|Year : 2021 | Volume
| Issue : 6 | Page : 555-563
Clinical effect of simvastatin gel with bone graft in grade II furcation defects: A randomized controlled clinical trial
Darshanaa Arunachalam, Sheeja S Varghese, Arvina Rajasekar
Department of Periodontology, Saveetha Dental College and Hospitals, Saveetha Institute of Medical and Technical Sciences, Chennai, Tamil Nadu, India
|Date of Submission||01-Jun-2021|
|Date of Decision||21-Sep-2021|
|Date of Acceptance||06-Sep-2021|
|Date of Web Publication||30-Nov-2021|
Dr. Sheeja S Varghese
Department of Periodontology, Saveetha Dental College and Hospitals, Saveetha Institute of Medical and Technical Sciences, Chennai, Tamil Nadu.
Source of Support: None, Conflict of Interest: None
Aim: To evaluate the effectiveness of 1.2 mg/mL simvastatin (SMV) gel with hydroxyapatite (HA) bone graft in the surgical treatment of mandibular Grade II furcation defects compared with HA bone graft, SMV, and placebo after open-flap debridement (OFD). Materials and Methods: The present study was a single-center, triple-blind randomized controlled clinical trial wherein 23 mandibular grade II furcation defects from 15 chronic periodontitis patients were randomly assigned for treatment with either placebo gel (group 1; n = 5), HA (group 2; n = 6), SMV (group 3; n = 6), and SMV + HA (group 4; n = 6). Clinical parameters at the furcation defect site, such as horizontal and vertical probing depth (HPD and VPD), vertical clinical attachment level (VCAL), radiologic parameters, such as vertical defect depth in intraoral periapical radiograph (IOPA), vertical and horizontal defect depth, and volume of defect in cone-beam computed tomography (CBCT) were recorded at baseline, 3, and 6 months postoperatively and analyzed using SPSS software. For intragroup comparison, paired t test and Wilcoxon test were used, and for intergroup comparison, ANOVA and Kruskal-Wallis test were used. Results: SMV + HA group had improvement in all the clinical parameters when compared to baseline but were not significantly different when compared to other groups. However, statistically significant improvement in HPD was evident in SMV + HA group at 3 months (1.8 ± 1.3; P = 0.019; P < 0.05) when compared to HA group. In CBCT, SMV + HA group had significant improvement in VDD, HDD, and volume of the defect whereas in IOPA, there was no significant findings. Conclusion: Simvastatin with HA is more effective in reducing the horizontal component of grade II furcation defects.
Keywords: Bonegrafts, Periodontitis, Furcation, Simvastatin
|How to cite this article:|
Arunachalam D, Varghese SS, Rajasekar A. Clinical effect of simvastatin gel with bone graft in grade II furcation defects: A randomized controlled clinical trial. J Int Oral Health 2021;13:555-63
|How to cite this URL:|
Arunachalam D, Varghese SS, Rajasekar A. Clinical effect of simvastatin gel with bone graft in grade II furcation defects: A randomized controlled clinical trial. J Int Oral Health [serial online] 2021 [cited 2022 Jan 26];13:555-63. Available from: https://www.jioh.org/text.asp?2021/13/6/555/331579
| Introduction|| |
Periodontitis is an inflammatory disease caused by bacterial infection which affects the supporting tissues of teeth. The bacterial interaction with the host results in the release of inflammatory mediators notably, tumor necrosis factor (TNF)-α, prostaglandin E2, interleukin (IL)-1, IL-6, and other cytokines related to the host response and tissue destruction. The association between these biomarkers and the severity of the periodontal disease is well studied.,, After the disease initiation, it progresses with the loss of collagen fibers, apical migration of the junctional epithelium, deepening of the gingival sulcus, formation of periodontal pockets, bone loss, furcation involvement, tooth mobility, and subsequent tooth loss.
When the disease affects the bifurcation and trifurcation of multirooted teeth, the management is challenging to the clinician., Attempts to treat furcation lesions have led to therapies ranging from nonsurgical periodontal therapy such as scaling and root planing (SRP) alone or SRP plus systemic or local antimicrobial agents to surgical flap debridement, root resection, hemisection, and regenerative therapy. Regenerative periodontal therapy could be a means for grade 2 furcation involvement, which includes the use of various bone grafts, guided tissue regeneration techniques, platelet concentrates, growth factors, and enamel matrix derivatives.
Porous hydroxyapatite (HA) is an osteoconductive bone graft used to fill periodontal intrabony defects which permits the outgrowth of osteogenic cells from existing bone surfaces into the adjacent bone defect. Statins are widely used to lower blood cholesterol levels. It has been suggested that statins can stimulate bone formation by stimulating the production of bone morphogenetic protein-2. Simvastatin (SMV) is a chemical modification of lovastatin, enhances alkaline phosphatase activity and mineralization, and increases the expression of bone sialoprotein, osteocalcin, and type I collagen. It decreases the production of IL-6 and IL-8 and promotes osteoblast differentiation and bone formation. Various animal studies showed that SMV assists in bone regeneration as well as in reducing inflammation when delivered or applied locally.,
Regeneration of furcation defects is still a challenge to clinicians due to its complex morphology and difficulty in assessing the defect characteristics with the conventional clinical and radiographic methods. It has been reported that cone-beam computed tomography (CBCT) is superior to intraoral digital radiography for the assessment of grade II furcation defects. Thus incorporating CBCT into the conventional clinical and radiographic method will be more useful in evaluating the effectiveness of any agent in the management of furcation involvement. In this study, we hypothesized that a combination of SMV and HA would be more effective than their individual usage in the surgical management of furcation defects. To date, limited research has been carried out to evaluate the effects of SMV along with bone graft in the surgical management of grade II furcation defects. The present study was attempted to evaluate the effectiveness of 1.2 mg/mL SMV gel with HA bone graft compared with HA bone graft, SMV, and placebo placed after open-flap debridement (OFD) in the surgical treatment of mandibular grade II furcation defects at 3 and 6 months post-surgery.
| Materials and Methods|| |
Setting and design
This study, a single center, triple-blind randomized controlled clinical trial was conducted from January 2018 to December 2018. Fifteen patients, aged between 25 and 59 years (8 males and 7 females) from the outpatient section of the Department of Periodontics, Saveetha Dental College, Chennai, diagnosed with chronic periodontitis (American Academy of Periodontology Criteria 1999), contributing 23 grade II furcation sites were enrolled for the study. The sample size was calculated from the data obtained in a previous study using G power with a power of 0.95.
Patients with chronic periodontitis having periodontal probing depth of >3 mm with attachment loss and horizontal probing depth at the furcation site clinically and vertical and horizontal inter-radicular bone loss radiographically in one or more mandibular molars were included for this study. Patients on systemic statins and non-steroidal anti-inflammatory drugs (NSAIDs), aggressive periodontitis patients, current smokers, patients with systemic illness, and pregnant and lactating females were excluded.
The independent variables included age of the patient, the furcation location along with the grouping variables, whereas the dependant variables included horizontal and vertical probing depth (HPD and VPD), vertical clinical attachment level (VCAL), vertical defect depth (VDD) from intraoral periapical radiograph (IOPA), VDD and horizontal defect depth (HDD), and volume of defect assessed by CBCT
Randomization and allocation process
All selected patients received scaling and root planning and were instructed to rinse with 0.2% chlorhexidine (Clohex Plus mouthwash, Dr Reddy’s Lab Ltd., Hyderabad, India) twice daily for 2 weeks. SMV gel was prepared as described by Thylin et al. in 2002. The selected sites were randomly assigned as either of the 4 following sites: Placebo (group 1), HA bone graft (group 2), SMV (group 3), SMV + HA bone graft (group 4) using an online randomizing application. Randomization was done using an online random allocation software (RandomAlloc.exe.Version 1.0) where number of groups of samples, number of samples per group, and number range is fed, following which it generated random numbers. Each defect was allotted a number based on the order of surgery according to which they were allocated to different groups. The treatment allocation of the patients was prepared and sealed in the numbered opaque envelopes and was opened during surgery immediately after completing the defect debridement. Allocation protocol was unavailable to the periodontal examiner (SV) throughout the study. All the participants, surgeon, and examiner who assessed the parameters were blinded to avoid any type of bias. Patients were masked for allocation to a particular group and treatment. All the surgical procedures in four groups were performed by a trained periodontist (DA). The pre-operative and post-operative assessments were performed by another examiner (SV) without knowledge of the nature of the intervention. Only mandibular grade II furcations were included in the study to reduce the sample variability.
A standard open flap surgical procedure was performed for all the 4 groups. In group 1 defect site, 0.1 mL of placebo gel (methylcellulose gel; Merk Life Sciences Private Ltd., Mumbai, without SMV) was placed. In group 2 defect site, hydroxyapatite bone graft (Sybograf Plus®, Eucare Pharmaceuticals Private Ltd., Chennai, India) was placed. In group 3 defect site, 0.1 mL (1.2 mg/0.1 mL) of SMV gel was placed and in group 4 defect site, hydroxyapatite bone graft plus 0.1 mL (1.2 mg/0.1 ml) of SMV gel was placed. The surgical site was protected with a non-eugenol periodontal dressing after suturing. Antibiotics and analgesics were prescribed for three days.
Clinical parameters at the furcation defect site, such as horizontal [Figure 1] and vertical [Figure 2] probing depth (HPD and VPD) and VCAL, were recorded at baseline and at the end of 3 and 6 months postoperatively. For radiographic evaluation, long cone paralleling technique using intraoral direct digital periapical Radiovisiograph (RVG-Aditya medical systems [AMS] Model no. 6010E) was used. Exposures were made at 70 KVp, 7 ma for 0.2 s. The focus to photostimulable phosphor (PSP) plate (Durr Dental SE image plate) distance was 20 cm, and a dental film positioner (Alpha Dental Equipment and Co. Ltd.) was used with a putty stent to record the bite of patients to minimize errors. PSP plates were scanned using Vistascan mini image plate scanner. VDD was assessed as the vertical distance between furcation fornix and deepest defect depth by IOPA with superimposed film counting grid (Bluedent, India) [Figure 3]. The VDD was determined by counting the number of grids at 0, 3, and 6 months. VDD and HDD and volume of defect were assessed by CBCT (Orthophos XG 3D unit from Dentsply Sirona) at 0 and 6 months. VDD was measured by using the line distance between the furcation fornix to the most apical point of the radiolucency and HDD was measured from the outermost point of entry between the 2 roots to the deepest point of the radiolucency. These measurements were taken using Galileos implant software from Dentsply Sirona. Volume of the defect was assessed using the medical image viewer from Osirix ICOM [Figure 4] viewer by live wire free hand modeling.
The data obtained were analyzed using Statistical Package for Social Sciences (SPSS) Version 23 (SPSS Inc., Chicago, IL). Paired t test and Wilcoxon test were used to compare all the parameters between different time frames within each group. ANOVA and Kruskal-Wallis test were used to compare different clinical and radiographic parameters between the 4 groups. For pairwise comparison between the groups, Post hoc test was used in case of Gaussian distribution and Mann-Whitney test was used for non-Gaussian distribution. In all the tests, P < 0.05 was considered significant.
| Results|| |
In this randomized controlled clinical trial, 23 mandibular furcation defects from 15 patients were treated with OFD + placebo gel (group 1 n = 5), HA with OFD (group 2 n = 6), 1.2 mg SMV gel (group 3 n = 6), 1.2 mg SMV gel + HA with OFD (group 4 n = 6). Follow-up was completed on 19 of the 23 sites enrolled in the trial. Out of 15 patients, 3 patients (4 defects) dropped out (1 in each group) over the course of the study. Consequently, the statistical analysis is based on clinical data from 18 sites in 6 months, 19 sites in 3 months, and 23 sites in baseline [Figure 5]. There were no adverse effects following the intervention in any of the patients enrolled in the study. The mean age of the patients was 39.95 ± 10.92. Buccal defects were 47.83%, and 52.17% of the defects were lingual. Group-wise mean age, furcation baseline characteristics are given in [Table 1]. There were no statistically significant differences in baseline clinical and radiographic characteristics.
While comparing within the group from baseline to 3 months and to 6 months, in the placebo group, there was no significant reduction in clinical parameters at furcation defect and radiographic parameter (VDD) in IOPA, whereas statistically significant reduction in horizontal defect depth in 6 months was seen in CBCT (P = 0.040). In the HA group and SMV group from baseline to 3 months and 6 months, there were no statistically significant improvement in all the clinical parameters and radiographic parameters in IOPA were observed. Whereas statistically significant improvement was observed in all the parameters (VDD, HDD, volume) in CBCT at 6-month follow-up (P < 0.05: significant). In the SMV + HA group, statistically significant reduction was observed in horizontal probing depth from the baseline to 3 months (P = 0.037) [Table 2] and from baseline to 6 months (P = 0.021) along with significant improvement in all the parameters in CBCT (VDD, HDD, volume) at 6 months (P < 0.05) [Table 3].
While comparing all the three groups in terms of HPD, VPD, VCAL, VDD (IOPA), VDD (CBCT), HDD, and volume at different time points (from baseline to 3 months and to 6 months) using ANOVA, no statistical significance (P > 0.05) was noted [Table 4]. When pairwise comparison was done using post hoc analysis, statistically significant difference was noted only in HPD at 3 months in SMV + HA group when compared with HA group with a mean difference of 2 (P = 0.019) and also in volume of the defect in CBCT at 6 months in SMV + HA group when compared with placebo group with a mean difference of 1.75 (P = 0.050) [Table 5]. On post hoc power analysis done using G power with the existing sample size, the power was less than 80% at 95% confidence interval.
| Discussion|| |
Periodontal research scholars are on the constant lookout for newer regenerative materials. This study investigated the regenerative potential of statins when combined with HA bone graft in the management of grade 2 furcation defects. Evaluation was done clinically as well as radiographically using both IOPA and CBCT. The intragroup comparisons done at three and six months showed that there was some improvement in the clinical parameters when compared with the baseline measurements but was not statistically significant for all the groups except for SMV + HA group where there was a significant improvement in HPD at six months. None of the groups showed any significant change for VDD measurements taken from IOPA at three and six months from baseline measurements. All the outcome parameters measured from CBCT (VDD, HDD, and volume) at six months showed a significant improvement from baseline for all the groups except the placebo group wherein the improvement was observed only in HDD measurements. On intergroup comparison, the SMV + HA group showed a significant improvement in volume measurements as compared to the placebo group. Similarly, the SMV + HA group showed a significant improvement in HPD measurements as compared to the HA group.
In the present study, when baseline clinical and radiographic parameters were compared, there was no significant difference between the groups. In intragroup comparison, all the groups showed reduction in clinical and radiographic parameters at 3 months and 6 months from the baseline. This is in accordance with a study by Pradeep et al. 2012, where there was significant improvement within the groups (SMV and placebo) from baseline to 3 months and 6 months in grade II furcation defects. However, there was no significant reduction in clinical parameters at 3 months and 6 months from the baseline. This may be due to the complex morphology of furcation defects and its inaccessibility. Also, unlike intrabony defects, furcation defects are not surrounded by bony wall on all sides; it is surrounded by cemented wall on 60% of its surfaces. The clinical success of furcation therapy also appears to be strongly related to defect morphology as enumerated by Bowers et al.
When radiographic parameters assessed in IOPA were compared within the groups, there was no significant difference in VDD at 3 months and 6 months from the baseline. This is in agreement with a study by Khashu and Vandana, mandibular grade 2 furcation defects were evaluated at 9 months after treatment with Pepgen-15 and atrisorb and was found that changes in furcation defect in IOPA were not evident and difficult to interpret in 75% of the radiographs (out of 30 radiographs). On the contrary, a study reported a highly significant improvement in bone fill % in IOPA from baseline to different time parameters in SMV and placebo groups. However, it was used in intraosseous bony defects. These findings emphasize the drawback of IOPA in assessing the furcation morphology
When radiographic parameters assessed in CBCT were compared, there was a significant reduction in VDD, HDD, and the volume of the defect at 3 and 6 months from the baseline within all the groups except placebo. To the best of our knowledge, there was no clinical trial where CBCT was used to assess the efficiency of statins or any regenerative material in grade 2 furcation defects. Although we could observe improvement in the radiographic parameters in CBCT, IOPA was not showing the same. This disparity could be a result of the horizontal component of furcation defect not being appreciable in IOPA due to overlapping of the buccal and lingual cortex.,
In the present study, there was no significant difference in the clinical parameters assessed at the furcation site between the groups at 3 months and 6 months. A study by Khashu and Vandana where grade 2 furcation defects were evaluated after treatment with Pepgen-15 and atrisorb also failed to show a difference in furcation defect site clinical parameters. This result highlights the difficulty in regenerating the furcation defects especially with respect to clinical parameters. However, there was a significantly lesser volume of the defect measured in CBCT in the SMV + HA group when compared with placebo at 6 months in the present study.
In an intergroup comparison of the improvements between the furcation defect site clinical parameters, there was a significantly greater improvement in horizontal probing depth in the SMV + HA group when compared with the HA group at 3 months. This is in accordance with Priyanka et al. who demonstrated greater reduction in horizontal probing depth in the SMV when compared with placebo. Anabolic effect of statin on bone metabolism could be the possible reason behind this. While comparing the improvements in furcation defect site radiographic parameters in CBCT, there was a significant improvement at 6 months in volume of the defect in the SMV + HA group when compared with the placebo group. These findings were also in accordance with a study that demonstrated a significant fill of the defect measured in IOPA in the SMV group compared with placebo from baseline to 6 months.
The reasons behind the beneficial effects of statins in periodontal therapy have been reported by many authors. Anti-inflammatory effect of SMV suggests a possible role in host modulation, and it might be a newer agent as a host modulator in the management of the periodontal disease. A study by Mundy et al. suggests that statins can stimulate bone formation by stimulating the production of bone morphogenetic protein-2 (BMP-2), which may be the reason for the radiographic improvement observed in our study.
In the present study, the sample size calculation was done at a power of 95% based on the results from the study done by Pradeep et al wherein subgingival delivery of SMV gel was done as nonsurgical management of grade 2 furcation defects. But on post hoc analysis with the existing sample size, the power was less than 80% as the actual effect size of the present study was lesser than the previous study. This might be a possible reason for not getting statistically significant results in many of the parameters, although there were promising results in favor of adding SMV to bone grafts. Nevertheless, within the limitations of this study, it can be concluded that SMV, when incorporated with HA bone graft, is having a promising effect in reducing the horizontal component of grade II furcation defects both clinically and radiographically when compared with HA bone graft, SMV, and placebo placed after OFD. Studies with more sample size with much longer follow-up will confirm the additive effect of SMV in the management of grade 2 furcation defects.
| Conclusion|| |
SMV with HA is more effective in reducing the horizontal component of grade II furcation defects. Therefore, SMV as a novel and safe therapeutic agent can be used as a viable alternative for periodontal regeneration in grade II furcation defects.
Special thanks to the management of Saveetha Institute of Medical and Technical Sciences for the constant support for the research.
Financial support and sponsorship
Self-funded project with partial funding from the University (SIMATS).
Conflicts of interest
There are no conflicts of interest.
SSV contributed to study conception, study design, data collection, analysis, interpretation, and manuscript preparation; DA contributed to Study Execution, data collection, data interpretation, and manuscript preparation; AR contributed to statistical analysis and manuscript preparation.
Ethical policy and institutional review board statement
Ethical clearance for the study was received from the Institutional Ethical Committee of Saveetha Dental College and Hospitals (SRB/SDMDS/15PER3). Study was carried out with the ethical protocols by the Helsinki Declaration. Clinical Trials Registry–India (CTRI) Registration Number: CTRI/2018/03/012740.
Patient declaration of consent
The authors certify that all the participants have provided their written consent to participate in the research and to publish the analyzed data. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.
Data availability statement
Data are available upon a valid request to the corresponding author.
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[Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5]
[Table 1], [Table 2], [Table 3], [Table 4], [Table 5]