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HOST MODULATION IN PERIODONTAL THERAPY

Comprehensive Theory Examination Notes

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1. DEFINITIONS

• Host: "The organism from which a parasite obtains its nourishment," or in the transplantation of tissue, "the individual who receives the graft." (Taber's Medical Dictionary, 2004)
• 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)
• Host modulation: A term incorporated into dental jargon - in diseases of the periodontium initiated by bacteria, the "host" is the individual who harbors these pathogens; modulation of the host response to these pathogens and other stimuli is aimed at reducing breakdown of the attachment apparatus.

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2. HISTORICAL PERSPECTIVE

• Host modulation is fairly new to the field of dentistry but is universally understood by most physicians who routinely apply its principles to the management of chronic progressive disorders such as arthritis and osteoporosis.
• 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."

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3. SCIENTIFIC BASIS / RATIONALE

3A. Paradigm Shift

• Previous belief: periodontal disease was an inevitable consequence of aging; disease severity was directly correlated with plaque levels; disease progressed in a continuous, linear manner.
• Current understanding (paradigm shift): Periodontal disease is not a natural consequence of aging; severity is not necessarily correlated with plaque levels; there is a subset of disease-resistant patients and a subset of disease-susceptible patients.
• The host response to the bacterial challenge presented by subgingival plaque is "perhaps the most important determinant of disease severity, rate of progression, and even response to therapy."

3B. Role of Host Response in Periodontal Destruction

• "The great majority of the destructive events occurring in the periodontal tissues result from the activation of destructive processes that occur as part of the host immune-inflammatory response to plaque bacteria."
• "The host response is essentially protective by intent but, paradoxically, can also result in significant tissue damage, including breakdown of connective tissue fibers in the periodontal ligament (PDL) and resorption of alveolar bone."
• "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 cascade of destructive events that occur as part of the inflammatory response."
• Periodontal disease is characterized by high concentrations of MMPs, cytokines, and prostanoids in the periodontal tissues, whereas periodontal health is characterized by the opposite.

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4. DEFINITION OF HOST MODULATORY THERAPY (HMT)

"Host modulatory therapy (HMT) is a treatment concept that aims to reduce tissue destruction and stabilize or even regenerate the periodontium by modifying or downregulating destructive aspects of the host response and upregulating protective or regenerative responses."

• HMTs are systemically or locally delivered pharmaceuticals prescribed as part of periodontal therapy and used as adjuncts to conventional periodontal treatments such as SRP and surgery.
• The purpose of HMT is to restore the balance of proinflammatory/destructive mediators and anti-inflammatory/protective mediators to that seen in healthy individuals.
• HMT is a means of treating the host side of the host-bacteria interaction.
• 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.

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5. SPECIFIC ASPECTS OF DISEASE PATHOGENESIS AS POTENTIAL TARGETS FOR HOST MODULATION

FLOWCHART: Pathogenesis of Periodontitis and HMT Targets

Microbial Challenge (subgingival plaque bacteria, LPS, antigens)
        |
        v
Host Immune-Inflammatory Response
  [Influenced by: Genetic risk factors + Environmental/Acquired risk factors]
        |
        v
+----------------------------------+
| Upregulated destructive cascade  |
|  - Cytokines (IL-1, IL-6, TNF-α) | <--- TARGET: Anti-cytokine therapy / NSAIDs
|  - Prostanoids (PGE2)            | <--- TARGET: NSAIDs (COX inhibitors)
|  - MMPs (MMP-8, MMP-13)          | <--- TARGET: SDD / CMTs
+----------------------------------+
        |
        v
Connective tissue and bone metabolism dysregulation
  [RANKL↑ / OPG↓ → Osteoclast activation]  <--- TARGET: Bisphosphonates / HRT
        |
        v
Clinical signs of disease:
  - CAL loss
  - Pocket formation
  - Alveolar bone resorption

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6. PRO-INFLAMMATORY AND ANTI-INFLAMMATORY MEDIATORS

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7. CLASSIFICATION OF HOST MODULATORY AGENTS

A. Agents Preventing Destruction

• 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 supplementation of anti-inflammatory cytokines (IL-4, IL-10)

• Sub-antimicrobial dose of doxycycline (SDD) - Periostat® 20 mg BID
• Chemically Modified Tetracyclines (CMTs)

• 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

B. Agents Promoting Resolution and Healing

• Lipoxins
• Resolvins of the E-series (RvE)
• Resolvins of the D-series (RvD)
• Protectins

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8. DRUG CLASSES EVALUATED AS HOST MODULATION AGENTS

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9. SYSTEMICALLY ADMINISTERED HMT AGENTS

9A. NONSTEROIDAL ANTI-INFLAMMATORY DRUGS (NSAIDs)

• NSAIDs inhibit the formation of prostaglandins, including PGE2, which is produced by neutrophils, macrophages, fibroblasts, and gingival epithelial cells in response to the presence of LPS (a component of the cell wall of gram-negative bacteria).
• PGE2 has been extensively studied because it upregulates bone resorption by osteoclasts; levels of PGE2 are 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.

• The salicylates (e.g., aspirin), indomethacin, and the propionic acid derivatives (e.g., ibuprofen, flurbiprofen, and naproxen).
• Multiple NSAIDs - indomethacin, flurbiprofen, ibuprofen, naproxen, meclofenamic acid and piroxicam - have demonstrated ability to reduce gingivitis and progression of periodontitis in animal models.
• Ketoprofen - an NSAID which can inhibit both cyclooxygenase and lipoxygenase pathways - has received considerable attention.

• Systemic NSAIDs such as indomethacin, flurbiprofen, and naproxen, administered daily for up to 3 years, significantly slowed the rate of alveolar bone loss compared with placebo.
• Short-term administration of NSAIDs showed a reduction of GCF MMP-8 levels, but no statistically significant differences were observed in CAL levels.
• Studies have suggested that low-dose aspirin as an adjunct periodontal therapy may be beneficial in reducing periodontal attachment loss.

• Daily administration for extended periods is necessary for periodontal benefits to become apparent.
• Associated with significant side effects: gastrointestinal problems, hemorrhage (from decreased platelet aggregation), and renal and hepatic impairment.
• "Rebound effect" - periodontal benefits of long-term NSAIDs are lost when patients stop taking the drugs, with a return to or even acceleration of the rate of bone loss seen before NSAID therapy.
• For these reasons, the long-term use of NSAIDs as an adjunctive treatment for periodontitis has never been established or clinically recommended.

• Topical administration of NSAIDs has been considered as an alternative method of delivery.
• Agents evaluated: ketorolac tromethamine rinse and S-ketoprofen dentifrice.
• Further studies are required to determine efficacy as adjuncts to SRP.
• Lipoxins - a series of oxygenated arachidonic acid derivatives functioning as endogenous inflammatory mediators - have been tried for topical use; in animal models, at a metabolically stable state, they block neutrophil infiltration induced by P. gingivalis and reduce PGE2 levels.
• Triclosan - a compound that has received interest as both antibacterial and anti-inflammatory agent - dentifrice containing sodium fluoride, triclosan, and a copolymer has been tested.

9B. BISPHOSPHONATES

• A new class of drugs used to manage osteoporosis, which may also have beneficial effects on the periodontium.
• Through the mechanism of chelation of cations, they inhibit MMP activity, thereby inhibiting osteoclastic activity.
• They can be used as targets for host modulation - "drugs can be administered to downregulate osteoclastic activity and ultimately to inhibit bone resorption by these cells."

• Alendronate has been evaluated in ligature-induced periodontitis models.

• Although alendronate inhibited loss of bone density in animal models, human trials have shown minimal effects on clinical parameters.
• Further studies are required to evaluate the effectiveness of these drugs in the treatment of periodontal diseases.

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10. SUB-ANTIMICROBIAL DOSE DOXYCYCLINE (SDD)

⭐ MOST IMPORTANT HMT AGENT - FDA APPROVED ⭐

• Previously called: "Low-dose doxycycline" (LDD)
• Current name: Sub-antimicrobial dose doxycycline (SDD)
• Trade name: Periostat® (marketed by CollaGenex Pharmaceuticals)
• Dose: 20 mg BID (twice daily) - once in the morning and once in the evening

"The FDA-approved agent for host modulation treatment of periodontal disease is sub-antimicrobial dose doxycycline (SDD) 20 mg/day."

10A. Rationale and Background

• "No class of drugs has had more of an impact on periodontal therapy than the tetracyclines."
• The tetracyclines have been used locally and systemically as antimicrobial agents and, more recently, systemically as a host modulation agent (SDD).
• At sub-antimicrobial doses, doxycycline does not exhibit antimicrobial effects but can effectively lower MMP levels.
• "The development of SDD as an HMT, driven by research into the pathogenesis of periodontal disease, is a great example of how translational research can lead to new treatments."

10B. Mechanisms of Action (Pleiotropic)

1. Downregulates MMPs - a family of zinc-dependent enzymes capable of degrading extracellular matrix molecules including collagen. The predominant MMPs in periodontitis are particularly MMP-8 (neutrophil collagenase) and MMP-13 (bone-type collagenase).
2. Suppresses pro-inflammatory cytokines including IL-1, IL-6, and TNF-α as well as PGE2
3. Scavenges and inhibits production of reactive oxygen species (ROS) produced by PMNs (e.g., HOCl, which activates latent MMPs)
4. Inhibition of MMPs and ROS protects α1 proteinase inhibitor (α1-PI), thereby indirectly reducing tissue proteinase activity
5. Stimulates fibroblast collagen production
6. Reduces osteoclast activity and bone resorption
7. Blocks osteoclast MMPs
8. Stimulates osteoblast activity and bone formation

10C. Biochemical Evidence

• A 2-month regimen of SDD significantly decreased:
  • Levels of MMP-8 and MMP-13 (neutrophil and bone-type collagenases) in GCF
  • ICTP (carboxy-terminal peptide, a pyridinoline-containing cross-linked peptide of type I collagen) - a fragment of type I collagen indicating reduced bone-type collagen breakdown

10D. Clinical Research Evidence

• The 9-month, randomized, double-blind, placebo-controlled trial conducted at five dental centers demonstrated clinical efficacy and safety of SDD versus placebo as an adjunct to SRP.
• Statistically significant reductions in probing depths and gains in clinical attachment levels as well as the prevention of disease progression.
• When SDD administration was discontinued after 9 months, the incremental improvements were maintained for at least 3 months - there was no rebound effect.

10E. Special Patient Populations

• PST-positive patients (Periodontitis Susceptibility Test - IL-1 gene polymorphism / PAG - Periodontitis-Associated Genotype): A 5-month preliminary study by Ryan et al. showed that SDD may provide PST-positive patients with a therapeutic strategy that specifically addresses their exaggerated host response.
• Smokers: SDD was used in susceptible patients with severe generalized periodontitis; more than 50% of the study patients were smokers. SDD as an adjunct to repeated mechanical debridement resulted in clinical improvement.
• SDD may also be of benefit in cases refractory to treatment, as well as in patients with risk factors such as smoking, diabetes, osteoporosis/osteopenia, and genetic susceptibility, in whom the treatment response might be limited.

10F. Indications (Treatable Periodontal Conditions)

• Indicated in the management of chronic periodontitis and aggressive periodontitis (nonsurgical treatment).
• Emerging studies have supported the efficacy of SDD as an adjunct to periodontal surgery.
• SDD should NOT be used in conditions such as:
  • Gingivitis
  • Periodontal abscess
  • When an antibiotic is indicated

10G. Contraindications

• History of allergy or hypersensitivity to tetracyclines
• Pregnant or lactating women
• Children less than 12 years old (because of the potential for discoloration of the developing dentition)
• Doxycycline may reduce the efficacy of oral contraceptives; alternative forms of birth control should be discussed

10H. Side Effects

"Doxycycline at antibiotic doses (≥100 mg) is associated with adverse effects, including photosensitivity, hypersensitivity reactions, nausea, vomiting..."

• There is a risk of increased sensitivity to sunlight (manifested by exaggerated sunburn) seen with higher doses of doxycycline, although this has not been reported in the clinical trials using the sub-antimicrobial dose.

10I. Compliance Instructions

• Tablet must be taken twice daily (once in the morning and once in the evening).
• Should not be taken with calcium supplements.
• Compliance may be improved by the administration of a modified-release SDD capsule taken only once a day.
• "HMT is not a substitute for excellent plaque control" - nor a substitute for excellent debridement and root surface instrumentation by the clinician.

10J. Combination with Other Treatments

• SDD + SRP + local delivery systems (e.g., Atridox): These two approaches target different aspects of the pathogenic process:
  • Local delivery systems deliver antimicrobial concentrations directly into the periodontal pocket
  • SDD is a systemic host response modulator
  • Preliminary results (6-month, 180-patient clinical trial): patients receiving the combination experienced more than a 2-mm improvement in mean attachment gains and probing depth reductions (p < 0.0001) compared with SRP alone.
• SDD + periodontal surgery: Emerging data showed better probing depth reductions in surgically treated sites >6 mm compared with placebo; SDD group demonstrated greater reductions in ICTP.

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11. CHEMICALLY MODIFIED TETRACYCLINES (CMTs)

• 10 different CMTs have been developed; 9 of which inhibit MMPs and do not possess antimicrobial properties.
• These are tetracycline analogues modified at specific positions to eliminate antibacterial activity while preserving the MMP-inhibitory and anti-inflammatory properties.
• In animal models, CMTs have been reported to reduce the progression of experimentally induced periodontitis.
• Inhibition of human periodontitis is still not established.
• CMT-3 in particular: "significantly improved clinical parameters of periodontitis, and decreased alveolar bone loss in beagle dogs."

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12. TETRACYCLINES - WHY THEY WORK WELL AS HOST MODULATION AGENTS

"Golub et al. suggested that tetracyclines could reduce the incidence of acute myocardial infarction by blocking collagenase and stabilizing the collagen cap on the atheroscleromatous arterial plaques."

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13. LOCALLY ADMINISTERED HMT AGENTS

13A. NSAIDs (Topical)

• Ketorolac tromethamine rinse and S-ketoprofen dentifrice - evaluated for topical administration as alternatives to systemic delivery.
• Topical agents also include lipoxins and triclosan.

13B. Enamel Matrix Proteins, Growth Factors, and Bone Morphogenetic Proteins

• These locally administered agents have been classified as HMTs that upregulate protective and regenerative responses.

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14. ARACHIDONIC ACID METABOLISM - DETAILED MECHANISM

FLOWCHART: Arachidonic Acid Metabolic Pathway

Tissue damage (bacterial + host factors)
          |
          v
Phospholipids in plasma membrane of cells
          |
          v  [Phospholipase A2]
Free Arachidonic Acid
          |
    +-----+-----+
    |             |
    v             v
Cyclooxygenase  Lipoxygenase
pathway         pathway
    |             |
    v             v
Prostaglandins  Leukotrienes
Prostacyclins   Hydroxyeicosatetraenoic
Thromboxane     acids (HETEs)
    |
    v
PGE2 (elevated in GCF in gingivitis and periodontitis)
[Stimulates osteoclastic bone resorption]
[Inhibits fibroblast function]

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

• Resolvins are derived from omega-3 fatty acids eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA); classified as E-series resolvins (RvE) and D-series resolvins (RvD).
• Omega-3 fatty acids have been found to have immunomodulatory properties.
• Omega-3 plus low-dose aspirin as adjunctive treatment of chronic periodontitis has been studied (clinical and biochemical study).
• These are listed among the drug classes evaluated as host modulation agents in the 14th edition of Newman & Carranza's.

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16. PROBIOTICS AS EMERGING HMT

• Proposed future host modulation agents include lipoxins, resolvins, and probiotics (lactobacilli and bifidobacteria).
• Recent innovations include stem cell research presenting possibilities for application in novel HMT strategies.
• Human periodontal stem cells can modulate neutrophil function and reduce excessive inflammation.
• Bone marrow-derived mesenchymal stem cells have shown great potential for periodontal regeneration in animal models.

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17. ANTI-CYTOKINE THERAPY

• Protective aspects of host response include recruitment of neutrophils, production of protective antibodies, and release of anti-inflammatory cytokines including TGF-α and IL-4, IL-10, and IL-12.
• Perpetuation of host response due to persistent bacterial onslaught may disrupt the homeostatic mechanism and result in release of mediators including proinflammatory cytokines (e.g., IL-1, IL-6, and TNF-α), MMPs (proteases), and PGE2, which can promote extracellular matrix destruction and stimulate bone resorption.
• Cytokines that can suppress the action of pro-inflammatory cytokines include IL-4, IL-10, IL-11, and TGF-α; when administered therapeutically, these antagonists can reduce inflammation.
• Unresolved issues: identifying an ideal method to maintain or inhibit cytokines for long periods; understanding systemic implications of altering cytokine levels on tissue homeostasis.

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18. HOST MODULATION AND COMPREHENSIVE PERIODONTAL MANAGEMENT

Risk Reduction Strategies Involving HMT

Who Requires HMT?

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19. HMT IN SYSTEMIC DISORDERS (PERIODONTAL MEDICINE PERSPECTIVE)

• "In susceptible patients demonstrating an excessive local inflammatory response to the bacterial stimuli leading to periodontal disease, another consideration involves the loss of epithelial integrity in the periodontal pocket."
• This allows bacterial penetration into inflamed tissues and eventual entry of bacteria into the systemic circulation.
• Patients with untreated periodontitis have an increased risk of transient bacteremias; bacteremia and associated endotoxemia may incite the overproduction of destructive pro-inflammatory mediators at distant sites.
• Individuals with periodontal disease are "almost twice as likely to have a fatal heart attack and three times as likely to have a stroke."
• In CVD: MMPs and cytokines play a major role in weakening the atherosclerotic plaques, leading to rupture, thrombosis, and infarction. Golub et al. suggested 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 also play a role in 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).

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20. SUMMARY: SDD IS THE ONLY FDA-APPROVED HMT

"SDD is the only systemically administered HMT currently approved and indicated as an adjunct to SRP for treating periodontitis."

1. Antibacterial treatments (SRP, plaque control, oral hygiene instruction, local antimicrobials, periodontal surgery)
2. Host response modulation (SDD)
3. Assessment and management of periodontal risk factors

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21. COMPARISON OF VIEWPOINTS ACROSS REFERENCES

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22. RECENT TERMINOLOGY CHANGES

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23. IMPORTANT EXAMINER KEYWORDS (Highlighted Summary)

• Host Modulatory Therapy (HMT)
• Sub-antimicrobial dose doxycycline (SDD) / Periostat®
• Matrix metalloproteinases (MMPs) - MMP-8 (neutrophil collagenase), MMP-13 (bone-type collagenase)
• ICTP - carboxy-terminal peptide of type I collagen (biomarker of bone collagen breakdown)
• GCF - Gingival Crevicular Fluid (medium for MMP measurement)
• PGE2 - Prostaglandin E2 (key prostanoid in bone resorption)
• IL-1, IL-6, TNF-α - pro-inflammatory cytokines (targets of HMT)
• RANKL/OPG - osteoclast-osteoblast axis regulation
• α1-proteinase inhibitor (α1-PI) - naturally occurring protective mediator
• PST test - Periodontal Susceptibility Test / Periodontitis-Associated Genotype (PAG)
• Pleiotropic mechanisms - multiple non-antimicrobial mechanisms of doxycycline
• Translational research - science transfer from lab to clinical application
• Rebound effect - acceleration of bone loss on cessation of NSAIDs
• Bisphosphonates - chelate cations, inhibit MMPs and osteoclastic activity
• Alendronate - bisphosphonate evaluated in ligature-induced periodontitis
• Resolvins, lipoxins, protectins - proresolution mediators (emerging HMTs)
• CMT - Chemically Modified Tetracyclines
• Williams (1990) and Golub et al. (1992) - founders of HMT concept in dentistry
• Periodontal medicine - HMT applicable beyond periodontium to systemic diseases (CVD, diabetes)
• Ketoprofen - inhibits both COX and LOX pathways

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24. KEY POINTS TO REMEMBER

1. "Currently, one systemically administered agent is available for modulation of host, i.e., subantimicrobial dose doxycycline marketed as Periostat® by CollaGenex Pharmaceuticals." (Essentials, S. Reddy)
2. "The future holds much hope for application of HMT not only for managing the periodontitis patients but also for the practice of periodontal medicine." (Essentials, S. Reddy)
3. "SRP alone, although effective for improving clinical parameters such as probing depths, may not be sufficient to reduce excessive levels of many underlying destructive mediators, particularly in more susceptible patients." (Carranza 10th ed., Chapter 53)
4. HMT does not eliminate the need for conventional therapy - bacteria must still be controlled via SRP; HMT addresses the host side of the host-bacteria interaction.
5. Tetracyclines have been advocated for management of patients with systemic diseases such as diabetes, rheumatoid arthritis, and rosacea (Oracea) - doxycycline has led to improvements in periodontal health of compromised diabetic patients and long-term markers of glycemic control (glycated hemoglobin).

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1. Newman & Carranza's Clinical Periodontology and Implantology, 14th Edition - Chapter 55: Host Modulation (Ryan, Gu)
2. Carranza's Clinical Periodontology, 10th Edition - Chapter 16: Host Modulation (Ryan, Preshaw); Chapter 53: Host Modulation Agents (Preshaw, Ryan, Giannobile)
3. Essentials of Clinical Periodontology and Periodontics, S. Reddy - Chapter 15: Host Modulation in Periodontal Therapy
4. Clinical Periodontology and Implant Dentistry, 6th Edition - Aggressive Periodontitis section (Host Modulation subsection)