A Medical-Dental Dialogue: Periodontal Disease and Systemic Health

Web Sites

American Dental Education Association
ADEA servers the predoctoral, postdoctoral, and allied dental education community. ADEA provides advocacy, professional development, and a wealth of expert information and resources. The association addresses contemporary issues influencing education, research, and the delivery of oral health care for the improvement of public health.

Journal of the American Dental Association
The American Dental Association publishes this monthly journal of peer-reviewed articles.

Multi-Ethnic Study of Atherosclerosis
The Multi-Ethnic Study of Atherosclerosis (MESA) is a medical research study involving more than 6,000 men and women from six communities in the United States. MESA is sponsored by the National Heart Lung and Blood Institute of the National Institutes of Health. Participants in MESA are seen at clinics in the following universities: Columbia University, New York; Johns Hopkins University, Baltimore; Northwestern University, Chicago; UCLA, Los Angeles; University of Minnesota, Twin Cities; Wake Forest University, Winston Salem.

National Health and Nutrition Survey Examination
The National Health and Nutrition Examination Survey is a population-based survey designed to collect information on the health and nutrition of the U.S. household population.

National Periodontal Disease Coalition
A sponsor of this conference, the NPDC is a group of leading business people, health care practitioners, dentists, periodontists, practice management consultants, insurance companies, communications experts, dental industry executives, educators, and others committed to raising the profile of this most common but underrecognized infection in the mouth. In addition to information about the related advocacy organization Oral Health America, the site also features links to additional resources.

Obstetrics and Periodontal Therapy (OPT) Study
The purpose of this study is to determine if non-surgical periodontal (gum) treatment can reduce the incidence of preterm birth and low birth weight babies in mothers with periodontitis (gum disease).

The Periodontitis and Vascular Events (PAVE) Study
The purpose of this study is to determine if treating periodontal infections (gum problems) will lead to fewer heart problems in patients at high risk for cardiovascular disease.

Journal Articles

Periodontal Infections and Atherosclerotic Vascular Diseases

D'Aiuto F, Parkar M, Nibali L, et al. 2006. Periodontal infections cause changes in traditional and novel cardiovascular risk factors: results from a randomized controlled clinical trial. Am. Heart J. 151: 977-984.

D'Aiuto F, Ready D, Tonetti MS. 2004. Periodontal disease and C-reactive protein-associated cardiovascular risk. J. Periodontal Res. 39: 236-241.

Jespersen CM, Als-Nielsen B, Damgaard, the CLARICOR Trial Group, et al. 2006. Randomised placebo controlled multicentre trial to assess short term clarithromycin for patients with stable coronary heart disease: CLARICOR trial. BMJ 332: 22-27. Full Text

Nelson JC, Jiang XC, Tabas I, et al. 2006. Plasma sphingomyelin and subclinical atherosclerosis: findings from the multi-ethnic study of atherosclerosis. Am. J. Epidemiol. 163: 903-912. Full Text

Nibali L, D'Aiuto F, Griffiths G, et al. 2007. Severe periodontitis is associated with systemic inflammation and a dysmetabolic status: a case-control study. J. Clin. Periodontol. 34: 931-937.

Sacco RL, Benson RT, Kargman DE, et al. 2001. High-density lipoprotein cholesterol and ischemic stroke in the elderly: the Northern Manhattan Stroke Study. JAMA 285: 2729-2735. Full Text

Shea S, Aymong E, Zybert P, et al. 2003. Fasting plasma insulin modulates lipid levels and particle sizes in 2- to 3-year-old children. Obes. Res. 11: 95-103. Full Text

Tonetti MS, D'Aiuto F, Nibali L, et al. 2007. Treatment of periodontitis and endothelial dysfunction. N. Engl. J. of Med. 356: 911-920. Full Text

Periodontal Infections and Adverse Pregnancy Outcomes

Goepfert AR, Jeffcoat MK, Andrews WW, et al. 2004. Periodontal disease and upper genital tract inflammation in early spontaneous preterm birth. Obstet. Gynecol. 104: 777-783. Full Text

Goldenberg RL, Culhane JF. 2006. Preterm birth and periodontal disease. N. Engl. J. Med. 355: 1925-1927.

Goldenberg RL, Goepfert AR, Ramsey PS. 2005. Biochemical markers for the prediction of preterm birth. Am. J. Obstet. Gynecol. 192(5 Suppl): S36-46.

Jeffcoat MK, Geurs NC, Reddy MS, et al. 2001. Current evidence regarding periodontal disease as a risk factor in preterm birth. Ann. Periodontol. 6: 183-188.

Jeffcoat MK, Geurs NC, Reddy MS, et al. 2001. Periodontal infection and preterm birth: results of a prospective study. J. Am. Dent. Assoc. 132: 875-880. Full Text

Jeffcoat MK, Hauth JC, Geurs NC, et al. 2003. Periodontal disease and preterm birth: results of a pilot intervention study. J. Periodontol. 74: 1214-1218.

Michalowicz BS, Durand R. 2007. Maternal periodontal disease and spontaneous preterm birth. Periodontol 2000 44: 103-112.

Michalowicz BS, Hodges JS, DiAngelis Ajet al; OPT Study. 2006. Treatment of periodontal disease and the risk of preterm birth. N. Engl. J. Med. 355: 1885-1894. Full Text

Offenbacher S, Boggess KA, Murtha AP, et al., 2006. Progressive periodontal disease and risk of very preterm delivery. Obstet. Gynecol. 107: 29-36. Full Text

Offenbacher S, Katz V, Fertik G, et al. 1996. Periodontal infection as a possible risk factor for preterm low birth weight. J. Periodontol. 67(10Suppl): 1103-1113.

Pihlstrom BL, Michalowicz BS, Johnson NW. 2005. Periodontal diseases. Lancet 366: 1809-1820.

Periodontal Infections and Renal Disease

Beck JD, Couper DJ, Falkner KL, et al. 2008. The Periodontitis and Vascular Events (PAVE) pilot study: adverse events. J. Periodontol. 79: 90-96.

Couper DJ, Beck JD, Falkner KL, et al. 2008. The Periodontitis and Vascular Events (PAVE) pilot study: recruitment, retention, and community care controls. J. Periodontol 79: 80-89.

Moss KL, Serlo AD, Offenbacher S, et al. 2007. The oral and systemic impact of third molar periodontal pathology. J. Oral Maxillofac. Surg. 65: 1739-1745.

Nickolas TL, Frisch GD, Opotowsky AR, et al. 2004. Awareness of kidney disease in the US population: findings from the National Health and Nutrition Examination Survey (NHANES) 1999 to 2000. Am. J. Kidney Dis. 44: 185-197.

Offenbacher S, Barros SP, Singer RE, et al. 2007. Periodontal disease at the biofilm-gingival interface. J. Periodontol. 78: 1911-1925.

Radhakrishnan J, Kiryluk K. 2006. Acute renal failure outcomes in children and adults. Kidney Int. 69: 17-19.

Policy Implications and Inter-Professional Relationships

Bresch JE, Luke GG, McKinnon MD, et al. 2006. Today's threat is tomorrow's crisis: advocating for dental education, dental and biomedical research, and oral health. J. Dent. Educ. 70: 601-606. Full Text

Glick M. 2007. A bird's eye view of dentistry in the U.S. Br. Dent. J. 203: 225.

Glick M. 2007. Risky liaisons: what is the relationship between oral conditions and nonoral diseases? J. Am. Dent. Assoc. 138: 1056-1059.

Glick M, Greenberg BL. 2005. The potential role of dentists in identifying patients' risk of experiencing coronary heart disease events. J. Am. Dent. Assoc. 136: 1541-1546. Full Text

Greenberg BL, Glick M, Goodchild J, et al. 2007. Screening for cardiovascular risk factors in a dental setting. J. Am. Dent. Assoc. 138: 798-804.

Johnson NW, Glick M, Mbuguye TN. 2006. Oral health and general health. Adv. Dent. Res. 19: 118-121. Full Text

Krol DM. 2004. Educating pediatricians on children's oral health: past, present, and future. Pediatrics 113: e487-492. Full Text

Krol DM. 2003. Dental caries, oral health, and pediatricians. Curr. Probl. Pediatr. Adolesc. Health Care. 33: 253-270.

Krol DM. 2003. The effort to make oral health a more visible issue to pediatricians. Ambul. Pediatr. 3: 109-110.

Sinkford JC, Valachovic RW, Harrison SG. 2008. Women's oral health: The evolving science. J. Dent. Educ. 72: 131-134.

Sponsors

Columbia University College of Dental Medicine

Columbia University College of Physicians and Surgeons

National Periodontal Disease Coalition

Supporters

Aetna Dental

Colgate Oral Pharmaceuticals

Johnson and Johnson Oral Health Care Products

Oral Health America

OraPharma, Inc.

Speakers:
Steven Shea, Columbia University College of Physicians and Surgeons
Maurizio Tonetti, European Research Group on Periodontology

Highlights

• The Multi-Ethnic Study of Atherosclerosis revealed that obesity is a major risk for cardiovascular disease and is associated with hypertension, glucose intolerance, greater carotid intimal wall thickness, higher coronary artery calcium scores, and greater left ventricular mass.
• The Hispanic Children's Health Study showed correlations between obesity and insulin resistance and inflammation in two- to three-year-old children living in Manhattan.
• Whether infection/inflammation causes cardiovascular disease is controversial; epidemiological studies suggest yes, but recent intervention trials showed that giving systemic antibiotics did not decrease mortality or cardiovascular events.
• Periodontal disease is an infection; mechanistic studies suggest it could trigger the onset of atherogenesis through its inflammatory components or directly precipitate cardiovascular events.
• Intensive periodontal therapy improves markers of inflammation, but whether or not such treatment influences systemic vascular disease is still an open question.

Heart disease risks

Cardiovascular disease is a leading killer worldwide. And what's particularly worrisome is the fact that today, even very young children are showing risk factors, said Steven Shea of Columbia University College of Physicians. Shea, a principal investigator for the multicenter Multi-Ethnic Study of Atherosclerosis (MESA) and for the Hispanic Children's Health Study in New York City, reviewed data from these observational studies as a means of informing the audience about risk factors for subclinical cardiovascular disease.

Obesity emerged as a major risk in both studies: in MESA, which enrolled adults ages 45–84 with no clinical evidence of heart disease, obesity was associated with hypertension, glucose intolerance, greater carotid intimal wall thickness, higher coronary artery calcium scores, and greater left ventricular mass. In the Hispanic Children's Health Study, which enrolled healthy two- to three-year-olds, obesity was linked to insulin resistance and to increases in markers of inflammation such as c-reactive protein (CRP).

A role for infection?

How do these findings relate to periodontal disease? Maurizio Tonetti of the European Research Group on Periodontology described the efforts of his group and others to draw the connections. He noted that a large portion of the risk factors for atherosclerosis are not known; more than 50% of individuals who have a heart attack or unstable angina do not have "classical" risk factors, such as diabetes, high levels of low-density lipoprotein cholesterol, or hypertension. Epidemiological research as well as mechanistic studies over the past decade suggest that chronic infection increases the risk of cardiovascular disease, and especially early atherogenesis.

Studies have shown an association between periodontitis and increased CRP levels, but this does not prove cause and effect.

However, large intervention trials, such as the Claricor trial, in which people with stable heart disease or angina were given antibiotic therapy or placebo, showed the therapy did not result in a decrease in mortality or cardiovascular events. "So, skepticism [about the link between infection and heart disease] developed, and there's still quite a bit of discussion" about the hypothesis, Tonetti acknowledged. That said, he is among those who are convinced that the connection between infection and heart disease is real. And in this context, periodontitis—which is "just another [form of] chronic infection"—could be an important risk. "When you see a patient with pus oozing out from the gums, tremendous pocketing, and bone loss, no one in the audience would believe that the [rest of the] body isn't sensing what's happening in the mouth," he said.

Two major hypotheses describe plausible mechanisms by which periodontitis might influence cardiovascular health. The inflammatory components of periodontitis might have an impact on the onset of atherogenesis; or periodontitis might, in and of itself, precipitate cardiovascular events. "Both hypotheses are valid and supported by mechanistic studies," Tonetti said. But only intervention trials can provide definitive proof: "If we remove the cause [periodontitis], we should see an attenuation of the effect, and that would prove causality."

Treatment of periodontitis clears up the inflammation.

A number of case-control studies have shown an association between periodontitis and increased CRP levels, but this does not prove a cause-and-effect relationship, Tonetti explained. For example, one study showed that treatment of periodontitis with extraction of hopeless teeth and mechanical removal of plaque, calculus, and the subgingival biofilm that causes periodontal disease cleared up the inflammation. At six months followup, reductions were seen in serum concentrations of interleukin-6, also a marker of inflammation, as well as CRP. Subsequent analyses revealed a dose-dependent effect of periodontal treatment in that people who responded better to the treatment—that is, they had little residual bleeding and few pockets—had a greater reduction in CRP levels.

However, although the number of pockets decreased from 77 to 23 on average after treatment, infection was not eradicated. "This troubled us," Tonetti acknowledged. "We wondered whether standard periodontal treatment is best for a trial. Is standard treatment enough to not only cure the local issue of periodontitis, but to also bring about a systemic effect?"

Exploring interventions

Tonetti and his colleagues explored a number of other treatment approaches, including scaling, root planing (removal of calculus and bacteria by scraping them away from the root surface below the gum line), and oral hygiene instruction and found that the variability in patient response was linked mainly to local disease—pocket depth, location of the pocket, types of pathogens harbored—and not to the systemic state of the patient.

They thought about adding a systemic antibiotic to the treatment plan, since previous studies had shown that antibiotic use improves outcomes significantly in people with severe periodontal disease. But they faced a problem: "We couldn't use systemic antibiotics with scaling and root planing if we wanted to prove causality [between periodontitis and cardiovascular disease]; there would still be a doubt, since we might end up treating an occult chronic infection elsewhere in the body," Tonetti explained.

So the team explored local antibiotic delivery in the periodontal pockets instead. Earlier studies suggested that local drug delivery in combination with scaling and root planing could result in significantly less recolonization of bacteria and consequently better reductions in pockets, gum bleeding, and other manifestations of periodontitis six months after treatment. "Taken together with recent meta-analyses on the effects of local drug delivery at the site of infection, [it seemed that local delivery yielded] the same benefit as did systemic."

With scaling, planing, and local delivery of an antibiotic, "we thought we might finally have a treatment that could show a reduction in systemic infection," Tonetti said. But another problem emerged. Scaling and root planing actually induced a short-term bacteremia, with inflammation, coagulation, and vascular dysfunction. These short-term systemic effects might mitigate the long-term benefit, and so treatment still had to be optimized.

Early indications

Moving ahead, the team conducted two pilot studies in patients with severe periodontitis. The first compared standard periodontal treatment versus intensive treatment—including scaling, planing, subgingival instrumentation, other periodontal measures, plus microspheres of the antibiotic minocycline delivered locally—versus no treatment of periodontitis. Intensive treatment produced better periodontal and systemic outcomes as measured by reductions in CRP, interleukin-6 and other markers of inflammation. Therefore, the study supported the hypothesis that periodontitis is a potential cause of systemic inflammation, Tonetti said.

The second pilot compared intensive versus standard treatment over six months. Here again, intensive treatment gave a greater benefit, earlier than standard treatment, and confirmed that there may be causality between periodontal disease and systemic disease. A recent meta-analysis that examines the effect of periodontal treatment on CRP serum concentrations suggests a significant improvement after intensive periodontal therapy.

The team went on to conduct a primary prevention trial to determine the effect of intensive periodontal treatment on endothelial dysfunction (measured by flow-mediated vasodilatation) compared with standard community-based treatment in adults with severe generalized periodontitis. Intensive treatment was successful in ameliorating periodontitis; at six months, the average number of periodontal lesions went from 82 to 14 in the intensive treatment group, whereas the number of lesions was unchanged in the community treatment group.

Intensive periodontal treatment was associated with improvement in endothelial function at six months, but the studies have limitations.

Intensive treatment also translated into changes in endothelial function in a biphasic manner: one day after treatment, there was a decrease in elasticity of the arteries. But the arteries became more flexible over time so that at six months, intensively treated patients were actually better off than they were at the beginning. There was also an association between flow-mediated dilation and sites with bleeding on probing (a clinical sign of gingival inflammation). "The better the bleeding went, the better the flow-mediated dilation went," Tonetti said. These findings suggest that periodontitis is a possible cause of endothelial dysfunction, and that periodontal treatment might reverse this first step in cardiovascular disease.

But these studies have limitations, in that they are valid only for individuals with very severe periodontitis who are systemically healthy, Tonetti acknowledged. Could periodontal treatment prevent cardiovascular events in a high-risk population? The multi-center Periodontitis and Cardiovascular Events (PAVE) study, a pilot secondary prevention trial, actually asked this question. That study found no statistically significant difference in event-free survival in individuals who underwent intensive periodontal treatment at the study center compared with a community-based control group who received treatment at their own dentist. A definitive study is now needed to answer this question.

Looking ahead

"The results are interesting because they show us the direction we need to go," said Tonetti. "We need to differentiate primary versus secondary prevention, and we need to ask ourselves about the intervention, since it seems that periodontitis may be more difficult to treat than we think. Also, when we look at a population, we need to establish the extent and severity of their periodontitis as well as their systemic status. These issues are likely to be key to the success of future studies."

Speakers:
Sherry Glied, PhD, Columbia University
Michael Glick, DMD, Arizona School of Dentistry and Oral Health
Richard W. Valachovic, DMD, MPH, American Dental Education Association
David Krol, MD, MPH, FAAP, University of Toledo

Highlights

• Research findings linking oral heatlh and non-oral diseases and conditions have implications for dental and medical education, as well as the financing of dental services.
• Associations between oral health and systemic conditions are exciting, but also wrought with potential biases and misinterpretations.
• Oral health is important for its own sake, not just because of potential connections to systemic health.
• Until recently, there has been no viable effort to integrate the academic and practice components of medicine and dentistry.
• Physicians should be able to provide oral health guidance, and dentists should be involved in screening and referral for relevant systemic conditions.

Separation of mouth and body

In his introduction to this session on the policy implications of the "oral-medical connection," session co-chair Burton L. Edelstein of Columbia University College of Medicine observed that "like mammals and marsupials, medicine and dentistry live side by side but don't mate." He briefly described the origin of the two professions in the United States, which dates back to 1840. At that time, physicians at the University of Baltimore rejected the idea of starting a "department of oral stomatology" for those interested in dentistry. From that point on, medicine and dentistry evolved as separate professions, with separate schools and curricula, licensure, professional groups, care-delivery sites, para-professionals, insurance, and cultures. At the same time, the mouth became "unplugged" from the rest of the body—not included in routine medical care—creating a disconnect that continues today.

Can the mouth now be plugged back into the body? Yes, according to the speakers in this session—but to do so requires "substantive clinical, health systems, and public policy changes," Edelstein acknowledged.

Integrating the systems

One of the consequences of the separation between dental and medical care is that the two are financed differently. And whereas many people have health insurance to cover medical needs, relatively few have dental insurance. As a result, "lots of people are not getting dental care," and the ones who don't tend to be the same lower income individuals who are most at risk for the systemic problems described in the previous sessions, said Sherry Glied of the Mailman School of Public Health. She cited a recent study showing that only about 42% of adults ages 18 to 64 went to the dentist in the previous year—among them, only 38% of pregnant women and 44% of those with heart disease.

In light of the "growing evidence" linking systemic conditions to oral health, "we need a holistic vision of medical care," Glied said. "We need to expand our thinking about what constitutes medicine to include dental health," and to do so will require new models of integration. She suggested following some of the lessons learned over the past 30 years in trying to integrate mental health and medicine.

It would be feasible to embark on a model wherein dental insurance is integrated with medical insurance.

For example, it would be feasible to embark on a model wherein dental insurance is integrated with medical insurance, with insurers playing a key role in making the connection between professions. Rather than doctors and dentists talking to each other about their patients, they would each talk to the insurers about their patients. For this type of model to work, it would have to be "organizationally" based to ensure good communication among all parties, and the medical and dental plans would have to work in concert from a financial perspective—that is, there would have to be "dental carve-outs" embedded in medical health plans. Glied pointed to Aetna as a company that is using this type of model.

But she also warned that "you have to be very careful before you go down this path, based on our experience with mental health. It's dangerous to say that the reason you want to integrate or provide dental insurance is because it's going to save money on medical insurance or do something good on the medical side. Dental care is valuable because oral health is valuable in and of itself. If oral health gives you better treatment for heart disease, that's a bonus. Otherwise, you have to be tremendously convinced by the science that the connection is there, that the intervention [the dentist makes] matters, and also that the intervention saves you money down the line. And that's tremendously difficult to show." The other caveat in going with the insurance-based model is that it misses people who don't have coverage—the population most in need of services, because they're not going to the dentist at all.

Glied suggests using this type of holistic model but at the same time, expanding dental coverage. "The evidence shows that giving people dental insurance really improves oral health, and that expanding dental coverage will not set off an avalanche of use," she concluded.

Professional responsibilities

Once people are going to the dentist, what are the oral health professional's responsibilities in a partnership with other medical and health professionals? Michael Glick of the Arizona School of Dentistry and Oral Health provided a "roadmap" containing five key directives. The first is to "create"—that is, build a knowledge base grounded in education, training, and research. The second is to accurately "interpret" the results of research. He reminded the audience that, for example, the same statistics may sometimes be used to draw opposing conclusions; that epidemiological studies do not show causality; and that odds ratios and relative risks cannot be used to assess an individual patient's risk.

"We need to get it straight because if we come out with different messages all the time, it dilutes the right message. We need to look at data we have, be critical of what we have, and not put in the abstract and conclusion [of a writeup] what we really wish had happened in the study," said Glick, who is editor of the Journal of the American Dental Association. In the context of this event, "getting it straight" means not overinterpreting the current data on the oral-systemic connection. While the associations described earlier and in the literature may be "exciting," they are also "wrought with potential biases and misinterpretations."

The next responsibility, when publishing data, is to "translate" research findings in a forthright way, rather than trying to hedge one's bets by not stating upfront that there are uncertainties.

Dental professionals are also responsible for disseminating accurate information to the public. Glick pointed to an online ad by a law office that stated the following:

If you or someone you know had periodontal disease, diagnosed or undiagnosed, and either ignored or treated unsuccessfully, before or during the same time as any of the mentioned systemic diseases [e.g., diabetes, heart disease, stroke], you may be eligible for damages caused by these systemic diseases.

"Science, not the legal profession, should fuel what we know and what we tell our patients. This [involvement of the legal profession] is what happens because there's a lot of misinformation out there," Glick stressed.

In the future, dentists should also screen for and monitor medical conditions.

Finally, clinicians should be willing to "implement" changes in their practice when data are available. At this point, that means that dentists should provide dental care; recognize changes in the oral cavity; screen for underlying medical conditions; monitor present medical conditions; and intervene to reduce unhealthy behaviors. Carrying out those responsibilities might include doing a blood pressure reading, a chair-side cholesterol test, or glucose screening, he suggested. "There's a lot of spa dentistry out there, and I would love to see medically oriented dental clinics, as well. We would identify individuals at risk for medical conditions and do referrals. Our patients would go to physicians who will make diagnoses and prescribe treatments. And eventually our patients would come back to us, we'd monitor them, and the circle would continue. That's what we need to do, but we're not there yet," he acknowledged. "Fifteen years ago, I would have said I hope every dentist out there does this within the next five years. I'm wiser now, and so I'm saying that if 5% to 10% do something, that will have an impact."

Moving ahead

The session concluded with two speakers who emphasized the need to integrate medicine into the dental curriculum and vice versa in order to "mold" new professionals coming into these fields. Picking up on the theme alluded to by Edelstein, Richard W. Valachovic of the American Dental Education Association described in detail the long-standing separation of medical and dental education in the United States and emphasized that for change to occur, the gap between the two must be bridged. This won't be easy, he affirmed. Most dental schools don't provide a medical knowledge base or have a relationship with a local medical laboratory for routine screening. The curriculum in both dental and medical schools is already "overloaded," he said. "So if we want dentists to recognize systemic problems and refer patients to physicians, and we want physicians to recognize oral health problems and refer patients to dentists, the first thing people in charge of the curricula will say is 'ok, what do we stop teaching [in order to add this new knowledge]?'"

Politically, the time may be ripe to start integrating the two professions.

But somehow, the information has to become part of required learning. Valachovic noted that today, young people have very different expectations from their health professionals than even 10 years ago. So much information is available online, he said, that they'll be wondering, why isn't my dentist asking about systemic issues? Why isn't my doctor looking at oral health?

Politically, the time may be ripe to start integrating the two professions, he continued. Congress is taking an "incredible" interest in dental care—specifically, access to care. New technologies such as salivary diagnostics are overlapping the two professions. "Will routine salivary testing also be part of what we dentists do?" he wondered.

Finally, legal considerations, as depicted by Glick, will continue to have an impact on the direction of such collaborations, Valachovic stressed. The bottom line, he said, is that "we [dentists and physicians] need to learn to collaborate in a more aggressive way, have curricula that reflect that collaboration, and learn to refer to each other as appropriate."

Incorporating oral health into the medical curriculum

In the closing presentation, pediatrician David M. Krol of the University of Toledo College of Medicine addressed the need for more oral health education in medical schools. There's no shortage of places in the curriculum for such information, he noted. At the undergraduate level, oral heath and potential systemic health connections could be taught in anatomy courses, biochemistry, microbiology, pathology, preventive medicine, and in most disciplines—for example, primary care, family medicine, internal medicine, obstetrics/gynecology, pediatrics, emergency medicine, and geriatrics. Those same disciplines could incorporate oral health at the level of graduate medical education. And in fact, the topic could be taught on its own in any continuing medical education program, he added.

Yet studies continue to document the dearth of such education. A recent survey by the American Academy of Pediatrics found that:

• 66% of graduating residents feel pediatricians should conduct oral health assessments;
• 32% received no oral health training during residency;
• 75% had less than three hours of training;
• 14% had clinical observation time with a dentist; and
• The majority of residents want more oral health training.

Similarly, a previous study of continuing medical education among pediatricians found that more than 60% received no instruction in dental health via CME, and among those who did, the mean number of hours of instruction was less than two.

The situation is changing, albeit slowly, Krol said. For example, the current U.S. Medical Licensing Examination specifies disorders of mouth, salivary glands, oropharynx, including dental disorders, under "Nutritional and Digestive Disorders," and lists "teething syndrome, dental caries, stomatitis, disorders of teeth/jaw, and malignant neoplasms of lip, oral cavity, and pharynx" as content areas. Several medical schools are beginning to incorporate dental health into the curriculum, as are some residency programs. Novel continuing medical education programs dealing with oral health are being developed and disseminated.

While these are steps in the right direction, there is still room for improvement, Krol urged. He called for oral health to be included explicitly as part of the required content for primary care graduate medical education, and as content areas covered in board certification examinations in internal medicine and obstetrics/gynecology. Oral health should also be on the radar screen of professional societies and clinicians in practice, he concluded.

Is periodontal disease a risk factor for cardiovascular disease?

Can periodontal treatment attenuate the risk of cardiovascular events? If so, what types of treatments might work, and which patients are likely to benefit?

Does periodontitis increase the risk of renal impairment?

Does periodontitis increase the risk of cardiovascular disease/events in end-stage renal failure?

If periodontitis is a risk for these conditions, could treatment reduce morbidity and mortality?

Does periodontal therapy delivered prior to conception affect birth outcomes?

Do comprehensive approaches that address all infections/chronic inflammatory states as well as deleterious habits and lifestyles improve birth outcomes?

What is the effect of periodontitis on early pregnancy losses?

Are periodontitis and preterm birth risk features of a common phenotype?

How can compliance with periodontal treatment in randomized controlled trials be improved?

How can oral health be better integrated into medical practice, and vice versa?

How can oral health be better integrated into the medical school and continuing medical education curricula?

What is the role of dental health professionals with respect to systemic health?

How can the medical and dental professions collaborate better in the interest of their patients?

Speakers:
Jai Radhakrishnan, Columbia University College of Physicians and Surgeons
Steven Offenbacher, University of North Carolina School of Dentistry

Highlights

• The incidence of chronic kidney disease (CKD) is growing worldwide.
• Diabetes and hypertension are the two most common conditions associated with CKD.
• Renal fibrosis, the primary pathological correlate of clinical progression of CKD, results from the combined effects of various abnormalities, including inflammation and local release of cytokines.
• Periodontal disease is associated with renal disease and kidney failure; in end-stage renal disease, periodontal disease, which may also be atherogenic, may contribute to cardiovascular disease.
• Interventional trials are needed to determine whether periodontitis is a risk factor for renal impairment, and whether treatment might reduce cardiovascular disease mortality in patients with end-stage renal disease.

Kidney disease: common, hard to detect

In his introduction, nephrologist Abhijit V. Kshirsagar of the University of North Carolina at Chapel Hill called the session on periodontal infections and renal disease "the most exciting part of this get-together." He acknowledged that much of the emerging evidence of an association between oral disease and renal disese is preliminary; however, since kidney disease and cardiovascular disease share many of the same risk factors, and inflammation is considered a risk factor for cardiovascular disease, couldn't inflammation [induced by periodontal infections] also be a risk for renal disease?

Most people diagnosed with kidney disease have had it for months, since early detection is difficult.

In order to answer this question, it's important to understand the pathobiology of the kidney, said Columbia University's Jai Radhakrishnan, who undertook to explain the basics. Radhakrishnan noted that chronic kidney disease is an "epidemic" whose incidence is growing throughout the world. Most people diagnosed with the disease have had it for months, since it's hard to detect early on. "That's the tragedy," he said. "Dialysis units are filled with people who have never seen a doctor, and most will progress to end stage without ever having symptoms." Kidney disease is considered "chronic" when an individual has it for more than three months, which is the case with many patients with diabetes and/or hypertension. Age is also a risk factor; the recent Third National Health and Nutrition Examination Survey (NHANES III) found that 11% of individuals older than 65 years without hypertension or diabetes had stage 3 or worse chronic kidney disease (stage 5 is considered end-stage renal disease).

What are the systemic effects of kidney disease? Simply put, as the nephron deteriorates, individuals develop the uremic syndrome. Toxins, salt, and water accumulate in the blood; the individual gets bone disease because of a decreased synthesis of vitamin D. Proteinuria—excess protein in the urine—may occur. This protein leakage leads to an elaboration of inflammatory processes, so that one of the principal aims of treatment is "to bring down urine protein, no matter what," Radhakrishnan explained.

On a structural level, increased renal sympathetic nerve activity and angiotensin may contribute to efferent arteriolar vasoconstriction and glomerular hypertension. The molecules promoting vasoconstriction also cause long-term detrimental effects on the kidney by stimulating the production of molecules that expand and alter the composition of the extracellular matrix in the interstitium.

Both glomerular hypertension and proteinuria are associated with oxidative stress that can cause activation of circulating leukocytes that then invade the vessel wall and interstitium, stimulating the release of cytokines and growth factors that lead to progressive sclerosis of both the glomerulus and tubules, and ultimately, loss of nephrons. "Once you get into a cycle of inflammation and fibrosis, it sustains itself and moves toward kidney failure," Radhakrishnan said. "The other big problem is, although this is going on in the kidney, it also affects other parts of the body. Kidney damage actually leads to inflammation."

Renal disease also makes an individual vulnerable to increased cardiovascular events, according to Radhakrishnan. "As you go lower and lower on the scale of glomerular filtration rate [above 60ml/min is considered adequate; less than 15ml/min, near dialysis], the risk of dying from a heart attack or stroke is 14 times greater than if you had normal kidney function. The moment you have a diagnosis of chronic kidney disease, you're at major risk for a serious cardiovascular event."

Periodontal connection?

How does all this relate to periodontal disease? As noted earlier, periodontal disease adds to the inflammatory burden and also seems to play a role in atherogenesis, thereby potentially increasing the risk of a cardiovascular event in individuals with kidney disease. In his presentation on the "plausibility and emerging evidence" for a connection between the two conditions, Steven Offenbacher of the University of North Carolina at Chapel Hill reviewed recent studies showing associations between renal disease and periodontitis, and offered a vision of how the two might interact to increase an individual's risk of more severe systemic disease.

Severe periodontal pocketing is associated with increased odds for elevated serum creatinine.

An analysis of data from the NHANES III study showed that severe periodontal pocketing (eight or more sites with a pocket depth of more than 4 mm) is associated with increased odds for elevated serum creatinine, a marker of renal insufficiency. The Dental Atherosclerosis Risk in Communities (DARIC) study, which looked at periodontal disease in 5534 people in four communities in the United States—Forsyth County, North Carolina; Jackson, Mississippi; the northwestern suburbs of Minneapolis, Minnesota; and Washington County, Maryland—showed that those with severe periodontitis had an increased risk of renal impairment (defined as an estimated glomular filtration rate less than 60) compared with those with no or mild periodontal disease; individuals with severe disease also had elevated IgG titers to the oral organisms P. gingivalis, C. rectus, and A. actinomycetemcomitans.

In addition, in patients with end-stage renal disease, periodontal disease was associated with elevated serum CRP, more severe carotid atherosclerosis, and lower levels of serum albumin—a clinical predictor of mortality—compared to those without periodontal disease.

Probing deeper

In light of these observations, Offenbacher and colleagues sought to better characterize periodontal disease and assess the potential relationship to systemic disease. Currently, different studies use different parameters to try to make these connections.

"When we see a patient with periodontal disease, we have to remember it's not pockets that cause disease. The disease is related more to some infectious component and inflammatory areas that may spread the organisms and allow them to get into the systemic circulation," Offenbacher said. "When we just look clinically, we don't know what components of the presenting problem relate to an underlying biological phenotype."

Offenbacher used a complex systems biology approach that takes a wide range of factors into consideration when characterizing periodontal disease. These factors include personal variables, such as whether the person is a smoker, has diabetes, or is obese; the individual's genetic and epigenetic makeup, including gender; and the biological phenotype, which includes cellular and molecular responses and inflammatory patterns.

"Nested within this is what we see clinically—a combination of all these parameters coming together to give us a clinical presentation of disease at the biofilm gingival interface (BGI)," Offenbacher explained. His group endeavored to identify the components of periodontal disease that might be important in explaining this "interface between the bacteria and us"—specifically, those components of periodontal disease that are related to inflammation and the infectious burden in different individuals. Their investigations revealed that:

• Plaque is an important etiological component of oral disease, associated with both gingivitis and periodontitis;
• Bleeding on probing is a better marker than gingival index for defining disease severity;
• Pocket depth is a better marker than attachment level (the latter is a historical measure and doesn't reflect the current phenotype) for defining disease severity;
• Levels of P. gingivalis and C. rectus are also related to disease severity;
• Individual characteristics such as race, gender, and the presence of diabetes also contribute to disease severity.

In light of these findings, Offenbacher commented that traditional definitions of periodontal disease [used in the literature] are "woefully inadequate" for discriminating underlying biological components related to the clinical phenotype.

His team then attempted to characterize the local inflammatory response and found it, too, was much more complicated than anticipated. So many different cytokines are involved that it was difficult to point to a specific inflammatory process that might involved. "That was unsettling to me because I was hoping it would be more direct—that the inflammatory response would lead to direct tissue destruction and pathways [from periodontitis to vascular responses] we could delineate," Offenbacher said. "It raised a real question in my mind. I thought, 'inflammation is important, but there's got to be more to it.'"

Then came an "Aha!" moment. While studying pregnancy outcomes in mice, Offenbacher discovered that oral organisms that made it to the placenta were "having a field day," causing abnormalities in placental structure. Further investigation revealed insulin-like growth factor—which is important for fetal growth—was suppressed, and that this suppression was associated with hypermethylation of the DNA that encodes the growth factor.

Oral biofilm changes the methylation pattern of the host's DNA, thereby altering the metabolism of the cells.

What do methylated genes in mice have to do with human disease at the BGI? Offenbacher suggested that oral biofilm in fact changes the methylation pattern of the host's DNA, thereby altering the metabolism of the cells in the infected region. Moreover, an ulceration in the tissue, caused by the microbial biofilm, becomes a site for invasive organisms to gain access to the systemic circulation. "In essence, periodontal disease creates an open wound that permits the access of invasive organisms to spread through the vascular tree," he explained. This ultimately leads to a microbial and inflammatory challenge that affects the liver, promotes atherogenesis, and increases arterial plaque instability, thereby increasing the risk for heart attack and stroke.

Indeed, the dental ARIC study showed that individuals with no periodontal disease tended to have reduced intimal wall thickness (less atherosclerosis) compared with those who had periodontal disease; and a larger percentage of those with periodontal disease had thicker intimal walls even if they had no history of cardiovascular disease.

On the infectious side, individuals with thicker intimal walls as well as glomular filtration rates of less than 60 tended to have greater dental plaque accumulation, higher bacterial loads, and high antibody titers to C. rectus, P. gingivalis, C. dentalis, and A. actinomycetemcomitans—the same pathogens implicated in severe periodontal disease.

Offenbacher ended his presentation with a summary of major observational studies that link periodontal disease with impaired renal function; pinpoint oral biofilm as a potential cause of renal impairment; show that periodontal disease in patients with end-stage renal disease (ESRD) is associated with elevated serum CRP, more severe carotid atherosclerosis, and lower levels of serum albumin; and suggest that periodontal disease may increase risk of death from cardiovascular disease in patients with ESRD.

Taken together, the findings present a proof of principle that periodontal disease and oral organisms present a challenge in ESRD and "provide the impetus for large studies, including interventional trials to determine whether periodontitis is a risk factor for renal impairment and whether treatment may reduce cardiovascular disease mortality in ESRD patients," Offenbacher concluded.

What is the relationship between oral health and systemic health? Is the mouth really a "harbinger" for systemic conditions, as suggested in the 2000 U.S. Surgeon General's report, Oral Health in America? Population-based studies document associations between periodontal disease and heart disease, adverse pregnancy outcomes, and renal disease, among others. Are these associations causal or coincidental? Can healing disease in the mouth influence disease in the body? Should a dentist alert a physician or other health care professional to the potential consequences of oral disease in a particular patient? Or vice versa? How does insurance—or lack thereof—affect an individual's ability to maintain oral health, and what are the consequences for overall health and wellbeing?

Can healing disease in the mouth influence disease in other parts of the body?

These were among the many issues raised at a full-day symposium at the New York Academy of Sciences on January 18, 2008. The event brought together "leaders in epidemiology, clinical research, and public policy with the collective expertise to investigate linkages, examine causality and to set policy for education and practice within the medical and dental professions," said David A. Albert of Columbia University College of Dental Medicine, in opening remarks. Albert, a member of the symposium's scientific organizing committee and a course director for this continuing education event, observed that "physicians and dentists are rarely provided the opportunity to discuss oral-systemic linkages in an academic forum such as this." The symposium aimed to "reattach the head to the body" as part of an overall effort to improve interdisciplinary communication, collaboration, and education.

No easy answers

The first three sessions of the symposium explored evidence linking periodontal infections with atherosclerotic vascular disease, adverse pregnancy outcomes, and renal disease—the latter being an emerging area of research. Each session paired a physician researcher with a dental researcher, both of whom provided perspectives on the topic.

Steven Shea opened with a review of data from two large studies on risk factors for subclinical cardiovascular disease. Obesity emerged as a major risk in both studies: in the multicenter Multi-Ethnic Study of Atherosclerosis (MESA), obesity in adults ages 18 to 64 was associated with hypertension, glucose intolerance, greater carotid intimal wall thickness, higher coronary artery calcium scores, and greater left ventricular mass. In the Hispanic Children's Health Study, which enrolled healthy two-to-three-year olds, obesity was linked to insulin resistance and to increases in markers of inflammation such as c-reactive protein (CRP). Inflammation, whether caused by periodontal disease or other factors, is getting increasing scrutiny for its potential role in cardiovascular and other diseases.

Maurizio Tonetti of the European Research Group on Periodontology described the efforts of his group and others to draw connections between oral disease and cardiovascular disease. He noted that more than 50% of individuals who have a heart attack or unstable angina do not have "classical" risk factors, such as diabetes, high levels of low-density lipoprotein cholesterol, or hypertension. Other risks, including periodontal disease, could be at work. However, despite plausible mechanisms by which periodontal disease might influence cardiovascular risk, and many observational studies linking the two, whether or not the link is causal is still an open question. Interventional studies are equivocal at best. In fact, the multi-center Periodontitis and Vascular Events (PAVE) study, a secondary prevention trial, showed no statistically significant difference in event-free survival between individuals with heart disease who underwent intensive periodontal treatment compared with a control group who did not receive the vigorous treatment.

Similarly, the link between periodontal disease and adverse pregnancy outcomes, also documented in many epidemiological studies, has not withstood the test of an interventional trial. As Bryan S. Michalowicz of the University of Minnesota School of Dentistry noted in his presentation, the multi-center randomized controlled Obstetrics and Periodontal Therapy Trial found that non-surgical treatment of periodontal disease in mothers was safe and effective, but the intervention was not associated with improved pregnancy outcomes.

The possible connection between periodontal disease and renal disease is an emerging area of study. But here, too, despite a wealth of observational studies and elegant research on potential mechanisms by which the two conditions might interact, interventional studies are needed showing that, in fact, treating periodontal disease will have a real impact on clinical renal disease.

After each session, participants rated their perceptions of the connection between periodontal disease and specific systemic diseases using an audience response system. Given the paucity of hard data indicating a cause-and-effect relationship, several of the presenters expressed surprise at how many audience members were convinced of a connection. For example, 74% of the audience were convinced that periodontal disease is linked to pregnancy problems, despite the fact that interventional trials found that intensive treatment of periodontal disease had no effect on pregnancy outcome. This disconnect between what the studies said and what the audience believes probably warrants further discussion.

Inter-professional relationships

Even though more vigorous studies are needed to confirm a causal link between oral and systemic health, there is no question that oral health is important in its own right. For these reasons, the conference organizers and presenters are urging changes in public policy, insurance, and medical/dental education that would facilitate better collaboration between the two professions.

But they acknowledged that such changes are unlikely to come quickly. The professions have been separate for more than 150 years, observed Richard W. Valachovic of the American Dental Education Association. Part of the change will require adding information on oral medicine and various medical conditions to already "overcrowded" curricula in medical and dental schools. Many different stakeholders would have to work together to create programs and policies that expand insurance coverage for dental health and enhance communication among insurers, practitioners, and patients, added Sherry Glied of the Mailman School of Public Health.

Michael Glick of the Arizona School of Dentistry and Oral Health, editor of the Journal of the American Dental Association, observed that he would "love" to see medically oriented dental clinics. "We would identify individuals at risk for medical conditions and do referrals. Our patients would go to physicians who will make diagnoses and prescribe treatments. And eventually our patients would come back to us, we'd monitor them, and the circle would continue. That's what we need to do, but we're not there yet," he acknowledged. "Fifteen years ago, I would have said I hope every dentist out there does this within the next five years. I'm wiser now, and so I'm saying that if 5% to 10% do something, that will have an impact."