[BOOK] HOST MODULATION

chap 48

Host Modulatory Therapy (HMT)

Adjunctive treatment → used in addition to conventional therapies

Focuses on modifying the host response, not just bacteria

Conventional Periodontal Therapy

• Mechanical:

  • Surgery

  • Scaling and root planing (SRP)

• Early adjunctive therapies:

  • Antiseptics

  • Antibiotics (local/systemic)

Purpose of HMT

reduce destructive inflammatory responses

enhance protective and healing responses

• balance shifts toward:

  • healing (resolution of inflammation, tissue repair)

  • away from disease progression

Why HMT is Needed

• SRP reduces bacteria but:

  • Does not eliminate all bacteria

  • Recolonization occurs

• Host response causes most tissue destruction

• Helps manage risk factors:

  • Smoking

  • Diabetes

  • Genetic susceptibility

• Can increase anti-inflammatory/protective mediators

How HMT Works

• Does NOT stop normal defense or inflammation

• Modulates excessive/pathologic inflammation

• Targets:

  • Enzymes

  • Cytokines

  • Prostanoids

• Regulates:

  • Osteoclast activity (bone resorption)

  • Osteoblast activity (bone formation)

• Maintains normal tissue turnover

other inflammatory conditions that benefit from HMT

Arthritis

Cardiovascular disease

Dermatologic conditions

Diabetes

Rheumatoid arthritis

Osteoporosis

Existing Medications with HMT Effects

NSAIDs

Bisphosphonates

Tetracyclines

Cytokine-targeting drugs

Drug Classes Studied for HMT

NSAIDs

Bisphosphonates

Tetracyclines

Enamel matrix proteins

Growth factors

Bone morphogenetic proteins

Systemically Administered Agents

Used as host modulatory therapy (HMT)

Affect the whole body, not just local periodontal tissues

MOA of NSAIDs

• Inhibit prostaglandin production (especially PGE2)

• PGE2:

  • Increases bone resorption by osteoclasts

  • Inhibits fibroblast function

  • Modulates immune response

• Result:

  • Reduced inflammation

  • Decreased osteoclast activity

  • Not indicated for periodontal HMT

examples of NSAIDs

Aspirin (salicylates)

Indomethacin

Ibuprofen

Flurbiprofen

Naproxen

NSAIDs Effects in Periodontal Disease

Slows alveolar bone loss with long-term use

Requires daily use for extended periods (up to 3 years)

Significant side effects of NSAIDs

Gastrointestinal problems

Hemorrhage (↓ platelet aggregation)

Kidney (renal) impairment

Liver (hepatic) impairment

• Rebound effect:

  • Bone loss returns or accelerates after stopping drug

COX-2 Inhibitors

Target COX-2 enzyme → reduce inflammation

Initially promising (fewer GI side effects)

Later found to cause serious adverse effects

Some drugs withdrawn from market

Not indicated for periodontal HMT

MOA of Bisphosphonates

• Inhibit bone resorption by disrupting osteoclast activity

• May:

  • Interfere with osteoblast metabolism

  • Reduce collagen breakdown (anticollagenase effect)

bisphosphonates effects in Periodontal Disease

Increase bone density

Improve alveolar bone status

Reduce bone resorption (animal and human studies)

side effects of bisphosphonates

Inhibit normal bone calcification

Alter white blood cell counts

• Risk of osteonecrosis of the jaw:

  • Especially after dental extractions

  • More common with intravenous use

Sub-Antimicrobial-Dose Doxycycline (SDD)

20 mg dose of doxycycline (Periostat)

Used as an adjunct to scaling and root planing (SRP)

Indicated for chronic periodontitis

• Only systemic HMT:

  • Approved by FDA

  • Accepted by ADA

dosage of SDD

20mg, twice daily

• Duration:

  • 3 months standard

  • Up to 9 months maximum

MOA of SDD

• Not antibacterial at this dose

• Works by:

  • Inhibiting enzymes

  • Reducing cytokines

  • Decreasing osteoclast activity

side effects of SDD

• No detectable effect on:

  • Oral flora

  • Bacterial flora in other body sites

• Provides clinical benefits when combined with SRP

Oracea

Modified-Release SDD

• Approved for rosacea (skin condition)

• Also studied in periodontitis:

  • Showed greater clinical benefits than SRP alone

treatment strategies in periodontitis

Locally Administered Agents

Applied directly to periodontal sites

Used as adjuncts, often with surgical procedures

Not approved as local HMTs for periodontitis

Approved by FDA for surgical adjunctive use

examples of locally administered agents

topical NSAIDs

enamel matrix proteins (Emdogain)

Insulin-like growth factor

platelet-derived growth factors (GEM 21S)

bone morphogenetic proteins (BMP-2 (INFUSE) BMP-7)

examples of Topical NSAIDs

Ketorolac mouthrinse

Ketoprofen (local use)

effects of Topical NSAIDs

Reduce PGE2 levels in gingival crevicular fluid (GCF)

Decrease inflammation

May halt bone loss

EMP, GF, BMP

• Improve wound healing

• Promote regeneration of:

  • Bone

  • Periodontal ligament

  • Cementum

• Assist in:

  • Clinical attachment gain

  • Bone regeneration

  • Ridge and sinus augmentation

Management

is broader than treatment

Focus on long-term control of a chronic disease

management includes

Medical and dental history

Clinical exam and radiographs

Risk factor assessment

Diagnosis and treatment planning

Reevaluation and maintenance

Prognosis assessment

indications of HMT

• Patients with:

  • Nonmodifiable risks (genetics)

  • Difficult-to-modify risks (smoking, diabetes)

• Avoid taking with calcium

Risk Factor Modification

• Smoking

  • Major risk factor

  • Reduces treatment success

  • Smoking cessation is essential

• Diabetes

  • Poor control increases risk

  • Periodontal therapy may improve diabetic control

  • Requires medical collaboration

• Other Factors

  • Genetics

  • Gender

  • Race

Comprehensive Treatment Strategies

Patient education and motivation

Oral hygiene instruction

Antiseptics (rinses, toothpaste, irrigation)

Scaling and root planing (SRP)

Local or systemic antimicrobial therapy

Host modulation therapy (HMT)

Risk factor modification

Periodontal surgery (± HMT)

Sub-Antimicrobial-Dose Doxycycline (SDD)

Only FDA-approved systemic HMT for periodontitis

Used with scaling and root planing (SRP)

Not used alone (no monotherapy)

Previously called low-dose doxycycline (LDD)

Marketed as Periostat

Belongs to the tetracycline family

Tetracyclines

major impact in periodontal treatment

• Used:

  • With SRP (nonsurgical therapy)

  • With surgical procedures (resective & regenerative)

• Can be:

  • Local or systemic antimicrobials

  • Systemic host modulation agents (SDD)

• Used for:

  • Chronic periodontitis

  • Aggressive periodontitis

• Also used in systemic conditions:

  • Diabetes

  • Rosacea (e.g., Oracea)

• Benefits:

  • Improved periodontal health

  • Better glycemic control (↓ glycated hemoglobin)

• Enhance:

  • Reattachment

  • New attachment formation

  • Bone formation

Matrix Metalloproteinase (MMP) Inhibition

moa of SDD

• Downregulates MMPs (collagen-degrading enzymes)

• MMPs:

  • Produced by fibroblasts, keratinocytes, macrophages, PMNs, endothelial cells

  • Break down extracellular matrix (especially collagen)

• Disease Association

  • MMP levels:

    • Increase with disease severity

    • Decrease after treatment

  • Excess MMPs → connective tissue breakdown → clinical signs of periodontitis

Key MMPs in Periodontitis

MMP-8

MMP-9

Derived mainly from PMNs

Degrade type I collagen (major component of gingiva & periodontal ligament)

Additional Actions of SDD

Reduces cytokine levels

Stimulates osteoblast activity

Promotes new bone formation

Increases collagen production

Tetracyclines as Host Modulation Agents

• Effective due to pleiotropic effects (act on multiple host response components)

• Only MMP inhibitors approved for periodontal treatment

• Doxycycline:

  • More effective than tetracycline and minocycline

  • Preferred due to:

    • Safety

    • Good absorption

    • Favorable pharmacokinetics

Development of SDD

• Created to reduce:

  • Side effects of long-term tetracycline use

  • Risk of antibiotic resistance

• Dose:

  • 20 mg (vs. 50–100 mg antimicrobial doses)

• Microbial Safety

  • No changes in:

    • Oral flora composition

    • Bacterial resistance levels

    • Fecal or vaginal microflora

  • No overgrowth of opportunistic pathogens (e.g., Candida)

Short-Term Use Effects on MMPs and Collagenase

• 2-week regimen:

  • Reduced collagenase in GCF and gingival tissues

1-Month Use Effects on MMPs and Collagenase

Reduced collagenase levels

Rebound effect after stopping (returns to baseline)

3-Month Use Effects on MMPs and Collagenase

• Sustained reduction in collagenase

• No rebound after stopping

• Greater reduction vs. placebo:

  • SDD: ~47.3%

  • Placebo: ~29.1%

• Associated with:

  • Gains in clinical attachment

Clinical Trial Findings (3, 6, 9 months)

• Reduced:

  • Probing depth

  • Collagenase activity

• Increased:

  • Clinical attachment levels

• Protected:

  • α1-antitrypsin (protective mediator)

• Biochemical Effects

  • Decreased:

    • Bone collagen breakdown products (ICTP)

    • MMP-8 and MMP-13 levels