BBI Contributing Writer

CHICAGO, Illinois – Periodontal disease was one of the most-discussed topics at the Chicago Dental Society's annual midwinter meeting, held at the McCormack Place convention center in late February. More than 600 companies featured thousands of new dental products and services during the meeting, one of the largest marketplaces of any dental conference in the U.S.

Periodontal disease affects an estimated 67 million Americans, with less than one-fifth of them receiving treatment (see Table 1). Periodontal disease is a serious infection that leads to tooth loss and has recently been associated with systemic diseases. It begins by a build up of bacteria around the teeth in pockets of gum tissue, which eventually destroys the supporting gum tissue and bone, and leads to tooth loss. The severity of periodontal disease is measured in part by the depth of these "pockets." The disease process starts with the accumulation of bacteria, which then incites an inflammatory response and an accompanying release of enzymes. It is the overproduction of these tissue-dissolving enzymes in certain individuals that is responsible for the destruction of tissues that surround and support the teeth.

Table 1-Periodontal Disease Populations
67 million Americans have periodontal disease
46 million diagnosed by dentist
13 million get treatment
Source: The BBI Newsletter

Difficult market

Although this appears to be a large untapped market opportunity, there are mitigating factors that render it a difficult market to tap. The patient numbers are large but many go undiagnosed, so treatment is often not presented. The disease is painless, so treatment is often not accepted once it is diagnosed. Newer treatment modalities require a pharmaceutical sales force which dentists are not used to receiving. These facts point to education for both patients and dentists as the key to product acceptance, and education is expensive (see Table 2 on page 88).

Table 2-Periodontal Market Developers/Detractors
Market Developers
Large opportunity (67 million Americans)
Twofold treatment opportunity (can address both
     bacteria and enzyme components)
Research heightens importance of periodontal disease
     prevention and treatment
Market Detractors
Disease is painless, so patients don't seek treatment
Two-thirds of dentists don't diagnose and treat disease
Education of dentists, patients is key to market growth
     and is costly
Selling a pharmaceutical into dental market is difficult
Source: The BBI Newsletter

Harris Interactive, a national polling organization, reported recently: "Though nearly one in every three adults in the U.S. – many of them between the ages of 35 and 45 years – has some form of periodontal disease, a recent national survey of 1,000 adults aged 35 and older found that a surprising majority of those polled knew little, if anything, about the disease, its symptoms, available treatment, and most concerning, its consequences."

New information may drive market

But new research may drive both patients and dentists into a closer look at this disease. Recently, scientific research has uncovered an apparent relationship between periodontal disease and other serious health conditions including heart disease, diabetes, stroke, bacterial pneumonia and pre-term, low-birth-weight childbirth. Studies at the University of North Carolina (Chapel Hill, North Carolina) have linked periodontal disease with increased risk of heart attacks. Efthymios Deliargyris, MD, an interventional cardiologist and a member of the Center for Oral and Systemic Diseases at UNC, found significantly higher levels of C-reactive protein (CRP) in heart attack patients and in patients with periodontal disease. The one thing the two conditions share is that they initiate an immune or inflammatory response in the body. The most common marker for this response is CRP. This inflammatory response may be the basis for other systemic diseases associated with periodontal disease (see Table 3).

Table 3-Risk Factors Linked to Periodontal Disease
Smoking 5 times greater risk of getting periodontal disease
Diabetes 2.3 times greater risk of getting periodontal disease
Genetic predisposition 7 to 19 times greater risk of getting periodontal disease
Heart disease 2.3 times greater risk of getting periodontal disease
Presence of P. gingivalis 1.7 times greater risk than if pathogen not present
Heart attack 2-3 times greater when one of three known oral
     pathogens is present*
Second heart attack Significantly greater chance of having second heart
     attack if patient has periodontal disease**
Stroke Two times greater if patient has periodontal disease***
Sources: Susan Larson Consulting, Minneapolis, Minnesota;
*Robert Genco, University of Buffalo;
**David Williamson, University of North Carolina;
***Tiejian Wu, University of Buffalo

In a separate but related study, Robert Genco, DDS, PhD, of the University of Buffalo (Buffalo, New York) also found that patients with moderate or advanced periodontal disease had a greater prevalence of cardiovascular disease than patients with no periodontal disease. Results showed that the heart-attack patients were heavily infected with all bacteria types, but that the risk of heart attack was related significantly only to three types of bacteria: B. forsythus, P. gingivalis and C. recta, organisms thought to cause periodontal disease in adults. (Not all oral bacteria cause periodontal disease.) Depending on the bacterial concentration, the increased risk of heart attack in persons with one or another of these bacteria ranged from 200% to 300%, compared to people with no evidence of the bacteria.

The first major study to look at stroke and periodontal disease was led by Tiejian Wu, MD, PhD, research assistant professor in the University of Buffalo School of Medicine and Biomedical Sciences' department of social and preventive medicine. Results showed that periodontitis was a significant and independent risk factor for any cerebrovascular event and was associated with a twofold increase in risk for non-hemorrhagic stroke.

Wu said periodontal disease is thought to increase the risk of stroke in much the same way it increases the risk of heart attack. "Bacteria, endotoxins and other bacterial products from gum pockets enter the circulation and may promote an inflammatory response, causing cells to proliferate in the blood vessels and the liver to increase production of clotting factors." Additionally, "several periodontal pathogens can induce platelet aggregation and may promote plaque formation that can cause blockages and clotting," he said. An earlier study conducted by University of Buffalo researchers found periodontal bacteria in samples of carotid arterial plaque removed during surgery.

Frank Scannapieco, DMD, PhD, associate professor of oral biology in the University of Buffalo's School of Dental Medicine, was lead author of another study that showed an association between chronic respiratory disease and periodontal disease in an analysis of data from a large national database.

Diagnostics

Diagnostic tests have entered and exited this market several times. The problem is that oral pathogens are present in all mouths in various amounts. Determining the amount of pathogens does not determine if disease is present. What could be considered a pathogenic amount for one individual is not for another. (Although some studies have reported a higher risk of having periodontal disease if the pathogens P. gingivalis, B. forsythus, and/or C. recta is present.) It is the host response to the pathogens that determines whether or not periodontal disease exists and not the mere presence of pathogens. Nor does measuring the amount of enzymes present provide an accurate test because enzyme levels vary in each individual whether or not the disease is present.

A good clinical exam and measurement of pocket depth remains the gold standard for diagnosis. Florida Probe (Gainesville, Illinois) has developed a computerized probe that measures, records and compares patient data from visit to visit, eliminating some human error inherent in measuring pocket depth.

The only diagnostic test other than a good clinical exam that measures pocket depth, is one that determines the patient's risk of developing severe periodontal disease. Kimball Genetics (Denver, Colorado) is a genetic testing laboratory specializing in DNA analysis for common genetic disorders that are preventable or can be treated. They have developed the PST test that identifies patients genetically predisposed to severe periodontal disease. This genetic predisposition increases the likelihood of periodontal disease seven to 17 times greater than for individuals who do not have the genetic predisposition (Table 3).

Treatments

Since the cause of periodontal disease is a combination of both the amount and type of bacteria present, along with the destructive enzymes that are produced in response to those bacteria, optimal treatment should also be twofold. The gold standard for reducing the amount of bacteria present is a procedure performed by a dentist/hygienist called root planing and scaling, which is a manual scraping of the plaque off the tooth. This process is critical to drastically reduce the amount of bacteria present in the tooth pockets. All of the new products listed in Table 4 are used as an adjunct to the root planing and scaling in treating this disease.

Table 4-Periodontal Disease Products on the Market
Company Product Name Type of Product Action
Block Oral Co.
(Jersey City, New Jersey)
Atridox Locally applied
gel
Bacteriostatic
Collagenex Pharmaceuticals
(Newtown, Pennsylvania)
Periostat Oral doxycycline Systemic oral enzyme
suppressant; reduces collagenase
Orapharma
(Warminster, Pennsylvania)
Arestin Locally delivered mino-
cycline microspheres
Local antibiotic delivered by
microspheres
Dexcel Pharma
(Cincinnati, Ohio)
Periochip Locally delivered
chlorohexaden
gelatinous chip
Bateriocidal
Kimball Genetics
(Denver, Colorado)
PST genetic test Diagnostic test Identifies patients genetically
predisposed to severe
periodontal disease
Florida Probe
(Gainesville, Illinois)
Florida Probe Computerized probe Measures, records and compares
depths of "pockets"
Source: The BBI Newsletter

Historically, it was assumed that bacteria were the sole cause of the disease and most treatments focused on reducing the bacterial load. These products were often bacteriocidal or bacteriostatic agents delivered locally into the affected tooth pocket. Although these have been shown to be effective as an adjunct to root planing and scaling, there are some concerns associated with their use. Migration of the product as well as maintaining the concentration of the active agent over a sufficient amount of time, are the two main issues using this form of treatment. The trailblazer of these products was Actisite, which was designed to be packed into the pocket. This was followed by Atridox, which is a syringe-delivered gel, and Periochip, which looks like a popcorn kernel but adheres to the tooth upon contact with moisture.

The newest entry into this market is Arestin, manufactured by Orapharma (Warminster, Pennsylvania). Arestin also is a locally administered antibiotic that is encapsulated in microspheres that adhere to the tooth and maintain therapeutic drug concentration for 14 days. It was just approved in February and product launch is set for this month.

Recent research has shown that the tissue destruction is actually caused by the enzymes produced in response to the presence of bacteria. This new understanding has given rise to the development of treatments that modulate the host response to suppress the enzymes that are the direct cause of tissue destruction. The first of these new medications, Periostat (doxycycline hyclate), manufactured by Collagenex Pharmaceuticals (Newtown, Pennsylvania), was approved by the FDA in September 1998. Periostat modulates the host response pharmaceutically, reducing the amount of destructive enzymes produced. Although initial concerns were that the systemic use of Periostat might cause either drug resistance or other systemic problems, the mechanism of action focuses only on collagenase (the destructive enzyme) suppression and has demonstrated no antibacterial effects, including induction of bacterial resistance.

Another group of medications in the early stages of investigation as possible host response modulators in periodontitis is bisphosphonates, which currently are used to treat osteoporosis. The host response component of periodontitis plays a much more prominent role in the progression and severity of disease than was once realized. Modulating the host response offers a new option in the treatment of periodontitis – and new hope for discovering treatments for other similar systemic diseases.

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