Host Modulation.ppt

SEMINAR ON
HOST MODULATION THERAPY
IN TREATMENT OF
PERIODONTAL DISEASES

CONTENTS
 Introduction
 Host response and periodontal disease
 Host response modulation in periodontal disease
 Host modulatory therapy
 SYSTEMICALLY ADMINISTERED AGENTS
 Nonsteroidal Antiinflammatory Drugs
 Subantimicrobial-Dose Doxycycline
 Bisphosphonates
 Modulation of Host cell Receptors
 Modulation of Nitric oxide Synthase (NOS) Activity
 LOCALLY ADMINISTERED AGENTS
 Nonsteroidal Antiinflammatory Drugs
 Enamel Matrix Proteins, Growth Factors, and Bone Morphogenetic
Proteins
 Emerging host modulatory therapies
 Conclusion
 References

 Periodontal diseases encompass multi-factorial diseases involving bacterial biofilms
and the generation of an inflammatory response, including the production of
cytokines, eicosanoids and matrix metalloproteinases (MMPs).
 Bacterial biofilms have been shown to be the primary aetiological factor in the
initiation of gingival inflammation and subsequent destruction of periodontal tissues
(Haffajee & Socransky 1994).
 Although chronic bacterial and endotoxin exposure is a prerequisite for gingival
inflammation and periodontal tissue destruction to occur, its presence alone accounts
for a relatively small proportion (i.e. 20%) of the variance in disease expression
(Grossi et al. 1994).

 The major component of soft- and hard-tissue destruction associated with
periodontal disease is the result of activation of the host's immuno-inflammatory
response to the bacterial challenge.
 The underlying biological mechanisms of this response are characterized by the
expression of endothelial cell and inter-cellular adhesion molecules and by the
production of host-derived inflammatory mediators including cytokines and lipids
by neutrophils, monocytes, lymphocytes and fibroblasts.
 Acquired and environmental risk factors, such as diabetes mellitus, cigarette
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
bacterial challenge and, eventually, the susceptibility to the disease (Kornman & Di
Giovine 1998, Salvi et al. 1998, Kinane & Chestnutt 2000, Albandar 2002).

HOST RESPONSE AND PERIODONTAL DISEASE.
 Plaque biofilm and associated host responses are involved in the pathogenesis of
periodontitis.
 Current data suggest that a small group of predominately Gram-negative, anaerobic
or microaerophilic bacteria within the biofilm are often associated with disease
initiation and progression.
 Organisms strongly implicated as etiologic agents include Porphyromonas
gingivalis, Actinobacillus actinomycetemcomitans, and Tannerella forsythia.
 The microbial challenge consisting of antigens, lipopolysaccharide (LPS), and other
virulence factors stimulates host responses which result in disease limited to the
gingiva (i.e., gingivitis) or initiation of periodontitis.

 Protective aspects of the host response include recruitment of
neutrophils, production of protective antibodies, and possibly the
release of anti-inflammatory cytokines including transforming growth
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
challenge disrupts homeostatic mechanisms and results in release of
mediators including proinflammatory cytokines (e.g., IL-1, 1L-6,
tumor necrosis factor-a [TNF-a]), proteases (e.g., matrix
metalloproteinases), and prostanoids (e.g., prostaglandin E2 [PGE2])
which can promote extracellular matrix destruction in the gingiva and
stimulate bone resorption (Page 1998).

 Also neutrophils and macrophages cells subsequently release
mediators including reactive oxygen species, which are antagonistic to
plaque biofilms, but which in excess may initiate inflammation. For
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
implicated in a variety of inflammatory conditions.
 Other host inflammatory mediators being investigated for modulation
include nuclear factor kappa B and endothelial cell adhesion
molecules. However, the role of these inflammatory mediators in
periodontitis needs to be elucidated.

HOST RESPONSE MODULATION IN PERIODONTAL DISEASE
 Host modulation is a new term that has been incorporated into our dental
vocabulary, but it has not been well defined.
 Host can be defined as "the organism from which a parasite obtains to nourishment,"
or in the transplantation of tissue, "the individual who receives the graft."
 Modulation is defined is "the alteration of function or status of something in
response to a stimulus or an altered chemical or physical environment" (Taber's
Medical Dictionary, 2004).
 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
whether it was possible to modulate the host response to these pathogens. Host
modulation with chemotherapeutic therapy or drugs is a promising new adjunctive
therapeutic option for the management of periodontal disease.

 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
host modulation to the management of a number of chronic progressive disorders,
such as arthritis and osteoporosis.
 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
profession.
 In 1990, Williams concluded, "There are compelling data from studies in animals
and human trials ; that pharmacologic agents that modulate the host responses
believed to be involved in the pathogenesis of periodontal destruction may be
efficacious in slowing the progression of periodontitis."
 In 1992, Golub and colleagues discussed "host modulation with tetracyclines and
their chemically modified analogues." The future that these authors described has
arrived, and to better understands this new era in disease management.

HOST MODULATORY THERAPY
 Host modulatory therapy (HMT) is a treatment concept that aims to reduce tissue
destruction and stabilize or even regenerate the periodontium by modifying or
downregulating destructive aspects of the host response and upregulating protective
or regenerative responses.
 HMTs are systemically or locally delivered pharmaceuticals that are prescribed as
part of periodontal therapy and are used as adjuncts to conventional periodontal
treatments, such as scaling and root planing (SRP) and surgery.
 Interest in the potential application of HMTs in treating periodontitis has been
driven by improved understanding of periodontal pathogenesis and awareness of the
importance of the host response in disease susceptibility and progression.

 The purpose of host modulatory therapy is to restore the balance of proinflammatory
destructive mediators and antiinflammatory or protect mediators to that seen in
healthy individuals.
 Intervention in periodontal disease can now include host modulatory therapy (HMT)
as one of the available adjunctive treatment options.
 The term adjunctive is meant to imply "in addition to conventional therapies" or in
addition to other established therapies." For the management of periodontal diseases,
conventional approaches were initially mechanical in nature, that is, surgery as well
as scaling and root planing.
 Initially, adjunctive therapies were solely antimicrobial, such as the use of
antiseptics and antibiotics. New adjunctive approaches involve modulation of the
host response.

 When considering factors that increase an individual's risk for developing
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
susceptibility to developing this disease.
 These risk factors may lead to the imbalance between the proinflammatory and
antiinflammatory mediators seen in susceptible individuals.
 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 to reduce
a patient's susceptibility.

 Risk assessment and therapy may include smoking cessation, improved control of
diabetes, nutritional supplementation, improved oral hygiene, changes in
medication, stress management, and more frequent dental visits.
 The use of chemotherapeutic agents or drugs specifically designed to treat
periodontal diseases is emerging to aid in this risk assessment and reduction
strategy.
 Chemotherapeutic agents can include adjuncts such as locally applied and
systemically delivered antimicrobials and host modulatory therapies. HMT can be
used to reduce excessive levels of enzymes, cytokines, and prostanoids as well as to
modulate osteoclast and osteoblast function.
 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
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
the successful medical care of diabetic or cardiac patients.

 Clearly, when considering the imbalance in destructive or proinflammatory
mediators versus protective or antiinflammatory mediators in the diseased state,
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
health and to prevent further progression of disease and improve therapeutic
outcomes.
 As with current approaches, future host modulatory therapies for the management of
periodontal diseases will primarily target the excessive levels of pro-inflammatory
mediators. In addition, host modulatory agents might be used to increase the levels
of a person's own protective or antiinflammatory mediators.

 Use of systemic HMTs for treatment of a patient's periodontal
condition may also provide benefits for other inflammatory disorders,
such as arthritis, cardiovascular disease, dermatologic conditions,
diabetes, and osteoporosis.
 Also, patients who are currently taking host modulatory agents, such
as nonsteroidal antiinflammatory drugs (NSAIDS), bisphosphonates,
or tetracyclines, as well as newer agents targeting specific cytokines
for the management of medical conditions, may be experiencing
periodontal benefits from these systemic medications.

 HMT is a means of treating the host side of the host-bacteria interaction. The host
response is responsible for most of the tissue breakdown that occurs, leading to
clinical signs of periodontitis.
 HMTs offer the opportunity for modulating or reducing this destruction by treating
aspects of the chronic inflammatory response. HMTs do not "switch off" normal
defense mechanisms or inflammation; instead, they ameliorate excessive or
pathologically elevated inflammatory processes to enhance opportunities for wound
healing and periodontal stability.
 A variety of different drug classes have been evaluated as host modulation agents,
including the nonsteroidal antiinflammatory drugs (NSAIDs), bisphosphonates,
tetracyclines, cytokine antagonists, nitric oxide Synthase inhibitors, enamel matrix
proteins, growth factors and bone morphogenetic proteins.

SYSTEMICALLY ADMINISTERED AGENTS
Nonsteroidal Antiinflammatory Drugs
 AA is a 20-carbon polyunsaturated fatty acid (eicosanoid) liberated
from membrane phospholipids by the action of phospholipase A2.
Free AA is metabolized via either the cyclooxygenase (COX) or the
LO pathways.
 AA is enzymatically oxidized by either COX to form unstable
cycloendoperoxide intermediates (PGG2 and PGH2) leading to
prostanoid synthesis (prostaglandins, prostacyclin and thromboxane)
or by the action of LO to form the LTs and other monohydroxy-
eicosatetraenoic acids. This process is referred to as the AA cascade.

 Goodson et al. (1974) demonstrated with in vivo experiments that
prostaglandins were implicated in the bone resorption process. A rapid
bone resorption could be induced within 7 days after injection of a
PGE1-containing solution under the skin of rat calvaria. In addition to
prostaglandins, other AA metabolites such as prostacyclin and LT
appeared to be actively involved in bone resorption.
 Prostacyclin (PGI2) is an endothelial cell product capable of
preventing platelet aggregation and platelet adhesion to vessel walls
(de Leval et al. 2004). Findings from tissue culture experiments
demonstrated that PGI2 stimulated bone resorption (Raisz et al. 1979,
Neuman & Raisz 1984

Modulation of AA metabolites with non-steroidal anti-
inflammatory drugs (NSAIDs)
 Over decades, AA metabolites have been established as mediators of tissue
destruction in various inflammatory diseases including rheumatoid arthritis and
periodontal diseases (Offenbacher et al. 1993, O'Dell 2004).
 The fact that NSAIDs can suppress alveolar bone resorption suggests that the
synthesis of AA metabolites may represent a critical regulatory pathway for
potentially blocking periodontal disease progression.
 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
production of prostaglandins, thromboxane and prostacyclin (Fitzgerald & Patrono
2001).

In vitro experiments
 After the first report (Vane 1971) that aspirin and aspirin-like drugs inhibited the
production of prostaglandins by inhibiting the COX enzyme, additional experiments
followed (Ferreira et al. 1971, Smith & Willis 1971).
 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
resorption of up to 50%. Other researchers (Gomes et al. 1976, Heijl et al. 1976)
suggested that prostaglandins synthesized during an acute inflammatory response
may be important mediators involved in bone resorption.
 The amount of prostaglandins released from gingival monkey fragments into the
culture medium could be reduced by at least 90% by indomethacin, indicating that
over 90% of the released prostaglandins were synthesized during tissue culture
(Gomes et al. 1976).

Animal experiments
 The fact that elevated levels of PGE2 levels stimulated bone
resorption and that this process could be inhibited with NSAIDs
prompted Nyman et al. (1979) to test the efficacy of systemic doses of
indomethacin on the suppression of alveolar bone resorption and
gingival inflammation in a ligature-induced periodontitis model in
beagle dogs.
 The results showed that indomethacin delayed the onset and
suppressed the magnitude of the acute inflammatory response and
decreased the amount of alveolar bone resorption. This report
represented the beginning of a long series of animal experiments
investigating the effects of NSAIDs on periodontal disease
progression.

Clinical studies
 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
periodontal disease.
 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
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
period.
 Thereafter, one group received flurbiprofen (50 mg bid), whereas the second group
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
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
reduction in the rate of alveolar bone loss at 12 and 18 months of administration
when compared with those patients on placebo.
 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
study participation.
 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
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
the authors were able to conclude that flurbiprofen was a potent inhibitor of bone
loss in the human for an 18-months period.

Lipoxins (LXs): Endogenous modulators of inflammation
 Recent evidence suggests that LXs are a class of both structurally and functionally
unique eicasonoids involved in counter-regulation of inflammatory responses
(Kantarci & Van Dyke 2003).
 These lipid mediators also appear to facilitate the resolution of the acute
inflammatory response (Van Dyke & Serhan 2003). In short, resolution of
inflammation is an active process.
 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
1995).

 To counteract the known proinflammatory effects of PGE2 in periodontal disease,
the potential protective contribution of lipoxins was investigated in the murine air
pouch model (Pouliot et al. 2000).
 Porphyromonas gingivalis was introduced in the dorsal air pouch eliciting
leucocyte infiltration concomitant with an upregulated expression of COX-2 mRNA
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
and decreased PGE2 levels within cellular exudates.
 Collectively, data have shown that lipoxins are capable of preventing gingival
inflammation and bone loss in animal experimental periodontitis.

TRICLOSAN
 A compound which has received interest as both an antibacterial and anti-
inflammatory agent is triclosan. Triclosan (2, 4, 41-trichloro-2-hydroxy-diphenyl
ether) is a non-ionic antimicrobial agent. Triclosan also inhibits CO and LO and thus
may interfere with the production of AA metabolites.
 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
ether maleic acid copolymer) reduced the frequency of deep periodontal pockets and
the number of sites exhibiting attachment and bone loss in patients deemed highly
susceptible to periodontitis (Rosling B et al 1997).
 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
reduction of plaque, calculus, gingivitis, and caries.

Modulation of Matrix Metalloproteinases (MMPs)
Role of MMPs in connective tissue breakdown and periodontal
disease
 MMPs encompass a family of zinc-dependent membrane-bound and secreted
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.
1993, Ryan & Golub 2000).
 The extracellular matrix consists of collagenous and non-collagenous (e.g.
glycoproteins and proteoglycans) proteins. In order for the collagenases to have
access to the collagen substrate, proteoglycans and fibronectin must be removed first
by the action of specific MMPs such as stromelysin (MMP-3).
 Deregulation of MMPs activity is involved in a variety of pathological conditions
such as rheumatoid arthritis, tumour cell metastasis and periodontal disease (Yoon et
al. 2003). Periodontal tissue cells including fibroblasts, keratinocytes, neutrophils,
macrophages and endothelial cells constitute the primary source of MMPs.

 Under healthy periodontal conditions, collagen homeostasis is a tightly regulated
process controlled extracellularly by fibroblast-derived collagenase (e.g.
collagenase-1 or MMP-1). Inflammatory mediators such as IL-1, TNF-α and PGE2
(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
upregulate MMP production in several in vitro models.
 For example, IL-1β-induced MMP-3 production was downregulated by PGE2 in
human fibroblasts from healthy gingiva and upregulated by PGE2 in fibroblasts
from periodontally diseased tissue (Ruvanpura et al. 2004). Moreover, production of
MMP-1 and MMP-3 by gingival fibroblasts was downregulated by interferon-γ
(IFN-γ) (Wassenaar et al. 1999).
 Experimental studies indicate that MMPs activation plays an important role in
extracellular matrix degradation during periodontal tissue destruction (Achong et al.
2003, Cesar Neto et al. 2004). Regulation of MMP functions involves activation of
endogenous tissue inhibitors of MMPs (TIMPs) and α-macroglobulins.

Subantimicrobial-Dose 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
chronic periodontitis. It is taken twice daily for 3 months, up to a maximum of 9
months of continuous dosing.
 The 20-mg dose exerts its therapeutic effect by enzyme, cytokine, and osteoclast
inhibition rather than by any antibiotic effect. Research studies have found no
detectable antimicrobial effect on the oral flora or the bacterial flora in other regions
of the body and have identified clinical benefit when used as an adjunct to SRP.
 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
accepted by the American Dental Association (ADA)

 In addition to its antibiotic properties, doxycycline (as well as the
other members of the tetracycline family) has the ability to
downregulate matrix metalloproteinases.
 The rationale for using SDD as an HMT in the treatment of
periodontitis is that doxycycline downregulates the activity of MMPs
by a variety of synergistic mechanisms, including reductions in
cytokine levels, and stimulates osteoblastic activity and new bone
formation by upregulating collagen production.

Mech. of doxycycline inhibiting conn. tissue
breakdown

Suggested Uses and Other Considerations
 Until relatively recently, treatment options for periodontal disease have focused
solely on reducing the bacterial challenge by nonsurgical therapy, surgery, and
systemic or local antimicrobial therapy.
 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
new treatments. By better understanding the biochemical processes that are
important in periodontal disease, a pharmacologic principle (doxycycline
downregulates MMP activity) has been used in the development of a new drug
treatment.
 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
words, dentists now have the opportunity to use SDD for patient care, with the aim
being to enhance the treatment response to conventional therapy.

Candidate Patients
 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
willingness to take a systemic drug treatment.
 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
than 12 years old (because of the potential for discoloration of the developing
dentition).
 Doxycycline may reduce the efficacy of oral contraceptives, and therefore
alternative forms of birth control should be discussed, if necessary.
 There is a risk of increased sensitivity to sunlight (manifested by an exaggerated
sunburn) seen with higher doses of doxycycline, although this has not been reported
in the clinical trials using the subantimicrobial dose.

Treatable Periodontal Conditions
 SDD is indicated in the management of chronic periodontitis, and studies to date
have focused on chronic and aggressive forms of periodontitis.
 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
periodontitis who are being treated nonsurgically.
 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
treatment, as well as in patients with risk factors such as smoking or diabetes, in
whom the treatment response might be limited.

Adverse Effects
 Doxycycline at antibiotic doses (>100 mg) is associated with adverse effects,
including photosensitivity, hypersensitivity reactions, nausea, vomiting, and
esophageal irritation.
 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
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.
 Furthermore, there was no evidence of adverse events that could be attributed to
antimicrobial effects of treatment and no evidence of developing antibiotic
resistance of the microflora. Therefore the drug appears to be well tolerated, with a
very low incidence of adverse effects.

Sequencing Prescription with Periodontal Treatment
 SDD is indicated as an adjunct to mechanical periodontal therapy and should not be
used as a standalone therapy.
 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.
 Modification of any risk factors, such as smoking, nutrition, stress, contributing
medications, faulty restorations, poor oral hygiene, and poor diabetic control, can
also be addressed at this time.

Combining with Periodontal Surgery or Local Delivery Systems
 Most clinical research to date has focused on using SDD as an adjunct to
nonsurgical periodontal treatment.
 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
sites greater than 6 mm compared with surgically treated sites in patients given
placebo (Gapski et al 2004).
 Furthermore, the SDD group demonstrated greater reductions in ICTP (carboxy-
terminal peptide, a breakdown product of collagen) than the placebo group,
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
periodontal pocket through sustained-delivery systems.
 The two treatment approaches target different aspects of the pathogenic process:
local delivery systems deliver antimicrobial concentrations of an antibacterial agent
directly into the site of the pocket, whereas SDD is a systemic host response
modulator.
 Thus, combining these two complementary treatment strategies is another example
of how antibacterial therapy (SRP + local antibiotics) can be combined with HMT
(SDD) to maximize the clinical benefit for patients.

In vitro and animal evidence for pharmacological
modulation of MMPs
 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 &
Golub 1983).
 Later, the direct and indirect non-antimicrobial mechanisms by which tetracyclines
inhibit MMPs activities, thus preventing connective tissue breakdown and bone
resorption (Ryan & Golub 2000).
 Recent studies using the experimentally induced periodontitis model in rats and
hamsters have investigated the effects of MMP inhibition with subantimicrobial
doses of tetracyclines ( Ramamurthy et al. 2002a) and other MMP inhibitors
(Ramamurthy et al. 2002b, Escartin et al. 2003, Buduneli et al. 2004).

Clinical studies on pharmacological modulation of
MMPs
 A subantimicrobial dose (20 mg twice daily) of doxycycline (SDD)
with the purpose of long-term administration in patients suffering
from periodontitis was introduced and shown to downregulate
collagenase activity without the emergence of doxycycline-resistant
microorganisms or typical adverse events (Golub et al. 1990, 1994,
Thomas et al. 2000).
 The findings of the first clinical study prescribing SDD as an adjunct
to mechanical debridement (i.e. scaling and root planing, SRP)
showed statistically significant reductions in GCF concentrations of
MMP-8, MMP-13 and ICTP (i.e. a fragment of type-1 collagen)
compared with placebo (Golub et al. 1997).

 The clinical, biochemical and microbiological effects of SDD on the
modulation of wound healing have recently been reported in a pilot
study comparing access flap surgery with SDD (20 mg bid for 6
months) or placebo in patients with advanced chronic periodontitis
(Gapski et al. 2004).
 The findings showed that postsurgical wound healing was
significantly enhanced compared with placebo with respect to probing
pocket depth reduction at sites of 7 mm and that adjunctive SDD
administration did not induce significant shifts on the periodontal
microbiota beyond those attributed to surgery alone.

Modulation of Bone Remodelling
 Several studies have demonstrated a relationship between tooth loss and
osteoporosis (Daniel HW 1983). Preliminary evidence also suggests that
osteoporosis and osteopenia may be risk indicators for periodontal diseases (Tezal
M 2000).
 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
of disease, or medications). Thus, therapeutic strategies used to prevent and manage
osteoporosis and osteopenia may also inhibit periodontal bone loss.
 In this regard, large epidemiological studies have been performed to determine
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
conflicting results regarding the use of HRT and tooth retention.

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

Bisphosphonates
 Bisphosphonates represent a class of chemical compounds structurally related to
pyrophosphate, a natural product of human metabolism present in the serum and
urine with calcium-chelating properties (Rodan 1998, Rogers et al. 2000).
 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
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) results
in the formation of a bisphosphonate molecule. This compound is chemically stable
and completely resistant to enzymatic hydrolysis via pyrophosphatase and alkaline
phosphatase.

 Given their affinity to bind to hydroxyapatite crystals and prevent
their growth and dissolution and to their ability to increase osteoblast
differentiation and inhibit osteoclast recruitment and activity,
bisphosphonates are widely used in the management of systemic
metabolic bone disorders such as tumour-induced hypercalcaemia,
osteoporosis and Paget's disease (Fleisch 1997).
 More recent evidence has suggested that bisphosphonates also possess
anticollagenase properties. The ability of bisphosphonates to modulate
osteoclast activity clearly may be useful in the treatment of
periodontitis.

 Research is at an early stage, but in naturally occurring periodontitis in beagles,
treatment with the bisphosphonate alendronate significantly increased bone density
compared with placebo (Reddy MS et al 1995).
 In animal models of experimentally induced periodontitis, bisphosphonates reduced
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 the management of periodontal disease-associated bone loss, administration of
bisphosphonates may have potential applications.
 Findings from in vitro experiments demonstrated that bisphosphonates
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).

Adverse effects
 Some bisphosphonates have the unwanted effects of inhibiting bone
calcification and inducing changes in white blood cell counts.
 Also, there have been recent reports of avascular necrosis of the jaws
following bisphosphonate therapy, with the resultant risk of bone
necrosis following dental extractions (Carter G et al).
 As with NSAIDs, at present there are no bisphosphonate drugs that
are approved and indicated for treatment of periodontal disease

Modulation of Host cell Receptors
 Cytokines are defined as regulatory proteins controlling the survival, growth,
differentiation and functions of cells.
 Cytokines are produced transiently at generally low concentrations, act and are
degraded in a local environment. This is documented by the fact that cytokine-
producing cells are often physically located immediately adjacent to the responding
cells.
 Moreover, the responding cell destroys the cytokine that it responds to in the process
of receptor-mediated endocytosis.
 Several cytokines bind to elements of the extracellular matrix, thus restricting their
spread beyond the site of action and increasing their bioavailability to the
responding cells.

 Cytokines function as a network, are produced by different cell types and share
overlapping features. This phenomenon is called biological redundancy.
 While very few biological responses are mediated by only one cytokine, many
responses can be achieved by several different cytokines. Thus, important cellular
functions are usually backed up in mechanisms where one cytokine can compensate
for the loss of another.
 Consequently, blocking one inflammatory mediator or cytokine will not assure that a
receptor-mediated response will not be activated by alternate pathways.
 This would require the development of polypharmaceutical approaches controlling
all pathways associated with inflammation and tissue destruction.

 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
increased production of these cytokines may play an important role in periodontal
tissue destruction.
 To counteract tissue destruction and maintain homeostasis, cytokine antagonists
such as IL-1 receptor antagonist (IL-1Ra) or soluble TNF receptors can
competitively inhibit receptor-mediated signal transduction (Dinarello 2004, Levine
2004).
 In vivo application of soluble receptors of IL-1 or TNF-α has been demonstrated to
inhibit a number of pathologic processes including arthritis and septic shock. IL-1ra
is currently approved for treating rheumatoid arthritis.

 In diabetics, the chronically elevated glucose levels result in an accelerated
formation of advanced glycation end-products (AGEs).
 AGEs represent a heterogeneous class of non-enzymatically glycated proteins and
lipids found in plasma, vessel walls and tissues.
 Endothelial cells and monocytes possess specific receptors for AGEs called RAGEs
located on their cell surfaces (Hudson & Schmidt 2004).
 Studies have shown that the interaction of AGEs with their receptors (RAGEs) plays
an important role in the development of diabetic complications.

 The interaction of macrophages with AGEs has been shown to stimulate increased
secretions of cytokines such as TNF-α and IL-1 (Vlassara et al. 1988).
 In diabetic mice, blockade of RAGEs with soluble receptors (sRAGEs) suppressed
periodontitis-associated bone loss and reduced the levels of IL-6, TNF-α and MMPs
(Lalla et al. 2000).
 In conclusion, blockade of cytokine receptors (IL-1ra, TNF-αR1, TNF-αR2) soluble
cytokines (rhIL-11) and soluble receptor for advanced glycation end-products
(sRAGEs) reduce periodontal attachment and bone loss in animal experimental
periodontitis.

Modulation of Nitric oxide Synthase (NOS)
Activity
 Nitric oxide (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
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
concentrations in response to inflammatory stimuli such as bacterial LPS via
inducible forms of NOS (iNOS) (Southan & Szabo 1996).
 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
(Brennan et al. 2003).

 An exaggerated production of NO has been implicated in the pathophysiology of
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).
 Animal experiments have shown that pharmacological inhibition of iNOS with
mercaptoalkylguanidines was associated with decreased inflammation,
haemorrhagic shock and arthritis scores (Zingarelli et al. 1997, Brahn et al. 1998,
Cuzzocrea et al. 1998).
 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),
(ii) scavenge peroxinitrite (i.e. the product of NO and superoxide) (Szabo et al.
1997) and (iii) block iNOS (Szabo et al. 1996).

 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 MEG
(Lohinai et al. 1998).
 Animals treated with intra-peritoneal injection of MEG exhibited significantly less
plasma extravasation and bone loss at ligated sites compared with vehicle-treated
controls.
 These preliminary results demonstrated that ligature-induced periodontitis increased
NO production and MEG administration protected against bone loss, suggesting that
NO and peroxynitrite played an important role in the pathogenesis of experimental
periodontitis.

Locally Administered Agents
Nonsteroidal Antiinflammatory Drugs
 Topical NSAIDs have shown benefit in the treatment of periodontitis.
One study of 55 patients with chronic periodontitis who received
topical ketorolac mouth rinse reported that gingival crevicular fluid
levels of PGE2 were reduced by approximately half over 6 months
and that bone loss was halted (Jeffcoat et al 1995).
 In addition, locally administered ketoprofen has been investigated. To
date, topically administered NSAIDs have not been approved as local
HMTs for the management of periodontitis.

Enamel Matrix Proteins, Growth Factors, and Bone Morphogenetic
Proteins
 A number of local host modulation agents have been investigated for
potential use as adjuncts to surgical procedures, not only to improve
wound healing but also to stimulate regeneration of lost bone,
periodontal ligament, and cementum, restoring the complete
periodontal attachment apparatus.
 These have included enamel matrix proteins (Emdogain), bone
morphogenetic proteins (BMP-2, BMP-7), growth factors (platelet-
derived growth factor, insulin-like growth factor), and tetracyclines.
The only local host modulation agent currently approved by the FDA
for adjunctive use during surgery is Emdogain.

EMERGING HOST MODULATORY THERAPIES
 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 chemically
modified tetracydines (CMTs).
 These nonantibiotic tetracycline analogs are tetracycline molecules that have been
modified to remove all antibiotic properties, but which retain host modulatory,
anticollagenolytic effects.
 The CMTs are also designed to be more potent inhibitors of proinflammatory
mediators and can increase levels of antiinflammatory mediators such as interleukin-
10 (IL-10).
 This would enable the clinician to increase the dose for patients with more risk
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
anti-MMP activity) have been shown to inhibit osteoclastic bone resorption and
promote bone formation, enhance wound healing, and inhibit proteinases produced
by periodontal pathogens (Greiner D et al 2002).
 CMTs also are being studied for other effects, such as inhibition of tumor cell
invasion and attenuation of intimal thickening after arterial injury.
 CMTs will likely emerge as drugs that have beneficial effects in a variety of disease
states because of their host modulation capabilities.

CONCLUSION
 In the future a range of HMTs targeting different aspects of the
destructive cascade of breakdown events in the periodontal tissues are
likely to be developed as adjunctive treatments for periodontitis. The
further development of these agents will permit dentists to treat
specific aspects of the underlying biochemical basis for periodontal
disease.
 The goal is to maximize the treatment response by reducing
inflammation and inhibiting destructive processes in the tissues, which
will result in enhanced periodontal stability after conventional
periodontal treatments such as SRP. The dentist is now in the exciting
position to be able to combine established treatment strategies with
new systemic and local drug treatments for this common, chronic
disease.

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

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