Effectiveness of non-fluoride agents in combination with fluorides for dental caries prevention: A systematic review and meta-analysis

Tony Joseimage

Highlights

Combining fluoride with agents like chlorhexidine, CPP-ACP, povidone iodine, or herbal products may improve remineralization and antimicrobial effects in prevention.

Meta-analysis showed fluoride combined with non-fluoride agents, especially CPP-ACP, reduced caries activity and lesion area more effectively short term than fluoride alone.

Non-fluoride remineralizing agents may support fluoride-based caries management, but long-term multicenter randomized trials are needed to confirm lasting benefits.

Abstract

Although fluoride has been known as anti-caries agents for many years, its usage is associated with some side-effects. Owing to antimicrobial and remineralization-enhancing properties, non-fluoride agents such as chlorhexidine, povidone iodine, casein phosphopeptide-amorphous calcium phosphate (CPP-ACP), and various herbal products have gained attention as remineralization strategies for the prevention and management of dental caries. The present study aimed to evaluate the effectiveness of combined therapy using topical fluoride (TF) with these non-fluoride agents over TF monotherapy for the prevention of dental caries. Following PRISMA guidelines, a literature search was conducted across PubMed, ScienceDirect, SpringerLink, Wiley Online Library and Google Scholar for studies published between 2005 and 2025. Articles that evaluated the use of non-fluoride agents (chlorhexidine, CPP-ACP, povidone iodine, herbal products) in combination with fluoride-containing products were included. Totally, 21 articles were included in the review and 17 articles were included in the meta-analysis. Most of the reviewed studies used CPP-ACP as non-fluoride remineralizing agents, while only few used povidone iodine and chlorhexidine. Findings revealed that fluoride, when used in combination with non-fluoride agents, was significantly more effective than fluoride monotherapy in reducing caries activity in less than two months and at three months in both primary and permanent teeth. Additionally, this combination therapy resulted in a significant reduction in lesion area after three months of treatment. However, no statistically significant difference was observed between fluoride combination therapy and fluoride monotherapy with respect to caries increment in either the short-term or long-term follow-up. Fluoride, when combined with non-fluoride agents, particularly CPP-ACP, showed better remineralization potential compared with fluoride alone, particularly in the short-term basis. These findings support the adjunctive use of such combinations in caries management; however, further long-term, multicenter RCTs are warranted to confirm their clinical durability and sustained effectiveness.

Keywords: Chlorhexidine, CPP-ACP; Dental Caries; Fluoride; Povidone Iodine

Author Affiliations

  1. Dental Department, Muaither Health Center, Primary Health Care Corporation, Qatar (Correspondence:dr.tonyjose@live.com)
  1. Pokhrel S. Hydroxyapatite: Preparation, Properties and Its Biomedical Applications. Adv Chem Eng Sci 2018;8:225-240
  2. Sohn HS, Oh JK. Review of bone graft and bone substitutes with an emphasis on fracture surgeries. Biomater Res 2019;23:4-10
  3. Lu J, Yu H, Chen C. Biological properties of calcium phosphate biomaterials for bone repair: A review. RSC Adv 2018;8:2015-2033
  4. Detsch R, Hagmeyer D, Neumann M, Schaefer S, Vortkamp A, Wuelling M, et al. The resorption of nanocrystalline calcium phosphates by osteoclast-like cells. Acta Biomater 2010;6:3223-3233
  5. Mahboobi Z, Pakdaman A, Yazdani R, Azadbakht L, Montazeri A. Dietary free sugar and dental caries in children: A systematic review on longitudinal studies. Heal Promot Perspect 2021;11:271-280
  6. Selwitz R, Ismail A, Pitts N. Dental Caries. Lancet 2007;369:51-59.
  7. Spatafora G, Li Y, He X, Cowan A, Tanner ACR. The Evolving Microbiome of Dental Caries. Microorganisms 2024;12.
  8. Urquhart O, Tampi MP, Pilcher L, Slayton RL, Araujo MWB, Fontana M, et al. Nonrestorative Treatments for Caries: Systematic Review and Network Meta-analysis. J Dent Res 2018;98:14-26.
  9. Frencken JE, Sharma P, Stenhouse L, Green D, Laverty D, Dietrich T. Global epidemiology of dental caries and severe periodontitis – a comprehensive review. J Clin Periodontol 2017;44:S94-S105.
  10. Elamin A, Garemo M, Mulder A. Determinants of dental caries in children in the Middle East and North Africa region: a systematic review based on literature published from 2000 to 2019. BMC Oral Health 2021;21.
  11. Qin XF, Zi H, Zeng XJ. Changes in the global burden of untreated dental caries from 1990 to 2019: A systematic analysis for the Global Burden of Disease study. Heliyon 2022;8:e10714.
  12. Whelton HP, Spencer AJ, Do LG, Rugg-Gunn AJ. Fluoride Revolution and Dental Caries: Evolution of Policies for Global Use. J Dent Res 2019;98:837-846.
  13. Zampetti P, Scribante A. Historical and bibliometric notes on the use of fluoride in caries prevention. Eur J Paediatr Dent 2020;21:148-152.
  14. Dorozhkin SV. Functionalized calcium orthophosphates (CaPO4) and their biomedical applications. J Mater Chem B 2019;7:7471-7489.
  15. Zhang J, Sardana D, Li KY, Leung KCM, Lo ECM. Topical Fluoride to Prevent Root Caries: Systematic Review with Network Meta-analysis. J Dent Res 2020;99:506-513.
  16. ten Cate JM, Buzalaf MAR. Fluoride Mode of Action: Once There Was an Observant Dentist… J Dent Res 2019;98:725-730.
  17. Kanduti D, Sterbenk P, Artnik. Fluoride: a Review of Use and Effects on Health. Mater Socio Medica 2016;28:133.
  18. Dey S, Giri B. Fluoride Fact on Human Health and Health Problems: A Review. Med Clin Rev 2016;2:1-6.
  19. Ullah R, Zafar MS, Shahani N. Potential fluoride toxicity from oral medicaments: A review. Iran J Basic Med Sci 2017;20:841-848.
  20. Shen Y, Yu F, Qiu L, Gao M, Xu P, Zhang L, et al. Ecological influence by colonization of fluoride-resistant Streptococcus mutans in oral biofilm. Front Cell Infect Microbiol 2023;12:1-16.
  21. Liao Y, Brandt BW, Li J, Crielaard W, Van Loveren C, Deng DM. Fluoride resistance in Streptococcus mutans: a mini review. J Oral Microbiol 2017;9.
  22. Park KJ, Meißner T, Günther E, Schmalz G, Kottmann T, Krause F, et al. Arrest of root caries with an adjuvant chlorhexidine–fluoride varnish over a 12-months observation period: a QLF-analyzed, placebo-controlled, randomized, clinical trial (RCT). Odontology 2022;110:193-202.
  23. Milgrom P, Tut O, Rothen M, Mancl L, Gallen M, Tanzer J. Addition of Povidone-Iodine to Fluoride Varnish for Dental Caries: A Randomized Clinical Trial. JDR Clin Transl Res 2021;6:195-204.
  24. Meeral PR, Doraikannan S, Indiran MA. Efficiency of casein phosphopeptide amorphous calcium phosphate versus topical fluorides on remineralizing early enamel carious lesions – A systematic review and meta analysis. Saudi Dent J 2024;36:521-527.
  25. Saikia AM, Sivasubramanian A, Muthu MS, Ganesh A, Chandrasekaran K, Kirubakaran R. Herbal Mouthrinses for Prevention of Dental Caries in Children and Adolescents: A Systematic Review. Int J Clin Pediatr Dent 2024;17:S100-S111.
  26. Gupta A, Sharda S, Nishant, Shafiq N, Kumar A, Goyal A. Topical fluoride-antibacterial agent combined therapy versus topical fluoride monotherapy in preventing dental caries: a systematic review and meta-analysis. Eur Arch Paediatr Dent 2020;21:629-646.
  27. Gupta A, Nishant, Sharda S, Kumar A, Goyal A, Gauba K. Comparing the effectiveness of topical fluoride and povidone iodine with topical fluoride alone for the prevention of dental caries among children: A systematic review and meta-analysis. Int J Clin Pediatr Dent 2020;13:559-565.
  28. Cavalcante BGN, Wenning AS, Szabó B, Márk CL, Hegyi P, Borbély J, et al. Combined Casein Phosphopeptide-Amorphous Calcium Phosphate and Fluoride Is Not Superior to Fluoride Alone in Early Carious Lesions: A Meta-Analysis. Caries Res 2024;58:1-16.
  29. Tao S, Zhu Y, Yuan H, Tao S, Cheng Y, Li J, et al. Efficacy of fluorides and CPP-ACP vs fluorides monotherapy on early caries lesions: A systematic review and meta-analysis. PLoS One 2018;13:4-7.
  30. Page MJ, Mckenzie JE, Bossuyt PM, Boutron I, Hoffmann TC, Mulrow CD, et al. The PRISMA 2020 statement: An updated guideline for reporting systematic reviews. BMJ 2021;88:105906.
  31. Sterne JAC, Savović J, Page MJ, Elbers RG, Blencowe NS, Boutron I, et al. RoB 2: A revised tool for assessing risk of bias in randomised trials. BMJ 2019;366:1-8.
  32. Bobu L, Murariu A, Topor G, Beznea A, Vasluianu R. Comparative evaluation of casein phosphopeptide – Amorphous calcium phosphate and fluoride in managing early caries lesions. Rev Chim 2019;70:3746-3749.
  33. Yazicioğlu O, Yaman B, Güler A, Koray F. Quantitative Evaluation of the Enamel Caries Which Were Treated with Casein Phosphopeptide-amorphous Calcium Fluoride Phosphate. Niger J Clin Pract 2017;20:686-692.
  34. Güçlü ZA, Alaçam A, Coleman NJ. A 12-Week Assessment of the Treatment of White Spot Lesions with CPP-ACP Paste and/or Fluoride Varnish. Biomed Res Int 2016;2016.
  35. Parsa A, Sakki S. Combined efficacy of topical iodine and fluoride varnish as against fluoride varnish alone in preventing dental caries in children- A comparative study. Int J Med Sci Adv Clin Res 2021;4:180-203.
  36. Singh S, Singh SP, Goyal A, Utreja AK, Jena AK. Effects of various remineralizing agents on the outcome of post-orthodontic white spot lesions (WSLs): a clinical trial. Prog Orthod 2016;17.
  37. Mendes AC, Restrepo M, Bussaneli D, Zuanon AC. Use of Casein Amorphous Calcium Phosphate (CPP-ACP) on White-spot Lesions: Randomised Clinical Trial. Oral Health Prev Dent 2018;16:27-31.
  38. Llena C, Leyda AM, Forner L. CPP-ACP and CPP-ACFP versus fluoride varnish in remineralisation of early caries lesions. A prospective study. Eur J Paediatr Dent 2015;16:181-186.
  39. Esparza-Villalpando V, Fernandez-Hernandez E, Rosales-Berber M, Torre-Delgadillo G, Garrocho-Rangel A, Pozos-Guillén A. Clinical Efficacy of Two Topical Agents for the Remineralization of Enamel White Spot Lesions in Primary Teeth. Pediatr Dent 2021;43:95-101.
  40. Mekky AI, Dowidar KML, Talaat DM. Casein Phosphopeptide Amorphous Calcium Phosphate Fluoride Varnish in Remineralization of Early Carious Lesions in Primary Dentition: Randomized Clinical Trial. Pediatr Dent 2021;43:17-23.
  41. Al-Batayneh OB, Jbarat RA, Al-Khateeb SN. Effect of application sequence of fluoride and CPP-ACP on remineralization of white spot lesions in primary teeth: An in-vitro study. Arch Oral Biol 2017;83:236-240.
  42. Al-Batayneh O, Bani Hmood E, Al-Khateeb S. Assessment of the effects of a fluoride dentifrice and GC Tooth Mousse on early caries lesions in primary anterior teeth using quantitative light-induced fluorescence: a randomised clinical trial. Eur Arch Paediatr Dent 2019;21:85-93.
  43. Beerens MW, Van Der Veen MH, Van Beek H, Ten Cate JM. Effects of casein phosphopeptide amorphous calcium fluoride phosphate paste on white spot lesions and dental plaque after orthodontic treatment: A 3-month follow-up. Eur J Oral Sci 2010;118:610-617.
  44. Beerens MW, Cate JMT, Buijs MJ, Van Der Veen MH. Long-term remineralizing effect of MI Paste Plus on regression of early caries after orthodontic fixed appliance treatment: A 12-month follow-up randomized controlled trial. Eur J Orthod 2018;40:457-464.
  45. Bröchner A, Christensen C, Kristensen B, Tranæus S, Karlsson L, Sonnesen L, et al. Treatment of post-orthodontic white spot lesions with casein phosphopeptide-stabilised amorphous calcium phosphate. Clin Oral Investig 2011;15:369-373.
  46. Zhan L, Featherstone JDB, Gansky SA, Hoover CI, Fujino T, Berkowitz RJ, et al. Antibacterial treatment needed for severe early childhood caries. J Public Health Dent 2006;66:174-179.
  47. Pukallus ML, Plonka KA, Barnett AG, Walsh LJ, Holcombe TF, Seow WK. A randomised, controlled clinical trial comparing chlorhexidine gel and low-dose fluoride toothpaste to prevent early childhood caries. Int J Paediatr Dent 2013;23:216-224.
  48. Sundell AL, Ullbro C, Koch G. Evaluation of preventive programs in high caries active preschool children. Swed Dent J 2013;37:25-31.
  49. Sitthisettapong T, Phantumvanit P, Huebner C, Derouen T. Effect of CPP-ACP paste on dental caries in primary teeth: A randomized trial. J Dent Res 2012;91:847-852.
  50. El-Housseiny A, Farsi N. The effectiveness of two antibacterial regimens on salivary Mutans Streptococci and Lactobacilli in children. J Clin Pediatr Dent 2005;30:145-152.
  51. İlisulu SC, Gürcan AT, Şişmanoğlu S. Remineralization efficiency of three different agents on artificially produced enamel lesions: A micro-CT study. J Esthet Restor Dent 2024;36:1536-1546.
  52. Kour S, Malik A, Choudhary T, Kumar A, P RP, Dhani R. Laser – fluorescence based evaluation of remineralization in artificial enamel lesions using three commercially available re-mineralizing agents – An invitro study. IP Indian J Conserv Endod 2023;8:97-101.
  53. Sitthisettapong T, Doi T, Nishida Y, Kambara M, Phantumvanit P. Effect of CPP-ACP paste on enamel carious lesion of primary upper anterior teeth assessed by quantitative lightinduced fluorescence: a one-year clinical trial. Caries Res 2015;49:434-441.
  54. Shen P, Walker GD, Yuan Y, Reynolds C, Stanton DP, Fernando JR, et al. Importance of bioavailable calcium in fluoride dentifrices for enamel remineralization. J Dent 2018;78:59-64.
  55. Shen P, Fernando JR, Yuan Y, Walker GD, Reynolds C, Reynolds EC. Bioavailable fluoride in calcium-containing dentifrices. Sci Rep 2021;11:1-6.
  56. Wang J, Mo Y, Liu Y. Research progress of CPP-ACP promoting enamel remineralization. Int J Front Med 2022;4:12-17.
  57. Cross K, Huq N, Reynolds E. Casein phosphopeptides in oral health-chemistry and clinical applications. Curr Pharm Des 2007;13:793-800.
  58. Thimmaiah C, Shetty P, Shetty SB, Natarajan S, Thomas NA. Comparative analysis of the remineralization potential of cpp-acp with fluoride, tri-calcium phosphate and nano hydroxyapatite using SEM/EDx-an in vitro study. J Clin Exp Dent 2019;11:e1120-e1126.
  59. Fernando JR, Shen P, Sim CPC, Chen YY, Walker GD, Yuan Y, et al. Self-assembly of dental surface nanofilaments and remineralisation by SnF2 and CPP-ACP nanocomplexes. Sci Rep 2019;9:1-10.
  60. Atia NSM, El-nemr RA, Abo-Elsoud AAE. Effect of lactoferrin on enamel characteristics of primary and permanent teeth: an in-vitro study. BMC Oral Health 2023;23:1-7.
  61. De Menezes Oliveira MAH, Torres CP, Gomes‐Silva JM, Chinelatti MA, De Menezes FCH, Palma‐Dibb RG, et al. Microstructure and mineral composition of dental enamel of permanent and deciduous teeth. Microsc Res Tech 2010;73:572-577.
  62. Kim DS, Kwon JM, Park SH, Choi SC, Kim SY. Mechanical and micromorphological evaluation of chlorhexidine-mediated dentin remineralization. Scanning 2012;34:151-158.
  63. Neeraja R, Anantharaj A, Praveen P, Karthik V, Vinitha M. The effect of povidone-iodine and chlorhexidine mouth rinses on plaque Streptococcus mutans count in 6- to 12-year-old school children: an in vivo study. J Indian Soc Pedod Prev Dent 2008;26:S14-S18.
  64. Amin MS, Harrison RL, Benton TS, Roberts M, Weinstein P. Effect of povidone-iodine on Streptococcus mutans in children with extensive dental caries. Pediatr Dent 2004;26:5-10.
  65. Monteiro ELO, Ladeira LLC, Costa CM, Monteiro MCC, Rebelo MAB, Alves CMC, et al. Behavior Risk Factors for Noncommunicable Diseases and Caries in Adolescents: A Population Study. Caries Res 2025.
  66. Giacaman RA, Fernández CE, Muñoz-Sandoval C, León S, García-Manríquez N, Echeverría C, et al. Understanding dental caries as a non-communicable and behavioral disease: Management implications. Front Oral Heal 2022;3:1-10.
  67. Methuen M, Kukkonen VF, Anttonen V, Mikkonen S, Väistö J, Soininen S, et al. Dietary Factors and Dental Caries among Adolescents : Eight-Year Follow-up Study. JDR Clin Transl Res 2025;11:40-52.
  68. Lam PP, Chua H, Ekambaram M, Lo EC, Yiu CK. Risk predictors of early childhood caries increment—A systematic review and meta-analysis. J Evid Based Dent Pract 2022;22:101732.

Article Info

Contemp Pediatr Dent 2026:7(1):10-36

Received: 04 November 2025

Accepted: 18 March 2026

Online First: 22 April 2026

DOI: 10.51463/cpd.2025.70

27 views

Full Text

Attachments

Attachments

How to Cite 

				
					Tony Jose. Effectiveness of non-fluoride agents in combination with fluorides for dental caries prevention: A systematic review and meta-analysis. Contemp Pediatr Dent 2026:7(1):10-36

Related Articles

Share Article

Under a Creative Commons license
Tagged ,
Register Now