Latha G et al: Host modulation therapy www.jrmds.

in

Review Article

Host modulation therapy- An innovative paradigm in dentistry

Latha G1, Suchetha A1, Darshan B Mundinamane1, Apoorva SM1, Divya Bhatt1, Vinaya Shree MP1
1
Department of Periodontics, DAPMRV Dental College, Banglore, India

DOI: 10.5455/jrmds.2016412

ABSTRACT

Inflammation comprises a series of events that leads to a host response against trauma and microbial invasion,
resulting in liquefaction of surrounding tissues to prevent microbial metastasis, and eventually to healing of injured
tissue compartments. Thus, by definition, the host response involves not only the mechanisms of defence but also
processes of repair of damage that occurs by the direct effect of invaders or trauma or host systems. Periodontal
diseases are inflammatory processes in which microbial etiologic factors induce a series of host responses that
mediate an inflammatory cascade of events in an attempt to protect and heal the periodontal tissues. The adjunctive
use of host modulation therapy can enhance therapeutic responses, slow the progression of the disease, and allow
for more predictable management of patients, particularly in those patients at increased risk caused by factors
beyond the reach of conventional therapeutic approaches.

Key words: Host modulation, NSAIDs, Bisphosphonates, immune-inflammatory response, MMPs

INTRODUCTION This concept was developed in parallel to the

advances on the understanding of the immune
Periodontal disease is a chronic bacterial infection of response, and research on periodontal disease has
the periodontium affecting the tissues surrounding been emphasizing mechanisms of host-microbial
and supporting the teeth. Periodontal disease interactions to understand the disease process, as
progression is associated with subgingival bacterial well as for the development of novel therapeutic
colonization and biofilm formation resulting in strategies [2]. The importance of host-microbial
inflammation of soft tissues, degradation of collagen interactions is reinforced by epidemiological data
fibers, as well as resorption of the alveolar bone indicating different susceptibilities to periodontal
there by weakening the periodontium surrounding the disease among individuals, in spite of the long-term
teeth. Since the fundamental role of microorganisms presence of oral biofilm [3-5]. Other studies
in its etiology was systematically demonstrated some demonstrating increased susceptibility and greater
forty years ago, research efforts have long focused on severity of periodontal disease in individuals with
identifying the pathogenic microorganisms and their impaired immune response due to systemic
virulence factors [1]. To treat periodontal diseases as conditions also indicate the significance of the host
an infectious disease, numerous therapeutic response to the bacterial challenge [6].
strategies aimed at eradication of periodontal
pathogens have been studied over the years, Host can be “the organism from which a parasite
including local and systemic delivery of antimicrobial obtains its nourishment,” or in the transplantation of
and antibiotic agents. the tissue, “the individual who receives the graft.”
Modulation is “the alteration of function or status of
In the current paradigm of periodontal disease, something in response to a stimulus or an altered
specific periodontal pathogens are necessary for chemical or physical environment”. Host modulation
disease initiation. However, the extent and severity of therapy (HMT) is a treatment concept that aims to
tissue destruction are largely dependent on the nature reduce tissue destruction and stabilize or even
of the host-microbial interactions. These interactions regenerate the periodontium by modifying or down
are dynamic, since both the microbial composition of regulating destructive aspects of the host response
the dental biofilm and the competency of host immune and up regulating protective or regenerative
responses can vary, in the same individual, over time. responses [7].

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Latha G et al: Host modulation therapy www.jrmds.in

HISTORICAL ASPECT bacterial components, environmental factors, and

host–genetic variations associated with disease.
By the 1930s, it was generally believed that all Level A depicts the biologic mechanisms involved in
bacteria on the teeth could cause periodontal disease immunoinflammatory responses and in bone and
and that the amount of bacteria accumulated was connective tissue metabolism, and level B depicts the
directly related to the incidence and severity of observable clinical parameters and biomarkers. In
disease. In 1973 Socransky and his collegues found level B, the products produced by different microbial
that sites of advanced bone loss harbored an complexes are represented by arrays. These products
anaerobic microaerophilic Gram-negative flora that activate the immunoinflammatory mechanisms, which
was totally different from the primarily facultative subsequently influence the behavior of bone and
Gram-positive organisms found at adjacent healthy connective tissue metabolism.
sites. In 1976, Page and Schroeder summarized the
pathogenesis of periodontitis with regard to the major Fig.1: Biologic systems model
histopathologic events that occurred from health to
advanced disease with the description of four lesions:
the initial lesion, the early lesion, the established
lesion, and the advanced lesion. [8] These important
findings lead to the birth of the concept of Host
Modulation which aimed to control the destructive
aspects of the host response in periodontal disease
without compromising the host immunity. HMT was
first introduced to dentistry by Ray C Williams and
Lorne Golub (1990).

PATHOGENESIS OF PERIODONTITIS

Various models of disease, has been putforth to

describe the etiopathogenesis of periodontal disease
which includes,
Fig. 2: Potential target for host modulation
Linear model depicting the principal etiologic role for
bacteria in the initiation and progression of
periodontal disease [9].

Circa model emphasizing a central role for the host

immunoinflammatory response in the clinical
development and progression of periodontal disease
[10].

In 1997, non-linear model demonstrating various

factors contributing to the pathogenesis of
periodontitis based on pathways and processes
known at the time. The model implied that there were
a range of host responses and a range of clinical
expressions of disease that were primarily determined
In the past, therapeutic efforts were focused on the
by genetic and environmental factors that modified
mechanical or chemotherapeutic removal of bacterial
the host response. Each combination of genetic
flora. It has been recognized that genetic (IL-1
variations and environmental factors may define a
composite phenotype), environmental (smoking) and
specific gene expression pattern [10].
acquired (diabetes) risk factors can increase a
patient‟s susceptibility to developing periodontitis. For
Biologic systems model (Kornman KS 2008).
such individuals, extreme bacterial control or host
(Figure-1)
modulation along with bacterial control seem to be an
A biologic systems model (Figure-1) representing the
appropriate strategy.
pathogenesis of periodontitis may be defined by the

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Latha G et al: Host modulation therapy www.jrmds.in

“There are compelling data from studies in animals INHIBITION OF ARACHIDONIC ACID
and humans indicating that pharmacologic agents that METABOLITE: THROUGH NSAIDS
modulate host response may be efficacious in slowing
down the progression of periodontitis” (Williams RC, Von Euler (1939) first described a characteristic
1990) [11]. vasoactive fatty acids from human seminal vesicle
fluid capable of decreasing blood pressure in rabbits
HOST MODULATION THERAPY (HMT) and was named „„prostaglandin‟‟ because it was
assumed to originate from the prostate gland.
Periodontal therapy basically constitutes the non
surgical and surgical therapeutic procedures. One of the pathway involved in periodontal disease
Changing paradigm in clinical research lead to the pathogenesis is the synthesis and release of
newer treatment approach of host modulation prostaglandins and other arachidonic acid (AA or
therapy. HMT is a treatment concept that aims to ARA) metabolites within periodontal tissues. AA can
reduce tissue destruction and stabilize or even be metabolized via the cycloxygenase (CO) or
regenerate the periodontium by modifying or down lipoxygenase (LO) pathways [15].
regulating destructive aspects of the host response
and upregulating protective or regenerative response. Nonsteroidal anti-inflammatory drugs inhibit the
These are systemically or locally delivered formation of prostaglandins, including prostaglandin
pharmaceuticals that are prescribed as part of E2, which is produced by a variety of resident and
periodontal therapy and used as adjuncts to infiltrating cell types in the periodontium in response
conventional periodontal therapy. to lipopolysaccharide. Various NSAIDs which are
under research for HMT are indomethacin,
Rationale of HMT is treating the host side of the host- flurbiprofen, naproxen, sulindac, meloxicam,
bacterial interaction. The purpose of host modulation ketoprofen and ibuprofen.
therapy is to restore the balance of proinflammatory
or destructive mediators and anti-inflammatory or Daily administration for extended periods of time
protective mediators to that seen in healthy (years rather than months) is necessary for
individuals [12]. periodontal benefits to become apparent. Prolonged
NSAIDs intake leading to the suppression of renal
Manipulation of the immune response to suppress prostaglandin synthesis may result in increased
unwanted reactions is desirable in conditions such as sodium retention, reduced renal blood flow and
autoimmunity, allergy, or graft rejection. It is also eventually renal failure, damage to the gastrointestinal
required in the case of infectious disease to stimulate tract, Hemorrhage, may affect cardiovascular risks
the protective processes. Strategies to achieve these through various mechanisms and has rebound effect.
goals are collectively referred to as modulation of host While our understanding of the role of COX-2 in the
response and provide a novel concept in treatment. pathogenesis of periodontitis suggests that inhibition
Compared to other modes of treatment against of COX-2 might be a desirable target for therapeutic
infection, host response modulation potentially has intervention, serious adverse effects of current
fewer side-effects, is not invasive, and does not formulations preclude their use as an adjunct to
require complicated application methods [13, 14]. periodontal therapy [16].

Various methods of HMT have been developed to ANTI- PROTEINASE BLOCKING OF MATRIX
block or modify the pathways of periodontitis, as METALLOPROTEINASES (MMP’S)
follows,
 Inhibition of arachidonic acid metabolite: NSAIDs Matrix Metallo Proteinases (MMPs) belong to a group
 Inhibition of matrix metalloproteinase (MMPs): of Zn dependent and calcium requiring
Tetracyclines endopeptidases, which play a central role in many
 Modulation of bone metabolism: biological processes like embryogenesis, normal
Bisphosphonates tissue remodeling, wound healing, and angiogenesis,
 Regulation of immune and inflammatory and in diseases such as atheroma, arthritis, cancer,
response: IL1 and TNF-α receptor antagonist, and tissue ulceration [17].
NO2 inhibition, vaccination, Infusion/
supplementary anti-inflammatory cytokines Tissue inhibitors of metalloproteinases (TIMPs) are
important controlling factors in the actions of matrix

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Latha G et al: Host modulation therapy www.jrmds.in

metalloproteinases, and tissue destruction in disease chemically modified tetracycline and Sub antimicrobial
processes often correlates with an imbalance of dose doxycycline with their merits and demerits in
matrix metalloproteinases over tissue inhibitors of clinical application.
metalloproteinases. They are of two types:
1. Endogenous inhibitors examples are TIMPs CHEMICALLY MODIFIED TETRACYCLINE’S
and α-2 Macroglobulin: TIMP‟s probably
control MMP activities pericellularly whereas Presently, it is accepted that destruction of supporting
α2-macroglobulin functions in body fluids. periodontal tissues is primarily related to host derived
During inflammation, however, α2- enzymes, cytokines and inflammatory mediators. This
macroglobulin escapes the vasculature and has led to increased interest in the development of
also functions in the extracellular matrix. agents. Chemically modified tetracycline‟s (CMTs) are
2. Exogenous: (synthetic inhibitors) one such group of drugs which have been viewed as
Exogenous inhibitors include zinc and potential host modulating agents. Currently ten CMTs
calcium chelating agents, phosphorous are available but their clinical application is under
containing peptides, sulfur based inhibitors, research.
hydroxamic acid inhibitors.
Sub antimicrobial dose of tetracycline (SDD)
Tetracycline is a broad spectrum antimicrobial agent
which, apart from their antimicrobial activity also Doxycycline tends to be highly concentrated in GCF
exhibit anticollagenase activity by inhibiting matrix at levels 5-10 times greater than serum and show
metalloproteinase‟s. It is one of the effective agents substantivity as they bind to the tooth structure and
used in host modulation therapy. In addition to its are slowly released as still active agents. To avoid
antimicrobial activity, this group of compounds has antibiotic resistance a low dose of 20 mg twice daily
the capability of inhibiting the activities of neutrophils, was introduced, which was shown, after 2 weeks, to
osteoclasts, and matrix metalloproteinases, thereby inhibit collagenase activity by 60–80% in the gingival
working as an anti-inflammatory agent that inhibits tissues and crevicular fluid of patients with chronic
bone destruction. periodontitis [19, 20]. SDD is currently the only FDA
approved systemically administered HMT indicated
Fig. 3: Mechanisms of tetracycline in prevention of specifically in the treatment of periodontitis. It was
connective tissue breakdown previously called LDD and is currently marketed as
Periostat.

BISPHOSPHONATES(BPS)

Bisphosphonates were introduced in 1990 for the

treatment of osteoporosis and osteolytic tumors. They
are second group of drugs under investigation for
their ability to modulate the bone loss and prevent
bone resorption. They are primarily used to treat
hypercalcemia, Paget‟s disease and osteoporosis.
These drugs are non-biodegradable analogs of
pyrophosphate that have a high affinity for calcium
phosphate crystals and inhibit osteoclast activity [21].
BPs are drugs that suppress bone turnover, primarily
through effects on osteoclasts, and are commonly
prescribed to prevent skeletal-related events in
malignancy and for benign bone diseases such as
osteoporosis [22]. Given their affinity to bind to
hydroxyapatite crystals and prevent their growth and
Tetracyclines prevent connective tissue breakdown by dissolution and to their ability to increase osteoblast
various mechanisms as shown in figure-3. [18] differentiation and inhibit osteoclast recruitment and
activity, bisphosphonates are widely used in the
Clinical research on the use of tetracycline has lead to management of systemic metabolic bone disorders
the invention of various modifications such as

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Latha G et al: Host modulation therapy www.jrmds.in

such as tumour-induced hypercalcaemia, contact between a resorbing osteoclast and a bone

osteoporosis and Paget‟s disease [23]. surface.

Mechanism of action Long-term use may suppress bone turnover and

compromise healing of even physiologic micro-injuries
Several modes of action have been investigated within bone. Clinically, ONJ is essentially exposed
including BP mediated inhibition of the development bone in the maxilla or mandible that does not heal
of osteoclasts, induction of osteoclastic apoptosis, within 8 weeks of identification. Patients with
reduction of activity, prevention of the development of previous dental problems might have a higher risk of
osteoclasts from hematopoietic precursors, and osteonecrosis of the jaw [26].
stimulation of production of an osteoclast inhibitory
factor. It has also been shown that the BP Mode of administration of bisphosphonates: Oral and
alendronate caused a rise inintracellular calcium intravenous route has been utilized to administration
levels in an osteoclast-like cell line. This finding is of of BPs . The risk of esophageal irritation places
great interest since it could suggest the presence of a special requirements on how this oral drug is taken.
receptor for BPs on osteoclasts. The proven efficacy The patient should take the drug only upon rising for
of BPs to inhibit osteoclastic bone resorption has led the day with 8 oz. of water, and stand, walk, or sit,
to their use in the management of periodontal and remain fasting for 30–45 minutes afterwards
diseases as a host modulating factor in the (preferably 1–2 hours), then eat breakfast. No other
perspective of preventing the alveolar bone loss. BPs medications should be taken for this time. Lying down
could be used in conjunction with regenerative or reclining after taking the drug and prior to eating
therapies, and even for stimulation of bone growth breakfast may cause gastroesophageal reflux and
into and around endosseous implants [24, 25]. esophageal irritation.

Classification: Bisphosphonates are classifies as, ANTI-CYTOKINE THERAPY

 Non-nitrogenousn Non-N-containing
bisphosphonates: Etidronate (Didronel) - 1 Cytokines are defined as regulatory proteins
(potency relative to that of etidronate) controlling the survival, growth, differentiation and
Clodronate functions of cells. Cytokines are produced transiently
Tiludronate at generally low concentrations, act and are degraded
in a local environment. This is documented by the fact
Non-nitrogenous bisphosphonates are metabolized in that cytokine-producing cells are often physically
the cell to compounds that replace the terminal located immediately adjacent to the responding cells.
pyrophosphate moiety of ATP, forming a Moreover, the responding cell destroys the cytokine
nonfunctional molecule that competes with adenosine that it responds to in the process of receptor-mediated
triphosphate (ATP) in the cellular energy metabolism. endocytosis. Cytokines function as a network, are
The osteoclast initiates apoptosis and dies, leading to produced by different cell types and share
an overall decrease in the breakdown of bone. overlapping features. This phenomenon is called
biological redundancy. While very few biological
 Nitrogenous N-containing bisphosphonates: responses are mediated by only one cytokine, many
Pamidronate (APD, Aredia) responses can be achieved by several different
Neridronate Olpadronate cytokines [27].
Alendronate (Fosamax)
Ibandronate (Boniva) Down regulation of cytokines is mainly brought
Risedronate (Actonel) about by three mechanisms:
Zoledronate (Zometa, Aclasta) i. cytokine receptor antagonist: Cytokine receptor
antagonists bind to the receptor present on the target
Nitrogenous bisphosphonates act on bone cell and prevent the cytokine from binding to the
metabolism by binding and blocking the enzyme target cell. Therefore, there is no activation of the
essential for connecting some small proteins to the target cell.
cell membrane. These proteins can affect ii. Soluble cytokine receptors: Soluble cytokine
osteoclastogenesis, cell survival, and cytoskeletal receptors are derived from the proteolytic cleavage of
dynamics. In particular, the cytoskeleton is vital for the extracellular domain of cell-bound cytokine
maintaining the "ruffled border" that is required for receptors. Soluble receptors can be found in blood

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Latha G et al: Host modulation therapy www.jrmds.in

and extracellular fluid. They cause: Inhibitors to RANK/RANKL Interaction

1.Downregulation- Soluble receptors bind to the RANKL is a member of the tumor necrosis factor
cytokine in solution and prevent signaling. (TNF) cytokine family which is a ligand for
2. Transactivation-Soluble receptors bind the cytokine osteoprotegerin and functions as a key factor for
and docks on otherwise non-responsive cells and osteoclast differentiation and activation. RANKL also
activate them. Out of all these soluble receptors (sIL- has a function in the immune system, where it is
1R, sTNF-RI, sTNF-RII, sIL-6R) only sIL-6R is an expressed by T helper cells and is thought to be
agonist in function, the rest are all antagonist in involved in dendritic cell maturation. This protein was
function and bring about the down regulation of shown to be a dendritic cell survival factor and is
cytokines [28]. involved in the regulation of T cell-dependent immune
response. T cell activation was reported to induce
iii. Anti-cytokine antibodies: are also antagonist in expression of this gene and lead to an increase of
function and them lower down the levels of cytokines. osteoclastogenesis and bone loss. Expression of the
(Anti IL-6 Ab, Anti TNF- Ab) RANKL gene in osteoblasts/stromal cells is enhanced
by:VitaminD3 , PTH, IL-1, IL-6, IL- 17 , TNF-α , BMP-
Commercially Available Preparations anti- 2 , PGE2 [34].
cytokines [29]
Infliximab (Remicade, Monoclonal Ab to TNF-α) RESOLVINS
Etanercept (Enbrel) (soluble form of TNF receptor)
Anakinra (Kineret) (Ril-1RA) :It is an interleukin-1 (IL- The term resolvins (resolution-phase interaction
1) receptor antagonist. products synthesized from omega 3 PUFA – EPA
However, the harsh enzymatic environment in (Eicosapantaenoic acid) and DHA (Docosahexaenoic
periodontal lesions may destroy the soluble cytokine acid)) was first introduced to signify that the new
antagonists prior to their peak activity, which may structures were endogenous mediators possessing
necessitate more frequent administration of the active potent anti-inflammatory and immunomodulatory
agents to the defects. actions demonstrated in the nanogram dose range in
vivo. Hence, named resolvins E and D respectively.
NO INHIBITORS These include reducing neutrophil traffic and pro-
inflammatory cytokines, as well as lowering the
`NO is one of the few gaseous signaling molecules magnitude of the inflammatory response in vivo. The
known and is additionally exceptional due to the fact terms protectin and neuroprotectin (when generated
that it is a radical gas. It is a key vertebrate biological in neural tissues) were introduced given the anti-
messenger, playing a role in a variety of biological inflammatory as well as the protective actions of the
processes. Nitric oxide, known as the 'endothelium- DHA-derived mediator NPD1/PD1 in neural systems,
91
derived relaxing factor', or 'EDRF', is biosynthesized stroke and Alzheimer‟s disease. 18R E Series
endogenously from L-arginine, oxygen and NADPH Resolvins from EPA, 17S and 17 R D Series
by various nitric oxide synthase enzymes. In animal Resolvins from DHA are under study for their
experimental periodontitis, the use of pharmacological application clinically [35].
inhibitors of NO and poly ADP ribose polymerase
(PARP) synthases reduces periodontal attachment STATINS
and bone loss [30, 31].
Recent studies suggest that statins possess
Antagonists to Cell Adhesion Molecules antiinflammatory properties owing to their ability to
P-selectin is a cell adhesion molecule (CAM) on the reduce the number of inflammatory cells in
surfaces of activated endothelial cells, which line the atherosclerotic plaques. The mechanisms have yet to
inner surface of blood vessels, and activated be fully elucidated but may involve inhibition of
platelets. P-selectin plays an essential role in the adhesion molecules, such as intercellular adhesion
initial recruitment of leukocytes to the site of injury molecule-1 (ICAM-1), which are involved in the
during inflammation. Several E-selectin and recruitment of inflammatory cells [26].
intercellular adhesion molecule-1 inhibitors such as
tepoxalin, sodium cromoglycate are under research to CONCLUSION
be applied in host modulation therapy clinically [32,
33]. The adjunctive use of host modulation therapy can
enhance therapeutic responses, slow the progression

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Latha G et al: Host modulation therapy www.jrmds.in

of the disease, and allow for more predictable 13. Offenbacher S, Heasman PA, John GC.
management of patients, particularly in those patients Modulation of Host PGE2 Secretion as a
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