1. HOST MODULATION
AND AGENTS

2. CONTENTS
•
•
•
INTRODUCTION
DEFINITIONS
PATHOGENESIS OF PERIODONTITIS AND THE HOST
RESPONSE
HOST MODULATION THERAPY (HMT)
•
–
–
–
–
•
DEFINITION
RATIONALE
POTENTIAL TARGETS FOR HOST MODULATION
SYSTEMICALLY ADMINISTERED AGENTS
LOCALLY ADMINISTERED AGENTS
SUBANTIMICROBIAL DOSE DOXYCYCLINE (SDD)

3. • BISPHOSPHONATES
• MODULATION OF HOST CELL RECEPTORS
• MODULATION OF NITRIC OXIDE SYNTHASE (NOS)
ACTIVITY
• CHEMICALLY MODIFIED TETRACYCLINES
• SUMMARY
• REFERENCES

4. INTRODUCTION
In the past, the understanding of the etiology and
the pathogenesis of the periodontal disease
focused on the microbial aspect of the diseases
and thus, the therapeutic efforts focused on the
mechanical or the therapeutic removal of the
bacterial flora.
Recent therapeutic efforts focus on altering
(modulating) the host response.

5. DEFINITIONS
• Host – defined as……
• Modulation – defined as the alteration of
function………
• The concept of host modulation1st –William(1990) – concluded from……indicating
that pharmacolgical agents that modulate the host
response believed to be involved in………may be
efficacious in slowing the progression…..
Golub etal (1992) – discussed HM with………

6. Pathogenesis of
Periodontitis
• The assessment of the role of the host response
in the periodontal pathogenesis is required to
better understand the host factors that are to be
modulated.

7. Host-microbial interaction
& the Host response
• Periodontal disease doesn’t appear to act as a Classic
infection but, but more as Oppurtunistic infection ie
when certain, more virulent species exist in an
environment that allows for their presence in greater
proportion, there is opportunity for periodontal
destruction to occur
• Although, bacterial pathogens initiate the periodontal
inflammation, the host response to these pathogens is
equally imp in mediating connective tissue breakdown,
including the bone loss.

8. Pathogenesis of periodontitisSchematic representation
Pathogenesis of Periodontitis
Schematic representation

9. • Now, this response is essentially protective in intent, to combat the
bact infection and prevent the ingress of bact into the tissues.
• In Disease- resistant individuals, these primary defense mechanisms
control the infection and may persist as chronic inflammation .
• Where as in Disease- susceptible individuals, the inflammatory
events extend apically and laterally to involve the deeper CT and
alveolar bone.
Inflammation worsens
large no of PMNs migrate into the tissues
Secretion of Excessive quantities of destructive enzymes and

10.  The enzymes includes MMPs, such as collagenases, which
break down collagen fibres in the gingival and periodontal tissues.
disrupts the normal anatomy of the tissues
 Macrophages are recruited to the area and are activated, by
binding to LPS, to produce

PGs,

Interleukins(IL-1α,IL-1β, IL-6)

TNF-α

MMPs

11. • Concen of these enzymes and inflammatory mediators become
pathologically high in the PD tissues
• Under healthy conditions, the elevations are counter-balanced
by anti-inflammatory mediators (cytokines IL-4,IL-10,IL-1ra &
tissue inhibitors of MMP(TIMP)
• Thus, keep the host response to bacterial challenge in check
• And the individual is disease –resistant
In Susceptible patients, the excessive host response leads to an
imbalance in disease and health of the periodontium

12. Periodontal Balance
• Balance between the PD breakdown (disease) and the
PD stability (health)

13. Hence, the Host Modulation
Therapy offers the potential for
the downregulating destructive
aspects and upregulating
protective aspects of the host
response so that, in
combinations with conventional
treatments to reduce the bacterial
burden, the ‘balance’ is tipped in
the direction of a healing
response.

14. Host Modulation Therapy
• Defined as the treatment concept……….
• AIM:
To modify or reduce destructive aspects of the host
response so that the immune inflammatory
response to plaque is less damaging to the PD
tissues

15. RATIONALE:
HMTs offer the oppurtunity for modulating or reducing
destruction by treating aspects of the chronic inflammatory
response.
Used as an adjuncts to conventional PD treatments (SRP &
Surgery)
HMT’s do not “switch off” normal defense mechanisms or
inflammation; instead they ameliorate excessive or pathologically
elevated inflammatory processes to enhance the oppurtunities for
wound healing and periodontal stability.

16. Host Modulation
Bisphosphonates
CMT’S

17. Potential Targets for Host modulation

18. Modulating agents
•
A variety of different drug classes have been evaluated as Host
Modulation agents:
•
1.
2.
3.
Systemically administered Agents:
NSAIDs
Bisphosphonates
SDD (Subantimicrobial-Dose Doxycycline)
1.
2.
3.
4.
5.
Locally administered Agents:
Topical NSAIDs
Enamel Matrix Proteins
Growth factors
BMP
Tetracyclines

19. Nonsteroidal Anti-inflammatory Drugs
PGE2
– upregulates bone resorption bv osteoclasts
– levels have been shown to be elevated in patients with
periodontal disease
– inhibits fibroblast function
– inhibitory and modualtory effects on the immune response.
In addition to prostaglandins, other AA metabolites such as
Prostacyclin appeared to be actively involved in bone
resorption.
• NSAlDs inhibit the formation of prostaglandins, including
prostaglandin E2 (PGE2)

21. NSAIDs include the
– salicylates (e.g., aspirin)
– indomethacin
– propionic acid derivatives (e.g., ibuprofen,
flurbiprofen, naproxen).
• Studies have shown that systemic NSAIDsadministered daily for up to 3 years significantly
slowed the rate of alveolar bone loss compared
with placebo.

22. Disadvantages of NSAIDs
– Daily administration for extended periods is necessary for periodontal
benefits to become apparent
– Associated with significant side effects
• gastrointestinal problems
• hemorrhage (from decreased platelet aggregation)
• renal and hepatic impairment.
• “REBOUND Effect”
• Long-term use of NSAIDs as an adjunctive treatment for
periodontitis has never really developed beyond research studies.
• In summary, NSAIDs (including the selective cyclooxygenase-2
(COX-2) specific inhibitors) are presently not indicated as
adjunctive HMTs in the treatment of Periodontal disease.

23. Lipoxins (LXs):
• Endogenous modulators of inflammation
• LXs are a class of both structurally and functionally
unique eicasonoids involved in counter-regulation of
inflammatory responses.
• These lipid mediators also appear to facilitate the
resolution of the acute inflammatory response. 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

24. • 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).
• Collectively, data have shown that lipoxins are
capable of preventing gingival inflammation and
bone loss in animal experimental periodontitis.

25. Bisphosphonates
• bone-seeking agents that inhibit bone resorption
by disrupting osteoclast activity
• precise mechanism of action is unclear
• research has shown that bisphosphonates
interfere with osteoblast metabolism and
secretion of lysosomal enzymes.
• bisphosphonates also possess anticollagenase
properties.
• modulate osteoclast activity

26. • Side effects
– inhibiting bone calcification
– inducing changes in white blood cell counts
– have been recent reports of avascular necrosis of the
jaws following bisphosphonate therapy, with the
resultant risk of bone necrosis following dental
extractions
• At present there are no bisphosphonate drugs that
are approved and indicated for treatment of PD
disease.

27. Subantimicrobial-Dose
Doxycycline
• 20-mg dose of doxycycline hyclate (Periostat) approved and indicated as an adjunct to SRP in the
treatment of chronic periodontitis.
• 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
• At present, SDD is the only HMT specifically indicated
for the treatment of chronic periodontitis that is approved
by the (FDA) and (ADA)

28. • SDD is used as an adjunct to SRP and must not be used
as a stand--alone therapy (monotherapy).
• The tetracyclines have been used locally and
systemically as antimicrobial agents and, more recently,
systemically as a host modulation agent (Periostat).
• As an adjunct to mechanical therapies, the goal of
tetracycline therapy has been to enhance reattachment or
even to stimulate new attachment of the supporting
apparatus and osseous formation.

29. Action….
Modulation of different pro-inflammatory pathways by
Doxycycline

30. Indications……
• in the management of Chronic Periodontitis and
Aggressive Periodontitis.
• SDD can be used in patients with aggressive
periodontitis who are being treated nonsurgically.
• Emerging studies have supported efficacy of SDD as an
adjunct to periodontal surgery (Gapski et al 2004).
• 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.

31. Contraindications……..
• any patient with a history of allergy or hypersensitivity to
tetracyclines.
• It should not be given to pregnant or lactating women
• children less than 12 years old - because potential for
discoloration of the developing dentition
• Doxycycline may reduce the efficacy of OCPs, and therefore
alternative forms of birth control should be discussed.
• There is a risk if 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
subantimicrobial dose.

32. Side Effects…..
• Doxycycline at antibiotic doses (≥100mg) is associated
with adverse effects
• photosensitivity,
• hyper-sensitivity reactions,
• nausea,
• vomiting,
• esophageal irritation.

33. Various Studies…..
• Studies using SDD therapy adjunctive to routine scaling and
prophylaxis indicated continued reductions in the excessive
levels of collagenase in the GCF after 1 month of treatment.
• After cessation of SDD administration, however, there was
a rapid rebound of collagenase activity to placebo levels,
suggesting that a 1-month treatment regimen with this host
modulation agent was insufficient to produce a long-term
benefit. (Ashley RA 1999)
• In contrast, during the same study, a 3-month regimen
produced a prolonged drug effect without a rebound in
collagenase levels to baseline during the no-treatment phase
of the study.

34. • Golub et al. 1997 showed that a 2-month regimen of SDD
significantly decreased both the level of bone-type collagen
breakdown products and MMP-8 and MMP-13 enzyme levels
(neutrophil and bone-type collagenase) in chronic periodontitis
subjects
• The clinical relevance of such findings confirms the utility of an
MMP inhibitor in the management of chronic periodontitis.
• More recent phase IV clinical studies have revealed success using
SDD in particular populations of susceptible individuals.

35. Prescription with Periodontal
Treatment
• SDD is indicated as an adjunct to mechanical periodontal therapy
and should not be used as a stand-alone 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.
• After initial periodontal treatment, the patient is enrolled into
an intensive periodontal maintenance program

36. Combinations…..
• Combining with Periodontal Surgery
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.
Combining with local Delivery Systems
Preliminary results from a 6-month, 180-patient clinical trial
designed to evaluate the safety and efficacy of SDD combined with
a locally applied antimicrobial (Atridox) and SRP versus SRP alone
demonstrated that patients receiving the combination of treatments
experienced more than a 2-mm improvement in mean attachment
gains and probing depth reductions compared with SRP alone.

37. 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.

38. • 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).

39. • To prevent an uncontrolled inflammatory response
with rapid tissue destruction, the activities of IL-1
&TNF-α are naturally counteracted by the
production of cytokines- IL-4,10,11
• IL-11- has shown to inhibit the production of
IL-1β, TNF-α, IL-12 & NO in a no of
inflammatory conditions.

40. Modulation of 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).

41. • 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 NOS with mercaptoalkylguanidines was
associated with decreased inflammation, haemorrhagic
shock and arthritis scores (Zingarelli et al. 1997, Brahn
et al. 1998, Cuzzocrea et al. 1998).

42. Locally administered Agents
Topical NSAIDs –
• Have shown benefit in the treatment of periodontitis
• Ketorolac mouth rinse has reported that GCF levels of PGEs were
reduced by approx half over 6 months
• Not approved as local HMTs for management of periodontitis.
Enamel Matrix Proteins, Growth Factors, and Bone Morphogenetic
Proteins
– Enamel Matrix Proteins (Emdogain) - approved by the FDA for adjunctive use
during surgery
– Bone Morphogenetic Proteins (BMP-2, BMP-7),

43. – Growth factors (platelet-derived growth factor, insulin-like
growth factor)
• 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,PDL, and
Cementum, restoring the complete periodontal
attachment apparatus.
• The only local HM agent approved by FDA for adjuntive
use is Emdogain

44. Tetracyclines
Tetracyclines are known to inhibit collagenases, but not all,
matrix metalloproteinases or MMPs from a variety of cells:
Neutrophils,
Macrophages,
Osteoblasts,
Chondrocytes, and
A wide range of tissues: skin, gingiva, cornea, cartilage, and
rheumatoid synovium.

45. • Tetracyclines inhibit PMN but not fibroblast
collagenase
• It has been suggested that PMN’s provide the major
source of collagenase that mediates tissue breakdown
during inflammatory periodontal disease,
• Fibroblasts contribute the collagenase required for CT
remodeling in normal gingiva.
• Therapy with these drugs would be expected to reduce
pathologically elevated collagenolytic activity (e.g.,
during inflammation), but not the collagen turnover
required to maintain normal tissue integrity.

46. Chemically Modified Tetracyclines
(CMT’s)
• To identify the site of the anticollagenase property, Golub and coworkers 1991, synthesized 10 different analogs of tetracyclines
known as chemically-modified tetracyclines (CMTs 1-10).
• The proposed mechanism of action of CMT’s results from their
ability to bind metal ions, particularly Ca2+ and Zn2+, which are
required by enzymes to maintain its proper conformation and
hydrolytic activity.
• Inhibition of active or pro-MMP could occur due to chelation of
Zn2+ ions
resulting in disruption of normal conformation
of protein structure
•

47. TC effects on pro- collagenase activation:
PMN’s
Osteoblasts
Secretes
Procollagenase
Activated
ROS e.g. HOCL
by neutrophils
Collagenase
Inhibits 40 – 80%
CMT-1 100-400 µm

48. SUMMARY
• The concept of periodontal medicine is emerging, in which the
dentist treats not only the bacterial challenge (e.g., by SRP) but
also the host side of the host-bacterial interactions.
• The use of HMTs such as SDD offers the opportunity to improve
the treatment outcomes that can be anticipated following SRP
alone.
• Patients must be encouraged and motivated so that they become
an active participant in the management of their condition.
• HMT’s are an emerging treatment concept in the management
of periodontitis.

49. • . In the future a range of HMTs targeting different aspects of the
destructive cascade of breakdown events in the PD tissues are
likely to be developed as adjunctive treatments for periodontitis.
• The further dev 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.

50. REFERENCES
• Carranza’s Clinical Periodontology 10th Edition
• Host response modulation in the management of
periodontal disease. J Clin Periodontol 2005; 32(suppl 6):108-129
• Modulation of the host inflammatory mediators as a treatment
strategy for periodontal diseases. Periodontology 2000, vol
24,2000,239-52
• Host modulation in periodontal therapy. Annuals periodontol 1998,
vol 3:108-120
• Annuals Periodontol 2003, vol 8, no.1
• Adjunctive benefits of SDD in the management of generalized
chronic periodontitis. J Periodontol 2002;73:762-769
• Subgingival delivery of therapeutic agents in the treatment of
periodontal diseases. Crit Rev Oral biol Med 8(2):164-174(1997)