Efficacy of statins in tissue healing following tooth extraction: a systematic review of animal studies

Introduction

Tooth extraction starts a cascade of events, including inflammation, epithelialization, and remodeling. The socket heals via secondary intention and continues to remodel for up to one year following extraction (1). Autografts, allografts, xenografts, synthetic materials, and osteoinductive growth factors are currently used in clinical practice (2). Although the risk of disease transmission is sporadic, some patients may not prefer bone from another human or animal. Furthermore, due to the low concentration of bone growth proteins, they lack the osteoinductive capability (3). Similarly, synthetic materials have shortcomings, such as different resorption rates and a lack of intrinsic growth factors (4). The exponential development in regenerative medicine and tissue engineering has led to the use of recombinant human bone morphogenetic protein (rhBMP)-2, platelet rich plasma (PRP) products, progenitor cells, and various scaffolding systems to help with the delivery of some of these cellular elements (5-8).

Research and development in this arena have constantly evolved. Three-hydroxy-3-methylglutaryl-coenzyme A reductase (HMG-CoA) has appeared as a promising alternative to promote bone healing and regeneration in the past decade. HMG-CoA (statin) is a key regulatory enzyme in the cholesterol biosynthesis (9). Statins stimulate bone formation through early expression of vascular endothelial growth factors (VEGFs), causing angiogenesis and differentiation of mesenchymal cells into bone-forming cells (10,11). Statins also play a role in the upregulation of the gene expression of extracellular matrix proteins, namely bone morphogenetic protein-2 (BMP-2), osteocalcin, bone sialoprotein, and type 1 collagen, to accelerate new bone formation, while downregulating the gene expression for collagenase-1, and collagenase-3 (12). Statins have been shown to promote new bone formation in the tooth extraction sockets (13). Its application around implants has demonstrated increased osteogenesis osseointegration and soft tissue healing around implants (14-16). Studies have suggested that a single local injection of statin at tooth extraction can potentially decrease the risk of developing medication-related osteonecrosis of like lesions (17-19). Most studies have been conducted on animal models, documenting the healing potential of topical application of the statins in the extraction sockets and around implants (13,14,19-25). This review evaluated the effect of statins on bone and soft tissue healing. The specific aim was to assess bone and soft tissue healing in dental extraction sockets following the local application of statins. We present this article in accordance with the PRISMA reporting checklist (available at https://atm.amegroups.com/article/view/10.21037/atm-24-140/rc) (26).

Methods

Reporting format

The study’s focused question was, “Does local administration of statins enhance healing in the socket following dental extraction?”. This study was registered in the International Prospective Register of Ongoing Systematic Reviews (PROSPERO; CRD42022299247). Due to high heterogenicity, a meta-analysis was not performed.

Patients, interventions, control, outcome (PICO)

(P): experimental animal models in which tooth extraction was performed; (I): statin drug administration in the tooth extraction socket; (C): no statin drug administration in the tooth extraction socket; (O): tissue healing.

Eligibility criteria

The following were the eligibility criteria of the included studies: (I) original studies; (II) animal studies; (III) presence of intervention (tooth extraction with statin administration) and control groups (tooth extraction without statin administration); (IV) English language. The following exclusion criteria were applied: (I) case reports and series; (II) commentaries; (III) letters to the editor; (IV) review articles; (V) in-vivo or human studies.

Search strategy and data extraction

Indexed databases were searched electronically in PubMed, Cochrane Library, EMBASE, Ovid Medline, Scopus, Web of Science, EBSCOhost, and JSTOR by two authors (K.K. and M.K.). Relevant studies up to and including December 2023 were included. A combination of the following terms was used to identify pertinent studies: (I) tooth extraction; (II) dental extraction; (III) exodontia; (IV) statins; (V) HMG CoA reductase inhibitors and text words; (VI) tissue repair; (VII) tooth socket healing; (VIII) bone regeneration; (IX) alveolar ridge preservation; and (X) animal experiments. A combination of the following keywords was used: (I) statins AND tooth extraction; (II) statins AND dental extraction; (III) statins AND exodontia; (IV) HMG CoA reductase inhibitors AND tooth extraction; (V) HMG CoA reductase inhibitors AND dental extraction; and (VI) HMG CoA reductase inhibitors AND exodontia. Boolean operators (OR and AND) combined keywords to expand search results. Disagreements during the process were solved through discussion between the authors and consultation of a third author (P.G.).

Data collection, statistical analysis, and risk of bias

Data variables including study design, age range, study groups, group allocations, study duration, the primary site of the evaluation, primary parameters of the review, type of statin, dose, delivery method, frequency, and site of application were included to answer the research question by authors P.G., M.K., and J.K. The Systematic Review Centre for Laboratory Animal Experimentation (SYRCLE) was used to evaluate the studies’ bias. Specifically, the SYRCLE risk of bias tool, adapted from the Cochrane Risk of Bias tool for animal intervention studies, eased a thorough assessment of study quality, enhancing the credibility of preclinical evidence (Table 1; Figures 1,2).

Figure 1 Traffic plot.

Figure 2 Risk of bias of included studies.

Results

Study selection and general characteristics of study

An electronic database search found 412 manuscripts. After the removal for the following reasons: duplicate records (n=39), records marked as ineligible by automation tools (n=2), records removed for other reasons (n=5), 366 manuscripts remained. Following this title, abstract screening, and eligibility criteria, manuscripts met the inclusion and exclusion criteria of the present systematic review (Figure 3).

Figure 3 Study flowchart based on the PRISMA guidelines.

Animal model characteristics

Our study sample formed 403 animals. Eight studies utilized rat animal models (13,19-25), whereas one was performed on mongrel dogs (14). Seven studies reported the gender of animals (13,19-21,23-25). Their age ranged from 1 to 24 months. Of the nine studies, only five reported random group allocations for their study animals (13,19-21,25). The study duration ranged between 14 to 84 days (Table 2).

Statin administration

Out of the nine studies, five utilized local administration of simvastatin in the sockets of study group animals (13,14,20,21,23). The remaining four studies applied fluvastatin in the socket (19,22,24,25). The concentration of simvastatin across the studies ranged from 0.01 to 2.2 mg, with two studies employing simvastatin at a 1 mg/scaffold dosage (20,21). The concentration of fluvastatin across the studies ranged from 0.1 to 10 mg/kg (19,24,25). One study used fluvastatin-impregnated poly (lactic-co-glycolic acid) (PLGA) microspheres containing 20 or 40 µg·kg⁻¹ of fluvastatin (22). The frequency of administration consisted of a single application of the statin drug in the extraction sockets of the study animal (13,14,20,21,23,24). Some authors injected the statin drug in the gingivobuccal fold (22) and near tooth extraction sockets (25) (Table 3).

Tooth extraction, medication-related osteonecrosis of jaws (MRONJ), dental implants, soft tissue healing

Nine studies examined the effects of statin drugs on extraction sockets. Two assessed statins’ preventative and therapeutic effect on MRONJ. One evaluated statins’ healing potential around the dental implant, and three assessed soft tissue healing at the extraction site.

Primary outcome variables

Primary outcome variables were measured by applying the following tools: dual-energy X-ray absorptiometry (DXA) (20), micro-computed tomography (micro-CT) (19,22-25), soft X-ray photography (13), histomorphometry (19,25) and histology (13,14,19-25). Primary outcome variables used across all the studies were residual ridge height, messenger ribonucleic acid (mRNA) expression of transforming growth factor-beta 1 (TGF-β1), BMP-2, and VEGF, bone regeneration and neovascularization, bone and gingival healing, residual ridge height and width, inflammatory response, and bone turnover (BT), bone formation in tooth extraction socket, osteogenic healing in a tooth extraction socket, epithelial continuity, and new bone formation (13,14,19-25) (Table 4).

Residual ridge height

Study by Wu et al. reported a significantly greater height of the residual alveolar ridge in the experimental compared to the control group at 2, 4, 8, and 12 weeks after simvastatin application following tooth extraction. At 12 weeks, the relative height of the residual alveolar ridge in the control group was 0.922±0.018 compared to 0.960±0.026 in the experimental group (20). Radiographic images were reviewed to measure the height of the residual alveolar ridge (20). Study by Willett et al. concluded that bone mineralized matrix + simvastatin conjugate preserved the most interproximal bone height (P<0.01) based on the micro-CT measurements (23).

Bone density (BD), socket BD (SBD), and bone mineral density (BMD)

In addition to residual alveolar height Wu et al. also studied BMD. The authors reported that BMD values were significantly higher in the experimental than in the control group at 4, 8, and 12 weeks (20). Study by Willett et al. demonstrated that bone mineralized matrix infused with simvastatin preserved BD. The authors utilized micro-CT measurements to determine their findings (23). Study by Li et al. noted that the BD of the simvastatin-loaded microsphere hydrogel group was higher on the soft X-ray photographs than that of the simvastatin-free hydrogel group (13). Yasunami et al. examined the effect of sustained-release, fluvastatin-impregnated PLGA microspheres on bone healing. They concluded, based on their analysis of histological images, that at day 28, BD was significantly increased in PLGA containing 20 µg·kg⁻¹ fluvastatin and PLGA containing 40 µg·kg⁻¹ fluvastatin when compared with the control and (PLGA) microspheres (22). Study by Rakhmatia et al. noted that the BMD of the carbonate apatite-containing statin (COFS) group was higher than that of the other groups, thereby promoting bone healing in the socket (24).

mRNA expression of TGF-β1, BMP-2 and VEGF

Study by Liu et al. examined the effect of simvastatin on mRNA expression of TGF-β1, BMP-2, and VEGF in tooth extraction sockets via in situ hybridization. The authors noted that expression of TGF-β1 and BMP-2 mRNA in the tooth extraction sockets experimental group was significantly up-regulated after 1, 2, and 4 weeks (TGF-β1, P<0.05) and (BMP-2, P<0.01). Similarly, expression of VEGF mRNA was significantly increased after one and two weeks compared with that in the control group, indicating its positive influence on alveolar bone remodeling (21).

Osseointegration in immediate implants

Another study aimed to assess the regenerative potential of simvastatin as a grafting material proximal to immediate dental implants. The authors found that simvastatin granules allowed for osteogenesis around immediate implants, resulting in osseointegration via bone regeneration with neovascularization through histologic analysis (14).

MRONJ

One study investigated the ability of fluvastatin to prevent the development of MRONJ-like lesions (19). A significantly shorter length of necrotic bone was exposed in the oral cavity in the medium [1.0 mg/kg; medium statin concentration group (FS-M)] concentrations of fluvastatin and high concentrations [10 mg/kg; high statin concentration group (FS-H)] of fluvastatin FS-H groups than in the MRONJ group (Steel test, MRONJ vs. FS-M: P=0.028; MRONJ vs. FS-H: P=0.041). Furthermore, the distance between the edges of the epithelial surfaces was significantly shorter in the FS-M groups (19). Bone volume fraction calculated on micro-CT images was significantly more significant in the FS-H group than in the MRONJ group (19). Similarly, another study concluded that the distance between the edges of the epithelium, the length and area of the exposed necrotic bone, and the necrotic bone ratio were significantly smaller in the fluvastatin-administered group compared with the saline group (25).

Discussion

This systematic review assessed statins’ effect on healing following tooth extraction. The findings of this systematic review are threefold: (I) local application of statin preserves the residual alveolar bone by promoting bone formation and allows for soft tissue healing at the extraction site; (II) statins facilitate osteogenesis around immediate dental implants, resulting in their osseointegration; (III) statins have preventative and therapeutic effects on MRONJ. Several authors have studied the mechanism of statin-induced bone formation.

This study investigates the potential of statin drugs in enhancing tissue healing and bone regeneration in tooth extraction sockets. The loss in height and width of the residual alveolar ridge post-extraction is well-documented. A systematic review revealed that local administration of simvastatin carried by PLGA promoted new bone formation in the tooth socket and preserved residual alveolar ridge height in rats. This effect is attributed to simvastatin’s osteoinductive and anti-resorption properties. Studies by Wu et al. (20) and Yasunami et al. (22) further proved increased bone mineralization and connective tissue formation following simvastatin administration. Furthermore, statins have been reported to promote angiogenesis, inflammation reduction, and antibacterial activity, contributing to enhanced tissue healing post-extraction. Bisphosphonates (BPs) and denosumab have been associated with MRONJ in osteoporotic and cancer patients, showing a need for caution in dental procedures. Similar findings of statin drugs enhancing tissue healing in tooth extraction sockets have been observed in clinical studies (27-29). Interestingly, an animal study investigated the potential of statins to reduce the risk of developing jaw osteoradionecrosis and showed that a single injection of fluvastatin can reduce the risk of medication-related osteonecrosis following tooth extraction (19). A recent study experimentally explored the benefits of atorvastatin in managing MRONJ in rats (30). The study’s observations resonate with the current review’s findings that statin drugs potentially positively affect bone metabolism by stimulating osteoblastic activity in the site of interest. Notably, a recently published clinical study of 102 patients demonstrated a 32.4% improvement rate of osteoradionecrosis in their investigations. Although the findings are insufficient, the study concluded that statins may be a novel and effective treatment of jaw osteoradionecrosis (31). These recent novel findings, observed in experimental and clinical investigations, strengthen existing evidence to extend the scope of using statin drugs in dentistry, from tissue healing in tooth extraction sockets to managing complex dental conditions such as osteoradionecrosis of the jaw, thereby offering new hope for clinical practice. In contrast, statins have shown promising results in promoting bone formation, inflammation reduction, and tissue healing, making them potential candidates for managing tooth extraction sites. Sanda et al. reported epithelial continuity and new bone formation. They observed reduced necrotic bone in Fluvastatin-treated groups in rats (25), while the study by Adachi et al. reported reduced necrotic bone exposure and epithelial surface distances following fluvastatin administration post-extraction (19). Overall, the included studies suggest a positive influence of statins on soft and hard tissue remodeling at tooth extraction sites, highlighting their potential role in perfecting post-extraction healing processes.

This systematic review has limitations. First, due to the heterogeneity of the studies included, we could not perform a meta-analysis of the articles. Second, the chosen animal model may not fully replicate clinical conditions due to the use of rats at a developmental stage where growth is still ongoing. Therefore, future studies might consider using animal models that better align with the clinical context to enhance the validity and reliability of research outcomes. Despite these limitations, this study is significant because it is the first to review statin drug applications to promote tissue healing after tooth extraction. The application of statin drugs to promote tissue healing after tooth extraction has garnered attention due to their potential therapeutic benefits. Statins, primarily known for their cholesterol-lowering properties, have proved pleiotropic effects, including anti-inflammatory, angiogenic, and bone-stimulating properties. These attributes make them attractive candidates for enhancing wound healing processes.

Conclusions

In preclinical studies using animal models, local administration of statins, such as simvastatin and fluvastatin, has shown promising results in promoting tissue healing in tooth extraction sockets. These studies have reported increased new bone formation, reduced necrotic bone exposure, and enhanced epithelialization in statin-treated groups compared to control groups. Additionally, statins have been found to inhibit osteoclast formation and function, thereby potentially reducing bone resorption and preserving alveolar ridge height. While preclinical evidence is encouraging, further clinical research is needed to evaluate the efficacy and safety of statins in promoting tissue healing after tooth extraction in humans. Clinical trials assessing parameters such as wound closure, bone regeneration, and postoperative complications are called to confirm statin-based therapies’ translational potential in dental practice. Moreover, investigations into best dosages, delivery methods, and long-term effects of statins on oral tissues are essential for their successful clinical implementation. Overall, the application of statin drugs holds promise for improving tissue healing outcomes following a tooth extraction, potentially offering new avenues for enhancing patient care in dentistry.

Acknowledgments

None.

Footnote

Reporting Checklist: The authors have completed the PRISMA reporting checklist. Available at https://atm.amegroups.com/article/view/10.21037/atm-24-140/rc

Peer Review File: Available at https://atm.amegroups.com/article/view/10.21037/atm-24-140/prf

Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://atm.amegroups.com/article/view/10.21037/atm-24-140/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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