A brief description of all topics to recent advances,SDD, host modulation and diabetes, host modulation in smokers, chemically modified tetracyclines, bisphosphonates

1. HOST MODULATION
Presented by:-
Ganesh Nair
Part II PG
Guided by:-
Dr. Anita Panchal
Dr. Sachin K.
Dr. Bhaumik Nanavati
Dr. Rahul Shah
Dr. Mansi Pathak
Dr. Riddhi Gandhi

2. INDEX:
 Introduction
 Classification
 Inhibition of arachidonic acid
metabolism
 Bisphosphonates
 Matrix metalloprotineases
 Inhibition of MMPs
 CMTs and SDD
 SDD in smokers
 Protein antagonist strategies in the
treatment of periodontal diseases
 Hormone Replacement
 Regulation of Immune and
Inflammatory responses
 Other host modulatory agents
 Host modulation in diabetes
 Combination of host response
modulators
 Future of Host response modulation
 Conclusion

3. Introduction:
 Host can be defined as “the organism from which a parasite
obtains its nourishment”, Modulation is defined as “the
alteration of function or status of something in response to a
stimulus or an altered chemical or physical environment.”
(Taber’s medical dictionary,2004).
 The concept of host modulation was first introduced to
dentistry by Williams et al in 1990 and Golub et al in 1992.

4.  The immune-inflammatory response against bacterial plaque can
thus be viewed as a two-edged sword.
 Excessive quantities of destructive enzymes and inflammatory
mediators and; inflammatory response to bacterial challenge.
 Periodontal disease is characterized by high concentrations of
MMPs, cytokines and prostanoids in the periodontal tissues,
whereas periodontal health is characterized by the opposite.

5. Pathogenesis of human
periodontitis:
 Conceptual model
1997

6. Bartold PM, Van Dyke TE. Periodontitis: a host-mediated disruption of
microbial homeostasis. Unlearning learned concepts. Periodontol 2000 2013:

7.  Host modulatory therapy can be used to interrupt the positive
feedback loops (PGE2, interlukins, TNF-α, and MMPs)
 The inflammation extends apically, and osteoclasts themselves
are targets for host modulation.
 The elevation in the pro inflammatory or destructive mediators
in response to bacterial challenge are counterbalanced by
elevations in anti-inflammatory or protective mediators such as
cytokines IL-44 and IL-10, as well as other mediators, such as
IL-ra (receptor anagonist), and Tissue Inhibitors of
Metalloproteinases (TIMPs).

9. Classification:
 Various HMT have been developed or proposed to block
pathways responsible for periodontal tissue breakdown:
A. Inhibition of Matrix metalloproteinases (MMPs):
◦ Through Chemically Modified Tetracyclines (CMTs)
B. Inhibition of Arachidonic acid metabolites:
◦ Through NSAIDs
 COX – 1 inhibitors: Indomethacin, Naproxen,
Flurbiprofen
 COX – 2 inhibitors: Rofecoxib
 COX and LOX inhibitors: Triclosan, Topical Ketoprofen
 LOX inhibitors: Lipoxins

10. C. Modulation of bone metabolism:
◦ Bisphosphonates
◦ Hormone replacement therapy (HRT)
D. 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.

11. Inhibition of Arachidonic Acid
Metabolism:
 NSAIDs
 Lipoxins
 Omega 3 Fatty acids
 Triclosan

12.  NSAIDs: Nonsteroidal anti-inflammatory drugs inhibit the
formation of prostaglandins, including prostaglandin E2,
 The ability of NSAIDs drugs to block prostaglandin E2 production,
thereby reducing inflammation and inhibiting osteoclast activity, has
been investigated in patients with periodontal disease.
 Drugs like flurbiprofen (William RC et al. 1989),
indomethacin(William RC et al 1987), naproxen(Howell TH et al
1993), administered daily upto 3 years, showed significantly slowed
rate of alveolar bone resorption as compared to placebo.

13. COX-1 and COX-2:
 The enzyme cyclo-oxygenase, which metabolizes arachidonic
acid, exists in two functionally distinct isoforms:
 Cyclo-OXygenase-1 (which is constitutively expressed and
has antithrombogenic and cytoprotective functions); and
 Cyclo-OXygenase-2 (which is induced after stimulation with
various cytokines, growth factors and lipopolysaccharide).

14.  Inhibition of cyclo-oxygenase-1
 Results in the majority of the unwanted effects associated
with nonsteroidal anti-inflammatory drug use, such as
gastrointestinal ulceration and impaired hemostasis.
 Induction of cyclo-oxygenase-2
 Results in the production of elevated quantities of
prostaglandins, and therefore inhibition of cyclo-oxygenase-2
by selective inhibitors.
◦ These include NS-398, nimesulide, etodolac, meloxicam, celecoxib,
rofecoxib, etoricoxib, paracoxib, valdecoxib and lumiracoxib.

15. Locally administered agents
NSAIDs:
 NSAIDs that have been evaluated for topical administration
includes ketorolac tromethamine rinse and S – ketoprofen
dentifrice.
 Li et al. (1996) presented preclinical data on a topical ketoprofen
cream (1%) and its effects on spontaneous and ligature-induced
periodontitis in the rhesus monkeys.
 The investigators did not observe a clinical improvement in gingival
inflammation, they did note significant depression in prostaglandin
E2 and leukotriene B4 levels in gingival crevicular fluid and in
ketoprofen-treated animals versus placebo animals.

16. Disadvantages of NSAIDs:
 Once patients cease taking nonsteroidal anti-inflammatory drugs, a
return to, or even acceleration of, the rate of bone loss seen prior to drug
therapy occurs, sometimes referred to as a rebound effect.
 Non-steroidal anti-inflammatory drugs have been extensively reviewed
as potential host response modulators for the treatment of periodontal
disease, but unwanted effects (including the serious adverse effects of
the selective cyclo-oxygenase- 2 inhibitors such as bleeding, ulcers, and
perforation of the stomach or intestines) preclude their use as adjuncts
to periodontal treatment.

17. ANTI-INFLAMMATION VERSUS
RESOLUTION:
 Cyclooxygenase (COX)- inhibitors prevent prostaglandin
biosynthesis and are effective anti-inflammatory mediators;
however, they prolong the time to resolve and thus extend
tissue inflammation.
 But, for proresolving, it must be an agonist to resolution via
targeting cell types and events critical for the tissue to return
to homeostasis.
 Sehan et al. (1999) have recently described a novel series of
oxygenated arachidonic acid derivatives called ‘‘lipoxygenase
interaction products’’ or ‘‘lipoxins’’.

18. Mechanism of action of Omega-3
derivtives:
 Lipid-derived mediators are well positioned to play key role(s)
as signalling molecules in inflammation because they are small
molecules, local-acting, rapidly generated, and locally
inactivated.
 Pro-inflammatory prostaglandins and leukotriene B4 (LTB4)
control local blood flow, vascular dilation, and permeability
changes needed at the site for leukocyte adhesion, diapedesis,
and recruitment.

19.  The essential roles of omega-3 PUFAs in health were evident
in 1929. Omega-3 PUFAs are widely held to act via several
possible mechanisms, such as preventing conversion of
arachidonate to proinflammatory eicosanoids or serving as an
alternative substrate producing less-potent products.
 Serhan CN. A search for endogenous mechanisms of antiinflammation uncovers novel
chemical mediators: missing links to resolution. Histochem Cell Biol 2004;122:305-21.
 Proresolving lipid mediators are a novel genus of endogenous
chemical mediators, including Lipoxin(LXs), Resolvins(Rv),
and Protectins(PD), which are involved in acute
inflammation.
 They are actively biosynthesized in the resolution phase of
acute inflammation and are potent agonists that control the
duration and magnitude of inflammation.

20.  They are also potent chemoattractants, but act via a
noninflammatory mechanism: e.g., lipoxins activate
mononuclear cell infiltration without stimulating the release of
proinflammatory chemokines or activation of proinflammatory
gene pathways and products.
 They also stimulate the uptake of apoptotic Polymorphonuclear
neutrophils (PMNs) and activate endogenous antimicrobial
defense mechanisms as well as clearance on mucosal surfaces.
 Together, these dual actions are agonistic; via acting on separate
cell populations, they stimulate resolution of inflammation.

22. CHEMICAL MEDIATORS THAT HELP
IN RESOLUTION:
1. Lipoxins
2. Aspirin-triggered lipoxins
3. Rv(Resolvins)
4. PD(Protectins)

23. Lipoxins:
 The lipoxin series are trihydroxytetraene-containing bioactive
eicosanoids first isolated from human leukocytes.
 Lipoxins were the first mediators recognized to possess
specific proresolution actions.
 When platelets adhere to PMNs, the platelet–PMN aggregates
become a major intravascular source of LX that in turn halts
further PMN diapedesis and recruitment.
 Serhan CN et al 2008, Arita M et al 2005, Van Dyke TE et al 2003

24. Mucosal and vascular cell–cell interactions
 The lipoxin biosynthetic circuit in cells enriched in 15-LO initiates the
oxygenation of AA by 15-LO to generate 15S-H (p) ETE
(hydroperoxyeicosatetraenoic acid) transformed into an epoxytetraene
intermediate generated by leukocyte 5-LO and specifically open to
LXA4 and LXB4.
Platelet–leukocyte interactions
 Platelets adhering to neutrophils can pick up and transform released 5-
LO intermediate LTA4 and convert this to LXA4 and LXB4 by platelet
12-LO.
Membrane phospholipid priming, stored precursors of 15-HETE
 Membrane precursors other than AA could be released and converted to
bioactive substances. 15-HETE is stored in cell membrane containing
lipids that are then charged and/or primed to produce lipoxins on
activation of cells by releasing the stored 15-HETE that is taken up and
transformed by the neighbouring leukocyte.

26. Aspirin-triggered lipid
mediators:
 Aspirin impacts lipoxin generation. Aspirin triggers the
formation of the 15R-epimers of the lipoxins, specifically 15-
epi-LXA4 and 15-epi-LXB4. These epimers carry their
carbon-15 alcohol group in the R configuration.
 The aspirin-triggered epimers of lipoxins are longer acting
because they show reduced catalytic activity for enzyme
inactivation.

27. Rv and PD:
 The bioactive local mediators, or autacoids, that require enzymatic
generation from the omega-3 essential fatty acid EPA resolving
inflammatory exudates in vivo and carry potent stereoselective biological
actions. They were termed Resolvins of the E (RvE) series derived from
EPA.
 Those derived from DHA were termed Rv of the D series.
 The other family of bioactive chemical signals from DHA (i.e.,
docosanoids, oxygenated products from DHA), which specifically possess
a conjugated triene double-bond system in their structures, are denoted
protectins.

28.  The term Rv (resolution-phase interaction products) was first
introduced to signify that these new structures were
endogenous mediators, biosynthesized in the resolution phase
of inflammatory exudates, possessing very potent
antiinflammatory and immunoregulatory actions.
 Serhan CN, Yacoubian S, Yang R. Anti-inflammatory and proresolving lipid
mediators. Annu Rev Pathol Mech Dis 2008;3:279-312.
 These actions include reducing neutrophil traffic, regulating
cytokine and reactive oxygen species, and lowering the
magnitude of the response. The term neuroprotectin is applied
to protectin that is generated in the neural tissues and has
antiinflammatory properties.
 Van dyke TE. Control of inflammation and periodontitis. Periodontology
2000 2007;45:158-66.

29. LIPID MEDIATORS CLASS SWITCHING IN
RESOLUTION (AT THE TISSUE LEVEL):
 A key event in resolution is the temporal switch in the lipid
mediator class from pro- to anti-inflammatory eicosanoids,
which has direct implications for the treatment of
inflammatory diseases.

30. MATRIX
METALLOPROTEINASES
 Family of zinc and calcium dependent endopeptidases
secreted or released by a variety of host cells
 That function at neutral pH and utilize the various
constituents of extracellular matrix (e.g. collagen, gelatin,
laminin, fibronectin & proteoglycan) as their substrate.

31. PRODUCTION OF MMPs
 Both resident gingival and periodontal ligament fibroblasts
produce collagenases that are thought to be involved in normal
tissue turn over.
 Inflammatory cells such as neutrophils and macrophages produce
MMPs, with neutrophils being the major source of collagenase &
gelatinase in inflammatory diseases such as periodontitis.
 Matrixmetalloproteinases are not constitutively expressed in most
tissues but are induced temporarily in response to exogenous
signals such as various cytokines, growth factors, cell matrix
interactions, and altered cell-cell contact

32. CLASSIFICATION
 There are three major groups-
1. Specific collagenases
2. Gelatinases
3. Stromelysins
4. Others – these include matrilysin, metalloelastase and recently
cloned membrane bound metalloelastase. Which include
MMP’s- 7,12,14,15,16,17,24,25
 Total 19 types (MMP 1-26) with missing no.- 4,5,6,18,21,22,23
◦ Adapted from Hannas AR: Acta Odontol Scand 65:1-13, 200

33. FUNCTIONS
 The main function of MMPs is to catalyze the breakdown of
proteins in cell plasma membrane or within the extracellular
matrix.
 In periodontal disease MMPs play key roles in the
degradation of extracellular matrix, basement membrane and
protective serpins as well as in the modification of cytokines
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.

34. SOURCE OF MMP’s
 Several periodontal pathogens e.g. Porphyromonas gingivalis
& Actinobacillus actinomycetemcomitans produce MMPs,
including collagenase, these proteinases are not considered to
be the major destructive enzymes associated with disease
progression.
 The major contribution of proteinases is host-derived.

35. Inhibition of MMPs:
 One of the most promising groups of potential HMTs is the
chemically modified tetracyclines(CMTs).
 The CMTs are designed to be more potent inhibitors of anti-
inflammatory mediators such as IL-10.
 Chemically modified Tetracyclines are those which lack
dimethylamino group on the 4th carbon atom.

36.  Mechanism of action of chemically modified tetracyclines:
i. Inhibits or chelates the calcium atoms that Matrix metalloproteinase
(MMPs) requires for their action
ii. Inhibit already active MMPs
iii. Down – regulate MMPs expression
iv. Scavenges reactive oxygen species
v. Modulates the osteoclast functions
 CMTs such as CMT-3 and CMT-8 (both of which lack antibiotic activity
but retain anti-MMP activity), have been shown to inhibit osteoclastic
bone resorption and promote bone formation, enhance wound healing,
and inhibit proteinases produced by periodontal pathogens.

37. Sub Antimicrobial Dose
Doxycycline:
 SDD is currently the only FDA approved systemically
administered HMT indicated specifically in the treatment of
periodontitis.
 SDD is used as an adjunct to SRP and must not be used as a
monotherapy.

38. Mechanism and Effects of
doxycycline:
 In addition to its antibiotic properties, doxycycline has the ability to down
regulate MMPs, a family of zinc dependent enzymes that are capable of
degrading extracellular matrix molecules, including collagen.
 Direct inhibition of active MMPs by cation chelation (dependent on Ca2+-
and Zn2+-binding properties)
 Inhibits oxidative activation of latent MMPs (independent of cation-binding
properties)

39.  Down regulates expression of key inflammatory cytokines
(interleukin-1, interleukin-6 and tumor necrosis factor-α) and
prostaglandin E2
 Scavenges and inhibits production of reactive oxygen species
produced by neutrophils
 Inhibits MMPs and reactive oxygen species thereby protecting a1-
proteinase inhibitor, and thus indirectly reducing tissue proteinase
activity
 Stimulates fibroblast collagen production
 Reduces osteoclast activity and bone resorption
 Inhibits osteoclast MMPs

40.  Doxycycline was also confirmed as being a more effective
inhibitor of MMPs than either minocycline or tetracycline;
doxycycline has a much lower inhibitory concentration (IC50 =
15 lM) than minocycline (IC50 = 190 lM) or tetracycline (IC50
= 350 lM), indicating that a much lower dose of doxycycline is
necessary to reduce a given collagenase level by 50%compared
with minocycline or tetracycline.
 Golub LM, Evans RT, McNamara TF, Lee HM, Ramamurthy NS. A non
antimicrobial tetracycline inhibits gingival matrix metalloproteinases and bone
loss in Porphyromonas gingivalis-induced periodontitis in rats. Ann NY Acad Sci
1994: 732: 96–111
 Furthermore, doxycycline has also been found to be more
effective in blocking neutrophil collagenase activity (MMP-8)
than fibroblast collagenase activity (MMP-1).

41. Suggested Use of SDD:
 Candidate Patients:
◦ When deciding whether to use SDD as an adjunct to SRP, first
consider the patient's motivation toward periodontal care, the
medical history, and the patient's willingness to take a systemic
drug treatment.
◦ SDD is contraindicated in any patient with a history of allergy or
hypersensitivity to tetracyclines. It should not be given to
pregnant or lactating women or children less than 12 years old
(because of the potential for discoloration of the developing
dentition).
◦ Doxycycline may reduce the efficacy of oral contraceptives, and
therefore alternative forms of birth control should be discussed, if
necessary.

42.  Treatable Periodontal Conditions:
◦ SDD is indicated in the management of chronic
periodontitis, and studies to date have focused on chronic
and aggressive forms of periodontitis.
◦ SDD can be used in patients with aggressive periodontitis
who are being treated nonsurgically.
◦ Furthermore, emerging studies have supported efficacy of
SDD as an adjunct to periodontal surgery.
◦ SDD may also be of benefit in cases that are refractory to
treatment, as well as in patients with risk factors such as
smoking or diabetes, in whom the treatment response
might be limited

43.  Side Effects:
◦ Doxycycline at antibiotic doses (≥100 mg) is associated
with adverse effects, including photosensitivity,
hypersensitivity reactions, nausea, vomiting, and
esophageal irritation. In the clinical trials of SDD(20-mg
dose), the drug was well tolerated, however, and the profile
of unwanted effects was virtually identical in the SDD and
placebo groups .

44. Microbiological and safety
concerns:
 A concern expressed by many colleagues initially was that the
prolonged use of doxycycline, even at a dose of 20 mg twice
daily, may lead to the development of antibiotic resistance.
 This has been confirmed in several randomized studies in
which subgingival plaque samples were collected from
patients prior to and after 9–27 months of subantimicrobial
dose doxycycline therapy or placebo (Thomas J et al., Lee et
al., Walker et al.).

45.  Regarding safety data, the plasma concentration of
doxycycline following a subantimicrobial dose (20 mg) is
low, with pharmacokinetic studies revealing peak
concentrations of 0.7–0.8 µg⁄ ml and steady- state
concentrations of approximately 0.4 µg ⁄ ml, which are well
below the concentrations of 3– 4 µg ⁄ ml that can be expected
following antibiotic doses of 100–200 mg of doxycycline.
 Thus, unwanted effects are less likely to occur as a result of
treatment with subantimicrobial doses, compared with
antibiotic doses, of doxycycline.

46. Sequencing Prescription with
Periodontal Treatment:
 SDD should be prescribed to coincide with the first episode
of SRP and is prescribed for 3 months, up to a maximum of 9
months of continuous dosing.
 Modification of any risk factors, such as smoking, nutrition,
stress, contributing medications, faulty restorations, poor oral
hygiene, and poor diabetic control, can also he addressed at
this time.

47. Subantimicrobial dose
doxycycline in smokers:
 A study by Preshaw et al. 2005; 9 months of adjunctive
subantimicrobial dose doxycycline, such that nonsmokers
who received subantimicrobial dose doxycycline
demonstrated the greatest attachment gains and probing depth
reductions .
 Smokers who received subantimicrobial dose doxycycline
demonstrated an intermediate treatment response that was
broadly equivalent to that seen in nonsmokers who received
placebo.

48.  Smokers have also been reported to have significantly higher
crevicular fluid levels of tumor necrosis factor α than
nonsmokers and show suppressed levels of the crevicular
fluid protease inhibitors α1-antitrypsin and α2-macroglobulin,
suggesting that smoking has a direct effect on the
inflammatory response.
 The mechanism by which subantimicrobial dose doxycycline
may be of clinical benefit in smokers with periodontal disease
has not been clearly identified, but presumably relates to the
ability of doxycycline to downregulate MMPs, together with
other anti-inflammatory properties.

49. Triclosan:
 A compound which has received interest as both an
antibacterial and anti – inflammatory agent is triclosan.
Triclosan (2, 4, 41 – trichloro – 2- hydroxyl – diphenyl ether)
is an non – ionic antibacterial agent. Triclosan also inhibits
COX and LOX and thus, may interfere with the production of
AA metabolites.

50. Modulation of Bone
metabolism:
 Bisphosphonates: The bisphosphonates are bone seeking
agents that inhibit bone resorption by disrupting osteoclast
activity.
 They represent a class of chemical compounds structurally
related to pyrophosphate, which regulates mineralization by
binding to hydroxyl apatite crystals, but is not stable in vivo,
undergoing hydrolysis of its P-O-P bond as a result of
pyrophosphatase activity.

51.  They increase osteoblast differentiation and are used
extensively in the management of osteoporosis and other
bone resorptive conditions.
 In randomized, placebo controlled clinical trials in humans
with periodontal disease, bisphosphonate use resulted in
statistically significant reductions in the proportion of teeth
demonstrating alveolar bone loss after 9 months by Reddy
MS et al (1995) and statistically significant improvements in
alveolar bone height by Ryder MI et al (2002).

52.  These are non-biodegradable analogues of pyrophosphate that
have a high affinity for calcium phosphate crystals and that
inhibit osteoclast activity. These compounds also appear to
inhibit MMP activity through a mechanism that involves
chelation of cations.
 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).

53.  On their basis of their effects on macrophages,
bisphosphonates can be subgrouped into:
◦ Aminobisphonates – which sensitize macrophages to an
inflammatory stimulus, inducing an acute-phase
response.
◦ Nonaminobisphosphonates - which can be metabolized
by macrophages and which may inhibit the inflammatory
response of macrophages

54.  Modes of action of Bisphosphonates are:
1. Inhibition of the development of osteoclasts,
2. Induction of osteoclastic apoptosis,
3. Reduction of activity of osteoclast
4.Prevention of the development of osteoclasts from
hematopoietic precursors and
5. Stimulation of production of an osteoclast inhibitory factor.

55. Periodontal Host Modulation with Antiproteinase, Anti-Inflammatory, and
Bone-Sparing Agents. A Systematic Review; Michael S. Reddy,Nico C.
Geurs, and John C. Gunsolley:Annals of Periodontology;Volume 8(1)

56. Drawbacks of
Bisphosphonates:
 A recent development has been the publication of several case
reports of avascular necrosis of the jaws, particularly the mandible,
following bisphosphonate therapy, with an increased risk of bone
necrosis following dental extractions. This has been termed
Bisphosphonate Induced OsteoNecrosis of Jaw (BIONJ) and is a
significant and clinically serious complication of bisphosphonate
therapy.
 Lam DK, Sandor GK, Holmes HI, Evans AW, Clokie CM. A review of bisphosphonate-
associated osteonecrosis of the jaws and its management. J Can Dent Assoc 2007: 73:
417– 422

57. NOVEL PROTEIN ANTAGONIST STRATEGIES
IN THE TREATMENT OF PERIODONTAL
DISEASES

60. ◦ The discovery of a novel receptor called osteoprotegerin
(OPG) revealed a key regulatory mechanism in osteoclast
differentiation and activity.
◦ Opg and receptor activator of nuclear factor kappa β(nf-κβ)
ligand (rankl) are two molecules that regulate osteoclast
formation and bone resorption
◦ RANKL induces osteoclast differentiation and activation,
whereas OPG blocks this process by acting as a decoy
receptor for RANKL.
Disruption of the
RANKL/RANK/osteoprotegerin
axis

61.  RANKL mediates a signal for osteoclastogenesis through
RANK on pre-osteoclast cells.
 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.

62. Therapeutic Role
 The use of osteoprotegerin as a therapeutic agent was first
evaluated by Simonet et al. 1997
 An OPG mimetic drug called “DENOSUMAB” has been
introduced which has high affinity for RANKL and effects
osteoclasts by inhibiting their formation, function and
survival.
 Based on pre-clinical animal studies and on preliminary
human clinical studies, the osteoprotegerin/RANKL/RANK
axis is a new target for the treatment of destructive
periodontal disease and other bone resorption-related
diseases.

63. Hormone replacement:
 Osteopenia and Osteoporosis have been associated with menopausal
patients.
 The effects of Hormone Replacement Therapy (HRT) or Estrogen
Replacement Therapy (ERT) on the oral bone and tooth loss also are
under investigation. There is a lesser risk of tooth loss when post
menopausal women are placed on HRT.
 Improved BMD with HRT has been recognized benefit. Krall et al
in 1991 found the odds of being edentulous were reduced by 6% for
each 1 year increase in duration of HRT use.

64. Regulation of Immune and
Inflammatory responses:
 Suppressing proinflammatory cytokines:
◦ Cytokines function as a network and are produced by
different cell types and share overlapping features. This
phenomenon is called biological redundancy.
◦ To counteract tissue destruction and maintain homeostasis,
cytokine antagonists such as IL – 1 receptor antagonist (IL
– 1Ra) or soluble TNF receptors can competitively inhibit
receptor mediated signal transduction.

65.  Pro-inflammatory (e.g. IL-1α, IL-1β, IL-6, TNF-α, IFN-γ etc) and
anti-inflammatory cytokines (IL-4, IL-10 etc) hold a great
potential for controlling the adverse effects of the host immune
response, consequently HMT against cytokines (cytokine therapy)
may prove to be an effective strategy for treating periodontal
diseases.
 These therapies aim at:
◦ Antagonizing the pro-inflammatory cytokines.
◦ Disrupting inflammatory cell-signalling pathways
◦ Recombinant anti-inflammatory cytokine administration

66.  Antagonizing the pro-inflammatory cytokines via
• Cytokine receptor antagonist: Binds to the receptor present on
the target cell and prevents the cytokine from binding to the
target cell. E.g. interleukin-1 receptor antagonist (IL-1ra) which
is commercially available as Kineret (Anakinra, Amgen)
• Anti-cytokine antibodies: Some of the anticytokine antibodies
currently available are:
 Anti TNF-α antibody: Adalimumab (Humira,
manufacturered by Abbott Laboratories), Cetrolizumab pegol
(Cimzea, manufacturered by Union chimique belge),
Golimumab (Simponi, manufacturered by Centocor) etc.

67.  Anti IL-6 antibody: Tocilizumab (RoActemra, manufacturered by
Roche)
 Anti IL-15 antibody: AMG714 (AMG714, manufacturerd by
Novartis)
 Anti IL-12 and IL-23 antibody: Ustekinumab (Stelara,
manufacturered by Centacor)
 Anti IL-17 antibody: AIN457 (AIN457, manufacturered by
Novartis)
• Soluble cytokine receptors: Binds to the cytokines in solution and
prevents signaling. e.g. sIL-1R, sTNF-R, sIL-6R are the soluble
receptors against IL-1β, TNF-α and IL-6, respectively

68.  Disrupting inflammatory cell-signalling pathways:
◦ To inhibit the production of pro-inflammatory cytokines and/or
stimulate anti-inflammatory cytokine production
 Recombinant anti-inflammatory cytokine
administration:
◦ Martuscelli et al. (2000) demonstrated that subcutaneous
injections of recombinant human IL-11 (rh IL-11:
anti-inflammatory cytokine) were able to slow the progression of
attachment and radiographic alveolar bone loss in a
ligature-induced beagle dog model

69. Modulation of Nitric oxide
activity:-
◦ Nitric oxide (NO) is a short lived molecule implicated in a
wide range of biological processes. NO is a highly reactive
free radical reacting with metal and thiol residues leading
to lipid peroxidation, protein and DNA damages and
stimulation of cytokine release.

70. Inhibition of NO
 The pharmacological inhibition of NO synthases with
mercaptoalkylguanidine (aminoguanidine 2.5 to 10mg/kg/d) or L-
arginine methyl ester intraperitoneally is associated with decreased
inflammation.
 Lohinai et al. (1998) demonstrated the protective effects of
mercaptoethylguanidine (MEG), which is a selective inhibitor of
iNOS, against bone destruction in ligature-induced periodontitis in
the rat
 Ribeiro and Leitao et al (2005) found that nitric oxide synthase
inhibition prevents alveolar bone resorption in experimental
periodontitis in rats.

71. Mechanism of action
• Blocks inducible NO synthases
• Scavenges peroxynitrite
• Inhibits cyclooxygenase

72. Other Locally Administered agents:
 A number of local host modulation agents i.e enamel matrix
proteins, growth factors and bone morphogenetic proteins
have been investigated for potential use as adjuncts to
surgical procedures.
 To improve wound healing but also to stimulate regeneration
of lost bone, periodontal ligament and cementum and thus
,restoring the complete periodontal attachment apparatus

73. BONE MORPHOGENETIC
PROTEINS
 Bone morphogenetic proteins (BMP) are non-collagenous proteins
found in bone and are characterized by their ability to induce bone
and cartilage formation.
 fifteen BMPs isolated.
 Of the fifteen BMPs, BMP-2 through BMP-9 are structurally related
to one another.
 The bone morphogenic proteins (BMPs) are the only morphogens
“thus far found in mammalian species and are detected not only in
the embryonic, but also postfetal bone development” (Urist etal.
1994).

74. Various carrier systems for BMPs:
 Resorbable & non resorbable hydroxyapetite disc & granules
 Polylactic acid – Polyethylene glycol (PLA- PLG)
 Polylactide glycocide (PLGA) and autogenous blood
 Titanium
Ideal characteristics of Carrier system for BMPS:
 Noncollagenous
 Immunologically inert
 Osteoconductive
 Bioresorbable
 Support angiogenesis
 Subsequent vascularization

75. ENAMEL MATRIX DERIVATIVE
 In 1997, the concept of Enamel Matrix Protein Derivative
Guided Regeneration (EGR) was introduced.
 The clinical efficacy of enamel matrix derivative (EMD) in
terms of probing depth reduction and radiograph bone gain
was demonstrated in two multicenterd studies conducted by
groups of investigators (Heijl et at, 1997, Zetterstorm et al,
1997).
 These are the proteins secreted by hertwig’s epithelial root
sheath during the secretory stage of tooth development.

76.  Enamel proteins are generally believed to regulate the
initiation, propagation, termination and maturation of
enamel hydroxyapatite crystallites (Slavkin, H.C., 1976).
 It has also been shown to take part in cementogenesis
(Brookers S.J., Robinson C., Kirkham J., et al 1995).
 The predominant protein being composed of amelogenins
(90%).
 They are markedly hydrophobic and are supposed to play
an important role in the developing enamel by stabilizing
newly formed enamel crystal.

77.  The effects of Emdogain® on the various structures of the
Periodontium
1. It leads to the formation of acellular extrinsic fiber cementum
2. It enhances the proliferation of periodontal ligament (PDL) cells
but not epithelial cells.
3. It increases total protein production by PDL cells.
4. Acts as a positive matrix for cells at a regenerative site.
5. Emdogain® affects early stages of osteoblasts maturation
6. As the cells mature in the lineage, Emdogain® enhances
differentiation

78. Platelet derived Growth
factor:
 FDA has approved Growth-factor Enhanced Matrix, GEM 21S®
(Osteohealth, Shirley, NY) which is a combination of a bioactive
highly purified recombinant human PDGF-BB with an
osteoconductive bone matrix.
 Nevins et al. (2005) demonstrated that the purified rhPDGF-BB
mixed with bone allograft results in robust periodontal regeneration
in both Class II furcations and interproximal intrabony defects.

79. Hypochlorous Acid and
Taurine-N-Monochloramine:
 Lorenz et al. (2009) assessed the influence of 2 and 3%
N-chlorotaurine mouth rinse on dental plaque and
demonstrated that rinsing with 10 mL of the test solution two
times daily for 4 days reduced the plaque vitality

80. Cimetidine:
 Cimetidine is a powerful H2-(Histamine) receptor antagonist,
and hence eliminates histamine’s inhibitory effects on
immune response, thereby acting as a modulator of
inflammation and immunity by inhibiting neutrophil
chemotaxis and superoxide production.
 Hasturk et al. (2006) provided morphological and histological
evidence to prove that topically active cimetidine is a potent
inhibitor of P. gingivalis-elicited periodontal inflammation
and can arrest and/or prevent tissue destruction

81. Other host modulatory therapies:

82. Probiotics:
 Teughels et al. (2011) explored the use of probiotics in
influencing the periodontal microbiota and periodontal health
and concluded that probiotics might offer opportunities to
manipulate the oral microbiota, and periodontal health by
either direct microbiological interactions or by
immunomodulatory interaction

83. Periodontal vaccines:
 George Hajishengallis et al (2009) reported that toll like receptors (TLRs)
may offer novel targets for host-modulation therapy in periodontitis since
manipulation of TLR signalling may contribute to control of infection or
regulation of inflammation and, moreover, synthetic or natural TLR
agonists could serve as novel periodontal vaccine adjuvants.
 Yokoyama et al. in 2007 also demonstrated that egg yolk antibody against
Porphyromonas gingivalis (IgY-GP) proved to be an effective
immunotherapeutic agent in the treatment of periodontitis.
 Choi et al. In 2001 reported that prior immunization of mice to
Fusobacterium nucleatum modulated the host immune responses to
Porphyromonas gingivalis at the humoral, cellular and molecular level

84. Nutrients:
 Nutrients, which include major extracellular antioxidants, like
vitamin C, vitamin E, carotenoids, reduced glutathione and
omega 3 fatty acids can also act as modulators of
inflammation by scavenging free radicals as they are formed,
sequestering transition metal ions and catalyzing formation of
other molecules.
 Reddy S, Kaul S, Asutkar H, Bhowmik N, Amudha. Host modulation in periodontics.
e-Journal of Dentistry 2011;1:51-62

85. Host modulation in diabetes:
FUSANORI NISHIMURA, YOSHIHIRO IWAMOTO & YOSHIHIKO SOGA; the periodontal
host response with diabetes:periodontology 2000, vol. 43, 2007, 245–253

86. Hypoglycemic drugs:
 Recently, new medication was developed to recover insulin
sensitivity for diabetic subjects with insulin resistance, especially for
obese diabetic subjects. This medication, thiazolidinedione, is known
as glitazone.
 Glitazone also suppresses P. gingivalis- and Fusobacterium
nucleatumlipopolysaccharide- induced interleukin-6 production in
adipocytes.
 Glitazone acts to change the size of mature adipocytes from large to
small, and to increase the number of small pre-mature adipocytes,
thereby shutting down the expression of several genes characteristic
for mature adipocytes such as tumor necrosis factor-α.

87. Statins:
 Another candidate is the lipid-lowering drug, statin. Statin
essentially inhibits the activity of the enzyme 3-hydroxy-3-
methyl glutaryl coenzyme A reductase, which is the rate-
limiting enzyme for cholesterol synthesis.
 Administration of statin to diabetic mice has been reported to
suppress nuclear factor-κβ activity in the kidneys as well as
suppression of ICAM-1 expression and subsequent
macrophage infiltration

89. Combinations of host response
modulators:
 Host modulating drugs that target different aspects of the
pathogenic processes in periodontitis have been combined to
maximize therapeutic outcomes.
 Combination of CMT and flurbiprofen has also been studied.The
mechanism by which flurbiprofen promoted the uptake of the
tetracycline in the local inflammatory lesion is not known, but could
relate to an improved local blood flow in the lesion (thus improving
the local delivery of the chemically modified tetracycline) as a
result of the flurbiprofen therapy.

90.  Similarly, CMT-8 (a nonantimicrobial chemically modified
doxycycline), has been combined with a bisphosphonate
(clodronate) in rats with experimental periodontitis.
 After 1 week showed slight reductions in the levels of
MMP-8 and MMP-9.
 Subantimicrobial dose doxycycline has also been combined
with the locally delivered doxycycline gel, placed into
pockets of ±5 mm, in combination with root surface
instrumentation in a placebo-controlled study of 171 subjects.

91. The future of host response
modulation:
 Future developments in relation to subantimicrobial dose
doxycycline will include modified-release formulations that
achieve sustained plasma concentrations of doxycycline over
24 h, but only require once per day dosing, thereby improving
patient compliance.
 Furthermore, the development of chemically modified
tetracyclines is welcomed, as this will completely eliminate
all concerns about any possible antimicrobial effects of these
agents.

92.  Alternatively, targeting of mediators that play a particularly
important role in periodontal pathogenesis, such as
interleukin-1β or tumor necrosis factor- α, may constitute a
rational therapeutic strategy.
 Interleukin-11 has anti-inflammatory effects including
inhibition of tumor necrosis factor-α and recombinant human
interleukin-11 has been shown to result in significant
reductions in the rate of attachment and bone loss.

93. Conclusion:
 To summarize, host response modulators must be viewed as comprising
part of the overall management strategy for patients with periodontitis.
 Periodontal therapy in the 21st century should not only involve a high
standard of clinical treatment and monitoring, but should also focus on
patient involvement and improving the patient experience.
 At present, subantimicrobial dose doxycycline provides improvements in
probing depth reductions and attachment gains compared with root
surface instrumentation alone, and is the only licensed and approved host
response modulator available to dentists to date.

94. References:-
 Chp 49, host modulation; carranza,s clinical periodontology, 12th edition.
 Davidw. Paquette & ray c. Williams; modulation of host inflammatory mediators as
a treatment strategy for periodontal diseases:periodontology 2000, vol. 24, 2000,
239–252
 Philip m. Preshaw; host response modulation in periodontics:periodontology 2000,
vol. 48, 2008, 92–110
 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 periodontal diseases:periodontology 2000,
vol. 43, 2007, 294–315
 Chp 39, host modulatory therapy, perio revisited,shalu bhatla
 Michael s. Reddy,nico c. Geurs, and john c. Gunsolley;host modulation with
antiproteinase, anti-inflammatory, and bone-sparing agents volume 8 • number 1 •
december 2003;12-37
 Fusanori nishimura, yoshihiro iwamoto & yoshihiko soga; the periodontal host
response with diabetes:periodontology 2000, vol. 43, 2007, 245–253
 Gulati m, anand v, govila v, jain n. Host modulation therapy: an indispensable part of
perioceutics. J indian soc periodontol 2014;18:282-8.

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