SEMINAR ON SEMINAR ON HOST MODULATION THERAPY HOST MODULATION THERAPY

IN TREATMENT OF IN TREATMENT OF PERIODONTAL DISEASESPERIODONTAL DISEASES

CONTENTSCONTENTS IntroductionIntroduction Host response and periodontal diseaseHost response and periodontal disease Host response modulation in periodontal diseaseHost response modulation in periodontal disease Host modulatory therapyHost modulatory therapy SYSTEMICALLY ADMINISTERED AGENTSSYSTEMICALLY ADMINISTERED AGENTS Nonsteroidal Antiinflammatory DrugsNonsteroidal Antiinflammatory Drugs Subantimicrobial-Dose DoxycyclineSubantimicrobial-Dose Doxycycline BisphosphonatesBisphosphonates Modulation of Host cell ReceptorsModulation of Host cell Receptors Modulation of Nitric oxide Synthase (NOS) ActivityModulation of Nitric oxide Synthase (NOS) Activity LOCALLY ADMINISTERED AGENTSLOCALLY ADMINISTERED AGENTS Nonsteroidal Antiinflammatory DrugsNonsteroidal Antiinflammatory Drugs Enamel Matrix Proteins, Growth Factors, and Bone Morphogenetic Enamel Matrix Proteins, Growth Factors, and Bone Morphogenetic

ProteinsProteins Emerging host modulatory therapiesEmerging host modulatory therapies ConclusionConclusion ReferencesReferences

Periodontal diseases encompass multi-factorial diseases involving bacterial biofilms Periodontal diseases encompass multi-factorial diseases involving bacterial biofilms and the generation of an inflammatory response, including the production of and the generation of an inflammatory response, including the production of cytokines, eicosanoids and matrix metalloproteinases (MMPs). cytokines, eicosanoids and matrix metalloproteinases (MMPs).

Bacterial biofilms have been shown to be the primary aetiological factor in the Bacterial biofilms have been shown to be the primary aetiological factor in the initiation of gingival inflammation and subsequent destruction of periodontal tissues initiation of gingival inflammation and subsequent destruction of periodontal tissues (Haffajee & Socransky 1994). (Haffajee & Socransky 1994).

Although chronic bacterial and endotoxin exposure is a prerequisite for gingival Although chronic bacterial and endotoxin exposure is a prerequisite for gingival inflammation and periodontal tissue destruction to occur, its presence alone inflammation and periodontal tissue destruction to occur, its presence alone accounts for a relatively small proportion (i.e. 20%) of the variance in disease accounts for a relatively small proportion (i.e. 20%) of the variance in disease expression (Grossi et al. 1994).expression (Grossi et al. 1994).

The major component of soft- and hard-tissue destruction associated with The major component of soft- and hard-tissue destruction associated with periodontal disease is the result of activation of the host's immuno-inflammatory periodontal disease is the result of activation of the host's immuno-inflammatory response to the bacterial challenge. response to the bacterial challenge.

The underlying biological mechanisms of this response are characterized by the The underlying biological mechanisms of this response are characterized by the expression of endothelial cell and inter-cellular adhesion molecules and by the expression of endothelial cell and inter-cellular adhesion molecules and by the production of host-derived inflammatory mediators including cytokines and lipids production of host-derived inflammatory mediators including cytokines and lipids by neutrophils, monocytes, lymphocytes and fibroblasts. by neutrophils, monocytes, lymphocytes and fibroblasts.

Acquired and environmental risk factors, such as diabetes mellitus, cigarette Acquired and environmental risk factors, such as diabetes mellitus, cigarette smoking and stress, as well as genetically transmitted traits, such as interleukin-1 smoking and stress, as well as genetically transmitted traits, such as interleukin-1 (IL-1) gene polymorphisms, may accentuate the host inflammatory response to the (IL-1) gene polymorphisms, may accentuate the host inflammatory response to the bacterial challenge and, eventually, the susceptibility to the disease (Kornman & Di bacterial challenge and, eventually, the susceptibility to the disease (Kornman & Di Giovine 1998, Salvi et al. 1998, Kinane & Chestnutt 2000, Albandar 2002). Giovine 1998, Salvi et al. 1998, Kinane & Chestnutt 2000, Albandar 2002).

HOST RESPONSE AND PERIODONTAL DISEASE.HOST RESPONSE AND PERIODONTAL DISEASE.

Plaque biofilm and associated host responses are involved in the pathogenesis of Plaque biofilm and associated host responses are involved in the pathogenesis of periodontitis. periodontitis.

Current data suggest that a small group of predominately Gram-negative, anaerobic Current data suggest that a small group of predominately Gram-negative, anaerobic or microaerophilic bacteria within the biofilm are often associated with disease or microaerophilic bacteria within the biofilm are often associated with disease initiation and progression.initiation and progression.

Organisms strongly implicated as etiologic agents include Organisms strongly implicated as etiologic agents include Porphyromonas Porphyromonas gingivalis, Actinobacillus actinomycetemcomitans, gingivalis, Actinobacillus actinomycetemcomitans, and and Tannerella forsythia. Tannerella forsythia.

The microbial challenge consisting of antigens, lipopolysaccharide (LPS), and other The microbial challenge consisting of antigens, lipopolysaccharide (LPS), and other virulence factors stimulates host responses which result in disease limited to the virulence factors stimulates host responses which result in disease limited to the gingiva (i.e., gingivitis) or initiation of periodontitis. gingiva (i.e., gingivitis) or initiation of periodontitis.

Protective aspects of the host response include recruitment of Protective aspects of the host response include recruitment of neutrophils, production of protective antibodies, and possibly the neutrophils, production of protective antibodies, and possibly the release of anti-inflammatory cytokines including transforming growth release of anti-inflammatory cytokines including transforming growth factor- ß (TGF-ß), interleukin-4 (IL-4), IL-10, and IL-12 (Page 1998). factor- ß (TGF-ß), interleukin-4 (IL-4), IL-10, and IL-12 (Page 1998).

Perpetuation of the host response due to a persistent bacterial Perpetuation of the host response due to a persistent bacterial challenge disrupts homeostatic mechanisms and results in release of challenge disrupts homeostatic mechanisms and results in release of mediators including proinflammatory cytokines (e.g., IL-1, 1L-6, mediators including proinflammatory cytokines (e.g., IL-1, 1L-6, tumor necrosis factor-a [TNF-a]), proteases (e.g., matrix tumor necrosis factor-a [TNF-a]), proteases (e.g., matrix metalloproteinases), and prostanoids (e.g., prostaglandin E2 [PGE2]) metalloproteinases), and prostanoids (e.g., prostaglandin E2 [PGE2]) which can promote extracellular matrix destruction in the gingiva and which can promote extracellular matrix destruction in the gingiva and stimulate bone resorption (Page 1998).stimulate bone resorption (Page 1998).

Also neutrophils and macrophages cells subsequently release Also neutrophils and macrophages cells subsequently release mediators including reactive oxygen species, which are antagonistic mediators including reactive oxygen species, which are antagonistic to plaque biofilms, but which in excess may initiate inflammation. For to plaque biofilms, but which in excess may initiate inflammation. For example, nitric oxide (NO) is a free radical involved in host defense example, nitric oxide (NO) is a free radical involved in host defense that can be toxic when present at high levels and it has been that can be toxic when present at high levels and it has been implicated in a variety of inflammatory conditions. implicated in a variety of inflammatory conditions.

Other host inflammatory mediators being investigated for modulation Other host inflammatory mediators being investigated for modulation include nuclear factor kappa B and endothelial cell adhesion include nuclear factor kappa B and endothelial cell adhesion molecules. However, the role of these inflammatory mediators in molecules. However, the role of these inflammatory mediators in periodontitis needs to be elucidated.periodontitis needs to be elucidated.

HOST RESPONSE MODULATION IN PERIODONTAL DISEASEHOST RESPONSE MODULATION IN PERIODONTAL DISEASE

Host modulation Host modulation is a new term that has been incorporated into our dental is a new term that has been incorporated into our dental vocabulary, but it has not been well defined. vocabulary, but it has not been well defined.

Host Host can be defined as "the organism from which a parasite obtains to can be defined as "the organism from which a parasite obtains to nourishment," or in the transplantation of tissue, "the individual who receives the nourishment," or in the transplantation of tissue, "the individual who receives the graft."graft."

Modulation Modulation is defined is "the alteration of function or status of something in is defined is "the alteration of function or status of something in

response to a stimulus or an altered chemical or physical environment" response to a stimulus or an altered chemical or physical environment" (Taber's (Taber's Medical Dictionary, Medical Dictionary, 2004). 2004).

In diseases of the periodontium that are initiated by bacteria, the "host" clearly is the In diseases of the periodontium that are initiated by bacteria, the "host" clearly is the individual who harbors these pathogens; however, it was not clear for many years individual who harbors these pathogens; however, it was not clear for many years whether it was possible to modulate the host response to these pathogens. Host whether it was possible to modulate the host response to these pathogens. Host modulation with chemotherapeutic therapy or drugs is a promising new adjunctive modulation with chemotherapeutic therapy or drugs is a promising new adjunctive therapeutic option for the management of periodontal disease.therapeutic option for the management of periodontal disease.

The concept of host modulation is fairly new to the field of dentistry but is The concept of host modulation is fairly new to the field of dentistry but is universally understood by most physicians who routinely apply the principles of universally understood by most physicians who routinely apply the principles of host modulation to the management of a number of chronic progressive disorders, host modulation to the management of a number of chronic progressive disorders, such as arthritis and osteoporosis. such as arthritis and osteoporosis.

The concept of host modulation was first introduced to dentistry by Williams (1990) The concept of host modulation was first introduced to dentistry by Williams (1990) and Golub et al (1992). and then expanded on by many other scholars in the dental and Golub et al (1992). and then expanded on by many other scholars in the dental profession. profession.

In 1990, Williams concluded, "There are compelling data from studies in animals In 1990, Williams concluded, "There are compelling data from studies in animals and human trials ; that pharmacologic agents that modulate the host responses and human trials ; that pharmacologic agents that modulate the host responses believed to be involved in the pathogenesis of periodontal destruction may be believed to be involved in the pathogenesis of periodontal destruction may be efficacious in slowing the progression of periodontitis." efficacious in slowing the progression of periodontitis."

In 1992, Golub and colleagues discussed "host modulation with tetracyclines and In 1992, Golub and colleagues discussed "host modulation with tetracyclines and their chemically modified analogues." The future that these authors described has their chemically modified analogues." The future that these authors described has arrived, and to better understands this new era in disease management.arrived, and to better understands this new era in disease management.

HOST MODULATORY THERAPYHOST MODULATORY THERAPY

Host modulatory therapy (HMT) is a treatment concept that aims to reduce tissue Host modulatory therapy (HMT) is a treatment concept that aims to reduce tissue destruction and stabilize or even regenerate the periodontium by modifying or destruction and stabilize or even regenerate the periodontium by modifying or downregulating destructive aspects of the host response and upregulating protective downregulating destructive aspects of the host response and upregulating protective or regenerative responses. or regenerative responses.

HMTs are systemically or locally delivered pharmaceuticals that are prescribed as HMTs are systemically or locally delivered pharmaceuticals that are prescribed as part of periodontal therapy and are used as adjuncts to conventional periodontal part of periodontal therapy and are used as adjuncts to conventional periodontal treatments, such as scaling and root planing (SRP) and surgery. treatments, such as scaling and root planing (SRP) and surgery.

Interest in the potential application of HMTs in treating periodontitis has been Interest in the potential application of HMTs in treating periodontitis has been driven by improved understand ing of periodontal pathogenesis and awareness of the driven by improved understand ing of periodontal pathogenesis and awareness of the importance of the host response in disease susceptibility and progression.importance of the host response in disease susceptibility and progression.

The purpose of host modulatory therapy is to restore the balance of The purpose of host modulatory therapy is to restore the balance of proinflammatory destructive mediators and antiinflammatory or protect mediators proinflammatory destructive mediators and antiinflammatory or protect mediators to that seen in healthy individuals. to that seen in healthy individuals.

Intervention in periodontal disease can now include host modulatory therapy Intervention in periodontal disease can now include host modulatory therapy (HMT) as one of the available adjunctive treatment options. (HMT) as one of the available adjunctive treatment options.

The term The term adjunctive adjunctive is meant to imply "in addition to conventional therapies" or in is meant to imply "in addition to conventional therapies" or in addition to other established therapies." For the management of periodontal addition to other established therapies." For the management of periodontal diseases, conventional approaches were initially mechanical in nature, that is, diseases, conventional approaches were initially mechanical in nature, that is, surgery as well as scaling and root planing. surgery as well as scaling and root planing.

Initially, adjunctive therapies were solely antimicrobial, such as the use of Initially, adjunctive therapies were solely antimicrobial, such as the use of antiseptics and antibiotics. New adjunctive approaches involve modulation of the antiseptics and antibiotics. New adjunctive approaches involve modulation of the host response.host response.

When considering factors that increase an individual's risk for developing When considering factors that increase an individual's risk for developing periodontitis, it has been recognized that genetic, environmental (e.g., tobacco use), periodontitis, it has been recognized that genetic, environmental (e.g., tobacco use), and acquired risk factors (e.g., systemic disease) can increase a patient's and acquired risk factors (e.g., systemic disease) can increase a patient's susceptibility to developing this disease. susceptibility to developing this disease.

These risk factors may lead to the imbalance between the proinflammatory and These risk factors may lead to the imbalance between the proinflammatory and antiinflammatory mediators seen in susceptible individuals. antiinflammatory mediators seen in susceptible individuals.

Risk factors can affect onset, rate of progression, and severity of periodontal Risk factors can affect onset, rate of progression, and severity of periodontal disease, as well as response to therapy. Some of these risk factors can be modified disease, as well as response to therapy. Some of these risk factors can be modified to reduce a patient's susceptibility. to reduce a patient's susceptibility.

Risk assessment and therapy may include smoking cessation, improved control of Risk assessment and therapy may include smoking cessation, improved control of diabetes, nutritional supplementation, improved oral hygiene, changes in diabetes, nutritional supplementation, improved oral hygiene, changes in medication, stress management, and more frequent dental visits. medication, stress management, and more frequent dental visits.

The use of chemotherapeutic agents or drugs specifically designed to treat The use of chemotherapeutic agents or drugs specifically designed to treat periodontal diseases is emerging to aid in this risk assessment and reduction periodontal diseases is emerging to aid in this risk assessment and reduction strategy.strategy.

Chemotherapeutic agents can include adjuncts such as locally applied and Chemotherapeutic agents can include adjuncts such as locally applied and systemically delivered antimicrobials and host modulatory therapies. HMT can be systemically delivered antimicrobials and host modulatory therapies. HMT can be used to reduce excessive levels of enzymes, cytokines, and prostanoids as well as to used to reduce excessive levels of enzymes, cytokines, and prostanoids as well as to modulate osteoclast and osteoblast function. modulate osteoclast and osteoblast function.

HMT is key to addressing many of these risk factors that have adverse effects on the HMT is key to addressing many of these risk factors that have adverse effects on the host response, which are either not easily managed (e.g., smoking, diabetes) or host response, which are either not easily managed (e.g., smoking, diabetes) or cannot be changed (e.g., genetic susceptibility). A program of risk assessment and cannot be changed (e.g., genetic susceptibility). A program of risk assessment and reduction is critical to optimal periodontal therapy in the same way that it is key to reduction is critical to optimal periodontal therapy in the same way that it is key to the successful medical care of diabetic or cardiac patients.the successful medical care of diabetic or cardiac patients.

Clearly, when considering the imbalance in destructive or proinflammatory Clearly, when considering the imbalance in destructive or proinflammatory mediators versus protective or antiinflammatory mediators in the diseased state, mediators versus protective or antiinflammatory mediators in the diseased state, physicians should contemplate the use of pharmacologic agents or HMT. physicians should contemplate the use of pharmacologic agents or HMT.

HMT may be used systemically and locally to restore the balance that is present in HMT may be used systemically and locally to restore the balance that is present in health and to prevent further progression of disease and improve therapeutic health and to prevent further progression of disease and improve therapeutic outcomes.outcomes.

As with current approaches, future host modulatory therapies for the management As with current approaches, future host modulatory therapies for the management of periodontal diseases will primarily target the excessive levels of pro-of periodontal diseases will primarily target the excessive levels of pro-inflammatory mediators. In addition, host modulatory agents might be used to inflammatory mediators. In addition, host modulatory agents might be used to increase the levels of a person's own protective or antiinflammatory mediators.increase the levels of a person's own protective or antiinflammatory mediators.

Use of systemic HMTs for treatment of a patient's periodontal Use of systemic HMTs for treatment of a patient's periodontal condition may also provide benefits for other inflammatory disorders, condition may also provide benefits for other inflammatory disorders, such as arthritis, cardio vascular disease, dermatologic conditions, such as arthritis, cardio vascular disease, dermatologic conditions, diabetes, and osteoporosis. diabetes, and osteoporosis.

Also, patients who are currently taking host modulatory agents, such Also, patients who are currently taking host modulatory agents, such as nonsteroidal antiinflammatory drugs (NSAIDS), bisphosphonates, as nonsteroidal antiinflammatory drugs (NSAIDS), bisphosphonates, or tetracyclines, as well as newer agents targeting specific cytokines or tetracyclines, as well as newer agents targeting specific cytokines for the management of medical conditions, may be experiencing for the management of medical conditions, may be experiencing periodontal benefits from these systemic medications.periodontal benefits from these systemic medications.

HMT is a HMT is a means of treating the host side of the host-bacteria interaction. means of treating the host side of the host-bacteria interaction. The host The host response is responsible for most of the tissue breakdown that occurs, leading to response is responsible for most of the tissue breakdown that occurs, leading to clinical signs of periodontitis.clinical signs of periodontitis.

HMTs offer the opportunity for modulating or reducing this destruction by HMTs offer the opportunity for modulating or reducing this destruction by treating treating aspects of the chronic inflammatory response. HMTs do not "switch off" normal aspects of the chronic inflammatory response. HMTs do not "switch off" normal defense mechanisms or inflammation; instead, they ameliorate excessive or defense mechanisms or inflammation; instead, they ameliorate excessive or pathologically elevated inflammatory processes to enhance opportunities for wound pathologically elevated inflammatory processes to enhance opportunities for wound healing and periodontal stability. healing and periodontal stability.

A variety of different drug classes have been evaluated as host modulation agents, A variety of different drug classes have been evaluated as host modulation agents, including the nonsteroidal antiinflammatory drugs (NSAIDs), bisphosphonates, including the nonsteroidal antiinflammatory drugs (NSAIDs), bisphosphonates, tetracyclines, cytokine antagonists, nitric oxide Synthase inhibitors, enamel matrix tetracyclines, cytokine antagonists, nitric oxide Synthase inhibitors, enamel matrix proteins, growth factors and bone morphogenetic proteins.proteins, growth factors and bone morphogenetic proteins.

SYSTEMICALLY ADMINISTERED AGENTSSYSTEMICALLY ADMINISTERED AGENTSNonsteroidal Antiinflammatory DrugsNonsteroidal Antiinflammatory Drugs

AA is a 20-carbon polyunsaturated fatty acid (eicosanoid) liberated AA is a 20-carbon polyunsaturated fatty acid (eicosanoid) liberated from membrane phospholipids by the action of phospholipase A2. from membrane phospholipids by the action of phospholipase A2. Free AA is metabolized via either the cyclooxygenase (COX) or the Free AA is metabolized via either the cyclooxygenase (COX) or the LO pathways. LO pathways.

AA is enzymatically oxidized by either COX to form unstable AA is enzymatically oxidized by either COX to form unstable cycloendoperoxide intermediates (PGG2 and PGH2) leading to cycloendoperoxide intermediates (PGG2 and PGH2) leading to prostanoid synthesis (prostaglandins, prostacyclin and thromboxane) prostanoid synthesis (prostaglandins, prostacyclin and thromboxane) or by the action of LO to form the LTs and other monohydroxy-or by the action of LO to form the LTs and other monohydroxy-eicosatetraenoic acids. This process is referred to as the AA cascade.eicosatetraenoic acids. This process is referred to as the AA cascade.

Goodson et al. (1974) demonstrated with in vivo experiments that Goodson et al. (1974) demonstrated with in vivo experiments that prostaglandins were implicated in the bone resorption process. A prostaglandins were implicated in the bone resorption process. A rapid bone resorption could be induced within 7 days after injection of rapid bone resorption could be induced within 7 days after injection of a PGE1-containing solution under the skin of rat calvaria. In addition a PGE1-containing solution under the skin of rat calvaria. In addition to prostaglandins, other AA metabolites such as prostacyclin and LT to prostaglandins, other AA metabolites such as prostacyclin and LT appeared to be actively involved in bone resorption. appeared to be actively involved in bone resorption.

Prostacyclin (PGI2) is an endothelial cell product capable of Prostacyclin (PGI2) is an endothelial cell product capable of preventing platelet aggregation and platelet adhesion to vessel walls preventing platelet aggregation and platelet adhesion to vessel walls (de Leval et al. 2004). Findings from tissue culture experiments (de Leval et al. 2004). Findings from tissue culture experiments demonstrated that PGI2 stimulated bone resorption (Raisz et al. 1979, demonstrated that PGI2 stimulated bone resorption (Raisz et al. 1979, Neuman & Raisz 1984 Neuman & Raisz 1984

Modulation of AA metabolites with non-steroidal anti-Modulation of AA metabolites with non-steroidal anti-inflammatory drugs (NSAIDs)inflammatory drugs (NSAIDs)

Over decades, AA metabolites have been established as mediators of tissue Over decades, AA metabolites have been established as mediators of tissue destruction in various inflammatory diseases including rheumatoid arthritis and destruction in various inflammatory diseases including rheumatoid arthritis and periodontal diseases (Offenbacher et al. 1993, O'Dell 2004). periodontal diseases (Offenbacher et al. 1993, O'Dell 2004).

The fact that NSAIDs can suppress alveolar bone resorption suggests that the The fact that NSAIDs can suppress alveolar bone resorption suggests that the synthesis of AA metabolites may represent a critical regulatory pathway for synthesis of AA metabolites may represent a critical regulatory pathway for potentially blocking periodontal disease progression. potentially blocking periodontal disease progression.

The majority of NSAIDs are weak organic acids that selectively (COX-2) and non-The majority of NSAIDs are weak organic acids that selectively (COX-2) and non-selectively (COX-1) inhibit the synthesis of AA metabolites, thereby blocking the selectively (COX-1) inhibit the synthesis of AA metabolites, thereby blocking the production of prostaglandins, thromboxane and prostacyclin (Fitzgerald & Patrono production of prostaglandins, thromboxane and prostacyclin (Fitzgerald & Patrono 2001).2001).

In vitro experimentsIn vitro experiments

After the first report (Vane 1971) that aspirin and aspirin-like drugs inhibited the After the first report (Vane 1971) that aspirin and aspirin-like drugs inhibited the production of prostaglandins by inhibiting the COX enzyme, additional experiments production of prostaglandins by inhibiting the COX enzyme, additional experiments followed (Ferreira et al. 1971, Smith & Willis 1971). followed (Ferreira et al. 1971, Smith & Willis 1971).

In another series of experiments, Goldhaber et al. (1973) added indomethacin, a In another series of experiments, Goldhaber et al. (1973) added indomethacin, a known inhibitor of COX, to the culture media, observing a decrease in bone known inhibitor of COX, to the culture media, observing a decrease in bone resorption of up to 50%. Other researchers (Gomes et al. 1976, Heijl et al. 1976) resorption of up to 50%. Other researchers (Gomes et al. 1976, Heijl et al. 1976) suggested that prostaglandins synthesized during an acute inflammatory response suggested that prostaglandins synthesized during an acute inflammatory response may be important mediators involved in bone resorption. may be important mediators involved in bone resorption.

The amount of prostaglandins released from gingival monkey fragments into the The amount of prostaglandins released from gingival monkey fragments into the culture medium could be reduced by at least 90% by indomethacin, indicating that culture medium could be reduced by at least 90% by indomethacin, indicating that over 90% of the released prostaglandins were synthesized during tissue culture over 90% of the released prostaglandins were synthesized during tissue culture (Gomes et al. 1976).(Gomes et al. 1976).

Animal experimentsAnimal experiments

The fact that elevated levels of PGE2 levels stimulated bone The fact that elevated levels of PGE2 levels stimulated bone resorption and that this process could be inhibited with NSAIDs resorption and that this process could be inhibited with NSAIDs prompted Nyman et al. (1979) to test the efficacy of systemic doses of prompted Nyman et al. (1979) to test the efficacy of systemic doses of indomethacin on the suppression of alveolar bone resorption and indomethacin on the suppression of alveolar bone resorption and gingival inflammation in a ligature-induced periodontitis model in gingival inflammation in a ligature-induced periodontitis model in beagle dogs. beagle dogs.

The results showed that indomethacin delayed the onset and The results showed that indomethacin delayed the onset and suppressed the magnitude of the acute inflammatory response and suppressed the magnitude of the acute inflammatory response and decreased the amount of alveolar bone resorption. This report decreased the amount of alveolar bone resorption. This report represented the beginning of a long series of animal experiments represented the beginning of a long series of animal experiments investigating the effects of NSAIDs on periodontal disease investigating the effects of NSAIDs on periodontal disease progression. progression.

Clinical studiesClinical studies

In 1984, Williams and colleagues instituted a 3-year double-blind trial of the effect In 1984, Williams and colleagues instituted a 3-year double-blind trial of the effect of flurbiprofen on the progression of radiographic loss of alveolar bone in human of flurbiprofen on the progression of radiographic loss of alveolar bone in human periodontal disease. periodontal disease.

Fifty-four patients with radiographic evidence of advanced alveolar bone loss were Fifty-four patients with radiographic evidence of advanced alveolar bone loss were recruited for study. During a 6-months pretreatment period, a baseline rate of bone recruited for study. During a 6-months pretreatment period, a baseline rate of bone loss in each patient was determined. These patients were then randomly divided into loss in each patient was determined. These patients were then randomly divided into 2 treatment groups that had a similar mean rate of bone loss in the pretreatment 2 treatment groups that had a similar mean rate of bone loss in the pretreatment period. period.

Thereafter, one group received flurbiprofen (50 mg bid), whereas the second group Thereafter, one group received flurbiprofen (50 mg bid), whereas the second group received placebo capsules bid. All patients in both groups received a prophylaxis received placebo capsules bid. All patients in both groups received a prophylaxis every 6 months for a 2 year treatment period. The main variable studied by this every 6 months for a 2 year treatment period. The main variable studied by this group was the rate of alveolar bone loss measured radiographically over time. group was the rate of alveolar bone loss measured radiographically over time.

The data indicated that patients treated with 50 mg flurbiprofen bid had a significant The data indicated that patients treated with 50 mg flurbiprofen bid had a significant reduction in the rate of alveolar bone loss at 12 and 18 months of administration reduction in the rate of alveolar bone loss at 12 and 18 months of administration when compared with those patients on placebo. when compared with those patients on placebo.

Both groups showed some improvement in the first 12 months with a slowing on Both groups showed some improvement in the first 12 months with a slowing on bone loss, which was most likely due to an increase in overall good health based on bone loss, which was most likely due to an increase in overall good health based on study participation. study participation.

In their initial report (Williams et al., 1988, 1989), these investigators noted that by In their initial report (Williams et al., 1988, 1989), these investigators noted that by 24 months of flurbiprofen treatment the rate of bone loss between the two groups 24 months of flurbiprofen treatment the rate of bone loss between the two groups was statistically not significantly different with a loss of effect of flurbiprofen. was statistically not significantly different with a loss of effect of flurbiprofen.

At the time, no explanation was given for the loss of effect of flurbiprofen, although At the time, no explanation was given for the loss of effect of flurbiprofen, although the authors were able to conclude that flurbiprofen was a potent inhibitor of bone the authors were able to conclude that flurbiprofen was a potent inhibitor of bone loss in the human for an 18-months period. loss in the human for an 18-months period.

Lipoxins (LXs): Endogenous modulators of inflammationLipoxins (LXs): Endogenous modulators of inflammation

Recent evidence suggests that LXs are a class of both structurally and functionally Recent evidence suggests that LXs are a class of both structurally and functionally unique eicasonoids involved in counter-regulation of inflammatory responses unique eicasonoids involved in counter-regulation of inflammatory responses (Kantarci & Van Dyke 2003). (Kantarci & Van Dyke 2003).

These lipid mediators also appear to facilitate the resolution of the acute These lipid mediators also appear to facilitate the resolution of the acute inflammatory response (Van Dyke & Serhan 2003). In short, resolution of inflammatory response (Van Dyke & Serhan 2003). In short, resolution of inflammation is an active process.inflammation is an active process.

LX and aspirin-triggered lipoxin (ATL) are bioactive lipid mediators involved in the LX and aspirin-triggered lipoxin (ATL) are bioactive lipid mediators involved in the AA cascade and are formed by the interaction of 5- and 15-LOs (Claria & Serhan AA cascade and are formed by the interaction of 5- and 15-LOs (Claria & Serhan 1995). 1995).

To counteract the known proinflammatory effects of PGE2 in periodontal disease, To counteract the known proinflammatory effects of PGE2 in periodontal disease, the potential protective contribution of lipoxins was investigated in the murine air the potential protective contribution of lipoxins was investigated in the murine air pouch model (Pouliot et al. 2000).pouch model (Pouliot et al. 2000).

Porphyromonas gingivalisPorphyromonas gingivalis was introduced in the dorsal air pouch eliciting was introduced in the dorsal air pouch eliciting leucocyte infiltration concomitant with an upregulated expression of COX-2 mRNA leucocyte infiltration concomitant with an upregulated expression of COX-2 mRNA in recruited leucocytes and elevated levels of PGE2. The administration of stable in recruited leucocytes and elevated levels of PGE2. The administration of stable analogues of LX and of ATL blocked neutrophil migration into the air pouch cavity analogues of LX and of ATL blocked neutrophil migration into the air pouch cavity and decreased PGE2 levels within cellular exudates.and decreased PGE2 levels within cellular exudates.

Collectively, data have shown that lipoxins are capable of preventing gingival Collectively, data have shown that lipoxins are capable of preventing gingival inflammation and bone loss in animal experimental periodontitis.inflammation and bone loss in animal experimental periodontitis.

TRICLOSANTRICLOSAN

A compound which has received interest as both an antibacterial and anti-A compound which has received interest as both an antibacterial and anti-inflammatory agent is triclosan. Triclosan (2, 4, 41-trichloro-2-hydroxy-diphenyl inflammatory agent is triclosan. Triclosan (2, 4, 41-trichloro-2-hydroxy-diphenyl ether) is a non-ionic antimicrobial agent. Tri closan also inhibits CO and LO and ether) is a non-ionic antimicrobial agent. Tri closan also inhibits CO and LO and thus may interfere with the production of AA metabolites. thus may interfere with the production of AA metabolites.

Use of a dentifrice containing sodium fluoride (0.243%) and triclosan (0.3%) with Use of a dentifrice containing sodium fluoride (0.243%) and triclosan (0.3%) with 2.0% PVM/MA copolymer (the non-proprietary designation for a polyvinylmethyl 2.0% PVM/MA copolymer (the non-proprietary designation for a polyvinylmethyl ether maleic acid copolymer) reduced the frequency of deep periodontal pockets ether maleic acid copolymer) reduced the frequency of deep periodontal pockets and the number of sites exhibiting attachment and bone loss in patients deemed and the number of sites exhibiting attachment and bone loss in patients deemed highly susceptible to periodontitis (Rosling B et al 1997). highly susceptible to periodontitis (Rosling B et al 1997).

Additional studies are warranted to examine the effect of this combination of drugs Additional studies are warranted to examine the effect of this combination of drugs on periodontitis. At this time, the triclosan/copolymer dentifrice is indicated for the on periodontitis. At this time, the triclosan/copolymer dentifrice is indicated for the reduction of plaque, calculus, gingivitis, and caries.reduction of plaque, calculus, gingivitis, and caries.

Modulation of Matrix Metalloproteinases (MMPs)Modulation of Matrix Metalloproteinases (MMPs)

Role of MMPs in connective tissue breakdown and periodontal Role of MMPs in connective tissue breakdown and periodontal diseasedisease

MMPs encompass a family of zinc-dependent membrane-bound and secreted MMPs encompass a family of zinc-dependent membrane-bound and secreted proteolytic enzymes. Their main function is to catalyse the breakdown of proteins in proteolytic enzymes. Their main function is to catalyse the breakdown of proteins in the cell plasma membrane or within the extracellular matrix (Birkedal-Hansen et al. the cell plasma membrane or within the extracellular matrix (Birkedal-Hansen et al. 1993, Ryan & Golub 2000).1993, Ryan & Golub 2000).

The extracellular matrix consists of collagenous and non-collagenous (e.g. The extracellular matrix consists of collagenous and non-collagenous (e.g. glycoproteins and proteoglycans) proteins. In order for the collagenases to have glycoproteins and proteoglycans) proteins. In order for the collagenases to have access to the collagen substrate, proteoglycans and fibronectin must be removed access to the collagen substrate, proteoglycans and fibronectin must be removed first by the action of specific MMPs such as stromelysin (MMP-3). first by the action of specific MMPs such as stromelysin (MMP-3).

Deregulation of MMPs activity is involved in a variety of pathological conditions Deregulation of MMPs activity is involved in a variety of pathological conditions such as rheumatoid arthritis, tumour cell metastasis and periodontal disease (Yoon such as rheumatoid arthritis, tumour cell metastasis and periodontal disease (Yoon et al. 2003). Periodontal tissue cells including fibroblasts, keratinocytes, et al. 2003). Periodontal tissue cells including fibroblasts, keratinocytes, neutrophils, macrophages and endothelial cells constitute the primary source of neutrophils, macrophages and endothelial cells constitute the primary source of

MMPsMMPs. .

Under healthy periodontal conditions, collagen homeostasis is a tightly regulated Under healthy periodontal conditions, collagen homeostasis is a tightly regulated process controlled extracellularly by fibroblast-derived collagenase (e.g. process controlled extracellularly by fibroblast-derived collagenase (e.g. collagenase-1 or MMP-1). Inflammatory mediators such as IL-1, TNF-collagenase-1 or MMP-1). Inflammatory mediators such as IL-1, TNF-αα and PGE2 and PGE2 (Nakaya et al. 1997, Domeij et al. 2002, Ruvanpura et al. 2004) as well as bacterial (Nakaya et al. 1997, Domeij et al. 2002, Ruvanpura et al. 2004) as well as bacterial products (DeCarlo et al. 1998, Choi et al. 2001, 2003) have been shown to products (DeCarlo et al. 1998, Choi et al. 2001, 2003) have been shown to upregulate MMP production in several in vitro models.upregulate MMP production in several in vitro models.

For example, IL-1For example, IL-1ββ-induced MMP-3 production was downregulated by PGE2 in -induced MMP-3 production was downregulated by PGE2 in human fibroblasts from healthy gingiva and upregulated by PGE2 in fibroblasts human fibroblasts from healthy gingiva and upregulated by PGE2 in fibroblasts from periodontally diseased tissue (Ruvanpura et al. 2004). Moreover, production from periodontally diseased tissue (Ruvanpura et al. 2004). Moreover, production of MMP-1 and MMP-3 by gingival fibroblasts was downregulated by interferon-of MMP-1 and MMP-3 by gingival fibroblasts was downregulated by interferon-γγ (IFN-(IFN-γγ) (Wassenaar et al. 1999). ) (Wassenaar et al. 1999).

Experimental studies indicate that MMPs activation plays an important role in Experimental studies indicate that MMPs activation plays an important role in extracellular matrix degradation during periodontal tissue destruction (Achong et al. extracellular matrix degradation during periodontal tissue destruction (Achong et al. 2003, Cesar Neto et al. 2004). Regulation of MMP functions involves activation of 2003, Cesar Neto et al. 2004). Regulation of MMP functions involves activation of endogenous tissue inhibitors of MMPs (TIMPs) and endogenous tissue inhibitors of MMPs (TIMPs) and αα-macroglobulins. -macroglobulins.

Subantimicrobial-Dose DoxycyclineSubantimicrobial-Dose Doxycycline

Subantimicrobial-dose doxycycline (SDD) is a 20-mg dose of doxycycline Subantimicrobial-dose doxycycline (SDD) is a 20-mg dose of doxycycline (Periostat) that is approved and indicated as an adjunct to SRP in the treatment of (Periostat) that is approved and indicated as an adjunct to SRP in the treatment of chronic periodontitis. It is taken twice daily for 3 months, up to a maximum of 9 chronic periodontitis. It is taken twice daily for 3 months, up to a maximum of 9 months of continuous dosing. months of continuous dosing.

The 20-mg dose exerts its therapeutic effect by enzyme, cytokine, and The 20-mg dose exerts its therapeutic effect by enzyme, cytokine, and osteoclast inhibition rather than by any antibiotic effect.osteoclast inhibition rather than by any antibiotic effect. Research studies have Research studies have found no detectable anti microbial effect on the oral flora or the bacterial flora in found no detectable anti microbial effect on the oral flora or the bacterial flora in other regions of the body and have identified clinical benefit when used as an other regions of the body and have identified clinical benefit when used as an adjunct to SRP. adjunct to SRP.

At present, SDD is the only HMT specifically indicated for the treatment of chronic At present, SDD is the only HMT specifically indicated for the treatment of chronic periodontitis that is approved by the U.S. Food and Drug Administration (FDA) and periodontitis that is approved by the U.S. Food and Drug Administration (FDA) and accepted by the American Dental Association (ADA) accepted by the American Dental Association (ADA)

In addition to its antibiotic properties, doxycycline (as well as the In addition to its antibiotic properties, doxycycline (as well as the other members of the tetracycline family) has the ability to other members of the tetracycline family) has the ability to downregulate downregulate matrix metalloproteinases.matrix metalloproteinases.

The rationale for using SDD as an HMT in the treatment of The rationale for using SDD as an HMT in the treatment of periodontitis is that doxycycline downregulates the activity of MMPs periodontitis is that doxycycline downregulates the activity of MMPs by a variety of synergistic mechanisms, including reductions in by a variety of synergistic mechanisms, including reductions in cytokine levels, and stimulates osteoblastic activity and new bone cytokine levels, and stimulates osteoblastic activity and new bone formation by upregulating collagen production.formation by upregulating collagen production.

Mech. of doxycycline inhibiting conn. tissue Mech. of doxycycline inhibiting conn. tissue breakdownbreakdown

Suggested Uses and Other ConsiderationsSuggested Uses and Other Considerations

Until relatively recently, treatment options for periodontal disease have focused Until relatively recently, treatment options for periodontal disease have focused solely on reducing the bacterial challenge by nonsurgical therapy, surgery, and solely on reducing the bacterial challenge by nonsurgical therapy, surgery, and systemic or local antimicrobial therapy. systemic or local antimicrobial therapy.

The development of SDD as an HMT, driven by research into the pathogenesis of The development of SDD as an HMT, driven by research into the pathogenesis of periodontal disease, is a great example of how basic science research can lead to periodontal disease, is a great example of how basic science research can lead to new treatments. By better understanding the biochemical processes that are new treatments. By better understanding the biochemical processes that are important in periodontal disease, a pharmacologic principle (doxycycline important in periodontal disease, a pharmacologic principle (doxycycline downregulates MMP activity) has been used in the development of a new drug downregulates MMP activity) has been used in the development of a new drug treatment. treatment.

Data presented from research studies show the clinical benefits of adjunctive SDD, Data presented from research studies show the clinical benefits of adjunctive SDD, and the science behind SDD has been transferred into clinical practice. In other and the science behind SDD has been transferred into clinical practice. In other words, dentists now have the opportunity to use SDD for patient care, with the aim words, dentists now have the opportunity to use SDD for patient care, with the aim being to enhance the treatment response to conventional therapy.being to enhance the treatment response to conventional therapy.

Candidate PatientsCandidate Patients

When deciding whether to use SDD as an adjunct to SRP, first consider the patient's When deciding whether to use SDD as an adjunct to SRP, first consider the patient's motivation toward periodontal care, the medical history, and the patient's motivation toward periodontal care, the medical history, and the patient's willingness to take a systemic drug treatment. willingness to take a systemic drug treatment.

SDD is contraindicated in any patient with a history of allergy or hypersensitivity to SDD is contraindicated in any patient with a history of allergy or hypersensitivity to tetracyclines. It should not be given to pregnant or lactating women or children less tetracyclines. It should not be given to pregnant or lactating women or children less than 12 years old (because of the potential for discoloration of the developing than 12 years old (because of the potential for discoloration of the developing dentition). dentition).

Doxycycline may reduce the efficacy of oral contraceptives, and therefore Doxycycline may reduce the efficacy of oral contraceptives, and therefore alternative forms of birth control should be discussed, if necessary. alternative forms of birth control should be discussed, if necessary.

There is a risk of increased sensitivity to sunlight (manifested by an ex aggerated There is a risk of increased sensitivity to sunlight (manifested by an ex aggerated sunburn) seen with higher doses of doxycycline, although this has not been reported sunburn) seen with higher doses of doxycycline, although this has not been reported in the clinical trials using the subantimicrobial dose.in the clinical trials using the subantimicrobial dose.

Treatable Periodontal ConditionsTreatable Periodontal Conditions

SDD is indicated in the management of chronic periodontitis, and studies to date SDD is indicated in the management of chronic periodontitis, and studies to date have focused on chronic and aggressive forms of periodontitis.have focused on chronic and aggressive forms of periodontitis.

SDD should not be used in conditions such as gingivitis and periodontal abscess or SDD should not be used in conditions such as gingivitis and periodontal abscess or when an antibiotic is indicated. SDD can be used in patients with aggressive when an antibiotic is indicated. SDD can be used in patients with aggressive periodontitis who are being treated nonsurgically. periodontitis who are being treated nonsurgically.

Furthermore, emerging studies have supported efficacy of SDD as an adjunct to Furthermore, emerging studies have supported efficacy of SDD as an adjunct to periodontal surgery. SDD may also be of benefit in cases that are refractory to periodontal surgery. SDD may also be of benefit in cases that are refractory to treatment, as well as in patients with risk factors such as smoking or diabetes, in treatment, as well as in patients with risk factors such as smoking or diabetes, in whom the treatment response might be limited.whom the treatment response might be limited.

Adverse EffectsAdverse Effects

Doxycycline at antibiotic doses (>100 mg) is associated with adverse effects, Doxycycline at antibiotic doses (>100 mg) is associated with adverse effects, including photosensitivity, hyper sensitivity reactions, nausea, vomiting, and including photosensitivity, hyper sensitivity reactions, nausea, vomiting, and esophageal irritation.esophageal irritation.

In the clinical trials of SDD (20-mg dose), the drug was well tolerated, however, In the clinical trials of SDD (20-mg dose), the drug was well tolerated, however, and the profile of unwanted effects was virtually identical in the SDD and placebo and the profile of unwanted effects was virtually identical in the SDD and placebo groups. groups.

The types of adverse events did not differ significantly between treatment groups, The types of adverse events did not differ significantly between treatment groups, and the typical side effects of the tetracycline class were not observed. and the typical side effects of the tetracycline class were not observed.

Furthermore, there was no evidence of adverse events that could be attributed to Furthermore, there was no evidence of adverse events that could be attributed to antimicrobial effects of treatment and no evidence of developing antibiotic antimicrobial effects of treatment and no evidence of developing antibiotic resistance of the microflora. Therefore the drug appears to be well tolerated, with a resistance of the microflora. Therefore the drug appears to be well tolerated, with a very low incidence of adverse effects.very low incidence of adverse effects.

Sequencing Prescription with Periodontal TreatmentSequencing Prescription with Periodontal Treatment

SDD is indicated as an adjunct to mechanical periodontal therapy and should not be SDD is indicated as an adjunct to mechanical periodontal therapy and should not be used as a stand alone therapy.used as a stand alone therapy.

SDD should be prescribed to coincide with the first episode of SRP and is SDD should be prescribed to coincide with the first episode of SRP and is prescribed for 3 months, up to a maximum of 9 months of continuous dosing. prescribed for 3 months, up to a maximum of 9 months of continuous dosing.

Modification of any risk factors, such as smoking, nutrition, stress, contributing Modification of any risk factors, such as smoking, nutrition, stress, contributing medications, faulty restorations, poor oral hygiene, and poor diabetic control, can medications, faulty restorations, poor oral hygiene, and poor diabetic control, can also be addressed at this time.also be addressed at this time.

Combining with Periodontal Surgery or Local Delivery SystemsCombining with Periodontal Surgery or Local Delivery Systems

Most clinical research to date has focused on using SDD as an adjunct to Most clinical research to date has focused on using SDD as an adjunct to nonsurgical periodontal treatment.nonsurgical periodontal treatment.

However, emerging data in which SDD was used as an adjunct to access flap However, emerging data in which SDD was used as an adjunct to access flap

surgery in 24 patients revealed better probing depth reductions in surgically treated surgery in 24 patients revealed better probing depth reductions in surgically treated sites greater than 6 mm compared with surgically treated sites in patients given sites greater than 6 mm compared with surgically treated sites in patients given placebo (Gapski et al 2004). placebo (Gapski et al 2004).

Furthermore, the SDD group demonstrated greater reductions in ICTP (carboxy-Furthermore, the SDD group demonstrated greater reductions in ICTP (carboxy-terminal peptide, a breakdown product of collagen) than the placebo group, terminal peptide, a breakdown product of collagen) than the placebo group, indicating that collagenolytic activity was reduced in the patients taking SDD.indicating that collagenolytic activity was reduced in the patients taking SDD.

SDD treatment can also be combined with the local delivery of antibiotics into the SDD treatment can also be combined with the local delivery of antibiotics into the periodontal pocket through sustained-delivery systems. periodontal pocket through sustained-delivery systems.

The two treatment approaches target different aspects of the pathogenic process: The two treatment approaches target different aspects of the pathogenic process: local delivery systems deliver antimicrobial concentrations of an antibacterial agent local delivery systems deliver antimicrobial concentrations of an antibacterial agent directly into the site of the pocket, whereas SDD is a systemic host response directly into the site of the pocket, whereas SDD is a systemic host response modulator. modulator.

Thus, combining these two complementary treatment strategies is another example Thus, combining these two complementary treatment strategies is another example of how antibacterial therapy (SRP + local antibiotics) can be combined with HMT of how antibacterial therapy (SRP + local antibiotics) can be combined with HMT (SDD) to maximize the clinical benefit for patients.(SDD) to maximize the clinical benefit for patients.

In vitro and animal evidence for pharmacological In vitro and animal evidence for pharmacological modulation of MMPsmodulation of MMPs

The ability of tetracyclines and doxycycline, in particular, to inhibit MMP activity The ability of tetracyclines and doxycycline, in particular, to inhibit MMP activity was first identified in the early 1980s (Golub et al. 1983, 1985, Ramamurthy & was first identified in the early 1980s (Golub et al. 1983, 1985, Ramamurthy & Golub 1983). Golub 1983).

Later, the direct and indirect non-antimicrobial mechanisms by which tetracyclines Later, the direct and indirect non-antimicrobial mechanisms by which tetracyclines inhibit MMPs activities, thus preventing connective tissue breakdown and bone inhibit MMPs activities, thus preventing connective tissue breakdown and bone resorption (Ryan & Golub 2000).resorption (Ryan & Golub 2000).

Recent studies using the experimentally induced periodontitis model in rats and Recent studies using the experimentally induced periodontitis model in rats and hamsters have investigated the effects of MMP inhibition with subantimicrobial hamsters have investigated the effects of MMP inhibition with subantimicrobial doses of tetracyclines ( Ramamurthy et al. 2002a) and other MMP inhibitors doses of tetracyclines ( Ramamurthy et al. 2002a) and other MMP inhibitors (Ramamurthy et al. 2002b, Escartin et al. 2003, Buduneli et al. 2004).(Ramamurthy et al. 2002b, Escartin et al. 2003, Buduneli et al. 2004).

Clinical studies on pharmacological modulation of Clinical studies on pharmacological modulation of MMPsMMPs

A subantimicrobial dose (20 mg twice daily) of doxycycline (SDD) A subantimicrobial dose (20 mg twice daily) of doxycycline (SDD) with the purpose of long-term administration in patients suffering with the purpose of long-term administration in patients suffering from periodontitis was introduced and shown to downregulate from periodontitis was introduced and shown to downregulate collagenase activity without the emergence of doxycycline-resistant collagenase activity without the emergence of doxycycline-resistant microorganisms or typical adverse events (Golub et al. 1990, 1994, microorganisms or typical adverse events (Golub et al. 1990, 1994, Thomas et al. 2000). Thomas et al. 2000).

The findings of the first clinical study prescribing SDD as an adjunct The findings of the first clinical study prescribing SDD as an adjunct to mechanical debridement (i.e. scaling and root planing, SRP) to mechanical debridement (i.e. scaling and root planing, SRP) showed statistically significant reductions in GCF concentrations of showed statistically significant reductions in GCF concentrations of MMP-8, MMP-13 and ICTP (i.e. a fragment of type-1 collagen) MMP-8, MMP-13 and ICTP (i.e. a fragment of type-1 collagen) compared with placebo (Golub et al. 1997). compared with placebo (Golub et al. 1997).

The clinical, biochemical and microbiological effects of SDD on the The clinical, biochemical and microbiological effects of SDD on the modulation of wound healing have recently been reported in a pilot modulation of wound healing have recently been reported in a pilot study comparing access flap surgery with SDD (20 mg bid for 6 study comparing access flap surgery with SDD (20 mg bid for 6 months) or placebo in patients with advanced chronic periodontitis months) or placebo in patients with advanced chronic periodontitis (Gapski et al. 2004). (Gapski et al. 2004).

The findings showed that postsurgical wound healing was The findings showed that postsurgical wound healing was significantly enhanced compared with placebo with respect to probing significantly enhanced compared with placebo with respect to probing pocket depth reduction at sites of 7 mm and that adjunctive SDD pocket depth reduction at sites of 7 mm and that adjunctive SDD administration did not induce significant shifts on the periodontal administration did not induce significant shifts on the periodontal microbiota beyond those attributed to surgery alone.microbiota beyond those attributed to surgery alone.

Modulation of Bone RemodellingModulation of Bone Remodelling

Several studies have demonstrated a relationship between tooth loss and Several studies have demonstrated a relationship between tooth loss and osteoporosis (Daniel HW 1983). Preliminary evidence also suggests that osteoporosis (Daniel HW 1983). Preliminary evidence also suggests that osteoporosis and osteopenia may be risk indicators for periodontal diseases (Tezal osteoporosis and osteopenia may be risk indicators for periodontal diseases (Tezal M 2000).M 2000).

Both diseases begin to manifest their effects predominately after the age of 35 and Both diseases begin to manifest their effects predominately after the age of 35 and have common risk factors that may interfere with healing (e.g., smoking, influence have common risk factors that may interfere with healing (e.g., smoking, influence of disease, or medications). Thus, therapeutic strategies used to prevent and manage of disease, or medications). Thus, therapeutic strategies used to prevent and manage osteoporosis and osteopenia may also inhibit periodontal bone loss.osteoporosis and osteopenia may also inhibit periodontal bone loss.

In this regard, large epidemiological studies have been performed to determine In this regard, large epidemiological studies have been performed to determine whether hormone replacement therapy (HRT) can reduce the number of teeth lost in whether hormone replacement therapy (HRT) can reduce the number of teeth lost in post-menopausal women (Grodstein F et al 1996). These studies have reported post-menopausal women (Grodstein F et al 1996). These studies have reported conflicting results regarding the use of HRT and tooth retention. conflicting results regarding the use of HRT and tooth retention.

A potential source of bias in these studies is the possibility that patients who A potential source of bias in these studies is the possibility that patients who seek care to prevent osteoporosis may also pursue preventive dental care. seek care to prevent osteoporosis may also pursue preventive dental care.

At present, limited evidence exists to support the concept that calcium At present, limited evidence exists to support the concept that calcium supplementation (Nishida M et al 2000) or HRT (Norderyd OM et al 1993) can supplementation (Nishida M et al 2000) or HRT (Norderyd OM et al 1993) can reduce tooth loss or progression of periodontitis. reduce tooth loss or progression of periodontitis.

Longitudinal studies are in progress that addresses these issues. A new class of Longitudinal studies are in progress that addresses these issues. A new class of drugs used to manage osteoporosis which may have beneficial effects on drugs used to manage osteoporosis which may have beneficial effects on periodontium are the bisphosphonates.periodontium are the bisphosphonates.

BisphosphonatesBisphosphonates

Bisphosphonates represent a class of chemical compounds structurally related to Bisphosphonates represent a class of chemical compounds structurally related to pyrophosphate, a natural product of human metabolism present in the serum and pyrophosphate, a natural product of human metabolism present in the serum and urine with calcium-chelating properties (Rodan 1998, Rogers et al. 2000).urine with calcium-chelating properties (Rodan 1998, Rogers et al. 2000).

Pyrophosphate regulates mineralization by binding to hydroxyapatite crystals in Pyrophosphate regulates mineralization by binding to hydroxyapatite crystals in vitro but it is not stable in vivo, undergoing rapid hydrolysis of its labile P–O–P vitro but it is not stable in vivo, undergoing rapid hydrolysis of its labile P–O–P bond as a result of pyrophosphatase activity (Shinozaki & Pritzker 1996). bond as a result of pyrophosphatase activity (Shinozaki & Pritzker 1996).

The replacement of the linking oxygen atom with a carbon atom (e.g. P–C–P) The replacement of the linking oxygen atom with a carbon atom (e.g. P–C–P) results in the formation of a bisphosphonate molecule. This compound is chemically results in the formation of a bisphosphonate molecule. This compound is chemically stable and completely resistant to enzymatic hydrolysis via pyrophosphatase and stable and completely resistant to enzymatic hydrolysis via pyrophosphatase and alkaline phosphatase. alkaline phosphatase.

Given their affinity to bind to hydroxyapatite crystals and prevent Given their affinity to bind to hydroxyapatite crystals and prevent their growth and dissolution and to their ability to increase osteoblast their growth and dissolution and to their ability to increase osteoblast differentiation and inhibit osteoclast recruitment and activity, differentiation and inhibit osteoclast recruitment and activity, bisphosphonates are widely used in the management of systemic bisphosphonates are widely used in the management of systemic metabolic bone disorders such as tumour-induced hypercalcaemia, metabolic bone disorders such as tumour-induced hypercalcaemia, osteoporosis and Paget's disease (Fleisch 1997).osteoporosis and Paget's disease (Fleisch 1997).

More recent evidence has suggested that bisphosphonates also possess More recent evidence has suggested that bisphosphonates also possess anticollagenase properties. The ability of bisphosphonates to modulate anticollagenase properties. The ability of bisphosphonates to modulate osteoclast activity clearly may be useful in the treatment of osteoclast activity clearly may be useful in the treatment of periodontitis.periodontitis.

Research is at an early stage, but in naturally occurring periodontitis in beagles, Research is at an early stage, but in naturally occurring periodontitis in beagles, treatment with the bisphosphonate alendronate significantly increased bone density treatment with the bisphosphonate alendronate significantly increased bone density compared with placebo (Reddy MS et al 1995). compared with placebo (Reddy MS et al 1995).

In animal models of experimentally induced periodontitis, bisphosphonates reduced In animal models of experimentally induced periodontitis, bisphosphonates reduced alveolar bone resorption (Shoji et al 1995). In human studies, these agents resulted alveolar bone resorption (Shoji et al 1995). In human studies, these agents resulted in enhanced alveolar bone status and density (El-Shinnawi UM 2003). in enhanced alveolar bone status and density (El-Shinnawi UM 2003).

In the management of periodontal disease-associated bone loss, administration of In the management of periodontal disease-associated bone loss, administration of bisphosphonates may have potential applications. bisphosphonates may have potential applications.

Findings from in vitro experiments demonstrated that bisphosphonates Findings from in vitro experiments demonstrated that bisphosphonates downregulated activity levels of several MMPs (Teronen et al. 1999) including downregulated activity levels of several MMPs (Teronen et al. 1999) including MMP-3, MMP-8 and MMP-13 from human PDL cells (Nakaya et al. 2000).MMP-3, MMP-8 and MMP-13 from human PDL cells (Nakaya et al. 2000).

Adverse effectsAdverse effects

Some bisphosphonates have the unwanted effects of inhibiting bone Some bisphosphonates have the unwanted effects of inhibiting bone calcification and inducing changes in white blood cell counts. calcification and inducing changes in white blood cell counts.

Also, there have been recent reports of avascular necrosis of the jaws Also, there have been recent reports of avascular necrosis of the jaws following bisphosphonate therapy, with the resultant risk of bone following bisphosphonate therapy, with the resultant risk of bone necrosis following dental extractions (Carter G et al). necrosis following dental extractions (Carter G et al).

As with NSAIDs, at present there are no bisphosphonate drugs that As with NSAIDs, at present there are no bisphosphonate drugs that are approved and indicated for treatment of periodontal diseaseare approved and indicated for treatment of periodontal disease

Modulation of Host cell ReceptorsModulation of Host cell Receptors

Cytokines are defined as regulatory proteins controlling the survival, growth, Cytokines are defined as regulatory proteins controlling the survival, growth, differentiation and functions of cells. differentiation and functions of cells.

Cytokines are produced transiently at generally low concentrations, act and are Cytokines are produced transiently at generally low concentrations, act and are degraded in a local environment. This is documented by the fact that cytokine-degraded in a local environment. This is documented by the fact that cytokine-producing cells are often physically located immediately adjacent to the responding producing cells are often physically located immediately adjacent to the responding cells. cells.

Moreover, the responding cell destroys the cytokine that it responds to in the Moreover, the responding cell destroys the cytokine that it responds to in the process of receptor-mediated endocytosis.process of receptor-mediated endocytosis.

Several cytokines bind to elements of the extracellular matrix, thus restricting their Several cytokines bind to elements of the extracellular matrix, thus restricting their spread beyond the site of action and increasing their bioavailability to the spread beyond the site of action and increasing their bioavailability to the responding cells.responding cells.

Cytokines function as a network, are produced by different cell types and share Cytokines function as a network, are produced by different cell types and share overlapping features. This phenomenon is called biological redundancy. overlapping features. This phenomenon is called biological redundancy.

While very few biological responses are mediated by only one cytokine, many While very few biological responses are mediated by only one cytokine, many responses can be achieved by several different cytokines. Thus, important cellular responses can be achieved by several different cytokines. Thus, important cellular functions are usually backed up in mechanisms where one cytokine can compensate functions are usually backed up in mechanisms where one cytokine can compensate for the loss of anotherfor the loss of another. .

Consequently, blocking one inflammatory mediator or cytokine will not assure that Consequently, blocking one inflammatory mediator or cytokine will not assure that a receptor-mediated response will not be activated by alternate pathways. a receptor-mediated response will not be activated by alternate pathways.

This would require the development of polypharmaceutical approaches controlling This would require the development of polypharmaceutical approaches controlling all pathways associated with inflammation and tissue destruction.all pathways associated with inflammation and tissue destruction.

Based upon the increased expression of IL-1 and TNF in inflamed gingiva and high Based upon the increased expression of IL-1 and TNF in inflamed gingiva and high levels in the GCF of periodontitis patients, several studies have suggested that levels in the GCF of periodontitis patients, several studies have suggested that increased production of these cytokines may play an important role in periodontal increased production of these cytokines may play an important role in periodontal tissue destruction. tissue destruction.

To counteract tissue destruction and maintain homeostasis, cytokine antagonists To counteract tissue destruction and maintain homeostasis, cytokine antagonists such as IL-1 receptor antagonist (IL-1Ra) or soluble TNF receptors can such as IL-1 receptor antagonist (IL-1Ra) or soluble TNF receptors can competitively inhibit receptor-mediated signal transduction (Dinarello 2004, Levine competitively inhibit receptor-mediated signal transduction (Dinarello 2004, Levine 2004). 2004).

In vivo application of soluble receptors of IL-1 or TNF-In vivo application of soluble receptors of IL-1 or TNF-αα has been demonstrated to has been demonstrated to inhibit a number of pathologic processes including arthritis and septic shock. IL-1ra inhibit a number of pathologic processes including arthritis and septic shock. IL-1ra is currently approved for treating rheumatoid arthritis.is currently approved for treating rheumatoid arthritis.

In diabetics, the chronically elevated glucose levels result in an accelerated In diabetics, the chronically elevated glucose levels result in an accelerated formation of advanced glycation end-products (AGEs). formation of advanced glycation end-products (AGEs).

AGEs represent a heterogeneous class of non-enzymatically glycated proteins and AGEs represent a heterogeneous class of non-enzymatically glycated proteins and lipids found in plasma, vessel walls and tissues. lipids found in plasma, vessel walls and tissues.

Endothelial cells and monocytes possess specific receptors for AGEs called RAGEs Endothelial cells and monocytes possess specific receptors for AGEs called RAGEs located on their cell surfaces (Hudson & Schmidt 2004). located on their cell surfaces (Hudson & Schmidt 2004).

Studies have shown that the interaction of AGEs with their receptors (RAGEs) Studies have shown that the interaction of AGEs with their receptors (RAGEs) plays an important role in the development of diabetic complications. plays an important role in the development of diabetic complications.

The interaction of macrophages with AGEs has been shown to stimulate increased The interaction of macrophages with AGEs has been shown to stimulate increased secretions of cytokines such as TNF-secretions of cytokines such as TNF-αα and IL-1 (Vlassara et al. 1988). and IL-1 (Vlassara et al. 1988).

In diabetic mice, blockade of RAGEs with soluble receptors (sRAGEs) suppressed In diabetic mice, blockade of RAGEs with soluble receptors (sRAGEs) suppressed periodontitis-associated bone loss and reduced the levels of IL-6, TNF-periodontitis-associated bone loss and reduced the levels of IL-6, TNF-αα and MMPs and MMPs (Lalla et al. 2000).(Lalla et al. 2000).

In conclusion, blockade of cytokine receptors (IL-1ra, TNF-In conclusion, blockade of cytokine receptors (IL-1ra, TNF-ααR1, TNF-R1, TNF-ααR2) soluble R2) soluble cytokines (rhIL-11) and soluble receptor for advanced glycation end-products cytokines (rhIL-11) and soluble receptor for advanced glycation end-products (sRAGEs) reduce periodontal attachment and bone loss in animal experimental (sRAGEs) reduce periodontal attachment and bone loss in animal experimental periodontitis.periodontitis.

Modulation of Nitric oxide Synthase (NOS) Modulation of Nitric oxide Synthase (NOS) ActivityActivity

Nitric oxideNitric oxide (NO) is a short-lived molecule implicated in a wide range of biological (NO) is a short-lived molecule implicated in a wide range of biological processes ranging from immune homeostasis to cancer (Brennan et al. 2003). It is processes ranging from immune homeostasis to cancer (Brennan et al. 2003). It is synthesized in vivo from the substrate l-arginine by three isoenzymes called NOSs.synthesized in vivo from the substrate l-arginine by three isoenzymes called NOSs.

While low levels of NO are present in tissue homeostasis, NO is produced at higher While low levels of NO are present in tissue homeostasis, NO is produced at higher concentrations in response to inflammatory stimuli such as bacterial LPS via concentrations in response to inflammatory stimuli such as bacterial LPS via inducible forms of NOS (iNOS) (Southan & Szabo 1996). inducible forms of NOS (iNOS) (Southan & Szabo 1996).

NO is a highly reactive free radical reacting with metal and thiol residues leading to NO is a highly reactive free radical reacting with metal and thiol residues leading to lipid peroxidation, protein and DNA damages and stimulation of cytokine release lipid peroxidation, protein and DNA damages and stimulation of cytokine release (Brennan et al. 2003). (Brennan et al. 2003).

An exaggerated production of NO has been implicated in the pathophysiology of An exaggerated production of NO has been implicated in the pathophysiology of several inflammatory processes such as arthritis, colitis and ileitis (Boughton-Smith several inflammatory processes such as arthritis, colitis and ileitis (Boughton-Smith et al. 1993, Middleton et al. 1993, Miller et al. 1995, Brahn et al. 1998). et al. 1993, Middleton et al. 1993, Miller et al. 1995, Brahn et al. 1998).

Animal experiments have shown that pharmacological inhibition of iNOS with Animal experiments have shown that pharmacological inhibition of iNOS with mercaptoalkylguanidines was associated with decreased inflammation, mercaptoalkylguanidines was associated with decreased inflammation, haemorrhagic shock and arthritis scores (Zingarelli et al. 1997, Brahn et al. 1998, haemorrhagic shock and arthritis scores (Zingarelli et al. 1997, Brahn et al. 1998, Cuzzocrea et al. 1998). Cuzzocrea et al. 1998).

This may be explained by the fact that this class of drugs (e.g. This may be explained by the fact that this class of drugs (e.g. mercaptoethylguanidines (MEGs)) is able to (i) inhibit COX (Zingarelli et al. 1997), mercaptoethylguanidines (MEGs)) is able to (i) inhibit COX (Zingarelli et al. 1997), (ii) scavenge peroxinitrite (i.e. the product of NO and superoxide) (Szabo et al. (ii) scavenge peroxinitrite (i.e. the product of NO and superoxide) (Szabo et al. 1997) and (iii) block iNOS (Szabo et al. 1996).1997) and (iii) block iNOS (Szabo et al. 1996).

The ligature-induced periodontitis model in rats was used in a proof-of-principle The ligature-induced periodontitis model in rats was used in a proof-of-principle experiment to investigate the role of iNOS and the effects of its inhibition with experiment to investigate the role of iNOS and the effects of its inhibition with MEG (Lohinai et al. 1998). MEG (Lohinai et al. 1998).

Animals treated with intra-peritoneal injection of MEG exhibited significantly less Animals treated with intra-peritoneal injection of MEG exhibited significantly less plasma extravasation and bone loss at ligated sites compared with vehicle-treated plasma extravasation and bone loss at ligated sites compared with vehicle-treated controls. controls.

These preliminary results demonstrated that ligature-induced periodontitis increased These preliminary results demonstrated that ligature-induced periodontitis increased NO production and MEG administration protected against bone loss, suggesting that NO production and MEG administration protected against bone loss, suggesting that NO and peroxynitrite played an important role in the pathogenesis of experimental NO and peroxynitrite played an important role in the pathogenesis of experimental periodontitis.periodontitis.

Locally Administered AgentsLocally Administered AgentsNonsteroidal Antiinflammatory DrugsNonsteroidal Antiinflammatory Drugs

Topical NSAIDs have shown benefit in the treatment of periodontitis. Topical NSAIDs have shown benefit in the treatment of periodontitis. One study of 55 patients with chronic periodontitis who received One study of 55 patients with chronic periodontitis who received topical ketorolac mouth rinse reported that gingival crevicular fluid topical ketorolac mouth rinse reported that gingival crevicular fluid levels of PGE2 were reduced by approximately half over 6 months levels of PGE2 were reduced by approximately half over 6 months and that bone loss was halted (Jeffcoat et al 1995).and that bone loss was halted (Jeffcoat et al 1995).

In addition, locally administered ketoprofen has been investigated. To In addition, locally administered ketoprofen has been investigated. To date, topically administered NSAIDs have not been approved as local date, topically administered NSAIDs have not been approved as local HMTs for the management of periodontitis.HMTs for the management of periodontitis.

Enamel Matrix Proteins, Growth Factors, and Bone Morphogenetic Enamel Matrix Proteins, Growth Factors, and Bone Morphogenetic ProteinsProteins

A number of local host modulation agents have been investigated for A number of local host modulation agents have been investigated for potential use as adjuncts to surgical procedures, not only to improve potential use as adjuncts to surgical procedures, not only to improve wound healing but also to stimulate regeneration of lost bone, wound healing but also to stimulate regeneration of lost bone, periodontal ligament, and cementum, restoring the complete periodontal ligament, and cementum, restoring the complete periodontal attachment apparatus. periodontal attachment apparatus.

These have included enamel matrix proteins (Emdogain), bone These have included enamel matrix proteins (Emdogain), bone morphogenetic proteins (BMP-2, BMP-7), growth factors (platelet-morphogenetic proteins (BMP-2, BMP-7), growth factors (platelet-derived growth factor, insulin-like growth factor), and tetracyclines. derived growth factor, insulin-like growth factor), and tetracyclines. The only local host modulation agent currently approved by the FDA The only local host modulation agent currently approved by the FDA for adjunctive use during surgery is Emdogain.for adjunctive use during surgery is Emdogain.

EMERGING HOST MODULATORY THERAPIESEMERGING HOST MODULATORY THERAPIES

In the future a variety of HMTs will likely be developed as adjunctive treatments In the future a variety of HMTs will likely be developed as adjunctive treatments for periodontitis. One of the most promising groups of potential HMTs is the for periodontitis. One of the most promising groups of potential HMTs is the chemically modified tetracydines chemically modified tetracydines (CMTs). (CMTs).

These nonantibiotic tetracycline analogs are tetracycline molecules that have been These nonantibiotic tetracycline analogs are tetracycline molecules that have been modified to remove all antibiotic properties, but which retain host modulatory, modified to remove all antibiotic properties, but which retain host modulatory, anticollagenolytic effects.anticollagenolytic effects.

The CMTs are also designed to be more potent inhibitors of proinflammatory The CMTs are also designed to be more potent inhibitors of proinflammatory mediators and can increase levels of antiinflammatory mediators such as mediators and can increase levels of antiinflammatory mediators such as interleukin-10 (IL-10). interleukin-10 (IL-10).

This would enable the clinician to increase the dose for patients with more risk This would enable the clinician to increase the dose for patients with more risk factors and who might be more difficult to manage. factors and who might be more difficult to manage.

CMTs such as CMT-3 and CMT-8 (both of which lack antibiotic activity but retain CMTs such as CMT-3 and CMT-8 (both of which lack antibiotic activity but retain anti-MMP activity) have been shown to inhibit osteoclastic bone resorption and anti-MMP activity) have been shown to inhibit osteoclastic bone resorption and promote bone formation, enhance wound healing, and inhibit proteinases produced promote bone formation, enhance wound healing, and inhibit proteinases produced by periodontal pathogens (Greiner D et al 2002). by periodontal pathogens (Greiner D et al 2002).

CMTs also are being studied for other effects, such as inhibition of tumor cell CMTs also are being studied for other effects, such as inhibition of tumor cell invasion and attenuation of intimal thickening after arterial injury. invasion and attenuation of intimal thickening after arterial injury.

CMTs will likely emerge as drugs that have beneficial effects in a variety of disease CMTs will likely emerge as drugs that have beneficial effects in a variety of disease states because of their host modulation capabilities.states because of their host modulation capabilities.

CONCLUSIONCONCLUSION

In the future a range of HMTs targeting different aspects of the In the future a range of HMTs targeting different aspects of the destructive cascade of breakdown events in the periodontal tissues are destructive cascade of breakdown events in the periodontal tissues are likely to be developed as adjunctive treatments for periodontitis. The likely to be developed as adjunctive treatments for periodontitis. The further development of these agents will permit dentists to treat further development of these agents will permit dentists to treat specific aspects of the underlying biochemical basis for periodontal specific aspects of the underlying biochemical basis for periodontal disease. disease.

The goal is to maximize the treatment response by reducing The goal is to maximize the treatment response by reducing inflammation and inhibiting destructive processes in the tissues, inflammation and inhibiting destructive processes in the tissues, which will result in enhanced periodontal stability after conventional which will result in enhanced periodontal stability after conventional periodontal treatments such as SRP. The dentist is now in the exciting periodontal treatments such as SRP. The dentist is now in the exciting position to be able to combine established treatment strategies with position to be able to combine established treatment strategies with new systemic and local drug treatments for this common, chronic new systemic and local drug treatments for this common, chronic disease.disease.

REFERENCESREFERENCES Periodontology 2000, vol. 24, 2000, 239-252Periodontology 2000, vol. 24, 2000, 239-252 Periodontology 2000, 1997; 14: 9-11Periodontology 2000, 1997; 14: 9-11 J Periodontol 2002; 73: 460-472J Periodontol 2002; 73: 460-472 J Periodontol 1993; 64: 474-484J Periodontol 1993; 64: 474-484 Ann Periodontol 1998; 3: 108-120Ann Periodontol 1998; 3: 108-120 J Periodontol 2000; 71: 1158-1166J Periodontol 2000; 71: 1158-1166 JCP 2005; 32: 108-114JCP 2005; 32: 108-114 Carranza’s Clinical Periodontology 10th Ed. Carranza’s Clinical Periodontology 10th Ed.