A Prospective, Blinded Randomized, Active-controlled Clinical Trial to Evaluate the Success of Double Antibiotic Paste in Pulpally Infected Primary Molars

ABSTRACT

Background

An irreversibly infected carious primary tooth is often treated by pulpectomy or lesion sterilization and tissue repair (LSTR), with the latter employing a triple mix of antibiotics (metronidazole, ciprofloxacin, and minocycline). Recently, double antibiotic paste (DAP—metronidazole and ciprofloxacin) has been shown to be safer with good antimicrobial efficacy and better biocompatibility with stem cells at concentrations of 1 mg/mL drug mix.

Aim

To assess the clinical and radiographic success of 1 mg/mL DAP and compare it with calcium hydroxide−iodoform pulpectomy in carious infected primary molars.

Methods

Thirty-three infected primary teeth in 7–10-year-old children were randomly selected and divided into two groups—DAP and pulpectomy. After treatment, teeth were restored with stainless steel crowns. The clinical and radiographic success were evaluated every 3 and 6 months respectively, till 1 year.

Results

The clinical success was 67% (10/15) in the DAP group and 83% (15/18) in the pulpectomy group at 12 months and was statistically nonsignificant (p-value 0.4184). One case each in both groups could not be assessed radiographically because of clinical failure at 3 months. The radiographic success was 36% (5/14) in the DAP group and 53% (9/17) in the pulpectomy group at 12 months and was statistically nonsignificant (p-value 0.3374).

Conclusion

The study showed a favorable clinical outcome but a low radiographic success of 1 mg/mL DAP in pulpally infected carious primary molars.

Clinical significance

In poor prognostic teeth, DAP may be considered a clinically viable option over the conventionally used high-concentration antibiotic pastes for up to 1 year.

How to cite this article

Sharma U, Gill NC, Passi S, et al. A Prospective, Blinded Randomized, Active-controlled Clinical Trial to Evaluate the Success of Double Antibiotic Paste in Pulpally Infected Primary Molars. Int J Clin Pediatr Dent 2025;18(6):653–659.

INTRODUCTION

Irreversible pulpitis, pulp necrosis, and dental abscess are sequelae of untreated dental caries, and pulpectomy is often the treatment of choice in a restorable tooth. The concept of noninstrumentation endodontic therapy (NIET) was introduced by the Cariology Research Unit, Niigata University, Japan, through lesion sterilization and tissue repair (LSTR).¹ The procedure uses triple antibiotic paste (TAP—metronidazole, ciprofloxacin, and minocycline), known to sterilize dentin, pulp, and periradicular tissues and initiate tissue repair.² It requires less chairside time, fewer patient visits, preserves root dentin thickness, and is inexpensive. TAP has been used successfully in permanent teeth in regenerative endodontics^3,4 and in pulpally infected primary teeth.^5,6 However, minocycline may get incorporated into dentinal tissues and stain the tooth.^7,8 An exclusion of minocycline led to the introduction of double antibiotic paste (DAP) having a comparable efficacy with TAP and greater efficacy than calcium hydroxide in significantly reducing biofilm formation by Enterococcus faecalis and Porphyromonas gingivalis.⁹ A comparable antibacterial efficacy and antibiofilm effect of 2-Mix (ciprofloxacin and metronidazole) over 3-Mix (ciprofloxacin, metronidazole, and clindamycin) pertaining to these bacteria has also been reported by A Algarni et al.,¹⁰ with a still stronger effect of DAP at extended dilutions.

However, the paste formulation of drugs used in clinical settings is a concentrated drug mix (1000 mg/mL), lethal to stem cells of apical papilla (SCAP) cells.^11,12 Studies have shown that diluted concentrations of TAP or DAP (≤1 mg/mL) avoid the cytotoxic effects on dental stem cells while being effective antibacterial agents.^10,11 Sabrah et al. (2015)¹³ also confirmed that concentrations of 0.5–1 mg/mL DAP were nontoxic to fibroblasts in the dental pulp and that 1 mg/mL TAP/DAP caused a near-complete elimination (>99.9999%) of the established E. faecalis biofilm. It was further observed that a concentration of ≤1 mg/mL had no adverse effect on SCAP cell viability,¹¹ had significant antibacterial effects,¹³ and did not negatively affect dental pulp stem cells (DPSC) proliferation on radicular dentin.¹⁴

However, the liquid form of 1 mg/mL necessitates the use of a vehicle for clinical applications.¹⁴ One such vehicle is methylcellulose, often used as a culture medium for stem cells and is noncytotoxic. A Algarni et al.¹⁰ observed that methylcellulose-based antibiotic gels with concentrations of 1 mg/mL of modified triple antibiotic paste (MTAP) and DAP exert a significant antibiofilm effect against E. faecalis and P. gingivalis.

The aim of the study was thus to compare the clinical and radiographic success of LSTR using 1 mg/mL DAP in a methylcellulose-based gel and compare it with pulpectomy using calcium hydroxide−iodoform in pulpally infected carious primary mandibular molars. The clinical and radiographic success was evaluated every 3 and 6 months respectively, and the patients were followed up to 1 year.

METHODS

The study design, in accordance with the Helsinki Declaration of Human Rights, was approved by the Panjab University Institutional Ethics Committee, Chandigarh, India, vide letter no. PUIEC201210-II-060 dated 22^nd January 2022. Parental consent and assent forms were also approved and obtained.

The study was conducted between the months of March and September 2022. A total of 7–10-year-old children reporting to the pediatric dental outpatient department with severe pain, pathologic tooth mobility, abscess or sinus formation, and/or furcation radiolucency in a restorable tooth were enrolled in the study. The ages of patients were rounded off for ease of convenience.

Children with a known sensitivity or allergy to drugs, medical conditions, extensive root resorption (>1/2), a perforated pulpal floor, and an unrestorable tooth were excluded.

Trial Design

A unicentric, prospective, randomized, parallel-group, and active-control clinical trial was conducted. The clinical trial registry number was CTRI/2022/02/040674.

Sample Size

The sample size was estimated based on a study conducted by Divya et al.¹⁵ comparing the clinical and radiographic success of pulpectomy and LSTR in primary molars.

The formula used for sample size calculation was n = (Zα/2 + Zβ)² × [p₁ (1 − p₁) + p₂ (1 − p₂)] / (p₁ − p₂)², where Zα/2 was the critical value of the normal distribution at α/2, Zβ was the critical value of the normal distribution at β, and p₁ and p₂ were the expected sample proportions of the two groups. The final sample size was 15 teeth per group at a power of 80% and a confidence interval of 95%. For possible attrition, it was decided to include at least 40 teeth, 20 in each group.

Randomization and Allocation

Children who fulfilled the inclusion criteria were randomly assigned to two groups. The drug mix consisting of metronidazole and ciprofloxacin constituted group I (2-Mix or DAP). Group II comprised the Metapex pulpectomy group. The random sequence was generated through a computer-generated random method. Allocation concealment was performed through sequentially numbered, opaque, sealed envelopes.

A total of 44 teeth in 35 children were initially recruited for the study. Two patients (3 teeth) failed to report for treatment. One patient underwent complete treatment and follow-up of only one of his bilaterally affected teeth. Six children (7 teeth) were lost to follow-up. Hence, the final sample consisted of 33 teeth (in 27 children), of which 15 teeth were in group I (DAP) and 18 teeth in group II (pulpectomy) (Table 1).

Table 1:

Distribution of sample (n = 33)

Distribution of sample		Total sample size	DAP (15)	RCT (18)
Age in years	7	10	3	7
	8	13	7	6
	9	6	3	3
	10	4	2	2
Gender	Males	22	8	14
	Females	11	7	4
Tooth number	74	4	1	3
	75	16	9	7
	84	2	0	2
	85	11	5	6

Blinding

The study was both participant- and clinical assessor-blinded.

Method of Preparation of Double Antibiotic Paste

To prepare 1 mg/mL of DAP, 100 mg of pure antibiotic powders consisting of equal amounts of ciprofloxacin and metronidazole were obtained. About 50 mg of each drug was dissolved in 100 mL of sterile, double-distilled water. The drug combination was magnetically stirred at 1500 rpm for 10 minutes to ensure uniform mixing. The drug combination was kept at 40°C and maintained at the same temperature. To this heated drug solution, 4 gm of methylcellulose (Loba Chemie Pvt. Ltd., Mumbai, India) were added and stirred at 1500 rpm for 1.5 hours with a magnetic stirrer. The drug mix was converted into a homogeneous gel. Stirring and heating were discontinued. The formulation was allowed to cool for increased viscosity. The resultant gel preparation had a shelf life of 3 months at room temperature and was prepared afresh twice for its use during the study. All precautions were taken to keep the formulation aseptic.

Procedure

The preclinical and preradiographic status of teeth were recorded. The dental treatment was performed by a single operator. Local anesthesia containing 2% lignocaine and 1:2,00,000 adrenaline (Lox, Neon Laboratories Ltd., Mumbai, India) was administered where required. Access was gained to the pulp chamber using a round carbide bur (Dentsply Maillefer, Ballaigues, Switzerland), and the pulp chamber was deroofed using a nonend cutting bur (Dentsply Maillefer, Ballaigues, Switzerland). The coronal pulp tissue, if any, was removed with a small round bur (Dentsply Maillefer, Ballaigues, Switzerland) and/or a sterile spoon excavator (Hu-Friedy, Prime Dental Supply Inc., New York, USA). The radicular pulp was extirpated using chemomechanical means including barbed broaches (Mani Dental Inc., Japan) without canal preparation. The canals were irrigated with 1% sodium hypochlorite followed by 0.9% normal saline, and dried using sterile absorbent paper points (Dentsply Maillefer, Ballaigues, Switzerland). The tooth was isolated using cotton rolls. Antibiotics were prescribed only to those patients who had systemic signs of infection.

Group I (Double Antibiotic Paste)

About 15% w/w ethylenediaminetetraacetic acid (EDTA) gel with 10% w/w carbamide peroxide (Avue Prep, BLV Healthcare Pvt. Ltd., Gurugram, India) was applied on the pulp chamber for 1 minute. The tooth was then irrigated with normal saline and dried with cotton. The drug gel mix was placed in the pulp chamber with a spoon excavator (Hu-Friedy, Prime Dental Supply Inc., New York, USA) and slightly agitated several times with an explorer (Hu-Friedy, Prime Dental Supply Inc., New York, USA) to permit penetration through the porous pulpal floor. No medication cavity was designed. The tooth was sealed with glass ionomer cement (Ketac Molar, 3M ESPE AG, Germany) at the same appointment. The procedure was repeated, and the medicament was placed again at the next appointment if infection persisted. After 1 week, stainless-steel crowns (3M ESPE, St. Paul, MN, USA) were cemented using glass ionomer luting agent (GC Gold Label, GC Corporation, Tokyo, Japan).

Group II (Pulpectomy)

The root canals were biomechanically prepared using pediatric dental Kedo-S Square rotary files (Kedo Dental, Chennai, India) connected to an endodontic motor (X-Smart Plus, Dentsply Sirona, Charlotte, NC, USA). Irrigation was performed using 1% sodium hypochlorite and 0.9% w/v normal saline. The length of the file was kept 2 mm short of the radiographic apex. After preparation, the canals were dried using sterile paper points (Dentsply Maillefer, Ballaigues, Switzerland) and obturated with calcium hydroxide−iodoform paste (Metapex, Meta Biomed Co. Ltd., Chungbuk, Korea) using reamers (Mani Dental Inc., Japan) and pluggers (Mani Dental Inc., Japan). Multivisit pulpectomy procedure was performed in all cases. A postobturation radiograph was obtained to evaluate the adequacy of obturation, and the canals were refilled if found deficient. The tooth was immediately sealed with glass ionomer cement (Ketac Molar, 3M ESPE AG, Germany). The patients were recalled the next day to evaluate their clinical status. After 1 week, stainless-steel crowns (3M ESPE, St. Paul, MN, USA) were cemented using glass ionomer luting agent (GC Gold Label, GC Corporation, Tokyo, Japan).

Evaluation Criteria

The criteria for clinical success were absence of pain, abscess/sinus formation, and/or tooth mobility. These findings were recorded every 3 months. Another pediatric dentist, not the operator, was the independent clinical assessor to record the clinical status.

The criteria for radiographic success were no enhanced pathologic resorption, no new radiographic lesions, evidence of bone formation, and static or resolved furcation radiolucency. The findings were recorded at 6 and 12 months by two independent investigators, also pediatric dentists. Any difference in the radiographic interpretation of results was resolved by discussion until a consensus was reached.

Statistical Analysis

The data were subjected to statistical analysis. Categorical variables were reported as counts and percentages. Group comparisons were made using the Chi-squared test or Fisher's exact test. Continuous data were presented either as a mean and standard deviation or as a median and an interquartile range. A p-value < 0.05 was considered significant. Analysis was conducted using IBM Statistical Package for the Social Sciences (SPSS) statistics software (version 22.0).

RESULTS

The distribution of age, gender, tooth type, and the treatment rendered is presented in Table 1.

The pre- and posttreatment clinical findings are presented in Table 2. After 3 months, an abscess was observed in one patient each in both groups. At 6 months, one patient in the DAP group developed pain, swelling, and tooth mobility. Two more patients in the DAP group developed tooth mobility but were devoid of pain or swelling. These teeth were extracted because of extensive root resorption and were considered treatment failures. At 9 months, one patient in the pulpectomy group presented with pain and swelling due to cystic transformation of an adjacent carious tooth, which was extracted. At 12 months, clinical failure occurred in one tooth each in both groups, one with a sinus (DAP group) and the other with tooth mobility that was otherwise asymptomatic (pulpectomy group). Thus, the study resulted in 8 clinical failures (5 in the DAP group and 3 in the pulpectomy group).

Table 2:

Pre- and posttreatment clinical findings

Clinical findings	Positive findings		Posttreatment
			3 months		6 months		9 months		12 months
	DAP (15)	RCT (18)	DAP	RCT	DAP	RCT	DAP	RCT	DAP	RCT
Pain	15	18	0	1	1	0	0	1	0	0
Swelling	5	6	1	1	1	0	0	1	0	0
Sinus	0	0	0	0	0	0	0	0	1	0
Abnormal tooth mobility	3	4	0	0	3	0	0	0	0	1
Tenderness on percussion	6	8	0	0	0	0	0	0	0	0
Clinical failures (total) − 8	5	3	1	1	3	0	0	1	1	1

The posttreatment radiographic findings differed from the clinical findings (Table 3). One tooth each in both groups could not be assessed radiographically due to clinical failure at 3 months. No cases of internal resorption or calcification were encountered pre- or posttreatment. Bone regeneration was also not evident. Pretreatment furcation radiolucency was observed in 6 cases in the DAP group and 5 cases in the pulpectomy group. However, an intergroup comparison showed no statistically significant difference at 12 months (p-value 0.6629).

Table 3:

Pre- and posttreatment radiographic findings

Total initial sample			DAP (15)	RCT (18)
Radiographic findings not assessed (clinical failure at 3 months)			1	1
Sample assessed for radiographic interpretation			14	17
Furcation radiolucency (FRL)	Pretreatment		6	5
	6 months	New	2	4
		Increased	4	2
		Decreased/static	2	2
	12 months	New	1	2
		Increased	5	4
		Decreased/static	1	2
Pathologic root resorption (PRR)	Pretreatment	4	1
	6 months	New	5	1
		Increased	2	1
		Static	1	2
	12 months	New	0	2
		Increased	8	2
		Static	0	2
Internal resorption	Pre- and posttreatment	0	0
Calcific metamorphosis	Pre- and posttreatment	0	0

Pretreatment pathological root resorption (PRR) was evident in 4 cases in the DAP group (Table 3). New/increased PRR was seen in 7 and 8 cases at 6 and 12 months, respectively. In the pulpectomy group, pretreatment PRR was seen in 1 case. New/increased PRR was seen in 2 and 4 cases at 6 and 12 months, respectively. Three teeth underwent extraction in the DAP group and one tooth underwent exfoliation in the pulpectomy group due to extensive PRR and an erupting successor tooth.

After 1 year of follow-up, our study resulted in a clinical success of 67% (10/15) in the DAP group and 83% (15/18) in the pulpectomy group (p-value 0.4184) and a radiographic success of 36% (5/14) in the DAP group and 53% (9/17) in the pulpectomy group (p-value 0.3374, Table 4).

Table 4:

Clinical and radiographic success of treatment

Treatment success	Posttreatment	DAP n = 15 (%)	RCT n = 18 (%)	Total n = 33 (%)	p-value
Clinical success	3 months	14/15 (93)	17/18 (94)	31/33 (94)	1.000
	6 months	11/15 (73)	17/18 (94)	28/33 (85)	0.1528
	9 months	11/15 (73)	16/18 (89)	27/33 (82)	0.3747
	12 months	10/15 (67)	15/18 (83)	25/33 (76)	0.4184
Radiographic findings not assessed (clinical failure at 3 months)	1	1	1	2
Radiographic success	6 months	6/14 (43)	11/17 (65)	17/31 (55)	0.2238
	12 months	5/14 (36)	9/17 (53)	14/31 (45)	0.3374

The pre- and posttreatment photographs are provided in Figure 1.

Figs 1A to D:

DAP-treated tooth 85; (A) Pretreatment; (B) At 6 months; (C) 12 months; (D) Clinical photograph at 12 months-asymptomatic

DISCUSSION

The present study observed 67% clinical success and 36% radiographic success at 12 months with 1 mg/mL DAP in infected primary molars. Although no clinical studies using DAP in primary molars were available for comparison, studies employing TAP have demonstrated clinical success ranging from 27%–100%.^5,6,16–18 Differences related to age, tooth type, initial diagnosis, drug composition, and drug concentration may be responsible for the wide variation in results. The differences in the techniques of application, wherein TAP has been used not only as a pulp capping agent⁶ but also following pulpotomy¹⁸ and pulpectomy¹⁷ procedures, may also have resulted in varied outcomes, as mentioned in the subsequent paragraphs.

Takushige et al.,⁶ in 360 pulpitis cases, placed 3Mix-MP medicament (ciprofloxacin, metronidazole, and minocycline in a macrogol and propylene glycol base) on the floor of carious dentin in cases without pulp exposure (pulp capping), and on the pulpal floor of the chemically cleansed pulp in pulp exposure cases. The study attempted to preserve pulp tissue by not removing soft carious tissue, by not extending pulp exposures, and by permitting disinfection of lesions. One year after treatment, 95% of teeth had retained pulp vitality, 3% had required retreatment, and 6 cases had necrosed. Their results were better because most of their pulpitis cases had a vital pulp component, unlike the present study, where only cases of irreversibly inflamed pulp, abscessed and necrosed teeth, with or without furcation bone loss and preoperative root resorption, were included—all of which are suggestive of increased severity of the disease with a guarded prognosis.⁵ Vital pulp therapy has consistently shown better success, with more chances of pulp healing and recovery.¹⁹ Another reason may have been their retreatment of failure cases, unlike the present study, where no retreatment was performed.

Trairatvorakul and Detsomboonrat¹⁸ performed pulpotomy on 80 carious infected primary mandibular molars, placed 3Mix-MP, and sealed the cavity with GIC (glass ionomer cement), followed by 2–3 mm composite and stainless steel crown. The author had observed 95.8 and 75% clinical success and 45.8 and 36.7% radiographic success at 12 and 24–27 months, respectively. Their greater clinical success at 12 months could be attributed to multiple reasons, one of which could be the technique of placement of the medicament. The enlargement of orifice of the canals and subsequent deposition of drugs within the medication cavity may have permitted direct delivery of the medicament into the radicular canals, as compared to our study, where it was deposited only on the pulpal floor. Secondly, their “triple coronal seal” may have been better than the presently utilized “double coronal seal” comprising GIC and stainless steel crown to prevent the ingress of microbes. Lastly, the study had a relatively favorable chronological age of the patients at the time of recruitment (3.11–8.7 years) as compared to our study (7–10 years). A younger age is associated with more vascularity, better healing potential, and a higher tooth survival rate.²⁰ The author, despite the stringent radiographic criteria, had also reported better radiographic success at 45.8% as compared to our study, after 12 months, for possibly similar reasons.

Prabhakar et al.¹⁷ treated 60 carious infected primary molars with 3Mix-MP followed by GIC and composite resin and compared cases of radicular pulp extirpation (pulpectomy) to those without. One year after treatment, greater clinical and radiographic success (100% each) was observed in the former as compared to the latter (93 and 76.7%, respectively), highlighting the importance of infective pulp removal. Though the present study also underwent infected pulp removal, the results were lower than that of Prabhakar et al.¹⁷ The design of a medication cavity and inclusion of a lower age-group may have been contributory factors in their study. An additional finding was the greater number of bone regeneration cases in their radicular pulp extirpation group (83.3%) as compared to those without (36.7%). Bone regeneration has been reported in 30–60% other cases treated with TAP.^21,22 The present study, however, failed to observe bone regeneration in both groups despite pulp extirpation because of multiple reasons, one of which could be the inclusion of an older age-group with age changes occurring in the already compromised teeth,²³ the ongoing physiological resorption, with a reduced tendency to repair.²⁰ An exclusion of minocycline could be another reason why bone regeneration was not apparent in the DAP group. Minocycline, a broad-spectrum antibiotic, is known to inhibit bone resorption²⁴ and stimulate bone formation in both animal²⁵ and human²⁶ models. Rather, a favorable environment for bone healing would have possibly been created had a medicament with bone regeneration potential been deposited on the pulpal floor for easy penetration through the thin porous floor.

A comparison of the clinical success of antibiotic paste and pulpectomy in primary molars has shown different results. Nakornchai et al.⁵ treated 50 teeth with either 3Mix-MP or Vitapex pulpectomy in 3–8-year-old children, which were immediately restored with light-cured GIC and SSC. After 1 year, clinical success was 96% in both groups (p = 1.000), and radiographic success was 76 and 56%, respectively (p = 0.0681). It was concluded that both options could be used in the treatment of such teeth. The present study reported a clinical success of 67 and 83% and a radiographic success of 36% and 53% with DAP and Metapex pulpectomy, respectively, with a statistically nonsignificant intergroup comparison. However, the author reported better clinical results in both groups as compared to our study at 12 months. A younger age-group and the inclusion of maxillary molars may have been some of the contributory factors. A better prognosis of maxillary teeth can be attributed to their late eruption and less complex root canal system.^23–27 An inclusion of internal root resorption cases in their study may also have increased treatment success because of the presence of a vital pulp component resulting in better healing.⁵ The present study had not encountered any such case.

On the contrary, the present study observed better results than that of Daher et al.,¹⁶ who reported an overall success of 27% for CTZ pulpotomy (chloramphenicol, tetracycline, and zinc oxide) and 68.7% for pulpectomy in 53 primary molars diagnosed with either necrosis or irreversible pulpitis followed up for 1–26 months. Of the failures, 66.7% were exclusively radiographic, 3.7% were exclusively clinical, and 29.6% were both in the CTZ pulpotomy group. The differences in the extent of follow-up period may have been a crucial factor. The author reported 62.2% failures (23/37) among primary molars in the CTZ pulpotomy group at 12 months. The removal of infected pulp may also have resulted in an improved clinical success in our study, consistent with the study by Prabhakar et al.¹⁷ An additional factor may have been the posttreatment restoration, which was a lining of Vidrion GIC cement and composite in their study, whereas the present study had used stainless steel crowns, known for their strength, durability, and prevention of microleakage, with >95% clinical success over 1–5 years.^28–30 Yet another reason may have been the inclusion of static radiographic lesions as treatment success in our study, whereas these were considered as failures by the author.

The present study observed low radiographic success in both groups, which can be attributed to the selection criteria. Songvejkasem et al.³¹ observed that teeth with a preexisting radiolucency had 3.9 times more chances of pulpectomy failure compared to those without. A preexisting furcation and/or periapical radiolucency is indicative of bone destruction, most severe form of disease, resulting in compromised healing following pulpectomy and poor prognosis.³¹ Lin and Huang 2015³² found that such preexisting lesions had a higher failure rate than those without because of chronic apical periodontitis.

In contrast, the study also witnessed few cases with no or little evidence of clinical failure or resorption. The chemomechanical eradication of infection, removal of smear layer, use of medicament, and a tight coronal seal may have been contributory factors. Others such as immune response, microbial virulence, extent of infection, and anatomical variations may also have played a significant role in individual cases.

CONCLUSION

The present study showed a favorable clinical outcome but a low radiographic success of 1 mg/mL DAP at 1-year follow-up in pulpally infected carious primary molars in 7–10-year-old children. Although the clinical and radiographic success rates were comparable to pulpectomy, the higher radiographic failures in this double antibiotic gel formulation suggest that pulpectomy still remains the material of choice. However, in poor prognostic teeth, DAP in this concentration/formulation may be considered a clinically viable option over the conventionally used high-concentration antibiotic pastes for up to one year.

LIMITATIONS AND FUTURE RESEARCH

A large sample size and longer follow-up period is recommended for more conclusive evidence. Different drug formulations or techniques can be explored. Drug combinations with osteoinductive/osteoconductive properties may also be employed for bone healing and radiographic success.

ORCID

Leena Verma https://orcid.org/0000-0001-8791-2579

Archna Agnihotri https://orcid.org/0000-0002-9038-8648

Rosy Arora https://orcid.org/0000-0003-2542-4945

Indu P Kaur https://orcid.org/0000-0002-1237-2974