October 1, 2005
by Howard C. Tenenbaum DDS, PhD, FRCD(C)
Treatment of periodontal diseases has undergone a series of changes, although not quite a revolution, over the past 20 years.1-6 Importantly, regeneration of lost periodontal tissues has always been the primary goal of treatment. Unfortunately, this has proven to be an extremely challenging task that has only been met partially or modestly at best. Hence clinicians have had to aim for other more attainable goals those being treatments that lead to disease cessation and healing if not regeneration. That said, there are newer treatment strategies that may become available over time that will allow us to achieve limited or even more robust regeneration of the periodontium. Yet without reliable methods for regeneration, new approaches to disease control are also being pursued that will benefit those suffering from chronic periodontal diseases.7,8 It must also be recognized that current treatment modalities including both surgical and non-surgical approaches should still be regarded as important and useful modalities. Yet, it is also essential to recognize future possibilities that will be described below.
PERIODONTAL DISEASES– NOVEL THERAPEUTICS
From a historical perspective, regeneration of periodontal tissues lost as a result of periodontitis has been an elusive goal despite the presence of many surgical and grafting techniques that purport to lead to regeneration. For instance, approaches that have involved the use of bone grafts to replace lost bone, do not take into account the fact that bone is but one component of the connective tissues comprising the periodontium. In-as-much as bone loss has been considered one of the major sequelae of periodontitis, and is the most striking radiographic feature of periodontally diseased tissues, the use of bone grafting treatments has been popular. Yet, critical analyses of clinical, histological and radiographic data suggests that although correction of bone defects can be demonstrated, the regeneration of a new attachment apparatus following bone grafting including new bone, cementum and a functionally oriented periodontal ligament does not generally occur except at the very base of the periodontal defect.
Because bone grafting has been shown to have limited effectiveness with respect to regeneration of lost periodontium, other approaches have been developed that ostensibly would exploit the biological principles that describe cellular domains48 known as guided tissue regeneration but as time has progressed these methods have been shown to yield disappointing results except around implants (guided bone regeneration)47 (Zohar and Tenenbaum, JCDA in press).
Enamel matrix derivatives
Taking advantage of developmental biological studies of the periodontal attachment apparatus it was noted that prior to development of cementum and new periodontal ligament, enamel matrix proteins are deposited directly onto dentine surfaces.49,50 This observation led investigators to hypothesize enamel matrix proteins might play an important role in the signaling for and recruitment of cells required for production of a normal tooth attachment apparatus. This further led to the notion that such proteins could prove useful in regenerative therapy because it was thought that by adding such proteins to a previously diseased or exposed tooth root surface, they might signal a recapitulation of the embryological developmental sequence leading to the creation of a new gomphosis. Accordingly, a growing body of evidence is showing that enamel matrix proteins can be used for limited regeneration of the periodontium on the basis of randomized controlled trials.4,51 Further studies have demonstrated that these proteins may prove useful in periodontal plastics and root coverage procedures thereby reducing or eliminating the need for the harvesting of connective tissue.51,52
Bisphosphonates to inhibit bone loss
The bisphosphonates are a class of drugs related to pyrophosphate53 and one of the most important uses of bisphosphonates relates to their ability to inhibit bone resorption presumably by either direct or indirect inhibition of osteoclast cell activity,53 a property used for treatment of osteoporosis. This property could also prove useful in the development of future therapeutic approaches to the prevention of periodontal bone loss53,56 and possibly bone supported implants.57,58 In addition, it has been shown that local application of bisphosphonates will also reduce the bone loss that has been shown to occur following periodontal flap surgery.59
Bisphosphonates may stimulate bone formation
In addition to the bisphosphonates’ ability to inhibit bone formation it is also known that at certain concentrations they also inhibit mineralization.61 This particular effect was thought to be essentially deleterious, and in fact, 2nd and 3rd generation bisphosphonates were developed to increase their ability to inhibit bone resorption so that they could be used in lower doses, thereby not interfering with mineralization.62 This approach has proven to be effective, particularly for management of osteoporosis,62 however more recent studies have suggested that inhibition of mineralization, as long as it is a transitory phenomenon, might actually be useful. In relation to this it has been demonstrated that bone matrix (osteoid) formation is inversely proportional to mineralization.63 Hence, if mineralization is inhibited using the 1st generation bisphosphonate Etidronate (HEBP), osteoid formation has been shown to double both in vivo and in vitro.56,61,64
If the HEBP is continually present, more osteoid will form but it will be poorly mineralized. Alternatively, if HEBP treatment (in culture or in vivo) is stopped, the newly formed ‘excess’ osteoid will mineralize and as demonstrated in cell culture, the mineral will be even more dense than control. This property of HEBP, then, could be exploited to stimulate new bone formation in the periodontium and elsewhere. It could prove useful for acceleration of osseointegration about implants; however, the dosage regime in this model has not been clearly worked out. HEBP treatment has also been shown to induce the periodontal ligament to produce high levels of the bone protein bone sialoprotein (BSP) and to even induce the ligament to produce bone tissue. Thus, it’s possible that judicious local application or systemic administration of HEBP or similar agents could prove useful for regeneration of lost bone in implant or other sites and potentially even for acceleration of endosseous implant integration in the future.
BISPHOSPHONATES AND OSTEONECROSIS
Despite the potentially useful qualities of bisphosphonates for management of severe periodontitis and the possile use in regenerative therapy as described above, it is also becoming increasingly evident that under some circumstances, particularly in patients who may have been treated for malignancy and also received the newer and more powerful drugs such as Fosamax, a new risk has now been recognized; osteonecrosis. This may occur spontaneously, as a result of infection or after removal of a tooth or teeth in patients treated with bisphosphonates. It is less likely that this will be an issue for the pulsatile use of HEBP as proposed above. However, these concerns must not be ignored either and should be considered when treatment planning for patients at risk is being contemplated.60
Local delivery systems
It has been well established that most forms of periodontitis are related to chronic infection with periodontal pathogens,15 usually Gram negative anaerobic.34 As a result, there has been an extensive amount of investigation related to the development of effective antimicrobial regimes for treatment of chronic, refractory or other forms or periodontitis. Indeed, double blinded, placebo controlled randomized trials have demonstrated that antimicrobial treatment is an extremely useful adjunct for treatment of periodontitis.10,65
Prior to the advent of antimicrobial therapy, so-called refractory periodontitis (e.g. demonstrating downhill or extreme downhill course [Hirshfeld and Wasserman]) might constitute about 20 percent of all cases. However, now this figure is in the 5 percent range since it has been shown the previously difficult to treat cases, or cases that do not respond well to conventional periodontal treatments can be managed or improved with the use of antimicrobials.57,66 That said, the use of systemic antimicrobial medications to treat a local infection does have drawbacks including, for example, gastrointestinal side effects such as pseudomembranous colitis, allergic reaction,67 superinfection with commensal organisms, or development of resistant organisms. Therefore, there have been a number of attempts to develop locally delivered antimicrobials to infected periodontal pockets.57 The antimicrobials have included metronidazole in an ointment form (Elyzol), chlorhexidine (Periochip) as well as doxycycline either in a fiber form (Actisite),or also in a polymeric delivery system (Atridox).66
These locally delivered antimicrobials, and in particular Atridox, have been demonstrated to be efficacious in the treatment of localized periodontal pockets. On average, Atridox for example, seems to be equally as effective as scaling and root planing, but it is more difficult to administer this drug for generalized disease as opposed to using it for treatment of localized defects. This type of drug delivery system should definitely be considered for treatment of refractory periodontal pockets, infected implant sites, and possibly even in surgical sites. This approach may be particularly useful in the future for treatment of recall patients who present with localized sites showing recurrent disease.
Although local delivery of an agent such as doxycycline can be useful, the use of self polymerizing gels can be difficult when considering treatment of generalized periodontitis. Moreover, it has been demonstrated that full mouth ‘decontamination’ may lead to better short and possibly longer term outcomes when managing periodontal diseases as compared to staged decontamination approaches.68 Yet, agents delivered in gel or fiber form cannot readily be delivered to periodontal pockets within the whole mouth and certainly cannot be used eradication of periodontal pathogens from non-dental oral surfaces (e.g. cheeks, tongue, and tonsil bed in addition to periodontal pockets). In addition, although the antimicrobials mentioned above are delivered in high concentrations to minimize bacterial resistance, this does not preclude the possibility that resistant bacteria will be selected following treatment.
To address these problems, other approaches for antimicrobial therapy for periodontitis have been investigated including an approach known as photodynamic therapy (PDT). PDT essentially involves the use of light-activated drugs to kill periodontal pathogens. This therapeutic tool was initially investigated for treatment of malignancy since chemotherapeutic drugs could be given to patients systemically in an essentially inert form and then activated by administering (usually laser) light at the site of a tumour thereby killing tumour cells without making a patient ill from chemotherapy.69 PDT has also been used successfully for the management of macular degeneration.70
More recently it has been demonstrated (Wilson et al)71 that toluidine blue, when activated by laser light can be used to kill periodontal pathogens. Hence it was postulated that toluidine blue or other photoactivated drugs could be used to treat periodontitis, presumably by laser-activating such chemicals after they have been instilled within periodontal pockets. The problem with this approach however is that it would be necessary to irradiate every single pocket following lavage with the photoreactive agent, and full mouth decontamination would be equally as difficult as suggested above for locally delivered antimicrobials.72
At this time, clinical trials focused on the use of laser-activated drugs are under way for treatment of periodontitis (Supported by Ondine Inc.). This treatment would also prove useful for periodontal maintenance and during periodontal surgery and management of infected endosseous implant surfaces. In fact a new study has demonstrated that PDT can be used to treat endosseous implants that have perio-implantitis.82
Inhibition of matrix degradation
As discussed previously with respect to diagnostic tests, matrix degradation is a major hallmark and even predictor of bone and periodontal attachment loss. Hence there have been major efforts devoted to the development of approaches for treatment that interfere with or completely block matrix degradation. The bisphosphonates have already been addressed in relation to their ability to inhibit bone resorption but they do not inhibit destruction of connective tissue matrices, although our laboratory has some evidence suggesting that HEBP might interfere with MMP activity (unpublished data).
The majority of investigation in this area has focused on the use of tetracycline and its derivatives for prevention of connective tissue (and even hard connective tissue) destruction mediated by MMPs. To this end it has been suggested that given that the MMPs are elevated in the presence of periodontitis, particularly in diabetics, a major goal of therapy would be to reduce MMP activity. In addition to tetracycline’s antimicrobial actions it also has the ability to inhibit MMP activity.57,73,74
This non-antimicrobial action of MMP inhibition has also been demonstrated with the tetracycline derivative doxycycline.66 When administered in doses that are non-antibacterial, doxycycline has been shown to prevent periodontal breakdown due to its ability to inhibit MMP’s enzyme activity.57 This has given rise to the development and use of Periostat (Collagenix) a form of low dose doxycycline (LDD) for management of periodontitis. LDD may prove to be useful in the management of refractory periodontal diseases or other forms of chronic periodontitis that, for various reasons, cannot be managed with conventional therapy. For instance, patients who are medically compromised and cannot necessarily tolerate conventional in-office treatment could benefit from LDD. Indeed, LDD has proven to be very helpful, in the authors’ experience, in management of periodontitis in a large hospital based population of patients (young and old) for example.
Despite its effectiveness, it would not appear that LDD will be a 1st line choice of conventional periodontal therapy, but it definitely shows promise in management of difficult to treat patients or difficult to manage forms of periodontitis. Furthermore, it is probable that drugs designed to inhibit MMP or other proteinase activity will be further developed to be more specific to target proteinases of interest (e.g. MMP 8 in the case of periodontitis). Furthermore, it is also possible that the use of certain proteins or peptides related to decorin75 might prove to be useful therapeutic adjuncts. Decorin binds to collagen and may prevent its degradation.This could prove to be an interesting approach to management periodontal breakdown since in this case MMP activity would itself not be inhibited, rather the drug’s effects would be through alteration of the substrate(s).
Management of periodontal diseases in smokers
It has been demonstrated clearly that individuals who smoke cigarettes are at greater risk for the development of periodontitis, have more severe periodontitis and do not respond to treatment of periodontitis as well as those who do not smoke.8,10,76 This was thought to be a lifestyle issue (e.g. poor oral hygiene) but a number of studies have shown that smokers do not necessarily have more bacterial plaque, nor are their plaques populated by more periodontal pathogens than those who do not smoke.
This suggests then that there must be constituents of cigarette smoke that either trigger or act as co-factors to initia
tion and progression of periodontitis. For obvious reasons nicotine has received much attention in the literature, and indeed it does have the ability to cause a number of changes in the immune system as well as the vasculature that could lead to exacerbation of periodontal disease risk and severity.77-79 In addition, there are hundreds of other potentially toxic compounds in cigarette smoke that likely also damage periodontal tissues.
Our research group, however, has focused on a particular class of agents found in high levels in cigarette smoke as well as in the environment, aryl hydrocarbon.80 The most prevalent aryl hydrocarbons in cigarette smoke are benzo-a-pyrene, and dimethyl benzanthracene (BaP and DMBA respectively).81 BaP in particular has been shown to directly inhibit osteoblast differentiation.80 To carry out further studies we have also used a prototypical aryl hydrocarbon, dioxin (TCDD), to study the effects of these agents on bone tissues and bone cells.
These studies have confirmed that aryl hydrocarbons inhibit osteoblast differentiation and bone production. Moreover, they interfere with osteoclast cell formation (Tenenbaum et al., paper in preparation), an action that would lead to overall reductions in bone remodeling; a phenomenon that could also exacerbate periodontal diseases. Moreover our laboratory has demonstrated that the aryl hydrocarbon BaP acts in synergistic manner with lipopolysaccharide from one of the periodontal pathogens (B. gingivalis) described above in blocking bone cell differentiation and function.80 These deleterious effects have been shown to be mediated through the aryl hydrocarbon receptor (a cytosolic receptor).
Importantly, we have identified an agent commonly found in red wine, resveratrol, which is an aryl hydrocarbon receptor antagonist that inhibits the effects of aryl hydrocarbons. Hence, it may be possible in the future to utilize agents such as resveratrol or synthetic and more powerful analogues to ameliorate some of the effects of smoking on the periodontium and other tissues. Certainly, smoking cessation is the ultimate goal, but this has not proven to be as effective as its proponents would like. Thus, we should also consider other approaches such as the inhibition of aryl hydrocarbon effects, especially since these agents are found in high levels within the environment, not only cigarette smoke. It is with this in mind that a clinical trial focusing on the use of resveratrol to manage periodontitis in smokers is now under way.
It can be inferred from the foregoing that there are many new technologies that have either been developed or that are in development that could be used to enhance our ability to treat periodontitis. Not all of these technologies will bear fruit, but certainly some should and this will provide the clinicians of the 21st century with more effective means of treatment of periodontitis than have been available to date and these approaches will be based more on biological principles than purely mechanical ones.
H. C. Tenenbaum is a Professor of Periodontology and Associate Dean, Biological and Diagnostic Sciences, Faculty of Dentistry, Professor, Laboratory Medicine and Pathobiology, Faculty of Medicine, University of Toronto. He maintains a practice of periodontics in Toronto.
Oral Health welcomes this original article.
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