The Effect of Grape Seed Extract on the Alveolar, Jaw, and Skeletal Bone Remodeling: A Scoping Review

Abstract Herbal medicine has an important part in promoting and maintaining human health. One of them was grape seed extract (GSE). Various potentials of GSE in human health have been explored, and its potential for maintaining bone health is promising. Some initial research has provided evidence that the GSE was able to affect bone remodeling (bone resorption and bone formation). This scoping review analyzed and discussed all the reports on the effect of GSE on bone healing and bone remodeling in animals in the alveolar bone, jaw bone, and skeletal bone. The further purpose is to give an opportunity to research and development of supplementation of GSE for humans. The Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) 2020 guidelines were used to compose this scoping review through database on Scopus, PubMed, Science Direct, Web of Science, Embase, and manual search until December 2022. The inclusion criteria were a study that analyzed the effect of supplementation GSE on all bones. All included study was in vivo study with supplementation of GSE. The supplementation of GSE affects the alveolar bone, jaw bones, and skeletal bone by promoting bone formation and inhibiting bone resorption by suppressing inflammation, apoptosis pathways, and osteoclastogenesis. It not only supports bone remodeling in bone inflammation, osteonecrosis, osteoporosis, and arthritis but also the GSE increases bone health by increasing the density and mineral deposition in trabecula and cortical bone. The supplementation of GSE supports bone remodeling by interfering with the inflammation process and bone formation not only by preventing bone resorption but also by maintaining bone density.


Introduction
In recent years, the grape has explored its bioactive compounds, such as proanthocyanidins and phenolic acid, that are found in the skin, pulp, and seed. 1 The grape seed extract (GSE) has attracted the attention of the food industry and public health organizations. 2 GSE has potential health benefits because of rich proanthocyanidins, 3 approximately 74 to 78%, 4 and it possesses anti-inflammatory, antioxidant, 5 antiapoptotic and pro-proliferative properties. 6Besides its potential, the GSE is considered safe for humans, because it does not show any toxicity effects like changing the hematological parameter and organ changes. 7By that A GSE has been recognized by the Food and Drug Administration as Generally Recognized as Safe and is sold commercially as a dietary supplement, and is listed in the Everything Added to Food in the United States data. 8n dentistry, the GSE has been proved to prevent dental caries 9,10 by covering the acquired enamel pellicle and preventing bacterial adhesion to performed biofilm 11 and antibacterial in the root canal during endodontic treatment. 12The GSE also has been promoted as periodontitis medication because it is able to reduce oxidative stress and inflammation. 13In clinical randomized clinical trials, the GSE significantly reduced the probing depth and increased the attachment level. 14Recent research has shown GSE's influence in bone remodeling process in postorthodontic relapse prevention by inhibiting osteoclastogenesis. 15Bone remodeling is an active and dynamic process between bone resorption by osteoclasts and bone formation by osteoblasts that works in balance to maintain mineral homeostasis in the body. 16It is no exception that prevention of postorthodontic relapse also requires adequate bone remodeling, which is an important factor in maintaining bone thickness.During orthodontic tooth movement, bone resorption occurs in the pressure area, due to osteoclast activation, and bone formation in the pull area, due to osteoblast formation. 17Not only alveolar bone remodeling but also the changes that include periodontal ligament metabolism 18 and neural regulation occurr. 19This process should occur in a balanced manner until the teeth on the arch is achieved.The undesirable thing is that excessive resorption occurs without being followed by the bone formation in the tension area of the teeth involved.More importantly, the height of the alveolar bone and the thickness of the cortical bone must be maintained. 20he current data showed that with the consumption of 200 to 400 mg per day of GSE as food supplementation, no physiological or clinical abnormality was changed, and it was declared safe for consumption. 21The safety is related to high proanthocyanidins and safe to gastrointestinal mucosa. 22,23he proanthocyanidins exerted an antioxidant and antiinflammatory effect by inhibiting the production of a proinflammation cytokine through the inhibition of nuclear factor kappa B (NF-kB) 24 and the C-reactive protein (CRP). 25,26Recent research also provided that the supplementation of GSE containing high proanthocyanidins has great benefits for humans by providing antioxidative stress and anti-inflammation, 27 improving bone health such as preventing bone loss, 28 inhibiting bone resorption by inhibiting osteoclastogenesis through NF-kB and c-Jun N-terminal kinase (JNK) signaling, 29 inhibiting advance glycation end product, 30 increasing bone formation by increase bone mineral and density, 31 upregulating bone growth factors, such as bone morphogenetic protein 7 (BMP-7), 30 and increasing implant osseointegration. 28On the other hand, the GSE also provides a protective effect against osteoarthritis in the knee. 32With various potentials regarding GSE for various bone remodeling markers, due to limitations and explanations of the exact mechanism of GSE for alveolar bone, jaw bone, and skeletal bone remodeling, especially in treatmentrelated like postorthodontic relapse prevention, dental implant, periodontal treatment, or dental surgery, this scoping review was conducted to further explain the mechanism and provide an opportunity for further research to be performed.

Review Methodology
This scoping review of published studies on the effect of GSE on bone remodeling was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) 2020 guidelines.The focus question in this review was, "How does GSE affect bone remodeling (alveolar bone, jaw bone and skeletal bone)?
The Population, Intervention, Comparison, Outcome statement used for this study is the population included in all the studies investigating the potential effect of GSE on bone remodeling, including alveolar bone, jaw bones, and skeletal bone.Intervention is defined as the various dose and administrations of GSE.Any comparison (placebo or no control) was included.All clinical outcomes related to bone remodeling markers by in vivo research were included.

Information Sources
A comprehensive literature search was conducted on the following databases: PubMed, Scopus document, Science Direct, Web of Science, Embase, and manual search for all studies published.

Search Strategy
The keyword as [(grape seed) or (grape seed extract)] AND [(bone) or (bone remodeling)] were used in the research.Results were limited to studies published in English and in vivo studies.Review articles were not included in this review.

Study Design and Selection Process
All studies on those databases and fitting the criteria below were grouped together, and any duplicates were removed.The remaining studies were then filtered according to the title and the abstract.Studies that did not match were excluded at this stage.The remaining studies were screened at the final stage according to their full text, and those that did not meet the inclusion criteria were excluded.Mendeley reference manager was used to organize the study titles and abstracts and identify duplicates. 33This process was conducted by four independent investigators: EDW, AT, IGAWA, and MDCS.In the case of disagreements, the investigators reached their decision through discussion.
The inclusion criteria for this review included clinical or in vivo studies about GSE, studies describing its potential effect on bone remodeling, the dose of the treatment, and the marker analyzed.This process, documented by Microsoft Excel for Windows, was performed in the following order: the name of the first author, publication year, country, study design, and results.

Study Selection
After using a combination of keywords, 659 articles were found in the three databases.The titles were screened, and the duplicates were removed, resulting in 82 remaining articles.After reading the abstracts, all 82 articles were included in the next step of assessing the full text for eligibility.After this process, only 26 articles analyzed the effect of supplementation of GSE to the alveolar bone (7 articles), jaw bones (4 articles), skeletal bone (long and flat bone) (6 articles), and in the bone disease model (9 articles; ►Fig. 1).

The GSE Effect on Jaw Bone
The supplementation of GSE affected mandibular bone by 3 mg dose once a week for 3 and 6 weeks.The cortical and trabecular bone marked an increase in density and bone mineral content, calcium, phosphate, and improved bone strength (►Table 2).

The GSE Effect on Skeletal Bone
The supplementation of GSE affected the femur, calvaria, and tibia bone with osteotomy, defect and implant placement.The dose was 10 to 100 mg/kg.The bone remodeling showed bone healing and improvement after the defect, increased callus formation, bone volume, and increased torque of implant removal (►Table 3).

The GSE Effect on the Skeletal Bone with Disease
The supplementation of GSE also showed a good response for bone remodeling in bone diseases like bone inflammation by lipopolysaccharide (LPS), osteonecrosis, arthritis, and osteoporosis.GSE doses vary from 12 mL/kg to 300 mg/kg.

Discussion
Various studies have been reported regarding the potential of GSE for human health.1][62] GSE supplementation can also be used to improve and prevent cardiotoxicity, gastrointestinal toxicity, hepatotoxicity, nephrotoxicity, and mucositis caused by cancer radiation, like. 63In inflammation, GSE can significantly inhibit the formation of CRP. 64As a natural ingredient that is safe for consumption, GSE is also proven to be safe for the liver because it can improve levels of alanine aminotransferase, aspartate aminotransferase, and alkaline phosphatase. 65In addition, GSE is also able to provide antibacterial properties. 66ith various studies on the potential of existing, it seems that the potential for bone health has not been widely disclosed, so application and testing in humans have not been widely performed.Various in vivo studies have shown a lot of GSE potential for bone remodeling processes in the alveolar bone, jaw, and skeletal bones.One of the potentials of GSE for bone remodeling in the alveolar bone can be seen in various treatments in the field of dentistry, such as orthodontic, periodontal surgery, dental implant, or oral surgery.
During orthodontic treatment, tooth movement is strongly influenced by the processes of resorption and formation of the alveolar bone.GSE supplementation in the prevention of post orthodontic relapse provides an anti-inflammatory effect by decreasing the production of MDA in serum and gingival tissue. 35This decrease occurs because phenolic compounds in GSE can inhibit the formation of reactive oxygen species (ROS) and the formation of MDA. 67The further possible mechanism was explained through periodontitis-related alveolar bone resorption.The MDA maybe then decrease HIF-1α and MMP-8 expression, 36 resulting in a decrease in the inflammatory response, 35 and several osteoclasts. 15,36HIF-1α is one of the important factors in osteoclastogenesis, especially the hypoxia response that occurs in orthodontics tooth movement 68 and a factor in osteoclast activation, 69 through the increased of OPG secretion to bind to RANKL. 70On the other hand, GSE is also able to reduce RANKL and OPG, thereby reducing the number of osteoclasts 15,36 and increasing the osteoblast, 36 which results in an excessive decrease in alveolar bone resorption 35 or bone loss. 37Further, the mechanism of GSE to support bone formation was explained in the tooth extraction model, where the alveolar bone expressed increased osteoblast, and the bone growth factor was BMP-2 38,39 and osteocalcin for alveolar bone mineralization 36 (►Fig.2).
The antioxidant properties of GSE are also responsible for increasing the formation of GSH in serum, 35 thus supporting the formation of osteoblasts, 36 and maintaining the height of alveolar bones and preventing bone loss. 34,36This increase in GSH is due to the inhibition of ROS by the phenolic compound in GSE, which then affects the NF-κB signal pathway involved in osteoclast differentiation 71 (►Fig.2).
Although the exact mechanism of how GSE can affect bone remodeling is still unknown, some previous studies have confirmed this.GSE in vivo level research has been shown to affect mandibular bone 40,41 and mandibular condyle. 31,42SE supplementation for 3 to 6 weeks has been shown to increase trabecular density 31,40 and cortical density [40][41][42]45 and is implicated in increasing bone strength (►Fig. 3).Analysis of bone content also showed that levels of minerals, 40,41 calcium and phosphate in mandibular bones, 41,45 were significantly increased in the group that received GSE supplementation.The explanation of increasing jaw density and minerals, calcium, and phosphate is not fully understood.
Adequate bone remodeling is also needed during bone recovery due to bone disease.GSE supplementation was performed in some studies related to bone healing-related disease.4][55][56] In the bone inflammation and osteoporosis model, GSE maintained the bone structure, 49 by increasing the trabecular thickness 48,50 and bone mineral content. 50he exact mechanism decreased the number of osteoclasts. 48he proanthocyanidins are responsible for this mechanism because this active substance is able to inhibit the osteoclast through inhibition of activation of NF-kB and JNK signaling pathways. 29n the osteonecrosis model, the antioxidant properties of proanthocyanidins in GSE take place by controlling the radicals like SOD, 51 GSH, 51 MDA, 51 and pro-apoptosis proteins like caspase 3, 51 caspase 9, 52 and Bcl2. 52It has been researched that proanthocyanidins can inhibit mitochondrial stress and prevent the apoptosis process by inhibiting the intrinsic apoptosis pathways. 72In the orthodontic field, the force applied will activate the hypoxia, produce ROS, and activate the NF-kB, 71 which may increase alveolar bone resorption for tooth movement.For this reason, the supplementation of GSE to prevent post-orthodontic tooth movement (relapse) needs to be explored.
In the arthritis model, the GSE plays an antioxidant property in preventing bone destruction and inflammation through increased Sox6 expression.The SOX6 expression takes place during bone remodeling in the arthritis model. 53ox6 is the major factor for healing because it is able to enhance proliferation, inhibit apoptosis, and regulate osteogenesis-related gene expression. 73The sox family, Sox5, Sox6, and Sox9, is involved in the activation and maintenance of chondrogenesis during fracture healing and the enhancement of chondrogenesis by BMP-2 74 further Sox6 expression also determined bone mineral density. 75he other protein that influences bone remodeling is Runt-related transcription factor 2 (Runx2). 76This protein is essential for osteoblasts and osteoclasts differentiation. 77ome research also mentions that upregulated Runx2 and Sox6 also contribute to bone formation, especially for chondrocyte differentiation. 78Related to increased runx2 expression after supplementation of GSE on the arthritis model, 53 the supplementation also decreased the HIF-1α expression in the alveolar bone.But the relationships between Runx2 and HIF-1α have been explained by Lin et al., 2011, in which the inhibition of Runx2 and HIF-1α resulted in heterotopic ossification forming. 79In alveolar bone, the Runx2 also plays similar as skeletal bone, which is a role in osteoblast differentiation 80 and maintains the integrity of the dentogingival junction. 81FATc1 expression also decreases after GSE supplementation in the arthritis model. 53During the regeneration, GSE provides antioxidant properties due to its phenolic compound, and this substance is able to inhibit the inflammation process.The inflammation inhibition resulted in decreased activation of NF-κB and NFATc1. 82By decreasing the NF-kB, proinflammatory cytokine production, like IL-1β, 54 tumor necrosis factor-alpha (TNF-α), and IL17, 56 decreases.On the other hand, the decrease in NFATc1 expression also affected STAT3 for controlling osteoclast differentiation 83 and bone metabolism 84 to prevent bone resorption 85 and bone loss. 55ow-density lipoprotein receptor-related protein 4 (LRP-4) also decreased after GSE supplementation.Even the exact mechanism of LRP-4 is not fully understood, but also the role of LRP takes place and controls bone morphogenesis. 86nlike MMP-13, 54 this protein regulates osteoclast number and activity, bone resorption, and bone mass 80 and maintains mineralization in the bone. 87By affecting all proteins during bone remodeling, the process of bone regeneration occurs, marked by increased bone volume, 48     number and thickness, 48,50 and increased bone minerals like phosphor and calcium and also osteocalcin 54 (►Fig.4).By these various effects obtained in the in vivo model, it is promising that GSE can be applied to humans in case of bone regeneration, not limited to skeletal bone, but also to jaw bone and alveolar bone.

Conclusion
Finally, from the available data, we can conclude that the supplementation of GSE affects the alveolar bone, jaw bones, and skeletal bone by promoting bone formation and inhibiting bone resorption by suppressing inflammation, apoptosis pathways, and osteoclastogenesis.It not only supports bone healing in bone inflammation and bone remodeling in osteonecrosis, osteoporosis, and arthritis but also increases bone health by increasing the density and mineral deposition in trabecula and cortical, as well as increases the mineral, calcium, and phosphate deposition.The supplementation of GSE supports bone remodeling by interfering with the inflammation proses and bone formation by preventing bone resorption and maintaining bone health.The evidence in this scoping review gives the opportunity to conduct further research on humans.

Future Implication
The data presented showed that the GSE has a beneficial effect on human health, particularly in maintaining bone health.Future research should consider the supplementation of GSE not only for bone maintenance but also for treating and supporting bone remodeling in dentistry and orthopaedic treatment.In the field of dentistry, GSE supplementation during the retention phase may prevent postorthodontic relapses by promoting bone regeneration.However, the optimal supplementation dose needs to be determined to achieve a therapeutic effect.

Limitations
This review was limited by the scarcity of high-quality studies, with most of the available research conducted on animal models or in vivo.Additionally, the lack of information regarding the specific doses of GSE used and the duration of the treatment represent significant issues that should be addressed in future studies to enable a more comprehensive meta-analysis.

Fig. 1
Fig. 1 Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) flowchart.
GSE for Bone Remodeling Wahyuningtyas et al.75
GSE for Bone Remodeling Wahyuningtyas et al.81

Table 1
The effect of GSE administration on the alveolar bone of animals

Table 2
trabecular The effect of GSE administration on the jaw bone of animal Animals Journal of Dentistry Vol.18 No.1/2024 © 2023.The Author(s). European

Table 3
The effect of GSE administration on the skeletal bone of an animal European Journal of Dentistry Vol.18 No.1/2024 © 2023.The Author(s).GSE for Bone Remodeling Wahyuningtyas et al. 79

Table 4
The effect of GSE administration on the bone disease model of animal