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 Table of Contents  
Year : 2022  |  Volume : 9  |  Issue : 2  |  Page : 148-154

Comparative evaluation of regenerative potential of infrabony periodontal defects by using xenograft in combination with 1% alendronate and 1% metformin gels

Department of Periodontics, Panineeya Institute of Dental Sciences and Research Centre, Hyderabad, Telangana, India

Date of Submission26-Apr-2022
Date of Decision11-May-2022
Date of Acceptance23-May-2022
Date of Web Publication22-Aug-2022

Correspondence Address:
Jammula Surya Prasanna
Department of Periodontics, Panineeya Institute of Dental Sciences and Research Centre, Dilsuck Nagar, Hyderabad, Telangana
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/jdrr.jdrr_62_22

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Background: Deficiency of the alveolar bone is one of the trademarks of periodontitis. Thus, agents that have osteogenic potential play a meritorious role in disease prevention. There is evidence, that pharmacological agents such as Alendronate (ALN) and Metformin (MF) have such potential in bone regeneration. Objectives: The main aim of this study was to assess the competency of Xenograft (XG) alone and in combination with 1% ALN and 1% MF in the regeneration of periodontal bone defects. Materials and Methods: In this randomized interventional study, total of 36 infrabony defects were randomly assigned to three groups, each group comprised of 12 infrabony defects: Group I with 1% ALN gel + XG (test), II with 1% MF gel + XG (test) and III with only XG (active control). This was a split-mouth study. Clinical criteria such as pocket depth (PD), relative vertical clinical attachment level (RVCAL) were assessed. A radiographic parameter like linear bone growth (LBG) was measured with the help of a grid. The microbial count (MC) was estimated with the plaque sample. All the specifications were calculated before the beginning of the study and at 6 months. Statistical analysis was performed using the Chi-square and paired t-test. Results: The mean reduction of PD, gain in RVCAL, LBG and MC was statistically significant within the groups (P < 0.05) from baseline to 6 months. However, MC was insignificant in Group III (P = 0.294) within the group but was significant on the intergroup comparison. Conclusions: Overall, significant results were found in all three groups. Using XG alone as well as in combination with 1% ALN and 1% MF has given appreciable results.

Keywords: Alendronate, grid, metformin, regeneration, vertical bone defects, Xenograft

How to cite this article:
Prasanna JS, Madhusudhan M, Nandakumar S. Comparative evaluation of regenerative potential of infrabony periodontal defects by using xenograft in combination with 1% alendronate and 1% metformin gels. J Dent Res Rev 2022;9:148-54

How to cite this URL:
Prasanna JS, Madhusudhan M, Nandakumar S. Comparative evaluation of regenerative potential of infrabony periodontal defects by using xenograft in combination with 1% alendronate and 1% metformin gels. J Dent Res Rev [serial online] 2022 [cited 2022 Sep 28];9:148-54. Available from: https://www.jdrr.org/text.asp?2022/9/2/148/354207

  Introduction Top

Alveolar bone formation and resorption is a continuous process. If there is any disruption in the normal sequence, either excess bone formation or bone loss will be seen. Periodontitis is one such process which progressively leads to alveolar bone loss. The logical hypothesis is that therapeutic agents which control the bone resorption or accelerate bone formation could protect against alveolar bone loss.

Mechanical therapy is a gold standard to eradicate oral bacteria from periodontal pockets, but complete eradication is not possible because of the sustenance of some exceptional morphological variations and bacterial strands encircling the tooth structure.[1] As an adjunctive therapy, systemic antimicrobials are effective to some extent, but they had their deleterious effects such as allergy, systemic toxicity, and development of bacterial resistance. To overcome these adverse effects, extensive research was accomplished and many systematic reviews were thoroughly scrutinized about the efficacy of antimicrobial drug delivery.[2],[3],[4],[5] The local drug delivery systems are site-specific, having no detrimental effects seen with the systemic delivery, with excellent antimicrobial and amplified intra sulcular drug absorption.[6]

Among all the available drugs Bisphosphonates (BP) are one of the more important and effective group of anti-resorptive drugs. Alendronate (ALN) is the classic drug among the BP group. ALN has osteostimulative properties and hence acts as a dynamic inhibitor of bone resorption.[7] ALN has been postulated to help as a supportive treatment of chronic periodontitis (CP).[8] Metformin (MF) is a second-generation biguanide used to regulate type 2 diabetes mellitus. Studies have also proven the positive effect of MF on bone formation.[9] Marked up regulation of osteoblastic activity and down regulation of osteoclastic activity is the important function of MF thus accelerating the bone formation. Considering this beneficial property, MF is also being considered in the periodontitis treatment.[9],[10],[11] Bone grafts are bioresorbable agents which facilitate the bone genesis as well as wound healing by its space maintenance and scaffolding action. New bone formation is initiated by the mineral reservoir present in grafts. Grafts that are obtained from nonhuman species, i.e., animals are, the Xenografts (XGs) which are osteoconductive in nature with limited resorptive potential. In general, used XG in periodontal regeneration is deproteinized bovine bone mineral.[12],[13]

It is a proven fact that ALN and MF are effective bone-forming agents when administered systemically. However their effect when delivered locally in combination with a XG is not yet proven. Thus, in this study, based on null hypothesis we aimed to assess which of the two agents while used with XG have been greater effective in bone formation.

  Materials and Methods Top

This randomized, triple masked interventional analysis was conducted in the outpatient Department of Periodontology, Panineeya Institute of Dental Sciences, Hyderabad. The study was done from January, 2017 to July, 2018. Patients of both sexes, aged between 35 and 55 having CP participated. After an extensive explanation of the procedure, a written approval was acquired from all the patients. The institutional Ethical Committee and Review Board, assessed this study, and also this study was registered in http://ctri.nic.in as CTRI/2018/02/011881. Consolidated Standards of Reporting Trials standard procedure as well as the Helsinki Declaration for human research,[14] was followed for conducting this study. A complete intraoral soft-tissue examination was performed to register the oral mucosal condition at the inception of the study so that any changes in the course of the study could be identified and an assessment was made as to whether this variance could be related to the use of the test formulations. Healing was adequate without any significant visual inflammatory signs and no detrimental, as well as untoward effects were seen throughout the study.

The inclusion criteria for this study were as follows: CP patients with angular intrabony defects with pocket depth (PD) ≥5 mm or clinical attachment loss (CAL) ≥2 mm subsequent to scaling and root planing (SRP). At least three defects should be present in each patient. The exclusion criteria for this study were as follows: subjects with established systemic diseases (even suffering from a common cold), with obvious or established sensitivity to ALN and MF, systemic or local administration of ALN or any of the BP family drugs for any other reason, using any form of tobacco products and alcohol, previous 6 months of periodontal history and antibiotic therapy, pregnant and nursing mothers, immuno-compromised and mentally challenged patients, aggressive forms of periodontitis and patients taking any other medications even for any simple reason (e.g.: paracetamol).

According to selection criteria, initially a total of 60 patients with 120 infrabony periodontal defects were selected, few dropped out due to personal reasons and some could not accomplish the criteria. Among 120 defects only 90 defects were finalized and included in the study. Among these 36 defects from 24 CP patients was selected, and divided equally into three groups, each group comprised of 12 infrabony defects [Figure 1]. All the subjects underwent thorough SRP at baseline. Group I - ALN group - treated with 1% ALN gel along with XG. Group II - MF group - treated with 1% MF gel along with XG. Group III - XG group - treated with XG alone. Grouping was done by computer randomized allocation. Dissimilarities between all the three groups were evaluated in the same patient.
Figure 1: Study selection criteria

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Clinical measurements like Probing PD reduction and Relative Vertical CAL (RVCAL) gain were assessed. A radiographic parameter like Linear Bone Growth (LBG) was measured with the help of a grid. Microbial count (MC) was approximated with the collected sub gingival plaque specimens. At the initial stage of the study all the specifications were calculated and again after 6 month intervals. All the three groups were compared in the same patient only. Williams graduated probe (Hu-Friedy, Chicago, IL, USA.) was used to measure all the parameters. Conventional radiographs with parallel cone beam technique were taken along with GRID (Blue dent India, Ullagaram, Nanganallur, Chennai, India). Complete surgical procedure was done by one person, who didn't know the allocation and which type of medication was used in the allocated periodontal pocket, thus the study was completely randomized.

Calculations of radiographic bone height with the grid were a radio-opaque mesh or a grid with calibrations of 1 mm × 1 mm was positioned in between the exposing object and the radiographic film during the time of exposure. The adjoining two parallel grid lines should be at the equidistant of the film. Following formula was used for measurements:[15]

Measurements of the vertical distance were done by counting the squares of grid from the Cemento Enamel Junction (CEJ) to the Level of alveolar crest (AC) and the defect base. Defect fill was determined by the discrepancy in the difference from the CEJ to AC and to BD. The difference of bone gain was calculated from baseline to 6 months [Figure 2], [Figure 3], [Figure 4].
Figure 2: Group I (Alendronate group) clinical and radiographic pictures from baseline to 6 months

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Figure 3: Group II (Metformin group) clinical and radiographic pictures from baseline to 6 months

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Figure 4: Group III (Xenograft group) clinical and radiographic pictures from baseline to 6 months

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MC was carried out with the help of sterile paper points (pink blue, Bangalore, India), subgingival plaque was collected from infra bony pocket sites where regenerating graft material is going to place and transferred to preheated cooked meat medium 2 ml (Robertson's) for culture. Before the sample collection, supra gingival plaque was removed and the site was isolated with cotton roles to prevent contamination. An anaerobic culture was performed to evaluate the microbial growth at baseline and 6 months [Figure 5], [Figure 6], [Figure 7].
Figure 5: Microbial count in Group I (Alendronate group) from baseline to 6 months

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Figure 6: Microbial count in Group II (Metformin GROUP) from baseline to 6 months

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Figure 7: Microbial count in Group III (Xenograft GROUP) from baseline to 6 months

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Formulation of Gel: Alendronate[8]

The weighed quantity of corbopol with 1.5% concentration was dispersed in 25 ml of distilledwater temperature was static at 95°C. At this temperature, the diffusion was trembled with a magnetic stirrer for 20 min to accelerate hydration of corbopol gel. To the above formulations, the calculated volume of ALN (1%) and preservative was added slowly with constant stirring. The dispersion was diluted with tri-ethanolamine to adjust the pH. The dispersion was kept at 4°C overnight until to form a clear gel.

Analysis formula for alendronate:

Absorbance = 0.273; Wave length = 264 nm

Metformin gel[10]

The measured volume of Gellan gum with 1% concentration was disseminated in 25 ml of clarified water upholding the temperature at 95°C. At this temperature the diffusion was trembled with a magnetic stirrer for 20 min to promote dampness of Gellan gum. To the above formulations the measured volume of MF (1%) and preservative was added slowly with constant stirring. The dispersion was neutralized with triethanolamine to adjust the pH. The dispersion was kept at 4°C overnight until a clear gel was formed.

Analysis formula for metformin:

Absorbance = 0.111; Wave length = 233nm

Standardization of the drug delivery

An insulin syringe of 1 ml with 40 unit gradations (U-40 INSULIN) was used to standardize the quantity of the drug. 25 μl was delivered along with XG. 40 units = 1 ml. Each unit = 1/40 ml, i.e., 25 μl 0.025 ml). 1% = 1 g in 100 mL ≥10 mg in 1 ml. Hence, 1 ml contain 10 mg of drug ≥1 μl contain 10 μg. 10 μl contain 100 μg, i.e., 0.1 mg of drug. 1 μl contain 10 μg of drug. So, 25 μl contain 250 μg, i.e., 0.25 mg of drug.

In this analysis, 1% of ALN gel was prepared, but the drug was standardized as 25 μl to be delivered into the infrabony defect along with a XG.

All the patients underwent an initial examination and were thoroughly briefed about the treatment protocol (phase I periodontal therapy, i.e., SRP and plaque control measures) during the study period.

Under local anesthesia, surgical procedure was performed. A full-thickness flap was raised and after thorough debridement, sites which fulfilled the inclusion criteria received the drugs. The standardized injecting method was followed with the same quantity of drug delivery in all the defects. After approximation of the flaps with suture, a periodontal dressing was given. All the parameters were compared at baseline as well as at 6 months. The entire procedure was masked.

Primary and secondary aftermaths were measured; the primary aftermath of the study was to measure the change in radiographic LBG and microbiological count from baseline to 6 months. Secondary aftermaths measured were PD and RVCAL.

A power analysis was performed to estimate the sample size, based on a significance level of 0.05 and power of 80%. Design of the study was a randomized, prospective, parallel-arm, interventional clinical trial. All the statistical analyses in the present study were done using the Chi-square test. Inter-group comparison of mean values was done using ANOVA and intra-group comparison was done using paired t-test. The categorical variables were compared using the Chi-square test. P < 0.05 was considered statistically significant.

  Results Top

When PD was compared in all the groups, PD reduction was statistically significant from baseline to 6 months, in all the groups, P < 0.001. RVCAL also reduced from baseline to 6 months, P < 0.001in Group I and III, 0.044 in Group II. Bone level (LBG), alveolar bone gain was also statistically significant P value was (<0.001 in all the groups). Reduction was significant in MC in the Group I and II which was observed from baseline to 6 months, but there was no significance in Group III (P = 0.294) [Table 1].
Table 1: Intra and intergroup comparison of all the parameters at baseline to 6 months

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When the comparison was done between groups, PD, RVCAL, and LBG were not significant at baseline as well as at 6 months. But when MC was compared in between groups reduction was significant at baseline (P = 0.04) as well as at 6 months (0.000) [Table 1].

The results of this study have shown that the action of 1% ALN gel + XG, 1% MF gel + XG, and XG alone, were similar on all parameters from baseline to 6 months. However, more precise action was seen in relation to MC. Significant reduction of MC was seen in both inter and intragroup comparisons [Table 1].

  Discussion Top

Progression of periodontal disease causes increased PDs as well as alveolar bone destruction. To arrest the disease process, treatment is imperative. The eventual objective of therapy is to gain new attachment by reducing the PD and augmenting the bone height.[16] Various treatment approaches exist to treat periodontitis such as nonsurgical therapy (NST), surgical therapy (ST), and an ancillary application of pharmacological agents.[17]

Although mechanical NST and ST have shown benefits as alternative remedies in the periodontal disease treatment approaches, their failure to completely annihilate the re-established pathogens from externalities of other niches of the oral cavity may cause reinfection. Concomitant application of chemotherapeutic agents in different modalities may overcome these impediments.[18],[19] Usage of specific medications such as antimicrobials and host modulating agents help in the control of microbial flora of periodontitis. Additional benefits of these agents might be diminution of excessive proinflammatory enzyme levels by curtailing the activity of cytokines, prostaglandins, and osteoclasts.[20]

The advantages of intra pocket delivery systems over the systemic therapy are attaining high intra sulcular drug concentrations in smaller doses, and a sustained drug action to the targeted area. Moreover, dose reduction leads to increased patient compliance.[21] And also sometimes the need for periodontal surgery might be prevented if intra-pocket medicaments are used along with SRP.[22]

BP's are the hailed medicaments in the present pharmacological weaponry against osteoclast-mediated bone loss. BP can offer consequential clinical amelioration where disproportion of bone formation and resorption takes place due to osteoblast and osteoclast hostility during predisposed disease pathology.[23],[24] ALN is a second generation nitrogen-containing BP, which promotes osteoclast apoptosis and is perspicuous from that of the nonnitrogen-containing BP.[25] Systematization of osteoclast activities inclusive of stress fiber assembly, membrane ruffling, and survival are inhibited by BP's, ultimately leading to osteoclast apoptosis.[24] The main advantage of BP is binding capacity with hydroxyapatite, the important inorganic material found in the bone.[26] Research suggests that BP's reciprocate the actions synchronously with osteoclasts and osteoblasts so that not only resorption is minimized but also early bone formation is observed.[27] In addition, BP counteracts the functions of various matrix metalloproteinases involved in the periodontal connective tissue breakdown.[28],[29] Ko et al. found BP withdrawal affected bone formation.[30]

MF is a first-line therapy for type-2diabetes mellitus. In vitro studies delineated that MF is osteogenic, can also induce osteoblastic cell differentiation and bone matrix synthesis. Apart from this Bone Morphogenic Protein-2 (BMP-2) was expressed by MF, which helps in the regeneration of bone in irradiated tissues. Further cartilage formation and bone induction are carried out.[31],[32] MF stimulates osteoblastic bone formation by interacting with the transcription factor Runt-related transcription factor 2 (Runx2).[33] Possibly via stimulation of Runx2 MF increases osteoblastic proliferation, alkaline phosphatase activity leads to form mineralized nodules in osteoblasts, further the action of MF on bone marrow mesenchymal cell progenitors will have an osteogenic effect.[34],[35]

XG is the type of graft taken from another species. Currently organic, bovine, equine-derived and coral skeleton bones are being extensively used for periodontal regeneration. After different purification procedures, all organic components were removed and an uninterrupted inorganic form of the graft is made in different particle sizes. Available in both cancellous and cortical bone forms. The only constraint of XG is, it is only osteoconductive in nature and does not have osteogenic and osteoinductive properties.[36],[37]

On intragroup comparison, MC in Group 3 was not significant, but when we compared inter-group, MC was significant and remaining parameters were not significant.

These study results are in accordance with the study done by Ipshita et al.,[38] when they had tried 1% ALN alone in furcation defects significant results in a reduction of PD, gain in RVCAL were seen. Meta-analysis and a systematic review, done by Chen et al.[39] and Akram et al.[40] about ALN, their conclusions were also with accordance to this study results. In another systematic review by Akram et al.[41] and Najeeb et al.,[42] MF has given significant results after scaling which is in accordance to this study results except for RVCAL. This study results were also partially in accordance with two studies done by Pradeep et al.[10],[11]

Above named materials, when compared individually conflicting results were seen. As very minimal research was done in combination therapy, drawing results are inconclusive. The said and done studies compared only clinical parameters but are not relevant to microbes. The fascinating feature in this article is combination therapy was used and evaluating its effect on the MC. The distinguished impediments found were a smaller extent of the study samples and the drug release period was not calculated. Sustainability of the gel in the pockets was unexplained. Since conventional radiographs were taken, manual errors and misinterpretation could be possible. Intrabony defects were not subcategorized.

  Conclusions Top

Regeneration of intrabony defects is being carried out with a plethora of agents for many years. MF and ALN were shown to enhance osseous regeneration by their osteoblast-promoting and osteoclast-inhibiting actions. In this frame of reference, MF and ALN were used as additives to the XG and delivered at the site of interest as a combination therapy. Results showed the action of 1% ALN gel + XG, 1% MF gel + XG, and XG alone, were similar on all parameters from baseline to 6 months. But more precise action was seen in relation to MC. Significant reduction of MC was seen in both inter and intragroup comparisons. Delivering the drug at the specific site would minimize the adverse effects seen with the systemic delivery and also has added benefits of controlled drug release, sustained action, and more patient compliance. The results yielded better treatment outcomes. Future research should focus on various other combination therapies for the regeneration of deeper infrabony defects with more patient compliance.

Ethical clearance

Ethical clearance Protocol Ref No: 00106.

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Conflicts of interest

There are no conflicts of interest.

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  [Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5], [Figure 6], [Figure 7]

  [Table 1]


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