Evaluation of Clinical Efficacy of Locally Delivered Vitamin D3 Gel as an Adjunct to Nonsurgical Periodontal Therapy in the Treatment of Periodontitis

INTRODUCTION

Periodontal disease [PD] is an immuno-inflammatory destructive disease of periodontal tissues characterized by the loss of soft tissue attachment and alveolar bone loss caused by pathogenic microorganisms resulting in pocket formation and/or gingival recession [1]. Periodontal disease is one of the most common chronic infectious diseases among adults and is caused by the accumulation of bacterial biofilm. [1,2]

The periodontal pocket is a pathologically deepened gingival sulcus caused by the apical migration of junctional epithelium. The coronal movement of the gingival margin without the destruction of underlying periodontal tissues creates a pseudo pocket or gingival pocket, whereas the apical migration of the junctional epithelium with the destruction of supporting periodontal tissues is responsible for developing a true pocket or periodontal pocket. [3]

Non-surgical periodontal therapy (NSPT) is considered as a “golden standard” treatment protocol for periodontal pockets because it involves scaling and root planing (SRP) to remove supra and subgingival biofilm, plaque and calculus from diseased root surfaces. [4,5] It is proven that the non-surgical approach is an effective treatment strategy with periodontal pockets measuring less than the critical probing depth of 4.2 mm. However, in cases of deep periodontal pockets, surgical periodontal therapy along with periodontal regeneration stands to be a viable option, as complete debridement of biofilm and local deposits remains crucial due to the presence of extensive periodontal tissue destruction.

Periodontal pockets present an ideal site for treatment using localized drug delivery systems. Within the field of periodontics, there are established approaches for delivering drugs directly in to subgingival sites or periodontal pockets. These systems release antimicrobial agents either instantly or in a controlled and sustained manner, effectively countering microbial threats while minimizing potential adverse effects on non-oral parts of the body. Currently, a range of local drug delivery systems are available, including fibers, gels, strips, films, irrigating systems, and microparticles. [6,7,8]

Vitamin D is best known as a principal factor that maintains calcium homeostasis and is required for bone development and maintenance. However, it is becoming clear that vitamin D has profound

effects on immunity and inflammation as well. The active form of vitamin D, 1,25(OH)2D3, can induce the expression of antimicrobial peptides and other innate immune mediators in a variety of cell types. Furthermore, 1,25(OH)2D3 exhibits anti-inflammatory activity through the inhibition of pro-inflammatory cytokine gene expression. [9] In a previous study [10] a greater reduction of PPD was observed after six weeks after oral supplementation of Vitamin D3 as compared to SRP alone in patients with periodontitis leading to periodontal pocket shrinkage and decrease in pocket depth.

In rural/remote areas where there are lack of resources and in medically compromised individuals or physically or mentally challenged children where periodontal surgical therapy is perplexing to be performed, there is a need for simultaneous hard and soft tissue regeneration at the very first visit/ appointment of the patient undergoing SRP. There is a need to introduce a novel prodigious material that would not only help in the soft and hard tissue regeneration of the periodontal tissues but also serve to reduce the inflammatory load at the infected site selectively.  Nevertheless, no literature till date is available evaluating the effect of local delivery of Vitamin D3 as an adjunct to SRP in patients with periodontitis. So, this study was planned to evaluate clinical efficacy of locally delivered vitamin D3 gel as an adjunct to nonsurgical periodontal therapy in the treatment of periodontitis.

Aims and Objectives

1.     Evaluation of the clinical efficacy of locally delivered vitamin D3 gel as an adjunct to nonsurgical periodontal therapy in the treatment of periodontitis.

2.     To determine the effect of local delivery of Vitamin D3 gel on reduction in gingival inflammation.

3.     To determine the effect of local delivery of Vitamin D3 gel on reduction in pocket depth and gain in clinical attachment level.

Review of literature

1. Satue et al. [11] in an experimental study, evaluated the biological effect of titanium implants coated with UV-activated 7-dehydrocholesterol (7-DHC), the precursor of vitamin D3, on cytotoxicity and osteoblast differentiation. According to these results, 7-DHC coated titanium implants had positive effects on osteoblast proliferation and differentiation compared to control implants (implants without 7-DHC coating).
2. Sahu et al.  2023 [12] evaluated the efficacy of sub-gingivally delivered propolis nanoparticles in the non-surgical management of periodontal pockets in 40 periodontitis patients. The results indicated that there was a significant improvement in BOP, PPD, RAL in the test sites compared with the control sites at the end of the study. The gingival index at one month and three months was found to be significantly better in the SRP with propolis group than the SRP with saline group.
3. Menzel et al. [13] in 2019 examined the novel local mechanism of vitamin D activation in Gingival epithelial cells on a mouse model of periodontal disease due to vitamin D insufficiency. They also studied the feasibility of delivering inactive vitamin D to the oral cavity to regulate innate immune gene expression to maintain periodontal health. Effect of vitamin D on basal IL-1α expression in mice was determined by topical administration to the gingiva of wild-type mice, followed by qRT-PCR. Topical application of both vitamin D3 and 1,25(OH)2D3 to the gingiva of mice led to rapid inhibition of IL-1α expression, a prominent pro-inflammatory cytokine associated with inflammation. They concluded that vitamin D can be applied directly to the gingiva to prevent or treat periodontal disease.
4. Lie et al.[14] created a polylactic acid microsphere loaded with 25-hydroxyvitamin D3 (25OHD). 40 rats were enrolled that were divided into four groups based on the type of treatment received: a control group (healthy), an untreated group, the group treated with drug-free microspheres (DPF) and a group treated with 25OHD-loaded microspheres. Diabetes and periodontitis were inducted in rats; in particular periodontitis was prompted in the second maxillary molars. From the histologic analyses emerged that in the group treated with DPV, there was an important bone formation (p < 0.05) in the inter-proximal area between the first and second molar.
5. A study by Peric et al [15] 2020 assessed the effects of weekly vitamin D (VD) supplementation on clinical and biological parameters after scaling and root planning (SRP) in the treatment of periodontitis and served to validate the VD dosage regimen. Patients were allocated to test group (SRP + VD 25,000 international units (IU)/week) or the control group (SRP + placebo). The reduction in PPD was found to be greater in the test group.

Primary Research Question: Is there any additional beneficial effect of locally delivered Vitamin D3 gel along with SRP in the treatment of periodontitis?

Null Hypothesis: There is no additional beneficial effect of locally delivered Vitamin D3 gel along with SRP in the treatment of periodontitis.

Alternative Hypothesis: There is considerable beneficial effect of locally delivered Vitamin D3 gel along with SRP in the treatment of periodontitis.

Materials and Methods

The present study is a prospective, double-blind, split mouth, randomized clinical trial.

Study Area: The study will be conducted among patients visiting the outpatient Department of Periodontics and Implant Dentistry, Ranjeet Deshmukh Dental College and Research Centre, Nagpur.

Sample size:

The sample size was determined based on the results of a study by Pandya et al. [16] 2021. A power analysis was established by G*Power version 3.1.9 (Franz Faul universitat, Kiel, Germany). Total minimum calculated sample size of 26 (13 for each group) would yield 95% power to detect significant differences and significance level at 0.05.

Inclusion criteria

1. Systemically healthy patients within the age group of 18–65 years.

2. Patients should have at least 14 natural teeth in the oral cavity.

3. Patients with no history of allergies.

4. Patients who are diagnosed with generalized periodontitis of stages II and III (According to World Workshop of Periodontology, 2017 with bilateral periodontal pockets with probing pocket depth of between 4 and 6 mm.

Exclusion Criteria

1. Smokers.

2. Pregnant and lactating mothers.

3. Patients who received radiotherapy, chemotherapy or immunosuppressive treatment, systemic corticosteroids, and/or anticoagulants 30 days prior to intervention.

4. Patients with any systemic disease.

5. Patients under the influence of non-steroidal anti-inflammatory drugs (NSAIDS) or any other anti-inflammatory medications, antibiotics, steroids that can alter the course of periodontitis progression and treatment.

The selected patients will be taken for SRP procedure. The bilateral pockets will be randomly divided into the following treatment groups.

Group 1: Sites treated with SRP followed by local delivery of placebo gel

Group 2: Sites treated with SRP followed by local delivery of Vitamin D3 Gel.

On their first visit, all patients will be clinically examined and the following indices will be recorded using UNC 15 Periodontal Probe-Plaque index (PI) (site specific Plaque index by Löe and Silness in 1967), Gingival index (GI) (Löe and Silness, 1963), Sulcus bleeding index (SBI) (Muhlemann and Son, 1971), Probing pocket depth (PPD), and Clinical attachment level (CAL).

These indices or outcomes will be measured at all six surfaces of the selected tooth (mesio-buccal,

mid-buccal, disto-buccal, mesio-lingual, mid-lingual, and disto-lingual). The gingival parameters including the colour, contour, consistency, surface texture, position and width of keratinized tissue will also be recorded. These parameters will be recorded at baseline and 3 and 6 months after the therapy.

Randomization and Blinding

The randomization will be carried out using computer generated table of random numbers. The allocated groups will be concealed using opaque sealed envelopes, which will be opened prior to the sub-gingival delivery of LDD Vitamin D3. The study will be double-blind, where both the participants and investigator will be unaware of the substance to be delivered.

Technique for Local Delivery of Vitamin D3 gel

After baseline examination the test sites will be treated with SRP followed by subgingival administration of Vitamin D3 gel through blunt cannula, and control sites will be treated with SRP followed by subgingival administration of saline as a placebo through a blunt cannula.

Method of data analysisStatistical analysis will be performed using Statistical Package for Social science (SPSS) version 20 for Windows. Descriptive quantitative data will be expressed in mean and standard deviation respectively. Data normality will be checked by using Shapiro – Wilk test. Comparison between two groups will be done using parametric t test and comparison between more than two groups will be done using ANOVA test (if the data follows normality conditions) or non-parametric Mann Whitney U test (if data does not follow normality conditions).  Association between categorical variables will be checked using chi square test (non-parametric test).

Reference

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2.     Richards, D. Review Finds That Severe Periodontitis Affects 11% of the World Population. Evid. Based Dent. 2014; 15, 70–71.

3.     Bosshardt DD. The periodontal pocket: pathogenesis, histopathology and consequences. Periodontol 2000. 2018;76(1):43-50.

4.     Cobb, C.M. Non-Surgical Pocket Therapy: Mechanical. Ann. Periodontol. 1996, 1, 443–490.

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6.     Goodson J.M, Haffajee A, Socransky S.S. Periodontal Therapy by Local Delivery of Tetracycline. J. Clin. Periodontol. 1979;6,83–92.

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8.     Addy M, Martin, M. Systemic Antimicrobials in the Treatment of Chronic Periodontal Diseases: A Dilemma. Oral Dis. 2003; 9, 38–44.

9.     Jeffery LE, Burke F, Mura M, et al. 1,25-Dihydroxyvitamin D3 and IL-2 combine to inhibit T cell production of inflammatory cytokines and promote development of regulatory T cells expressing CTLA-4 and FoxP3. J Immunol. 2009;183(9):5458‐5467.

10.  Mishra SM, Ravishankar PL, Pramod V, et al. Effect of Supplementation of Vitamin D in Patients with Periodontitis Evaluated before and after Nonsurgical Therapy [retracted in: Biomed Res Int. 2023 Sep 27;2023:9850874]. Biomed Res Int. 2022;2022:5869676.

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12.  Sahu S.A, Panda S, Das AC, Mishra L, Rath S, Sokolowski K, et al. Efficacy of Sub-Gingivally Delivered Propolis Nanoparticle in Non-Surgical Management of Periodontal Pocket: A Randomized Clinical Trial. Biomolecules 2023; 13, 1576.

13.  Menzel LP, Ruddick W, Chowdhury MH, et al. Activation of vitamin D in the gingival Epithelium and its role in gingival inflammation and alveolar bone loss. J Periodont Res. 2019;00:1–9.

14.  Li H, Wang Q, Xiao Y, et al. 25-Hydroxyvitamin D3-loaded PLA microspheres: in vitro characterization and application in diabetic periodontitis models. AAPS Pharm Sci Tech 2013; 14: 880–889.

15.  Perić M, Maiter D, Cavalier E, Lasserre JF, Toma S. The Effects of 6-Month Vitamin D Supplementation during the Non-Surgical Treatment of Periodontitis in Vitamin-D-Deficient Patients: A Randomized Double-Blind Placebo-Controlled Study. Nutrients. 2020; 12(10):2940.

16.  Pandya S, Kulloli A, Shetty S, Martande S et al. Evaluation of Efficacy of Locally Delivered 10% Azadirachta indica (Neem) Gel as an Adjunct to Scaling and Root Planing in the Treatment of Chronic Periodontitis Patients with Type II Diabetes Mellitus: Clinico-Microbiological StudyInt J Med Res Health Sci 2021; 10(5): 139-152.