Post Graduate Department Of Periodontics &
Host Modulation Therapy
• Host:- defined as the “the organism from which a parasite obtains
its nourishment” or in the transplantation of the tissue,’ the
individual who receives graft.
• Modulation is defined as “ alteration of function or status of
something in response to a stimulus or an altered chemical or
• Concept of host modulation was 1st introduced by Williams (1990)
and Golub et al (1992)
• Periodontists previously believed that p. disease was an
consequence of aging and uniformly distributed.
• Thought that severity was directly correlated with plaque
• Disease progression occurred in a continuous, linear manner
• Better epidemiologic data, there has been shift about prevalence and
progression of periodontitis
• Well established that periodontitis is not related to aging
• Disease severity is not correlated with plaque
pts with abundant plaque and calculus deposits with widespread gingivitis
but have minimal deep pockets,
In contrast ; despite maintaining high standard of plaque control , succumb to
aggressive forms of periodontitis with deep pockets , tooth mobility and
early tooth lost,
the former group of patients is periodontal disease resistant,
Whereas the latter is periodontal disease susceptible.
• This host response to the bacterial challenge presented by subgingival
plaque is the important determinant of disease severity.
• Although plaque bacteria are capable of causing direct damage to the
periodontal tissues(antigens, lipopolysaccharide (LPS), and other
virulence factors stimulates like H2S, butyric acid, other enzymes ).
• majority of the destructive events occurring in the periodontal
tissues result from activation of destructive processes that occur as
part of the host immune-inflammatory response to plaque bacteria.
– Host response is essentially protective bt paradoxically can also
result in tissue damage : breakdown of connective tissue fibers in
the periodontal ligament and resorption of alveolar bone.
• The nature of host response to the presence of plaque is modified by
genetic factors( seen in aggressive periodontitis) and systemic and
environmental factors( smoking , diabetes, stress).
to modify or reduce destructive aspects of host response: so
that immune-inflammatory response to plaque is less
damaging; host modulation therapies has been developed;
– Treatment concept that aims to reduce tissue
destruction and stabilize or even regenerate the
periodontium by modifying or downregulating
destructive aspects of host response and upregulating
protective or regenerative responses.(CARRANZA)
• HMTs are systemically or locally delivered pharmaceuticals that are
prescribed as part of periodontal therapy and are used as adjuncts to
conventional periodontal treatments.
• Historically , treatment has focused on reducing the bacterial
challenge by the use of SRP, improved oral hygiene, and periodontal
– However , the outcomes ( chronic disease) are not always predictable
• Periodontal disease and health can be seen as balance between
Persisting bacterial burden and proinflammatory destructive events
in the tissue.
• Removal of plaque by SRP targets one aspect by reducing bacterial burden
• Antigenic challenge that drives the inflammatory response in the host tissue.
• Bacterial challenge is never completely eliminated after SRP and recolonization
HMTs offers the potential for downregulating destructive aspects
and upregulating protective aspects of host response,
• In combination with conventional treatments to reduce the bacterial
burden, the balance between health ( resolution of inflammation and
wound healing) and disease progression ( continued proinflammatory
events) is tipped in the direction of healing.
• Poor oral hygiene Normal Exogenous infection
Pathogenic flora Antibody response
Pocketing and bone loss Gingivitis
Inflammation & tissue destruction Bacterial penetration
mediation Monocyte lymphocyte axis Systemic exposure
The host monocyte-lymphocytic axis is stimulated,
local release of inflammatory mediators such as arachidonic acid
metabolites and cytokines.
intern directly cause the local tissue destruction,
as periodontal pocketing and
alveolar bone loss in patients.
In addition, local environmental conditions secondary to these
inflammatory and destructive events (such as low oxygen
tension and iron availability) continue to support a pathogenic
flora and perpetuate the cycle of events proposed.
• HMTs offer the opportunity for modulating or reducing this
destruction by treating aspects of the chronic inflammatory
• HMTs do not “switch off” normal defense mechanism or
inflammation; instead, they ameliorate excessive of
pathologically elevated inflammatory processes to enhance
opportunities for wound healing.
• Specific aspects of disease pathogenesis for modulation
a) Regulation of immune and inflammatory responses.
b) Regulation of excessive production of matrixmetalloproteinase’s
c) Regulation of arachidonic acid metabolites
d) Regulation of bone metabolism.
• NSAIDs inhibit the formation of prostaglandins, including
prostaglandin E2 (PGE2) (Grenier et al 2002).
– Produced by neutrophils, macrophages, fibroblasts, and gingival epithelial cells in
response to lipopolysaccaride(LPS).
• Upregulates bone resorption by osteoclasts;(Heasman PA and Collins j
• Levels of PGE2 are elevated in pts with periodontitis ( Plamondon and
sorsa jp 2002)
• It also inhibits fibroblasts function and has inhibitory effects on the
immune response (Grossi and Genco Ann Periodontics 1997).
Nonsteroidal antiinflammatory drugs
• Inhibits prostaglandins
• Reduce inflammation
– Used to treat pain, acute inflammation, and chronic inflammatory
– Inhibits osteoclastic activity in periodontitis (Howell TH in oral bio med
• NSAIDs such as indomethacin(williams RC jp 1987), flurbiprofen
(jeffcoat MK JP 1989), and naproxen(Howell TH 1993) administered
daily for up to 3 years, significantly slowed the rate of alveolar bone
loss compared with placebo.
Disadvantages when used as a HMT for periodontitis.
• Administration for extended periods is necessary for periodontal
benefits to become apparent, and are associated with significant
– gastrointestinal problems,
– hemorrhage (from decreased platelet aggregation),
– and renal and hepatic impairment.
• research shows that the periodontal benefits of taking long-term
NSAIDs are lost when patients stop taking the drugs, with a return
to or even an acceleration of the rate of bone loss seen before
NSAID therapy, often referred to as a “rebound effect.”[ (William
RC j dent res 1991)
selective cyclooxygenase-2 (COX-2) inhibitors offers as
adjunctive treatments in the management of periodontitis.
• cyclooxygenase, which converts arachidonic acid to
prostaglandins, exists in two functionally distinct isoforms,
COX-1 and COX-2.
• COX-1 has antithrombogenic and cytoprotective functions.
• inhibition of COX-1 by nonselective NSAIDs causes side effects
– gastrointestinal ulceration
– and impaired hemostasis.
– use of selective COX-2 inhibitors reduce periodontal inflammation
without the side effects typically observed after long-term
(nonselective) NSAID therapy.
– selective COX-2 inhibitors slowed alveolar bone loss in animal
models(Bezerra MM jp 1993) and modified prostaglandin
production in human periodontal tissues
(Vardar S JPeriodontol 2003). However, the selective COX-2
inhibitors were later identified to be associated with significant and
life-threatening adverse effects, resulting in some drugs being
withdrawn from the market.
NSAIDs (including the selective COX-2 specific
inhibitors) are presently not indicated as adjunctive
HMTs in the treatment of periodontal disease
tissues play a role
blocking of the
et al (1973)
Nyman et al
Dybvig et al
et al (1987)
periods up to three
in rate of
bone loss, major
Author Purpose Host M
Parameters Subjects Results
isolated from a.a
PGE2 and IL-
Mouse PGE2 and IL-1
weber hp et
To study the effects of
and plaque formation
Beagle dogs Significantly inhibit
the development of
Szeto B et al
To evaluate the
effect on bone
Aspirin (asp) or
Radiographs Humans Percentage bone loss
for the entire
dentition was lower
S, Odle BM
et al (1989)
(co) during the
Flurbiprofen Crevicular fluid
levels of PGE2
prevented rise in
TXB2, but did
affect increase in
PA, et al
flurbiprofen (50mg) on
of PGE2, TXB2
Human control gingival
• The bisphosphonates are bone-seeking agents . inhibit bone
resorption by disrupting osteoclast activity.
• interfere with osteoclastic metabolism and secretion of lysosomal
enzymes (Weinreb M et al J Periodontal 1994) possess
anticollagenase properties (Nakaya H et al J Periodontol 2000)
• treatment with the bisphosphonate significantly increased bone
density compared with placebo ( Reddy MS et al J
• In human studies, these agents resulted in enhanced alveolar bone
status and density (Rocha M et al J Periodontol 2001)
• The ability of bisphosphonates to modulate osteoclast activity clearly
may be useful in the treatment of periodontitis,
• Some bisphosphonates have the unwanted effects
– inhibiting bone calcification
– inducing changes in white blood cell counts.
– avascular necrosis of the jaws following bisphosphonate therapy, with the
resultant risk of bone necrosis following dental extractions (Carter G, Goss AN
Med J Aust 2005)
• Bisphosphonate-related osteonecrosis of the jaw, although primarily
associated with intravenous administration of bisphosphonates rather
than oral administration,
• has impeded the development of bisphosphonates as an HMT to
• As with NSAIDs, at present there are no bisphosphonate drugs that
are approved and indicated for treatment of periodontal diseases
Author Purpose Host
Risendronate Bone mineral
Rats. In preventing bone
M young H ,
P ark JY et al
(2 001 )
evaluate the clinic
in auto genous
free bone grafts
Rats Clinical application of
decreasing resorption of
Durate P M ,
Gurgel B C D
e t a l
(2 0 0 5
around titan ium
rats . Alendronate may prevent
negative influence of
estrogen deficiency on
bone healing around
humans improves the
clinical outcome of
therapy and may be
adjunctive treatment to
» Sub-Antimicrobial-Dose Doxycycline
• Sub-antimicrobial-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.
• therapeutic effect by enzyme, cytokine, and osteoclast
inhibition rather than by any antibiotic effect.
Sub-antimicrobial dose doxycycline
• studies have found no detectable antimicrobial effect on the
oral flora or the bacterial flora in other regions of the body.
• At present SDD (Periostat) is the only systemically
administered HMT specifically indicated for the treatment of
chronic periodontitis that is approved by the US Food and
Drug Administration (FDA) and accepted by the American
Dental Association (ADA).
• In addition, a modified-release SDD was recently approved by the
FDA (Oracea) for the treatment of the common skin disorder rosacea
and is routinely prescribed within the dermatology community.
• Studies conducted by Preshaw et al in J Periodontol 2008 utilizing
this same modified-release SDD versus placebo with periodontitis as
an adjunct to SRP resulted in significantly greater clinical benefits
than SRP alone in the treatment of periodontitis.
• There has also been considerable off-label use of this new modified-
release SDD for the treatment of periodontal diseases based on the
understanding that once-a-day administration can increase the level
of compliance as compared to twice-a-day oral administration.
• Tetracycline's work well as host modulation agents because of their
pleiotropic effects on multiple components of the host response . The only
enzyme (MMP) inhibitors that have been approved for clinical use and
tested for the treatment of periodontitis .
• Golub et al (J Periodont Res 1985). reported that the semisynthetic
compound (e.g., doxycycline) was more effective than the parent
compound tetracycline in reducing excessive collagenase activity in the
GCF of chronic periodontitis patients.
Mechanisms of Action
• doxycycline was found to be a more effective inhibitor of
collagenase than either minocycline or
tetracycline (Burns FR 1989) and
• because of its safety profile, pharmacokinetic properties, and
ready systemic absorption. to eliminate the side effects of
long-term tetracycline therapy, especially the emergence of
tetracycline-resistant organisms, SDD capsules were prepared
and tested( Golub LM1985)
• Each capsule contained 20 mg of doxycycline versus the commercially
available 50 mg and 100 mg, antimicrobially effective, capsules or
• clinical studies using sub-antimicrobial doses of doxycycline have
shown no difference in the composition or resistance level of the oral
flora (Thomas J; jp 2000)
• no appreciable differences in either fecal or vaginal microflora
( Walker C; J Clin Periodontol 2005)
• no overgrowth of opportunistic pathogens, such as Candida, in the oral
cavity, gastrointestinal system, or genitourinary system.
• doxycycline ( other members of the tetracycline
family) has the ability to downregulate MMPs,
• a family of zinc-dependent enzymes that are capable of
degrading extracellular matrix molecules, including
collagen (Birkedal-Hansen H J Periodontol 1993
• MMPs are secreted by fibroblasts, keratinocytes,
macrophages, PMNs, endothelial cells and play a key role in
• Excessive MMPs are released in inflamed periodontal
tissues, resulting in breakdown of the connective tissue
• The predominant MMPs in periodontitis, particularly MMP-8 and
MMP-9, derive from PMNs (Golub LM et al J Clin Periodontol 1995) and
are extremely effective in degrading type I collagen, the most abundant
collagen type in gingiva and periodontal ligament (Mariotti A Periodontol
• Levels of PMN-type MMPs have been shown to increase with severity
of periodontal disease and decrease after therapy (Golub LM, Ciancio et al
J Periodontal Res 1990)
• The rationale for using SDD as a 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
Golub et al 1985 reported that a 2-week regimen of SDD reduced
collagenase in GCF and in the adjacent gingival tissues surgically excised
for therapeutic purposes.
He found using SDD therapy adjunctive to routine scaling and
prophylaxis cause 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 , 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.
these reductions in collagenase levels were gains in the relative attachment
levels in the SDD group( Ashley RA 1999)
history of allergy or hypersensitivity to tetracyclines.
pregnant or lactating women or children less than 12 years old (because
of the potential for discoloration of the developing dentition).
reduce the efficacy of oral contraceptive.
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 using the sub-antimicrobial dose.
Doxycycline at antibiotic doses (≥100 mg) is associated with adverse
photosensitivity, hypersensitivity reactions, nausea, vomiting, and
SDD (20-mg dose), it was reported that the drug was well tolerated,
and the profile of unwanted effects was virtually identical in the SDD
and placebo groups (Caton JG JP2000; Novak MJ J
• Combining with Periodontal Surgery or Local Delivery
• SDD was used as an adjunct to flap surgery revealed better
probing depth reductions in surgically treated sites greater than
6 mm compared with surgically treated sites in patients given
placebo (Gapski R J Periodontol 1999)
• 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 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
– local delivery systems deliver antimicrobial concentrations of an antibacterial
agent directly into the site of the pocket, whereas SDD is a systemic host
• (SRP + local antibiotics) can be combined with HMT (SDD) to
maximize the clinical benefit for patients (Novak MJ J
Author Purpose Host
Parameters Subjects Results
check for potency
of low dose
CAL, PD and GCF
Collagenase activity and
Human LDD inhibits tissue
destruction in the
Long term LDD could be
useful adjunct to
Golub LM, Lee
HM et al (1997)
inhibitor of matrix
P’s) administered to
human , can reduce
bone type collagen
Human Reduction of excessive
MMP activity with
in collagen degradation
Golub LM ,
T F et al
(2 001 )
(SDD) as an
adjunctive therapy in
Doxycycline Clinical attachment level
Human s significant potential as
an oral adjunctive
the long term
of adult periodontitis
Novak M J ,
Dawson D R , e t
a l 2 0 0 8
combination of systemically
therapy & locally
antimicrobialtherapy , as
adjuncts to scaling and root
significantly improved clinical
benefits in the treatment of
untreated moderate to severe
(CAL) ,(BOP), and
role in disrupting
• Nonsteroidal Antiinflammatory Drugs
– Topical NSAIDs have shown benefit in the treatment of periodontitis.
– chronic periodontitis who received topical ketorolac mouthrinse reported
that gingival crevicular fluid (GCF) levels of PGE2 were reduced by
approximately half over 6 months and that bone loss was halted
( Jeffcoat MK et al:. J Periodontol 1995..
– topically administered NSAIDs have not been approved as local HMTs for
the management of periodontitis.
Locally Administered Agents
– Enamel Matrix Proteins, Growth Factors, and Bone
local HMTs used 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
– bone morphogenetic proteins (BMP-2, BMP-7),
– growth factors (platelet-derived growth factor,
– Insulin like growth factor.
– and tetracyclines.
• The locally applied HMTs currently approved by the FDA for
adjunctive use during surgery are
– enamel matrix proteins (Emdogain),
– recombinant human platelet-derived growth factor-BB
– and BMP-2 (INFUSE).
• The initial local host modulatory agent approved by the FDA
for adjunctive use during surgery to assist with clinical
attachment gain and wound healing was Emdogain;
• this has been followed by platelet-derived growth factor
combined with a resorbable synthetic bone matrix (GEM
21S) to assist in regenerative procedures , wound healing,
particularly in patients with diabetes
• rhBMP-2 (INFUSE) soaked on to an absorbable collagen
sponge to assist with ridge and sinus augmentation and
healing of fractures by the orthopedic community.
• NO synthase inhibitors:-
• Lietao et al (2005) reported that nitric oxide synthase (NOS) inhibitors
have protective effects against bone resorption and inflammatory process
in periodontitis in rats.
• Lappin et al. in 2000 reported that inducible NOS (iNOS) is responsible
for nitric oxide (NO) production by epithelial and inflammatory cells in
response to proinflammatory cytokines in some inflammatory diseases
such as rheumatoid arthritis and periodontal disease.
Newer Agents for Host Modulation
Although NO has an antimicrobial protective activity, its
elevated concentration in the tissues has a cytotoxic effect
toward the host cells.
Leitao et al. in 2005 found a reduction of alveolar bone loss and
gingival inflammation after the use of a selective iNOS inhibitor
– mercaptoethylguanidine – confirming that NO has a
deleterious role in the pathophysiology of periodontitis and that
its modulation may prevent tissue destruction.
– Recombinant human interleukin-11
According to Trepicchion et al 1995, IL-11 was shown to have anti-
inflammatory effects by inhibition of TNF-α and other
Leng et al. in 1995 observed that it indirectly minimizes tissue injury
through stimulation of tissue inhibitor of metalloproteinase-1 (TIMP-
Martuscelli et al. in 2000 investigated the ability of recombinant
human IL-11 (rhIL-11) to reduce periodontal disease progression.
– Significant reduction in the rate of clinical attachment and radiographic
bone loss were observed after an 8-week period of rhIL-11 administration
twice a week (Elias JA. J Immunol. 1997)
• Omega-3 fatty acid
• Vardar et al. in 2005 evaluated the use of omega-3 fatty acids for
blocking arachidonic acid cascade in induced periodontal disease
• results in the inhibition of production of not only prostaglandins
derived from the COX pathway but also leukotrienes derived
from the lipooxygenase pathway. The combined use of omega-
3 fatty acid with celecoxib, acts as synergism for anti-
• Therapy resulted in significant superior reductions on
periodontal tissue levels of prostaglandins, leukotriene B4, and
• Disruption of Cell Signaling Pathway
• preventing cell activation seek to inhibit the intracellular transduction of
signals produced when ligands bind to their membrane receptors.
• Inhibition of signal transduction pathways abolish both cell activation by
cytokines or other stimuli and the production of proinflammatory
• Cytokines and bacterial components activate many signal transduction
– include the mitogen-activated protein kinase (MAPK) pathway,
– phosphatidylinositol-3 protein kinase (PI3) pathway,
– janus kinase-signal transducer and activator of transcription (Jak-STAT),
– and nuclear factor kappa B (NF-kB) .
• Therapeutic strategies have been directed toward many of these
major signaling pathways, notably MAPK and NF-kB, which are
• MAPK inhibitors
• Inhibit LPS-induced MMP, cytokine (IL-1b, TNF-α, IL-6, IL-8), and
prostaglandin expression.( Lee JC, Immunopharmacology. 2000)
• NF-kB family inhibitors
• Inhibit NF-kB–dependent expression (IL-1, TNF-α, IL-6, IL-8),
MMPs, and others (Kimura A1998)
• Disruption of the
• The RANKL/RANK interaction is responsible for differentiation and
maturation of osteoclast precursor cells to activate osteoclasts.
• Osteoprotegerin acts as a decoy receptor, expressed by osteoblastic
cells, which binds to RANKL and inhibits osteoclast development
(Kong YY 1999) Several studies have shown the opposite effect of
RANKL and osteoprotegerin in bone modulation.
• Periodontal pathogens and destructive host responses are
involved in the initiation and progression of periodontitis.
• Therefore the successful long-term management require a
treatment strategy that address both etiologic components.
• Evidence for the role of MMPs, cytokines, and other mediators
in the pathogenesis of periodontal disease distinguishes them as
viable targets for a chemotherapeutic approach.
• adjunctive therapies such as host modulation to enhance the
efficacy of existing mechanical procedures contributes
favorably to an integrated approach for the long-term,
clinical management of periodontitis.
• HMTs are an emerging treatment concept in the
management of periodontitis.
• The use of HMT as an adjunct may be particularly useful in
susceptible, high-risk patients in whom a prolonged and excessive
host response occurs to presence of bacteria ,promotes the
activity of MMPs and osteoclasts.
• SDD is the only systemically administered HMT currently
approved and indicated as an adjunct to SRP for treating
periodontitis. Clinical trials have demonstrated a clear treatment
benefit when using SDD versus SRP alone.
• 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
• 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 and surgery.
• the use of HMT to better manage chronic periodontal disease have
applications to other chronic systemic diseases such as arthritis,
diabetes, osteoporosis, and cardiovascular disease.
• In addition, studies utilizing locally applied antimicrobials as part
of an intensive periodontal therapy (IPT) regimen have shown very
promising results both in periodontal disease and overall health
status of high risk patients..
• The proper management of local infection and inflammation
(periodontitis) will have a significant impact on general overall
health of the population.