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Table of Contents
Vol. 42, No. 3, 2008
Issue release date: May 2008
Section title: Original Paper
Caries Res 2008;42:171–184
(DOI:10.1159/000128561)

The Anticariogenic Effect of Sugar-Free Gum Containing CPP-ACP Nanocomplexes on Approximal Caries Determined Using Digital Bitewing Radiography

Morgan M.V.a · Adams G.G.a · Bailey D.L.a · Tsao C.E.a · Fischman S.L.b · Reynolds E.C.a
aCooperative Research Centre for Oral Health Science, School of Dental Science, Bio21 Institute, University of Melbourne, Parkville, Vic., Australia; bSchool of Dental Medicine, State University of New York at Buffalo, Buffalo, N.Y., USA
email Corresponding Author

Abstract

This study investigated, using digital bitewing radiography, the progression and regression of approximal caries in adolescent subjects chewing a sugar-free gum containing 54 mg CPP-ACP relative to the identical gum without CPP-ACP. 2,720 subjects from 29 schools were randomly assigned to one of the two gums and were instructed to chew their assigned gum for 3 × 10 min/day, with one session supervised on school days, over the 24-month study period. Standardized digital bitewing radiographs were taken at the baseline and 24-month clinical examinations for each subject. The radiographs, scored by a single examiner, were assessed for approximal surface dental caries at both the enamel and dentine level. Surface level transitions were scored using a transition matrix. Caries progression or regression was analysed using proportional-odds ordered logistic regression modelling of the transition scores at the tooth surface level. There was a statistically significant difference in the frequency distributions of the transition scores between the two gum groups (OR = 0.82, p = 0.03). For subjects chewing the CPP-ACP gum the odds of a surface experiencing caries progression were 18% less than those of a surface experiencing caries progression for subjects chewing the control gum. In conclusion, the 54 mg CPP-ACP sugar-free gum significantly slowed progression and enhanced regression of approximal caries relative to a control sugar-free gum in a 24-month clinical trial.

© 2008 S. Karger AG, Basel


  

Key Words

  • Approximal caries progression
  • Casein phosphopeptide-amorphous calcium phosphate nanocomplexes
  • Digital bitewing radiography
  • Enamel remineralization
  • Ordinal categorical data
  • Randomized clinical trial
  • Sugar-free chewing gum

References

  1. Ahn C, Jung SH, Donner A: Application of an adjusted χ2 statistic to site-specific data in observational dental services. J Clin Periodontol 2002;29:79–82.
  2. Alanen P, Isokangas P, Gutmann K: Xylitol candies in caries prevention: results of a field study in Estonian children. Community Dent Oral Epidemiol 2000;28:218–224.
  3. Bader JD, Shugars DA, Bonito AJ: Systematic reviews of selected dental caries diagnostic and management methods. J Dent Educ 2001;65:960–968.
  4. Bailey DL, Adams GG, Tsao CE, Morgan MV: Standardisation of digital bitewing radiographs during a clinical caries trial (abstract 62). Caries Res 2006;40:324.
  5. Beck JD, Lawrence HP, Koch GG: Analytic approaches to longitudinal caries data in adults. Community Dent Oral Epidemiol 1997;25:42–51.
  6. Beiswanger BB, Boneta AE, Mau MS, Katz BP, Proskin HM, Stookey GK: The effect of chewing sugar-free gum after meals on clinical caries incidence. J Am Dental Assoc 1998;129:1623–1626.
  7. Biesbrock AR, Chesters RK, Ellwood RP, Smith SR: The challenges of validating diagnostic methods relative to a conventional two-year caries clinical trial. J Dent Res 2004;83:C53–C55.
  8. Burnside G, Pine CM, Williamson PR: The application of multilevel modelling to dental caries data. Stat Med 2007;26:4139–4149.
  9. Burt BA: The use of sorbitol- and xylitol-sweetened chewing gum in caries control. J Am Dental Assoc 2006;137:190–196.
  10. Cai F, Manton DJ, Shen P, Walker GD, Cross KJ, Yuan Y, Reynolds C, Reynolds EC: Effect of addition of citric acid and casein phosphopeptide-amorphous calcium phosphate to a sugar-free chewing gum on enamel remineralization in situ. Caries Res 2007;41:377–383.
  11. Campain AC, Morgan MV, Evans RW, Ugoni A, Adams GG, Conn JA, Watson MJ: Sugar-starch combinations in food and the relationship to dental caries in low-risk adolescents. Eur J Oral Sci 2003;111:316–325.
  12. Chesters RK, Pitts NB, Matuliene G, Kvedariene A, Huntington E, Bendinskaite R, Balciuniene I, Matheson JR, Nicholson JA, Gendvilyte A, Sabalaite R, Ramanauskiene J, Savage D, Mileriene J: An abbreviated caries clinical trial design validated over 24 months. J Dent Res 2002;81:637–640.
  13. Cohen J: A coefficient of agreement for nominal scales. Educ Psychol Meas 1960;20:37–46.

    External Resources

  14. Cook SR: A longitudinal radiographic study of caries progression in dental students. Aust Dent J 1984;29:315–320.
  15. Cross KJ, Huq NL, Palamara JE, Perich JW, Reynolds EC: Physicochemical characterization of casein phosphopeptide-amorphous calcium phosphate nanocomplexes. J Biol Chem 2005;280:15362–15369.
  16. DeRouen TA, Mancl L, Hujoel P: Measurement of associations in periodontal diseases using statistical methods for dependent data. J Periodontal Res 1991;26:218–229.
  17. Donner A, Banting D: Analysis of site-specific data in dental statistics. J Dent Res 1988;67:1392–1395.
  18. Donner A, Banting D: Adjustment of frequently used chi-square procedures for the effect of site-to-site dependencies in the analysis of dental data. J Dent Res 1989;68:1350–1354.
  19. Dummer PMH, Addy M, Oliver SJ, Shaw WC: Changes in the distribution of decayed and filled tooth surfaces and the progression of approximal caries in children between the ages of 11–12 years and 15–16 years. Br Dent J 1988;164:277–282.
  20. Gales MA, Nguyen TM: Sorbitol compared with xylitol in prevention of dental caries. Ann Pharmacother 2000;34:98–100.
  21. Granath L, Kahlmeter A, Matsson L, Schroder U: Progression of proximal enamel caries in early teens related to caries activity. Acta Odontol Scand 1980;38:247–251.
  22. Grondahl HG, Hollender L, Malmcrona E, Sundquist B: Dental caries and restorations in teenagers. Swed Dent J 1977;1:45–50.
  23. Hannigan A, O’Mullane DM, Barry D, Schafer F, Roberts AJ: A re-analysis of a caries clinical trial by survival analysis. J Dent Res 2001;80:427–431.
  24. Hayes C: The effect of non-cariogenic sweeteners on the prevention of dental caries: a review of the evidence. J Dent Educ 2001;65:1105–1109.
  25. Hintze H: Approximal caries prevalence in Danish recruits and progression of caries in the late teens: a retrospective radiographic study. Caries Res 2001;35:27–35.
  26. Hopcraft MS, Morgan MV: Comparison of radiographic and clinical diagnosis of approximal and occlusal dental caries in a young adult population. Community Dent Oral Epidemiol 2005;33:212–218.
  27. Hujoel PP, Loesche WJ, DeRouen TA: Assessment of relationships between site-specific variables. J Periodontol 1990;61:368–372.
  28. Iijima Y, Cai F, Shen P, Walker G, Reynolds C, Reynolds EC: Acid resistance of enamel subsurface lesions remineralized by a sugar- free chewing gum containing casein phosphopeptide-amorphous calcium phosphate. Caries Res 2004;38:551–556.
  29. Imrey PB, Kingman A: Analysis of clinical trials involving non-cavitated caries lesions. J Dent Res 2004;83:C103–C108.
  30. Isokangas P, Alanen P, Tiekso J, Mäkinen KK: Xylitol chewing gum in caries prevention: a field study in children. J Am Dental Assoc 1988;117:315–320.
  31. Källestål C, Holm AK: Allocation of dental caries prevention in Swedish teenagers. Community Dent Oral Epidemiol 1994;22:100–105.
  32. Kandelman D, Gagnon G: A 24-month clinical study of the incidence and progression of dental caries in relation to consumption of chewing gum containing xylitol in school preventive programs. J Dent Res 1990;69:1771–1775.
  33. Kidd EAM, Mejàre I, Nyvad B: Clinical and radiographic diagnosis; in Fejerskov O, Kidd EAM (eds): Dental Caries: The Disease and Its Clinical Management. Oxford, Blackwell, 2003, pp 111–128.
  34. Kidd EAM, Pitts NB: A reappraisal of the value of the bitewing radiograph in the diagnosis of posterior approximal caries. Br Dent J 1990;169:195–200.
  35. LaVange LM, Koch GG, Schwartz TA: Applying sample survey methods to clinical trials data. Stat Med 2001;20:2609–2623.
  36. Lawrence HP, Benn DK, Sheiham A: Digital radiographic measurement of approximal caries progression in fluoridated and non-fluoridated area of Rio de Janeiro, Brazil. Community Dent Oral Epidemiol 1997;25:412–418.
  37. Lawrence HP, Sheiham A: Caries progression in 12- to 16-year-old schoolchildren in fluoridated and fluoride-deficient areas in Brazil. Community Dent Oral Epidemiol 1997;25:402–411.
  38. Liang KY, Zeger SL: Longitudinal data analysis using generalized linear models. Biometrics 1986;73:13–22.

    External Resources

  39. Lingström P, Holm AK, Mejàre I, Twetman S, Söder B, Norlund A, Axelsson S, Lagerlöf F, Nordenram G, Petersson LG, Dahlgren H, Källestål C: Dietary factors in the prevention of dental caries: a systematic review. Acta Odontol Scand 2003;61:331–340.
  40. Llena-Puy C, Forner L: A clinical and radiographic comparison of caries diagnosed in approximal surfaces of posterior teeth in a low-risk population of 14-year-old children. Oral Health Prev Dent 2005;3:47–52.
  41. Machiulskiene V, Nyvad B, Baelum V: Caries preventive effect of sugar-substituted chewing gum. Community Dent Oral Epidemiol 2001;29:278–288.
  42. Maguire A, Rugg-Gunn AJ: Xylitol and caries prevention – is it a magic bullet? Br Dent J 2003;194:429–436.
  43. Mäkinen KK, Bennett CA, Hujoel PP, Isokangas PJ, Isotupa KP, Pape Jr HR, Mäkinen PL: Xylitol chewing gums and caries rates: a 40-month cohort study. J Dent Res 1995;74:1904–1913.
  44. Mäkinen KK, Mäkinen PL, Pape HR Jr, Peldyak J, Hujoel PP, Isotupa KP, Isokangas PJ, Allen P, Bennett C: Conclusion and review of the ‘Michigan Xylitol Programme’ (1986–1995) for the prevention of dental caries. Int Dent J 1996;46:22–34.
  45. McCullagh P: Regression models for ordinal data. J R Statist Soc B 1980;42:109–142.
  46. Mejàre I, Källestål C, Stenlund H: Incidence and progression of approximal caries from 11 to 22 years of age in Sweden: a prospective radiographic study. Caries Res 1999;33:93–100.
  47. Peng B, Petersen PE, Bian Z, Tai B, Jiang H: Can school-based oral health education and a sugar-free chewing gum program improve oral health? Results from a two-year study in PR China. Acta Odontol Scand 2004;62:328–332.
  48. Pitts NB: The use of film holding, beam collimating and aiming devices in bitewing radiography: a suggested design for routine and research use. Dentomaxillofac Radiol 1983;12:77–82.
  49. Pitts NB: Systems for grading approximal carious lesions and overlaps diagnosed from bitewing radiographs: proposals for future standardization. Community Dent Oral Epidemiol 1984;12:114–122.
  50. Pitts NB: Score system for behaviour of radiologically diagnosed approximal carious lesions. Community Dent Oral Epidemiol 1985;13:268–272.
  51. Pitts NB: The use of bitewing radiographs in the management of dental caries: scientific and practical considerations. Dentomaxillofac Radiol 1996;25:5–16.
  52. Pretty IA: Caries detection and diagnosis: novel techniques. J Dent 2006;34:727–739.
  53. Radike AW: Criteria for diagnosis of dental caries; in Conference on the Clinical Testing of Cariostatic Agents. American Dental Association, 1972, pp 87–88.
  54. Reynolds EC: Anticariogenic complexes of amorphous calcium phosphate stabilized by casein phosphopeptides: a review. Spec Care Dentist 1998;18:8–16.
  55. Reynolds EC, Cai F, Shen P, Walker GD: Retention in plaque and remineralization of enamel lesions by various forms of calcium in a mouthrinse or sugar-free chewing gum. J Dent Res 2003;82:206–212.
  56. Reynolds EC, Cain CJ, Webber FL, Black CL, Riley PF, Johnson IH, Perich JW: Anticariogenicity of calcium phosphate complexes of tryptic casein phosphopeptides in the rat. J Dent Res 1995;74:1272–1279.
  57. Scheie AA, Fejerskov OB: Xylitol in caries prevention: what is the evidence for clinical efficacy? Oral Dis 1998;4:268–278.
  58. Shen P, Cai F, Nowicki J, Vincent J, Reynolds EC: Remineralization of enamel subsurface lesions by sugar-free chewing gum containing casein phosphopeptide-amorphous calcium phosphate. J Dent Res 2001;80:2066–2070.
  59. Stenlund H, Mejàre I, Källestål C: Caries incidence rates in Swedish adolescents and young adults with particular reference to adjacent approximal tooth surfaces: a methodological study. Community Dent Oral Epidemiol 2003;31:361–367.
  60. Szöke J, Bánóczy J, Proskin HM: Effect of after-meal sucrose-free gum-chewing on clinical caries. J Dent Res 2001;80:1725–1729.
  61. Therapeutic Goods Administration: Note for guidance on good clinical practice (cpmp/ich/135/95) annotated with TGA comments. Canberra, Therapeutic Goods Administration, 2000.
  62. van Loveren C: Sugar alcohols: what is the evidence for caries-preventive and caries-therapeutic effects? Caries Res 2004;38:286–293.
  63. Wenzel A, Fejerskov O: Validity and diagnosis of questionable caries lesions in occlusal surfaces of extracted third molars. Caries Res 1992;26:188–194.
  64. Whitehead J: Sample size calculations for ordered categorical data. Stat Med 1993;12:2257–2271.

  

Author Contacts

Eric C. Reynolds
School of Dental Science, University of Melbourne
720 Swanston Street
Parkville, Vic. 3010 (Australia)
Tel. +61 3 9341 1547, Fax +61 3 9341 1597, E-Mail e.reynolds@unimelb.edu.au

  

Article Information

Received: March 14, 2007
Accepted after revision: February 14, 2008
Published online: April 29, 2008
Number of Print Pages : 14
Number of Figures : 1, Number of Tables : 10, Number of References : 64

  

Publication Details

Caries Research

Vol. 42, No. 3, Year 2008 (Cover Date: May 2008)

Journal Editor: Shellis R.P. (Bristol)
ISSN: 0008–6568 (Print), eISSN: 1421–976X (Online)

For additional information: http://www.karger.com/CRE


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References

  1. Ahn C, Jung SH, Donner A: Application of an adjusted χ2 statistic to site-specific data in observational dental services. J Clin Periodontol 2002;29:79–82.
  2. Alanen P, Isokangas P, Gutmann K: Xylitol candies in caries prevention: results of a field study in Estonian children. Community Dent Oral Epidemiol 2000;28:218–224.
  3. Bader JD, Shugars DA, Bonito AJ: Systematic reviews of selected dental caries diagnostic and management methods. J Dent Educ 2001;65:960–968.
  4. Bailey DL, Adams GG, Tsao CE, Morgan MV: Standardisation of digital bitewing radiographs during a clinical caries trial (abstract 62). Caries Res 2006;40:324.
  5. Beck JD, Lawrence HP, Koch GG: Analytic approaches to longitudinal caries data in adults. Community Dent Oral Epidemiol 1997;25:42–51.
  6. Beiswanger BB, Boneta AE, Mau MS, Katz BP, Proskin HM, Stookey GK: The effect of chewing sugar-free gum after meals on clinical caries incidence. J Am Dental Assoc 1998;129:1623–1626.
  7. Biesbrock AR, Chesters RK, Ellwood RP, Smith SR: The challenges of validating diagnostic methods relative to a conventional two-year caries clinical trial. J Dent Res 2004;83:C53–C55.
  8. Burnside G, Pine CM, Williamson PR: The application of multilevel modelling to dental caries data. Stat Med 2007;26:4139–4149.
  9. Burt BA: The use of sorbitol- and xylitol-sweetened chewing gum in caries control. J Am Dental Assoc 2006;137:190–196.
  10. Cai F, Manton DJ, Shen P, Walker GD, Cross KJ, Yuan Y, Reynolds C, Reynolds EC: Effect of addition of citric acid and casein phosphopeptide-amorphous calcium phosphate to a sugar-free chewing gum on enamel remineralization in situ. Caries Res 2007;41:377–383.
  11. Campain AC, Morgan MV, Evans RW, Ugoni A, Adams GG, Conn JA, Watson MJ: Sugar-starch combinations in food and the relationship to dental caries in low-risk adolescents. Eur J Oral Sci 2003;111:316–325.
  12. Chesters RK, Pitts NB, Matuliene G, Kvedariene A, Huntington E, Bendinskaite R, Balciuniene I, Matheson JR, Nicholson JA, Gendvilyte A, Sabalaite R, Ramanauskiene J, Savage D, Mileriene J: An abbreviated caries clinical trial design validated over 24 months. J Dent Res 2002;81:637–640.
  13. Cohen J: A coefficient of agreement for nominal scales. Educ Psychol Meas 1960;20:37–46.

    External Resources

  14. Cook SR: A longitudinal radiographic study of caries progression in dental students. Aust Dent J 1984;29:315–320.
  15. Cross KJ, Huq NL, Palamara JE, Perich JW, Reynolds EC: Physicochemical characterization of casein phosphopeptide-amorphous calcium phosphate nanocomplexes. J Biol Chem 2005;280:15362–15369.
  16. DeRouen TA, Mancl L, Hujoel P: Measurement of associations in periodontal diseases using statistical methods for dependent data. J Periodontal Res 1991;26:218–229.
  17. Donner A, Banting D: Analysis of site-specific data in dental statistics. J Dent Res 1988;67:1392–1395.
  18. Donner A, Banting D: Adjustment of frequently used chi-square procedures for the effect of site-to-site dependencies in the analysis of dental data. J Dent Res 1989;68:1350–1354.
  19. Dummer PMH, Addy M, Oliver SJ, Shaw WC: Changes in the distribution of decayed and filled tooth surfaces and the progression of approximal caries in children between the ages of 11–12 years and 15–16 years. Br Dent J 1988;164:277–282.
  20. Gales MA, Nguyen TM: Sorbitol compared with xylitol in prevention of dental caries. Ann Pharmacother 2000;34:98–100.
  21. Granath L, Kahlmeter A, Matsson L, Schroder U: Progression of proximal enamel caries in early teens related to caries activity. Acta Odontol Scand 1980;38:247–251.
  22. Grondahl HG, Hollender L, Malmcrona E, Sundquist B: Dental caries and restorations in teenagers. Swed Dent J 1977;1:45–50.
  23. Hannigan A, O’Mullane DM, Barry D, Schafer F, Roberts AJ: A re-analysis of a caries clinical trial by survival analysis. J Dent Res 2001;80:427–431.
  24. Hayes C: The effect of non-cariogenic sweeteners on the prevention of dental caries: a review of the evidence. J Dent Educ 2001;65:1105–1109.
  25. Hintze H: Approximal caries prevalence in Danish recruits and progression of caries in the late teens: a retrospective radiographic study. Caries Res 2001;35:27–35.
  26. Hopcraft MS, Morgan MV: Comparison of radiographic and clinical diagnosis of approximal and occlusal dental caries in a young adult population. Community Dent Oral Epidemiol 2005;33:212–218.
  27. Hujoel PP, Loesche WJ, DeRouen TA: Assessment of relationships between site-specific variables. J Periodontol 1990;61:368–372.
  28. Iijima Y, Cai F, Shen P, Walker G, Reynolds C, Reynolds EC: Acid resistance of enamel subsurface lesions remineralized by a sugar- free chewing gum containing casein phosphopeptide-amorphous calcium phosphate. Caries Res 2004;38:551–556.
  29. Imrey PB, Kingman A: Analysis of clinical trials involving non-cavitated caries lesions. J Dent Res 2004;83:C103–C108.
  30. Isokangas P, Alanen P, Tiekso J, Mäkinen KK: Xylitol chewing gum in caries prevention: a field study in children. J Am Dental Assoc 1988;117:315–320.
  31. Källestål C, Holm AK: Allocation of dental caries prevention in Swedish teenagers. Community Dent Oral Epidemiol 1994;22:100–105.
  32. Kandelman D, Gagnon G: A 24-month clinical study of the incidence and progression of dental caries in relation to consumption of chewing gum containing xylitol in school preventive programs. J Dent Res 1990;69:1771–1775.
  33. Kidd EAM, Mejàre I, Nyvad B: Clinical and radiographic diagnosis; in Fejerskov O, Kidd EAM (eds): Dental Caries: The Disease and Its Clinical Management. Oxford, Blackwell, 2003, pp 111–128.
  34. Kidd EAM, Pitts NB: A reappraisal of the value of the bitewing radiograph in the diagnosis of posterior approximal caries. Br Dent J 1990;169:195–200.
  35. LaVange LM, Koch GG, Schwartz TA: Applying sample survey methods to clinical trials data. Stat Med 2001;20:2609–2623.
  36. Lawrence HP, Benn DK, Sheiham A: Digital radiographic measurement of approximal caries progression in fluoridated and non-fluoridated area of Rio de Janeiro, Brazil. Community Dent Oral Epidemiol 1997;25:412–418.
  37. Lawrence HP, Sheiham A: Caries progression in 12- to 16-year-old schoolchildren in fluoridated and fluoride-deficient areas in Brazil. Community Dent Oral Epidemiol 1997;25:402–411.
  38. Liang KY, Zeger SL: Longitudinal data analysis using generalized linear models. Biometrics 1986;73:13–22.

    External Resources

  39. Lingström P, Holm AK, Mejàre I, Twetman S, Söder B, Norlund A, Axelsson S, Lagerlöf F, Nordenram G, Petersson LG, Dahlgren H, Källestål C: Dietary factors in the prevention of dental caries: a systematic review. Acta Odontol Scand 2003;61:331–340.
  40. Llena-Puy C, Forner L: A clinical and radiographic comparison of caries diagnosed in approximal surfaces of posterior teeth in a low-risk population of 14-year-old children. Oral Health Prev Dent 2005;3:47–52.
  41. Machiulskiene V, Nyvad B, Baelum V: Caries preventive effect of sugar-substituted chewing gum. Community Dent Oral Epidemiol 2001;29:278–288.
  42. Maguire A, Rugg-Gunn AJ: Xylitol and caries prevention – is it a magic bullet? Br Dent J 2003;194:429–436.
  43. Mäkinen KK, Bennett CA, Hujoel PP, Isokangas PJ, Isotupa KP, Pape Jr HR, Mäkinen PL: Xylitol chewing gums and caries rates: a 40-month cohort study. J Dent Res 1995;74:1904–1913.
  44. Mäkinen KK, Mäkinen PL, Pape HR Jr, Peldyak J, Hujoel PP, Isotupa KP, Isokangas PJ, Allen P, Bennett C: Conclusion and review of the ‘Michigan Xylitol Programme’ (1986–1995) for the prevention of dental caries. Int Dent J 1996;46:22–34.
  45. McCullagh P: Regression models for ordinal data. J R Statist Soc B 1980;42:109–142.
  46. Mejàre I, Källestål C, Stenlund H: Incidence and progression of approximal caries from 11 to 22 years of age in Sweden: a prospective radiographic study. Caries Res 1999;33:93–100.
  47. Peng B, Petersen PE, Bian Z, Tai B, Jiang H: Can school-based oral health education and a sugar-free chewing gum program improve oral health? Results from a two-year study in PR China. Acta Odontol Scand 2004;62:328–332.
  48. Pitts NB: The use of film holding, beam collimating and aiming devices in bitewing radiography: a suggested design for routine and research use. Dentomaxillofac Radiol 1983;12:77–82.
  49. Pitts NB: Systems for grading approximal carious lesions and overlaps diagnosed from bitewing radiographs: proposals for future standardization. Community Dent Oral Epidemiol 1984;12:114–122.
  50. Pitts NB: Score system for behaviour of radiologically diagnosed approximal carious lesions. Community Dent Oral Epidemiol 1985;13:268–272.
  51. Pitts NB: The use of bitewing radiographs in the management of dental caries: scientific and practical considerations. Dentomaxillofac Radiol 1996;25:5–16.
  52. Pretty IA: Caries detection and diagnosis: novel techniques. J Dent 2006;34:727–739.
  53. Radike AW: Criteria for diagnosis of dental caries; in Conference on the Clinical Testing of Cariostatic Agents. American Dental Association, 1972, pp 87–88.
  54. Reynolds EC: Anticariogenic complexes of amorphous calcium phosphate stabilized by casein phosphopeptides: a review. Spec Care Dentist 1998;18:8–16.
  55. Reynolds EC, Cai F, Shen P, Walker GD: Retention in plaque and remineralization of enamel lesions by various forms of calcium in a mouthrinse or sugar-free chewing gum. J Dent Res 2003;82:206–212.
  56. Reynolds EC, Cain CJ, Webber FL, Black CL, Riley PF, Johnson IH, Perich JW: Anticariogenicity of calcium phosphate complexes of tryptic casein phosphopeptides in the rat. J Dent Res 1995;74:1272–1279.
  57. Scheie AA, Fejerskov OB: Xylitol in caries prevention: what is the evidence for clinical efficacy? Oral Dis 1998;4:268–278.
  58. Shen P, Cai F, Nowicki J, Vincent J, Reynolds EC: Remineralization of enamel subsurface lesions by sugar-free chewing gum containing casein phosphopeptide-amorphous calcium phosphate. J Dent Res 2001;80:2066–2070.
  59. Stenlund H, Mejàre I, Källestål C: Caries incidence rates in Swedish adolescents and young adults with particular reference to adjacent approximal tooth surfaces: a methodological study. Community Dent Oral Epidemiol 2003;31:361–367.
  60. Szöke J, Bánóczy J, Proskin HM: Effect of after-meal sucrose-free gum-chewing on clinical caries. J Dent Res 2001;80:1725–1729.
  61. Therapeutic Goods Administration: Note for guidance on good clinical practice (cpmp/ich/135/95) annotated with TGA comments. Canberra, Therapeutic Goods Administration, 2000.
  62. van Loveren C: Sugar alcohols: what is the evidence for caries-preventive and caries-therapeutic effects? Caries Res 2004;38:286–293.
  63. Wenzel A, Fejerskov O: Validity and diagnosis of questionable caries lesions in occlusal surfaces of extracted third molars. Caries Res 1992;26:188–194.
  64. Whitehead J: Sample size calculations for ordered categorical data. Stat Med 1993;12:2257–2271.