Treating the patient, not just the bacteria
by Nichole Dicke, LDH, BSNonsurgical efforts to treat and control periodontal diseases typically begin with debridement to remove calculus and biofilm, ultimately ridding the oral cavity of gram-negative, anaerobic bacteria. The goal is to remove the offending pathogens and, therefore, reduce the infection and inflammation as well as prevent their recurrence. This approach is often sufficient, especially for patients who experience periodontal disease due to many years of inadequate oral hygiene care. For such patients, once the debridement removes the
Patients who suffer from chronic periodontitis are not usually so fortunate. As dental clinicians, we understand that damage to the periodontium is not caused solely by the bacteria and their byproducts. The body's immune response to the pathogens plays a key role in the periodontal disease story.
For some patients, periodontal disease may actually be caused by an autoimmune disorder, causing their body to overreact to pathogenic oral bacteria.1 The presence of other autoimmune disorders, such as diabetes, can further increase the patient's risk of periodontal diseases. The varying host-response to bacterial disease has been established as a genetic trait,2, 3, 4, 5, 6, 7 explaining why periodontitis sometimes appears to "run in the family." For other patients, it is unknown why their immune system is causing periodontal destruction in response to the bacterial infection.
Regardless, our knowledge of the host-response mechanism should be utilized when treating patients. Why address the bacteria, but not the host?
A review of published literature reveals a plethora of research in host modulation with periodontal disease. Pharmaceuticals are available for reducing the immune response. Over-the-counter nonsteroidal anti-inflammatory drugs (NSAIDs) have also been proposed as a method of controlling inflammation. Other theories suggest adding dietary supplements, vitamins, and minerals to the home-care regimen to help control the immune response. The most researched/most promising examples of these possibilities will be explored and discussed.
Host modulation therapy
In periodontitis, the periodontium is broken down, resulting in the loss of periodontal ligament and alveolar bone. In health, the alveolar bone is constantly undergoing equal cycles of resorption (by osteoclasts) and formation (by osteoblasts). In periodontitis, however, this equilibrium is disrupted, allowing resorption to occur much faster than formation.
The body's immune system reacts to the bacterial infection by releasing inflammatory mediators, including cytokines, chemokines, destructive enzymes (such as matrix metalloproteinases or MMPs), and prostaglandins.8 Such pro-inflammatory mediators are kept under control by antiinflammatory mediators and enzyme inhibitors. Host modulation therapy aims to balance the activity of the pro- and anti-inflammatory mediators, thus preventing damage.8
► Subantimicrobial dose doxycycline (SDD) – Doxycycline is an antimicrobial from the tetracycline group. When administered in subantimicrobial doses (20 mg twice daily), it no longer kills bacteria, but works as a host modulator by inhibiting the production of MMPs.9
SDD is the only approved drug for host modulation purposes.8 SDD has been shown to maintain alveolar height in periodontitis patients compared to placebo in a study spanning six months.10
Another study investigated the use of SDD in conjunction with scaling and root planing (SRP). The amount of benefit received from the SDD treatment increased with the severity of the periodontal pocket.11 Other studies have verified that SDD does appear to enhance the effectiveness of SRP by increased gains in clinical attachment levels, and greater reductions in pocket depths.12, 13
SDD has also shown promising evidence of improved healing response to access flap surgery in severe periodontitis cases. The patients who received SDD experienced reduced postsurgery bleeding on probing, reduced periodontal pocket depths, and reduced bone absorption.14 Yet another potential benefit of SDD is the possibility of maintaining alveolar bone mass in patients with overall reduced bone mass (such as postmenopausal osteoporosis).15,16
These results are likely caused by reduced pro-inflammatory mediators. Researchers have studied the levels of different types of inflammatory markers in patients receiving SDD treatment. When compared to placebo, patients on an SDD regimen had significantly lower MMP levels in their gingival crevicular fluid (GCF).17, 18 A possible explanation to this MMP reduction was identified during a recent study that discovered SDD caused a reduction in the cytokines, which release the MMPs. In this study, researchers reduced levels of cytokine and chemokine in the GCF of patients taking SDD. The mediators measured, which were reduced by SDD treatment, included tumor necrosis factor-α, several interleukins (IL-6, IL-4, IL-10, IL-17), and monocyte chemoattractant protein 1.19
The destructive enzyme collagenase was also observed to be significantly reduced by the use of SDD in a study involving postmenopausal osteopenic women.20 A recent study involving postmenopausal women reported a decrease in blood serum levels of C-reactive protein (a serum biomarker of inflammation) and MMPs, as well as an increase in high-density cholesterol levels after two years of SDD therapy.21 Another possible SDD mechanism of action is the reduction of osteoclast activity. Studies involving laboratory mice have demonstrated the ability of tetracyclines, including doxycycline, to induce apoptosis (programmed cell death) in osteoclasts.22, 23
Concerns arise anytime an antibiotic medication is used long term. However, because SDD is taken at such low doses, the concerns are alleviated. In fact, the SDD research has included regimens up to two years in length. A common theme runs through the discussions of the research to date: There has been no evidence of microbial resistance or changes in bacterial flora in patients taking SDD long term.
SDD is accepted as a safe and effective method of modulating the host immune response. Additionally, previous research indicates a potential for residual effect of taking SDD. After a three-month SDD regimen, patients still experienced reduced levels of cytokines and chemokines nine months after the regimen ended.19 This indicates a potential for prescribing SDD therapy in time intervals. Because the safety of SDD use beyond 12 months has not been thoroughly researched, the FDA-recommended use is for periods up to nine months.
► NSAIDs – NSAIDs reduce inflammation by antagonizing the pro-inflammatory mediators, namely prostaglandins.8,24 Studies have indicated NSAIDs may result in greater bone support results when used with nonsurgical periodontal therapy.12 Adverse reactions, dangers of long-term use (particularly the risk of developing gastrointestinal bleeding), and contraindications limit their use.8, 24
Flurbiprofen is an NSAID used for treating periodontitis and may be used as a topical rinse or systemic medication.25 Many studies have reported the ability of flurbiprofen to aid in healing and bone remodeling in both surgical and nonsurgical periodontal treatment. Success was evident with both short-term and long-term use of the medication.26, 27, 28, 29
Research investigating the effectiveness of topical flurbiprofen applications had favorable results in clinical and radiographic bone levels following nonsurgical periodontal therapy compared to placebo groups.30,31 The ability to use topical flurbiprofen reduces concerns of toxicity from long-term ingestion. Systemic flurbiprofen may increase the risk of circulatory problems, including heart attack. Patients who are taking aspirin, beta-blockers, anticoagulants, or ACE-inhibitors may not be candidates for systemic flurbiprofen use.
Other NSAIDs, including naproxen and ibuprofen, have similarly been shown to slow alveolar bone destruction and preserve the crest height.32, 33, 34, 35 Aspirin is noteworthy for its unique characteristics as an anti-inflammatory drug and is quite different from other NSAIDs. Aspirin deactivates the destructive enzyme COX-2, similar to other NSAID action. However, when aspirin deactivates COX-2, a new enzyme is created, and a lipoxin called aspirin-triggered lipoxin (ATL) results.36 ATL is a more bioavailable and more potent lipoxin (anti-inflammatory mediator), which aids in resolving inflammation.37, 45
Other NSAIDs, while inhibiting pathways to producing pro-inflammation mediators (thus reducing acute inflammation), may also inhibit pathways to producing anti-inflammatory mediators, resulting in chronic low-grade inflammation.38, 39, 40 This chronic state of inflammation may contribute to the increased cardiovascular risk associated with long-term use of some NSAIDs.40 Studies have suggested aspirin may help reduce bleeding on probing, reduce pocket depth, and increase gains in clinical attachment.41,42 In another report, individuals taking aspirin for five years to treat arthritis experienced significantly fewer sites of interproximal alveolar bone loss.43
Of course, aspirin use also has associated risks. Patients should consult their physicians before taking aspirin if they have a history of asthma, liver or kidney disease, ulcers, gout, or bleeding/clotting disorders.
► Dietary supplements – Dental clinicians may also help their patients fight periodontal disease by recommending dietary supplements, including co-enzyme Q10 (CoQ10), omega-3 fatty acids, and vitamins and minerals. We all recognize the importance of diet on the development of caries and soft tissue irritations such as aphthous ulcers. Dietary supplements may also help boost a patient's resistance to inflammation.
One of the most studied supplements for periodontal use is omega-3 fatty acid. A 2010 longitudinal study identified a relationship between periodontal disease occurrence and intake of docosahexaenoic acid (DHA), which is an omega-3 fatty acid. Individuals with low DHA intake appear to experience significantly more episodes of periodontal disease.44
A previous study concluded that ingestion of omega-3 fatty acids was correlated with lower bone loss in inoculated laboratory mice.45 This may be due to the ability of fatty acids, including arachidonate acid (AA), DHA, and eicosapentaenoic acid (EPA) to generate mediators that aid in inflammation resolution. The fatty acid AA synthesizes lipoxin (which was discussed earlier), DHA synthesizes resolvin, and EPA synthesizes the mediator protectin. Lipoxin exists solely to aid in resolving inflammation by returning vascular permeability to its natural balance.45 Resolvin possesses powerful anti-inflammatory properties and helps control the immune response by reducing neutrophils, regulating cytokines, and minimizing the degree of immune response. Protectin also reduces neutrophil infiltration and promotes healing.46
The two-part role of these mediators – both fighting inflammation as well as working to resolve it – gives omega-3 fatty acid supplements the potential to impact patients' ability to control periodontal diseases.
It has been theorized that patients with periodontal disease may be experiencing a deficiency in coenzyme Q10 (CoQ10), and CoQ10 supplements may help in treatment.47, 48, 49, 50, 51 Inadequate research has been conducted to investigate the ability of CoQ10 supplements to aid in fighting and/or resolving inflammation; therefore, advising patients to use CoQ10 as a method of treatment should be done with caution.52
While CoQ10 is considered a safe supplement, there are some precautions for certain patients. CoQ10 may decrease blood sugar levels, decreasing the insulin requirements for diabetic patients. There are also reports of increased blood pressure and lowered liver enzymes (both reported rarely). The usual dosage is 500 to 1,200 mg daily. Finally, a topical application of 85mg per ml suspension may be administered weekly to the gingiva using a plastic syringe to treat periodontitis.53
Dietary nutrients may play a supporting role in the body's defense against periodontal disease.6 The epithelium provides a physical barrier against invading pathogens and their byproducts. Nutrients such as protein, zinc, folic acid, iron, vitamin A, and vitamin C are necessary components of a healthy epithelial barrier.
Dietary protein is essential for the body's ability to produce and repair protein structures, which include teeth, bones, and ligaments. Vitamin D is necessary for adequate blood calcium levels, which calcifies osseous tissues.52 Individuals over age 50 may experience greater attachment loss when their level of vitamin D is deficient.54 Vitamin D deficiency has also been associated with gingival bleeding.55 Low levels of vitamin K have been linked to decreased bone density.52
In individuals over age 60, a higher rate of periodontal disease was found among those with low serum levels of folate.56 Vitamin C is necessary for collagen formation; deficiency has been related to an increased risk of periodontal disease.52,57,58,59 Inadequate calcium intake has been associated with more severe periodontal disease;60 similarly, individuals with the highest dairy intake were found to have the lowest occurrence of periodontitis.61
Balanced nutrition with adequate intake of vitamins and minerals is necessary for good health and may also increase host resistance to periodontal diseases. Any nutrient deficiency should be addressed and supplemented if necessary. While more research is necessary to investigate the impact of individual vitamins and minerals on the periodontal disease process, recommending a balanced and complete diet to patients will only benefit their overall health, in addition to potential periodontal benefits.
Is host modulation therapy the missing link?
Many periodontal patients respond well to traditional, nonsurgical therapy methods such as ultrasonic debridement and root planing. Some patients require surgical intervention. Yet other patients continue to experience active disease regardless of treatment efforts.
For the cases of chronic and unresponsive periodontitis, host modulation therapy may be the missing link in treatment. Reducing the host response to pathogenic bacteria may also be indicated for patients who are at a heightened risk of systemic complications from periodontal disease.
SDD is currently the only approved host modulation therapy drug and has been proven safe for use up to nine consecutive months. SDD reduces the amount of pro-inflammatory mediators released by the patient and also inhibits osteoclast activity.
There is potential for the use of NSAIDs as conjunctive host modulation therapy, particularly for aspirin, which possesses anti-inflammatory as well as pro-resolution properties. However, contraindications and safety concerns may limit the long-term use of NSAIDs.
Studies indicate dietary supplements (omega-3 fatty acids, coenzyme Q10, vitamins, and minerals) are prospective contenders for supporting host resistance to periodontal disease, though more research is necessary before clinicians begin recommending these supplements as periodontal treatment.
In the near future, dental clinicians may see a shift in the periodontal therapy paradigm; treatment may become more focused on host response and less focused on bacterial debridement alone. In the meantime, clinicians should consider including the proven use of SDD (short-term to enhance root planing or long-term for chronic/unresponsive cases) in their periodontal therapy armamentarium.
Nichole Dicke, LDH, BS, has been working as a dental hygienist since 2003.She practices part-time in a general dentistry office and part-time as a clinical instructor in the dental hygiene program at Indiana University Purdue University Fort Wayne. Nichole is completing thesis requirements for the master's of dental hygiene degree from Idaho State University.
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