 10 (SD 7.31)%, and non-osteoblastic bone 46 (SD 12.05)%. In the control group, the amount of vital bone was slightly lower 17.2 (SD 10.019)% (P < 0.7), non-vital bone 35 (SD 18.55)% (P < 0.8), trabecular bone 10.1 (SD 10.59)% (P < 0.9), amorphous bone 7.3 (SD 5.27)% (P < 0.5), and non-osteoblastic bone 47.8 (SD 10.71)% (P < 0.9). Degala et al. [22] reported bone density at four time points: 1, 4, 8, and 12 weeks. In the first week, the test group had a bone density of 70.03 (SD 6.41) MGV, while the control group had 66.33 (SD 6.09) (P = 0.001). Bone density gradually increased, especially in the study group, and after 12 weeks reached 110.45 (SD 6.7) MGV, compared to 4 in the control group, the difference being statistically significant (P = 0.001). Chauhan et al. [23] recorded a statistically significant increase in bone density measured 1 day after the procedure up to three months in the test group from 66.7 (min 47.1; max 80.8) to 125.5 (min 102.6; max 152) versus 78 (min 44.3; max 78.773.43) (P = 0.036) and 102.6 (min 85.3; max 111.1) (P = 0.000) in the control group. Saifi et al. [24] evaluated extraction sites over eight and sixteen weeks. In the test group, bone density of 79.09 (SD 3.66) MGV at eight weeks and 91.65 (SD 3.55) MGV at sixteen weeks was registered. In the control group, healing extraction sockets showed lower MGV values of 73.43 (SD 3.38) (P < 0.00001) at eight weeks and 82.33 (SD 4.01) (P < 0.00001) at sixteen weeks.

Pain

Pain assessment was reported using different scales across four included studies (Table 7). Harsha et al. [19] utilized a five-point visual analogue scale (VAS), where 0 represented no pain, 1 mild pain, 2 moderate pain, 3 severe pain, and 4 very severe pain. On the first day, pain in the test group was recorded as 2.94 (SD 0.71), while the control group showed slightly higher pain level at 3.14 (SD 0.61) (P = 0.134). By the seventh day, pain had significantly reduced in both groups, measuring 0.3 (SD 0.51) in the test group and 0.32 (SD 0.55) (P = 0.85) in the control group. Cruz et al. [20] used a scale ranging from 0 to 10. The test group reported a median pain score of 4, whereas the control group reported a slightly higher median score of 5 (P = 0.23). Degala et al. [22] also used a 0 to 10 scale. On the first day, pain in the test group was 2.93 (SD 0.69) and in the control group was 2.66 (SD 0.71) (P < 0.05). By the seventh day, pain levels dropped to 0.23 (SD 0.43) in the test group and 0.16 (SD 0.37) (P < 0.05) in the control group. Chauhan et al. [23] measured pain daily using a five-point VAS. On the first day, the study group reported a pain score of 2, while the control group reported a pain score of 1.9 (P < 0.05). Pain scores in both groups gradually decreased and on the seventh day, pain level remained at 0 in the study group and 0.1 in the control group (P < 0.05).

Swelling

Three studies reported swelling in test group compared to the control group (Table 7). Harsha et al. [19] recorded measurements on the first and seventh days. On the first day, the test group showed horizontal swelling of 10.34 (SD 0.79) and vertical swelling of 9.55 (SD 0.76), while the control group reported horizontal swelling of 10.13 (SD 0.81) (P = 0.192) and vertical swelling of 9.49 (SD 0.77) (P = 0.695). By the seventh day, swelling in both groups had decreased, but no statistically significant changes were recorded. Degala et al. [22] also assessed swelling at the same time points. On the first day, the test group presented horizontal swelling of 10.66 (SD 1.48) and vertical swelling of 9.79 (SD 1.24), while the control group showed horizontal swelling of 9.94 (SD 1.37) (P = 0.001) and vertical swelling of 9.76 (SD 1.21) (P = 0.541). On the seventh day, the horizontal swelling of the test group showed statistically significantly (P = 0.018) lower horizontal and vertical (P = 0.012) swelling compared to the control group. Chauhan et al. [23] measured mean percent increase of facial swelling on the second, third, and seventh days. No statistically significant (P < 0.05) changes were recorded in all periods when comparing the test and control groups.

This review evaluates the effect of local simvastatin on bone regeneration after tooth extraction and the impact of postoperative pain and swelling.

Harsha et al. [19] reported a steady increase in bone density at all measured timepoints, with the simvastatin group consistently outperforming the control group over twelve weeks. Degala et al. [22] observed similar trends, with higher gray-scale values in the test group across one, four, and eight weeks, demonstrating enhanced bone regeneration. Cruz et al. [20] found that the simvastatin treated group had less horizontal and vertical bone loss, indicating better preservation of alveolar ridge dimensions. Sezavar et al. [21] showed that the test group had a higher percentage of vital bone two months post-extraction, suggesting superior bone quality. Saifi et al. [24] recorded significantly higher mean grey values and mineralization percentages in the test group at both eight and sixteen weeks, with more notable results in mandibular sites. Chauhan et al. [23] demonstrated that bone density was consistently higher in the simvastatin group over three months, with no increase in postoperative pain or swelling.

Harsha et al. [19] reported that both pain and swelling decreased steadily in the test and control groups, with no significant differences by the seventh day. Cruz et al. [20] found slightly lower median pain scores in the simvastatin group, suggesting a possible mild benefit without added discomfort. Degala et al. [22] observed similar trends in both groups, with pain and swelling decreasing over time and no notable differences between them. Chauhan et al. [23] reported nearly identical pain scores in both groups throughout the first week, with swelling peaking early and resolving by day seven in both cases.

These findings align with extensive research highlighting the role of statins in bone regeneration. Wu et al. [4] demonstrated that bone regeneration was significantly greater in statin-treated groups at multiple time points, particularly at 4, 8, and 12 weeks. Statins not only accelerated early bone healing but also helped maintain bone integrity over time, showing that statin effect on bone quality and volume preservation. These findings are critical as they suggest that statins actively participate in both the initiation and maintenance phases of bone regeneration. Abu Sheehah et al. [25] demonstrated that simvastatin, when locally applied with a gelatin sponge carrier, significantly enhanced bone density in extraction sockets compared to the control group. This suggests that simvastatin effectively promotes new bone formation and may serve as a valuable biomaterial for socket preservation. However, despite its beneficial effect on bone quality, it did not show a statistically significant impact on preserving alveolar bone height over the four-month follow-up period. Moriyama et al. [26] and Ayukawa et al. [27] further reinforced these results by demonstrating that statins enhance new bone formation while simultaneously suppressing osteoclast activity, reducing bone resorption, and increasing overall bone density. The histomorphometric findings from these studies revealed an increased percentage of bone volume in statin-treated groups, supporting their role in improved bone healing and stability. This evidence suggests that statins may play a dual role not only promoting osteogenesis but also preventing unnecessary bone breakdown, leading to more predictable long-term outcomes. Beyond structural improvements, Pradeep et al. [28] demonstrated that local statin application leads to significantly greater bone formation in patients with furcation defects, confirming that statins enhance bone formation even in compromised periodontal conditions. Maciel-Oliveira et al. [29] observed accelerated bone regeneration in extraction sockets, suggesting that local statins could be highly beneficial in post-extraction healing. The versatility of local statin across different clinical scenarios, including implant site preparation, bone defect healing, and periodontal regeneration, underscores their potential as a valuable adjunct in dental and maxillofacial treatments. local statin not only contribute to bone regeneration but also appear to play a role in minimizing postoperative complications. Ismail [30] found that statins do not exacerbate inflammation or swelling on the other hand they reported reinforcing their safety and suitability for clinical use. In addition to their osteogenic effects, statins possess antibacterial and anti-inflammatory properties that may enhance healing outcomes. Kanabar et al. [31] and Kabra et al. [32] reported that statins regulate the host immune response which reducing inflammation while simultaneously promoting soft tissue healing. Statin ability to facilitate both hard and soft tissue regeneration further supports their use as an adjunctive therapy in regenerative treatments. This broader biological activity suggests that statins may not only improve bone healing but also help create a more favourable local environment for overall tissue repair and regeneration. Roca-Millan et al. [33] found that locally applied statins may serve as a promising treatment for bone defect regeneration, due to their osteogenic and angiogenic effects.

In contrast, Noronha Oliveira et al. [34] did not observe a significant bone regeneration benefit from simvastatin combined with PLGA/HA/β-TCP scaffolds. Although the 2.0% simvastatin concentration was safe and appeared to reduce complications compared to scaffolds without simvastatin, the difference was not statistically significant. Limited bone formation was likely due to low scaffold porosity, stiffness and possible incompatibility with the carrier which may have impaired osteoconduction. Additionally, graft loss was more frequent in PLGA-based scaffold groups, particularly those without simvastatin.

Limitations

The included studies in this review contain several limitations such as the differ in sample size, follow-up periods and how statin was delivered which makes it difficult to compare results directly. This review focused on short-term outcomes, indicates that still there is not enough information about the long-term stability of the regenerated bone. Also, different tools were used to measure regenerated bone morphology pain and swelling, making it hard to draw consistent conclusions about patient comfort. More well-designed clinical trials with standardized methods are needed to confirm the best dosage, delivery systems and long-term benefits of local statin use in dental treatments after tooth extraction.

Statins have been shown to improve bone regeneration, with measurable improvements in morphology and structural preservation after tooth extraction. The clinical data indicate that application of local statins does not exacerbate postoperative pain or swelling.