Journal of the Formosan Medical Association (2016) 115, 523e530

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ORIGINAL ARTICLE

Comparison of mineral trioxide aggregate

and calcium hydroxide for apexification of
immature permanent teeth: A systematic
review and meta-analysis
Jia-Cheng Lin, Jia-Xuan Lu, Qian Zeng, Wei Zhao, Wen-Qing Li,
Jun-Qi Ling*

Guanghua School of Stomatology, Guangdong Provincial Key Laboratory of Stomatology, Sun Yat-sen
University, Guangzhou, China

Received 6 November 2015; received in revised form 14 January 2016; accepted 20 January 2016

KEYWORDS Background/purpose: Calcium hydroxide and mineral trioxide aggregate (MTA) are used for
apexification; inducing a calcific barrier at an open tooth root (apexification). The purpose of this study
calcium hydroxide; was to compare the efficacy of calcium hydroxide and MTA for apexification of immature per-
immature teeth; manent teeth.
mineral trioxide Methods: Medline, Cochrane, EMBASE, and Google Scholar were searched until November 24,
aggregate 2015, using the keywords apexification, permanent teeth, MTA, and calcium hydroxide.
Results: Of 216 studies identified, four studies were included. There were no differences in the
clinical success rate [pooled odds ratio (OR) Z 3.03, 95% confidence interval (CI): 0.42e21.72,
p Z 0.271], radiographic success rate (pooled OR Z 4.30, 95% CI: 0.45e41.36, p Z 0.206), or
apical barrier formation rate (pooled OR Z 1.71, 95% CI: 0.59e4.96, p Z 0.322) between cal-
cium hydroxide and MTA groups. The time required for apical barrier formation was signifi-
cantly less in the MTA group (pooled difference in means Z 3.58, 95% CI: from 4.91 to
2.25, p < 0.001).
Conclusion: While both materials provide similar success rates, the shorter treatment time
with MTA may translate into higher overall success rates because of better patient compliance.
Copyright ª 2016, Formosan Medical Association. Published by Elsevier Taiwan LLC. This is an
open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/
by-nc-nd/4.0/).

Conflicts of interest: All authors declare that no conflicts of interest exist.

Funding/support statement: This study was provided by the Sun Yat-sen University Clinical Research 5010 Programme (No. 2012016).
* Corresponding author. Guanghua School of Stomatology, Sun Yat-sen University, Number 56 Lingyuanxi Road, Guangzhou, Guangdong
510055, China.
E-mail address: lingjq@mail.sysu.edu.cn (J.-Q. Ling).

http://dx.doi.org/10.1016/j.jfma.2016.01.010
0929-6646/Copyright ª 2016, Formosan Medical Association. Published by Elsevier Taiwan LLC. This is an open access article under the
CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
524 J.-C. Lin et al.

Introduction reference lists of potentially relevant articles were also

hand-searched. A third reviewer was consulted where there
Apical periodontitis can lead to pulpal necrosis and arrest was uncertainty regarding eligibility, and a decision arrived
of root development, and is especially challenging to treat at by consensus.
in immature permanent teeth in children.1 Untimely or
incorrect management can result in loss of permanent Study selection criteria and data extraction
teeth, disorders of mandibular growth and masticatory
function, and even speech disorders and facial cosmetic Study inclusion criteria were: (1) randomized controlled
impairment.1,2 Thus, correct treatment to prevent any loss trials, prospective and retrospective studies, and case se-
of these teeth is vitally important. Apexification is a ries; (2) patients had permanent immature teeth for which
nonsurgical method of inducing a calcific barrier at the apexification was indicated; (3) compared calcium hy-
open root apex of nonvital teeth.1,2 The barrier prevents droxide versus MTA; and (4) reported quantitative clinical
toxins and bacteria from entering periradicular tissue, and or radiographic outcomes. Letters, comments, editorials,
facilitates placement of a root canal sealant and filling case reports, proceedings, and personal communications
material.3 However, an ideal apexification material has yet were excluded. Studies that were performed in vitro and
to be determined. those that did not report a quantitative primary outcome
Calcium hydroxide is commonly used for apexification as were also excluded. The following information/data were
it has no adverse periapical reactions, predictable results, extracted from studies that met the inclusion criteria: the
and can be mixed with a number of different substances name of the first author, year of publication, study design,
(camphorated mono chlorophenol, distilled water, saline, number of participants in each group, participants’ age and
anesthetic solutions, chlorhexidine, and cresatin) to induce sex, intervention, and clinical outcomes.
apical closure.1,2 However, calcium hydroxide has a number
of limitations including variable treatment time ranging Quality assessment
from 5 months to 20 months, apical closure in relationship
to treatment time is unpredictable, an increased risk of
The methodological quality of each study was assessed
tooth fracture, and poor patient compliance with follow-up
using the risk-of-bias assessment tool outlined in the
due to the extended treatment time, all of which can affect
Cochrane Handbook for Systematic Reviews of In-
treatment outcomes.1,2
terventions (version 5.1.0).8 Briefly, six domains are eval-
Mineral trioxide aggregate (MTA) is used as an apical
uated: (1) random sequence generation; (2) allocation
barrier for teeth with immature apices, repair of root
concealment; (3) blinding of patients and personnel; (4)
perforations, root-end filling, pulp capping, and pulpotomy
blinding of outcome assessment; (5) incomplete outcome
procedures.4 MTA has a number of favorable characteristics
data; and (6) selective reporting risk. Risks of bias figures
including biocompatibility, antimicrobial activity and pre-
were generated using Cochrane RevMan version 5.3 (The
vention of bacterial leakage, no cytotoxicity, and can
Nordic Cochrane Centre, Copenhagen, Denmark).
stimulate cytokine release from bone cells to promote hard
tissue formation.5,6 It also has a shorter treatment time
compared with calcium hydroxide, and a more predictable Outcome measures and data analysis
time to apical closure.5,6 However, MTA has some limita-
tions such as nonreinforcement of root canal dentin and a The primary outcome was the clinical success rate. Sec-
higher cost than calcium hydroxide.5,6 In addition, there ondary outcomes were radiographic success rate, apical
are few studies examining the long-term efficacy of MTA for barrier formation rate, and the time required for apical
endodontic treatment in primary teeth.4 barrier formation.
Few high-quality studies have directly compared the Pooled odds ratios (ORs) were calculated for the
outcomes of calcium hydroxide and MTA for apexification, clinical success rate, radiographic success rate, and api-
and thus there is no consensus as to which may be associ- cal barrier formation rate, and compared between the
ated with superior outcomes. Thus, the purpose of the calcium hydroxide and MTA groups. Differences in means
current study is to perform a meta-analysis comparing the for the time required for apical barrier formation were
outcomes of calcium hydroxide and MTA for the apex- calculated and compared between the two groups. The
ification of immature permanent teeth. Cochran Q and the I2 statistic were used to assess het-
erogeneity among studies. A value of p < 0.10 of the Q
statistic was considered to indicate statistically significant
Methods heterogeneity. The I2 statistic indicates the percentage of
the observed between-study variability due to heteroge-
Strategy of literature search neity rather than chance, and a value > 50% was
considered to indicate significant heterogeneity. If either
PRISMA guidelines were used when conducting this sys- the Q statistic or I2 statistic indicated heterogeneity was
tematic review and meta-analysis.7 Medline, Cochrane, present, a random-effects model of analysis was used
EMBASE, and Google Scholar were searched from inception (DerSimonianeLaird method). If no heterogeneity was
until November 24, 2015, using combinations of the key- present, a fixed-effects model (ManteleHaenszel method)
words apexification, permanent teeth, MTA, and calcium was used. Sensitivity of the meta-analysis was assessed
hydroxide. Searches were performed by two independent using the leave-one-out approach. A two-sided p
reviewers to identify potentially relevant articles, and the value < 0.05 was considered to indicate statistical
Calcium hydroxide or MTA for apexification 525

significance. If there were five or less studies, publication Figure 1. Thus, four studies were included in the meta-
bias was not assessed because more than five studies are analysis.10e13
required to detect funnel plot asymmetry.9 All statistical A total of 80 teeth were included in the four studies, and
analyses were performed using the statistical software a summary of the characteristics and outcomes of the four
Comprehensive Meta-Analysis, version 2.0 (Biostat, Eng- studies are shown in Table 1. The total number of teeth in
lewood, NJ, USA). the MTA groups ranged from 10 to 15, the total number of
teeth in the calcium hydroxide group ranged from 10 to 15,
Results and the patient ages ranged from 6 years to 12 years. The
clinical success rate ranged from 93% to 100% in the MTA
Study characteristics groups, and from 87% to 100% in the calcium hydroxide
groups. The radiographic success rate was 100% in the MTA
A flow diagram of the study selection is shown in Figure 1. groups and ranged from 87% to 93% in the calcium hydroxide
A total of 216 studies were identified in the database groups. The number of teeth with apical barrier formation
search, and 201 nonrelevant studies were excluded. The ranged from seven to 18 in the MTA groups, and from 10 to
full texts of 15 articles were examined for eligibility and 10 13 in the calcium hydroxide groups, while the time required
were excluded, the reasons for which are shown in for apical barrier formation ranged from 3.0 months to

Figure 1 Flow diagram of the study selection.

526 J.-C. Lin et al.

Table 1 Basic characteristics of studies included in the meta-analysis.

Study (y) No. of No. Intervention Age Male No Clinical Radiographic Apical Time required for
patients of (y) (%) tenderness success success (%) barrier apical barrier
teeth to (%) formation formation (mo)a
percussion
Bonte 17 NR MTA 10.2 47 16/17 NR NR 13 NR
et al10 (2.8)a
(2015) 16 NR Calcium 10.9 63 15/16 NR NR 8 NR
hydroxide (3.6)a
Damle 15 15 MTA Range: NR 15/15 100 100 13 4.5 (1.56), n Z 14
et al11 15 15 Calcium 8e12 NR 15/15 93.3 93.3 13 7.93 (2.53), n Z 14
(2012) hydroxide
El Meligy & 15 15 MTA Range: NR 15/15 100 100 15 NR
Avery12 15 Calcium 6e12 NR 15/15 87 87 13 NR
(2006) hydroxide
Pradhan NR 10 MTA NR NR NR 100 NR 7 3.0 (2.9), n Z 7
et al13 NR 10 Calcium NR NR NR 100 NR 10 7.0 (2.5), n Z 10
(2006) hydroxide
MTA Z mineral trioxide aggregate; NR Z not reported.
a
Mean (standard deviation).

4.5 months in the MTA groups and from 7.0 months to group (pooled OR Z 4.30, 95% CI: 0.45e41.36, Z Z 1.26,
7.9 months in the calcium hydroxide groups. p Z 0.206).

Clinical success rate

Apical barrier formation rate
There was no significant heterogeneity when data from the
three studies reporting clinical success rate11e13 were All four studies provided apical barrier formation rate data
pooled (Q Z 0.44, df Z 2, p Z 0.801, I2 Z 0%); therefore, a and were included in the analysis.10e13 There was no sig-
fixed-effects model of analysis was used (Figure 2). The nificant heterogeneity when data from the four studies
analysis revealed that there was no statistical difference in were pooled (Q Z 4.70, df Z 3, p Z 0.195, I2 Z 36.20%);
clinical success rate between the MTA group and calcium therefore, a fixed-effects model of analysis was used
hydroxide group (pooled OR Z 3.03, 95% CI: 0.42e21.72, (Figure 3B). The analysis revealed there was no statistical
Z Z 1.10, p Z 0.271). difference in the apical barrier formation rate between the
MTA group and the calcium hydroxide group (pooled
Radiographic success rate OR Z 1.71, 95% CI: 0.59e4.96, Z Z 0.99, p Z 0.322).

Only two studies11,12 reported radiographic success rate Time required for apical barrier formation
data. There was no significant heterogeneity when data
from the two studies were pooled (Q Z 0.06, df Z 1, Two studies11,13 reported the time required for apical
p Z 0.810, I2 Z 0%); therefore, a fixed-effects model of barrier formation. There was no significant heterogeneity
analysis was used (Figure 3A). The analysis revealed there when data from the two studies were pooled (Q Z 0.14,
was no statistical difference in the radiographic success df Z 1, p Z 0.711, I2 Z 0%); therefore, a fixed-effects
rate between the MTA group and the calcium hydroxide model of analysis was used (Figure 3C). The time required

Figure 2 Forest plot for the meta-analysis of clinical success rate. CI Z confidence interval; MTA Z mineral trioxide aggregate.
Calcium hydroxide or MTA for apexification 527

Figure 3 Forest plots for the meta-analysis of: (A) radiographic success rate; (B) apical barrier formation rate; (C) time required
for apical barrier formation. CI Z confidence interval; MTA Z mineral trioxide aggregate.

for apical barrier formation was significantly less in the MTA Publication bias
group (pooled difference in means Z 3.58, 95% CI: from
4.91 to 2.25, Z Z 5.27, p < 0.001). Publication bias was not assessed for these outcomes
because more than five studies are required to detect
funnel plot asymmetry.

Sensitivity analysis
Quality assessment
The results of meta-analysis using the leave-one-out
approach to assess sensitivity are summarized in Figure 4. Results of the quality assessment of the studies are shown
The direction and magnitude of the pooled estimates of in Figures 5A and 5B. Three of the four included studies had
clinical success rate did not vary considerably when indi- low risk of bias in random sequence generation. All
vidual studies were removed in turn, indicating that the included studies had low risk of bias in incomplete outcome
meta-analysis had good reliability. data and selective reporting. However, two of the four

Figure 4 Results of the sensitivity analysis to examine the influence of individual studies on pooled estimates for clinical success
rate using the leave-one-out approach. CI Z confidence interval; MTA Z mineral trioxide aggregate.
528 J.-C. Lin et al.

Figure 5 Quality assessment results using the risk-of-bias assessment tool outlined in the Cochrane Handbook for Systematic
Reviews of Interventions (version 5.1.0): (A) risk of bias summary; and (B) overall assessment of risk of bias.

studies had high risk of bias in blinding of participants and outcomes for the apexification of immature permanent
personnel, and three studies had an unclear risk of bias in teeth, as no consensus has been reached with respect to
intention-to-treat bias. Overall, the included studies had the use of these two materials and they both have unique
low risk in attrition bias and reporting bias, but had high advantages and drawbacks. The results showed that both
risk in performance bias. materials had similar clinical success rates, radiographic
success rates, and apical barrier formation rates. However,
MTA was associated with a significantly shorter time to
Discussion achieve apical barrier formation than the calcium hydrox-
ide. This is of significance because many failures with cal-
The purpose of this meta-analysis was to determine cium hydroxide are due to poor patient follow-up because
whether calcium hydroxide or MTA provides better of the extensive treatment time.
Calcium hydroxide or MTA for apexification 529

Calcium hydroxide has long been considered the Other studies that did not meet the inclusion criteria for
method of choice for apexification, but its disadvantages this analysis support the use of MTA. Lee at al17 divided 40
including a prolonged treatment time have resulted in necrotic open-apex incisors in 40 children 6.5e10 years of
the search for new material.1,2 MTA is a mixture of age into four treatment groups: Group 1, ultrasonic filing
Portland cement and bismuth oxide that contains dical- and MTA placement; Group 2, ultrasonic filing and calcium
cium silicate, tricalcium silicate, tricalcium aluminate, hydroxide; Group 3, hand filing and MTA; and Group 4, hand
and tetracalcium aluminoferrite, as well as other mineral filing and calcium hydroxide. Ultrasonic filing plus MTA had
oxides.14 The pH of 12.5 after setting is similar to that of the shortest time for apical hard tissue barrier formation,
calcium hydroxide.14 MTA is unique in that it is the first whereas calcium hydroxide apexification was better than
material that has been shown to consistently allow for MTA with respect to elongation of apical root length.
over growth of cementum and promote periodontal tissue Qudeimat et al18 randomly assigned 64 permanent first
regeneration.6 While there are many animal studies that molars with carious pulp exposures in children to apex-
have examined MTA, high quality human studies ification with calcium hydroxide or MTA. With an average
comparing MTA and calcium hydroxide for apexification of follow-up of 34.8  4.4 months there was no statistical
immature teeth are few. difference in the success rate of teeth treated with calcium
Only one other systematic review has compared calcium hydroxide (91%) or MTA (93%) and a radiographic hard tissue
hydroxide and MTA for the apexificaiton of immature per- barrier under calcium hydroxide was seen in 55% of teeth as
manent teeth. In a meta-analysis published in 2011 by compared with 64% of teeth under MTA (p Z 0.4). Moretti
Chala et al15 comparing calcium hydroxide and MTA, 300 et al19 randomly assigned 45 primary mandibular molars
studies of interest were identified but based on strict with dental caries in 23 children aged between 5 years and
criteria only two were included, and they were two studies 9 years to receive calcium hydroxide, MTA, or control
that were included in the current analysis.12,13 Based on treatment (zinc oxide-eugenol paste). With a follow-up
those two studies, the authors concluded that the results of period of 24 months, clinical and radiographic success was
the two compounds were comparable. A 2010 review noted in all treated teeth in the control and MTA groups and
compared the use of formocresol and MTA in primary teeth dentine bridge formation was detected in 29% of the teeth
pulpotomy, and considering the frequency of radiographic treated with MTA. In teeth treated with calcium hydroxide,
findings such as furcation involvement and the potential 64% of the teeth had clinical and radiographic failures
cytotoxicity of formocresol the authors concluded that MTA during the follow-up period, and internal resorption was a
was preferable.16 frequent radiographic finding.
Individually, the four studies included in the current There are a number of limitations to this study. The
meta-analysis support the use of MTA. El Meligy and Avery12 number of studies was small, and their quality was not high.
performed apexification with calcium hydroxide or MTA in Results of apexification can be operator dependent. In
15 children with at least two necrotic permanent teeth and addition, the definitions of clinical and radiographic success
performed clinical and radiographic evaluations at may have varied between the studies. We did not examine
3 months, 6 months, and 12 months after treatment. the outcomes of the two compounds with respect to their
Persistent periradicular inflammation and tenderness to use for root fractures. These limitations suggest that future
percussion was present at 6 months and 12 months in two of high-quality studies are needed to compare the results of
15 teeth treated with calcium hydroxide and in none of the the two treatments.
teeth treated with MTA. Pradhan et al13 treated 20 nonvital In summary, while both calcium hydroxide and MTA
permanent maxillary incisors with unformed apices with provide similar clinical success and radiographic success
apexification with MTA or calcium hydroxide. The mean rates and apical barrier formation rates, MTA is associated
time taken for apical biological barrier formation for the with a significantly shorter time for apical barrier forma-
MTA and calcium hydroxide groups were 3  2.9 months and tion, thus shortening the treatment time. The shorter
7  2.5 months, respectively, (p Z 0.008), and the total treatment time with MTA may translate into higher overall
treatment times for the two groups were success rates because of better patient compliance with
0.75  0.49 months and 7  2.5 months, respectively. treatment completion.
Damle et al11 treated 30 permanent incisors with necrotic
pulps and open apices with either MTA or calcium hydroxide
with follow-up at 12 months. The mean time to barrier
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