2. C
O
N
T
E
N
T
S
Definitions
Introduction
History
Rationale
Targets of host modulation therapy
Modulation of arachidonic acid metabolites
NSAIDS
COX1 and COX2 inhibitors
Selective COX2 inhibitors
Lipoxins
Triclosan
Omega 3 fatty acids
Modulation of Bone remodeling
Bisphosphonates
osteoprotegerin
estrogen, selective estrogen receptor
Modulation of Matrix metalloproteinases
Exogenous
Tetracyclines
SDD
Chemically modified Tetracyclines
2
3. C
O
N
T
E
N
T
S
3
endogenous
TIMP
αmacroglobulins
Modulation of Cytokines
Modulation of other host inflammatory mediators
Nitrous oxide
nuclear factor kappa B
Periodontal vaccines
local host modulating agents
Combination therapy
Disruption of cell signaling pathways
NFkB pathway
MAPK pathway
disruption of RANK/RANKL/osteoprotegerin axis
conclusion
4. Definitions:
Host : “The organism from which a parasite obtains its
nourishment.”
Modulation: “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)
4
5. Host modulation therapy:
Treatment concept that aims to reduce
tissue destruction and stabilize or even
regenerate the periodontium by modifying
or down regulating destructive aspects of
host response and up regulating protective
or regenerative responses.(CARRANZA10th ed)
5
8. The concept of host modulation was first introduced to dentistry by Williams
(1990) and Golub et al (1992).
In 1990, Williams concluded, "There are compelling data from studies in animals
and human trials ; that pharmacologic agents that modulate the host responses
believed to be involved in the pathogenesis of periodontal destruction may be
efficacious in slowing the progression of periodontitis."
In 1992, Golub host modulation with tetracyclines and their chemically modified
analogues.
Initially, adjunctive therapies were solely antimicrobial, such as the use of
antiseptics and antibiotics. New adjunctive approaches involve modulation of the
host response.
History
8
9. • To aid host in its fight against infectious agents by supplementing the
natural inherent defensive mechanisms
• To modify host response by changing the course of inflammatory system
Arachidonic acid metabolites
Matrix metalloproteinases
Cytokines
Other inflammatory mediators
Nitric oxide
Nuclear factor kappa β
Endothelial cell adhesion molecules
Reactive oxygen species
Bone metabolism
9
10. When considering factors that increase an individual's risk for developing
periodontitis, it has been recognized that genetic, environmental (e.g., tobacco
use), and acquired risk factors (e.g., systemic disease) can increase a patient's
susceptibility to developing this disease.
These risk factors may lead to the imbalance between the proinflammatory and
anti-inflammatory mediators seen in susceptible individuals
HMTs are systemically or locally delivered pharmaceuticals that are prescribed as
part of periodontal therapy and are used as adjuncts to conventional periodontal
treatments, such as scaling and root planing (SRP) and surgery.
10
11. • Use of systemic HMTs for treatment of a patient's periodontal condition may also
provide benefits for other inflammatory disorders, such as arthritis, cardio-
vascular disease, dermatologic conditions, diabetes, and osteoporosis
HMTs do not "switch off" normal defense mechanisms or inflammation; instead,
they ameliorate excessive or pathologically elevated inflammatory processes to
enhance opportunities for wound healing and periodontal stability.
And also they can affect onset, rate of progression, and severity of periodontal
disease, as well as response to therapy. Some of these risk factors can be
modified to reduce a patient's susceptibility
11
17. • Various NSAIDs have been studied in regulating periodontal
disease.
• They are
Non selective COX inhibitors
IBUPROFEN
KETOPROFEN (3% or enantiomer capsules 10mg)
FLURBIPROFEN
COX-2 INHIBITORS
PREFERENTIAL COX-2 INHIBITORS
MELOXICAM
SELECTIVE COX-2 INHIBITORS
CELECOXIB
ROFECOXIB
• First HMT with NSAID was with Indomethacin in ligature induced canine periodontitis
rat model.
17
18. Disadvantages as a HMT for periodontitis.
• Administration for extended periods is necessary for periodontal
benefits to become apparent, and are associated with
significant side effects:
– Gastrointestinal problems,
– Hemorrhage (from decreased platelet aggregation),
– Renal and hepatic impairment.
– Rebound effect
18
19. – use of selective COX-2 inhibitors reduce periodontal inflammation without
the side effects typically observed after long-term (nonselective) NSAID
therapy.
– selective COX-2 inhibitors slowed alveolar bone loss in animal
models(Bezerra MM jp 1993) and modified prostaglandin production in
human periodontal tissues (Vardar S JPeriodontol 2003). However, the
selective COX-2 inhibitors were later identified to be associated with
significant and life-threatening adverse effects, resulting in some drugs
being withdrawn from the market.
19
20. Role of
arachidonic acid
metabolites.
Mode of
interception
Significant
Contributors
Agents
employed
Author’s coments
Prostaglandins
and other
arachidonic acid
metabolites
within
the periodontal
tissues play a role
in the
pathogenesis.
Inhibition of
arachidonic acid
metabolite by
blocking of the
cyclooxygenase
pathway
Goldhaber
et al (1973)
Nyman et al
(1979)
Weaks-
Dybvig et al
(1982)
Offenbacher
et al (1987)
Jeffcoat et
al (1991)
Indomethacin,
Flurbiprofen,
S-Ketoprofen,
Triclosan.
Systemic daily
administration for
periods up to three
years ,showed
significant reduction
in rate of
bone loss, major
disadvantage of
rebound effect
20
21. Author Purpose Host M
Agent
Parameters Subjects Results
Ishihara y,
nishihara t
et al
(1991)
demonstrate the
lipopolysaccharide
isolated from a.a
comitans strain
induced bone
resorption
Indomethacin
dexamethasone
PGE2 and IL-
1
levels
Mouse PGE2 and IL-1
participate in LPS
induced bone
resorption in
vitro.
Howell th,
fiorellini i,
weber hp et
al (1991)
To study the effects of
piroxicam in
preventing gingival
inflammation
and plaque formation
Piroxicam Gingival
inflammation
plaque index
Beagle dogs Significantly inhibit
the development of
gingival
inflammation
Roy S,
Feldman,
Szeto B et al
(1983)
To evaluate the
effect on bone
resorption: A
retrospective study
Aspirin (asp) or
aspirin plus
indomethcin
Radiographs Humans Percentage bone loss
for the entire
dentition was lower
in
asa group
Offenbacher
S, Odle BM
et al (1989)
metabolites of
cyclooxygenase
(co) during the
progression of
periodontitis
Flurbiprofen Crevicular fluid
levels of PGE2
and TXB2
Rhesus
monkey
prevented rise in
TXB2, but did not
affect increase in
PGE2.
Heasman
PA, et al
(1993)
efficacy of
flurbiprofen (50mg) on
both
developing and
established
gingivitis
Flurbiprofen GCF
concentration
of PGE2, TXB2
and LTB4,
Bleeding index
Human control gingival
inflammation with
both
preventive and
therapeutic
Properties shown after
9 months
21
22. • A series of oxygenated arachidonic acid derivatives
• They have a number of immunomodulatory and anti-inflammatory
actions
22
23. • Lipoxins are short lived endogenously produced substances
• At present two lipoxins have been identified; lipoxin A4 (LXA4) and lipoxin
B4 (LXB4).
• Recently observed from peripheral blood neutrophils in patients with aggressive
periodontitis
• Also found in GCF
• Disrupts the chemotaxis of PMN.
• Administration of metabolically stable analogues of lipoxins blocked P.Gingivalis
induced neutrophil infiltration and also reduced PGE2 levels
• Suggests that these may involve in regulation of acute local inflammatory
response
Academy report, Modulation of host response in periodontal therapy,J
Periodontol 2002,73,460-47
23
24. • Well known and widely used lipid soluble anti bacterial
agent
• Have anti-bacterial and anti-inflammatory agent
• Inhibits cyclooxygenase and lipooxygenase pathways
• Reduced TNFα levels
• Use of dentifrice containing sodium fluoride
(0.243%),triclosan (0.3%) with 2.0% PVM/MA copolymer
(poly vinyl methyl maleic acid) reduced the PD and CAL.
Gaffar, A.,Scherl, D:The effect of triclosan on mediators of gingival inflammation.,J Clin
Periodontol 1995,22,480-484
24
25. • Inhibition of cyclooxygenase and lipooxygenase pathway
(arachidonic acid cascade
• Reduction of prostanoids and leukotriens especially
leukotriene B4
Vardar S, Buduneli E, Baylas H, Berdeli AH, Buduneli N,
Individual and combined effects of selective cyclooxygenase-2 inhibitor and omega-
3 fatty acid on endotoxin-induced periodontitis in rats. J Periodontol 2005:76: 99–
106 25
• Omega-3 fatty acid regulates inflammatory cytokine/mediator
messenger RNA expression in Porphyromonas gingivalis-
induced experimental periodontal disease
27. • The bisphosphonates are bone-seeking agents . inhibit bone resorption by
disrupting osteoclast activity.
• Two types non nitrogenous and nitrogenous
• Interfere with osteoclastic metabolism and secretion of lysosomal enzymes
(Weinreb M et al J Periodontal 1994) possess anticollagenase properties
(Nakaya H et al J Periodontol 2000)
• Treatment with the bisphosphonate significantly increased bone density
compared with placebo ( Reddy MS et al J Periodontol 1995)
• In human studies also, these agents resulted in enhanced alveolar bone
status and density (Rocha M et al J Periodontol 2001)
• The ability of bisphosphonates to modulate osteoclast activity may be useful
in the treatment of periodontitis,
Bisphosphonates
27
28. • Some bisphosphonates have the unwanted effects
– inducing changes in white blood cell counts.
– avascular necrosis of the jaws following bisphosphonate therapy, with
the resultant risk of bone necrosis following dental extractions
(Carter G, Goss AN Med J Aust 2005)
• Bisphosphonate-related osteonecrosis of the jaw, although
primarily associated with intravenous administration of
bisphosphonates rather than oral administration,
• Has impeded the development of bisphosphonates as an HMT to
manage periodontitis.
• As with NSAIDs, at present there are no bisphosphonate drugs that
are approved and indicated for treatment of periodontal diseases
28
30. Tissue level Cellular level molecular level
• ↓osteoclast recruitment
• ↑increased osteoclast
apoptosis
• ↓osteoclast adhesion
• ↓depth of resorption rate
• ↓release of cytokines by
macrophages
• Inhibit mevalonate
pathway – increase in
apoptosis
• Post translational
phenylation of GTP
binding proteins
• ↓bone
resorption
• ↓bone turnover
• ↑Number of
new bone
multicellular
units
• New positive
whole body
bone balance
30
31. Author Purpose Host
modulating
agent
Parameters Subjects Results
Shoji
K,Horiuchi
H (1995)
Efficacy of
risendronate to
prevent
alveolar bone
resorption
Risendronate Bone mineral
density
Rats. In preventing bone
resorption in
periodontitis
M young H ,
P ark JY et al
(2 001 )
evaluate the clinic al
availability
of bisphosphonate
in auto genous
free bone grafts
Bisphosphonates Clinical
measurements,
histomorphologic
al review
Rats Clinical application of
bisphosphonates for
decreasing resorption of
grafted bone
Durate P M ,
Gurgel B C D e
t a l
(2 0 0 5
To evaluate whether
alendronate (ald)
influence
Bone healing around
titan ium
implants
Alendronate Estrogen levels rats . Alendronate may prevent
negative influence of
estrogen deficiency on bone
healing around titanium
implants
Howell 1991,
His-
Ming 2004,
Holzhausen
2005,
Gurkan 2005,
Durate 2005.
Inhibition of
osteoclast/MM
P activity
through
chelation of
cations.
Bisphosphonates
(Alendronate),
Hormone
replacement
therapy.(HRT),
OPG- Fc
therapeutic
agents
Osteoporosis
and
osteopenia
may be
indicators for
periodontal
diseases.
humans improves the
clinical outcome of
nonsurgical periodontal
therapy and may be an
appropriate adjunctive
treatment to preserve
periodontal bone mass.
31
32. • Inhibits bone loss, bone turnover
• Increases bone density
• As inhibits osteoclastic activity and differentiation by
regulating production of stimulatory cytokines. Promotes
osteoclasts apoptosis
32
Academy report, Modulation of host response in periodontal therapy,J Periodontol 2002,73,460-47
34. 34
• Matrix metalloproteinases(MMPs) are considered to be primary proteinases
involved in periodontal tissue destruction by degradation of extracellular matrix
molecules
35. • Polymorphonuclear leukocyte type collagenase (MMP-8)
and gelatinase (MMP-9) as the source of excess active
enzymes present (Golub et al, 1997)
• 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.
(Golub et al, 2001)
•
35
• Found in neutrophils, macrophages, fibroblasts, epithelial
cells, osteoblasts and osteoclasts
37. • Several synthetic MMP inhibitors are being studied in clinical trails
• Some Zinc and calcium chelating agents (EDTA and phenanthroline) are
potent inhibitors of enzyme activity invitro but are toxic and not used
invivo.
• Multiple synthetic peptides have been formulated in an attempt to
synthesize more specific chelators including phosphorus-containing
peptides, sulfur-based inhibitors and peptidyl hydroxamic acid
derivatives, these also found as toxic in vivo
• The synthetic MMP inhibitors most extensively investigated are the
family of tetracycline antibiotics, which can inhibit host-derived MMPs
by mechanisms independent of their antimicrobial properties.
37
39. • Sub-antimicrobial-dose doxycycline (SDD) is a 20-
mg dose of doxycycline that is approved and
indicated as an adjunct to SRP in the treatment of
chronic periodontitis.
• It is taken twice daily for 3 months, up to a
maximum of 9 months of continuous dosing.
39
Sub antimicrobial dose of doxycyclines as an adjunct to scaling and root planing : post
treatment effects, J Clin Periodontol 2001; 28: 782–789
40. • Studies have found no detectable antimicrobial effect
on the oral flora or the bacterial flora in other regions
of the body.
• At present SDD is the only systemically administered
HMT specifically indicated for the treatment of chronic
periodontitis that is approved by the US Food and Drug
Administration (FDA) and accepted by the American
Dental Association (ADA).
40
41. Courtesy: Philip M preshew,Host response modulation in periodontitis Periodontology 2000,vol 48,
2008,92-110 41
42. • Golub et al (J Periodont Res 1985). reported that the
semisynthetic compound (e.g., doxycycline) was more
effective than the parent compound tetracycline in
reducing excessive collagenase activity in the GCF of
chronic periodontitis patients.
• Because of its safety profile, pharmacokinetic properties,
and ready systemic absorption. to eliminate the side
effects of long-term tetracycline therapy, especially the
emergence of tetracycline-resistant organisms, SDD
capsules were prepared and tested( Golub LM1985)
42
43. • Each capsule contained 20 mg of doxycycline versus the
commercially available 50 mg and 100 mg, antimicrobially
effective, capsules or tablets.
• clinical studies using sub-antimicrobial doses of
doxycycline have shown no difference in the composition
or resistance level of the oral flora (Thomas J; jp 2000)
• No overgrowth of opportunistic pathogens, such
as Candida, in the oral cavity, gastrointestinal system, or
genitourinary system.
43
44. Golub et al 1985 reported that a 2-week regimen of
SDD reduced collagenase in GCF and in the adjacent
gingival tissues surgically excised for therapeutic
purposes.
He found using SDD therapy adjunctive to routine
scaling and prophylaxis cause continued reductions
in the excessive levels of collagenase in the GCF after
1 month of treatment.
44
45. 45
After cessation of SDD administration, however,
there was a rapid rebound of collagenase activity ,
suggesting that a 1-month treatment regimen with
this host modulation agent was insufficient to
produce a long-term benefit(Ashley RA 1999)
In contrast, during the same study, a 3-month
regimen produced a prolonged drug effect without a
rebound in collagenase levels to baseline during the
no-treatment phase of the study. these reductions in
collagenase levels were gains in the relative
attachment levels in the SDD group( Ashley RA 1999)
46. allergy or hypersensitivity to tetracyclines.
pregnant or lactating women or children less than 12
years old (because of the potential for discoloration of
the developing dentition).
reduce the efficacy of oral contraceptive.
There is a risk of increased sensitivity to sunlight
(manifested by an exaggerated sunburn) seen with
higher doses of doxycycline, although this has not
been reported in using the sub-antimicrobial dose.
46
47. 47
During the late 1980s, it was discovered that tetracyclines have an inhibitory
effect on MMP activity
This led to the development of chemically modified tetracyclines (CMTs), which
have lost their antimicrobial activity but retain their anti-MMP activity.
Development of resistant bacteria and gastrointestinal toxicity seen with parent
tetracyclines is not produced by CMTs
CMT 1–10 has proposed till now
CMT-3 and -8 appear to be the most potent inhibitors of MMP activity. CMT-1
also affects MMP activity, but it is less powerful
A marked decrease of MMP-2 mRNA levels is found in keratinocytes by CMT-1
and CMT-3
Chemically modified tetracyclines stimulate matrix metalloproteinase-2 production by
periodontal ligament cells, J Periodont Res 2006; 41; 463–470
48. TIMPS (Tissue inhibitors of MMPS)
Forms classic non-covalent bio-molecular complexes with MMPs.
inhibit the activity of the fully competent MMP.
Block or retard the MMP precursor activation.
So balance should be there
Though TIMP levels increases in pathological conditions this increase may
not compensate for elevated concentrations of MMPs
Recombinant TIMPs can reduce bone resorption
Hill P, Raynolds, Inhibition of stimulated bone resorption in vitro by TIMP 1,
TIMP2. Biochem biophys Acta 1993, 1171-1174 48
α2 macroglobulin
• Regulates MMPS in body fluids
50. 1. IL-1 Receptor antagonist
2. TNF-α Receptor antagonist
• Catabolic activities of cytokines are regulated by endogenous inhibitors like
× The progression of inflammatory cells
towards alveolar crest
× The recruitment of osteoclasts
× Periodontal attachment and bone loss
• IL4, IL10,IL11, TGFβ are natural counteract for pro inflammatory cytokines
• Recombinant IL11 reduced disease progression in ligature induced periodontitis
canine model (Martscelli et al2000)
50
52. • Nitric oxide
• Administration of NO inhibitor (mercaptoethylguanide) -
decreased bone loss in rat model (Lohinal et al 1998)
52
• inducible NOS (iNOS) is responsible for nitric oxide (NO)
production by epithelial and inflammatory cells in response
to proinflammatory cytokines in some inflammatory
diseases (Lappin et al. 2000)
• Although NO has an antimicrobial protective activity, its
elevated concentration in the tissues has a cytotoxic effect
toward the host cells.
53. 53
Periodontal vaccines
local host modulating agents
Combination therapy
Disruption of cell signaling pathways
NFkB pathway
MAPK pathway
disruption of RANK/RANKL/osteoprotegerin axis
JAK-STAT pathway
conclusion
54. 54
The development of vaccines is an important strategy against serious infectious
diseases that do not have effective treatments
recent findings of associations between periodontitis and other systemic diseases may
provide a rationale for the development of a vaccine against periodontitis
Vaccination is the most effective medical intervention against viral pathogens
As the association of Epstein–Barr virus and periodontitis was suggested (Slots J,
Contreras, Oral Microbiol Immunol2000:15: 277–280.)
Phosphoryl choline is a common bacterial antigen, and a substantial proportion of the
bacteria in dental plaque (30–40%) bear phosphoryl choline antigen(Schenkein HA et
al, Infect Immun1999:67: 4814–4818)
Antibody to phosphoryl choline is produced by B-1 cells, and is increased in
periodontitis patients.
B-2 cells reside in lymphnodes and also produce high affinity antibodies.
55. 55
• In a non-human primate model, formalin killed P. gingivalis
whole-cell vaccine induced serum antibody
• The induced antibody inhibited prostaglandin E2 production by
mononuclear cells stimulated with lipopolysaccharide.
(Roberts FA, Houston LS, Lukehart SA, Mancl LA, Persson GR, Page
RC. Periodontitis vaccine decreases local prostaglandin E2 levels in
a primate model. Infect Immun 2004:72: 1166–1168)
• Among the P. gingivalis antigens, fimbriae and enzymes such as
arginine-specific gingipains and lysine-specific gingipain have
been investigated as possible candidates for vaccine antigens.
• Immunization with P. gingivalis fimbriae also protected against
periodontal destruction in rats(Evans RT, Infect Immun 1992:60:
2926–2935.)
59. ¶ Enamel matrix proteins
¶ Bone morphogenetic proteins (BMP-2, BMP-7),
¶ Growth factors (platelet-derived growth factor)
¶ Insulin like growth factor.
¶ Tetracyclines.
59
Philip M preshew,Host response modulation in periodontitis Periodontology 2000,vol 48, 2008,92-
110
60. • The locally applied HMTs currently approved by the FDA for
adjunctive use during surgery are
– Enamel matrix proteins (Emdogain),
– Recombinant human platelet-derived growth factor-BB
(GEM 21S),
– BMP-2 (INFUSE).
All topically administered NSAIDs have not been approved as local
HMTs for the management of periodontitis.
Eg : ketoprofen racemic cream 1%,enantiomer dentifrice 0.3%,
60
Academy report, Modulation of host response in periodontal therapy,J Periodontol 2002,73,460-47
61. • The initial local host modulatory agent approved by the FDA for adjunctive use
during surgery to assist with clinical attachment gain and wound healing was
Emdogain;
• EMD may affect gingival health by ways other than cell proliferation/survival, i.e.
by stimulation of TIMP-3 production,which could improve the MMP–TIMP
balance in gingival tissue and extracellular matrix destruction when applied
locally.
(Zeldich, E et al Journal of Periodontal Research. Apr2010, Vol. 45 Issue 2, p200-206)
• platelet-derived growth factor combined with a resorbable synthetic bone matrix
(GEM 21S) to assist in regenerative procedures , wound healing, particularly in
patients with diabetes
• rhBMP-2 (INFUSE) soaked on to an absorbable collagen sponge to assist with
ridge and sinus augmentation and healing of fractures by the orthopedic
community.
61
63. • NO synthase inhibitors:-
• Nitric oxide synthase (NOS) inhibitors have protective
effects against bone resorption and inflammatory process
in periodontitis in rats.
• Lappin et al. in 2000 reported that inducible NOS (iNOS) is
responsible for nitric oxide (NO) production by epithelial
and inflammatory cells in response to proinflammatory
cytokines in some inflammatory diseases such as
rheumatoid arthritis and periodontal disease.
63
64. Although NO has an antimicrobial protective activity, its
elevated concentration in the tissues has a cytotoxic effect
toward the host cells.
Leitao et al. in 2005 found a reduction of alveolar bone loss
and gingival inflammation after the use of a selective iNOS
inhibitor – mercaptoethylguanidine – confirming that NO has
a deleterious role in the pathophysiology of periodontitis and
that its modulation may prevent tissue destruction.
64
67. • Bacterial components activate many signal transduction pathways
.
– Mitogen-activated protein kinase (MAPK)
pathway,
– Phosphatidylinositol-3 protein kinase (PI3)
pathway,
– Janus kinase-signal transducer and activator of
transcription (Jak-STAT),
– Nuclear factor kappa B (NF-kB) .
67
68. TRAF
NFkB + IkB
iKB Kinase
NFkB
Proteasome
inhibitors
• Inhibition of IkB
degradation
• Over expression of
IkB
• Inhibition of protein
kinases that activates
IkB
68
74. • RANKL : OPG is increased in periodontitis patients in GCF
• Other cells like CD4-Tcells also express RANKL during inflammation
• Osteoprotegerin can be used as therapeutic agent (simonet et al)
• Eg: murine osteoprotegerin- Fc Protein
• Gene therapy for the lifelong delivery of osteoprotegerin has also been
proposed
• Osteoprotegerin expressing adenovirus vectors provided sustained
and efficacious levels of circulating osteoprotegerin
• AMGN-0007 a genetically engineered osteoprotegerin- Fc construct
was shown to be effective in inhibiting bone resorption (Teng et al
2001)
74
75. References
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2. Host response modulation in periodontics., Periodontology 2000, Vol. 48, 2008,
92–110
3. Host responses in periodontal diseases: a preview, Periodontology 2000, Vol. 43,
2007, 9–13
4. Toll gates to periodontal host modulation and vaccine therapy, Periodontology
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5. Host-Response Therapeutics for Periodontal Diseases, J Periodontol 2008;79:1592-
1600.
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470.
7. Modulation of Host PGE2 Secretion as a Determinant of Periodontal Disease
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8. Host-Response Therapeutics for Periodontal Diseases, J Periodontol 2008;79:1592-
1600.
9. Chemically modified tetracyclines stimulate matrix metalloproteinase-2
production by periodontal ligament cells., J Periodont Res 2006; 41; 463–470
10. A Decade of Bisphosphonate Bone Complications: What It Has Taught Us About
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75
76. 11. Bisphosphonates in Periodontal Treatment: A Review ., Oral Health Prev Dent 2009;
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sparing agents, a systematic review.,Ann Periodontal,vol8, number 1, December 2003.
76