The influence of calcium silicate-based cement on osseous healing: A systematic review and meta-analysis

Abstract

Objectives:

The purpose of this systematic review was to analyze the effect of commercially available calcium silicate-based bioactive endodontic cement (BEC) on treatment outcome when used as root repair material in human permanent teeth and to compare it with traditional materials.

Methods:

PubMed, Embase, and Cochrane Library were searched until June 2020. Randomized clinical studies and observational studies with a minimum 1-year follow-up and sample size of at least 20 were included. Risk of bias (ROB) was assessed using Cochrane's ROB tool and the National Institutes of Health Quality Assessment Tool.

Results:

Thirty-nine studies were included in the systematic review. Majority of the studies used mineral trioxide aggregate. The pooled success rate for BEC was estimated by a random-effects method as 90.49% (95% confidence interval [CI]: 88.4992.34, I² = 54%). Eleven studies comparing BEC with traditional materials were included in the meta-analysis. The use of BEC significantly improved the treatment outcome when compared to traditional materials with odds ratio (OR) = 2.15 (95% CI: 1.57–2.96, I² = 0.8%, P = 0.433).

Conclusion:

Very low-to-moderate-quality evidence suggests that the use of BEC as root repair material enhanced the treatment outcome. High-quality studies are required for the newer BEC to establish their clinical performance. Registration: PROSPERO CRD42020211502.

INTRODUCTION

Mineral trioxide aggregate (MTA), the first calcium silicate-based bioactive endodontic cement (BEC), was introduced to the field of endodontics in the early 1990s as root-end filling (REF) material. Due to the superior biological and clinical performance of MTA as compared to traditional materials, it soon emerged as the material of choice for several endodontic applications.[1] However, given the poor handling properties and longer setting time of MTA, a number of BEC with modifications have continued to develop over the years. These newer materials have varied composition, but bioactivity is a common feature to all of them, hence the term BEC was recently suggested.[2] MTA is considered the gold standard against which newer BEC are often compared.

BEC have been shown to possess the ability to upregulate the differentiation of osteoblasts, cementoblasts, and pulpal cells.[3] Of particular interest to clinicians is the ability of BEC to induce osteogenic responses when applied to bony defects, as complete resolution of periapical lesions is one of the important parameters to judge the success of surgical endodontic treatment.[4,5,6] When BEC are used as root repair material, they come in direct contact with the periradicular tissues and can potentially stimulate osseous healing by the release of signaling molecules such as osteocalcin and alkaline phosphatase.[7,8] In addition to excellent biocompatibility, these materials possess excellent sealing ability, higher washout resistance, and antimicrobial properties and allow periodontal and cementum regeneration.[9,10,11]

While choosing a suitable root repair material in a clinical situation, the decision should be based on strong scientific evidence.[12] Extensive literature exists on the use of BEC for endodontic applications in the form of in vitro and in vivo studies, but whether the results shown by BEC in these studies translate to better clinical outcomes remains to be validated.

A systematic review is an essential tool that provides accurate and reliable high-quality evidence-based recommendations that help clinicians in decision-making.[13] In the systematic reviews conducted so far, the effect of MTA in specific clinical situations such as apexification or periapical microsurgery has been analyzed.[14,15,16] However, a number of clinical studies have been published with larger sample size, longer follow-up period with 3D radiographic healing assessment, which can further strengthen the existing evidence. Furthermore, newer BEC have not been taken into consideration in any of the systematic reviews so far. Hence, this study aimed to conduct a systematic review with a wider search strategy to determine the success rate of commercially available BEC as root repair material.

The detailed review question was as follows: Population: human permanent teeth presenting with periapical lesions of endodontic origin, treated by root-end surgery, apexification, or perforation repair. Intervention: root repair using BEC. Control: use of material other than BEC for root repair or no control group. Outcome: success rate in terms of clinical and radiographic treatment outcome (the use of either intraoral periapical radiographs or cone-beam computed tomography for radiographic assessment). Study design: randomized controlled trials (RCTs) and observational studies (prospective/retrospective cohorts).

METHODS

The present systematic review was carried out in accordance with PRISMA 2020 guidelines.[17]

Eligibility criteria

The selection of articles for inclusion in the systematic review was made by applying the criteria listed in Table 1.

Table 1.

The detailed inclusion and exclusion criteria for the systematic review

Inclusion criteria	Exclusion criteria
Studies (randomized trials and observational studies) done on human permanent teeth, in vivo	Follow-up period was <1 year
Clinical studies that assess the influence of BEC on osseous healing of periradicular lesions	Publications were in the form of letters, commentaries or narratives, and case reports
Studies that mention BEC as root repair material for periradicular lesions	Patients with impaired immune response, bone disorder, diabetics or receiving long-term medication
Studies that have reported sufficient data relating to the sample size (minimum 20)	Tooth under consideration had periradicular lesions associated with periodontal defects, vertical root fracture, or missed canals
Studies that conform to the parameters for osseous healing assessment and determined through clearly defined criteria before and after treatment follow-up	Studies in which adjunctive osteo-inductive materials were used along with BEC as root repair materials
Studies that have mentioned radiographic and clinical findings for all follow-up examinations for a minimum follow-up period of 12 months

BEC: Bioactive endodontic cement

Information sources

On November 6, 2020, two independent investigators (PJP and SG) consulted the databases PubMed, Embase, and Cochrane Central Register of Controlled Trials from the inception of each database to June 2020 by using the following keywords: Calcium silicate based cements endodontics, MTA, root end filling, perforation repair, apexification, Calcium enriched mixture cement, EndoSequence root repair material, Biodentine, Tricalcium silicate cement endodontics, apexification outcome, perforation repair outcome endodontics, and periapical surgery outcome endodontics. These keywords were identified by going through the relevant articles, words used in their titles/abstracts, keywords, and Medical Subject Headings terms enlisted for them.

Search strategy

During PubMed search, the displayed results were sorted by best match and no additional filters were applied. During Embase search, the same search method was employed and the source was limited to “Embase only” [Supplementary Table S1]. A “snowball” search of the Journal of Endodontics and International Endodontic Journal was performed to identify additional studies, and references of the included studies were also handsearched. The search strategy was validated by checking whether it could retrieve five relevant studies[18,19,20,21,22] identified by the two investigators (RRN and SY).

Supplementary Table S1.

Search strategy for the databases - PubMed, Embase, and Cochrane Central Register of Controlled Trials

Database	Search strategy
PubMed	((((((((((calcium silicate based cements endodontics [All fields] AND (1000/1/1:2020/6/30[pdat])) OR ((MTA [All fields]) AND (root end filling [All fields]) AND (1000/1/1:2020/6/30[pdat]))) OR ((MTA [All fields]) AND (perforation repair [All fields]) AND (1000/1/1:2020/6/30[pdat]))) OR ((MTA [All fields]) AND (apexification [All fields]) AND (1000/1/1:2020/6/30[pdat]))) OR (Calcium enriched mixture cement [All fields] AND (1000/1/1:2020/6/30[pdat]))) OR (Endosequence root repair material [All fields] AND (1000/1/1:2020/6/30[pdat]))) OR (Biodentine [All fields] AND (1000/1/1:2020/6/30[pdat]))) OR (Tricalcium silicate cements endodontics [All fields] AND (1000/1/1:2020/6/30[pdat]))) OR (apexification outcome [All fields] AND (1000/1/1:2020/6/30[pdat]))) OR (perforation repair outcome endodontics [All fields] AND (1000/1/1:2020/6/30[pdat]))) OR (periapical surgery outcome endodontics [All fields] AND (1000/1/1:2020/6/30[pdat])) Filters: from 1000/1/1-2020/6/30 Details of search translation: (((“calcium silicate”[Supplementary Concept] OR “calcium silicate”[All Fields]) AND (“based”[All Fields] OR “basing”[All Fields]) AND (“cement s”[All Fields] OR “cementable”[All Fields] OR “cementation”[MeSH Terms] OR “cementation”[All Fields] OR “cementations”[All Fields] OR “cementing”[All Fields] OR “dental cementum”[MeSH Terms] OR (“dental”[All Fields] AND “cementum”[All Fields]) OR “dental cementum”[All Fields] OR “cement”[All Fields] OR “dental cements”[MeSH Terms] OR (“dental”[All Fields] AND “cements”[All Fields]) OR “dental cements”[All Fields] OR “cemented”[All Fields] OR “cements”[All Fields]) AND (“endodontal”[All Fields] OR “endodontic”[All Fields] OR “endodontical”[All Fields] OR “endodontically”[All Fields] OR “endodontics”[MeSH Terms] OR “endodontics”[All Fields]) AND 1000/01/01:2020/06/30[Date - Publication]) OR (“MTA”[All Fields] AND ((“plant roots”[MeSH Terms] OR (“plant”[All Fields] AND “roots”[All Fields]) OR “plant roots”[All Fields] OR “root”[All Fields]) AND “end”[All Fields] AND (“filled”[All Fields] OR “filling”[All Fields] OR “fillings”[All Fields] OR “fills”[All Fields])) AND 1000/01/01:2020/06/30[Date - Publication]) OR (“MTA”[All Fields] AND ((“perforant”[All Fields] OR “perforants”[All Fields] OR “perforate”[All Fields] OR “perforated”[All Fields] OR “perforates”[All Fields] OR “perforating”[All Fields] OR “perforation”[All Fields] OR “perforations”[All Fields] OR “perforative”[All Fields] OR “perforator”[All Fields] OR “perforator s”[All Fields] OR “perforators”[All Fields]) AND (“repairability”[All Fields] OR “repairable”[All Fields] OR “repaire”[All Fields] OR “repaired”[All Fields] OR “repairment”[All Fields] OR “wound healing”[MeSH Terms] OR (“wound”[All Fields] AND “healing”[All Fields]) OR “wound healing”[All Fields] OR “repair”[All Fields] OR “repairing”[All Fields] OR “repairs”[All Fields])) AND 1000/01/01:2020/06/30[Date - Publication]) OR (“MTA”[All Fields] AND (“apexification”[MeSH Terms] OR “apexification”[All Fields] OR “apexifications”[All Fields]) AND 1000/01/01:2020/06/30[Date - Publication]) OR ((“calcium enriched mixture cement”[Supplementary Concept] OR “calcium enriched mixture cement”[All Fields] OR “calcium enriched mixture cement”[All Fields]) AND 1000/01/01:2020/06/30[Date - Publication]) OR ((“endosequence root repair material”[Supplementary Concept] OR “endosequence root repair material”[All Fields] OR “endosequence root repair material”[All Fields]) AND 1000/01/01:2020/06/30[Date - Publication]) OR ((“tricalcium silicate”[Supplementary Concept] OR “tricalcium silicate”[All Fields] OR “biodentine”[All Fields]) AND 1000/01/01:2020/06/30[Date - Publication]) OR ((“tricalcium silicate”[Supplementary Concept] OR “tricalcium silicate”[All Fields]) AND (“cement s”[All Fields] OR “cementable”[All Fields] OR “cementation”[MeSH Terms] OR “cementation”[All Fields] OR “cementations”[All Fields] OR “cementing”[All Fields] OR “dental cementum”[MeSH Terms] OR (“dental”[All Fields] AND “cementum”[All Fields]) OR “dental cementum”[All Fields] OR “cement”[All Fields] OR “dental cements”[MeSH Terms] OR (“dental”[All Fields] AND “cements”[All Fields]) OR “dental cements”[All Fields] OR “cemented”[All Fields] OR “cements”[All Fields]) AND (“endodontal”[All Fields] OR “endodontic”[All Fields] OR “endodontical”[All Fields] OR “endodontically”[All Fields] OR “endodontics”[MeSH Terms] OR “endodontics”[All Fields]) AND 1000/01/01:2020/06/30[Date - Publication]) OR ((“apexification”[MeSH Terms] OR “apexification”[All Fields] OR “apexifications”[All Fields]) AND (“outcome”[All Fields] OR “outcomes”[All Fields]) AND 1000/01/01:2020/06/30[Date - Publication]) OR ((“perforant”[All Fields] OR “perforants”[All Fields] OR “perforate”[All Fields] OR “perforated”[All Fields] OR “perforates”[All Fields] OR “perforating”[All Fields] OR “perforation”[All Fields] OR “perforations”[All Fields] OR “perforative”[All Fields] OR “perforator”[All Fields] OR “perforator s”[All Fields] OR “perforators”[All Fields]) AND (“repairability”[All Fields] OR “repairable”[All Fields] OR “repaire”[All Fields] OR “repaired”[All Fields] OR “repairment”[All Fields] OR “wound healing”[MeSH Terms] OR (“wound”[All Fields] AND “healing”[All Fields]) OR “wound healing”[All Fields] OR “repair”[All Fields] OR “repairing”[All Fields] OR “repairs”[All Fields]) AND (“outcome”[All Fields] OR “outcomes”[All Fields]) AND (“endodontal”[All Fields] OR “endodontic”[All Fields] OR “endodontical”[All Fields] OR “endodontically”[All Fields] OR “endodontics”[MeSH Terms] OR “endodontics”[All Fields]) AND 1000/01/01:2020/06/30[Date - Publication]) OR ((“periapical”[All Fields] OR “periapically”[All Fields] OR “periapicals”[All Fields]) AND (“surgery”[MeSH Subheading] OR “surgery”[All Fields] OR “surgical procedures, operative”[MeSH Terms] OR (“surgical”[All Fields] AND “procedures”[All Fields] AND “operative”[All Fields]) OR “operative surgical procedures”[All Fields] OR “general surgery”[MeSH Terms] OR (“general”[All Fields] AND “surgery”[All Fields]) OR “general surgery”[All Fields] OR “surgery s”[All Fields] OR “surgerys”[All Fields] OR “surgeries”[All Fields]) AND (“outcome”[All Fields] OR “outcomes”[All Fields]) AND (“endodontal”[All Fields] OR “endodontic”[All Fields] OR “endodontical”[All Fields] OR “endodontically”[All Fields] OR “endodontics”[MeSH Terms] OR “endodontics”[All Fields]) AND 1000/01/01:2020/06/30[Date - Publication])) AND (1000/1/1:2020/6/30[pdat])
Embase	(Calcium silicate based cements endodontics) OR (MTA AND root end filling) OR (MTA AND perforation repair) OR (MTA AND apexification) OR (Calcium enriched mixture cement) OR (Endosequence root repair material) OR (Biodentine) OR (Tricalcium silicate cements endodontics) OR (apexification outcome) OR (perforation repair outcome endodontics) OR (periapical surgery outcome endodontics)
CENTRAL	(Calcium silicate based cements endodontics) OR (MTA AND root end filling) OR (MTA AND perforation repair) OR (MTA AND apexification) OR (Calcium enriched mixture cement) OR (Endosequence root repair material) OR (Biodentine) OR (Tricalcium silicate cements endodontics) OR (apexification outcome) OR (perforation repair outcome endodontics) OR (periapical surgery outcome endodontics)

*Keywords used during the database search (PubMed, Embase, and Cochrane)-Calcium silicate based cements endodontics, MTA, REF, perforation repair, apexification, calcium enriched mixture cement, endosequence root repair material, biodentine, tricalcium silicate cements endodontics, apexification outcome, perforation repair outcome endodontics, and periapical surgery outcome endodontics, CENTRAL: Cochrane Central Register of Controlled Trials, REF: Root-end filling

Selection and data collection process

The records identified through all the sources were retrieved and duplicate records were removed. All titles and abstracts were screened according to the inclusion and exclusion criteria by two independent investigators (SG and PJP). Dissent regarding the same was addressed by consulting a third senior reviewer (RRN) when necessary. For final screening, full texts of the selected studies were obtained. At every stage, complete documentation of the reasons for exclusion was performed.

Data items

The parameters recorded for eligible studies for qualitative analysis are listed in Table 2.

Table 2.

Characteristics of studies included in systematic review and meta-analysis (in the order of year of publication) and summary of results of risk-of-bias assessment

Authors, year of publication	Type of study	Type of application	Repair material	Sample size	Follow-up period		Follow-up percentage
Chong et al., 2003[23]	Randomized clinical trial	Root end surgery	MTA and IRM	183	24 months		59
Lindeboom et al., 2005[24]	Randomized clinical trial	Root end surgery	MTA and IRM	100	12 months		100
El-Meligy and Avery 2006[25]	Randomized clinical trial	Apexification	MTA and CH	30	12 months		100
Simon et al., 2007[26]	Prospective cohort	Apexification	MTA	57	12 months		75
Von arx et al., 2007[27]	Prospective cohort	Root end surgery	MTA and super-EBA and retroplast	194	12 months		98.5
Holden et al., 2008[28]	Retrospective cohort	Apexification	MTA	20	24.4 months		100
Christiansen et al., 2009b[29]	Randomized clinical trial	Root end surgery	MTA	52	12 months		88
Mente et al., 2009[30]	Retrospective cohort study	Apexification	MTA	78	12 -68 months (median=30.9)		72
Mente et al., 2010[31]	Retrospective cohort	Perforation repair	MTA	26	12 -65 (median=33)		81
Von Arx et al., 2010[32]	Nonrandomized prospective clinical/interventional study	Root end surgery	MTA and retroplast	353	1 year		96
Annamalai and Mungara, 2010[33]	Prospective cohort	Apexification	MTA	30	12 months		100
Moore et al., 2011[34]	Nonrandomized prospective clinical study	Apexification	MTA (ProRoot and angelus)	22	23.4 months		100
Song et al. 2011b[35]	Retrospective cohort	Root end surgery	MTA, IRM and super-EBA	907	>12 months		54
Jeeruphan et al., 2012[36]	Retrospective cohort	Apexification	MTA, CH, and revascularization	79	14.21 months		77.2
Von Arx et al. 2012[37]	Prospective cohort study	Root end surgery	MTA, super-EBA, retroplast	191	5 years		89
Song and Kim 2012b[38]	Prospective randomized controlled study	Root end surgery	MTA, super-EBA	260	12 months		MTA-69, super-EBA-78 Total 70
Pontius et al., 2013[39]	Multi-center retrospective cohort study	Perforation	MTA	70	6 -116 months (mean=37)		71
Krupp et al., 2013[40]	Retrospective cohort	Root perforation	MTA	128	1 years-minimum; but mean follow-up period was 3.4 years		70.3
Mente et al., 2013[18]	Retrospective cohort study	Apexification	MTA	252	12 -128 months (21 median)		88
Mente et al., 2014[41]	Retrospective cohort study	Root perforation	MTA	64	12 -107 months (median=27.5)		85
Von Arx et al., 2014[42]	Nonrandomized prospective clinical study	Root end surgery	MTA and retroplast	339	5 years		80
Bonte et al., 2015[43]	Prospective randomized controlled study	Apexification	MTA, CH	34	12 months		88
Shinbori et al., 2015[44]	Retrospective cohort study	Root end surgery	ERRM	113	14.5 months		100
Bücher et al., 2016[45]	Retrospective cohort	Apexification	MTA	98	30 months		90.1
Kim et al., 2016b[19]	Prospective randomized controlled study	Root end surgery	MTA, super-EBA	260	4 years		MTA 64, super-EBA 76 Overall 70
Kruse et al., 2016[46]	Randomized clinical trial	Root end surgery	MTA	52	6 years		75
Çalışkan et al., 2016[47]	Prospective clinical Study	Root end surgery	MTA	108	2 -6 years		83
Gorni et al., 2016[48]	Prospective cohort	Perforation repair	MTA	110	24 months		98.2
Von arx et al., 2016[49]	Prospective cohort	Root end surgery	MTA	61	12 months		100
Wang et al., 2017[50]	Prospective cohort study	Root end surgery	MTA	98	12 -30 months (median=17.2)		75.5
Silujjai and Linsuwanont 2017[51]	Retrospective cohort study	Apexification	MTA, revascularization	75	1296 months (median 44)		57.33
Schloss et al., 2017[20]	Retrospective cohort	Root end surgery	MTA	51	Mean 23.7 months		100
Zhou et al., 2017[52]	Randomized controlled study	Root end surgery	MTA, iRoot BP plus RRM	240	12 months		65.83
Kandemir Demirci et al., 2020[53]	Randomized clinical trial	Apexification	MTA and CH	90	12 -48 months (median=32.3)		81.1
Safi et al., 2019[22]	Randomized clinical trial	Root end surgery	MTA and ERRM	243	24 months (mean=15 months)		49.4
Von Arx et al., 2019a[21]	Prospective clinical study	Root end surgery	MTA	69	12 -60 months		66.1
Von arx et al., 2019b[54]	Prospective cohort	Root end surgery	MTA	195	10 years		61.0
Taha et al., 2021[56]	Prospective cohort study	Root end surgery	TotalFill FS	50	12 months		95
Von arx et al., 2020[55]	Prospective cohort	Root end surgery	BCRRM	174	12 months		97.7
Authors, year of publication	Standardization of radiographic technique	Radiographic assessment index (scoring index)	Success rate			Included in meta-analysis	ROB
Chong et al., 2003[23]	Yes	ESE criteria	MTA: 91.8% (56/61) IRM: 87.2% (41/47)			Yes	High bias
Lindeboom et al., 2005[24]	Paralleling technique	Rud and Molven	MTA: 92% (46/50) IRM: 86% (43/50)			Yes	High bias
El-Meligy and Avery 2006[25]	NM	PAI	MTA: 100% (15/15) CH: 86.7%(13/15)			Yes	High bias
Simon et al., 2007[26]	Paralleling	PAI	MTA: 81.4% (35/43)			Yes	Low bias
Von arx et al., 2007[27]	Paralleling	Rud and Molven	MTA: 90.2%(46/51) Super-EBA: 76.4% (42/55) Retroplast: 84.7% (72/85)			No	Low bias
Holden et al., 2008[28]	NM	PAI	MTA: 90% (18/20)			Yes	Low bias
Christiansen et al., 2009b[29]	Yes	Molven criteria	MTA: 96%, GP: 52%			No	High bias
Mente et al., 2009[30]	Paralleling	PAI	MTA: 84% (47/56)			No	Low bias
Mente et al., 2010[31]	NM	PAI	MTA: 86% (18/21)			No	Low bias
Von Arx et al., 2010[32]	Paralleling	Molven criteria	MTA: 91.3% (158/173), Retroplast: 79.5% (132/166)			No	Moderate bias
Annamalai and Mungara, 2010[33]	NM	ESE criteria	MTA: 100% (30/30)			Yes	High bias
Moore et al., 2011[34]	NM	PAI	MTA: 95.5% (21/22)			Yes	Low bias
Song et al. 2011b[35]	No	Molven criteria	MTA 86.9% (186/214) EBA 85.6% (95/111) IRM 79.4% (81/102)			Yes	Moderate bias
Jeeruphan et al., 2012[36]	Calibration using computer software	Friedman and Mor	MTA: 94.7% (18/19)			Yes	Moderate bias
Von Arx et al. 2012[37]	Paralleling	Rud and Molven criteria	MTA: 86.4% (38/44), super-EBA 67.3% (33/49), Retroplast 75.3% (58/77)			Yes	Low bias
Song and Kim 2012b[38]	3 different horizontal angles	Molven criteria	MTA 95.6% (86/90) Super-EBA: 93.1% (95/102)			No	High bias
Pontius et al., 2013[39]	No	PAI, root perforation index	MTA: 92% (34/37)			Yes	High bias
Krupp et al., 2013[40]	Paralleling	No	MTA: 73.30% (66/90)			Yes	Moderate bias
Mente et al., 2013[18]	Yes	PAI	MTA: 90% (227/252)			Yes	Low bias
Mente et al., 2014[41]	Yes	PAI	MTA: 86% Healed (55/64)			Yes	Low bias
Von Arx et al., 2014[42]	Paralleling	Molven criteria	MTA: 92.5% (124/134), Retroplast: 76.6% (105/137)			Yes	Moderate bias
Bonte et al., 2015[43]	Yes	PAI	MTA: 82.4%, CH: 75%			Yes	Low bias
Shinbori et al., 2015[44]	-	Rud and Molven criteria	ERRM: 92% (104/113)			Yes	Low bias
Bücher et al., 2016[45]	Yes	PAI	MTA: 90.2% (74/82)			Yes	Moderate bias
Kim et al., 2016b[19]	3 different horizontal angles	Molven criteria	MTA: 91.6% (76/83), super-EBA: 89.9%			Yes	High bias
Kruse et al., 2016[46]	Paralleling	Rud and Molven criteria	MTA: 84% (16/19), GP: 55% (11/20)			Yes	High bias
Çalışkan et al., 2016[47]	Paralleling	Molven criteria	MTA: 80% (72/90)			Yes	Low bias
Gorni et al., 2016[48]	NM	-	MTA: 93.5% (101/108)			Yes	Moderate bias
Von arx et al., 2016[49]	Yes	CBCT RACB criteria	MTA: 80.3% (49/61)			No	Low bias
Wang et al., 2017[50]	Paralleling	Rud and Molven criteria	MTA: 90.5% (67/74)			Yes	Moderate bias
Silujjai and Linsuwanont 2017[51]	Paralleling	Modified Friedman and Mor	MTA: 80.77% (21/26), Revascularization 76.47% (13/17)			Yes	Moderate bias
Schloss et al., 2017[20]	Yes	Molven’s criteria and Modified Penn 3D criteria	PA: 92.2% (47/51) CBCT: 92.2% (47/51)			Yes	Low bias
Zhou et al., 2017[52]	No	Rud and Molven criteria	MTA: 93.1% (81/87) iRoot BP Plus RRM 94.4% (67/71)			Yes	High bias
Kandemir Demirci et al., 2019[53]	Paralleling	PAI index	MTA: 92.3% (36/39) CH: 91.1%(31/34)			Yes	Low bias
Safi et al., 2019[22]	PA radiograph: NM CBCT done with 3 different machines	Rud and Molven criteria Modified Penn 3-dimensional criteria	PA: MTA: 94.7% (54/57) ERRM: 92% (58/63) CBCT: MTA: 86% (49/57) ERRM: 84% (53/63)			Yes	Low bias
Von Arx et al., 2019a[21]	CBCT	RAC/B criteria	B indicates the overall healing Success rate at 1 year: 85.1% (40/47) Success rate at 5 years: 95.7%(45/47)			Yes	Moderate bias
Von arx et al., 2019b[54]	Paralleling	Rud and Molven	MTA: 81.5% (97/119)			Yes	Moderate bias
Taha et al., 2021[55]	Paralleling	Rud and Molven criteria	ERRM: 93% (41/44)			Yes	Low bias
Von arx et al., 2020[56]	No	Rud and Molven	BCRRM: 94.1% (160/170)			Yes	Moderate bias

RAC/B: R-resection plane, A: Apical area, C: Cortical plate, B: Bone healing overall, MTA: Mineral trioxide aggregate, IRM: Intermediate restorative material, CH: Calcium hydroxide, Super-EBA: Super ethoxybenzoic acid, RRM: Root repair material, ERRM: EndoSequence RRM, BP: Blood pressure, BCRRM: Bioceramic Root Repair Material, PA: Cone-beam computed radiography, CBCT: Cone-beam computed radiography, ESE: European Society of Endodontology, PAI: Periapical index, RACB: Calcium elevation, renal dysfunction, anemia, and bone disease, GP: Gutta-percha, NM: Not mentioned, ROB: Risk of bias, FS: Fast setting

Risk-of-bias assessment

Two independent investigators (RRN and SY) performed risk-of-bias (ROB) assessment of all selected studies, and discrepancies were resolved by discussion with a third investigator (RKM). Cochrane ROB tool was used for RCTs.[57,58] Whereas, the National Institutes of Health (NIH) tool was used for cohort studies[15](https://www.nhlbi.nih.gov/health-pro/guidelines/in-develop/cardiovascular-risk reduction/tools/cohort). Six criteria were included in Cochrane's ROB tool (randomization process, blinding, deviation from intended intervention, incomplete outcome measures, selective reporting, and other sources of bias). In NIH tool, a total of 11 relevant criteria were assessed (research question, study population and eligibility criteria clearly specified, sample size calculation, sufficient time frame to see an outcome, timing of exposure, exposure measure, outcome measure, evaluator blinded, attrition bias, and appropriate statistical analysis).

Effect measures

For dichotomous statistical analysis, successful outcome was defined as the absence of clinical signs and symptoms and complete/incomplete radiographic healing. Whereas, the presence of clinical signs and symptoms or uncertain/unsatisfactory healing was considered failure.

Synthesis methods

The data were extracted for primary outcome, i.e., success rate of BEC and traditional materials. The meta-analysis of the eligible studies was performed using “Metan package” STATA version 12.0 (College Station, TX, USA, StataCorp LP.) to obtain pooled odds ratio (OR) and its 95% confidence interval (CI) and Metafor package available in R-software version 3.6.1 for calculating pooled success rates. Freeman–Tukey double-arcsine transformation was done to stabilize the variance, and Clopper–Pearson interval method was applied for determining the 95% CI of an individual study. The heterogeneity between the studies was determined using Higgins index (I²). As it was >50%, a random effect model was used for meta-analysis. DerSimonian and Laird method was used for estimating the variance between the studies. In case of OR, Mantel–Haenszel pooling model was used for both fixed effect and random effect.

The effect of BEC on success rate was compared with other traditional materials using z-test. Subgroup analysis was done based on treatment rendered. The meta-regression was done to find the effect of duration and year of publication on success percentage. P < 0.05 was considered statistically significant.

Reporting bias assessment

The potential publication bias was assessed by visual inspection of funnel plot and verified using Egger's and Begg's test and considered indicative of statistical significance of publication bias when P < 0.1. Trim-and-fill analysis was also performed to find any missing studies in case publication bias was detected.

Certainty of evidence grading

Certainty of evidence was assessed using the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) approach.[59,60] RCTs were rated initially as “high” certainty of evidence and were downgraded based on five parameters – ROB, inconsistency, indirectness, imprecision, and publication bias. All the observational studies were rated initially as “low” certainty of evidence. Observational studies were downgraded based on the five parameters mentioned before or upgraded based on large magnitude of effect or dose–response gradient. The overall certainty of evidence was rated as “very low,” “low,” “moderate,” or “high” quality.

RESULTS

Search selection

The search process yielded 4710 articles; on removing duplicates, 2819 articles were included. After reading their titles and abstracts, 2732 studies were excluded. Finally, the full texts of 88 articles that remained were studied in detail. Out of these 88 articles, 39 studies qualified for systematic review [Table 2].[18,19,20,21,22,23,24,25,26,27,28,29,30,31,32,33,34,35,36,37,38,39,40,41,42,43,44,45,46,47,48,49,50,51,52,53,54,55,56] Reasons for exclusion for 49 articles were documented [Supplementary Table S2]. PRISMA flowchart depicting the entire search process is depicted in Figure 1. Of the 39 selected articles for the systematic review, 32 articles were found to be suitable for pooling of data for meta-analysis. Seven articles[27,29,30,31,32,38,49] were excluded because the same study population (or along with new subjects) was subsequently published after a longer follow-up time.

Supplementary Table S2.

Studies excluded after full-text review along with reason for exclusion

Authors	Reason(s) for exclusion
Karan and Aricioğlu 2020[61], Asgary and Ehsani 2013[62], Pace et al., 2007[63], Pace et al., 2008[64], Erdem and Sepet 2008[65], Nosrat et al., 2011[66], Sarris et al., 2008[67], Main et al., 2004[68], Sutter et al., 2020[69], Fu et al., 2011[70], Xu et al., 2007[71], De Chevigny et al., 2008[72], Ng et al., 2011a[73], Chen and Chen 2016[74]	Sample size inadequate or not defined
Rahbaran et al., 2001[75], Danin et al., 1999[76], Rapp et al., 1991[77], Park et al., 2009[78], Lin et al., 2017[79], Ajayi et al., 2018[80], Taschieri et al., 2007[81]	Tricalcium silicate-based cement not used
Kurt et al., 2014[82], Damle et al., 2012[83], Demiriz and Hazar Bodrumlu 2017[84]	Poor methodology (root-end resection not performed in endodontic surgery/extremely poor quality radiographs making the outcome assessment biased)
Kim et al., 2018[85]	Assessment of effect of REF material on osseous healing not assessed
Ghoddusi et al., 2007[86], Tanomaru-Fllho et al., 2015[87], Nayar et al., 2009[88], Saunders 2008[89], Witherspoon et al., 2008[90], Damle et al., 2016[91], Öğütlü and Karaca 2018[92], Chan et al., 2020[93], Ghaziani et al., 2006[94]	Inadequate/in-homogenous follow-up or follow-up <1 year
Witherspoon and Ham 2001[95], Ree and Schwartz 2017[96]	Case report, case series
Lyons et al., 1995[97]	Commentary
Bryce et al., 2013[98]	Adjunctive osseo-inductive materials used along with tricalcium silicate cement as root repair materials
Lee et al., 2015[99], Christiansen et al., 2009a[100], Uğur Aydın et al., 2019[101], Aminov et al., 2012[102]	Outcome measures not mentioned in terms of success
Kim et al., 2016a[103], Song et al., 2012a[104], Song et al., 2011a[105], Kim et al., 2008[106], Alobaid et al., 2014[107]	Outcome measures not reported separately for different REF or apexification materials
Crossen et al., 2019[108]	The type of REF material not mentioned
Huang et al., 2020[109]	Inclusion of teeth with combined periodontal endodontic involvement

REF: Root-end filling

Figure 1.

PRISMA 2020 flowchart of the selection process for including studies in systematic review and meta-analysis

Study characteristics

The relevant characteristics of the 39 eligible studies are mentioned in Table 2. Out of these, 11 were randomized clinical trials, and 28 were observational studies. 17, 11, and 4 studies were identified for endodontic surgery, apexification, and perforation repair, respectively. In total, there were 2453 teeth where BEC (MTA, ERRM, Totalfill, and iRoot BP Plus) were used and 778 teeth where other traditional materials (intermediate restorative material (IRM), super ethoxybenzoic acid (super-EBA), calcium hydroxide, and retroplast) were used. Out of 32 studies, thirty used ProRoot MTA variant. The median sample size of studies was 98 (min-max: 20–107) and the follow-up duration varied from minimum 1 year to a maximum of 10.6 years. The median follow-up percentage was 82.05% (min-max: 49.5%–100%).

Meta-analysis for studies comparing bioactive endodontic cement to other traditional materials

Out of 32 studies, 11 studies compared BEC to other traditional materials (IRM, super-EBA, calcium hydroxide, and retroplast). To compare the success of BEC with other traditional materials, OR was calculated using a random-effects method. Overall BEC had significantly higher odds of success than any other material (OR = 2.15, 95% CI = 1.57–2.96, I² = 0.8%) [Figure 2a]. The visual impact of the funnel plot for these 11 studies showed some asymmetries, but when tested by Egger's and Begg's test, P value was statistically insignificant with P = 0.065 and P = 0.312, respectively [Figure 2b].

Figure 2.

Forest plot showing the odds ratio for studies comparing the success rate of bioactive endodontic cement with other traditional materials (a). Funnel plot for assessment of publication bias (b)

Meta-analysis for pooled success rate of bioactive endodontic cement (mineral trioxide aggregate versus newer bioactive endodontic cement)

The pooled success rate for BEC was estimated by a random method as 90.49% (95% CI: 88.49-92.34, I² = 54%) as the overall heterogeneity was moderate [Supplementary Figure S1 ^{(1.2MB, tif)} ]. When material-wise comparison was made, the pooled success rate for MTA and newer BEC (ERRM, Totalfill FS, and iRoot BP Plus) was 90.13% (95% CI: 87.82–92.23) and 92.32% (95% CI: 88.98–94.40), respectively. Regression test for asymmetry was insignificant with P = 0.608, but funnel plot revealed mild deviation [Supplementary Figure S2 ^{(180.1KB, tif)} ]. Nevertheless, trim-and-fill analysis found no addition of studies indicating the absence of publication bias.

Risk-of-bias assessment of included studies

The quality appraisal of the 32 studies revealed that 14 studies reported low bias, 10 moderate bias, and 8 high bias [Figure 2 and Supplementary Table S3]. Among the RCTs, six were rated as high ROB and three as low ROB. An inter-examiner reliability analysis on overall assessment by using the kappa statistics indicated an inter-examiner reliability of 0.860 among the RCTs and 0.81 between the cross-sectional studies, suggesting excellent agreement.

Supplementary Table S3.

Risk of bias in observational cohort and cross-sectional studies published by the National Institutes of Health

Authors	Study design	Research question	Study population clearly specified	Uniform eligibility criteria	Sample size calculation	Timing of exposure assessment	Sufficient time frame to see an effect	Exposure measures	Outcome measures	Blinding of outcome evaluators	Follow- up >80%	Statistical analysis	Overall
Simon et al. 2007	PC	Yes	Yes	Yes	No	Yes	Yes	Yes	Yes	Yes	No	Yes	Low
Holden et al. 2008	RC	Yes	Yes	Yes	No	Yes	Yes	Yes	Yes	Yes	Yes	Yes	Low
Annamalai et al. 2010	PC	Yes	Yes	No	No	Yes	Yes	Yes	No	Yes	Yes	Yes	High
Moore et al. 2011	PC	Yes	Yes	Yes	No	Yes	Yes	Yes	Yes	Yes	Yes	Yes	Low
Song et al. 2011b	RC	Yes	Yes	Yes	No	Yes	Yes	Yes	Yes	No	No	Yes	Moderate
Von arx et al. 2012	PC	Yes	Yes	Yes	No	Yes	Yes	Yes	Yes	Yes	Yes	Yes	Low
Jeeruphan et al. 2012	RC	Yes	Yes	Yes	No	Yes	Yes	Yes	Yes	No	Yes	Yes	Moderate
Pontius et al. 2013	RC	Yes	Yes	Yes	No	Yes	Yes	Yes	No	Yes	No	No	High
Krupp et al. 2013	RC	Yes	Yes	Yes	No	Yes	Yes	Yes	Yes	Yes	No	yes	Moderate
Mente et al. 2013	RC	Yes	Yes	Yes	Yes	Yes	Yes	Yes	Yes	Yes	Yes	Yes	Low
Mente et al. 2014	RC	Yes	Yes	Yes	Yes	Yes	Yes	Yes	Yes	Yes	Yes	Yes	Low
Von arx et al. 2014	PC	Yes	Yes	Yes	No	Yes	Yes	Yes	Yes	No	Yes	Yes	Moderate
Shinbori et al. 2015	RC	Yes	Yes	Yes	No	Yes	Yes	Yes	Yes	Yes	Yes	Yes	Low
Gorni et al. 2016	PC	Yes	Yes	Yes	No	Yes	Yes	Yes	No	No	Yes	Yes	Moderate
Caliskan et al. 2016	PCS	Yes	Yes	Yes	No	Yes	Yes	Yes	Yes	Yes	Yes	Yes	Low
Bucher et al. 2016	RC	Yes	Yes	Yes	No	Yes	Yes	Yes	Yes	No	Yes	Yes	Moderate
Schloss et al. 2017	RC	Yes	Yes	Yes	No	Yes	Yes	Yes	Yes	Yes	Yes	Yes	Low
Sillujai et al. 2017	RC	Yes	Yes	Yes	No	Yes	Yes	Yes	Yes	No	No	No	Moderate
Wang et al. 2017	PC	Yes	Yes	Yes	No	Yes	Yes	Yes	Yes	Yes	No	Yes	Moderate
Von arx et al. 2019a	PC	Yes	Yes	Yes	No	Yes	Yes	Yes	Yes	Yes	No	Yes	Moderate
Von arx et al. 2019b	PC	Yes	Yes	Yes	No	Yes	Yes	Yes	No	Yes	No	Yes	Moderate
Von arx et al. 2020	PC	Yes	Yes	Yes	No	Yes	Yes	Yes	No	Yes	Yes	Yes	Moderate
Taha et al. 2021	PC	Yes	Yes	Yes	No	Yes	Yes	Yes	Yes	Yes	Yes	Yes	Low

*PC: Prospective cohort, RC: retrospective cohort, PCS: Prospective clinical study

Sensitivity analysis

The results of leave-one-out analysis revealed that all the studies had an equal effect on the success rate. The overall estimate of the success rate varied between 90% and 91% [Supplementary Figure S3 ^{(863.3KB, tif)} ]. The meta-regression was applied considering individual predictor: duration of study and year of publication. The year of publication did not have any influence on the success rate while the duration of the study had a significant negative correlation with success rate (data not shown).

Certainty of evidence

The results of certainty of evidence assessment are shown in Supplementary Table S4. The GRADE evaluation showed that the evidence was of very low-to-moderate quality.

Supplementary Table S4.

Certainty of evidence based on Grading of Recommendations, Assessment, Development, and Evaluation approach

Study type	n	Initial rating	ROB	Indirectness (PICO and applicability)	Imprecision (blinding/loss to follow-up)	Inconsistency (heterogeneity)	Publication bias	Certainty of evidence rating
RCTs (19, 27,28, 29, 47, 50, 57)	7	High	Major concerns	No concerns	Some concerns	No concerns	No concerns	Moderate
Observational studies (39, 40, 41, 46)	4	Low	Major concerns	No concerns	Some concerns	No concerns	No concerns	Very low

PICO: Population, Intervention, Comparison, and Outcomes, ROB: Risk of bias, RCTs: Randomized controlled trials

DISCUSSION

The main goal of the endodontic treatment is to remove the source of infection, thereby creating a favorable environment for inducing periapical healing.[23] The biocompatibility and sealing ability of the endodontic materials can have a significant effect on the treatment outcome. During the last two decades, there has been an increase in the number of published literature related to bioactive materials. This is partly because of the increased acceptance of these bioactive materials by treating dentists and because of the willingness of the patient to save their natural teeth. Hence, this systematic review was conducted to analyze if the use of BEC as root repair material translates to better treatment outcome.

Literature search strategy

Before starting this systematic review, existing literature and PROSPERO database were searched to check if similar systematic review has been carried out or is in process. To ensure extensive coverage of literature, three electronic databases were searched to ensure low selection bias. Cochrane handbook also recommends these three databases for a systematic review of RCTs.[57] Involvement of three authors in screening process also ensured the absence of selection bias.[110]

Applicability of the evidence

The age group of the participants in the included studies ranged from 8 to >65 years and included male and female genders. Both anterior and posterior teeth were included. High-quality studies using BEC for a broad scope of clinical applications were included instead of focusing on a particular treatment application. The present systematic review was conducted with broader inclusion criteria to include all BEC. The pooled success rate for MTA and newer BEC was estimated to be 90.13% and 92.32%, respectively, with no significant difference between the two, indicating that the newer alternatives also show promising results. Among the 39 eligible studies, newer BEC were only used in periapical surgery as REF. Two studies wherein MTA and newer BEC materials were compared were also included in the present review.[22,52] Both the studies recorded a higher success rate for newer BEC, with no significant difference between MTA and newer BEC. However, most of the studies on newer BEC lack long-term follow-up and the results should be extrapolated cautiously.

Of the 32 eligible studies, 11 studies compared BEC with other traditional materials. All these 11 studies used MTA. Studies comparing newer BEC with traditional materials are lacking in literature. Out of these 11 studies, 7 were randomized trials indicating strong level of evidence. The use of BEC significantly improved the treatment outcome compared to other conventional materials for apexification and periapical surgery (OR = 2.15).

Study design of the included studies

For a systematic review analysis, RCTs are preferred type of studies for inclusion due to their low ROB. However, in the present review, both RCTs and observational studies were included to take into consideration studies with longer follow-ups. In the present meta-analysis, most of the randomized trials had a mean follow-up of 12 months. The longest follow-up time was 10 years for a prospective cohort in periapical surgery.[54] While, retrospective cohorts for apexification and perforation repair showed maximum follow-up times of 10.6 years and 9.6 years, respectively.[18,39]

Follow-up time is a crucial factor for clinical studies investigating the treatment outcome. Previous studies have shown that longer follow-ups may change the success rates for a given treatment.[111,112] This finding was corroborated in one of the included studies with a 10 year follow up after endodontic surgery.[54] It noted a significant reduction in healed cases during the observation period from 5 to 10 years (91.4% to 81.5%). In addition, long-term follow-up can help in identification of additional prognostic factors, which were not significant in short-term follow-up studies. For example, a long-term follow-up study conducted by Mente et al. with a larger sample concluded that operator's experience and the presence of periapical lesion had a significant effect on outcome of MTA apexification.[18] However, the authors in their previous study with smaller study cohort and shorter follow-up time did not identify these prognostic factors.[30]

Risk of bias and quality of the study

ROB evaluation constitutes an important factor in assessing the quality of included studies. As studies with different study designs were included in the present meta-analysis, two different tools were used for ROB assessment. On evaluation, three out of nine RCTs were found to be of low bias, while six showed high bias. Attrition bias or missing outcome data was seen in five of these studies.[19,23,24,46,52] Sufficient information was missing related to randomization process and allocation concealment in five of the included RCTs indicating potential selection bias.[23,24,25,46,52] Well-designed RCTs are considered gold standard of research, however, high-bias studies may present the exaggerated effect of the intervention.[113] Hence, future studies should focus on addressing these issues.

Among the included cohort studies, major source of bias was in the measurement of the outcome due to nonblinding of the evaluators, the use of nonstandardized radiographs, and lack of report on inter-examiner and intra-examiner agreement and reliability. Given the nature of the clinical study, it may not be always possible to blind the participant and caregiver. Nevertheless, the evaluator should be blinded to the study groups during radiographic evaluation by randomly numbering the pre- and postoperative radiographs of different groups. In addition, inviting independent evaluators who are not involved in the procedure can also reduce the bias in outcome assessment. It was difficult to rate several cohort studies as barring a few[18,41] most studies did not mention their power calculation for sample size. It is relevant to note that some of the previously conducted systematic reviews for BEC did not take into account the ROB of eligible studies.[14,16]

Influence of bioactive endodontic cement on different treatment applications

The success of periapical surgery is strongly influenced by the properties of REF material. BEC have gained popularity as REF material due to their excellent sealing ability and biocompatibility. Some of the previous studies could not find any significant difference between the success rates of BEC and other materials. Kim et al. found no significant difference in the outcomes of endodontic surgery when super-EBA and MTA were used as REF material at 4-year follow-up.[19] However, the results of the present review suggest BEC to have a definitive advantage when used as REF material, as they clearly showed higher odds of success (OR = 2.1) when compared to other materials in RES subgroup.

For apexification subgroup, BEC were associated with significantly higher odds of success (OR = 2.73). Several prognostic factors have been shown to affect the treatment outcome of apexification. Mente et al. in a historical cohort evaluated the effect of potential prognostic factors on long-term outcome (up to 128 months) of MTA apexification.[18] They concluded that only preoperative periapical radiolucency and operator's experience had a significant impact on the treatment outcome. Teeth without preoperative periapical lesion showed a success rate of 96% compared to 85% for teeth with preoperative periapical lesion. Whereas, Kandemir Demirci et al. concluded that the healed rate of MTA apexification (92%) was similar to that of CH apexification at 1-year follow-up (91%) and none of the tested clinical factors (age/gender/root development stage) had a significant impact on the outcome of apexification.[53]

Four studies were identified for perforation repair, but none of these compared BEC with traditional materials. Several prognostic factors are known to have an influence on the success of perforation repair. Mente et al.[41] assessed the long-term outcome of root perforation repair managed with orthograde placement of MTA and found that the success rates of perforation repair with MTA remained consistently high (86%), even after follow-up periods of up to 9 years. They also stated that the use of BEC like MTA, as perforation repair materials, reduced the impact of the earlier known potential prognostic factors such as location/size of perforation and time lapsed on the outcome of perforation repair.

Cone-beam computed radiography for radiographic outcome assessment

Three studies where bony healing was assessed three dimensionally using cone-beam computed radiography (CBCT) were also included in this review which augmented our understanding of osseous healing. Modified Penn criteria and RAC/B criteria were used for measuring treatment outcome in these studies.[20,21,22] CBCT can be particularly helpful in distinguishing between inconclusive and incomplete healing. Schloss et al. compared the accuracy of CBCT and periapical radiographs in assessing osseous healing after endodontic surgery, and found a statistically significant difference between the two methods. The number of completely healed cases was significantly lower with CBCT, indicating that periapical radiography often results in overassessment of success rate.[20] In another long-term prospective clinical study, 5-year follow-up CBCT scans revealed that cortical bone formation was incomplete in almost 50% of the cases even after 5 years of apical surgery.[21] In summary, the overall success rate tends to be lower with CBCT imaging due to its superior accuracy. This finding can be attributed to the fact that CBCT has higher sensitivity as compared to periapical radiographs in detection of periapical lesions.[114] However, future studies are desired to validate the correlation between CBCT and histopathological findings of periapical lesions.

Strengths and limitations

Strength of this meta-analysis lies in the fact that it investigated a large number of teeth treated with BEC as root repair material (2493 teeth). Among the BEC, studies for MTA had longer follow-up (up to 10 years) and larger sample sizes, indicating high level of evidence for MTA. Studies with short follow-up (<12 months) and small sample size (n <20) were not included in the systematic review as such studies are underpowered. Furthermore, these studies are usually associated with additional biases, which adversely affect the likelihood, that a statistically significant finding actually reveals a true effect.[115]

To the best of our knowledge, this is the first systematic review to analyze the success rate of newer BEC and included studies wherein CBCT-based assessment of osseous healing was done. As MTA gets gradually replaced with newer BEC, the results of the present systematic review can help the clinicians in making an informed choice.

However, the present review has certain limitations. Moderate heterogeneity was seen among the included studies as indicated by I² value of 30%–60%. The sources of heterogeneity can be clinical, methodological, and statistical. However, I² is a measure of only statistical heterogeneity. To address the statistical heterogeneity, a random-effects model was used for meta-analysis.

CLINICAL IMPLICATIONS AND CONCLUSIONS

From the systematic review, there is a clear evidence to support the fact that BEC can potentially improve the clinical and radiographic treatment outcome. The body of evidence that this conclusion is based on is of “very low” to “moderate” certainty. Investigations with higher level of evidence are mainly limited to MTA. Well-conducted randomized trials are required to determine whether the newer BEC enjoy the same success as MTA when used as root repair material. In addition, future studies evaluating osseous healing using CBCT are needed.

Registration

The protocol was registered in the International Prospective Register of Systematic Reviews (PROSPERO) under the registration number: CRD42020211502.

Availability of data and other materials

Analytic data and other materials will be made available only upon request. Contact Person: Dr. Sudha Yadav (email ID: sudhayadav2788@gmail. com).

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

Supplementary Figure 1

Forest Plot showing weighed pooled success rates for bioactive endodontic cement and proportion of success in MTA and newer BEC. MTA: Mineral trioxide aggregate, BEC: Bioactive endodontic cement

Supplementary Figure 2

Funnel plot for assessment of publication bias in studies assessing treatment outcome with calcium silicate-based cement

Supplementary Figure 3

Results of leave-one-out analysis for sensitivity analysis to calculate the overall success rate of calcium silicate-based cement