Fluoride release of conventional GIC versus fluoride containing composite resin a quantitative systematic review

Aim Fluoride release of conventional GIC versus fluoride containing composite resin a quantitative systematic review The MI Review Group Objectives to appraise and present detailed quantitative evidence in answer to the review question, whether conventional glass ionomer cement (GIC) releases more fluoride than fluoride containing composite resin. Search strategy The trials were identified from a search of the PubMed database on 01 September 2009 using the terms: Search ("Fluorides"[Mesh] AND "Glass Ionomer Cements"[Mesh]) AND "Composite Resins"[Mesh]. References of accepted articles were checked for additional studies suitable for inclusion. Inclusion criteria Relevant to review question; Published in English language; 2-arm prospective longitudinal study (in-vitro, in-situ, in-vivo) Data collection and analysis The systematic literature search found 317 trials of which 37 were identified to be in line with the inclusion criteria. Of these, 36 in vitro trials could be traced for review. From the reviewed trials, 11 were excluded and 25 accepted. Of these, 163 individual datasets were extracted and analyzed. Of the 163 datasets, 72 were combined in 22 separate meta-analyses and 91 datasets were analyses independently. Main results and conclusion The results show that glass-ionomer cements release more fluoride than composite regardless of the type of outcome measured, time period or interval or in which media they were submerged. Correspondence address: P.O. Box 2779 Houghton / Johannesburg South Africa email: midentistry@global.co.za This systematic review aims to appraise and present detailed quantitative evidence in answer to the review question, whether conventional glass ionomer cement (GIC) releases more fluoride than fluoride containing composite resin. Materials and methods Data collection PubMed was systematically searched for articles reporting on clinical trials up to 01 September 2009. The string of MeSH and text search terms with Boolean operators: Search ("Fluorides"[Mesh] AND "Glass Ionomer Cements"[Mesh]) AND "Composite Resins"[Mesh] was used. Articles were selected for review from the search results on the basis of their compliance with the inclusion criteria: Relevant to review question Published in English language 2-arm prospective longitudinal study (invitro, in-situ, in-vivo) Where a relevant title without a listed abstract was available, a full copy of the article was assessed for inclusion. References of accepted articles were checked for additional studies suitable for inclusion. Article review and data extraction Article inclusion and subsequent data extraction was conducted independently by two reviewers. Disagreements were solved by discussion and consensus. Where possible, missing data were calculated from information presented in the text or tables. Authors of articles were also contacted, in order to obtain missing information. Data were extracted in the form of continuous datasets, each containing the number of evaluated samples (n) and the mean result of the measured outcome with standard deviation (SD) for both material groups. Articles were excluded if no computable data could be extracted. Statistical Analysis A random effects model in RevMan Version 4.2 statistical software, developed by The Nordic Cochrane Centre, The Cochrane Collaboration (Copenhagen; 2003), was used. Differences in treatment groups were computed on the basis of Mean Differences (MD) with 95% Confidence Intervals (CI). Datasets extracted from the accepted articles were assessed for their clinical and methodological heterogeneity, following Cochrane guidelines. The percentage of total variations across datasets (I 2 ) was used in assessing statistical heterogeneity. Only identified homogeneous datasets were considered suitable for meta-analysis. Pooled datasets are assigned a Mantel-Haenszel weight directly proportionate to their sample sizes. Search results Number of articles found = 317; Number of articles included based on the inclusion criteria = 37 trials; 127

Number of traced trials excluded = 11 [1-11]; Number of traced trials accepted = 25 [12-36]. Number of trials not traced = 1 [37]; Excluded trials with reason for exclusion are listed in Table 1. Quantitative synthesis The systematic literature search identified and traced 25 in-vitro trials in line with the inclusion and exclusion criteria. From these, a total of 163 independent datasets were extracted. Details of these datasets are provided in Table 2. The trials investigated the difference between glassionomer cement and fluoride containing composite resin material in cumulative fluoride release after periods of time and the fluoride release after certain time intervals. Of the 163 datasets, 72 were combined in 22 separate meta-analyses and 91 datasets were analyses independently. The results are presented in Table 3 (cumulative fluoride release after periods of time) and Table 4 (fluoride release after certain time intervals). Quality of studies Only in-vitro studies were identified and no quality assessment conducted. Conclusion The result of the dataset analyses show that glassionomer cements release more fluoride than composite regardless of the type of outcome measured, time period or interval or in which media they were submerged. References 1. Can-Karabulut DC, Batmaz I, Solak H, Tastekin M.Linear regression modeling to compare fluoride release profiles of various restorative materials. Dent Mater 2007; 23: 1057-65. 2. Chan WD, Yang L, Wan W, Rizkalla AS. Fluoride release from dental cements and composites: a mechanistic study.dent Mater 2006; 22: 366-73. 3. Karantakis P, Helvatjoglou-Antoniades M, Theodoridou-Pahini S, Papadogiannis Y. Fluoride release from three glass ionomers, a compomer, and a composite resin in water, artificial saliva, and lactic acid. Oper Dent 2000; 25: 20-5. 4. Glasspoole EA, Erickson RL, Davidson CL. A fluoride-releasing composite for dental applications. Dent Mater 2001; 17: 127-33. 5. Preston AJ, Mair LH, Agalamanyi EA, Higham SM. Fluoride release from aesthetic dental materials. J Oral Rehabil 1999; 26: 123-9. 6. de Araujo FB, García-Godoy F, Cury JA, Conceição EN. Fluoride release from fluoride-containing materials. Oper Dent 1996; 21: 185-90. 7. Suljak JP, Hatibovic-Kofman S. A fluoride release-adsorption-release system applied to fluoride-releasing restorative materials. Quintessence Int 1996; 27: 635-8. 8. Forsten L. Short- and long-term fluoride release from glass ionomers and other fluoride-containing filling materials in vitro. Scand J Dent Res 1990; 98: 179-85. 9. Forss H, Seppä L. Prevention of enamel demineralization adjacent to glass ionomer filling materials. Scand J Dent Res 1990; 98: 173-8. 10. Asmussen E, Peutzfeldt A. Long-term fluoride release from a glass ionomer cement, a compomer, and from experimental resin composites. Acta Odontol Scand 2002; 60: 93-7. 11. Nagamine M, Itota T, Torii Y, Irie M, Staninec M, Inoue K. Effect of resinmodified glass ionomer cements on secondary caries. Am J Dent 1997; 10: 173-8. 12. Yap AU, Khor E, Foo SH. Fluoride release and antibacterial properties of newgeneration tooth-colored restoratives. Oper Dent 1999; 24: 297-305. 13. Okuyama K, Murata Y, Pereira PN, Miguez PA, Komatsu H, Sano H.Fluoride release and uptake by various dental materials after fluoride application. Am J Dent. 2006; 19: 123-7. 14. Itota T, Al-Naimi OT, Carrick TE, Yoshiyama M, McCabe JF.Fluoride release from aged resin composites containing fluoridated glass filler. Dent Mater. 2005; 21: 1033-8. 15. Itota T, Carrick TE, Rusby S, Al-Naimi OT, Yoshiyama M, McCabe JF. Determination of fluoride ions released from resin-based dental materials using ion-selective electrode and ion chromatograph. J Dent 2004; 32: 117-22. 16. Attar N, Turgut MD.Fluoride release and uptake capacities of fluoride-releasing restorative materials. Oper Dent 2003; 28: 395-402. 17. Xu X, Burgess JO. Compressive strength, fluoride release and recharge of fluoridereleasing materials. Biomaterials. 2003; 24: 2451-61. 18. Attar N, Onen A. Fluoride release and uptake characteristics of aesthetic restorative materials. J Oral Rehabil 2002; 29: 791-8. 19. Preston AJ, Agalamanyi EA, Higham SM, Mair LH. The recharge of esthetic dental restorative materials with fluoride in vitrotwo years' results. Dent Mater 2003; 19: 32-7. 20. Hotta M, Kawano S, Sekine I. Direct tensile strength of visible light-cured restorative materials containing fluoride. J Oral Rehabil 2001; 28: 854-9. 21. Gao W, Smales RJ. Fluoride release/uptake of conventional and resinmodified glass ionomers, and compomers. J Dent 2001; 29: 301-6. 22. Helvatjoglu-Antoniades M, Karantakis P, Papadogiannis Y, Kapetanios H. Fluoride release from restorative materials and a luting cement. J Prosthet Dent 2001; 86: 156-64. 128

23. Xu HH, Eichmiller FC, Antonucci JM, Flaim GM. Single-crystalline ceramic whiskerreinforced carboxylic acid-resin composites with fluoride release. Oper Dent 2000; 25: 90-7. 24. Vermeersch G, Leloup G, Vreven J. Fluoride release from glass-ionomer cements, compomers and resin composites. J Oral Rehabil 2001; 28: 26-32. 25. Peng D, Smales RJ, Yip HK, Shu M. In vitro fluoride release from aesthetic restorative materials following recharging with APF gel. Aust Dent J 2000; 45: 198-203. 26. Vieira AR, de Souza IP, Modesto A. Fluoride uptake and release by composites and glass ionomers in a high caries challenge situation. Am J Dent 1999; 12: 14-8. 27. Carvalho AS, Cury JA. Fluoride release from some dental materials in different solutions. Oper Dent 1999; 24: 14-9. 28. Aboush YE, Torabzadeh H. Fluoride release from tooth-colored restorative materials: a 12-month report. J Can Dent Assoc 1998; 64: 561-4. 29. Kan KC, Messer LB, Messer HH. Variability in cytotoxicity and fluoride release of resinmodified glass-ionomer cements. J Dent Res 1997; 76: 1502-7. 30. Tam LE, Chan GP, Yim D. In vitro caries inhibition effects by conventional and resinmodified glass-ionomer restorations. Oper Dent 1997; 22: 4-14. 31. Burgess JO, Re GJ, Jordan T. Fluoride release and shear bond strength of seven base materials. Gen Dent 1993; 41: 301-4. 32. Takahashi K, Emilson CG, Birkhed D. Fluoride release in vitro from various glass ionomer cements and resin composites after exposure to NaF solutions. Dent Mater 1993; 9: 350-4. 33. Ulukapi H, Benderli Y, Soyman M. Determination of fluoride release from lightcured glass-ionomers and a fluoridated composite resin from the viewpoint of curing time. J Oral Rehabil 1996; 23: 197-201. 34. Young A, von der Fehr FR, Sønju T, Nordbø H. Fluoride release and uptake in vitro from a composite resin and two orthodontic adhesives. Acta Odontol Scand 1996; 54: 223-8. 35. Weidlich P, Miranda LA, Maltz M, Samuel SM. Fluoride release and uptake from glass ionomer cements and composite resins. Braz Dent J 2000; 11: 89-96. 36. Gjorgievska E, Nicholson JW, Gjorgovski I, Iljovska S. Aluminium and fluoride release into artificial saliva from dental restoratives placed in teeth. J Mater Sci Mater Med 2008; 19: 3163-7. 37. Bala O, Uçtasli M, Can H, Türköz E, Can M. v J Nihon Univ Sch Dent 1997; 39: 123-7. 129

Table 1: Excluded articles and reasons for exclusion Article Reason for exclusion Can-Karabulut DC, Batmaz I, Solak H, Tastekin M.Linear regression modeling to compare fluoride release profiles of various restorative materials. Dent Mater 2007; 23: 1057-65. [1] Chan WD, Yang L, Wan W, Rizkalla AS. Fluoride release from dental cements and composites: a mechanistic study.dent Mater 2006; 22: 366-73. [2] Karantakis P, Helvatjoglou-Antoniades M, Theodoridou-Pahini S, Papadogiannis Y. Fluoride release from three glass ionomers, a compomer, and a composite resin in water, artificial saliva, and lactic acid. Oper Dent 2000; 25: 20-5. [3] Glasspoole EA, Erickson RL, Davidson CL. A fluoride-releasing composite for dental applications. Dent Mater 2001; 17: 127-33. [4] Preston AJ, Mair LH, Agalamanyi EA, Higham SM. Fluoride release from aesthetic dental materials. J Oral Rehabil 1999; 26: 123-9. [5] de Araujo FB, García-Godoy F, Cury JA, Conceição EN. Fluoride release from fluoride-containing materials. Oper Dent 1996; 21: 185-90. [6] Suljak JP, Hatibovic-Kofman S. A fluoride release-adsorption-release system applied to fluoride-releasing restorative materials. Quintessence Int 1996; 27: 635-8. [7] No computable data Forsten L. Short- and long-term fluoride release from glass ionomers and other fluoride-containing filling materials in vitro. Scand J Dent Res 1990; 98: 179-85. [8] Forss H, Seppä L. Prevention of enamel demineralization adjacent to glass ionomer filling materials.scand J Dent Res 1990; 98: 173-8. [9] Asmussen E, Peutzfeldt A. Long-term fluoride release from a glass ionomer cement, a compomer, and from experimental resin composites. Acta Odontol Scand 2002; 60: 93-7. [10] Nagamine M, Itota T, Torii Y, Irie M, Staninec M, Inoue K. Effect of resinmodified glass ionomer cements on secondary caries. Am J Dent 1997; 10: 173-8. [11] 130

Table 2. Extracted datasets from accepted articles Article DS Outcome Composite GIC Yap et al. (1999) [12] 001 002 003 004 Cumulative Fluoride Release Tetric Ceram Fuji II Cap 005 006 Okuyama et al. (2006) [13] 007 Fluoride release at time intervals Unifil F Fuji Ionomer Type II Itota et al. (2005) [14] 008 009 010 011 Cumulative Fluoride Release Unifil S Ketac Fil Plus Aplicap 012 013 014 Itota T et al. (2004) [15] Attar et al. (2003) [16] Xu et al. (2003) [17] Attar et al. (2002) [18] Preston et al. (2001) [19] Hotta et al. (2001) [20] 015 016 017 018 019 020 021 022 023 024 025 026 027 028 029 030 031 032 033 034 035 036 037 038 039 040 041 042 043 044 045 046 Fluoride release at time interval - using ion-selective electrode (ISE) Fluoride release at time interval -using ion Chromatograph (IC) Cumulative Fluoride Release - using ion Chromatograph (IC) Fluoride release at time interval Heliomolar Heliomolar Flow Tetric Flow Ketac Fil Plus Aplicap Chem Flex Chem Flex Seringa 047 Ariston Miracle Mix 048 Soltaire Ketac Silver Cumulative fluoride release 049 Surefil Fuji IX 050 Tetric Ceram Ketac Molar 051 052 053 054 055 Fluoride release at time interval Tetric Ceramfil B 056 057 058 059 Heliomolar Chem Fil Fluoride release at time interval 060 Concise Ketac Fil 061 Cumulative fluoride release Heliomolar HY-bond 062 Radiopaque Glasionomer F 063 064 Helio Progress Chelon-Fil 131

065 066 067 068 069 070 Gao et al. (2001) [21] 071 072 Fluoride release at time interval Z100 GI-1 073 074 075 076 Antoniades et al. (2001) [22] 077 078 079 080 081 082 Fluoride release at time interval Tetric Fuji ionomer type III 083 084 085 086 087 Xu et al. (2000) [23] 088 089 090 091 Cumulative fluoride release TPH Ketac Bond 092 093 094 Vermeersch et al. (2001) [24] 095 Tetric Ketac Fil Aplicap 096 Cumulative fluoride release 097 Heliomolar Ketac Molar 098 Peng et al. (2000) [25] 099 Cumulative fluoride release Ariston PC Chem Flex Vieira et al. (1999) [26] 100 101 102 103 104 105 106 107 Fluoride release at time interval Heliomolar Chelon Fil 108 109 110 111 112 113 Carvalho et al. (1999) [27] 114 115 Cumulative fluoride release Tetric Chelon Fil 116 Aboush et al. (1998) [28] 117 118 Cumulative fluoride Released Tetric Fuji II Cap Kan et al. (1997) [29] 119 120 Fluoride release at time interval Silux Plus Ketac Fil 121 Tam et al. (1997) [30] 122 123 124 Cumulative fluoride Released Bis-Fil Chem Fil 125 126 127 VCL Dycal Ketac Bond Burgess et al. (1993) [31] 128 Cumulative fluoride Released Timeline GC Liner 129 Cavalite Vitrebond Takahashi et al. (1993) [32] 130 Heliomolar RO Ketac Silver 131 Cumulative fluoride Released 132 Prisma AP Fuji II 133 Ulukapi et al. (1996) [33] 134 Fluoride release at time interval Heliomolar RO XR Ionomer 132

Young et al. (1996) [34] 135 136 137 138 139 140 141 142 143 144 145 146 147 Fluoride release at time interval Tetric Ketac Fil 148 149 150 151 Heliomolar Fuji IX Weidlich et al. (2000) [35] 152 153 154 155 Fluoride release at time interval 156 157 158 Z 100 Chelon Fil 159 160 161 Gjorgievska et al. (2008) [36] 162 163 Cumulative fluoride Released Unifil flow Fuji IX DS = dataset number; GIC = glass-ionomer cement. 133

Table 3. Difference in the cumulative fluoride release between both materials after period of time t Dataset number Outcome 95%CI p-value Medium (unit of measurement) [029,032,089,117] WMD-9.60-18.53, -0.67 =0.04* Measured in deionized water (µg/cm 2 ) 122 MD- 15.94-17.90, -13.98 <0.00001* Measured in deionized water (ppm) 1 d 061 MD- 19.50-20.84, -18.16 <0.00001* Measured in deionized water (mg L -1 ) 064 MD- 21.03-21.91, -20.15 <0.00001* 6 d 009 MD 10.67 5.33, 16.01 <0.00001 010 MD- 4.15-4.67, -3.63 <0.00001* Measured in aquatic lactic acid (µg/cm 2 ) 7 d/ 1 w 14 d / 2 w [030,030,090] WMD-32.69-51.78, -13.60 =0.0008* Measured in deionized water (µg/cm 2 ) [095,097,123] WMD-10.71-14.26, -7.15 <0.00001* Measured in deionized water (ppm) 002 MD- 36.23-67.61, -4.85 =0.02* Measured in deionized water (µg/mm 2 ) 130 MD- 2.06-2.18, -1.94 <0.00001* 132 MD- 2.75-2.89, -2.61 <0.00001* Measured in deionized water (mmol/l) [091,114] WMD-15.54-30.26, -0.82 =0.04* Measured in deionized water (µg/cm 2 ) 124 MD- 51.94-58.80, -45.08 <0.00001* Measured in deionized water (ppm) 003 MD- 10.11-12.88, -7.34 <0.00001* Measured in deionized water (µg/mm 2 ) 011 MD- 1.80-2.30, -1.30 <0.00001* Measured in aquatic lactic acid (µg/cm 2 ) 115 MD- 7.48-8.06, -6.90 <0.00001* 15 d 116 MD- 1.19-1.25, -1.13 <0.00001* Measured in artificial saliva/water (µg/cm 2 ) 3 w 004 MD- 6.39-7.34, -5.44 <0.00001* Measured in deionized water (µg/mm 2 ) 22 d 012 MD- 1.78-2.52, -1.04 <0.00001* Measured in aquatic lactic acid (µg/cm 2 ) 4 w 005 MD- 5.23-5.82, -4.64 <0.00001* Measured in deionized water (µg/mm 2 ) [031,034,047,048,049,050] WMD-99.50-131.24,-67.75 <0.00001* Measured in deionized water (µg/cm 2 ) 125 MD- 58.95-64.83, -53.07 <0.00001* Measured in deionized water (ppm) 013 MD- 3.27-4.35, -2.19 <0.00001* Measured in aquatic lactic acid (µg/cm 2 ) 30 d / 062 MD- 52.87-55.94, -49.80 <0.00001* 1m 065 MD- 44.20-45.90, -42.50 <0.00001* Measured in deionized water (mg L -1 ) 162 MD- 3.41-3.74, -3.08 <0.00001* 163 MD- 0.60-1.72, -0.52 =0.29 Measured in artificial saliva (ppm) 001 MD-432.87-432.88,-432.86 <0.00001* 35 d / 006 MD- 3.84-4.17, -3.51 <0.00001* Measured in deionized water (µg/mm 2 ) 5 w 131 MD- 4.06-4.35, -3.77 <0.00001* 133 MD- 4.90-5.15, -4.65 <0.00001* Measured in deionized water (mmol/l) 36 d 014 MD- 3.23-3.97, -2.49 <0.00001* Measured in aquatic lactic acid (µg/cm 2 ) 6 w 076 MD-227.40-236.26,-218.54 <0.00001* Measured in artificial saliva (ppm) 099 MD- 10.24-20.10, -0.38 =0.04* Measured in artificial saliva (µg/mm 2 ) 2 m 093 MD- 42.29-44.15, -40.43 <0.00001* Measured in deionized water (µg/cm 2 ) 10 w 126 MD-155.92-180.42,-131.42 <0.00001* Measured in deionized water (ppm) [008,094] WMD-74.69-117.89,-31.49 =0.0007* Measured in deionized water (µg/cm 2 ) [096,098,127,128,129] WMD-35.85-46.40,-25.30 <0.00001* Measured in deionized water (ppm) 3 m 063 MD- 57.04-60.34, -53.74 <0.00001* Measured in deionized water (mg L -1 ) 066 MD- 47.98-49.92, -46.04 <0.00001* 1 y 118 MD-458.00-494.86,-421.14 <0.00001* Measured in deionized water (µg/cm 2 ).t = period of time; d = day(s); w = week(s); m = month(s); y = year; WMD = Weighted mean difference; MD = mean difference; CI = confidence interval, [] = Datasets combined through meta-analysis. * Result in favor of GIC 134

Table 4. Difference in fluoride release at time intervals between both materials t Dataset number Outcome 95%CI p-value Medium (unit of measurement) 4 h 077 MD- 1.45-1.52, -1.38 <0.00001* Measured in deionized water (µg/mm 2 ) 6 h 067 MD-30.30-31.88, -28.72 <0.00001* Measured in artificial saliva (ppm) 8 h 078 MD- 0.65-0.71, -0.59 <0.00001* 12 h 079 MD- 0.51-0.61, -0.41 <0.00001* Measured in deionized water (µg/mm 2 ) [015,022] WMD-16.81-18.08, -15.55 <0.00001* Measured in deionized water (µg/cm 2 ) [035,041,051,119,134,135,136] WMD-11.89-17.52, -6.27 <0.00001* Measured in deionized water (ppm) 100 MD 10.53-11.95, -9.11 <0.00001* Measured in demineralization solution (µg/cm 2 ) 148 MD- 0.36-0.51, -0.21 <0.00001* 1 d 155 MD- 0.62-0.97, -0.27 =0.0005* Measured in deionized water (µg/cm 2 ) 068 MD-23.60-24.83, -22.37 <0.00001* Measured in artificial saliva (ppm) 080 MD- 0.41-0.48, -0.34 <0.00001* Measured in deionized water (µg/mm 2 ) 059 MD- 1.46-1.82, -1.10 <0.00001* 060 MD- 3.18-3.53, -2.83 <0.00001* Measured in artificial saliva (µg/mm 2 /h) 101 MD-10.38-11.29, -9.47 <0.00001* Measured in demineralization solution (µg/cm 2 ) 149 MD- 0.08-0.10, -0.06 <0.00001* 156 MD- 0.18-0.22, -0.14 <0.00001* 2 d 069 MD-19.10-19.80, -18.40 <0.00001* Measured in artificial saliva (ppm) 081 MD- 0.47-0.55, -0.39 <0.00001* Measured in deionized water (µg/mm 2 ) [016,023] WMD- 6.60-7.32, -5.88 <0.00001* Measured in deionized water (µg/cm 2 ) [036,038,042,052,137,139] WMD- 6.29-9.47, -3.11 <0.0001* Measured in deionized water (ppm) 102 MD- 5.08-5.69, -4.47 <0.00001* Measured in demineralization solution (µg/cm 2 ) 3 d 082 MD- 0.52-0.57, -0.47 <0.00001* Measured in deionized water (µg/mm 2 ) [037,043,053,140,141,142] WMD- 6.05-7.28, -4.83 <0.00001* Measured in deionized water (ppm) 103 MD- 3.70-3.90, -3.50 <0.00001* Measured in demineralization solution (µg/cm 2 ) 4 d [017,024] WMD- 9.28-10.25, -8.32 <0.00001* Measured in deionized water (µg/cm 2 ) [054,120] WMD-21.46-53.81, 10.88 =0.19 Measured in deionized water (ppm) 104 MD- 2.24-2.39, -2.09 <0.00001* Measured in demineralization solution (µg/cm 2 ) 5 d 150 MD- 0.16-0.18, -0.14 <0.00001* 157 MD- 0.33-0.44, -0.22 <0.00001* 055 MD- 5.92-6.23, -5.61 <0.00001* Measured in deionized water (ppm) 6 d 105 MD- 1.79-2.04, -1.54 <0.00001* Measured in demineralization solution (µg/cm 2 ) [018,025] WMD- 8.30-10.58, -6.22 <0.00001* Measured in deionized water (µg/cm 2 ) [121,143,144,145] WMD- 3.95-6.14, -1.75 =0.0004* Measured in deionized water (ppm) 7 d / 1 w 070 MD- 36.00-37.41, -34.59 <0.00001* Measured in artificial saliva (ppm) 083 MD- 0.68-0.78, -0.58 <0.00001* Measured in deionized water (µg/mm 2 ) 106 MD- 2.79-2.99, -2.59 <0.00001* 8 d 107 MD- 3.04-3.31, -2.77 <0.00001* Measured in demineralization solution (µg/cm 2 ) 9 d 108 MD- 3.06-3.26, -2.86 <0.00001* [038,044] WMD- 1.04-1.18, -0.90 <0.00001* Measured in deionized water (ppm) 109 MD- 3.61-3.97, -3.25 <0.00001* Measured in demineralization solution (µg/cm 2 ) 10 d 151 MD- 0.40-0.53, -0.27 <0.00001* 158 MD- 0.44-0.59, -0.29 <0.00001* 11 d 110 MD- 4.52-4.86, -4.18 <0.00001* 12 d 111 MD- 3.44-3.69, -3.19 <0.00001* Measured in demineralization solution (µg/cm 2 ) 13 d 112 MD- 4.82-5.08, -4.56 <0.00001* 084 MD- 0.74-0.76, -0.72 <0.00001* Measured in deionized water (µg/mm 2 ) 14 d / 2 w 071 MD- 31.49-32.45, -30.53 <0.00001* Measured in artificial saliva (ppm) [019,026] WMD-12.78-15.32, -10.24 <0.00001* Measured in deionized water (µg/cm 2 ) 113 MD- 4.66-5.02, -4.30 <0.00001* Measured in demineralization solution (µg/cm 2 ) 056 MD- 4.84-5.10, -4.58 <0.00001* Measured in deionized water (ppm) 15 d 152 MD 0.00-0.01, 0.01 =1.00 159 MD 0.00-0.02, 0.02 =1.00 [039,045] WMD- 1.32-1.98, -0.66 <0.00001* Measured in deionized water (ppm) 20 d 153 MD 0.00-0.01, 0.01 =1.00 160 MD- 0.03-0.06, 0.00 =0.04* 3 w [077,020,027] WMD- 6.98-13.52, -0.45 =0.04* Measured in deionized water (µg/mm 2 ) 072 MD- 25.79-27.19, -24.39 <0.00001* Measured in artificial saliva (ppm) 25 d 161 MD- 0.17-0.23, -0.11 <0.00001* 154 MD- 0.33-0.34, -0.32 <0.00001* 28 d 085 MD- 0.56-0.59, -0.53 <0.00001* Measured in deionized water (µg/mm 2 ) 30 d / 4 w / [040,046,057] WMD- 1.43-2.31, -0.55 =0.002* Measured in deionized water (ppm) 1 m 073 MD-22.39-23.53, -21.25 <0.00001* Measured in artificial saliva (ppm) 135

[021,028] WMD- 7.61-9.35, -5.88 <0.00001* Measured in deionized water (µg/cm 2 ) 5 w 074 MD- 20.39-21.53, -19.25 <0.00001* 6 w 075 MD- 18.29-19.43, -17.15 <0.00001* Measured in artificial saliva (ppm) 56 d 086 MD- 0.68-0.71, -0.65 <0.00001* 60 d 058 MD- 1.78-1.98, -1.58 <0.00001* Measured in deionized water (µg/mm 2 ) 112 d 087 MD- 0.84-0.88, -0.80 <0.00001* Measured in deionized water (µg/mm 2 ).t = time interval; h = hour(s); d = day(s); w = week(s); m = month(s); y = year; WMD = weighted mean difference; MD = mean difference; CI = confidence interval, [] = datasets combined through meta-analysis. * Result in favor of GIC 136