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HOST MODULATING AGENTS

Comprehensive Theory Examination Short Notes

Postgraduate Periodontology Examination

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1. DEFINITION AND INTRODUCTION

• Host modulation is defined using Taber's Medical Dictionary (2004) as "the alteration of function or status of something in response to a stimulus or an altered chemical or physical environment."
• In periodontal diseases initiated by bacteria, the "host" is the individual who harbors the pathogens; host modulation with chemotherapeutic agents or drugs is the latest adjunctive therapeutic option for the management of periodontal diseases.
• The concept was first introduced to dentistry by Williams (1990) and Golub et al. (1992), and then expanded on by many other scholars.
  • Williams (1990): "there are compelling data from studies in animals and human trials indicating 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."
  • Golub et al. (1992): discussed "host modulation with tetracyclines and their chemically modified analogues."
• Host modulation is universally understood by physicians who manage chronic progressive disorders such as arthritis and osteoporosis.

[Source: Newman & Carranza's Clinical Periodontology and Implantology, 14th ed., Ch. 55; Carranza's 10th ed., Ch. 53]

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2. RATIONALE / PATHOGENESIS BASIS

• The majority of periodontal breakdown (bone loss, attachment loss) is caused by host-derived destructive enzymes (MMPs) and inflammatory mediators (prostaglandins, interleukins) that are released during the destructive inflammatory response.
• Periodontal disease is characterized by high concentrations of MMPs, cytokines, and prostanoids in the periodontal tissues; periodontal health is characterized by the opposite.
• The purpose of HMT is to restore the balance of proinflammatory or destructive mediators and anti-inflammatory or protective mediators to that seen in healthy individuals.

Key Mediators in Disease vs Health (The Periodontal Balance)

[Source: Essentials of Clinical Periodontology and Periodontics, Table in Ch. 15; Newman 14th ed., Fig. 55.2]

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3. FLOWCHART: PATHOGENESIS AND TARGETS FOR HOST MODULATION

Plaque Biofilm (Gram-negative anaerobes: LPS)
          |
          v
Neutrophils (PMNs) recruited
          |
          +---> Release of MMPs (MMP-8, MMP-9) -----> Collagen breakdown / Connective tissue destruction
          |
          v
Macrophages activated by LPS binding
          |
          +---> PGE2, IL-1α, IL-1β, IL-6, TNF-α, MMPs
                     |
                     v
              Fibroblasts stimulated
                     |
                     +---> Positive feedback: more PGE2, IL-1, TNF-α, MMPs
                     |
                     v
              Osteoclast activation
                     |
                     v
              ALVEOLAR BONE RESORPTION
                     |
                     v
            Pocket formation → Apical migration →
            Further destruction → Attachment loss / Tooth loss

=== THERAPEUTIC TARGETS FOR HOST MODULATION ===

1. MMPs         ---> SDD (Periostat), CMTs, CMCs, PEZBINs
2. Cytokines    ---> Anti-TNF-α (Infliximab, Etanercept), Anti-IL-6 (Tocilizumab), IL-1ra
3. Prostanoids  ---> NSAIDs (Indomethacin, Flurbiprofen, Naproxen), COX-2 inhibitors
4. Osteoclasts  ---> Bisphosphonates (Alendronate)
5. Resolution   ---> Resolvins (RvE1, RvD), Lipoxins, SPMs, Omega-3 PUFAs
6. Microbiome   ---> Probiotics (Lactobacillus-based)

[Source: Newman 14th ed., Fig. 55.3; Essentials, Flowchart 15.1]

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4. CLASSIFICATION OF HOST MODULATORY AGENTS

As per Essentials of Clinical Periodontology and Periodontics (S. Reddy):

• Suppressing pro-inflammatory cytokines (IL-1 and TNF-α receptor antagonists)
• Nitric Oxide (NO) Synthase Inhibitors
• Use of periodontal vaccines to produce protective antibodies
• Infusion or supplementary anti-inflammatory cytokines (IL-4, IL-10)

• Sub-antimicrobial dose of doxycycline (SDD)
• Chemically modified tetracyclines (CMTs)

• Non-steroidal anti-inflammatory drugs (NSAIDs)
  • COX-1 inhibitors: Indomethacin, Naproxen, Flurbiprofen
  • COX-2 inhibitors: Rofecoxib
  • Lipoxygenase (LOX) inhibitors: Lipoxins
  • COX and LOX inhibitors: Triclosan, topical Ketoprofen

• Bisphosphonates
• Hormone replacement therapy (HRT)
• Calcium supplementation

• Lipoxins
• Resolvins of the E-series
• Resolvins of the D-series
• Protectins

• Emdogain - described as the only local host modulation agent currently approved by the FDA (per this reference)

• PDGF (platelet-derived growth factor)
• IDGF (insulin-derived growth factor)
• Bone morphogenetic proteins (BMP-2, BMP-7)

[Source: Essentials of Clinical Periodontology and Periodontics, S. Reddy, Ch. 15]

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5. BIOLOGICAL MECHANISM AND CLINICAL APPLICATION TABLE

[Source: Essentials of Clinical Periodontology and Periodontics, Table 15.2]

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6. SUB-ANTIMICROBIAL DOSE DOXYCYCLINE (SDD) — THE ONLY FDA-APPROVED SYSTEMIC HMT

6a. Background and Approval

• Previously called "low-dose doxycycline" (LDD); currently marketed as Periostat.
• Based on a sub-antimicrobial dosage of doxycycline, a member of the tetracycline family.
• In 1998, the FDA approved Periostat (from CollaGenex) for use in the USA — contains 20 mg of doxycycline in tablets to be taken orally twice a day for at least 3 months as adjunctive therapy in patients with chronic periodontitis (CP) undergoing the initial phase of periodontal treatment (SRP).
• SDD (Periostat) 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).

[Source: Newman 14th ed., Ch. 55; Antibiotics and Antiseptics in Periodontal Therapy, Ch. 3; Carranza 10th ed., Ch. 53]

6b. Mechanisms of Action (Pleiotropic Effects)

• Doxycycline downregulates MMPs (a family of zinc-dependent enzymes capable of degrading extracellular matrix molecules including collagen) by a variety of synergistic mechanisms, independent of any antibiotic properties, as summarized by Walker (2008):

[Source: Antibiotics and Antiseptics in Periodontal Therapy, Ch. 3; Newman 14th ed., Ch. 55 Fig. 55.5; Carranza 10th ed., Ch. 53]

6c. Why Doxycycline is Superior Among Tetracyclines

• Doxycycline was found to be a more effective inhibitor of collagenase than either minocycline or tetracycline.
• Minocycline, doxycycline, and tetracycline were all shown to inhibit collagenolytic activity, whereas non-tetracycline antibiotics had no effect on collagenase levels.
• Doxycycline was selected because of its safety profile, pharmacokinetic properties, and ready systemic absorption.
• The semisynthetic compound doxycycline was more effective than the parent compound tetracycline in reducing excessive collagenase activity in GCF of chronic periodontitis patients (Golub et al.).

[Source: Newman 14th ed., Ch. 55; Antibiotics and Antiseptics in Periodontal Therapy, Ch. 3]

6d. Key Pharmacological Distinction

• SDD (20 mg) dose has no detectable antimicrobial effect on the oral flora or bacterial flora in other regions of the body.
• Multiple clinical studies using SDD have shown no difference in the composition or resistance level of the oral flora.
• No overgrowth of opportunistic pathogens (e.g., Candida) in oral cavity, GI system, or genitourinary system.
• No evidence of developing antibiotic resistance of the microflora after 2 years of continuous use.
• The 20-mg dose exerts therapeutic effect by enzyme, cytokine, and osteoclast inhibition rather than by any antibiotic effect.

[Source: Newman 14th ed., Ch. 55; Antibiotics and Antiseptics in Periodontal Therapy, Ch. 3]

6e. Key Clinical Research Data

• A review paper revealed adjunctive therapy with SRP and SDD results in a 70% improvement in CAL (with SRP alone providing a 35% improvement); adjunctive SDD resulted in an additional 0.35-mm gain in CAL above and beyond SRP alone.
• Caton et al. (2000): 9-month double-blind, placebo-controlled study. SRP + SDD (90 subjects) vs. SRP + placebo (93 subjects). Statistically significant improvements in mean CAL change and PD reduction at both 4-6 mm and 7+ mm pockets. (Table 53-1 / Table 55.1 in references).
• Novak et al. (2002): Severe generalized periodontitis patients (70% smokers). SDD as adjunct to mechanical therapy resulted in significantly greater mean probing depth reductions in pockets of 7 mm or greater at baseline as early as 1 month after therapy (2.52 mm vs. 1.25 mm). Improvements maintained at 3 months after stopping drug therapy (3.02 mm vs. 1.41 mm). No rebound effect occurred.
• Preshaw et al. (2004): 107 SDD vs. 102 placebo. Statistically significant improvements in PD and CAL in moderately and severely diseased sites.
• Ryan et al.: In PST-positive (PAG) patients – after SRP alone, no change in IL-1β and MMP-9 levels; after SDD, a significant decrease (50%-61%) in IL-1β and MMP-9 levels.
• Golub et al.: A 2-week regimen of SDD reduced collagenase in GCF and adjacent gingival tissues. A 3-month regimen produced a prolonged drug effect without rebound in collagenase levels; mean levels of GCF collagenase significantly reduced (47.3% from baseline) in SDD group vs. placebo (29.1%).
• After cessation of 1-month regimen: rapid rebound of collagenase activity to placebo levels (insufficient for long-term benefit). After 3 months: no rebound.

[Source: Newman 14th ed., Ch. 55; Carranza 10th ed., Ch. 53; Antibiotics and Antiseptics in Periodontal Therapy, Table 3.4]

6f. Prescribing Protocol / Sequencing

• SDD is indicated as an adjunct to mechanical periodontal therapy and should not be used as a stand-alone or monotherapy.
• Should be prescribed to coincide with the first round of SRP.
• Prescribed for 3 months, up to a maximum of 9 to 24 months of continuous dosing depending on patient's risk.
• Fits well with the typical maintenance recall interval of 3 months (based on the duration for recolonization of treated periodontal pockets).
• Patients may cycle between phases of "active" treatment (SRP + SDD) and long-term periodontal maintenance.
• Can be combined with locally applied antimicrobials and periodontal surgery.
• The two treatment approaches (SDD + local delivery) target different aspects of the pathogenic process: local delivery systems deliver antimicrobial concentrations (targeting bacteria); SDD targets the host response (inhibiting MMPs systemically).

[Source: Newman 14th ed., Ch. 55; Carranza 10th ed., Ch. 53]

6g. Side Effect Profile

• Doxycycline at antibiotic doses (≥100 mg) is associated with: photosensitivity, hypersensitivity reactions, nausea, vomiting, esophageal irritation.
• In clinical trials of SDD (20-mg dose): drug was well tolerated and profile of unwanted effects was virtually identical in SDD and placebo groups.
• The typical side effects of the tetracycline class were not observed, indicating side effects are dose-related.
• No evidence of adverse events attributable to antimicrobial effects.

[Source: Newman 14th ed., Ch. 55]

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7. CHEMICALLY MODIFIED TETRACYCLINES (CMTs)

• A promising group of potential HMTs (not yet licensed for periodontal use).
• These are nonantibiotic tetracycline analogs — tetracycline molecules modified to remove all antibiotic properties, but which retain host modulatory and anticollagenolytic effects.
• 10 different CMTs have been developed (CMT-1 through CMT-10), none possessing antimicrobial properties.
• CMTs inhibit MMPs through: Zn²⁺ chelation, downregulation of MMP mRNA expression, interference with protein processing during activation, and rendering MMPs more susceptible to degradation.
• CMTs are also designed to be more potent inhibitors of proinflammatory mediators and can increase levels of anti-inflammatory mediators such as IL-10.
• Because they have no antimicrobial properties, the clinician would be able to increase the dose for more susceptible patients without experiencing antibiotic side effects.

Key CMTs studied:

• CMTs have been studied for: inhibition of osteoclastic bone resorption and promotion of bone formation; enhanced wound healing; inhibition of proteinases produced by periodontal pathogens; inhibition of tumor cell invasion; attenuation of intimal thickening.
• "CMTs will likely emerge as drugs that have beneficial effects in a variety of disease states because of their host modulation capabilities."
• In animal models, CMTs have been reported to reduce the progression of experimentally induced periodontitis; however, inhibition of human periodontitis is still not established.

[Source: Newman 14th ed., Ch. 55; Carranza 10th ed., Ch. 53; Essentials, Ch. 15; Antibiotics and Antiseptics in Periodontal Therapy, Ch. 3]

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8. NON-STEROIDAL ANTI-INFLAMMATORY DRUGS (NSAIDs)

• NSAIDs inhibit the formation of prostaglandins, including PGE2, produced by neutrophils, macrophages, fibroblasts, and gingival epithelial cells in response to LPS (component of cell wall of gram-negative bacteria).
• PGE2 has been extensively studied in periodontal disease because it upregulates bone resorption by osteoclasts. Levels of PGE2 have been shown to be elevated in patients with periodontal disease compared with healthy patients. PGE2 also inhibits fibroblast function and has inhibitory and modulatory effects on the immune response.
• NSAIDs include: salicylates (aspirin), indomethacin, propionic acid derivatives (ibuprofen, flurbiprofen, naproxen).

NSAID Research Findings:

• COX-2 selective inhibitors were later identified to be associated with significant and life-threatening adverse effects (myocardial infarction), resulting in some drugs being withdrawn from the market (e.g., Rofecoxib).
• Significant disadvantages for periodontal use: Daily administration for extended periods necessary; serious side effects including gastrointestinal problems, hemorrhage (from decreased platelet aggregation), and renal and hepatic impairment.
• "NSAIDs (including the selective COX-2 specific inhibitors) are presently not indicated as adjunctive HMTs in the treatment of periodontal disease."

[Source: Newman 14th ed., Ch. 55; Essentials, Ch. 15]

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9. BISPHOSPHONATES

• Bone-seeking agents that inhibit bone resorption by disrupting osteoclast activity.
• Precise mechanism of action unclear, but research has shown bisphosphonates interfere with osteoblast metabolism and secretion of lysosomal enzymes. More recent evidence suggests they also possess anticollagenase properties.

Structure:

• Chemical structure consists of two phosphate groups covalently bonded to a central carbon.
• The R1 and R2 side chains determine the specific drug properties.
• R2 contains nitrogen in aminobisphosphonates.

Two Main Types:

• Ability to increase bone mass discovered after animal studies in 1966.
• Half-life of bisphosphonates in bone is estimated to be 10 years.

Periodontal Research Evidence:

• In naturally occurring periodontitis in beagle dogs, treatment with the bisphosphonate alendronate significantly increased bone density compared with placebo.
• In animal models of experimentally induced periodontitis, bisphosphonates reduced alveolar bone resorption.
• In human studies, these agents resulted in enhanced alveolar bone status and density.

Adverse Effects / Limitations:

• Some bisphosphonates have unwanted effects of inhibiting bone calcification and inducing changes in white blood cell counts.
• Reports of avascular necrosis of the jaws (osteonecrosis) following bisphosphonate therapy — resultant risk of bone necrosis following dental extractions.
• Bisphosphonate-related osteonecrosis of the jaw (BRONJ/ARONJ/ONJ) — first described in 2003 — primarily associated with IV administration (cancer treatment) rather than oral administration.
• Incidence among patients taking oral bisphosphonates for osteoporosis: estimated at 0.007% (appears to be low).
• "At present there are no bisphosphonate drugs that are approved and indicated for treatment of periodontal diseases."

Terminology Note (Recent Change):

• The condition has been called by multiple names in the literature: avascular necrosis, bisphosphonate-associated ONJ, bisphosphonate-induced ONJ, and bisphosphonate-related ONJ (BRONJ); the current preferred term is MRONJ (Medication-Related Osteonecrosis of the Jaw).

[Source: Newman 14th ed., Ch. 55 and Ch. 25; Carranza 10th ed., Ch. 53]

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10. ANTI-CYTOKINE THERAPY

• Anti-cytokine therapy utilizes monoclonal antibodies against cytokines or cytokine receptor antagonists to reduce destructive inflammatory processes.
• Developed originally for the management of rheumatoid arthritis, a disease with a pathobiology similar to periodontitis.

Key Agents:

• These disease-modifying anti-rheumatic drugs (DMARDs) are associated with significant unwanted side effects; additional studies are necessary.
• Anti-cytokine therapy could offer potential benefits given the importance of inflammatory cytokines, such as TNF-α and IL-6, in periodontal pathogenesis.

[Source: Newman 14th ed., Ch. 55; Carranza 10th ed., Ch. 53]

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11. OMEGA-3 POLYUNSATURATED FATTY ACIDS (PUFAs) AND RESOLVINS

Omega-3 PUFAs:

• Studies have indicated that n-3 polyunsaturated fatty acids (n-3 PUFAs; fish oil), as an adjunct to oral hygiene instructions, can significantly lower GCF IL-8, IL-6, and PGE2 levels compared to placebo controls.
• A combination therapy with n-3 PUFA and low-dose aspirin as an adjunct to regenerative procedures utilizing decalcified freeze-dried bone allografts results in greater mean PD reductions (P < .001) and gains in CAL (P < .05) accompanied by a trend for modulation of the cytokine profile of IL-1β and IL-10 in GCF.
• PUFAs have therapeutic effects on treating various chronic inflammatory diseases such as CVD, diabetes, and COVID.

Specialized Pro-Resolving Mediators (SPMs):

• There is an active biochemical resolution phase involved in inflammation — this is now recognized as a key component of the normal inflammatory process.
• Failure of this resolution pathway can cause prolonged chronic inflammation, delayed wound healing, and can play a role in the pathogenesis of many medical conditions including periodontal diseases.
• Specialized pro-resolving mediators (SPMs) are a family of agents including lipoxins, resolvins (Resolvin Ds and Es), and protectins, derived from PUFAs.
• They promote restoration of normal cellular function and resolution of inflammation.

Resolvins:

• Aspirin-modified COX-2 converts EPA to E-series resolvins.
• SPMs can inhibit inflammatory cell infiltration, promote phagocytosis to remove dead cells and foreign objects, and ultimately restore tissue homeostasis.
• Resolvin E1 (RvE1) — Key Animal/Human Studies:
  • In rabbit animal models of periodontitis, topical application of RvE1 was shown to protect bone loss mediated by osteoclasts.
  • In a rat model, RvE1 was shown to reverse periodontal bone loss and inflammatory gene expression with reductions in osteoclast density.
  • A small-scale human clinical study with localized aggressive periodontitis showed RvE1 can restore impaired macrophage cell function.
• "To date, resolvins have demonstrated great potential as an HMT drug candidate to resolve inflammation and reduce the severity of periodontal diseases."

[Source: Newman 14th ed., Ch. 55; Essentials, Ch. 15]

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12. PROBIOTICS

• Studies have revealed that probiotics can be beneficial in the management of periodontitis.
• Lactobacillus-based probiotics demonstrated potential therapeutic effects on reduction of GI (gingival index) and PD, with gains in CAL compared with a placebo control when administered as adjunctive treatment to SRP.
• Probiotics seem to modulate both the periodontal pathogens and host inflammatory responses.
• Probiotics reduce levels of gram-negative bacteria, temporarily shifting the oral microbial environment to a more healthy microbiome.
• With regards to host modulation, it is proposed that probiotics can modulate T-regulatory cell activity to inhibit inflammation and periodontal bone loss, and may play a role in the inhibition of nitric oxide synthesis.
• "More extensive studies of probiotics demonstrating safety and efficacy are needed before this approach can be available clinically."

[Source: Newman 14th ed., Ch. 55]

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13. EMERGING/NEW HOST MODULATORY AGENTS

13a. Poly-Enolic Zinc-Binding Compounds (PEZBINs)

• New collagenase (MMP) inhibitors — based on the natural product curcumin, which contains a calcium and zinc binding β-diketone moiety similar to that found in tetracyclines.
• Anti-inflammatory properties demonstrated in periodontal disease, CVDs, cancer, arthritis, and diabetes.
• A novel group of chemically modified curcumins (CMC) with increased bioavailability and improved anti-inflammatory activity has been tested.
• In vitro and in vivo findings: these new agents can decrease pathologically elevated MMP levels in plasma and gingiva of animal models of periodontitis.
• In experimental diabetic rat model, CMC shown to have resolving-like activity to restore impaired macrophage function, increase RvD1 levels, resolve chronic inflammation, and attenuate alveolar bone loss.

13b. Semi-Synthetic Glycosaminoglycan Ether (SAGE)

• A sulfated polysaccharide that suppresses inflammatory mediators in high-risk individuals (diabetes, smokers).
• Mechanism: ability to reduce the impact of advanced glycation end products (AGEs), resulting in reductions of pro-inflammatory mediators.
• Systemic administration of SAGE significantly reduced local and systemic inflammation by modulating the production of cytokines and MMPs.
• Periodontal bone loss significantly attenuated in diabetic rats with Pg-infection.

13c. Stem Cell-Based Therapies

• Human periodontal stem cells can modulate neutrophil function and reduce excessive inflammation.
• Bone marrow-derived mesenchymal stem cells have shown potential for periodontal regeneration in animal models.

13d. Other Categories Being Investigated

• Complement inhibitors
• Homeostatic proteins with epidermal growth factor-like and discoidin-like domains

[Source: Newman 14th ed., Ch. 55]

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14. HOST MODULATION AND SYSTEMIC DISEASE CONNECTIONS

• MMPs and cytokines have been found to play a major role in weakening the plaques formed by CVD (cardiovascular disease), leading to rupture and eventual thrombosis and infarction.
• Golub et al. suggested that tetracyclines could reduce the incidence of acute myocardial infarction by blocking collagenase and stabilizing the collagen cap on atheroscleromatous arterial plaques.
• In diabetes: the same MMPs and cytokines involved in periodontitis (the sixth long-term complication of diabetes) also play a role in other well-known diabetic complications — nephropathy, angiopathy, retinopathy, and wound-healing problems.
• Doxycycline has led to improvements in both the periodontal health of compromised diabetic patients and long-term markers of glycemic control (e.g., glycated hemoglobin).
• SDD significantly reduced the progression of periodontal attachment loss and the severity of gingival inflammation and alveolar bone loss in postmenopausal osteopenic women (Reinhardt et al.; Payne et al.; Golub et al.).

[Source: Newman 14th ed., Ch. 55]

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15. COMPLEMENTARY TREATMENT STRATEGIES (INTEGRATED APPROACH)

COMPLEMENTARY TREATMENT STRATEGIES IN PERIODONTITIS
(Best chance for clinical improvement = all 3 strategies combined)

+-------------------------------+     +------------------------------+     +---------------------------+
|  REDUCTION OF BACTERIAL       |     |  HOST RESPONSE MODULATION    |     |  RISK FACTOR MODIFICATION |
|  BURDEN                       |     |                              |     |                           |
|  SRP (gold standard)          |  +  |  Sub-antimicrobial-dose      |  +  |  Smoking cessation        |
|  Topical antimicrobials       |     |  doxycycline (SDD) for       |     |  Diabetes control         |
|  Surgical pocket reduction    |     |  inhibition of MMPs          |     |  Nutritional supplement   |
+-------------------------------+     +------------------------------+     +---------------------------+

[Source: Newman 14th ed., Ch. 55, Fig. 55.4]

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16. PATIENTS MOST LIKELY TO REQUIRE HMT

• Genetic susceptibility (e.g., PAG/PST-positive patients — IL-1 polymorphism)
• Smoking
• Diabetes (poorly controlled)
• Osteoporosis / Postmenopausal osteopenic women
• Institutionalized geriatric patients
• Severe generalized periodontitis
• Non-modifiable or difficult-to-modify risk factors

[Source: Newman 14th ed., Ch. 55; Carranza 10th ed., Ch. 53]

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17. ARACHIDONIC ACID PATHWAY (HOST MODULATION TARGET)

Flowchart (from Essentials / Newman):

TISSUE DAMAGE (Bacterial + Host factors)
        |
        v
Phospholipids in plasma membrane become available to
        PHOSPHOLIPASE A2
        |
        v
FREE ARACHIDONIC ACID
        |
   +----------+----------+
   |                     |
   v                     v
CYCLOOXYGENASE        LIPOXYGENASE
PATHWAY               PATHWAY
   |                     |
   v                     v
Prostaglandins         Leukotrienes
Prostacyclins          Hydroxyeicosatetraenoic acids (HETEs)
Thromboxane
   |
   v
PGE2 (elevated in GCF in
gingivitis and periodontitis)
   |
   v
UPREGULATES OSTEOCLASTIC
BONE RESORPTION

[Source: Essentials of Clinical Periodontology, Ch. 15, Flowchart 15.1]

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18. COMPARISON TABLE: DIFFERENT REFERENCE VIEWPOINTS

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19. KEY EXAMINER POINTS / KEYWORDS TO REMEMBER

• Periostat = trade name for SDD (20 mg doxycycline BID)
• Pleiotropic effects = multiple mechanisms of action of doxycycline on host response
• LDD → SDD = terminology change (low-dose doxycycline → sub-antimicrobial dose doxycycline)
• BRONJ / ARONJ / MRONJ = terminological evolution for bisphosphonate-related jaw osteonecrosis
• Paradigm shift = from purely plaque-associated disease to host response-centered understanding
• Only systemically administered FDA/ADA-approved HMT = SDD (Periostat)
• Only locally administered FDA-approved HMT = Emdogain (EMD) (per Essentials)
• No rebound effect = after SDD cessation following a 3-month regimen (vs. 1-month regimen = rebound)
• PAG / PST = periodontitis-associated genotype / periodontal susceptibility test — IL-1 polymorphism
• MMP-8 and MMP-9 = predominant MMPs in periodontitis, derived from PMNs
• ICTP = carboxy-terminal peptide of type I collagen — biochemical marker of bone resorption used in SDD studies
• SPMs = specialized pro-resolving mediators (lipoxins, resolvins, protectins)
• DMARDs = disease-modifying anti-rheumatic drugs (Infliximab, Etanercept, Tocilizumab) — anti-cytokine agents
• PEZBINs = poly-enolic zinc-binding compounds (curcumin-based new MMP inhibitors)
• CMC = chemically modified curcumins
• SAGE = semi-synthetic glycosaminoglycan ether / sulfated polysaccharide
• TIMPs = tissue inhibitors of metalloproteinases (endogenous MMP inhibitors — natural health-promoting molecules)

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20. SUMMARY — CURRENT STATUS OF HMTs

[Source: Newman & Carranza 14th ed., Ch. 55; Carranza 10th ed., Ch. 53; Essentials of Clinical Periodontology and Periodontics, Ch. 15; Antibiotics and Antiseptics in Periodontal Therapy, Ch. 3]

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