| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
|
|
|
|||||||
|
|||||||||
PROCEEDINGS |
1 Procter & Gamble Company, Cincinnati, OH, USA;
2 Unilever Dental Research, Port Sunlight, Bebington, UK;
3 Colgate-Palmolive, Dental Health Unit, Manchester, UK; and
4 GlaxoSmithKline, Weybridge, UK;
corresponding author, Biesbrock.ar{at}pg.com
 |
ABSTRACT |
|---|
 TOP ABSTRACT INTRODUCTIONREFERENCES |
|---|
KEY WORDS: caries • clinical trials • validation • early caries detection • diagnostics
|
INTRODUCTION |
|---|
|
TOPABSTRACTINTRODUCTIONREFERENCES |
|---|
In 1968, the American Dental Association sponsored a Conference on Clinical Testing of Cariostatic Agents. The conference proceedings led to publication of consensus guidelines for caries prevention studies that have remained a standard in caries testing in the United States over the past 30–40 years, with very little evolution from the original design elements. Specifically, a randomized, controlled clinical study with an ideal duration of two to three years was advocated. The clinical endpoint was a carious tooth surface (as opposed to sound) as detected by visual-tactile examination supplemented with radiographs. The effectiveness of this design as a tool to differentiate products based on cariostatic activity has been remarkably long-lived, since the current ADA guidelines for caries testing still recognize a conventional two-year study as a necessity for proof of anti-caries activity. Current FDI guidelines also recognize conventional two-year studies as the standard, but also discuss provisions for shorter studies (Reich, 1999). During this same timeframe, significant advances have been made with respect to our understanding of the molecular basis of caries and our ability to measure early enamel demineralization and caries progression. Many believe that the science has reached a juncture which may justify alternative modern clinical methods and designs as replacements for conventional two- to three-year caries prevention studies.
To entertain the replacement of the accepted standard, we need to fully understand the strengths and weaknesses of the two- to three-year caries study design. Recognize that the primary objective of two- to three-year randomized, controlled caries trials is to test a precisely framed hypothesis (O’Mullane, 1976). In the case of caries studies, that hypothesis centers around the determination of an experimental product’s efficacy relative to a control product. The external validity of conventional two- to three-year caries clinical studies, with respect to their value as a tool to differentiate cariostatic products from one another, is well-accepted. Fluoride dose-response effects have been repeatedly demonstrated with different product forms, by different examiners, and in diverse populations (Table
).
|
However, the current design of caries clinical trials is not without its limitations and has increasingly been viewed as inefficient with respect to measuring the disease process in a holistic manner. The endpoint of a caries lesion with loss of enamel integrity (cavitation), which is most frequently used in conventional caries studies, focuses on one end of the caries progression continuum at the expense of early caries initiation and progression (demineralization which occurs at a level that cannot always be detected by the naked eye). This early mineral loss is part of the caries process and an absolute necessity to reach the eventual clinical determination of cavitation at the enamel surface. Several early caries detection methods have been developed that correlate with mineral loss of the tooth surface (including light fluorescence, electroconductivity, etc.). These diagnostic methods fundamentally differ from conventional visual-tactile and radiographic methods in that they are capable of detecting subclinical lesions (lesions undetectable to the naked eye) and generate continuous as opposed to categorical (dichotomous) data. Clearly, these appear to be attractive features for a disease diagnostic.
Invariably, as modern diagnostic methods become accepted, they will lead to novel, more efficient study designs that diverge from the standard conventional two- to three-year caries prevention studies. Alternatively, interest in the field of caries research may continue to drive efficient study designs based on variations of conventional measurement endpoints that diverge from the standard conventional two- to three-year caries prevention studies. A measurement diagnostic that demonstrates a strong correlation with demineralization as measured by an accepted standard (histology, polarized light, TMR, etc.) becomes a candidate for replacing or supplementing visual-based techniques in the cross-sectional diagnosis of caries. However, this finding by itself, although essential, does not justify replacing two- to three-year clinical trials to differentiate among products based on cariostatic activity. A diagnostic method that is capable of detecting caries lesions in dental practice may not bring greater efficiency to a clinical study with respect to examination time and/or balancing the signal-to-noise ratio. Evidence of enhanced diagnostic sensitivity does not address this issue. Modification of the existing two- to three-year conventional caries design for the assessment of product effectiveness, whether by the introduction of a new diagnostic method or by modification of the overall clinical design, must result in a clinical design that is able to differentiate between and among known treatments on the basis of caries-prevention efficacy.
This concept has been observed with other diseases, such as osteoporosis, which is an excessive, proportional reduction in trabecular and cortical bone mineral and matrix, leading to increased skeletal fragility. This disease shares several similarities with dental caries, highlighted by the fact that both involve a compromise in the structural integrity of calcified tissue, which ultimately leads to a loss of function. The disease typically presents after the age of 45 in women and 55 in men (Courpron, 1981). The disease is largely asymptomatic until clinical symptoms that include pain, skeletal deformity, and spontaneous overt fracture manifest. The vertebrae, hip, pelvis, ribs, and femoral neck are at greatest risk of fracture. The pathogenesis of the disease centers around a shift in the metabolic equilibrium between normal rates of bone loss and formation. The primary endpoint of the majority of clinical studies has been osseous fracture (vertebral, hip, femur). Development of additional primary endpoints has been an arduous process, with various radiography-based measurements, clinical biomarkers, and quantitative bone mass measurements examined.
It seems intuitive that increases in bone mass should correlate well to reductions in bone fracture, and in fact, measurement technologies which measure bone mass and product interventions which promote bone mass have been heavily explored for the management of osteoporosis. For example, multiple studies have demonstrated that sodium fluoride stimulates bone formation in women with osteoporosis by 8% per year and prevents vertebral fracture by 4% per year (Riggs et al., 1990; Riggs and Melton, 1992). Radiography measurements clearly demonstrate increased bone mass following sodium fluoride, which intuitively suggests a benefit for osteoporotic patients. However, sodium fluoride therapy has also been associated with increased femoral neck and hip fracture (Gutteridge et al., 1984; Hedlund and Gallagher, 1989). Excessive fluoride content potentially leads to the development of qualitatively abnormal bone structure and increased fragility; thus, increased bone mass is not necessarily equivalent to increased bone strength and resistance to fracture (Carter and Beaupre, 1990; Riggs and Melton, 1992). For this reason, efforts to replace osseous fracture as the primary efficacy measurement in osteoporosis studies with bone mass and density measurements have been gradual. The analogy from this example to dental caries is that methods that measure changes in mineral content, without illuminating the quality of mineral structure, may or may not correlate well to the caries status of the tooth.
This is a substantive risk associated with accepting a novel caries diagnostic as a replacement for conventional measures in a conventional (or modified) two- to three-year caries study. Ultimately, if alternative detection methods or designs are to be used as tools to differentiate between and among products based on cariostatic activity, they should be required to demonstrate external validity similar to that demonstrated by conventional two- to three-year caries clinical studies. In this context, a minimum expectation for acceptance as a replacement for conventional testing should be that the method or design can differentiate products of known efficacy from one another, and that the efficacy relationship observed in a two- to three-year conventional study can be observed with the new method or design. It is desirable that the results be replicated in at least two studies to demonstrate the robustness of the methodology. If possible, populations in which validation studies are performed should have caries experience comparable with that of populations in which earlier caries clinical studies were performed. Given that the fluoride dose response has been characterized in the literature, this should form the basis of any validation package for new methodologies. This concept is wholly consistent with the standards that have been used in the validation of other caries measurement tools designed to differentiate product effectiveness, including in vitro pH cycling and in situ caries models. Importantly, during the validation process, results from the new methodology should be benchmarked relative to conventional two- to three-year caries clinicals to help determine the relative clinical significance of observed results with new methods, the primary concern being that product differences that are relatively small according to current study designs may appear more robust as methods evolve.
|
FOOTNOTES |
|---|
|
REFERENCES |
|---|
|
TOPABSTRACTINTRODUCTIONREFERENCES |
|---|
Beiswanger BB (1996). The clinical validation of early caries detection methodologies. In: Early detection of dental caries. Stookey GK, editor. Indianapolis: Indiana University, pp. 281–285.
Carter DR, Beaupre GS (1990). Effects of fluoride treatment on bone strength. J Bone Miner Res 5(Suppl 1):S177–S184.
Conti AJ, Lotzar S, Daley R, Cancro L, Marks RG, McNeal DR (1988). A 3-year clinical trial to compare efficacy of dentifrices containing 1.14% and 0.76% sodium monofluorophosphate. Community Dent Oral Epidemiol 16:135–138.[ISI][Medline]
Courpron P (1981). Bone tissue mechanisms underlying osteoporosis. Orthop Clin North Am 12:513–545.[ISI][Medline]
Fogels HR, Meade JJ, Griffith J, Miragliuolo R, Cancro LP (1988). A clinical investigation of a high-level fluoride dentifrice. J Dent Child 55:210–215.
Gutteridge DH, Price RI, Nicholson GC, Kent GN, Retallack RW, Deulin RD, et al. (1984). Fluoride in osteoporotic vertebral fractures—trabecular increase, vertebral protection femoral fractures. In: Osteoporosis: proceedings of the Copenhagen international symposium on osteoporosis. Christiansem C, editor. Copenhagen: Aalborg Stiftsbogtrykkeri.
Hedlund LR, Gallagher JC (1989). Increased incidence of hip fracture in osteoporotic women treated with sodium fluoride. J Bone Min Res 4:223–225.[ISI][Medline]
Koch G, Bergmann-Arnadottir I, Bjarnason S, Finnbogason S, Hoskuldsson D, Karlsson R, et al. (1990). Caries preventive effect of fluoride dentifrices with and without anticalculus agents: a 3-year controlled clinical trial. Caries Res 24:72–79.[ISI][Medline]
Lu KH, Ruhlman CD, Chung KL, Sturtzenberger OP, Lenhoff RW (1987). A three year clinical comparison of a sodium monofluorophosphate dentifrice with sodium fluoride dentifrices on dental caries in children. J Dent Child 54:241–245.
Marks RG, D’Agostino R, Moorhead JE, Conti AJ, Cancro L (1992). A fluoride dose-response evaluation in an anti-caries clinical trial. J Dent Res 71:1286–1291.
Mitropoulos CM, Holloway PJ, Davies TG, Worthington HV (1984). Relative efficacy of dentifrices containing 250 or 1000 ppm F– in preventing dental caries. Community Dent Oral Epidemiol 1:193–200.
O’Mullane DM (1976). Efficiency in clinical trials of caries preventative agents and methods. Community Dent Oral Epidemiol 4:190–194.[ISI][Medline]
Reich E (1999). Acceptance and application of new caries detection methods. In: Early detection of dental caries II. Stookey GK, editor. Indianapolis: Indiana University, pp. 415–420.
Riggs BL, Melton LJ (1992). The prevention and treatment of osteoporosis. N Engl J Med 327:620–627.[ISI][Medline]
Riggs BL, Hodgson SF, O’Fallon M, Chao EY, Wahner HW, Muhs JM, et al. (1990). Effect of fluoride treatment on the fracture rate in postmenopausal women with osteoporosis. N Engl J Med 322:802–809.[Abstract]
Stephen KW, Creanor SL, Russell JI, Burchell CK, Huntington E, Downie CFA (1988). A 3-year oral health dose response study of sodium monofluorophosphate dentifrices with and without zinc citrate: anti-caries results. Community Dent Oral Epidemiol 16:321–325.[ISI][Medline]
Zacherl WA (1981). A three year clinical caries evaluation of the effect of a sodium fluoride-silica abrasive dentifrice. Pharmacol Ther Dent 6:1–7.[Medline]
This article has been cited by other articles:
|
|
 |
|
  E. Barberia, M. Maroto, M. Arenas, and C. C. Silva A Clinical Study of Caries Diagnosis With a Laser Fluorescence System J Am Dent Assoc, May 1, 2008; 139(5): 572 - 579. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 N.B. Pitts and J.W. Stamm Preface J. Dent. Res., July 1, 2004; 83(suppl_1): C4 - C5. [Full Text] [PDF]
|
|
|
|
|
|
G.K. Stookey Optical Methods--Quantitative Light Fluorescence J. Dent. Res., July 1, 2004; 83(suppl_1): C84 - C88. [Abstract] [Full Text] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
| IADR Journals | Advances in Dental Research ® |
| Journal of Dental Research ® | Critical Reviews (1990-2004) |
