Advances in basic biomedical research have greatly enhanced our understanding of the etiology and pathogenesis of many diseases. From a clinician’s viewpoint, these advances are truly meaningful only if they can be translated into new technologies or methods that will improve clinical practice.
On occasion, a discovery is made that causes us to reassess our approach to therapy and results in a new paradigm of disease management. The periodontal diseases provide an example of such an instance. In this case, the established therapeutic paradigm was modified so as to include not only methods aimed at controlling the etiologic bacteria but also chemotherapeutic modulation of the host response to these bacteria and their products. This paper will review the changing paradigm of periodontal therapy and the role of subantimicrobial dose doxycycline (Periostat, Oral Science, Longueuil, Quebec, CA) as a modulator of the host response.
The essential role of bacteria as etiologic agents for the periodontal diseases has been well established.1 As microbiological methods have evolved to be able to detect a wider range of organisms, it has been possible to identify bacterial species, and complexes of bacterial species, associated with periodontal diseases of various severities.2 As a result, successful treatment of the periodontal diseases has traditionally been based on methods directed toward the control of the etiologic bacterial flora, primarily debridement of periodontal pockets via scaling and root planing, patient-performed daily plaque control procedures, and, when indicated, periodontal surgical procedures. For some patients, antibiotics have also been utilized in therapy, either systemically or via site-specific administration to affected sites. One of the more frequently used antibiotics has been tetracycline.3
While mechanical methods remain the mainstay of periodontal therapy, the recognition that much of the destruction of the periodontal tissues results from the patient’s inflammatory response to the etiologic bacteria suggests that treatment could be improved if there were a way of interfering with the host response as well, that is, by modulating the host response; for example, by inhibiting enzymes responsible for gingival, periodontal tissue, and bone matrix degradation.
In this way, not only would the etiologic bacteria be addressed, but the processes responsible for tissue destruction would be interfered with, thereby offering a two-pronged approach to therapy. A role for host modulation in the management of the periodontal diseases has become well recognized4,5 and studies have been, and are being, conducted to determine the most effective agents and dose regimens.
The area of host modulation was advanced significantly by the work of Golub and co-workers. During an experiment using diabetic rats, in which there is an excess of collagenase activity, they observed improvement in the gingiva of a group of germ-free rats treated with a tetracycline.6,7 Since the rats were germ-free and the gingival inflammation, therefore, could not have had a bacterial etiology, the investigators concluded that the improvement was most likely due to tetracycline inhibition of the host-derived enzyme collagenase. Collagenase is one of the matrix metalloproteinases (MMPs) that mediate connective tissue breakdown and plays an important role in the pathogenesis of periodontal diseases as destruction of collagen can lead to loss of the connective tissue attachment and supporting alveolar bone.
The observation that tetracycline administration resulted in an improved gingival condition of germ-free animals and the realization of its significance exemplify Louis Pasteur’s maxim “chance favors the prepared mind.” Rather than disregard this finding as an artifact of a faulty experiment, Golub and co-workers understood its importance and ultimately succeeded in translating this laboratory finding to the marketed chemotherapeutic host-modulating agent, Periostat.
The key was recognizing that the tetracyclines have two primary clinical activities: antimicrobial and MMP inhibition. This could potentially have presented a problem for the use of tetracyclines as host modulators, since it is generally desirable to minimize antibiotic use in order to diminish the possibility of inducing bacterial resistance.
However, the finding that tetracyclines inhibit MMP activity at levels considerably lower than those required for antimicrobial activity led to the development of low (subantimicrobial) dose doxycycline as an adjunct to traditional periodontal therapy. In fact, the non-antibiotic activity of tetracyclines has resulted in their investigation for treatment of a number of diseases including rosacea, cancer metastasis, and bullous dermatoses.8
It has also been discovered that the antimicrobial and anti-MMP activities are located in two different sections of the tetracycline molecule. This has led to the creation of chemically modified tetracyclines that retain anti-MMP activity but are no longer antimicrobial.3 (It should be noted that the significant contributions by Golub were recognized by his being selected recipient of the American Dental Association’s Gold Medal as well as the Norton Ross Award for Excellence in Clinical Research.)
CLINICAL EFFICACY STUDIES
The commercial version of subantimicrobial dose doxycycline (SDD), Periostat (20 mg doxycycline hyclate capsules), was approved for marketing by the U.S. Food and Drug Administration in 19989 and received Notice of Compliance from Health Canada in 2003.10 This is a prescription product indicated for use as an adjunct to scaling and root planing to promote attachment level gain and to reduce pocket depth in patients with adult chronic periodontitis.
The effectiveness of SDD as an adjunct to mechanical treatment of periodontitis has been demonstrated in a number of human clinical trials and, as will be discussed below, more recent trials have been conducted to determine whether clinical outcomes can be improved further if SDD is used in combination with other chemotherapeutic agents such as anti-inflammatory drugs and site-specific antibiotics.
The pivotal study leading to FDA approval was a 9-month clinical trial conducted at five university sites.11 This was a double-blind, parallel group designed study which evaluated an intent-to-treat subject population of 183 adult periodontitis patients, ages 30-72. Subjects received an initial scaling and root planing (SRP) of two selected quadrants and then were randomized to either a Periostat group or a placebo group. They were instructed to take their respective capsules twice daily for the nine month study period, once in the morning and once in the evening, one hour prior to meals.
A study conducted to explore various dosing regimens indicated that continuous drug therapy over a period of at least several months was needed to maintain collagenase levels at or near normal levels and maintain or improve attachment levels.12 Study quadrants were selected on the basis of disease severity, that is, each quadrant was required to have at least two sites on different teeth with a clinical attachment level (CAL) and pocket depth (PD) between five and 9mm and which bled on probing. The severity of disease was defined by baseline pocket depth, thus sites with PD 0-3mm were considered normal, sites with PD 4-6mm were considered to have mild-moderate disease, and sites with PD = 7mm were considered to have severe disease.
By creating these disease categories, it was possible to assess the effectiveness of adjunctive SDD on diseased sites that had the possibility of improvement without dilution by data from initially healthy sites, as well as to assess effectiveness on the basis of disease severity. Clinical measurements were made by trained, calibrated examiners at baseline, and at three, six, and nine months. Plaque samples were also taken from a subset of subjects for microbiologic assessments; these results will be considered later in
the paper.
With respect to changes in CAL and PD, both groups showed improvement relative to baseline at each of the three post-baseline evaluations. Given that SRP is the standard initial therapy for periodontitis, this finding was not unexpected. In fact, the historic effectiveness of SRP provides a considerable hurdle for an adjunctive chemotherapeutic agent to surpass in order to demonstrate significant effectiveness. Nevertheless, at each of the time periods, mean CAL increases and PD decreases were statistically significantly greater for the SDD group at both mild-moderately severe and severe sites, with the magnitude of improvement greater in the sites that were initially more severe.
At nine months, the mean CAL improvements for the SDD and placebo group for sites with baseline PDs 4-6mm were 1.03mm and 0.86mm, respectively, with corresponding improvements for sites with baseline PDs = 7mm of 1.55mm and 1.17mm. The improvements for the SDD group were statistically significantly greater than those for the placebo group (p<0.05). Similarly, PD decreases for sites with baseline PDs 4-6mm were 0.95 and 0.69 for the SDD and placebo group, respectively, with corresponding decreases for sites with baseline PDs = 7mm of 1.68mm and 1.20; these intergroup differences were also statistically significant (p<0.01).
The CAL and PD findings based on a comparison of group means present only one aspect of effectiveness, however. Another important parameter was the extent to which sites in each group worsened during the course of the study, as evidenced by the per-patient percentage of CAL loss. For the most severely involved sites at baseline (PD = 7mm), 0.3% of sites in the SDD group had CAL loss = 2mm compared to 3.6% of sites in the placebo group, a statistically significant (p<0.05) 12-fold difference. With a threshold CAL loss of = 3mm, the respective per-patient percentages were 0.17 and 0.63.
These results are of particular interest because attachment loss of = 2mm over a period of less than one year can be an indication of rapid disease progression and is, therefore, of clinical significance. Although the actual per-patient percentages in each group were small, this is an indication of the fact that a population of subjects with chronic adult periodontitis will have only a small percentage of active sites at any given time with which progression can be studied.
Nevertheless, these findings suggest that SDD in combination with SRP can have significant effectiveness in inhibiting progression of sites with severe periodontitis.
A frequent concern with the use of a chemotherapeutic agent is whether there will be any unfavorable changes, or disease rebound, once administration of the agent is discontinued. Accordingly, 146 subjects who completed the pivotal study participated in a follow-up study in which the outcome variables PD and CAL were measured after three months of discontinuing SDD or placebo.13 It was found that the improvements in PD and CAL seen at the end of the 9-month treatment period were maintained over the 3-month no-treatment period with no rebound effects seen.
The results of the pivotal study were confirmed in a second multicenter clinical trial utilizing the same study protocol in which 209 subjects participated.14 In this study, as well, the magnitude of improvement seen at 9 months was related to baseline PD. For sites with baseline PDs 4-6mm, CAL gains for the SDD and placebo groups were 1.27mm and 0.94mm, respectively, with corresponding PD reductions of 1.29mm and 0.96mm. The intergroup differences were statistically significant (p<0.001). For sites with baseline PDs = 7mm, CAL gains for the SDD and placebo groups were 2.09mm and 1.60mm, respectively, with corresponding pocket reductions of 2.31mm and 1.77mm. These intergroup differences were also statistically significant (p<0.05).
Using thresholds indicative of clinical improvement, for sites with baseline PD = 4mm, 42.3% of sites in the SDD group showed a CAL gain = 2mm compared to 32.0% of sites in the placebo group (p<0.01), and 15.4% of sites compared to 10.6% showed a CAL gain = 3mm (p<0.05). For sites with baseline PD = 6mm, the SDD and placebo group percentages for CAL gain = 2mm were 58.3 and 44.0 (p<0.05) and for CAL gain = 3mm were 33.2 and 20.0 (p<0.01). The results of this study confirm the previously reported findings indicating that SDD can significantly enhance the effectiveness of SRP when used adjunctively over a 9-month period.
Given the mechanism of action of SDD, it was hypothesized that this agent would demonstrate significant effectiveness in patients with a form of periodontitis resulting from an exaggerated host response. To test this hypothesis, a study was conducted to evaluate the adjunctive benefits of SDD in the non-surgical management of patients with the severe, generalized form of chronic periodontitis.15
Twenty male and female subjects, ages = 45 years, with at least 20 teeth with greater than 30% of sites having = 5mm CAL completed this double-blind, placebo-controlled, parallel group, 9-month study. A high percentage of subjects were current smokers (five in the placebo group and four in the SDD group) with another three in the placebo group and two in the SDD group having a past history of smoking. Insofar as smoking has been shown to be a significant risk factor for periodontitis,15,16 the adverse impact of smoking on periodontal health may have contributed to the severity of disease in these subjects.
Subjects were assigned to either a SDD (20mg doxycyline hyclate tablets) or a placebo group (10 per group) and instructed to take one of their assigned tablets twice daily starting on week one of the study and continuing for six months. The baseline examination included full mouth PD and CAL measurements. At the outset of the study, subjects received four weekly 1-hour sessions of full mouth supra- and sub-gingival debridement and oral hygiene instruction delivered by a dental hygienist.
Subjects were recalled four times: at 1, 3, and 5.25 months after completion of the initial treatment, and then three months after cessation of SDD or placebo. At each recall visit, clinical measurements were repeated, supra- and sub-gingival plaque and calculus were removed, and oral hygiene procedures were reinforced.
As in the previously discussed studies, the 3,427 sites evaluated in the 20 subjects were divided into three groups based on baseline PD and CAL: 0-3mm (44.2% of sites), 4-6mm (41.2%); and = 7mm (14.6%). In this study, the greatest effect of adjunctive SDD was seen with respect to PD reduction, especially at the deepest sites.
At nine months, the SDD group had a mean 3.02mm clinically significant reduction from baseline in sites with baseline PD = 7mm compared to a 1.42mm reduction in the placebo group. This intergroup difference was statistically significant (p<0.05). For sites with 4-6mm baseline pocket depths, the nine month SDD and placebo group means were 1.20mm and 0.97mm, respectively, and were not statistically significantly different.
There were no statistically significantly differences in CAL changes from baseline between the two groups. Of particular interest, however, was the percentage of sites with baseline PD = 7mm that were reduced by = 4mm over the course of the study. By nine months, this included 38% of pockets in the SDD group and fewer than 10% of pockets in the placebo group. With a threshold of = 3mm, the respective percentages were 55 and 24. When PD increases from baseline were considered using a threshold of = 4mm, 0.12% of sites in the SDD group and 0.68% in the placebo group worsened over the 9 months of the study.
Finally, while both groups had significant reductions from baseline in bleeding on probing, the intergroup differences were not statistically significant. These study results are of interest because the magnitude of PD reduction at the deepest sites is greater than that seen in the previous studies of chronic adult periodontitis subjects, and might impact favorably o
n future treatment needs at sites reduced from 7mm or greater to 3 or 4mm probing depth.
It should be noted that the study protocol included periodic recall appointments at which additional supra- and sub-gingival debridement and oral hygiene instruction were provided, thus the significant effectiveness of SDD should be appreciated in this context.
The successful treatment of periodontal disease in smokers presents a particular challenge because, as noted above, smoking is a major risk factor for periodontitis and has deleterious effects on the periodontal tissues. In order to assess the effectiveness of adjunctive SDD on smokers, a retrospective meta-analysis of data from the two nine-month clinical trials11,14 of subjects with moderate to severe chronic periodontitis was performed.18
This analysis comparing results in smokers with those in non-smokers showed that adjunctive SDD in smokers was statistically significantly effective in reducing PD and increasing CAL compared to placebo, though the effect in smokers was smaller than that seen in non-smokers. A subsequent 6-month controlled clinical of smokers failed to confirm a significant adjunctive effect for SDD in this population.19 However, as this study had a small sample size and may not have been adequately powered, additional studies are required to more precisely define the role of SDD therapy in the management of periodontitis patients who are smokers.
MICROBIOLOGIC ASSESSMENTS
A study of subgingival microbial samples obtained from a subset of 76 subjects from the initial pivotal clinical trial11 was conducted to determine whether SDD treatment had any antibacterial activity in vivo.20 Because the clinical protocol required that only two quadrants be scaled and root planed, it was possible to compare the flora at baseline with that at each recall interval through nine months in scaled and unscaled sites in the SDD and placebo groups. The samples were examined by darkfield microscopy and by enumeration on selective and non-selective media. The study design allowed for the separation of changes related to SRP from those related to SDD administration. With one exception, no intergroup differences between SDD and placebo were found in scaled or unscaled sites.
The one exception involved spirochetes: in SRP sites, the proportion of small spirochetes in the 3- and 6- month samples and of large spirochetes in the 6-month sample were significantly lower (p<0.05) in the SDD group than in the placebo group; in non-SRP sites, the proportions of small and large spirochetes in the 9-month sample were significantly lower (p<0.05) in the SDD group than placebo. The isolated spirochete findings were thought to result from ecologic changes in the pocket resulting from resolution of inflammation, rather than an antibacterial affect of SDD. The finding of no intergroup difference in an organism (Porphyromonas gingivalis) inhibited by a low level of tetracycline comparable to that shown to inhibit spirochetes supported the conclusion that SDD did not exhibit antimicrobial activity during the course of the study.
In addition, a series of four studies ranging from nine to 27 months was undertaken to assess whether long-term SDD administration affects the antibiotic susceptibility of the periodontal microflora.21 From these studies, the investigators concluded that long-term SDD does not result in changes in antibiotic susceptibility, either to doxycycline or to other commonly used antibiotics.
NEW DIRECTIONS
Given the host modulatory activity of SDD, a study has been conducted to determine if this activity could be enhanced by combining SDD with a non-steroidal anti-inflammatory drug. The study of the effect of combining SDD and low dose flurbiprofen on gingival MMP activity in chronic periodontitis patients has shown that the combination enhances the MMP-inhibiting activity of SDD alone and suggests that this combination therapy has a potential advantage for use in treating periodontitis patients.22
It is interesting to note that flurbiprofen alone had no inhibition of MMPs, but that combining flurbiprofen with SDD produced a marked synergistic effect in MMP inhibition. The superior adjunctive effectiveness of this combination of agents compared to that of SDD alone will have to be demonstrated in a properly controlled clinical trial.
A six-month, controlled multi-center clinical trial has been conducted to test the effectiveness of combining systemic 20mg doxycline hyclate b.i.d. with locally delivered 10% doxycycline hyclate gel.23 Qualifying subjects had moderate to advanced periodontitis. All subjects received a full mouth SRP at baseline and three months. The test group took SDD and had the 10% gel delivered to all periodontal pockets = 5mm deep at baseline and three months. The control group took placebo b.i.d. At six months, mean PD reductions for sites initially = 7mm were 2.43mm and 1.75mm for test and control groups, respectively, with corresponding CAL gains of 2.17mm and 1.61mm. For sites initially 4-6mm, PD reductions for test and control groups were 1.71mm and 1.23mm, respectively, with corresponding CAL gains of 1.54 and 1.27.
All differences between the test and control groups were statistically significant (p<0.05). Interestingly, the investigators attributed the effect of the doxycycline gel not to antimicrobial activity but, rather, to a local enhancement of MMP inhibition. While this combination of delivery methods might have therapeutic potential, since this study did not include a group that received SRP and SDD alone additional studies are needed to confirm that the topical administration of the doxycyline hyclate gel has a significant incremental effect compared to systemic SDD administration without topical gel.
CONCLUSIONS
The role of host modulation in regimens for treating various forms of periodontal diseases is based on the findings of biomedical research that have helped to elucidate disease pathogenesis. The pivotal study and supporting studies described in this paper demonstrate that the use of SDD as an adjunct to scaling and root planing can result in statistically significant increases in attachment level and reductions in pocket depth when tested on adult subjects with moderate-severe chronic periodontitis and generalized severe periodontitis. This conclusion is supported by the results of a formal systematic review of available clinical trials.24
In general, the effect was more pronounced at sites with deeper pockets and in conditions characterized by a more vigorous host response. It is likely that scaling and root planing alone will remain the treatment of choice for the majority of chronic adult periodontitis patients. However, for patients that may not respond well to scaling and root planing alone, such as patients with severe, generalized periodontitis, diseases such as diabetes, and “refractory” cases (including heavy smokers), the adjunctive administration of SDD may be of value in helping to significantly improve clinical parameters and inhibit disease progression. SDD, therefore, should be considered when developing a treatment plan for these patients.
Michael L. Barnett, DDS, is Clinical Professor, Periodontics/Endodontics, School of Dental Medicine, University at Buffalo.
Oral Health welcomes this original article.
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