Host Modulation &

Host Modulation Therapy

Dr. Baljeet Singh

Director (P.G. Studies)
Professor & Head
Department of Periodontology
Bhojia Dental College & Hospital, Baddi (H.P.)
CHEMOTHERAPEAUTIC
AGENTS

2
• ANTIBIOTICS are substances produced by
micro-organisms which suppress the growth
of or kill other micro-organisms at very low
concentrations.

• ANTISEPTIC is a chemical antimicrobial

agent that can be applied topically to mucous
membranes, wounds or intact dermal surfaces
to destroy microorganisms and to inhibit their
reproduction or metabolism.

• DISINFECTANTS are antimicrobial agents

that are generally applied to inanimate
surfaces to destroy microorganisms.
CLASSIFICATION OF ANTIMICROBIAL DRUGS

Based on Different Criteria:

A. CHEMICAL STRUCTURE
B. MECHANISM OF ACTION
C. TYPE OF ORGANISMS AGAINST
WHICH PRIMARILY ACTIVE
D. SPECTRUM OF ACTIVITY
E. TYPE OF ACTION
A. CHEMICAL STRUCTURE

1. Sulfonamides and related drugs: Sulfadiazine

and others, Sulfones – Dapsone (DDS),
Paraaminosalicylic acid (PAS)
2. Diaminopyrimidines:Trimethoprim,
Pyrimethamine.
3. Quinolones: Nalidixicacid, Norfloxacin,
Ciprofloxacin etc.
4. β-Lactam antibiotics: Penicillins,
Cephalosporins, Monobactams,
Carbapenems.
5. Tetracyclines: Oxytetracycline, Doxycycline
etc.
6. Nitrobenzene derivative: Chloramphenicol.
7. Aminoglycosides: Streptomycin,
Gentamicin, Neomycin etc.
8. Macrolide antibiotics: Erythromycin,
Roxithromycin, Azithromycin, etc.
9. Polypeptide antibiotics: Polymyxin-B,
Colistin, Bacitracin, Tyrothricin.
10. Glycopeptides : Vancomycin, Teicoplanin.
11. Oxazolidinone: Linezolid
12. Nitrofuran derivatives: Nitrofurantoin,
Furazolidone.
13. Nitroimidazoles: Metronidazole, Tinidazole.
14. Nicotinic Acid Derivatives: Isoniazid,
Pyrazinamide, Ethionamide.
15. Polyene antibiotics: Nystatin,
Amphotericin-B, Hamycin.
16. Azole Derivatives: Miconazole,
Clotrimazole, Ketoconazole, Fluconazole.
17. Others: Rifampicin, Lincomycin,
Clindamycin, Spectinomycin, Sod. Fisidate,
Cycloserine, Viomycin, Ethambutol,
Thiacetazone, Clofazimine, Griseofulvin.
B. MECHANISM OF ACTION
1. Inhibit Cell Wall Syntesis: Penicillins,
Cephalosporins, Cycloserine, Vancomycin,
Bacitracin.
2. Cause Leakage from Cell Membranes:
Polypeptides-Polymixins, Colistin, Bacitracin,
Polyenes-Amphotericin B, Nystatin, Hamycin.
3. Inhibit Protein Synthesis: Tetracyclines,
Chloramphenicol, Erythromycin, Clindamycin,
Linezolid.
4. Cause Misreading of m-RNA Code and
affect Permeability: Aminoglycosides –
Streptomycin, Gentamycin.
5. Inhibit DNA Gyrase:
Fluoroquinolones-e.g. Ciprofloxacin.

6. Interfere with DNA

Synthesis:Idoxuridine, Acyclovir,
Zidovudine.

7. Interfere with Intermediary

Metabolism: Sulfonamides, Sulfones,
PAS, Trimethoprim, Pyrimethamine,
Ethambultol.
C. Type of Organism Against Which
Primarily Active
1. Antibacterial: Penicillins,
Aminoglycosides, Erythromycin, etc.
2. Antifungal: Griseofulvin, Amphotericin
B, Ketoconazole, etc.
3. Antiviral: Idoxuridine, Acyclovir,
Amantadine, Zidovudine, etc.
4. Antiprotozoal: Chloroquine,
Pyrimethamine, Metronidazole,
Diloxanide, etc.
5. Anthelmintic: Mebendazole, Pyrantel,
Niclosamide, Diethyl Carbamazipine.
D. Spectrum of Activity:
• Broad Spectrum
• Tetracyclines
• Chloramphenicol
• Narrow Spectrum:
• Penicillin G
• Streptomycin
• Erythromycin
E. TYPE OF ACTION

1. Primarily Bacteriostatic
Sulfonamides, Tetracyclines,
Chloramphenicol, Erythromycin,
Ethambutol

2. Primarily Bactericidal:
Penicillins, Aminoglycosides, Polypeptides,
Rifampicin, Cotrimazole, Cephalosporins,
Vancomycin, Nalidixic Acid, Ciprofloxacin.
 CHEMOTHERAPY
Term used for the “treatment of systemic
infections with specific drugs that selectively
suppress the infecting micro-organisms without
significantly affecting the host.”

Due to ANALOGY between MALIGNANT CELL

and PATHOGENIC MICROBES, treatment of
neoplastic diseases with drugs is also called
Chemotherapy.
Therefore a better definition of CHEMOTHERAPY
would be:

“Use of a specific chemical agent to arrest the

progress of, or eradicate, disease in the body
without causing ireversible injury to healthy
tissues.”
Initially the term “CHEMOTHERAPEUTIC AGENT”
was restricted to ----- SYNTHETIC COMPOUNDS.
Presently this criteria has become irrelevant
as both SYNTHETIC &
MICROBIOLOGICALLY produced drugs are
considered together as chemotherapeutic
agent.

It will be more MEANINGFUL to use the term

ANTIMICROBIAL AGENT (AMA) for
synthetic and naturally obtained drugs.
 CHEMOTHERAPY IN PERIODONTAL
DISEASE
Antimicrobial agents can be used as a part of treatment of
periodontal diseases, broadly in 2 ways:
TOPICALLY (i.e. Local Application)
&
SYSTEMICALLY
LOCAL :
Advantages – No Systemic Adverse Effects.
Diminished chances of bacterial resistance.

Disadvantages : Overall not as effective as systemic, partially

explained by some of the ecological concepts.
SYSTEMIC:

ADVANTAGES
• Simple, easy administration of the drug to multiple
sites of disease activity.

• May also eliminate or reduce pathogens colonizing

on oral mucosa and on other extra dental sites
including the tongue and tonsilar areas.
DISADVANTAGES
• Inability of systemic drugs to achieve high
gingival crevice fluid concentration.

• Increased risk of adverse drug reactions.

• Increased selection of multiple antibiotic

resistant microorganisms.

• Uncertain patient compliance.

 RATIONALE FOR USE OF ANTIBIOTICS IN
PERIODONTAL DISEASE

The academic argument over the importance of

specific bacterial etiology for periodontal disease
may never be totally resolved.
• Scaling and root planing leads to reduction in
levels & proportions of some periodontal
pathogens (red and orange complexes and an
increase in Actinomyces species)

• But it alone does not cause a sufficiently significant

change in the subgingival microbial composition of
deep periodontal pockets, longitudinally.
In certain forms of Periodontitis:
• There is rapid loss of attachment.
• Extremely virulent Gram –ve organisms that
populate deep pockets.
• Bacteria can actually invade the connective
tissue
(GILLETT & JOHNSON 1982; SAGILE et al.
1982)

Under these circumstances, antibiotics provide a

useful adjunct to root planing, which by itself
may not remove all subgingival deposits &
certainly would not affect any invading
organisms that had already penetrated soft
tissues.
• All the 6-12 species of microorganisms
mentioned earlier to be responsible for majority
of cases of Periodontitis, have been shown, in
vitro, to be sensitive to a number of different
antibiotics.

• Treatment of Periodontitis is an ecological

intervention so SRP alone may not be
sufficient.

• Periodontal disease is an infection that affects

the entire mouth, including shallow sites, saliva,
tongue and cheeks. Localised therapies
restricted to deep pockets.
 GUIDELINES FOR THE USE OF
ANTIBIOTICS IN PERIODONTAL THERAPY
1. History and Diagnosis of the condition.
2. Disease activity – continuing attachment
loss, purulent exudate, bleeding on probing.
3. Microbiologic analysis.
4. As an Adjunct Therapy – From meta-
analysis of RCTs and quasi-experimental
studies: Antibiotics improve attachment
levels when used as adjuncts rather than
as stand alone therapy.
INDICATIONS FOR ANTIBIOTICS IN
PERIODONTAL THERAPY
The use of systemic antibiotics as an adjunct to routine
treatment modalities may be justified in following
cases:
1. Moderate or advanced cases of Periodontal
Disease which do not respond to conventioal
mechanical therapy.
2. In the management of cases of Periodontitis with
rapid attachment loss and irresponsive to
mechanical therapy.
3. Patients with acute periodontal infections
associated with systemic manifestations e.g.
ANUG, Acute Periodontal Abscess, Multiple
Abscess formation & gross periodontal infection.
4. For prophylaxis in medically- compromised patients:
• Patients with heart disease e.g. Congenital Heart Disease,
Prosthetic valves, Previous infective endocarditis, valvular
heart disease, etc.
• Asplenic patient – splenectomy.
• Patients with impaired immune systems.
• Transplantation patients – receiving life long
immunosuppressive treatment.
• Haematologic patients – e.g. Leukemias, Neutropenia.
• HIV Infection.
• Diabetic Patient – Uncontrolled cases with acute infection.
• Patients with Joint prosthesis.

5. As an adjunct to surgical & non-surgical, Periodontal

Therapy.
• AMA should be administered only after
careful case selection, & should not be a
sustitute for the routine and time
honoured treatment regimens.
 WHICH ANTIBIOTICS?
• Limited data availabe to identify which antibiotics
are suitable for which infection.

• No one best choice of antibiotic at present.

(i.e. there is no silver bullet).

• From the evaluation of RCTs in Latin America

(2001-2012) the most promising drugs for the
treatment of periodontal diseases are
Metronidazole or the combination of Metronidazole
+ Amoxicillin (originally proposed by Winkelhoff et
al. for AAC)
• Better results with this combination probably is the result of
the drugs in increasing proportions of the beneficial
Actinomyces sp. And Streptococcus sanguinis. This is
added advantage over the reduction of red and orange
complexes
• The microbial end point
------ 32% (SRP alone)
-----60% (SRP + Metronidazole)
------71% (SRP + Metronidazole + Amoxicillin)
• When selecting the adjunctive use of antimicrobials, the
point to be considered is not only that how reduction in
periodontopathogens takes place, but also the residual
proportion of periodontopathogens (red complex) & an
increase in beneficial species like Actinomyces and S.
sanguis as microbiological endpoint of treatment.
• Good & sustained clinical effects from
tretament require a very rapid and massive
reduction of the total bacterial levels
especially of the strictly anaerobic pathogens
inorder to allow the best possible
recolonization with host-compatible species.

• Use of Azythromycin in Aggressive

periodontitis, smokers and mild/moderate
chronic periodontitis.
• Certain periodontal conditions e.g. refractory or
apical periodontitis and periodontal destruction in
immunocompromised patients have been
associated with superinfecting or non-oral
microorganisms that might not respond to standard
antimicrobial regime e.g. beta lactamase producing
Staph. aureus, enteric gram negative rods,
pseudomonas species and Candida albicans. For
them a combination of Metronidazole and
Ciprofloxacin has been suggested.
• The species of orange complex preceed the
colonization of the red complex pathogens.

• The proper response of the smokers to periodontal

therapy is related to the persistence of putative
pathogens from the orange complex and not from red
complex.

• Subjects with advanced and very advanced

periodontitis benefit significantly from adjunctive
antibiotics.
• Use of adjunctive antibiotics in mild to moderate
periodontitis cases, not justified – generalised
view.

• But studies have shown that adjunctive

Metronidazole + Amoxicillin in moderate
periodontitis yields important and constant benefit.
WHAT IS THE IDEAL DOSE AND DURATION?

• Before prescribing systemic antibiotics we must

consider DESIRABLE (e.g. Infection Control) V/S
UNDESIRABLE effects (e.g. side effects, microbial
resistance)

• Antibiotic protocols (dose and duration) used in

dentistry are extrapolations of those recommended
for medical infections.

• In Periodontal cases this may result in erroneous

prescriptions because of some unique features of
Periodontal Disease.
• There is lack of clear guidelines and a single
protocol.

• Recommended from short term preliminary

dates. Adjunctive use of Metronidazole
(200/250/400 mg) + Amoxicillin 500mg for
14 days.
WHICH PHASE OF MECHANICAL
TREATMENT SHOULD THE
ANTIBIOTIC BE PRESCRIBED?
Q1. Should the antibiotics be administered during
the active phase of therapy or on re-evaluation?

• A rapid and striking reduction in the subgingival

microbiota is required to get the most beneficial
recolonization of the recently scaled pockets.

• Since recolonization is partially achieved at 3

months post scaling and root planing there is
chance that the antibiotic given at this stage work
almost as a maintenance scaling.
• Intense inflammation before mechanical
treatment may favour prescription of systemic
antibiotics before SRP as higher amount of
antibiotics can be delivered to the subgingival
areas due to increase in levels of GCF and
higher permeability of the capillaries.

• Antibiotics given at the initial phase of

periodontal therapy are to suppress the
overgrowth of species e.g. proteolytic
pathogens, that could benefit from tissue
damage during SRP.
Q2. Should the antibiotics be administered at the 1st or the
last session of SRP?

• If SRP is done before the prescription of antibiotics then

the protective effect of the biofilm will be reduced.

• As of now no important short term differences are

observed whether antibiotics are prescribed at 1st or last
session of SRP.

• Preferably the antibiotics should be administered during

the initial phase of treatment and decision about whether
or not to prescribe antibiotics should not be postponed to
the re-evaluation phase.
 Chemoprophylaxis
ANTIBIOTICS
Treatment of Infection

• Clindamycin is useful in penetrating bone (serious side

effect is antibiotic colitis)
• The more inflamed the gingival tissues, the greater the
risk and magnitude of the bacteremia.
• Bacteremia arising from dental treatment, oral hygiene
practices, or even chewing are of low grade intensity (1 x
10..1 to 2 x 10*2 CFU/ml of blood) and of short duration
(30-60 seconds)
 FULL MOUTH DISINFECTION APPROACH:

• Scaling and root planing of all affected teeth within

48 hours.

• Subgingival irrigation with Chlorhexidine.

• Chlorhexidine rinsing for 14 days after subgingival

treatment.

• Protective Risk Factor (for further periodontal therapy)

• More than one site with P.D. ≥ 5mm post-treatment.
 CONTENTS
• INTRODUCTION • SUB ANTI-MICROBIAL
• MODELS OF DOSE DOXYCYCLINE
PERIODONTAL • MATRIX
PATHOGENESIS METALLOPROTEINASES
• HOST MODULATION • CHEMICALLY MODIFIED
• HOST MODULATION TETRACYCLINES
THERAPY • ANTI-CYTOKINE DRUGS
• RATIONALE • LOCALLY ADMINISTERED
• CLASSIFICATION AGENTS
• ANTI-INFLAMMATORY • SUMMARY AND
DRUGS CONCLUSION
• BISPHOSPHONATES • REFERENCES
• ACKNOWLEDGEMENTS
2
As is the case with any other disease, Periodontal disease is
also basically the end result of interaction between 3
Factors:

HOST BACTERIA
P. D.

ENVIORNMENT

e.g. Smoking,
medications, faulty dentistry etc.
46
 PAST ERA
• Understanding of the etiology and
pathogenesis of periodontal disease
focused on the “ MICROBIAL ASPECT”.

• P.D. was an inevitable consequence of

aging and was uniformly distributed in
the population.

• Disease severity directly correlated

with plaque levels.

47
Non Specific plaque Hypothesis to
Specific Plaque Hypothesis

Disease Progression Continous, Linear

Manner Through Out
Life

Therapeutic efforts Focused Mainly On

Mechanical Or Chemotherapeutic
Removal Of Bacterial Flora

48
 FACT

Two categories of patients

Periodontal disease Periodontal disease

resistant susceptible
Abundant Plaque, Calculus Good oral hygiene
Gingivitis, some shallow pockets Minimal plaque
No signs of deep pockets & Deep pockets,mobility
mobility, Aggressive Bone loss Early tooth loss

49
Why the difference ?

Why is the response

so different in the
individuals?
50
 PRESENT ERA
A PARADIGM SHIFT
• P.D. is not a natural consequence of
aging.

• P.D. not related with the plaque levels

as far as severity is concerned.

• Pathogenesis of P.D. focuses not only

on just microbial aspect but an
important role is being given to HOST
RESPONSE.
51
 HOST
RESPONSE

ROLE IN ROLE IN
PROTECTION DESTRUCTION

52
• Need to modify or Modulate Host
Response
• Development of Host Modulation
Therapies to:

• Improve therapeutic outcomes.

• Slow the progression of diseases
• Allow for more predictable
management of patients.

53
 Models of Periodontal
Pathogenesis
1. Linear Model (Mid 1960’s Loe et al.)
2. Basic Conceptual Model (CIRCA MODEL,
1981, IVANYI L., LEHNER).
3. Critical Pathway Model (OFFENBACHER,
1996)
4. Non-Linear Model (The 1997 revised
model of basic conceptual model – R.C.
PAGE, K.S. KORNMAN)
5. Multilevel Hierarchal Model
6. Biologic Systems Models

(Models of periodontal pathogenesis – Pushpa Latha et al,

IndianJournal of Dental advancements, Vol.08 (1).
54
55
56
 HOST MODULATION
HOST
• Organism from which a parasite derive
its nourishment
Or
• The individual who receives the graft
Or
• In relation with periodontal diseases, an
individual who harbors pathogens
associated with periodontal diseases.

57
 MODULATION
The alteration of function or status of
something in response to a stimulus or
an altered chemical or physical
environment.

In terms of Periodontal disease: Host

Modulation means altering the host
/host periodontal tissue’s reaction to
the bacterial challenge.

58
 HOST MODULATION
THERAPY (H.M.T.)
A treatment concept that aims to
reduce tissue destruction and
stabilize or even regenerate the
periodontium by modifying or
down regulating destructive
aspects of the host response and
upregulating protective or
regenerative responses.

Introduced in Dentistry by William

et al(1990) and Golub et al (1992) 59
HMT’s are systemically or locally
delivered pharmaceuticals that are
prescribed as part of periodontal
therapy and are used as adjuncts
to conventional periodontal
treatments, e.g. scaling & root
planing and surgery.
60
 BALANCE BETWEEN PERIODONTAL
HEALTH AND DISEASE
PERIODONTAL
DISEASE
PERSISTENT
MICROBIAL UPREGULATION OF
BURDEN DESTRUCTIVE
IMMUNE
INFLAMMATORY
RESPONSE

PERIODONTAL HEALTH
61
 DOWN REGULATION
OF DESTRUCTIVE
PROCESS
RESOLUTION OF
INFLAMMATION

PERIODONTAL DISEASE

62
 RATIONALE

• Historically, the treatment of periodontal disease

has focused on reducing microbial burden by
better oral hygiene, scaling, root planing (SRP)
and periodontal surgery.

• But in the context of present knowledge of

pathogenesis of periodontal disease, the
conventional treatment targets only one aspect
of the pathogenic process i.e. reducing bacterial
load and antigenic challenge.
63
• However, the bacterial challenge is never
completely eliminated after SRP &
microbial re-colonization occurs.

• Host response is responsible for most of

the tissue breakdown that occurs, leading
to the clinical signs of periodontitis.

• The HOST-SIDE of the Host Bacteria

interaction can be taken care by HMT.

64
• HMTs, offer the potential for down-
regulating destructive aspects and up-
regulating protective aspects of the host
response.

• HMTs do not “switch off ” normal defense

mechanisms or inflammation, rather they
try to down play the excessive or
pathologically elevated inflammatory
processes to enhance the opportunities
for wound healing and periodontal
stability.

65
 So Rationale of HMT are:
• To down regulate destructive & up
regulate protective aspects of host
response.
• To modulate periodontal tissue
response to bacterial challenge.
• To stabilize or regenerate periodontal
tissues as an adjunct treatment.
• To act as a risk reduction strategy.

66
 CLASSIFICATION
On the basis of the modes of action of HMTs :
1. Inhibition of Matrix metalloproteinases (MMPs):
Chemically Modified Tetracyclines (CMTs)
SDD
2. Inhibition of Arachidonic acid metabolites:
NSAIDs
COX – 1 inhibitors: Indomethacin, Naproxen,
Flurbiprofen
COX – 2 inhibitors: Rofecoxib
COX and LOX inhibitors: Triclosan, Topical
Ketoprofen
LOX inhibitors: Lipoxins 67
3. Modulation of bone metabolism:
Bisphosphonates
Hormone replacement therapy (HRT)
4. Regulation of immune and inflammatory
responses:
Suppressing proinflammatory cytokines (IL – 1
and TNF – α receptor antagonists).
Nitric Oxide inhibition.
Generation of protective antibodies through
vaccines.
Infusion/supplementary anti – inflammatory
cytokines IL – 4 and IL – 10.

68
 ANTI-INFLAMMATORY
DRUGS
• The development of all periodontal diseases is a
consequence of the inflammatory & immunological
reaction of the host to bacterial plaque.

• Any drug that has anti-inflammatory properties,

therefore, should be capable of modifying the host’s
reactions to the bacterial insult & so have clinical
effect upon the progression of disease.

69
PATHWAY OF ARACHIDONIC ACID METABOLISM

i.e. How PROSTAGLADINS are synthesized?

PHOSPHOLIPIDS (from cell membrane)

E.g. LPS

Phospholipase A2
(mechanical or chemical stimuli
activate this enzyme)

ARACHIDONIC ACID
(free arachidonic acid acts as the substrate for enzyme
cyclo-oxygenase)

FLURBIPROFEN Cyclo-oxygenase
Acts here
PGG2
70
 PGG2

PGH2

TxA2 PGE2 PGD2 PGF2 PGI2

(Thromboxane) (Prostaglandins) (Prostacyclin)

*Prostaglandins are synthesized from arachidonic acid by all

mammalian tissue cells except erythrocytes. 71
Prostaglandins were first discovered by VON EULER in
1939

PGE2 has been extensively studied in periodontal

disease and is considered as one of the most potent
prostaglandins that upregulates bone resorption by
Osteoclast.

PGE2 also inhibits fibroblast function and has inhibitory

and modulatory effects on the immune response.

72
 Enzyme cyclooxygenase, which converts the
arachidonic acid into PG’s exist in two isoforms:-

COX-1 (CONSTITUTIVE FORM)

-Has antithrombogenic & cytoprotective
functions
-Inhibition by NSAIDS has side effects

Cyclo-oxygenase like G.I. ulerceration & impaired

hemostasis.

COX-2 (INDUCIBLE FORM)

-COX-2 inhibitors results in reduction of
inflammation
-Selective COX-2 inhibitors are without
the side effects of Non-Selective COX
Inhibitors
73
 TYPES OF NSAIDS
I. NON SELECTIVE COX INHIBITORS:- (i.e. Traditional
NSAIDS) e.g. Salicylates, Propionic acid derivatives,
Indole derivatives, Oxicam derivatives etc.
II. PREFERENTIAL COX-2 INHIBITORS:- e.g. Nimesulide,
Meloxicam, Nabumetone etc.
III. SELECTIVE COX-2 INHIBITORS:- e.g. Colecoxib,
Etoricoxib, Parecoxib etc.

 Studies have shown that systemic NSAIDS like

Flurbiprofen (William R.C. et al 1989), Indomethacin
(William R.C. et al 1989), & Naproxen (Howell T.H. et al
1993), when administered for upto 3yrs, significantly
slowed the rate of alveolar bone loss.
74
 DISADVANTAGES
i. For clinically apparent periodontal benefit, NSAIDs
need to be administered daily for a long period –Can
cause G.I. problems, haemorrhage, renal and
hepatic impairment etc.

ii. REBOUND EFFECT- Periodontal benefits of taking

long term NSAIDS are lost when patient stop taking
the drugs, with a return to or even an acceleration of,
the rate of bone loss seen before NSAIDs therapy.

75
• Administration of Selective COX -2 inhibitors
results in reduction of periodontal inflammation
without the side effects observed after long term
Non- Selective NSAIDS.

• They also modify the PGs production and slow

alveolar bone loss.

• However, selective COX-2 inhibitors have been

identified to be associated with significant and
life threatening adverse effects because of
which these drugs have been withdrawn.

76
 INFERENCE

NSAIDs ,including the COX-2 inhibitors

are presently not indicated as
adjunctive HMT’s in the management
of periodontal disease.

77
 BISPHOSPHONATES
• Definition: These are non-biodegradable bone seeking
analogues of pyrophosphate that have a high affinity
for calcium phosphate crystals and that inhibit
osteoclast activity.

Modes of action of Bisphosphonates are mainly

osteoclast centric:
1. Inhibition of the development of osteoclasts.
2. Induction of osteoclastic apoptosis.
3. Reduction of activity of osteoclasts.
4.Prevention of the development of osteoclasts from hematopoietic
precursors .
5. Stimulation of production of an osteoclast inhibitory factor.
78
 Classification of
Bisphosonates
• First – generation bisphosphonates: Alkyl side
chains (e.g. etidronate) characterize

• Second – generation bisphosphonates: include

aminobiphosphonates with an amino – terminal
group (e.g. alendronate and pamidronate).

• Third – generation bisphosphonates: have cyclic

side chains (e.g. risedronate).

79
• Bisphosphonates are used in metabolic bone
disorders e.g. Tumour induced
hypercalcemia, osteoporosis, Paget’s
disease etc.

• Animal studies have revealed increased

bone density and decreased bone resorption
in cases of periodontitis when treated with
bisphosphonates.

• In humans, enhanced alveolar bone status

and density.

80
Unwanted effects with some Bisphosphonates:
• Inhibits bone calcification.

• Induces changes in W.B.C. counts.

• Avascular necrosis of jaws in some cases, with risk

of post extraction necrosis.

Presently not approved and indicated for the

treatment of periodontal disease.

81
 Sub Anti-Microbial Dose
Doxycycline (SDD)
Trade names: SDD-Periostat in US, Canada &
Europe. Modified release SDD, Oracea(US),
Apprilon(Canada), Efracea(Europe)

• Long term use of full standard dose of

doxycycline i.e. 100mg. can have ill effects on
the body, prominent being super infection and
renal.

• A 20mg dose of doxycycline (PERIOSTAT)

approved and indicated as an adjunct to SRP
82
in the treatment of chronic periodontitis.
Dosage Schedule: 20mg twice a day for 3months,
up to a maximum of 9 months, continuous dosing.

• Presently the only systemically administered

HMT for chronic periodontitis, approved by U.S.
FDA and accepted by ADA & U.K. Medicines and
Healthcare Products Regulatory Agency.

• A modified- release SDD(Oracea) has been

recently approved by FDA for the treatment of
common skin disorder rosacea.

• To be used as an adjunct to SRP and not as a

stand alone therapy (monotherapy).
83
Mechanism of Action
• In addition to its antibiotic properties,
doxycycline has the ability to
downregulate MMPs, especially MMP-8
& MMP-9 (zinc dependent enzymes).

• Reduces cytokine levels.

• Stimulates osteoblastic activity and

new bone formation.

84
85
 Doxycycline
• Doxycycline has been confirmed to be more effective
inhibitor of MMPs than either Minocycline or Tetracycline.

• Doxycycline has a much low inhibitory concentration

(IC50=15IM), than Minocycline (IC50 =190IM) and
Tetracycline (IC50 = 350IM) indicating that much lower
dose of Doxycycline is necessary to reduce a given
collagenase level by 50% compared with Minocycline or
Tetracycline. (Golub et al 1994).

• Doxycycline has been found to be more effective in

blocking neutrophil collagenase activity (MMP-8) than
fibroblast collagenase activity (MMP-1).
86
 Indications of S.D.D.
As an Adjunct in:

1. Chronic and Aggressive Periodontitis

2. Refractory Periodontitis, especially in
smokers
3. Periodontitis cases associated with risk
factors like smoking and Diabetes Mellitus.
4. Patients with Periodontitis Associated
Genotype (PAG)- They have specific variation
in genes that regulate IL-1.

87
Classification of MMPs

88
 Inhibitors of MMPs
A. Endogenous inhibitors
• TIMPS
• Alpha -2 Macroglobulins
B. Exogenous Inhibitors
• CMTs
• SDD

Tissue Inhibitors of Metalloproteinases (TIMPs): Are of four types:

TIMP-1, TIMP-2, TIMP-3, TIMP-4.
They regulate matrix degradation both by proteinase inhibition and
by blockage of autolytic MMP activation (Declerck 1991)

Alpha -2 Macroglobulins: A protein present in blood which is

antiprotease. An inhibitor of MMPs - 2,9.
89
 Functions of MMPs

• The main function of MMPs is to catalyze the

breakdown of proteins in cell plasma
membrane or within the extracellular matrix,
i.e. remodelling of the extracellular matrix.

• They also play an important role in tissue

remodelling in physiological or pathological
processes e.g. morphogenesis,
angiogenesis, tissue repair etc.

90
• In periodontal disease MMPs play key roles
in the degradation of extracellular matrix,
basement membrane and protective serpins
(an acronym for Serine Protease Inhibitor)
as well as in the modification of cytokine’s
action and activation of osteoclasts.

• The predominant MMPs in periodontitis are

MMP-8 and MMP-9 which are derived from
polymorphonuclear leukocytes and are
extremely effective in degrading type I
collagen.
91
Chemically Modified
Tetracyclines (CMTs)

These are chemically modified, non-

antibiotic tetracycline analogs in which
the tetracycline molecules have been
modified to remove all antibiotic
properties but which retain host
modulatory , anti- collagenolytic effects.

92
• They are potent inhibitors of pro-inflammatory
mediators which increases the level of anti-
inflammotory mediators -IL-10.
• A series of CMTs (CMT-1 to CMT-10) are actively
under trail.

• CMT-3 & CMT-8 have been shown to inhibit osteoclastic

bone resorption and promote bone formation.
• CMT-3 : Most potent collagenolytic CMT.
• CMT-1,3,6,7,8 : Effective inhibitors of bone resorption.
• CMT-2,4 : Block PMN collagenase.

93
 Structure of CMT
• Antimicrobial and anticollagenase properties of
Tetracycline reside in different parts of four ringed
(A, B, C, D) structure.

• Carbon -4 position side is responsible for the

antimicrobial property of tetracyclines.

• GOLUB et al (1987) altered this structure by removing

the DIMETHYLAMINO GROUP from the carbon -4
portion of the A- ring.

• This resulted in the development of Chemically

94
Modified Tetracyclines (CMTs).
Chemical Structure of
Tetracycline

95
 The Non-Antimicrobial
Actions of CMTs
• Inhibition of mammalian collagenase.

• Inhibition of neutrophil chemotaxis.

• Increased fibroblast attachment to the root surface.

• Anti-inflammatory effects due to the inhibition of

prostaglandin synthesis (high doses).

• Inhibition of bone resorption and enhancement of

collagen synthesis. 96
 ANTICYTOKINE DRUGS
• Cytokines are regulatory proteins that control
different functions of cells and also play an
important role in immune response of periodontal
diseases.

• Pro-inflammatory cytokines like IL- 1 Beta and TNF-

Alpha play an important role in the initiation,
regulation and perpetuation of innate response of
periodontal diseases.

• Cytokines functions as a network, share

overlapping features- BIOLOGICAL REDUNDANCY.
97
• ANTICYTOKINES DRUGS are drugs that
target pro-inflammatory cytokines like IL-1β
and TNF- α

• Presently under investigation for use of

Periodontal cases but is being used in
cases of Rheumatiod Arthritis.

98
Classification of Anticytokine
Drugs

99
 LOCALLY ADMINISTERED
AGENTS
• These are the host modulation agents that have
been used to improve the wound healing and to
stimulate periodontal attachment apparatus.

• Eg. Enamel matrix proteins (Emdogain), BMP’s (BMP-2,

BMP-7), growth factors (PDGF, insulin like growth factor.)
etc

• ADVANTAGES:
Easy and targeted application.
High drug concentration, locally.
Reduced systemic side effects, e.g-G.I. disturbance.
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 EMDOGAIN
• Emdogain (gel) is a resorbable, implantable, biomimetic
biology based product, mainly consisting of enamel matrix
proteins(Amelogenins), which promotes the regrowth of
hard and soft tissues lost due to periodontal disease.

• EMPs mainly AMELOGENIN, are secreted by Hertwigs

epithelial root sheath during tooth development and it
induces acellular cementum formation.

• Pure Amelogenin is hydrophobic, so a career with low pH

like PGA (Propylene Glycol Alginate) is added to the gel.

101
• Human Tissues have neutral pH, this
difference leads to adhesion of active
substance to the tooth surface.

• Emdogain is obtained from developing

porcine teeth.

• Available as a viscous gel, 90% of the

protein content of the gel is formed by
Amelogenins.

• Presently emdogain is one of the local

host modulation agents approved for
adjunctive use during surgery. 102
 Mechanisms of action-
EMDs
• Exact mechanism still not clear.
• Promotes PDL fibroblast proliferation
and growth and inhibits epithelial cell
proliferation and growth.
• Stimulates release of autocrine growth
factors from PDL undifferentiated
mesenchymal cells.
• Stimulates osteoprotegrin, thus
triggering osteoblasts and indirectly
inhibiting osteoclasts

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 GEM 21S
• GEM 21S – Highly purified recombinant human
platelet derived growth factor (rhPDGF-BB) with an
osteoconductive matrix(β-TCP).

• It stimulates wound healing and bone regeneration

when implanted in body by triggering a cascade of
molecular events.

• rhPDGF-BB is released from the β-TCP matrix into

the surrounding environment and it binds to specific
cell surface receptors on target cells.

• The intracellular events lead to mitogenesis of 104

osteoblasts,PDL, fibroblasts and cementoblasts.
 BONE MORPHOGENETIC
PROTEINS(BMPs)
• They are a group of signaling molecules that mainly belong to
the Transforming Growth Factor(TGF-β) super family of
proteins.
• They are important from early development (cell growth,
proliferation, differentiation and apoptosis), embryogenesis,
organ system development to maintaining adult tissue
homeostasis.

 BMP-1 - (a metalloproteinase) doesn’t belong to the TGF- β superfamily.

 BMP-2 –only BMP to specifically induce osteoblastic differentiation from
MSCs.
 BMP-2,4,6,7,9,14 – have significant osteogenic properties.
 BMP-7 – also known as HUMAN OSTEOGENIC PROTEIN-1 (O.P-1), has
potent osteogenic and angiogenic properties.

105
 INFUSE
• It is a product (bone graft) consisting of recombinant
BMP-2(rh BMP-2) protein, soaked in an absorbable
collagen sponge (ACS) which is made from a material
found in bone and tendons.

• The ACS releases the proteins over time, providing a

scaffold on which new bone grows. As the graft site
heals, ACS is resorbed and replaced by bone.

• Rh BMP: is produced by a technique where in human

BMP genes are transplanted into bacterial cells, which
are regulated to produce the protein product called- Rh
BMP.
106
INDICATIONS OF INFUSE
As a bone graft material in :

• Periodontal bone defects

• Sinus augmentation

• Localized ridge augmentation

• Defects associated with extraction

sockets

107
 OTHER LOCALLY
ADMINISTERED HMT’S
UNDER TRAIL
• NSAIDs
• Tetracyclines
• Triclosan
• IGF
• Nuclear factor Kappa B (NF-KB)
• Endothelial cell adhesion
molecules

108
NEWER HOST MODULATION
AGENTS UNDER TRIAL
• NO Synthase Inhibitor
• Rh IL-11
• Omega-3 fatty Acid derivatives
• Metformin
• Cemetidine
• Azythromycin
• Probiotics
• Aloe Vera
• Chemically Modified CURCUMIN
• Sirtuins & Resveratol
109
Specialized Pro-resolving Mediators(SPMs)

They are endogenous lipid derived mediators generated by

the host in response to pathogens to regulate resolution of
inflammation
• Anti inflammatory mediators
• Includes RESOLVINS, LIPOXINS, PROTECTINS &
MARESINS
• Resolvins, protectins & maresins are biosynthesized from
omega 3 fatty acids(e.g. Human milk, fish oil etc.)
• Lipoxins are synthesized from endogenous fatty acids i.e.
Arachidonic Acid.

110
• LIPOXINS: Inhibits PMN infiltration & stimulates non
phlogistic recruitment of macrophages.

• PROTECTINS: Anti inflammatory action

-Reduces cytokine expression
-Reduces neutrophil transmigration

• MARESINS: Produced by macrophages & they stimulate

clearance of neutrophils.

• RESOLVINS: Anti inflammatory & pro resolution mediator.

3 types: E-series, D-series, Aspirin triggered epimers
111
SUMMARY AND CONCLUSION
• Even though periodontal pathogens are considered
as the initiating and central factor for periodontal
diseases, the host response play an important role in
the progression and ultimately the destruction of
periodontal tissues.

• Hence, the successful and overall management of

periodontal disease need to address both the
aspects of the pathogenesis.

• Considering the role of MMPs, cytokines and other

mediators in the pathogenesis, it is reasonable to
target them by chemotherapeutic agents.
112
• Host modulation, an emerging treatment concept in
the management of periodontitis, can be included in
the integrated approach for the long term
management of periodontitis.

• HMT’s can be used as an ADJUNCT to the non-

surgical and surgical modes of treatment, not to be
used as MONOTHERAPY.

• As of now, the recommended Host modulation agents

to be used as adjuncts in the management of
periodontitis are SDD, Emdogain, GEM 21S and rh
BMP-2.

113
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• Philip m. Preshaw; host response modulation in
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• Antush mittal, v. Ranganath, ashish nichani; omega fatty acids
and resolution of inflammation: a new twist in an old tale:journal of
indian society of periodontology - vol 14, issue 1, jan-mar 2010,3-7
• Keith l. Kirkwood, joni a. Cirelli, jill e. Rogers & william v.
Giannobile; novel host response therapeutic approaches to treat
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• Fusanori nishimura, yoshihiro iwamoto & yoshihiko soga; the
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• Bing wang, et al. Topical Host Modulating therapy for
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 REFERENCES OF
CHEMOTHERAPEUTICS

• Feres M et al. Systemic antibiotics in the treatment of

periodontitis. Perio 2000, Vol. 67; 131-86.
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• Knofler GU et al. Microbiologic findings 1 year after partial-
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Full-Mouth Scaling and Root Planing of Chronic Periodontitis.
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 ACKNOWLEDGEMENTS
Department of Periodontology & Implantology
Bhojia Dental College & Hospital, Baddi (H.P.)
• Dr. Tarun Nanda
• Dr. Deept Jain
• Dr. Tanvi Ohri
• Dr. Kanika Aggarwal
• Dr. Abhinav Bhaskar
• Dr. Manisha
• Dr. Jaspreet
• Dr. Shikha
• Dr. Vikram
119
• Dr. Sarvani
 For any query, contact at
120
baljeet065_singh@yahoo.co.in