ORIGINAL RESEARCH


https://doi.org/10.5005/jp-journals-10015-2294
World Journal of Dentistry
Volume 14 | Issue 9 | Year 2023

Comparative Study between 1% Metformin and 1% Alendronate Gel in the Treatment of Infrabony Defects: A Randomized Controlled Trial


Dipika Mitra1, Chaitrali Lakade2, Ankit Desai3, Prachi Gurav4, Bela Khobragade5

1-5Department of Periodontology, Terna Dental College and Hospital, Mumbai, Maharashtra, India

Corresponding Author: Prachi Gurav, Department of Periodontology, Terna Dental College and Hospital, Mumbai, Maharashtra, India, Phone: +9082996949; 9619361991, e-mail: prachigurav3196@gmail.com

Received on: 06 August 2023; Accepted on: 08 September 2023; Published on: 13 October 2023

ABSTRACT

Aim: This research was conducted to analyze and compare the regenerative ability of 1% alendronate (ALN) and 1% metformin (MF) in chronic periodontitis patients with infrabony defects.

Materials and methods: This study had a split-mouth design in which 26 sites with infrabony defects in chronic periodontitis patients were enrolled; 13 were aggregated to the group I (1% ALN gel) and 13 to group II (1% MF gel). A follow-up period of 3 and 6 months was observed postoperatively for the clinical parameters, and a follow-up of 6 months was observed radiologically, after which the data collected was analyzed.

Results: Both groups demonstrated statistically significant probing pocket depth reduction, defect depth reduction (DDR), and relative attachment level gain at an interval of 6 months. However, no statistically significant distinction was observed among the groups in both clinical and radiographic measures, as well as crestal bone loss.

Conclusion: Within the constraints of our study, no difference in the efficacy of 1% MF and 1% ALN was observed in periodontal therapy of chronic periodontitis patients with infrabony defects.

Clinical significance: About 1% ALN and 1% MF have been shown to regenerate periodontal structures and, hence, can be used in the treatment of periodontitis, owing to their antiresorptive and bone-stimulating ability.

Clinical significance: Mitra D, Lakade C, Desai A, et al. Comparative Study between 1% Metformin and 1% Alendronate Gel in the Treatment of Infrabony Defects: A Randomized Controlled Trial. World J Dent 2023;14(9):820–827.

Source of support: Nil

Conflict of interest: None

Keywords: Alendronate, Bone regeneration, Metformin, Periodontal regeneration, Periodontitis

INTRODUCTION

Periodontitis is a long-standing disease of periodontium, inflammatory in nature, that results in the loss of teeth and surrounding bone, affecting about 20–50% of the population.1 It is caused by the complex interaction of bacteria and the host response of the individual. As periodontal disease progresses, osseous defects are formed, which leads to further alveolar bone loss and, eventually, tooth loss. The ultimate goal of periodontal therapy is the creation of an environment suitable to maintain the patient’s dentition in health, comfort, and function.2

Periodontal surgery is primarily performed to gain access to deeper areas of the periodontal pocket, accomplish pocket reduction or eradication, and achieve new attachment development. Regeneration can be defined as the reproduction or reconstitution of a lost or injured part to restore the architecture and function of the periodontium.3 It results in the formation of new bone, cementum, and a functionally aligned periodontal ligament on a previously diseased root surface.4 Clinical studies have shown that conventional treatment modalities have limited potential to regenerate lost periodontal tissue.5

According to research, flap surgery in combination with biomaterials enhances the regeneration of periodontal structures to a larger amount in comparison to flap procedure alone.6

Alendronate (ALN) sodium, an amino bisphosphonate, is a pyrophosphate analog that is 10–100 times more effective at arresting bone resorption.7,8 It attaches to bone hydroxyapatite crystals, selectively binds to bone-resorbing sites, inhibits osteoclasts, and, thus, has a significant inhibitory impact on bone resorption.9,10 ALN also elicits osteostimulating ability, both in vitro and in vivo, by increasing matrix formation.11

Metformin (MF) has been demonstrated to increase alkaline phosphatase activity in osteoblasts and aid in collagen formation in these cells, promoting osteoblast differentiation and bone deposition.12,13 Therefore, by facilitating osteoblast differentiation, MF exhibits a favorable effect on alveolar bone in periodontitis.

There is evidence in the literature that both ALN14 and MF15 can be used as effective biomaterials to achieve regeneration. Hence, the present research aimed to treat chronic periodontitis patients with 1% ALN gel and 1% MF gel and compare its effectiveness in infrabony defects.

MATERIALS AND METHODS

Study Design

A split-mouth, single-blind study design was used in this randomized controlled trial. Subjects for the study were enrolled in the Periodontology Department’s outpatient department. G*power analysis version 3.10 was used to determine sample size based on the previous study’s results. The error was fixed to 5% (0.05), and the power at 80%. A total of 26 sites were split into two equal groups—group I (1% ALN gel) and II (1% MF gel). Randomization was accomplished using computer-assisted randomization. The Institutional Committee accorded ethical approval (TDCEC/30/2019). The registration of the trial was done in Clinical Trial Registry–India (CTRI/2021/08/015285.) The research was performed in line with the 1975 Declaration of Helsinki. The research was carried out between March 2020 and February 2022. Each patient signed a consent form outlining the nature, duration, and surgical procedure. The trial was conducted following the Consolidated Standards of Reporting Trials (CONSORT) checklist and flow diagram (Flowchart 1).

Flowchart 1: Consolidated Standards of Reporting Trials (CONSORT) flowchart

Inclusion Criteria

  • Systemically healthy subjects.

  • Patients maintaining proper oral hygiene status.

  • Patients with stage III grade B periodontitis requiring flap surgery that had at least two infrabony defects, one on each side of the same arch, having a probing pocket depth (PPD) of at least 5 mm and interproximal attachment loss >1 mm, after phase one therapy.

  • Subjects who gave consent.

Exclusion Criteria

  • Subjects who underwent periodontal surgery in the previous 6 months at the same location.

  • Pregnant females and lactating mothers.

  • Subjects consuming tobacco.

  • Patients with higher staging and grading of periodontitis.

  • Any drugs proven to have an impact on periodontal treatment results.

  • Allergy to bisphosphonates or MF or a history of systemic usage of either.

Clinical Parameters

  • Plaque index (PI)16

  • Gingival index (GI)17

  • PPD

Relative attachment level (RAL)18: Calculated from the lower border of the stent to the base of the pocket.

Radiographic Parameters

  • Defect depth reduction (DDR): Distance from a fixed point of reference (the cut end of the metal wire incorporated into the stent) to the deepest point of the bone defect.

  • Height of alveolar bone: Measured from reference point to alveolar bone crest.

For radiographic evaluation, intraoral periapical (IOPA) radiographs (Figs 1 and 2) were taken with the help of a stent in place using a position-indicating device (PID) and employing the paralleling angle technique. A 1 mm X-ray grid was used in the IOPA X-ray film.19 A divider and a scale were used to determine the distance. Despite the fact that all radiographs were taken with a PID and a parallel approach, each one was adjusted for elongation and shortening of each stainless-steel ball before being compared to the prior value. This was performed to remove the magnification error.

Figs 1A and B: (A) Preoperative X-ray at baseline; (B) 6 months postoperative X-ray

Figs 2A and B: (A) Preoperative X-ray at baseline; (B) 6 months postoperative X-ray

The following formulas20 were used:

Gel Preparation

Alendronate (ALN) gel and MF gel formulation8,21—1% ALN gel and 1% MF gel were formulated in the Biotechnology Laboratory of a reputed institution in Navi Mumbai. For 15 mL gel preparation, 1% ALN (0.15 gm) and 1% MF (0.15 gm) were accurately weighed by using Contech precision weighing balance and were further added with Sisco Research Laboratories (SLR) Pvt. Ltd grade 2% gellan gum (0.3 gm) and 20% gelatin (3 gm). Additionally, preservatives such as 0.18% methylparaben (0.027 gm) and 0.02% propylparaben (0.003 gm) were accurately weighed and mixed with both the above powders. For MF preparation, in addition to the above constituents, 20% mannitol (3 gm) and 0.5% sodium citrate (0.075 gm) were added. The constituents were gently mixed using a magnetic stirrer after the addition of 15 mL of distilled water. Further, the ALN gel and MF gel were autoclaved individually at 121°C at 15 lbs and aliquoted in the sterile centrifuge tube (Tarson make). These tubes were stored at 4°C till further use.

Presurgical Procedure

All patients received scaling and root planning (SRP) at baseline (phase I therapy). Reevaluation of the patients was done 4 weeks after phase I therapy. After this, the patients fulfilling the inclusion criteria were included in the study. An independent examiner who was blinded assigned the participants to two groups, who communicated with the surgeon prior to the procedure.

  • Group I—13 sites where intrabony defect + 1% ALN gel.

  • Group II—13 sites where intrabony defect + 1% MF gel.

Surgical Procedure

Clinical parameters were recorded at baseline. A skilled periodontist performed the surgery. All surgeries utilized the identical periodontal probe (UNC-15)ø. A preprocedural rinse with 0.2% chlorhexidine (CHX) was performed. Extraoral antisepsis was performed using povidone-iodine. Local anesthesia (2% lignocaine with 1:80000 adrenaline) was injected, and a mucoperiosteal flap was raised, exposing 1–2 mm of healthy bone by giving a crevicular incision with the help of a number 15 surgical blade. Gracey’s curettes# were used for the debridement of the defects. Ultrasonic scalers** and curettes were used to perform SRP. Presuturing was performed for both groups. The defects in group I were subsequently treated with 1% ALN, whereas group II was treated with 1% MF gel. 4-0 braided silk suture was used for suturing the flaps, and a periodontal dressing§§ was placed over the site.

During the early phases of healing, mechanical disturbance of the surgical areas was avoided. Therefore, patients were instructed to abstain from teeth brushing in the surgically treated regions for 1 week, and 0.2% CHX mouthwash was advised for a period of 2-week surgery.22 1 week after surgery, the periodontal pack and sutures were removed.23 The surgical procedure in group I and group II has been demonstrated in Figures 3 and 4, respectively.

Figs 3A to I: (A) 1% alendronate gel; (B) Preoperative pocket depth and RAL with an acrylic stent at baseline; (C) Sulcular incision; (D) Postdebridement exposing the defect site; (E) Placement of 1% alendronate in intrabony defects; (F) Suturing; (G) Periodontal dressing placed over the surgical site; (H) PPD and RAL after 3 months; (I) PPD and RAL after 6 months

Figs 4A to I: 1% metformin gel; (B) Preoperative pocket depth and RAL with an acrylic stent at baseline; (C) Sulcular incision; (D) Postdebridement exposing the defect site; (E) Placement of 1% metformin gel in intrabony defects; (F) Suturing; (G) Periodontal dressing placed over the surgical site; (H) PPD and RAL after 3 months; (I) Probing pocket depth and RAL after 6 months

Follow-up Period and Outcome Analysis

Evaluation of clinical parameters was done at baseline, 3 months, and 6 months, and radiological parameters at baseline and 6 months. The data on clinical and radiographic measures was compiled and analyzed using Statistical Package for the Social Sciences (SPSS) software version 16.0‖‖‖. One-way analysis of variance with post hoc Bonferroni Test was used for comparison within the group, and comparison among the groups was performed using a paired t-test. p ≤ 0.05 was fixed as the level of significance.

RESULTS

All of the 13 patients successfully completed the trial. Uneventful healing was seen in all subjects. There were no allergic responses reported by the subjects. No loss of follow-up was reported. Demographic data of the participants is provided in Table 1.

Table 1: Demographic data
Characteristics Participants
n 13
Mean age 44.5
Minimum age 34
Maximum age 55
Male frequency (%) 6 (46.1%)

n, total number of participants

Clinical parameters like PI, GI, PPD, and RAL were assessed at baseline (4 weeks after phase I therapy), 3, and 6 months after flap surgery.

In group I, the mean PPD at baseline was 6.92 ± 0.95 mm. It reduced to 4.62 ± 0.77 at 3 months and 2.92 ± 0.49 at 6 months. This reduction in PPD was statistically significant from baseline to all recall intervals (p = 0.000, p ≤ 0.005).

In group II, the mean PPD at baseline was 6.77 ± 0.83 mm. It reduced to 4.77 ± 0.83 at 3 months and 3.08 ± 0.64 at 6 months. The reduction in PPD was statistically significant from baseline to all recall intervals (p = 0.000, p ≤ 0.005)

No difference in clinical or radiographic variables among the two groups was seen that was statistically significant at baseline (Table 2).

Table 2: Baseline values (p-value of <0.05)
Parameters Group I Group II p-value
PI 0.65 ± 0.08 0.65 ± 0.08 0.876
GI 0.62 ± 0.11 0.62 ± 0.11 0.231
PPD 6.92 ± 0.95 6.77 ± 0.83 0.811
RAL 8.77 ± 1.24 8.23 ± 1.09 0.981
DD 11.08 ± 2.70 8.23 ± 1.09 0.778
ABH 9.73 9.28 0.445

ABH, alveolar bone height; DD, defect depth; GI, gingival index; PI, plaque index; PPD, probing pocket depth (mm); RAL, relative attachment level (mm)

A decrease in the PI, GI, and PPD and gain in RAL was noticed at 6 months in both groups (Fig. 5). However, no statistically significant difference was seen in the alveolar bone height from baseline to 6 months in both groups (Table 3).

Fig. 5: PI and GI at different intervals

Table 3: Comparison of PPD, RAL, DD, and ABH between the study groups at various intervals
Parameter n Mean SD t p
PPD
Baseline
Group I 13 6.92 0.95
Group II 13 6.77 0.83
3 Months
Group I 13 4.62 0.77 17.321 <0.0001
Group II 13 4.77 0.83 17.664 <0.0001
6 months
Group I 13 2.92 0.49 17.664 <0.0001
Group II 13 3.08 0.64 21.117 <0.0001
RAL
Baseline
Group I 13 8.77 1.24
Group II 13 8.23 1.09
3 Months
Group I 13 6.92 0.76 8.314 <0.0001
Group II 13 6.54 0.78 7.138 <0.0001
6 months
Group I 13 5.62 0.96 11.520 <0.0001
Group II 13 5.31 0.85 8.875 <0.0001
DD
Baseline
Group I 13 11.08 2.70
Group II 13 8.23 1.09
6 months
Group I 13 9.95 2.68 6.017 <0.0001
Group II 13 5.31 0.85 8.875 <0.0001
ABH
Baseline
Group I 13 9.73 2.28
Group II 13 9.28 2.29
6 months
Group I 13 9.80 2.40 −0.363 0.723
Group II 13 9.20 2.25 0.437 0.670

ABH, alveolar bone height; DD, defect depth; GI, gingival index; n, total number of participants; PI, plaque index; PPD, probing pocket depth (mm); RAL, relative attachment level (mm); SD, standard deviation; t, t-test; p < 0.05, statistically significant; p > 0.05, statistically significant

The intergroup comparison did not show any statistically significant results. However, a higher reduction was observed in PD, defect depth, and a greater gain in RAL and height of alveolar bone in group I in comparison with group II (Table 4).

Table 4: Reduction and percentage change in PPD, DD, gain, and percentage change in RAL and ABH at 3 and 6 months (p-value of <0.05)
Period PPD (mm) RAL (mm) DD (mm) ABH (mm)
Group I Group II p-value Group I Group II p-value Group I Group II p-value Group I Group II p-value
3 months 2.31 2 0.127 1.85 1.69 0.897
33.38% 29.76% 20.44% 20%
6 months 2 3.69 0.289 3.15 2.92 0.857 1.13 2.92 0.077 −0.08 0.08 0.776
57.55% 54.62% 35.65% 34.88% 10.50% 6.14% 0.72% 0.27%

CBH, crestal bone height; DD, defect depth; PPD, probing pocket depth (mm); RAL, relative attachment level (mm); p-value <0.05, statistically significant

Thus, according to the results of our study, both 1% MF and ALN resulted in a significant decrease in PPD and gain in clinical attachment level (CAL) at all recall intervals. No statistically significant difference was seen in the alveolar bone height from baseline to 6 months in both groups. However, no statistical difference was seen between the two groups for all clinical parameters. We did not find any difference in patient compatibility, as there were no adverse reactions in any subject.

DISCUSSION

Periodontal flap surgery combined with bone grafts, growth and differentiation factors, guided tissue regeneration, and root surface demineralization is a typical technique for treating infrabony deformities.15

Access therapy provides a limited potential toward achieving regeneration of periodontal structures. Therefore, employing biological mediators to achieve regeneration is in great demand. Therefore, the present research was conducted to analyze and compare the regenerative ability of two biomaterials, that is, 1% ALN gel and 1% MF gel, in infrabony defects.

Critical probing depth was evaluated by Heitz-Mayfield and Lang,24 and they found that pockets deeper than 5.4 mm depth demonstrated a greater increase of CAL after periodontal surgery. Thus, teeth with PPD ≥5 mm after phase I therapy were chosen for our study.

The split-mouth study design was chosen in this study as it allows the assessment of similar host responses in two different treatment measures while minimizing bias caused by individual differences in healing patterns. It also reduces variances due to systemic and environmental factors.

Metformin (MF) has lately been demonstrated to have bone regeneration capacity; hence, it was employed in our research. It is extensively used in the treatment of type 2 diabetes.25 MF activates osteoprotegerin and inhibits receptor-activated nuclear κ ligand activity in osteoblasts, thereby upregulating osteoblast differentiation and resulting in bone formation in periodontitis.26

Kurian et al.27 compared the efficacy of aloe vera gel and 1% MF in the management of intrabony defects and demonstrated that 1% MF gel achieved comparatively better results than aloe vera gel. Akram et al.28 reported that the use of locally injected MF as an adjuvant to SRP in the treatment of periodontal defects appeared to be successful for gain in bone defect fill and CAL and reduction in PPD. This was in accordance with our study.

Alendronate (ALN) causes upregulation of messenger ribonucleic acid expression during osteogenic differentiation. It enhances osteoblast differentiation and mesenchymal stem cell proliferation.29 Dutra et al.13 examined the efficiency of topical administration of 1% ALN gel in periodontal intrabony defects and reported that ALN gel produced greater reductions in PPD, gain in CAL, and beneficial effects on bone healing in comparison with placebo gel. In our research, we found similar outcomes. Sharma et al.12 studied the role of locally injected 1% ALN gel in chronic periodontitis and observed that it improved the clinical parameters in contrast to the placebo group.

Chen et al.30 determined the potential benefits of ALN in addition to SRP in periodontal therapy in his meta-analysis. The mean gains of locally administered ALN were a 38.25% increase in defect fill, a 2.29 mm reduction in PPD, and a 1.92 mm gain in CAL. Furthermore, ALN administered systemically with SRP caused a reduction in PPD by 0.36 mm and a 0.369 mm increase in CAL.

Certain limitations were noticed in the study: the sample size was limited to 26 periodontal infrabony defects, and a blinding procedure was not undertaken; therefore, the possibility of operator bias, short follow-up period, and the possibility of human error existed in the study as digital X-ray procedure and digital readings were not used. The outcomes of this research indicate that further extensive research is needed to demonstrate the ability of 1% ALN gel and 1% MF gel in patients with infrabony defects.

CONCLUSION

Both 1% ALN and 1% MF have been shown to regenerate periodontal structures and, hence, can be used in the treatment of periodontitis owing to their antiresorptive and bone-stimulating ability. However, when compared, there was no significant difference in the reduction of PPD, reduction in DD, and gain in RAL. There were no adverse reactions in any of our subjects. Hence, within the limitation of our study, it can be concluded that there is no difference in the efficacy of 1% ALN and 1% MF in the treatment of infrabony defects in chronic periodontitis patients. However, further studies with a larger sample size need to be conducted to justify our claims.

ENDNOTES

Ø, Hu-Friedy, Chicago, Illinois, United States of America

#, Gracey, Hu-Friedy, Chicago, Illinois, United States of America

**, EMS V-Dent, Shantou, Guangdong, China

§§, Coe-Pak, GC America Inc., Chicago, Illinois, United States of America

‖‖‖, Statistical Package for the Social Sciences (SPSS) version 16.0; SPSS, Chicago, United States of America

REFERENCES

1. Nazir MA. Prevalence of periodontal disease, its association with systemic diseases and prevention. Int J Health Sci (Qassim) 2017;11(2):72–80. PMID: 28539867.

2. Fenesy KE. Periodontal disease: an overview for physicians. Mt Sinai J Med 1998;65(5-6):362–369. PMID: 9844364.

3. Glossary of Periodontal terms. 4th edition. American Academy of Periodontology; 2001.

4. Meyer JR. The regenerative potential of the periodontal ligament. J Prosthet Dent 1986;55(2):260–265. DOI: 10.1016/0022-3913(86)90357-4

5. Sander L, Karring T. Healing of periodontal lesions in monkeys following the guided tissue regeneration procedure. A histological study. J Clin Periodontol 1995;22(4):332–337. DOI: 10.1111/j.1600-051x.1995.tb00156.x

6. Ivanovic A, Nikou G, Miron RJ, et al. Which biomaterials may promote periodontal regeneration in intrabony periodontal defects? A systematic review of preclinical studies. Quintessence Int 2014;45(5):385–395. DOI: 10.3290/j.qi.a31538

7. Rasmusson L, Abtahi J. Bisphosphonate associated osteonecrosis of the jaw: an update on pathophysiology, risk factors, and treatment. Int J Dent 2014;2014:471035. DOI: 10.1155/2014/471035

8. Reddy GT, Kumar TM, Veena Formulation and evaluation of alendronate sodium gel for the treatment of bone resorptive lesions in periodontitis. Drug Deliv 2005;12(4):217–222. DOI: 10.1080/10717540590952663

9. Lin JH, Duggan DE, Chen IW, et al. Physiological disposition of alendronate, a potent anti-osteolytic bisphosphonate, in laboratory animals. Drug Metab Dispos 1991;19(5):926–932. PMID: 1686238.

10. Jernberg GR, Jernberg Gary R, assignee. Delivery of agents and method for regeneration of periodontal tissues. United States patent US 6,123,957. 2000.

11. Sharma A, Raman A, Pradeep AR. Role of 1% alendronate gel as adjunct to mechanical therapy in the treatment of chronic periodontitis among smokers. J Appl Oral Sci 2017;25(3):243–249. DOI: 10.1590/1678-7757-2016-0201

12. Sharma A, Pradeep AR. Clinical efficacy of 1% alendronate gel in adjunct to mechanotherapy in the treatment of aggressive periodontitis: a randomized controlled clinical trial. J Periodontol 2012;83(1):19–26. DOI: 10.1902/jop.2011.110206

13. Carvalho Dutra B, Oliveira AMSD, Oliveira PAD, et al. Effects of topical application of 1% sodium alendronate gel in the surgical treatment of periodontal intrabony defects: a 6-month randomized controlled clinical trial. J Periodontol 2019;90(10):1079–1087. DOI: 10.1002/JPER.19-0160

14. Pradeep AR, Rao NS, Naik SB, et al. Efficacy of varying concentrations of subgingivally delivered metformin in the treatment of chronic periodontitis: a randomized controlled clinical trial. J Periodontol 2013;84(2):212–220. DOI: 10.1902/jop.2012.120025

15. Sculean A, Nikolidakis D, Nikou G, et al. Biomaterials for promoting periodontal regeneration in human intrabony defects: a systematic review. Periodontol 2000 2015;68(1):182–216. DOI: 10.1111/prd.12086

16. Silness J, Loe H. Periodontal disease in pregnancy. II. Correlation between oral hygiene and periodontal condition. Acta Odontol Scand 1964;22:121–135. DOI: 10.3109/00016356408993968

17. Löe H. The gingival index, the plaque index and the retention index systems. J Periodontol 1967;38(6):610–616. DOI: 10.1902/jop.1967.38.6.610

18. Pihlstrom BL. Measurement of attachment level in clinical trials: probing methods. J Periodontol 1992;63(12 Suppl):1072–1077. DOI: 10.1902/jop.1992.63.12s.1072

19. Kiliç AR, Efeoglu E, Yilmaz S. A new method for standardization of intraoral radiographs. Periodontal Clin Investig 1996;18(2):20–26. PMID: 9116467.

20. Li G, Engström PE, Nasstrom K, et al. Marginal bone levels measured in film and digital radiographs corrected for attenuation and visual response: an in vivo study. Dentomaxillofac Radiol 2007;36(1):7–11. DOI: 10.1259/dmfr/28315324

21. Mohapatra M, Parikh RK, Gohel MC. Formulation, development and evaluation of patient friendly dosage forms of metformin, part-II: oral soft gel. Asian J Pharm 2014;2(3):172–176. DOI: 10.22377/ajp.v2i3.207

22. Westfelt E, Nyman S, Lindhe J, et al. Use of chlorhexidine as a plaque control measure following surgical treatment of periodontal disease. J Clin Periodontol 1983;10(1):22–36. DOI: 10.1111/j.1600-051x.1983.tb01264.x

23. Sachs HA, Farnoush A, Checchi L, et al. Current status of periodontal dressings. J Periodontol 1984;55(12):689–696. DOI: 10.1902/jop.1984.55.12.689

24. Heitz-Mayfield LJ, Lang NP. Surgical and nonsurgical periodontal therapy. Learned and unlearned concepts. Periodontol 2000 2013;62(1):218–231. DOI: 10.1111/prd.12008

25. Bailey CJ. Metformin: historical overview. Diabetologia 2017;60(9):1566–1576. DOI: 10.1007/s00125-017-4318-z

26. Bak EJ, Park HG, Kim M, et al. The effect of metformin on alveolar bone in ligature-induced periodontitis in rats: a pilot study. J Periodontol 2010;81(3):412–419. DOI: 10.1902/jop.2009.090414

27. Kurian IG, Dileep P, Ipshita S, et al. Comparative evaluation of subgingivally-delivered 1% metformin and aloe vera gel in the treatment of intrabony defects in chronic periodontitis patients: a randomized, controlled clinical trial. J Investig Clin Dent 2018;9(3):e12324. DOI: 10.1111/jicd.12324

28. Akram Z, Vohra F, Javed F. Locally delivered metformin as adjunct to scaling and root planing in the treatment of periodontal defects: A systematic review and meta-analysis. J Periodontal Res 2018;53(6):941–949. DOI: 10.1111/jre.12573

29. Im GI, Qureshi SA, Kenney J, et al. Osteoblast proliferation and maturation by bisphosphonates. Biomaterials 2004;25(18):4105–4115. DOI: 10.1016/j.biomaterials.2003.11.024

30. Chen J, Chen Q, Hu B, et al. Effectiveness of alendronate as an adjunct to scaling and root planing in the treatment of periodontitis: a meta-analysis of randomized controlled clinical trials. J Periodontal Implant Sci 2016;46(6):382–395. DOI: 10.5051/jpis.2016.46.6.382

________________________
© The Author(s). 2023 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (https://creativecommons.org/licenses/by-nc/4.0/), which permits unrestricted use, distribution, and non-commercial reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.