|Year : 2015 | Volume
| Issue : 4 | Page : 243-249
Statin: A boon in periodontal therapy
Sahana Purushotham1, Melba Lisa D'Souza1, Ramaiah Purushotham2
1 Department of Periodontics, AJ Institute of Dental Sciences, Mangaluru, Karnataka, India
2 Department of Cardiology, AJ Institute of Dental Sciences, Mangaluru, Karnataka, India
|Date of Web Publication||23-Nov-2015|
Department of Periodontics, AJ Institute of Dental Sciences, Kuntikana, Mangaluru - 575 004, Karnataka
Source of Support: None, Conflict of Interest: None
Periodontitis is an inflammatory process causing gradual destruction of the periodontal tissues and alveolar bone loss. Various periodontal therapies have been introduced to lower the destruction, statin being one among them. They are cholesterol-lowering drugs which promote bone formation, hence proven to be effective in periodontal therapy. This article reviews the effects of statin and examines its potential role in periodontal regenerative therapy.
Keywords: Bone formation, periodontal therapy, periodontitis, statin
|How to cite this article:|
Purushotham S, D'Souza ML, Purushotham R. Statin: A boon in periodontal therapy. SRM J Res Dent Sci 2015;6:243-9
| Introduction|| |
"Statins" are a class of drugs that lower the level of cholesterol in the blood by reducing the production of cholesterol by the liver. Statins block the enzyme in the liver that is responsible for making cholesterol. Recently, interest has been focused on non cholesterol-dependent, pleiotropic effects of statins. Anti-inflammatory pleiotropic effects are supposed to result from the inhibition of isoprene modification of signal transducers of inflammation. Periodontitis is characterized by an inflammatory breakdown of the tooth supporting structures. Periodontal therapy aims at arresting this breakdown and restoring periodontal tissues to their original structure and function. The need to achieve greater regeneration warrants the use of an agent, which not only inhibits resorption of the alveolar bone but also stimulates new bone formation. Statin has proved to have a potential role in periodontal regenerative therapy.
| Classification of statin|| |
Statins differ in several ways. They differ with respect to their ring structure and these differences in structure affect the pharmacological properties of statins. The most obvious difference is in their ability to reduce cholesterol. Currently, atorvastatin (ATS) (Lipitor) and rosuvastatin (Crestor) are the most potent, and fluvastatin (Lescol) is the least potent.
One way to classify statins is by the way they are manufactured. Some are derived from micro-organisms through biotechnology. These are called as fermentation-derived or Type 1.
Others are made through chemical synthesis (no living organisms involved). These are synthetic or Type 2 statins. It is common for pharmaceuticals to be made through fermentation or through chemical synthesis [Table 1].
Water soluble versus fat soluble
Statins are soluble in both aqueous environments and oily environments. The solubility levels differ enough for it to be possible to classify some as hydrophilic (better solubility in water) or lipophilic (better solubility in fats) [Table 2].
The hydrophilic statins are excreted from the body, largely unmetabolized by the liver. Lipophilic statins are broken down in the liver by the cytochrome P450 system. Hydrophilic statins tend to have fewer interactions with other drugs.
The statins also differ in how strongly they interact with other drugs. Specifically, pravastatin (Pravachol) and rosuvastatin (Crestor) levels in the body are less likely to be elevated by other drugs that may be taken at the same time as the statins. This is so because the enzymes in the liver that eliminate pravastatin and rosuvastatin are not blocked by many of the drugs when compared to other statins. This prevents the levels of pravastatin and rosuvastatin from rising and leading to increased toxicity such as myopathy (inflammation of the muscles).
| Structure of statin|| |
The structures of statin can be broadly divided into three parts: 
- An analog of the target enzyme substrate, 3-hydroxy-3-methyglutaryl coenzyme A (HMG-CoA);
- A complex hydrophobic ring structure that is covalently linked to the substrate analogue and is involved in binding of the statin to the reductase enzyme;
- Side groups on the rings that define the solubility properties of the drugs and therefore many of their pharmacokinetic properties [Figure 1].
| Mechanism of action of statin|| |
Statin drugs work by blocking a step in the body's production of cholesterol. Cholesterol is a natural product of the liver; sometimes the liver produces too much cholesterol. These drugs block the enzyme linked to the liver's cholesterol production, HMG-CoA reductase, thus inhibiting the liver's ability to produce low-density lipoprotein (LDL). This causes an increase in the number of the LDL receptors on the surface of liver cells, resulting in more cholesterol being removed from the bloodstream and a reduction in risk for high cholesterol-related diseases. Statin drugs have been shown to lower LDL levels from 18% to 55% and to raise high-density lipoprotein levels from 5% to 15%. The reaction catalyzed by HMG-CoA reductase and inhibited by simvastatin (SMV) is the conversion of HMG-CoA to a compound called mevalonate via an intermediate. Thus, statin is an inhibitor of the mevalonate pathway and consequently cholesterol synthesis [Figure 2]. The reduction in mevalonate pathway intermediates with a subsequent inhibition of prenylation by statins, which is responsible for a large proportion of the pleiotropic effects of these drugs.
| Pleotropic effect of statin|| |
The effects observed with statins are higher than expected. Apart from lipid lowering properties, this drug has additional nonlipidic effects, responsible for its complex pharmacological profile demonstrated in clinical trials. Consistent with this, recent studies have shown various effects of statins on nonlipidic biological scopes known as "pleiotropic effects" of statins, which include the following: Antioxidant, antithrombotic, anti-inflammatory, immunomodulatory, and osteomodulatory properties [Figure 3].  All these pleiotropic effects of statins point out to it perhaps becoming one of the novel host modulation agent in periodontics.
SMV has been shown to inhibit the ability of macrophages to oxidize LDLs.  Various studies have shown that statins reduce the plasma levels of inflammatory markers such as C-reactive protein (CRP).  The addition of statins significantly decreased interleukin-6 (IL-6) production by these cells. It has also been suggested that the statin mediated decrease in CRP concentrations could be due to an inhibition of IL-6. Production of nicotinamide adenine dinucleotide phosphate oxidase, a major source of oxidant production is inhibited by statins.  Thus statins, including SMV, are believed to have biologically significant antioxidant and anti-inflammatory effects, which could prove to be beneficial in the treatment of periodontitis.
In addition, various experiments have shown statins to have immunomodulatory effects. Statins can inhibit tumor cell growth and enhance intracellular calcium mobilization. It was observed that inhibitors of HMG-CoA reductase induce a reduction in the formation of osteoclasts in rodents.  Another effect on immune system is mediated by binding of statins to leucocyte function associated with antigen and preventing its binding to intercellular adhesion molecule 1. This leads to inhibition of its function in leucocyte adhesion and extravasation.  Other studies have also demonstrated the free radical scavenging activity of statins. Direct scavenging reactive oxygen species prevents its interaction with lipids, proteins, and deoxyribonucleic acid. In this regard, SMV and ATS are more active against hydroxyl radical, and that fluvastatin is more active against peroxyl radical.  Various pleotropic effects of statin proves that it is a potential host modulating agent for the treatment of periodontal diseases.
| Application of statin in periodontal therapy|| |
Statin and its role in periodontal regeneration
Periodontal disease is a major oral health problem. Deep periodontal pockets liberate inflammatory mediators and cytokines, which affect the remote tissues. ,, Chronic periodontitis affects the systemic condition of the patients. It deteriorates the diabetic condition,  and causes increase in obstetric complications.  Over the years, various treatment modalities have been tried with varying success to correct periodontal attachment and alveolar bone loss resulting from this disease. Periodontal therapy is aimed at the restoration of tissues destroyed by disease. However, achieving greater predictability with regenerative therapy requires the introduction of an agent which not only hampers tissue destruction but also enhances the regenerative capabilities of the periodontal tissues. Statins have anti-inflammatory and bone stimulating properties that may positively affect chronic periodontitis.
SMV is not well absorbed, and <5% of an oral dose reaches the systemic circulation. Concentrations of statins in bone marrow have not been well established yet, but osteoblasts and osteoclasts may be exposed to very low concentrations of statin with existing oral regimens.
Osteogenic properties of statin in periodontal therapy
SMV has been reported to promote osteoblastic activity and inhibit osteoclastic activity. Transient exposure of bone to statins was enough to initiate a cascade of bone formation, probably induced by the local production of the bone morphogenic protein-2 (BMP-2). The BMP-2 promoter was utilized as a target to identify new compounds that stimulate its transcription and subsequent osteoblast differentiation. Small molecules are identified that enhance BMP-2 transcription and also increases endogenous BMP-2 messenger RNA and protein expression in human MG63 osteoblastic cells by two-fold. BMP-induced osteoblast differentiation occurs through antagonizing tumor necrosis factor (TNF)-α-to-Ras/Rho/mitogen activated protein kinase and augmenting BMP-S mad signaling. 
SMV has demonstrated to reverse the suppressive effects of TNF and prevents the inhibition of BMP-2 mediated by Smad 1, 5, and 8 phosphorylation. The decrease in osteoclast number was seen in a histological study. On oral administration of SMV, lowered activity of serum tartrate-resistant acid phosphatase 5b was reported, indicating the decreased osteoclast activity.  Since osteoblasts and marrow adipocytes originate from a common mesenchymal progenitor, few adipogenic agents have reported to suppress osteoblast differentiation. 
SMV enhances alkaline phosphatase activity and mineralization, as well as increases the expression of bone sialoprotein, osteocalcin, and Type 1 collagen, and it is shown to have anti-inflammatory effect by decreasing the production of IL-6 and IL-8. 
| Topical application of statin|| |
Local delivery of chemotherapeutic agents into the pockets via a syringe or irrigating device has been shown to have an effect on the subgingival flora. The local tissue concentration of a drug can be enhanced by incorporating the active agent into controlled release delivery systems which has to be placed directly in the periodontal pocket or the defect area. Periodontal therapy necessitates a focused effect in specific defects, suggesting the importance of local application of statin. Attempts have been made to escape its accumulation in the liver and to deliver the statins to the peripheral tissue by subcutaneous injection or transdermal patch. 
Statins also seem to modulate bone formation by increasing the expression of bone morphogenetic protein-2,  which assists in bone regeneration as well as the anti-inflammatory effect when delivered or applied locally. Topical delivery of biological molecules such as fibroblast growth factor  has also shown to enhance bone growth. SMV is reported to stimulate vascular endothelial growth factor (VEGF) release in dose-dependent manner and the authors suggested that statins may promote osteoblast differentiation and bone nodule formation by stimulating VEGF expression in bone tissue. 
Statin when administered in the prodrug form, is more lipophilic than the active beta-hydroxyacid form. Because of this property, the SMV molecule can effectively cross cellular membrane barriers by passive diffusion.  It also implies that it can be incorporated into hydrophobic delivery vehicles for local sustained release to achieve bone formation in periodontal defects. Therefore, SMV plays a significant role as a therapeutic agent in the treatment of periodontal disease.
| Carriers|| |
The successful use of SMV to promote bone formation in vivo depends on the local concentration of the drug and there have been continuous efforts to find an appropriate delivery system.  There are a number of advantages to an appropriate carrier; including localization and retention of the molecule to the site of application thus reducing the loading dose and providing a matrix for mesenchymal cell infiltration and a substrate for cell growth and differentiation. The carrier may also help in order to define the shape of resulting new bone and the optimal carrier has a degradation rate that does not inhibit bone growth and prevent fibrous tissue formation or fibrous encapsulation of the carrier. In one of the studies, SMV is indigenously prepared using methylcellulose and double distilled water in sterile conditions and inserted into the disease sites using a blunt cannula carrier.  In another study, statin is used as gelatine sponge which adapts easily to the shape of the defect because of its gel-like form.  A combination of 1mg of calcium sulfate and SMV was used in minute defects in rat calvaria. This combination promoted bone regeneration. 
| Animal model studies on the topical application of various statins|| |
Local application of SMV has been shown to stimulate bone formation in rodents both in vitro and in vivo and in human periodontal ligament cells in vitro.
Mundy et al. in 1999 tested the effects of more than 30,000 compounds on bone formation. They found that the addition of statins to neonatal murine calvarial bone in organ culture increased new bone formation by two- to three-fold. 
Paula et al. in 2010 did a study to evaluate the effect of ATS on alveolar bone loss induced in Wistar rats. A significant increase in radiographic density was seen in rats receiving ATS when compared to the control group. This showed that ATS caused reduction in alveolar bone loss. 
Vaziri et al. did a study in 2007 to evaluate the effect of SMV on ligature-induced bone resorption in the mandible of the ovariectomized rat. SMV was administered subperiosteally in the buccal fold of first molar twice a week during the study. SMV caused significantly less periodontal breakdown and had a protective effect on the attachment apparatus and alveolar bone. 
Various animal model studies have shown that local and systemic application of statin caused increase in bone formation (Skoglund et al. 2002; Seto H et al. 2008; Lee Y et al. 2008; Jeon JH et al. 2008; Lee Y et al. 2011; Sangwan A et al. 2013). ,,,,, The findings of these studies suggest that statin could play a significant role as a therapeutic agent in the treatment of periodontal disease as they demonstrate a direct effect of locally applied SMV on bone formation.
| Human model studies on the topical application of statin|| |
The studies conducted by Low and Al-Qawasmi in 2003 showed that the relationship between osteoprotegerin (OPG) and receptor activator of nuclear factor-kappaB ligand (RANKL) will affect the root resorption. Given that SMV increases OPG to RANKL ratio in periodontal tissues, it can be a factor in preventing root resorption. 
Yazawa et al. in 2005 analyzed the effect of SMV on cell proliferation and osteoblastic differentiation in periodontal ligament cells. The result of this study suggested that a low concentration (10−8 M) of SMV exhibited a positive effect on the proliferation and osteoblastic differentiation of human periodontal ligament cells and these effects were caused by the inhibition of mevalonate pathway. 
A study done by Yoshinari et al. in 2006 showed that immobilization of SMV onto titanium implants is suggested to promote osteogenesis in the bone tissue surrounding the implants through its topical application. [36 ]
Okamoto et al. in 2009 did a study on SMV, stating that it increases dentin sialophosphoprotein gene expression and osteocalcin. Both of these result in differentiation of odontoblasts and generation of hard dental tissues. 
Pradeep and Thorat in 2010 investigated the effectiveness of locally delivered SMV, 1.2 mg to improve clinical parameters and enhance bone formation. This study reported a greater decrease in gingival index and probing depth and more clinical attachment level gain with significant bone fill at sites treated with scaling and root planing and locally delivered SMV in patients with chronic periodontitis. 
| Dosage of statin to promote bone growth|| |
SMV possesses topical and systemic anti-inflammatory properties, but this property alters at high-dose local applications. Effective dosage range to treat hypercholesterol in humans by oral administration is up to 1.0 mg/kg/day. Animal testing indicated that high-dose SMV (20 mg/kg/day) increases bone formation, while low-dose SMV (1 mg/kg/day) decreases bone formation and increases bone resorption.  The authors considered a 10 mg/kg/day dose to rats about equivalent to 70 mg/day for humans, taking into account that metabolic process in rodents are 10 times faster than in humans. 
A number of studies reveal that long-term systemic administration of SMV for decreasing plasma cholesterol levels in humans has beneficial effects on the skeleton. Chan et al. in 2000 carried out a case-control study of women aged 60 years or older and found that regular statin use among them was associated with a more than 50% reduction in the risk of pathologic fracture.  Similarly, the findings of Wang et al. supported an association between statin use and a reduction in the risk of hip fracture in elderly patients. Doses should be chosen with caution considering benefits and risks, and further studies are needed to confirm the optimal dosage for the therapeutic effects [Table 3]. 
| Conclusion|| |
Within the limits of various studies that were conducted, it can be concluded that SMV shows protective features against the impact of periodontitis on the attachment apparatus and alveolar bone. This drug is able to achieve the goal of regeneration without any invasive procedures, thereby causing less discomfort to the patients. The patients on statin medication exhibit fewer clinical signs of periodontal inflammatory injury than subjects without the statin regime. It is proved that the antioxidant and anti-inflammatory properties of this compound could facilitate healing of osseous defects. Although relatively abundant information about statins indicates their possible beneficial effect on bone, available both in the preclinical and clinical field, there have been some conflicting results on the effect of SMV. This is due to the fact that the effects of SMVs may be influenced by a range of factors including the method of administration, duration of exposure, experimental animal model, and bioavailability. However, long-term clinical studies in human subjects are required to determine the optimal therapeutic threshold, mode of application, and the effectiveness in humans for bone regeneration and evaluate the potential benefits of statin in periodontal regenerative therapy.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2], [Figure 3]
[Table 1], [Table 2], [Table 3]