Primary etiology of periodontal diseases is bacterial infection 1 along with that the progression of periodontal disease is adversely influenced by a number of risk factors and risk indicators like diabetes, gender, age, hereditary and smoking 2. Traditional treatments focused on reducing the bacterial load through scaling and root planning, but they were not effective on every patient. Löe et al 3 in their study on Sri Lankan tea workers demonstrated that not all individuals have the same response to similar amounts of plaque accumulation.
Host modulation therapy (HMT) is a treatment concept that aims to reduce tissue destruction and stabilize or even regenerate the periodontium by modifying or down regulating destructive aspects of the host response and up regulating protective or regenerative responses.
The purpose of host modulatory therapy is to restore balance between on the one hand, proinflammatory mediators and destructive enzymes and on the other hand anti-inflammatory mediators and enzyme inhibitors. They can be systemically administered or locally delivered and used as adjuncts to scaling and root planning 4.
3) Pathogenesis of periodontal disease:
Presently the models of disease progression 5-6 demonstrate that the major component of connective destruction associated with periodontal disease is the result of activation of the host’s immuno-inflammatory response to the bacterial challenge. The underlying biological mechanisms of this response are characterized by the expression of endothelial cell and intercellular adhesion molecules and by the production of host-derived inflammatory mediators including cytokines and lipids by neutrophils, monocytes, lymphocytes and fibroblasts.
Model of periodontal disease pathogenesis
4) Balance of inflammatory mediators in periodontal health and disease:
The balance between inflammatory mediators and their counter-regulatory molecules is crucial for determining the outcome of immune pathology of periodontal diseases. In case of stable gingivitis lesion the pro and anti inflammatory response is supposed to be in balance, whereas the response is skewed towards the predominance of proinflammatory reactivity in progressive periodontitis lesion. In the context of tissue destruction, cytokines such as IL-1, IL-6 and IL-18 are likely to be important, as are their regulating cytokines IL-10 and IL-11.
As present data suggests that periodontal diseases have got a multi-factorial etiology, the risk factors are equally important in the final outcome of the disease progression. Following diagram shows the balance between various factors favouring periodontal health and disease.
Balance between various factors favouring periodontal health and disease
5) Initial research on host modulation:
In the 1930s, the discovery of prostaglandins and other metabolites of arachidonic acid led to a remarkable era of research into the origin of these molecules in tissues and their role in health and disease. Paul Goldhaber and Max Goodson in 1970s proposed that arachidonic acid metabolites are important inflammatory mediators of the bone loss in periodontitis. The metabolites of arachidonic acid metabolism such as prostaglandins, were implicated as major mediators of tissue loss in periodontal diseases because they are potent stimulators of bone resorption, are present in gingival tissues, and are elevated in diseased individuals 7-8.
Nyman et al in their experimental periodontitis study examined the modulation of arachidonic acid metabolites with systemic indomethacin and reported that the NSAID indomethacin, given by mouth, suppressed alveolar bone resorption and gingival inflammation in the beagle dogs 9.
Effects of indomethacin in squirrel monkeys with ligature-induced periodontitis were studied by Weaks-Dybvig et al and it was reported that animals treated with systemic indomethacin had significantly less alveolar bone resorption (height and mass) and suppressed osteoclast density as compared with control animals 10.
Williams et al studied the effects of NSAID flurbiprofen over a period of 12 months on the progression of naturally occurring periodontal diseases in an animal model. Their results indicated that daily administration of 0.02 mg/kg flurbiprofen by mouth significantly decreased the rate of radiographic alveolar bone loss at 3, 6, 9, and 12 months in both surgically and nonsurgically treated animal groups when compared with baseline levels. The rate of alveolar bone loss did not decrease significantly over the treatment period for placebo-treated animal groups 11.
Other studies done on NSAIDs include ibuprofen 12, Naproxen 13, piroxicam 14, ketoprofen 15, indomethacin 16 and ketorolac 17. These studies indicated that administration of NSAIDs reduced the rate of connective tissue destruction in periodontal diseases.
6) Host modulation therapeutic agents:
To understand the host modulation therapeutic agents, let us first try to understand the steps where these agents modulate the host response. The following diagram demonstrates various steps where therapeutic agents modulate host response and thus the final outcome of periodontal disease.
Diagram showing various Host modulation therapeutic agents
7) Classification of host modulation therapeutics:
I) Modulation of the immune response.
i) Pro-inflammatory cytokine inhibition
ii) Modulation of matrix metalloproteinase (MMP) activities
II) Modulation of arachidonic acid metabolites
i) Nonsteroidal anti-inflammatory Drugs
ii) Lipoxins and resolvins
III) Modulation of bone remodelling
i) Anti-Inflammatory Agents
iii) Chemically Modified Tetracyclines
iv) Hormone replacement therapy for post-menopause women
IV) Host Modulation by Promoting Periodontal Regeneration
V) Modulation of nitric oxide synthase (NOS) activity
VI) Modulation of cell signalling pathways in periodontal disease
I) Modulation of the immune response:
i) Pro-inflammatory cytokine inhibition:
Many studies have indicated that the biological activity of a variety of cytokines may be directly relevant to periodontal destruction 18-19. IL-1, IL-6 and tumor necrosis factor have all been found to be significantly elevated in diseased periodontal sites compared with healthy or inactive sites 20-23. Cytokines have synergistic effects. Acting together pro-inflammatory cytokines amplify the inflammatory condition. For example, IL-1β has synergistic activity with tumor necrosis factor-α or lymphotoxin in stimulating bone resorption 24. Blocking tumor necrosis factor-α has been proven to inhibit osteoclast formation effectively 25. As already explained in the previous sections, the balance between the pro and anti-inflammatory cytokines is crucial in the periodontal health and disease. So we can possibly regulate the disease progression by regulating the balance of anti-/pro-inflammatory cytokines, matrix metalloproteinases (MMPs)/tissue inhibitors of metalloproteinases (TIMPs) and receptor activator of nuclear factor-κB ligand (RANKL)/osteoprogerin (OPG). Imbalances between these mediators in the periodontal tissues are a major cause of periodontal destruction 26-28.
Pentoxifylline (PTX) is a methylxanthine derivative which blocks the synthesis of TNF-α by inhibiting gene transcription, thereby reducing the accumulation of TNF-α mRNA. The protective effect of PTX could be explained by its capacity to inhibit the production of inflammatory cytokines or to stimulate anti-inflammatory cytokine production 29.
Recombinant human IL-11, which inhibits production of TNF-α, IL-1, and NO 30-31 was used in a study which showed reduced disease progression in a ligature-induced periodontitis canine model 32.
i) Modulation of matrix metalloproteinase (MMP) activities:
The activity of MMP’s can be modulated by various ways which include modulation of production of MMPs, blocking activation of the proenzyme blocking activity of the enzyme and activating inhibitors 33. The matrix metalloproteinases (MMPs) are a family of zinc- and calcium-dependent endopeptidases secreted or released by a variety of infiltrating cells (i.e., neutrophils and macrophages) and resident cells (i.e., fibroblast, epithelial, osteoblast, and osteoclast) found in the periodontium 34. MMP’s include collagenases, gelatinases and metallo-elastases. MMPs have been strongly associated with periodontitis 35-39, and excellent reviews have been published discussing the role of MMP’s in periodontal diseases 40-43. For more details please read “Matrix Matelloproteinases (MMP’s) & their role in pathogenesis of periodontal diseases”.
While experimenting on germ free diabetic rats Golub et al 44-45 discovered the anti collagenase activity of tertacyclins. 10 different chemically modified tetracyclines (CMTs) have been developed, 9 of which inhibit MMPs and do not possess antimicrobial properties 46. In further studies using these different tetracyclines, Golub et al 47 reported that the semisynthetic compounds (ie, doxycycline) were more effective than tetracycline in reducing excessive collagenase activity in the GCF of adult periodontitis patients. Recent clinical trials have focused on doxycycline because it was found to be a more effective inhibitor of collagenase than minocycline or tetracycline 48-49 and because of its safety profile, pharmacokinetic properties, and systemic absorption. Presently host modulation therapy utilizing tetracyclines has primarily involved the use of a reduced dose of doxycycline (20 mg bid).
Periostat is a formulation containing a sub antimicrobial dose of Doxycycline (SDD) (Doxycycline hyclate 20 mg; Periostat, CollaGenex, Pharmaceuticals Newton PA) which is FDA approved and ADA accepted in 1998. It is indicated as an adjunct to scaling and root planning (SRP) taken twice daily for periods of 3–9 months in the treatment of chronic periodontitis. 20 mg dose of Doxycycline has been reported not to exhibit antimicrobial effects, but can effectively lower MMP levels 50.
Effect of doxycycline 51:
|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)|
|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 α1-proteinase inhibitor, and thus indirectly reducing tissue proteinase activity.|
|Stimulates fibroblast collagen production|
|Reduces osteoclast activity and bone resorption.|
|Inhibits osteoclast MMPs.|
A meta-analysis 56 of 6 selected clinical studies comparing long-term systemic SDD (20mg bid doxycycline) to placebo control in periodontal patients showed a statistically significant adjunctive benefit of SDD + SRP on clinical attachment levels (CAL) and probing depth, in both 4 to 6mm and ≥ 7mm pocket depth categories. Bleeding on probing (BOP) was not assessed in the meta-analysis but, in general, SDD did not improve this parameter when compared to placebo. No significant adverse effects were reported in any of the studies.
As far as bacterial resistance to the drug therapy is concerned, resistance associated with low-dose doxycyline therapy has not been seen 57.
II) Modulation of arachidonic acid metabolites
i) Nonsteroidal anti-inflammatory Drugs:
The fact that NSAIDs can suppress alveolar bone resorption suggests that the synthesis of AA metabolites may represent a critical regulatory pathway for potentially blocking periodontal disease progression activity 58. In arachidonic acid metabolism, the cyclooxygenase pathway produces prostaglandins, prostacyclin and thromboxane, called prostanoids. Some prostanoids have proinflammatory properties and have been associated with destructive process in inflammatory diseases. In periodontal diseases, Prostaglandin E2 (PGE2) has been extensively correlated to inflammation and bone resorption 59.
Multiple NSAIDs including indomethacin 60 , flurbiprofen 61, ibuprofen 62, naproxen 63, meclofenamic acid 64 and piroxicam 65 have demonstrated the ability to inhibit gingivitis 66 and progression of periodontitis in both ligature-induced 67-68 and naturally occurring periodontal disease animal models 69-71.
ii) Lipoxins and resolvins:
Bacteria and their products like lipopolysaccharides (LPS) initiate an inflammatory response when they are countered by protective host response. Many mediators produced by arachidonic acid pathway, including prostanoids, leukotrienes and related compounds, play an important roles in initiation and progression of inflammation and are thus termed “proinflammatory mediators 72-73.
In addition to the proinflammatory mediators, “anti-inflammatory mediators” are also produced during these interactions. These include lipoxins, aspirin-triggered 15-epi-lipoxins (ATLs), resolvins, docosatrienes and neuroprotectins. Lipoxins are trihydroxytetraene-containing eicosanoids that are generated within the vascular lumen during platelet-leukocyte interactions and at mucosal surfaces via leukocyte-epithelial cell interactions 74. The role of the neutrophil in lipoxin generation is crucial. It has been shown that primed neutrophils are another source of LX biosynthesis 75 . Lipoxin A (LXA4) gives potent counter regulatory signals in vitro and in vivo for endogenous proinflammatory mediators like Leukotrienes, PAF, TNF-α and IL-6 thus inhibiting leukocyte-dependent inflammation.
As these are a new class of endogenous mediator that are anti-inflammatory or serve for the “pro-resolution” of inflammation, research work is going on in this field to explore the future possibilities of their clinical use.
III) Modulation of bone remodelling:
i) Anti-Inflammatory Agents:
Arachidonic acid metabolites are proinflammatory mediators that have been implicated in a variety of bone resorptive processes including chronic periodontitis 76. These mediators can be inhibited by NSAIDs which include various drugs such as aspirin, ibuprofen, ketorolac, flurbiprofen, naproxen etc. As discussed earlier they inhibit the enzyme cyclooxygenase, thereby preventing the production of arachidonic acid metabolites which are involved in bone resorption.
Periodontitis is characterised by alveolar bone loss. One of the therapeutic modality of host modulation is to stop the alveolar bone resorption. Bisphosphonates are widely used in the management of systemic metabolic bone disorders such as osteoporosis and Paget’s disease. They have a primary indication of inhibiting bone resorption and thereby maintaining bone density 77-78 . They are used widely in conditions such as neoplastic hypercalcemia, multiple myeloma and bone metastases secondary to breast and prostate cancer, suggesting a direct antitumor effect of bisphosphonates.
Chemically bisphosphonates are pyrophosphate analogs characterized by two C–P bonds. They are identified by a common ending in their generic names (“……….. dronate”). These drugs can be subdivided into the nitrogen-containing bisphosphonates and the non-nitrogen bisphosphonates 79 . Small changes in the structure of the bisphosphonates can lead to extensive alterations in their physicochemical, biological, therapeutic, and toxicological characteristics.
Generations of bisphosphonates:
Bisphosphonates are classified into three generations according to the R1 and R2 groups present in their chemical structure.
(Non- Nitrogen Containing)
(R2 group contains nitrogen in form of a primary amino group)
(R2 group contains nitrogen but within a heterocyclic group)
(10-1000 more potent than the 1st generations)
(10,000- 100,000 more potent than 1st generation).
Bisphosphonates work by inhibiting the precipitation of calcium phosphate even at very low concentration 80 . They also slow down the dissolution of these crystals 81 . All these effects appear to be related to the marked affinity of these compounds for the solid-phase calcium phosphate to which they bind 82. These compounds inhibit osteoclastic activity by blocking acidification by local release and represent a class of chemical structures related to pyrophosphate 83. They also down regulate levels of several matrix metalloproteinases including matrix metalloproteinase-3, matrix metalloproteinase-8 and matrix metalloproteinase-13 from human periodontal ligament cells 84. The effects of bisphosphonates at tissue level, cellular level and molecular level are summarized below,
Effects of bisphosphonates at tissue level, cellular level and molecular level.
|↓sed Bone turnover due to ↓sed Bone resorption.
↓sed Number of new bone multicellular units.
Net positive whole body bone balance.
|↓sed Osteoclast recruitment
↑sed Osteoclast apoptosis
↓sed Osteoclast adhesion
↓sed Depth of resorption site
↓sed release of cytokines by macrophages.
↑sed Osteoblast differentiation and number.
|Inhibit mevalonate pathway (that result in perturbed cell activity and induction of apoptosis).
↓sed Post-translational prenylation of GTP- bonding proteins.
A serious adverse effect of bisphosphonates that has substantial dental implications is osteonecrosis of the jaws; other bones in the skeleton do not appear to be involved 85 . Good dental hygiene reduces the risk of osteonecrosis.
A lot of research work has been done on bisphosphonates and periodontitis. Sodium alendronate treatment in experimental periodontitis on wistar rats was studied and results showed that sodium alendronate preserves alveolar bone resorption and has anti-inflammatory and antibacterial activities in experimental periodontitis 86. MMP Inhibition and down regulation by Bisphosphonates has also been demonstrated by one study which observed the inhibition of MMP-1, -2, -3, -7, -8, -9, -12, -13, and -14 by clondronate, alendronate, pamidronate, zolendronate, nedrinate, and clodrinate 87.
A study was done to investigate the effect of oral alendronate (ALN) treatment on radiological and clinical measurements of periodontal disease on postmenopausal women without hormone replacement therapy. Results demonstrated that alendronate treatment improved periodontal disease and bone turnover in postmenopausal women 88.
As recent studies have demonstrated that osseointegration of titanium implants can be significantly reinforced with a nanostructure treated with anodic oxidation and heat treatment. An animal experimental study was done on machine-turned, anodized + heat-treated and anodized + heat treated+ bisphosphonate-treated implants. Results showed that surface loading with bisphosphonates significantly improved the degree of osseointegration of titanium implants with a nanostructure 89.
Bisphosphonate-related osteonecrosis of the jaw (BRONJ):
All the patients who are undergoing bisphosphonate related treatment for bony defects or implant therapy should be informed about all the complications associated with bisphosphonate treatment. Advisory Task Force on Bisphosphonate-Related Ostenonecrosis of the Jaws, 2007 has proposed following staging categories and treatment guidelines regarding BRONJ,
iii) Chemically Modified Tetracyclines:
As it is well established that CMT’s inhibit the Matrix Metalloproteinases so are indirectly involved in inhibition of bone resorption in periodontal diseases. CMT’s have already been discussed under MMP section.
iv) Hormone replacement therapy for post-menopause women:
The endocrine system plays an important role in the homeostasis of the periodontium 90. Osteoporosis, which is defined as a systemic condition characterized by a decrease in the bone mineral density of at least 2.5 times the normal values in a healthy young female, is a major health problem in postmenopausal women 91. It is a major cause of morbidity and mortality in post menopause women. The research work clearly indicates that low oestrogen production after menopause is associated with increased production of interleukin 1 (IL-1), IL-6, IL-8, IL-10, tumour necrosis factor alpha, granulocyte colony-stimulating factor and granulocyte-macrophage colony-stimulating factor, which stimulates mature osteoclasts, modulates bone cell proliferation, and induces resorption of both skeletal and alveolar bone 92-93. The American Academy of Periodontology considers osteoporosis to be a risk factor for periodontal disease 94.
Clinical changes in the periodontal tissues during menopause and post-menopause:
- Reduction in epithelial keratinisation 95.
- A reduction in salivary gland flow 96.
- Drying of the oral tissues 97.
- Redness and abnormal paleness of the gingival tissues 97.
- Bleeding on probing and brushing 97.
- Taste sensation may change, causing frequent complaints of a metallic taste 98.
Radiographic changes in the periodontal tissues during menopause and postmenopause:
Reduced bone mineral content in the jaws 99-100. Hormone replacement therapy (HRT) is used to relieve these symptoms and improve the quality of life of peri- or post-menopausal women 101-102. Many studies have suggested that using hormone replacement therapy in post-menopausal women can decease the periodontal destruction 103-104 and increase tooth retension 105.
Effects of HRT on the periodontal tissues:
- Protection against tooth loss 106.
- Reduction in gingival bleeding 107.
- Reduction in the risk of edentulousim 108.
IV) Host Modulation by Promoting Periodontal Regeneration:
Root surface conditioning, Growth factors and cytokines can be used to promote periodontal regeneration. Growth factors and hormones including platelet-rich plasma (PRP), bone morphogenic proteins (BMPs), platelet-derived growth factor (PDGF), parathyroid hormone (PTH) and enamel matrix proteins (EMD) have shown promise in enhancing regeneration, although their long-term predictability remains questionable, and their anticipated benefits are moderate 109-110. In 1976, Melcher presented the concept of “compartmentalization,” in which the connective tissues of the periodontium were divided into four compartments: the lamina propria of the gingiva (gingival corium), the periodontal ligament (PDL), the cementum, and the alveolar bone 111. Since then a lot of research has been done on periodontal regeneration. Regeneration has been broadly divided in to two categories; graft associated and non graft associated. For detailed study please read ‘Periodontal Regeneration’.
V) Modulation of nitric oxide synthase (NOS) activity:
Nitric oxide (NO) is a free radical involved in host defense that can be toxic when present at high levels and it has been implicated in a variety of inflammatory conditions. NO is produced by a wide variety of cells and appears to be an important regulator of various physiologic processes in both animals and humans 112. NO imbalances have been noted in a variety of chronic infectious and inflammatory conditions including periodontal disease 113-115. NO is generated within biologic tissues via the enzymatic conversion of L-arginine to L-citrulline by nitric oxide synthase (NOS). Nitric oxide synthase (NOS) exists in the body as three distinct isoforms: neuronal (nNOS or NOS-I), inducible (iNOS or NOS-II) and endothelial NOS (eNOS or NOS-III) 116.
NO has critical role in the regulation of vascular tone, smooth muscle proliferation, angiogenesis, coagulation, mitochondrial energy generation, neurotransmission, immunity, cell survival, and wound healing 117-120. The importance of NO in bone formation and remodelling has been highlighted from the observations of defective bone formation, volume, turnover and osteoblast function in eNOS and iNOS deficient mice 121-123.
Role of NO in periodontal diseases has been well investigated. LPS and other antigenic substances from putative periodontal pathogens such as A. actinomycetemcomitans, P. gingivalis, P. intermedia, P. nigrescens, and F. nucleatum have been shown to induce iNOS expression and NO production in murine macrophages 124-127. It has been demonstrated that iNOS expression and activity is induced in gingival fibroblasts and neutrophils following stimulation by periodontal pathogens, cytokines, and other inflammatory mediators 128. along with this neutrophils isolated from localized aggressive periodontitis patients were shown to display increased iNOS activity and subsequent chemotactic defects 129.
Inhibition of NOS can be beneficial in the modulation of periodontal disease by preventing the participation of NO and other reactive nitrogen species in a variety of pathways which are thought to be deleterious to the host 130. There are two kind of NOS inhibitors; non-selective and selective. non-selective inhibitors of nitric oxide synthase are not specific to any kind of NOS whereas selective are specific. The alkyl guanidines are a class of selective iNOS inhibitors, including mercaptoethylguanidine (MEG) and guanidinoethyldisulfide (GED), that have been demonstrated to be potent inhibitors of iNOS while also simultaneously limiting peroxynitrite formation (a powerful oxidant formed from the reaction of nitric oxide with superoxide), scavenging available peroxynitrite and NO, and inhibiting prostaglandin production via inhibition of COX 131-132.
Further research work is going on in this direction to use NOS inhibition as one of the strategy of host modulation therapy.
VI) Modulation of cell signalling pathways in periodontal disease:
As we know that bacterial biofilm present in the gingival sulcus around the tooth is source of various bacterial components and products, which initiate the host response. First of all the innate immune system counters the infection, but when not controlled, the acquired immune system is activated. The invader is recognised by the antigen presenting cells and presented to T-cells by MHC-I or MHC-II depending on which helper or cytotoxic-T cell mediated immune response is generated. Within 3-4 days a robust inflammatory response is generated, which initiates the connective tissue destruction.
Now this activation is done by various cellular signalling mechanisms, which leads to the synthesis of various cytokines and other inflammatory chemical mediators. When a signal is generated, it travels through the cytoplasm and reaches the nucleus, and ultimately the pattern of gene expression is altered by transcriptional and post-transcriptional mechanisms. Signal transduction depends on receptor-ligand interactions which usually involves some modification on the cytoplasmic proteins associated with these receptors. The most common modification associated with signal transduction is phosphorylation of specific amino acid residues by kinases, which induces a conformational change on the tri-dimensional structure of the protein. In the process of intracellular signalling, energy is transferred at every step which modulates the biological activity of the proteins involved.
In periodontal disease the most important pathways include the mitogen activated protein kinase (MAPK), nuclear factor kappa B (NF-κB) and janus tyrosine kinase-signal transducer and activator of transcription (JAK/STAT) 133-134 . Studies have shown that the inhibition of these signalling pathways can lead to reduction in the synthesis of pro-inflammatory cytokines. These findings have been demonstrated in patients with with inflammatory diseases such as rheumatoid arthritis and periodontal disease 135-140.
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