A systematic review on the effect of silver diamine fluoride for management of dental caries in permanent teeth

The objective of this review is to assess the available literature systematically related to the effect of silver diamine fluoride (SDF) for the management of occlusal and root carious lesions in permanent teeth regardless of age.


| INTRODUCTION
Dental caries is still an important public health problem. The World Health Organisation (WHO) indicated that this disease affects not only 60%-90% of schoolchildren but also the majority of adults. This noncommunicable disease is one of the main causes of loss of natural teeth in the aging population (Petersen et al., 2010).
Silver compounds such as silver nitrate have been used in dentistry due to their antimicrobial properties for many decades (Horst et al., 2017;Peng et al., 2012). The cariostatic effect of silver nitrate is believed to be related to the formation of calcified or sclerotic dentine (Stebbins, 1891). Although there was a decline in the use of silver compounds, these compounds have been reintroduced relatively recently due to their low cost and ease of application (Gao et al., 2018).
Silver diamine fluoride [SDF, Ag(NH 3 ) 2 F] is an alkaline (pH~8-9), and colorless topical agent comprising silver and fluoride (Shah et al., 2013). SDF combines the remineralizing effect of fluoride with the antimicrobial effect of silver, which makes SDF treatment effective in controlling carious lesions in comparison to other fluoride treatments such as sodium fluoride varnish (Shah et al., 2013). The mechanism of action is that silver ions (Ag + ) are reported to have antimicrobial effects, and metallic silver (Ag or Ag°) which is relatively inert. The metallic silver can interact with moisture in an oral environment and would release silver ions (Peng et al., 2012). These ions have been suggested to provide three main antimicrobial effects: the destruction of cell wall structure; denaturation of the cytoplasmic enzyme, and inhibition of microbic DNA replication. SDF penetrates the enamel to a depth of up to 25 µm, and approximately 2-3 times more fluoride could be retained in comparison to sodium fluoridemonophosphate, sodium fluoride, or stannous fluoride. Furthermore, the storage period of SDF is longer than that of AgF since Ag + in SDF can be stabilized by forming a silver-diamine complex, [Ag(NH 3 ) 2 F] (Liu et al., 2012).
The concentration of the most commonly used SDF was 38%, which has up to 44,800 ppm fluoride. The remineralization action of SDF on dental caries could be attributed to its high concentration of fluoride, alkaline property (pH = 8-9) and the presence of silver. SDF contains diamine groups, which might enable the formation of NH 4 OH (ammonium hydroxide) and would potentially promote the optimum required pH and conditions for the mineral formation and enhance antibacterial action. The addition of diamine groups would then stabilize silver ions in AgNO 3 (Sliver nitrate) solution, forming silver diamine nitrate (SDN), which is expected to enhance the mineral precipitation (Horst et al., 2017;Peng et al., 2012). SDF [Ag(NH 3 ) 2 F] reacts with hydroxyapatite (HA) to release calcium fluoride (CaF 2 ) and silver phosphate (Ag 3 PO 4 ), which arrest carious lesions.
SDF has therefore been regarded as an efficient, affordable, and safe cariostatic agent, therefore its application in dental caries management complies with the concept of Minimally invasive dentistry (MID) (Frencken et al., 2012). Previously, systematic reviews assessed the SDF effect on deciduous teeth and also for the treatment of root caries, specifically for the older population only. This current systematic review focused on permanent teeth both in adults and children regardless of age restrictions. Therefore, the aim of this systematic review was to assess the literature on the effects of SDF for the treatment of dental caries in permanent teeth (adults and children).

| Methodology
This review was conducted according to the guidelines of the Cochrane Handbook for Systematic Reviews of Interventions and Preferred Reporting Items for Systematic Review and Meta-Analyses (PRISMA) statement ( Figure 1). This systematic review followed the four-phase diagram of the PRISMA (Moher et al., 2009). The PICOS framework was used (Table 1) to formulate the following research question "Is there a difference in the efficacy of silver diamine fluoride in the treatment of dental caries in comparison to other minimally invasive approaches in permanent teeth?" The study protocol was registered with the PROSPERO international prospective register of systematic reviews.  (Table 1) were used with Boolean operators (OR, AND) to combine searches. The same keywords were used for all search platforms, following the syntax rules of each database, and the search terms were modified for each database (Table 2).
There were four main concepts used for the literature search strategy (Supporting Information: Table S1). The first concept was the use of SDF in clinical studies. The second concept was dental caries, where the outcome was assessing any positive effect, such as remineralization or the limitation of caries progression. The third concept was on permanent teeth in different age groups, such as adults and schoolchildren. The fourth concept was also related to the specific dental tissues; root or tooth types such as first permanent molars. Systematic reviews, laboratory-based/in vitro studies, and case studies were excluded. Studies on primary teeth only with the use of SDF were excluded.

| Inclusion and exclusion criteria
The following criteria were followed to include the studies: • Type of study: Randomized control trials, cohort studies.
• Population: Children, adolescents, and adults, including the aging population.
The following studies were excluded: • Type of study: Case report, in vitro study, laboratory-based studies, meta-analysis, systematic reviews, article comments, narrative reviews, studies excluding the use of SDF, studies excluding the use of dental varnish containing fluoride.
• Population: Infants with deciduous teeth and animals.

| Risk of bias assessment
The evaluation was based on the description of the following parameters for the quality assessment of the study: sample size calculation, teeth randomization, standardization of procedures, application by a single operator, blinding of the observer, and statistical analyses carried out. If the authors reported the parameter, the article had a Y (yes) for that specific parameter; if it was not possible to find the information, the article received an N (no). The studies that reported 1-3 items were classified as high risk of bias, 4-6 as medium risk, and 7-8 as low risk. The assessment was carried out by three reviewers, then any disagreements were resolved by discussion and followed up with a consensus.

| RESULTS
The literature was searched through a number of databases (PubMed, Mendeley, and Endnote). The search strategy was also applied to the search engine Google Scholar to include additional studies.
During the first stage of the title and abstract search, studies (n = 1675) that failed to meet three of the four search criteria were removed. The next stages of the process were assessed by two reviewers. Any disagreements were taken to be discussed with the fourth reviewer. A number of studies were removed as they were duplicates (n = 155). From the remaining papers (n = 346), an in-depth assessment of the title and abstract was undertaken. Papers deemed to be irrelevant by both reviewers were immediately removed (n = 294). Five studies were a cause for debate, however, after discussion with the fourth reviewer, these studies were also excluded.
A total of 52 studies were deemed as relevant to review the full texts. 41 publications were then excluded, as either the results were not presented, or the data provided were insufficient to be included.
Seventeen studies presented primary teeth or failed to specify the permanent teeth. Twelve studies of clinical trials have not been completed yet. The outcomes of four studies were related to parental acceptability and child comfortability of SDF, hypersensitivity, and cost-effectiveness of the SDF. As a result, 11 studies matched all the search criteria, were deemed as relevant by all three reviewers, and had sufficient data that could be analyzed and compared (

| Statistical analysis
The results of SDF were statistically significant for all studies that posted p-values except for one. There were noticeable differences in the duration of the studies, frequency of application, and method of assessments within each study. The statistical data also varied since some results were given in percentages while some presented either means and standard deviations or provided means of the results alone. Therefore, the included studies were found to be incomparable and too limiting to perform further statistical analyses, including meta-analysis. The remaining studies recorded SDF as having significant results (p < .05) when compared to the control groups for the treatment of dental caries in first permanent molars in children (  arrest caries progression but also inactivate present carious lesions.

| Comparison of the studies
These authors showed the greatest preventative fraction of 72%.
However, this data failed to match the other studies. This was due to the 6-monthly application of the SDF. Mauro et al. (2004) reported that the preventative fractions of ammonium bifluoride (56%) and SDF (57%) were almost identical.
This would indicate that ammonium bifluoride has similar efficacy in the treatment of dental caries in permanent first molars in children.
The use of sodium fluoride had a slightly lower preventative fraction of 47%. This demonstrates the correlation with Tan   Subsequently, Baraka et al. (2022)

| Variations in SDF applications
There were noticeable differences in the intervals for the SDF applications in all studies related to children (Table 4). However, SDF was applied once a year on root caries in the older population. It should be noted that the only consistent part was the concentration of SDF which was 38%.
Interestingly, the preventative fraction was 72% in Llodra et al. (2005), where SDF was applied every 6 months, while the preventative fractions were 71% and 57%, respectively, in Tan et al. (2010) and Mauro et al. (2004) where the application of the SDF was once a year. The preventative fraction observed by Llodra et al. (2005) was 31% and 15% greater than the values reported by Liu et al. (2012) and Mauro et al. (2004), respectively. It could be suggested that the optimum effect for the application of 38% SDF would be twice a year for the treatment of dental caries in permanent teeth (children and adults).
The preventative fraction of annual application of SDF in comparison with the GIC restorations and use of dental varnish containing fluoride was 45% in Mendiratta et al. (2021).

| Assessment of bias
The assessment of bias for all studies is presented in Table 5.
There is a lack of information available for Mauro et al. (2004) hence the risk of bias was unclear for all criteria. The generalization could give no further insight into the risk of bias for specific bias criterion subsets (Table 5).
Allocation concealment had an unclear risk of bias in a majority of the studies. Regarding Llodra et al. (2005), there was no indication regarding the allocation process for each child into different study groups. It should be noted that two previously calibrated examiners carried out the dental examinations of this study. There is evidence for higher intrareliability of an examiner when compared to interreliability between examiners (Banting et al., 2011). Therefore, the measurement reliability bias was unclear. Zhang et al. (2013) reported that participants were blinded to the type of applications, and these participants were assessed at baseline and after 24 months by the same examiner. However, the evidence was unclear if the examiner was blinded to the treatment groups. Therefore, the risk of allocation concealment was unclear. Overall, there was a low risk of bias for this study (Table 5).
The risk of bias for having balanced groups at baseline was unclear for all studies related to children (Table 5). The regions where the clinical trials were conducted share some similarities, which might explain this unclear risk of bias. Llodra et al. (2005) conducted a clinical trial in the city of Santiago de Cuba, Cuba. It should be noted that there was a low fluoride content in the drinking water (0.09 ppm fluoride). In addition, it was also compulsory for children to use a 0.5% sodium fluoride oral rinse once every 2 weeks in school.
Interestingly, there was widespread limited availability of fluoridated toothpaste in the city. Even though it was reported that the children were exposed to low levels of fluoride, there was no consideration in the study factoring in the bi-weekly use of the sodium fluoride oral rinse. There was also a lack of information with regard to drop-outs for the students. Therefore, the risk of selective reporting bias was unclear.
The clinical trial was conducted by Liu et al. (2012) in the Guangzhou province of China. There was a low fluoride content in the water system. This was the only study that added an anticipated 10% dropout rate. However, it was not clearly stated how this would affect the study. There was no explanation as to whether a 10% dropout was expected between all treatment groups or not.
The duration of this study was 24 months, with the SDF application T A B L E 5 Assessment of bias for each study. every 12 months. It was not clarified whether there would be an expected 10% dropout over the 24 months or every 12 months. In addition, the control group consisted of 128 allocated participants at baseline. The results at baseline were used to calculate p-values for a number of factors in the different treatment groups, such as dental visit history and snacking habits (Liu et al., 2012). All of the p-values recorded were >0.05, denoting no statistically significant differences between treatment groups and potential confounding factors. There were also p-values recorded for comparing factors related to tooth surfaces (such as early caries and fissure morphology). In addition, the p-values were >0.05, and there was no statistically significant difference between treatment groups. It was unclear if there was a 10% dropout calculation applied to each treatment group before the statistical tests were carried out. A lack of clarity with regard to the 19% predicted dropout was eminent. This was calculated throughout a period of 24 months that is, a 10% dropout was predicted after every application (12 months). Each different value from predicted dropout rates might have been able to influence the statistical tests to show no statistical significance, however, this was not the full picture. Therefore, the possibility of bias in the balance of individual treatment groups at baseline was unclear ( Table 4).
The clinical study was carried out in two locations ( (Table 5).
The preventative range following the use of SDF was between 42%-73% in all included studies. However, the study by Zhang et al. (2013). produced extremely low values (4%-33%). The source of this difference was unclear and could not be traced in the study (Table 5). Hamdi et al. (2022) conducted a double-blinded randomized clinical trial. The randomization was determined by online software and implementation steps prepared opaque and well-sealed envelopes as the assessor was not involved. The allocation for the early enamel lesions T baseline was unequal without any explanation.
Participants were recruited through social network advertisements and by hanging posters in the outpatient clinic. Interestingly, there was no dropout throughout the study. Therefore, these biases were low. Mendiratta et al. (2021) allocated participants using a sequence of random numbers. However, the authors failed to provide any further information regarding the allocation concealment and blinding processes that is, blinding of participants and assessors.
Water fluoride concentration is also high in parts of Khordha and Nayagarh districts in Odisha. Satyarup et al. (2017) reported one researcher assessed the follow-up examinations without providing any information with regard to intrareliability or interreliability.
In addition, the measurement reliability was unclear. There was no explanation for dropouts, which would mean that the selective reporting bias was unclear.
The randomized controlled trial by Baraka et al. (2022) was carried out a detailed blinding and allocation processes. Allocation was concealed from the investigators, participants, and statisticians.
The study provided details of dropout reasons, including changes in phone numbers and addresses; loss of contacts, and the COVID-19 pandemic. The range of fluoride content in the tap water was 0.330-0.377 mg/L, with an average of 0.36 mg/L in Alexandria, Egypt. The outcome measurements were evaluated using clinical visual assessments and radiographs. The sample size for each group at baseline was equal. Therefore, these risks of biases were low. Having studies that only include older participants/disabled individuals would limit this systematic review by not allowing for speculation towards adults of other age/background groups.
The three studies only assessed the effect of SDF on root caries while Satyarup et al. (2022) reported the effect of SDF use on enamel carious lesions. This was another limitation, as the SDF application was not explored in other types of dental caries.
Different durations for 11 studies were also noticed. Satyarup et al. (2022) conducted the clinical study for a period of six months while Baraka et al. (2022) had nine months only. Mauro et al. (2004) and Zhang et al. (2013) only reported results for the end of the study.
The lack of data for Zhang et al. (2013) at 12 months meant that there was less comparison available with the other two studies in older adults. Tan et al. (2010) and Li et al. (2017) both reported data every 12 months, for the first 24 months.
There were variations in the control groups. Li et al. (2017) included the combination of OHI+ tonic water as the control group, whereas the other two studies in older adults used OHI+ water only.
Further statistical analyses were unable to be performed due to the differences in study groups that were included in the current systematic review.
All the included studies indicated a double-blinded design.
However, the use of SDF for the treatment of dental caries in a blinded clinical trial comes with a flaw that is hard to counter. As Couple of studies investigated both the effect of SDF as well as SDF + KI when compared with tonic water alone (p < .001) or TCS, CPP-ACP applications (Hamdi et al., 2022;Li et al., 2017). The application of SDF alone (62%) had a preventative fraction that was 10% greater than the preventative fraction of SDF + KI (52%). This could indicate that the addition of KI, when used in conjunction with SDF, might limit the efficacy of SDF for the arrest of carious lesions.
However, the reason for these differences might totally be unrelated to the addition of KI. Both treatment groups were given oral health instructions. The treatment group of SDF only may have adhered to the instructions better than the treatment group of SDF + KI, which may have caused the difference in results. An analysis of covariance was carried out between the results for SDF and SDF + KI (p > .05) showing that there is a difference, however insignificant (Li et al., 2017). In addition, Hamdi et al. (2022) reported that the use of SDF-KI arrested 54.8% of early enamel carious lesions when compared to the TCS and CPP-ACP groups (100%) for a period of 24 months (p < .001). However, SDF-KI was applied annually only, while the CPP-ACP and TCS applications were twice a day throughout the study. The application frequency of SDI with or without KI is still unclear. There is also conflicting evidence on the level of stain reduction following the addition of KI and the efficacy of SDI plus KI on dental caries. Further research is required to assess the level of staining and efficacy on dental caries in all populations for SDF plus KI compared against SDF alone.
In summary, SDF is not commonly considered as a treatment option for dental caries in adults. Therefore, guidelines and policies need to consider including the use of SDF as part of the management of dental caries both for children and adults. However, further research is required on coronal caries in adults.

| CONCLUSION
Within the limitations of this systematic review, the use of SDF is promising with high preventative fractions in children and older populations when compared to other topical applications such as dental varnish containing sodium fluoride.

AUTHOR CONTRIBUTIONS
Alvin Mungur: Acquisition of data; analysis and interpretation of data; drafting the article. Haoran Chen: Acquisition of updated data; analysis and interpretation of data; drafting the updated results.
Saroash Shahid: Design of the study; editing of the publication. Aylin Baysan: The conception and design of the study; acquisition of data; interpretation of data; editing of the article; revising it critically for important intellectual content; final approval of the version to be submitted.

CONFLICT OF INTEREST STATEMENT
The authors declare no conflicts of interest.