2. Contents
• Introduction
• Basic concepts of host modulation
• Definition
• Historical Background
• Pathogenesis of Periodontal Disease
• Components of Periodontal Pathogenesis
• Rationale
• Indication for HMT
• Classification of HMT agents
• Locally used HMT agents
• Conclusion
• References
3. OLD SCHOOL OF THOUGHT
• Periodontal disease is a consequence of aging
• Severity was directly related to plaque.
• Disease progression occurred in linear
continuous manner.
NEW SCHOOL OF THOUGHT
• Periodontitis is not related to aging
• severity is not related to plaque
• Patients with severe plaque and
calculus- shallow
pockets(Periodontal disease
resistant patients)
• Patients with good oral hygiene-
deep periodontal
pocket(Periodontal disease
susceptible patients)
4. ANT
INTRODUCTION
PERIODONTITIS is associated with subgingival bacterial colonization and biofilm formation.
host releases inflammatory mediators
host response causes hard and soft tissue destruction.
• Described as double edge sword and represents the dominant natural factors responsible for
control of bacterial challenges and tissue destruction.
• Page stated that periodontal destruction - connective tissue degrading factors like- MMP’s and
inflammatory mediators( cytokines and prostaglandins)
HEALTH
ANT
PRO INFLAMMATORY
MEDIATORS
ANTI
INFLAMMATORY
MEDIATORS
DISEASE
ANT
ANT
ANTI
INFLAMMATORY
MEDIATORS
PRO INFLAMMATORY
MEDIATORS
The purpose of host modulation therapy is to
restore this balance
5. • HMT is targeted at the host response.
• As the result of host bacterial interaction there is the release of pro inflammatory mediators which cause
tissue destruction.
• Use of various therapeutic agents can downregulate or inibit production, activation or biological function of
the pro inflammatory mediators.
• This is the basic mechanism of action of host modulation therapy.
BASIC CONCEPT OF HOST MODULATION THERAPY(HMT)
6. DEFINITION
is an organism from which the
parasite derives its nutrtion or
in transplantation an individual
who receives the graft.
HOST MODULATION
alteration of the the function or
status of something in response
to a stimulus or an altered
chemical or physical
environment
HMT
regulating the destructive aspects of
host response so that deleterious
effects of various inflammatory
mediators on the tissue are reduced
7. DEFINITION- by CARRANZA
Treatment concept that aims to reduce tissue
destruction and stabilise or even regenerate
the periodontium by modifying or down
regulating the destructive aspects of host
response and up regulating protective or
regenerative responses.
8.
9. HISTORICAL
BACKGROUND
• Golub and William are considered the pioneers in the field of HMT in periodontics.
• While working on the diabetic rats which has excessive collagenase activity, they observed
improvement in gingival health after administration of tetracycline.
• The investigators concluded - improvement was mostly because of tetracycline inhibition of host
derived enzyme collagenases.
• Collagenase is one of the MMPs that mediate connective tissue breakdown and plays important role in
the pathogenesis of periodontal disease.
• This founded the basis for host modulation therepy.
10. PATHOGENESIS OF
PERIODONTAL DISEASE
• Periodontal disease have a well defined bacterial etiology.
• OTHER FACTORS INCLUDE-
GENETICS
ENVIRONMENTAL FACTOR
ACQUIRED RISK FACTORS
13. 1. INFLAMMATORY MEDIATORS AND INHIBITORS
• Initial host responses to bacterial infections include activation and recruitment of neutrophils and macrophages.
• Constituents of the biofilm also stimulate host cells to produce proinflammatory cytokines including IL- 1 BETA and TNF-
ALPHA, which can induce connective tissue and alveolar bone destruction.
• The catabolic activities of these cytokines are controlled by endogenous inhibitors - IL-1 and TNF receptor antagonists.
• When administered for therapeutic purposes, these antagonists can reduce inflammation.
• Cytokines implicated in suppression of the destructive inflammatory response include IL-4, IL-10, IL- 11, and TGF-BETA
IL-4 -also induces-
apoptosis, which reduces the number of infiltrating inflammatory macrophages.
Upregulate the production of IL-1 receptor antagonists.
IL-4 is deficient in diseased periodontal tissues and
IL-4 administration in experimental arthritis reduces inflammation
Suggest that use of this cytokine may provide a therapeutic benefit in the treatment of periodontal diseases.
14. 2. Production of Matrix Metalloproteinases
• The matrix metalloproteinases (MMPs) are a family of zinc- and calcium-dependent endopeptidases secreted or
released by a variety of infiltrating cells (i.e., neutrophils and macrophages) and resident cells (i.e., fibroblast,
epithelial, osteoblast, and osteoclast).
• Host cells stimulated directly or indirectly by components of the plaque biofilm secrete MMPs which result in-
Connective tissue destruction and Alveolar bone resorption.
• It is the Endogenous MMPs are primarily responsible for tissue destruction and not bacterial proteinases adds further
rationale for the investigation of host modulatory approaches in periodontal therapy.
• MMP 8,( collagenase) MMP 9(gelatinase), MMP-13 (collagenase-3) is believed to be a mediator of bone resorption and cartilage
destruction and has been identified in GCF from chronic periodontitis patients.
• Endogenous or natural inhibitors of MMP activity include -
tissue inhibitors of MMP (TIMP)
alpha 2-macroglobulin.
15. 3. Production of Archidonic Acid Metabolites
• Another pathway involved in periodontal disease pathogenesis involves the synthesis and release of prostaglandins and other
arachidonic acid metabolites within periodontal tissues.
• AA can be metabolized via the cyclooxygenase (CO) or lipoxygenase (LO) pathways.
• Two isoforms of cyclooxygenase are now recognized.
Cyclooxygenase 1 (COX-1) - continuously expressed and is important for physiologic functions including gastric cytoprotection.
Cyclooxgenase 2 (COX-2) - inducible, upregulated by proinflammatory cytokines, and thought to be involved in inflammation
.
The discovery that NSAIDs block the enzyme CO and reduce prostaglandin synthesis led to in vitro studies evaluating
NSAIDs as inhibitors of bone resorption.
16. RATIONALE FOR HOST MODULATION THERAPY
Rationale to host modulation therapy includes-
restoring the balance of pro inflammatory and anti inflammatory mediators
as an adjunct treatment option
to decrease patient susceptibility
to facilitate regeneration
18. CLASSIFICATION OF HOST MODULATORY AGENTS
1. Modulation of AA metabolites.
Nonsteroidal anti-inflammatory drugs (NSAIDs), Triclosan.
2. Modulation of MMPs.
Tissue inhibitor metalloproteinases (TIMPs), Tetracyclines.
3. Modulation of bone remodeling.
Bisphosphonates.
4. Modulation of host cell receptors:
Blockade of receptors for IL-1, tumor necrosis factor (TNF), and advanced glycation end products (AGEs).
5. Modulation of nitric oxide synthase (NOS) activity
Mercaptoethylguanide.
19. 1. Modulation of AA metabolites.
A. NSAIDS
as been extensively increased in gingival tissues and in the gingival crevice fluid, which correlates with inflammation and
20. Action of Nsaids
• Inhibits prostaglandins
• reduces inflammation
Used to treat Pain, acute and chronic inflammatory conditions
Inhibits the osteoclast activity in periodontitis
21. • NSAIDs like flurbiprofen, indomethacin, and naproxen-inhibit gingivitis and progression of periodontitis.
• Studies have shown that systemic NSAIDS when administered daily for upto 3 years significantly reduced the rate
of alveolar bone loss compared with placebo.
• However, adverse effects associated with prolonged systemic administration of nonselective NSAIDs that possess both
(COX-1 and COX-2 inhibitory activity include -
gastrointestinal upset and
hemorrhage,
renal and
hepatic impairment.
• Moreover studies have indicated that periodontal benefits of taking long term NSAIDS are lost when patient stop
taking these drugs followed by accelerated bone loss as compared to before referred as “REBOUND EFFECT”
22. • Therefore NSAIDS are not included in the treatment regimen of HMT
• Selective NSAIDs called coxibs (COX-2 inhibitors, nimesulide) have been developed that causes significantly fewer
serious gastrointestinal adverse events.
• To overcome these adverse effects, topical administration of NSAIDs has been studied. Lipophilic nature of these
drugs facilitated their absorption into gingival tissues.
• NSAIDs that have been evaluated for topical administration include ketorolac tromethamine rinse and S-
ketoprofen dentifrice.
23. B. Triclosan
It has both an antibacterial and anti-inflammatory property.
It inhibits COX and lipoxygenase, and thus may interfere with the production of AA metabolites.
Use of a dentifrice containing sodium fluoride (0.243%) and triclosan (0.3%) reduced the frequency of deep
periodontal pockets and the number of sites exhibiting attachment and bone loss in patients deemed highly susceptible
to periodontitis.
24. 2.Modulation of MMPs.
• These proteinases are involved in a number of physiological events such as -
embryonic development,
tissue remodeling, and
tooth eruption, in addition to various
pathological processes such as
periodontal disease,
arthritis,
cancer,
diabetes, and
osteoporosis.
• Inflammatory mediators such as IL-1, TNF-α, and PGE2 have been shown to upregulate MMP production in several in vitro
models.
• Subantimicrobial dose doxycycline (SDD) remains, at present, the only systemic host response modulator specifically
25. It is a 20-mg dose of doxycycline hyclate (PERIOSTAT) that is taken -
• twice daily for periods of 3-9 months as an adjunct to root surface instrumentation in the treatment of periodontitis.
• This dose does not exhibit antimicrobial effects, but can effectively lower MMP , cytokine and osteoclast level.
• This reduced dose has been referred to as Subantimicrobial dose doxycycline (SDD).
Studies show that a combination therapy of HMT (SDD) plus a locally delivered doxycycline hyclate gel and SRP provided
optimal improvement in clinical parameters when compared to SRP alone in treatment of moderate to severe periodontitis.
SDD have been used in conjunction with SRP as well as with both resective and regenerative surgical procedures.
Tetracyclines have been used to treat chronic periodontitis as well as aggressive periodontitis. It is also used to enhance
reattachment and stimulate new attachment.
27. CLINICAL RESEARCH DATA ON DISTINCT
PATIENT POPULATION
• Tetracyclines work well on multiple components of host response.
• Golub et al reported that doxycycline was more effective than tetracycline in reducing excessive collagenase activity.
• With regard to MMP, Golub et al reported 2 week regimen of SDD reduced collagenase in GCF and the adjacent gingival
tissues.
• 3 month regimen produced prolonged drug effect without a rebound in collagenase level in no treatment phase.
28. GENERAL PATIENT POPULATION STUDY
• Golub showed in 2 month regimen of SDD there is significant decrease of collagen breakdown and MMP 8 and MMP 13
enzyme level in chronic periodontitis.
• In Phase III trial when SDD administration was discontinued after 9 months of continuous therapy, improvements
demonstrated in SDD group were maintained for atleast 3 months.
• Meta analysis showed that SDD used as an adjunct to SRP revealed benefits when using SDD in smokers with periodontitis.
29. SPECIAL PATIENT POPULATION
• Genotype of periodontitis susceptible individuals are known as Periodontitis associated genotype(PAG)
• When PAG patients received SDD and results monitored at 2 and 4 months, a significant decrease in the IL 1 beta and
MMP 9 levels were noted after treatment with SDD.
• Because of the beneficial effects OF HMT , SDD are used in other susceptible populations like diabetes, osteoporosis etc.
Studies demonstrated that SDD reduce systemic inflammatory biomarkers in CVD patients and glycosylated haemoglobin
in patients taking hypoglycemic drugs.
30. CONSIDERATIONS OF SDD
Contraindicated in-
Allergy or hypersensitivity to tetracyclines
Pregnant or lactating women
Children younger than 12 years as results in discolouration of teeth.
Patient type
Treatable periodontal conditions
• Not used in gingivitis and periodontal abscess
• used in aggressive periodontitis to be treated non surgically
At antibiotic dose(>!00 mg) doxycycline causes
Photosensitivity
hypersensitivity reactions
nausea, vomiting
esophageal irritation
Side effects Prescription with periodontal treatment
• never used as monotherepy
• prescribed with the first round of SRP for 3 months upto
maximum of 9-24 months
SDD used as an adjunct in access flap revealed better probing than surgically treated sites given placebo.
SRP+local antibiotics + HMT maximizes the clinical benefits.
31. 3. Modulation of bone remodeling.
• Bisphosphonates are widely utilized in the management of systemic metabolic bone disease due to their ability to inhibit
bone resorption and anticollagenase property.
• They Increase osteoblastic differentiation and inhibit osteoclast activity, there exists a possible use for bisphosphonates
in the diagnosis and management of periodontal diseases.
• Bisphosphonates bind to the hydroxyapatite crystals of bone and prevent both their growth and dissolution.
• Bisphosphonate determined by its unique side chain- classified into generations-
Generation of bisphosphonates
First-generation bisphosphonates -Alkyl side chains (e.g., etidronate)
Second-generation bisphosphonates - aminobisphosphonates with an amino-terminal
group (e.g., alendronate and pamidronate).
Third-generation bisphosphonates have cyclic side chains (e.g., risedronate).
The antiresorptive properties of bisphosphonates increase approximately 10-fold between drug generations.
32. Mechanism of Action
• The effect of bisphosphonates is through the suppression of the interactions
between the receptor activator of nuclear factor kappa B (RANK) and its
ligand (RANKL) as well as osteoprotegerin.
• It has also been shown that the bisphosphonate alendronate caused
downregulation of bone resorption
• Limitations -on prolonged use it may lead to inhibition of bone mineralization
and subsequent osteomalacia, change in white blood cell counts, and
osteonecrosis of jaw (ONJ).
Currently they are still under investigation and may be soon available for
treatment of periodontitis.
33. 4. Modulation of host cell receptors:
IL and TNF have a variety of biological activities that cause tissue damage in chronic inflammation, like in
periodontitis.
Waykole et al., in 2009 have demonstrated cytokine therapy which aimed at antagonizing the proinflammatory
cytokines through following mechanisms:
Cytokine receptor antagonist
Binds to the receptor present on the target cell and prevents the cytokine
from binding to the target cell.
Eg:- IL-1 receptor antagonist (IL-1ra) which is commercially available as
Kineret.
Anticytokine antibodies:
Some of the anticytokine antibodies currently available are:
Anti TNF-α antibody: Adalimumab, cetrolizumab, golimumab, etc.
Anti IL-6 antibody: Tocilizumab
Anti IL-12 and IL-23 antibody: Ustekinumab
Anti IL-15 antibody: AMG714
Anti IL-17 antibody: AIN457
Soluble cytokine receptors:
Binds to the cytokines in solution and prevents signaling.
For example, sIL-1R, sTNF- R, and sIL-6R are the soluble receptors
against IL-1β, TNF-α, and IL-6, respectively.
34. • NO is a short-lived molecule implicated in a wide range of biological processes ranging from immune homeostasis
to cancer.
• NO is a highly reactive free radical reacting with metal and thiol residues leading to-
lipid peroxidation,
protein, and deoxyribonucleic acid (DNA) damages and
stimulation of cytokine release.
Mercaptoalkylguanidines
Pharmacological use of mercaptoalkylguanidines was associated with decreased inflammation, hemorrhagic shock,
and arthritis scores.
They -
1. Inhibit COX
An exaggerated production of NO has been implicated in the pathophysiology of several inflammatory
processes such as arthritis, colitis, and ileitis
35. Other Locally Administered Host Modulatory Agents
A number of local host modulatory agents like enamel matrix derivatives (EMDs), growth factors, and bone morphogenic
proteins have been investigated for potential use as adjuncts to surgical therapy.
The only local host modulatory agent approved by FDA for adjunctive use during
surgery is Emdogain.
36. a)Enamel matrix proteins
• During development of root and attachment apparatus, there is a secretory phase in which Hertwig’s
epithelial root sheaths secretes enamel-related matrix proteins.
• Commercially available for the treatment of periodontal defects is Emdogain® (Biora AB, Malmö,
Sweden) which has received FDA approval.
• The rationale behind using Emdogain is that it will act as a tissue-healing modulator that would mimic
the events that occur during root development and help stimulate periodontal regeneration.
• Enamel matrix proteins (EMD) initiates periodontal regeneration through recruitment of
cementoblasts to the root-surface.
• The above mentioned actions of EMD justify its role as a host modulating agent.
37. b)Bone morphogenetic protein
• Bone morphogenetic protein (BMP) guides modulation and differentiation of mesenchymal
cells into bone and bone marrow cells.
• Absorbable collagen sponge (ACS) containing recombinant human BMP-2 - used in alveolar
ridge augmentation.
• These ACS release the protein over time in the location where it is implanted and provides a
scaffold on which new bone can grow. As the graft site heals, the ACS is absorbed and
replaced by bone.
38. c) Platelet derived growth factor
• Platelet derived growth factor (PDGF), as a host modulating agent -
increase chemotaxis of neutrophils and monocytes,
stimulate fibroblasts proliferation and
extracellular matrix synthesis,
increase proliferation and differentiation of endothelial cells,
stimulate proliferation of mesenchymal progenitor cells and differentiation of fibroblasts.
Nevins et al. (2005) demonstrated that the purified rhPDGF‐mixed with bone allograft results in
robust periodontal regeneration in both Class II furcations and interproximal intrabony defects.
39. Clinical Relevence of Hostmodulating Agents
• Conventional SRP alone and SRP with periodontal surgical techniques, although effective for improving clinical
parameters such as probing depths, may not be sufficient to reduce excessive levels of many underlying destructive
mediators, particularly in more susceptible patients (systemic diseases, smokers, etc.).
• Adjunctive use of host modulatory agent will result in downregulation of various biological mediators of inflammation
and better clinical outcome.
• Studies have also shown role of host modulation therapy in successful implant treatment with less bone loss around
implant noted after 6 months.
40. CONCLUSION
• Periodontal pathogens and destructive host response are responsible for periodontitis.
• Therefore successful strategy involves long term treatment that address both the etiologic agents.
• HMT enhances the efficacy of existing mechanical procedures and contribute to the long term management of
periodontitis.
• Thus HMTs are emerging concepts in periodontitis.
41. References
1. Michael G. Newman; Henry Takei; Perry R. Klokkevold; Fermin A. Carranza (14 February 2011). Carranza's
Clinical Periodontology. Elsevier Health Sciences. pp. 814–817
2. Research, Science, and Therapy Committee. Informational Paper: Modulation of the Host Response in
Periodontal Therapy. Journal of periodontology. 2002 Apr 1;73(4):460-70.
3. Bhatt AK, Govila V, Sharma M. Host modulatory agents in periodontics: A step towards the future. Journal of the
International Clinical Dental Research Organization. 2015 Jul 1;7(2):130.
4. Minkle Gulati VA, Govila V, Jain N. Host modulation therapy: An indispensable part of perioceutics. Journal of
Indian Society of Periodontology. 2014 May;18(3):282.
5. Preshaw PM. Host modulation therapy with anti‐inflammatory agents. Periodontology 2000. 2018
Feb;76(1):131-49.