Periodontal disease and systemic conditions: a bidirectional relationship
Jemin Kim and Salomon Amar
Jemin Kim, Boston University Goldman School of Dental Medicine, Department of
Periodontology and Oral Biology, Boston, MA, USA.
All author affiliations.
Corresponding author.
The publisher's final edited version of this article is available at
Odontology.
For decades, physicians and dentists have paid close attention to their own
respective fields, specializing in medicine pertaining to the body and the oral
cavity, respectively. However, recent findings have strongly suggested that
oral health may be indicative of systemic health. Currently, this gap between
allopathic medicine and dental medicine is quickly closing, due to significant
findings supporting the association between periodontal disease and systemic
conditions such as cardiovascular disease, type 2 diabetes mellitus, adverse
pregnancy outcomes, and osteoporosis. Significant effort has brought numerous
advances in revealing the etiological and pathological links between this
chronic inflammatory dental disease and these other conditions. Therefore,
there is reason to hope that the strong evidence from these studies may guide
researchers towards greatly improved treatment of periodontal infection that
would also ameliorate these systemic illnesses. Hence, researchers must
continue not only to uncover more information about the correlations between
periodontal and systemic diseases but also to focus on positive associations
that may result from treating periodontal disease as a means of ameliorating
systemic diseases.
Etiology and pathogenesis of periodontal disease
Periodontal disease refers to the inflammatory processes that occur in the
tissues surrounding the teeth in response to bacterial accumulations, or dental
plaque, on the teeth. The bacterial accumulations cause an inflammatory
response from the body. The chronic and progressive bacterial infection of the
gums leads to alveolar bone destruction and loss of tissue attachment to the
teeth. Periodontal disease has many states or stages, ranging from easily
treatable gingivitis to irreversible severe periodontitis. Periodontal disease
is increased by several risk factors: cigarette smoking; systemic diseases;
medications such as steroids, anti-epilepsy drugs and cancer therapy drugs;
ill-fitting bridges; crooked teeth and loose fillings; pregnancy; and oral
contraceptive use. In addition to these variables, any medical condition that
triggers host antibacterial defense mechanisms, such as human immunodeficiency
virus (HIV) infection, diabetes, and neutrophil disorders, will likely promote
periodontal disease.1
The most prevalent form of periodontal disease is a mild form called
gingivitis. Gingivitis affects 75% of adults in the United States2 and is
characterized by inflammation of the gums, redness, swelling, and frequent
bleeding.3 More advanced forms of periodontitis are also prevalent, affecting
approximately 30% (moderate disease) and 10% (advanced disease) of the adult
population in the United States.4 The symptoms are similar to those of
gingivitis, but are more severe due to higher accumulations of bacteria and
stronger inflammatory responses.
In diagnosing the extent of periodontal disease, the probing depth is a good
indicator of the advance of the disease. In a healthy periodontium, there is no
loss of epithelial attachment or pocket formation, and the periodontal pocket
is less than 2 mm deep.5 Periodontal pockets can extend between 4 and 12 mm.
Clinically, patients with periodontal pockets of 4 mm or more are diagnosed
with periodontitis. Patients with periodontal pockets of 6 mm or more are
diagnosed with advanced or severe periodontitis.6,7 Due the minimal symptoms of
gingival bleeding and attachment loss, many individuals neglect to treat their
disease. Left untreated, gingivitis may progress to irreversible periodontitis,
resulting in tooth loss.
Once diagnosed, most periodontal diseases can be treated successfully. The
therapeutic goals in periodontal disease are: first, to alter or eliminate the
origin of the microbes as well as contributing risk factors, thereby preventing
the progression of the disease and preserving the healthy state of the
periodontium. Second, the recurrence of periodontitis must be prevented.
Finally, in severe cases, regeneration of the periodontal attachments must be
attempted.8 The first nonsurgical step involves special cleaning called scaling
and root planing. Supplemental treatment may include an antiseptic mouth rinse
and medication, either to aid the healing process or to further control the
bacterial infection. Often, antibiotics may be administered, which may offer an
effective alternative to scaling and root planing. Tetracycline or a
combination of amoxicillin and metronidazole may be used in order to kill a
broad range of bacteria.9,10 However, if overused, these agents may not kill
the bacteria. Another drawback to antibiotic therapy lies in the difficulty of
identifying and targetting a specific pathogen, due to the numerous species
residing in the plaque. Surgical treatment along with antibiotic therapy may
therefore be beneficial to periodontal disease patients. If the periodontal
pockets are not reduced, or if further loss of alveolar bone is observed, then
surgical intervention is clearly needed to try to prevent tooth loss.
Surgical treatment of periodontal disease by a periodontist consists of
removing inflamed tissues to reduce the damage to the alveolar bone around the
area of infection. Furthermore, surgery allows dentists to access areas where
scaling and root planing cannot remove tartar and plaque. The elimination of
bacterial accumulations helps regenerate bone and tissue, to help reduce
pockets. Additional procedures, such as bone grafts, target bone regeneration
and growth. If the periodontal disease has caused excessive loss of gum tissue,
then soft-tissue grafts may be performed to reduce further gum recession and
bone loss.
The oral cavity is an open system exposed to the environment. Furthermore, the
possibilities of foreign material entering the system from the oral cavity are
heightened due to the constant intake of food and liquids through the mouth.
The presence of the large numbers of bacteria can induce tissue destruction
indirectly by activating host defense cells, which in turn, produce and release
mediators that stimulate the effectors of connective tissue breakdown.
Components of microbial plaque have the capacity to induce an initial
infiltrate of inflammatory cells, including lymphocytes, macrophages, and
polymorphonuclear leukocytes (PMNs). Microbial components, especially
lipopolysaccharide (LPS), activate macrophages to synthesize and secrete a
variety of proinflammatory molecules, including the cytokines interleukin-1
(IL-1) and tumor necrosis factor-alpha (TNF-alpha); prostaglandins, especially
prostaglandin E2 (PGE2); and hydrolytic enzymes. Similarly, bacterial
substances activate T lymphocytes to produce IL-1 and lymphotoxin (LT), a
molecule with similar properties to TNF-alpha. These cytokines manifest potent
proinflammatory and catabolic activities, and play key roles in periodontal
tissue breakdown through collagenolytic enzymes such as metalloproteinases
(MMPs).11 These latent collagenolytic enzymes are activated by reactive oxygen
species in the inflammatory environment, giving rise to elevated levels of
interstitial collagenase in inflamed gingival tissue.12 The attachment loss
deepens the sulcus, creating a periodontal pocket. This provides a microbial
niche, such that periodontal pockets with depths of 4 to 12 mm can harbor on
the order of 107 to 109 bacterial cells.13 This event marks the transition from
gingivitis to periodontitis.
Several amplification and suppression mechanisms are also involved in the
process. The progression and extent of tissue degradation is determined in
large part by the relative concentrations and halflives of IL-1, TNF-alpha, and
related cytokines, of competing molecules such as the IL-1 receptor antagonist,
and of suppressive molecules such as transforming growth factor (TGF)-beta and
PGE2.14
Another effective host defense mechanism is the highly vascularized nature of
the gingival tissue, presenting an oxidative barrier to the penetration of
anaerobic bacteria from dental plaque.15 Conditions such as smoking and stress
are risk factors for periodontal disease, because they cause vasoconstriction
of the peripheral arterioles, thereby reducing blood flow to the gingival
tissue.This provides the anaerobes ample time to survive in the tissues and to
activate latent collagenases. The selection for anaerobes rather than for more
harmful facultative species may actually be beneficial to the host, because
facultative species, if dominant, have even worse effects, causing tissue
invasion and necrosis.1
In the past three decades, marked advances have occurred in our understanding
of the infectious agents of periodontal disease. Approximately 500 different
bacterial entities and various human viruses are associated with dental
microbial plaque.16 The most frequently identified periodontal pathogens
include three microaerophilic species (Actinobacillus actinomycetemcomitans,
Campylobacter rectus, and Eikenella corrodens) and seven anaerobic species
(Porphyromonas gingivalis, Bacteroides forsythus, Treponema denticola,
Prevotella intermedia, Fusobacterium nucleatum, Eubacterium, and spirochetes).
Socransky et al.17 divided the pathogens into two main clusters of
microorganisms and deemed them the "red" and "orange" complexes. Furthermore,
they defined "green", "yellow", and "purple" complexes as the bacterial
colonies that formed on the tooth surface prior to the colonization of the
"orange" and "red" complexes. The "red" complex consisted of three tightly
related species: T. forsythensis, P. gingivalis and T. denticola. This complex
is strongly related to pocket depth and bleeding on probing. Another complex
("orange" complex") included F. nucleatum/periodonticum subspecies, P.
intermedia, P. nigrescens, Peptostreptococcus micros, C. rectus, C. gracilis,
C. showae, Eubacterium nodatum, and Streptococcus constellatus, and seemed to
precede colonization by species of the "red" complex. The "yellow" complex
comprised six Streptococcus species: Streptococcus sp., S. sanguis, S. oralis,
S. intermedius, S. gordonii, and S. mitis, while Capnocytophaga ochracea,
Capnocytophaga gingivalis, Capnocytophaga sputigena, E. corrodens, and A.
actinomycetemcomitans serotype a made up the "green" complex. The fifth and
final complex, the "purple" complex, consisted of Veillonella parvula,
Actinomyces odontolyticus, A. actinomycetemcomitans serotype b, Selenomonas
noxia, and Actinomyces naeslundii genospecies 2 (Actinomyces viscosus), but
these did not constitute any cluster or ordination group.17 Within the past 7
years, various herpes viruses, such as human cytomegalovirus (HCMV) and
Epstein-Barr virus (EBV-1), have also emerged as pathogens in destructive
periodontal disease.18
Within the past 10 years, many studies have been published indicating a
positive or negative relationship between periodontal disease and various
systemic disorders and diseases. Depending on the outcome of the studies, a
positive correlation reflects a strong case for the relationship as opposed to
a negative or no correlation. Significant associations between periodontal
disease and cardiovascular disease, diabetes mellitus, preterm low birth
weight, and osteoporosis have been discovered, bridging the once-wide gap
between medicine and dentistry. Researchers have hypothesized the etiologic
role of periodontitis in the pathogenesis of these systemic illnesses.
Therefore, patients diagnosed with periodontal disease may be at higher risk
due to a compromised immune system. Infectious and opportunistic microbes
responsible for periodontal infection may thus bring a burden onto the rest of
the body. Furthermore, these microbes can release products that elicit an
inflammatory response. Periodontal lesions are recognized as continually
renewing reservoirs for the systemic spread of bacterial antigens,
Gram-negative bacteria, cytokines, and other proinflammatory mediators.19,20
Periodontal disease and cardiovascular disease (CVD)
Cardiovascular disease (CVD) is a common cause of death, accounting for 29% of
deaths worldwide.16 Estimates from the year 2002 show that more than 70 million
Americans were diagnosed with one of the forms of CVD, which include high blood
pressure, coronary heart disease (myocardial infarction and angina pectoris),
peripheral arterial disease, and stroke, with atherosclerosis as the principal
cause of all CVDs. Atherosclerosis is thus responsible for 50% of all mortality
in the United States, Europe, and Japan.21 After adjustment of other risk
factors, studies indicate that severe periodontal disease is associated with a
25% to 90% increase in risk for CVD.22 One study showed that 91% of patients
with CVD demonstrated moderate to severe periodontitis, while 66% of
cardiologically healthy patients had periodontitis. The same study showed a
statistically significant correlation between coronary artery disease and
periodontitis.13
Periodontal disease may be associated with CVD due to mutual risk factors for
atherogenesis and periodontal disease. In order to consider periodontal disease
as a risk factor for atherosclerosis and other CVDs, the presence of pathogens
associated with periodontal infection should be localized in serum or
atheromatous plaques.23 Investigating this by sampling carotid atheromatous
plaques, Cairo et al.24 detected T. forsynthensis DNA in 79%, F. nucleatum in
63%, P. intermedia in 53%, P. gingivalis in 37%, and A. actinomycetemcomitans
in 5% of the samples from carotid atheroma patients. In addition to carotid,
coronary, and aortic atherosclerotic plaques, these various oral bacteria were
also detected in occluded arteries from patients with Buerger Disease.25 One
would expect that these pathogens would induce the release of proinflammatory
cytokines. Etiologically, gentle mastication releases bacterial endotoxins from
the oral cavity into the bloodstream, inducing cytokine production (TNF, IL-1,
and PGE2).13 Further, animal studies should be able to demonstrate
atherosclerosis induced by periodontal pathogens.26 Animal models provide a
more thorough understanding of the pathogenesis of CVD; specifically, with the
use of gene-targeted animals such as the apolipoprotein E-knockout (apoE ?/?)
mouse.27-29
Etiologically, the chronic presence of periodontal microbes can lead to
atherogenesis via two pathways: (1) direct invasion of the arterial wall23 and
(2) the release, in response to infection, of systemic inflammatory mediators
with atherogenic effects.30 These pathogens, especially P. gingivalis, have
demonstrated the ability to interact with the endothelial surface and to induce
smooth-cell proliferation, causing damage and impairing the vasomotor
functionality of the endothelial cells.2,26,31,32 Serum C-reactive protein
(CRP) plays a role in endothelial dysfunction, and elevated levels of CRP
provide insight into the linking of periodontal disease and CVD.2,33-36 In
patients with periodontal disease who have elevated plasma levels of both
fibrinogen37 and TNF-alpha, there is an association with increased carotid
intima-media thickness (IMT).38 IMT and left ventricular mass (LVM) are
alternative, yet valuable tools in measuring carotid atherosclerosis.5,19,22,39
However, our understanding of the mechanism linking these inflammatory markers
with atherosclerosis progression is unclear.
Recent studies have shown that CRP may directly interfere with endothelial
nitric oxide (NO) availability, by both decreasing the expression of NO
synthase and simultaneously increasing the production of reactive oxygen, which
inactivates NO.40 Elevated CRP serum levels are the signal feature of the
transition from stable coronary artery disease to the formation of a
platelet-rich thrombus following plaque rupture or erosion.4 These findings
shed light on the fact that endothelial activity, associated with elevated CRP
serum levels, is characterized by the impaired systemic bioavailability of NO
in coronary artery disease patients. Further investigation of this hypothesis
(i.e., the rote of CRP on NO) has led to the discovery that CRP serum levels
are important in predicting the availability of NO in the systemic circulation
in coronary artery disease patients.41
Another mechanism through which the bioavailability of NO is decreased is
oxidative inactivation by reactive oxygen species. Triggered by bacterial
components such as LPS from P. gingivalis, macrophages and other cells release
cytokines, leading to the systemic activation of phagocytic cells. Thus, PGE2,
IL-1 beta, and TNF-alpha all reach high and potent systemic levels. These
macrophages can then transform into foam cells, inducing the production of
proinflammatory cytokines, leading to endothelial dysfunction.26 In a recent
study, Pussinen et al.42 found that the main serum mediators of macrophage
activation in response to periodontal disease were low-density lipoprotein
(LDL) cholesterol, LPS, ?2-glycoprotein I (?2-GPI), and modified phospholipids.
These results led to the conclusion that periodontitis was directly associated
with the ability of isolated LDL to activate macrophages through its main
mediators. Moreover, the binding of LDL and the formation of foam cells have
been shown to be mediated by CRP.42,43 Recent data suggest that the subtle but
broad effects of periodontitis on the metabolism and biochemical properties of
lipoproteins may be reversed by periodontal treatment.44 Pussinen et al.45
determined that periodontitis diminished the anti-atherogenic potency of
high-density lipoprotein (HDL), further increasing the risk of CVD. These
findings may prove valuable clinically, because impaired endothelium-dependent
vasodilation induced by increased CRP serum levels may be used as a precursor
in diagnosing CVD in the future. This information is considered important
enough that the American Heart Association deemed the use of CRP and LDL
cholesterol to be essential predictors of CVD.46
Another predictor of CVD, in particular coronary heart disease (CHD), may be
serum levels of antibodies directed against periodontal pathogens. Pussinen et
al.47 reported the association of CHD with serum antibodies, suggesting that
periodontal disease may play a role in the pathogenesis of CHD. In a linear
regression model, they concluded that the combined antibody response to P.
gingivalis and A. actinomyecetemcomitans were directly associated with
prevalent CHD.47 Two years later, these researchers supported their findings in
another study, in which measured serum antibody levels to major periodontal
pathogens were associated with the development of CHD. The study was the first
of its kind and was quite insightful in expanding beyond P. gingivalis,
suggesting that infection with A. actinomyecetemcomitans may also be associated
with an increased risk of CHD.48
An alternative approach for studying the link between periodontal disease and
CVD may be through the evaluation of peripheral arterial disease (PAD). PAD of
the legs is a state of insufficient tissue perfusion to meet metabolic demand.
PAD shares similar pathological features to both stroke and CHD, in that
atherosclerotic plaques are present. Recognizing the relationship between
periodontal disease and PAD is valuable in trying to understand the clinical
effect of periodontal diseases and how the treatment of these diseases may
reduce the risk of developing CVD.34
New findings have suggested that tooth loss, rather than periodontal disease,
may be the important link between CVD and oral health. Elter et al.6 concluded,
in their study, that edentulous individuals had 1.8-fold elevated chances of
developing CHD. However, the investigation of this claim has many limitations,
which explains the weaker association between periodontal disease and CHD in
older subjects.49 Based on these admitted limitations, the conclusion of Elter
et al.6 may need further support or supplemental research to directly support
the association between periodontal disease and CHD.
These important studies shed new light on the association between periodontal
disease and atherosclerotic events. Given that endothelial dysfunction appears
to be an early event in the development of atherosclerosis, also predicting for
plaque instability, these findings strengthen the link between periodontal
disease and atherosclerosis. Thus, it is now critical to test the hypothesis
that reversal of periodontal disease prevents atherosclerotic events, and to
explore different therapeutic approaches to achieve this aim. More studies that
elucidate mechanisms for possible anti-atheroscelorosis therapies are
needed.50,51
Periodontal disease and diabetes mellitus
Diabetes mellitus is a metabolic disorder characterized by hyperglycemia due to
the defective secretion or activity of insulin. The condition affects more than
16 million people in the United States.52 Diabetes mellitus can be divided into
three classifications according to signs and symptoms: type 1, type 2, and
gestational. Type 1 diabetes mellitus results from the destruction of
beta-cells within the islets of Langerhans of the pancreas, which leads to
complete insulin deficiency. Type 2 diabetes mellitus ranges from insulin
resistance progressively leading to pancreatic beta-cell failure. Lastly,
gestational diabetes mellitus is a glucose intolerance that begins during
pregnancy. The number of adults diagnosed with type 2 diabetes worldwide is
expected to grow from 135 million in 1995 to approximately 300 million in
2025.53 People with type 2 diabetes constitute 90% of the diabetic
population.54
A recent hypothesis links chronic subclinical inflammation with insulin
resistance, initiating the development of type 2 diabetes. The triggers of
inflammation are many and potentially include oral infection, which may lead to
a cascade of events, including increased cytokine production, activation of
acute-phase protein synthesis, and consequent insulin resistance that produces
pathogenic changes resulting in type 2 diabetes.16 Periodontal pathogens,
especially P. gingivalis, have the ability to invade deep vascular endothelium
associated with the periodontium, and can be found within pathological vascular
plaques.23,26 Studies have investigated the relative prevalence of five
periodontal pathogens (A. actinomycetemcomitans, Eikenella corrodens, T.
denticola, Candida albicans, and P. gingivalis) among individuals with type 1
and 2 diabetes mellitus. However, no statistically significant correlations
were revealed.55 Except for A.
actinomycetemcomitans, the prevalence of the periodontal pathogens was
significantly higher in diseased sites than in healthy sites in both type 1 and
type 2 diabetes patients. Furthermore, the results suggested that E. corrodens,
T. denticola, C. albicans, and P. gingivalis may play important roles in the
periodontitis of individuals with either type 1 or type 2 diabetes mellitus.56
Once periodontal pathogens are established in the diabetic host, periodontal
infection may aggravate microvascular complications (retinopathy, nephropathy,
and neuropathy), that can progress to macrovascular complications (coronary
artery disease, cerebrovascular disease, and peripheral vascular disease).2,54
Periodontal disease, more specifically periodontitis, is one of the many
complications resulting from type 1 and type 2 diabetes. Numerous studies have
found a higher prevalence of periodontal disease among diabetic patients than
among healthy controls;4 thus, an established relationship exists between
periodontal disease and diabetes. Recent studies have presented evidence
indicative of a bidirectional adverse interrelationship between both type 1 and
type 2 diabetes mellitus and periodontal diseases.57 The more direct
relationship is that periodontal disease may lead to type 2 diabetes; however,
the alternative view, that periodontal disease develops resulting from
complications from both type 1 and type 2 diabetes mellitus, further
strengthens the support for this bidirectional link between periodontal disease
and diabetes mellitus.
In patients with periodontal disease, chronic low-level systemic exposure to
periodontal microorganisms may exist, leading to significant changes in plasma
levels of cytokines and hormones. Due to the dynamic nature of the inflamed
periodontium, the tissue may serve as an endocrine-like source of inflammatory
mediators.Among the inflammatory biomarkers examined, CRP and IL-6 appear to be
promising, due to their plausible biological mechanisms, as exposed in studies
of links between periodontal disease and cardiovascular disease.58,59 Recently,
Bluher et al.60 investigated whether plasma concentrations of inflammatory
markers were associated with measures of obesity, insulin sensitivity, and
hyperglycemia. In parallel with the impairment of glucose tolerance, there was
a significant increase in IL-6 and CRP, and a significant decrease in
adiponectin and IL-10 plasma concentrations. Furthermore, Bluher et al.60
discovered significant correlations between the plasma concentrations of all
inflammatory markers examined and percent body fat, insulin sensitivity, and
fasting plasma glucose. Fasting plasma glucose was a significant determinant of
adiponectin, CRP, and IL-6 plasma concentrations, whereas body fat content was
a significant predictor only of CRP plasma concentration.60 In a similar study,
the MONICA/KORA Augsburg Study, the authors concluded that type 2 diabetes was
highest among subjects with elevated levels of both IL-18 and CRP or IL-18 and
IL-6, respectively.61 These observations suggest that an enhanced acute-phase
response is associated with insulin resistance, and may foreshadow the
development of type 2 diabetes.
Other studies have suggested that the presence of periodontal infection may be
linked to the control of diabetes. Results from the study by Grossi et al.62
indicated that the effective control of periodontal infection in diabetic
patients could reduce the level of advanced glycation end-products (AGEs) in
the serum. AGEs are known to cause hyperglycemia, which is a complication of
diabetes; thus, the level of glycemic control seems to be the key factor. Many
researchers have noted similar positive correlations of poor glycemic control
in patients with high tooth attachment loss.63-65 Prevention and control of
periodontal disease must be considered as an integral part of diabetes control.
Major efforts should be directed at preventing periodontitis in patients who
are at risk of diabetes, as well as in those patients with poor metabolic
control.
The complications of both type 1 and type 2 diabetes are related to the
long-term elevation of blood glucose concentrations (hyperglycemia).
Hyperglycemia results in the formation of AGEs.66 These AGEs make endothelial
cells and monocytes more susceptible to stimuli that induce the cells to
produce inflammatory mediators. Some have speculated that AGE accumulations in
the gingival tissue lead to increased vascular permeability, greater breakdown
of collagen fibers, and accelerated destruction of both nonmineralized
connective tissue and bone.67 Apart from the accumulation of AGEs, the
pathophysiology of diabetes is strikingly similar to that of periodontal
disease.54 It is understood that the connection is counterintuitive, due to the
fact that diabetes is a metabolic disorder and periodontal disease is an
infectious disease. However, the pathophysiological relationship between
diabetes and periodontal disease occurs through the ability of both conditions
to induce an inflammatory response, whether through AGE or bacterial
accumulation, respectively, leading to the production of inflammatory
mediators.
Epidemiological findings linking periodontal disease and diabetes are
strengthened by experimental studies demonstrating the hyperglycemic effects of
several proinflammatory cytokines, including IL-6 and TNF-alpha, both of which
derive in part from adipose tissue.68 In rodent models of glucose homeostasis,
IL-6 impairs the glucose-stimulated release of insulin from isolated pancreatic
beta cells.69 In humans, the exogenous administration of recombinant IL-6 has
been found to induce dose-dependent hyperglycemia and elevations in serum
levels of glucagons.70 Excessive TNF-alpha concentrations have been implicated
in the development of insulin resistance. TNF-alpha directly impairs glucose
uptake and metabolism by altering insulin-induced signal transduction.
TNF-alpha infusion into skeletal muscle, carried out by Plomgaard et al.,70
increased the signaling effects associated with impaired phosphorylation of Akt
substrate 160, the most proximal step in the insulin signaling cascade
regulating the translocation of glucose transporter-4 (GLUT4) and glucose
uptake. Thus, excessive concentrations of TNF-alpha negatively regulate insulin
signaling and glucose uptake in humans.71 Additionally, the elevated levels of
soluble TNF receptor 1 and 2 (sTNF-alphaRI and sTNF-alphaRII) shown in obese
patients72 may lead to a hyperinflammatory state, increasing the risk for
periodontal disease and also accounting, in part, for insulin resistance. The
hyperinflammatory state may be caused by adipocytes, which appear to secrete
proinflammatory cytokines, providing the link between the pathogenesis of type
2 diabetes, obesity, and periodontal disease. These findings are further
supported by information gathered from a population of 12367 nondiabetic
subjects. The highest levels of TNF-alpha and sTNF-alpha receptors were found
in those individuals in the highest quartile for body mass index (BMI). These
findings provide support for the idea that obesity is a significant predictor
of periodontal disease and that insulin resistance appears to mediate this
relationship.72
Periodontal disease and adverse pregnancy outcomes
The growing evidence that infection remote from the fetal-placental unit may
have a role in the preterm delivery of low-birth-weight infants has led to an
increased awareness of the potential role of chronic bacterial infections in
the body. Preterm low-birth weight (PLBW), as defined by the 29th World Health
assembly in 1976, is a birth weight of less than 2500 g with a gestational age
of less than 37 weeks. Low birth weight can be a result of this short
gestational period and/or retarded intrauterine growth. Some traditional risk
factors include genetic features; the use of alcohol; poor prenatal care; poor
maternal nutrition; urinary tract infection; and, in particular, smoking and
low socioeconomic status. A dose-response relationship between smoking and PLBW
was reported, with a positive correlation between the two.73 As for
socioeconomic status, Buduneli et al.74 took into account this risk factor by
evaluating post-partum women of a low socioeconomic level; the study suggested
that periodontal disease had a contributory role in PLBW, but cited a negative
correlation, due to the lack of a statistically significant link between
periodontitis and preterm birth. PLBW remains a significant public health
issue, because PLBW infants are at a higher risk for a number of acute and
chronic disorders, including respiratory distress syndrome, cerebral palsy,
pathologic heart conditions, epilepsy, and severe learning problems.75
Initially, the relationship between periodontal disease and PLBW was not so
evident in case-control studies.40,76 Despite these studies, which actually
showed a negative correlation for a link between periodontal disease and PLBW,
a growing number of studies show a positive association.77 For example,
contradictory results were revealed in Granada, Spain, where statistically
significant relationships were observed between low birth weight and maternal
periodontal probing depth;78 the authors of that study concluded that
periodontal disease was a significant risk factor for low birth weight, but not
for preterm delivery. Due to wavering conclusions in case-control studies and
many confounding variables, plausible biological hypotheses are needed to
support the link between maternal periodontal disease and PLBW.
The cause of low birth weight is sometimes unknown. Twenty-five percent to 50%
of PLBW deliveries occur without any known etiology.79 PLBW has been the
subject of epidemiologic investigations and a target for public health
interventions.16 Despite the significant advances in the use of drugs to arrest
preterm labor and in the understanding of reproductive physiology, the preterm
birth rate in the Western world appears to be increasing.80 However, it is
recognized that maternal infections affect the normal development of the fetus.
Periodontal disease is associated with chronic gram-negative infections, which
result in local and systemic elevations of proinflammatory prostaglandins and
cytokines. Furthermore, numerous citations have shown periodontal pathogens
entering the systemic circulation. Hence, maternal periodontal disease may be
connected with preterm delivery through mechanisms involving inflammatory
mediators or a direct bacterial assault on the amnion.
Many risk factors have been proposed to cause preterm rupture of membranes and
preterm labor. These risk factors include high/low maternal age, overweight and
underweight, parity, primiparous mothers, low socioeconomic status, little or
no education, alcohol and drug abuse, hyper-tension, Afro-American ethnicity
and genital and urinary tract infections. Smoking is regarded as a well-known
risk factor for both periodontitis and preterm birth. However, when Skuldbol et
al.81 studied a random group of Scandinavian women selected based on fairly
good health and high socioeconomic status, they concluded that no relationships
were revealed between periodontitis and preterm birth. They further concluded
that there was no relationship between smoking and preterm birth.81 Variables
leading to the latter conclusion may be due to the fact that periodontal
disease is seldom present in women of birth-giving age. It was mentioned that,
in Denmark, free access to comprehensive health care was available to the
public until the age of 18; thus, although oral infections may play a role,
other factors, such as smoking and socioeconomic status are stronger and so may
act as confounders.
Another highly studied risk factor for PLBW is infections of the genital and
urinary tracts. These include pathogens in the genital tract and also in other
organ systems, e.g., viral respiratory infections, diarrhea, and malaria. Also,
more localized infections of the genital and urinary systems can affect the
duration of gestation.82-84 The current concept is that associations between
chorioamnionitis, infection of the amniotic fluid, and PLBW have been
established.85 Gibbs et al.83 provided an excellent outline of the possible
association between infections and adverse pregnancy outcomes in their review
article. In their hypothesis, microorganisms and their LPS enter the uterine
cavity during pregnancy by an ascending route from the lower genital tract, or
by a blood-borne nongenital route, causing preterm birth.79 A variety of
studies have shown that spontaneous abortion, preterm labor, preterm birth, and
preterm rupture of the membranes, as well as chorioamnionitis, are all related
to the onset of bacterial vaginosis during pregnancy.86 Bacterial vaginosis is
a clinical condition caused by overgrowth of the vaginal flora with certain
aerobic and anaerobic bacteria. Other studies have also provided evidence that
distant, low-grade oral infection might trigger inflammation of the human
maternal-fetal unit in a manner analogous to that seen with bacterial
vaginosis.84 Bacterial invasion of the choriodecidual space can activate the
fetal membranes or trigger the maternal immune system to produce a variety of
cytokines and growth factors. The combination of increased fetal adrenal
cortisol production, increased prostaglandin production, the release of MMPs,
and increased cytokines and chemokines may lead to myometrial contractions,
membrane rupture, cervical ripening, and preterm delivery. Furthermore, the
inflammatory burden results in distress and fetal growth restriction.87
As mentioned earlier, periodontal disease is an infectious disease caused by
anaerobic gram-negative bacteria. Madianos et al.88 extended the work of
Socransky et al.,17 shifting the focus to examine the potential role of
maternal infection with specific organisms within both the "orange" and "red"
complexes, because these are the complexes most strongly correlated to severe
periodontal disease. The highest rate of prematurity (66.7%) was observed among
those mothers without a protective "red" complex IgG response coupled with a
fetal immunoglobulin M (IgM) response to "orange" complex microbes.88 These
data support the concept that maternal periodontal infection in the absence of
a protective maternal antibody response is associated with the systemic
distribution of oral organisms to the fetus, resulting in preterm
birth.Additionally, the high prevalence of elevated fetal IgM to C. rectus
among premature infants raises the possibility that this specific maternal oral
pathogen may serve as a primary fetal infectious agent eliciting preterm birth.
More recent findings support this claim: when subgingival bacteria were
evaluated together, P. micros and C. rectus were found to play a significant
role in increasing the risk for PLBW.89 Additionally, mouse studies found that
maternal C. rectus infection induced placental inflammation and decidual
hyperplasia, as well as a concomitant increase in fetal brain interferon
(IFN)-gamma, leading to brain damage in the hippocampal region of the neonatal
brain. The brain damage in mice is analogous to the white-matter damage seen in
humans due to the effects of maternal infections.74
Recently, F. nucleatum, a gram-negative anaerobe ubiquitous to the oral cavity,
was isolated from the amniotic fluid, placenta, and chorioamnionic membranes of
women delivering prematurely.90 To test the strength of this finding, pregnant
mice were infected with F. nucleatum, resulting in premature delivery,
stillbirths, and nonsustained live births. The bacterial infection was
restricted inside the uterus, without spreading systemically, although invasion
of the endothelial cells lining the blood vessels was also observed. The
bacteria then crossed the endothelium, proliferated in surrounding tissues, and
finally spread to the amniotic fluid. This pattern of infection paralleled that
observed in humans.
Upregulation of proinflammatory cytokines resulting from the normal host
response to an infectious agent may represent the key mechanism linking
periodontal disease to PLBW. Microbiological products such as endotoxin will
trigger a host immune response, causing both local inflammation and activation
of soluble proinflammatory mediators such as IL-1, TNF-alpha, and MMPs. These
inflammatory markers have been shown to cross the placental barrier and to
cause fetal toxicity, resulting in preterm delivery and low-birth-weight
babies.91 Therefore, fetal exposure to oral pathogens, as evidenced by an IgM
response, is associated with preterm birth, and the risk for preterm birth is
greatest among fetuses that demonstrate an inflammatory response.
Although case-control and prospective studies have shown preliminary evidence
of the treatment of periodontal disease as a method for preventing PLBW,92 a
consensus has emerged, emphasizing the need for more studies on the effects of
periodontal disease treatment in reducing the occurrence of PLBW. A great deal
of evidence supports the scenario of periodontal disease as a treatable
condition; thus, a positive correlation between periodontal disease and PLBW
should create momentum in programs to provide better periodontal care for
pregnant women.
Periodontal disease and osteoporosis
Bone loss is a feature shared between periodontal disease and osteoporosis.
Osteopenia is a reduction in bone mass due to an imbalance between bone
resorption and bone formation, favoring resorption, resulting in
demineralization and leading to osteoporosis.93 Osteoporosis is a skeletal
disorder characterized by compromised bone strength, predisposing to an
increased risk of fracture, with bone strength determined by both bone density
and bone quality.94 Similarly, periodontal disease is characterized by the
absorption of bone, specifically the alveolar bone, as well as by loss of the
soft-tissue attachment of the tooth. Due to the commonality of bone loss
between periodontal disease and osteoporosis, the outcomes of both are similar.
Furthermore, oral osteopenia and systemic osteopenia share risk factors,
including age,95 estrogen deficiency,3 and smoking.96
The underlying mechanism of increased bone resorption may be directed by
increased systemic/local osteoclastic activity, or by local cellular or
cytokine effects.16 Excessive osteoclastic resorption is a common feature of
chronic inflammatory processes such as periodontal disease. In physiological
bone remodeling, the cell-to-cell contact between receptor activator of nuclear
factor-?B ligand (RANKL)-expressing osteoblasts and RANK-expressing
monocyte/osteoclast precursor cells is crucial. In inflamma-tory processes,
activated T lymphocytes express RANKL, and it is therefore possible that
cell-to-cell contact between T lymphocytes and monocyte/osteoclast precursor
cells is involved in osteoclast formation.97 The activation of mature
osteoclasts is inhibited by osteoprotegerin (OPG) released by stromal cells and
osteoblasts. B lymphocytes may also participate in osteoclast formation, either
by expressing RANKL or by serving as osteoclast progenitor cells themselves.98
In periodontal infection, dense infiltrates of mononuclear leukocytes are found
in the gingiva, including T lymphocytes and monocyte/osteoclast progenitor
cells.99,100 This cell-to-cell contact between T cells and monocyte/lymphocyte
progenitor cells is important for osteoclast formation in periodontitis.
Interestingly, RANKL mRNA is upregulated in the gingiva of patients with
advanced periodontitis. On the other hand, OPG mRNA is downregulated.100
Furthermore, Nagasawa et al.101 demonstrated that OPG mRNA was upregulated by
LPS from P. gingivalis and A. actinomyecetemcomitans, shedding light on how
LPS-stimulated OPG may be involved in the control of osteoclast formation in
periodontal disease. The hypothesis linking OPG and periodontal disease is
strengthened by studies involving gram-negative bacteria.102,103 Due to the
transient nature of infection by these pathogens, exposure to periodontal
infection may trigger RANKL activation and subsequent osteoclast activation and
activity, inducing osteoporosis in patients with periodontal infection.
Estrogen deficiency is another dominant pathogenic factor for osteoporosis in
women.104 Estrogen, either directly or indirectly, modulates cytokines that are
important regulators of bone metabolism and also regulators of the host
inflammatory response, such as IL-1 alpha, IL-1 beta, TNF-alpha, and macrophage
colony-stimulating factor (M-CSF). Thus, estrogen deficiency initiates an
increase in the number of osteoclasts, driven by the same cytokines that
down-regulate osteoblast generation. This promotes an imbalance in bone
metabolism, leading to reduced bone mineral density (BMD).105 Periodontitis
also activates the host proinflammatory response, recruiting cytokines and
prostanoids, leading to the activation of osteoclasts, and thus inducing bone
resorption. Some cytokines, such as IL-1 beta, TNF-alpha, IL-6, and IL-8, have
been found at increased levels in inflamed human gingival tissue, in
concentrations capable of inducing bone resorption.106,107 Hence, many
investigations have found a statistically significant positive correlation
between periodontal disease and estrogen deficiency.108 Both of these risk
factors, acting cooperatively, may be sufficient to induce osteoporosis. A
recent study in Japan investigated this relationship between oral health and
BMD; the findings were that periodontitis and tooth loss after menopause (i.e.,
in estrogen-deficient women) may be useful indicators of metacarpal BMD (m-BMD)
loss.109 In a related study, Wactawski-Wende et al.110 determined a strong and
consistent association between alveolar crestal height (ACH) and osteoporosis
through measurements of bone density and ACH in postmenopausal women.
Using osteoporosis treatment as a basis, many studies have tried to use similar
approaches in treating periodontal disease, deepening the relationship between
the two diseases. Parathyroid hormone (PTH) functions as a mediator of bone
modeling and as an essential regulator of calcium homeostasis. PTH produces
several distinct effects on the entire bone remodeling process, because it
influences both bone formation and bone resorption. Recent studies have
indicated that intermittent doses of PTH can be an efficient anabolic
treatment, reducing bone loss due to estrogendeficiency-related osteopenia.111
Furthermore, daily injections of teriparatide, a portion of human PTH, have
been shown to stimulate new bone formation and increase BMD.112 Of note, NO has
anabolic and catabolic effects similar to those of PTH on bone metabolism. The
role of NO is controversial, in that low levels of NO maintain homeostasis,113
whereas high levels of NO, as seen in inflammatory conditions, induce bone
resorption.114 NO is beneficial in periodontal infection, in that it is an
important element of the host defense against P. gingivalis,a primary
periodontal infection pathogen.115 The administration of the NO donor,
isosorbide, to periodontitis-affected rats demonstrated reductions in
inflammatory cell infiltration, cementum resorption, and alveolar bone loss.116
Although significant advances have been made in determining the relationship
between periodontal disease and osteoporosis, further studies are needed to
clarify this correlation. In comparison to other systemic diseases, the
research done in elucidating the association is limited, and many researchers
have highlighted and stressed in their publications this great need for a
better understanding of the relationship. The clarification of this
relationship may provide useful and beneficial warnings for osteoporosis risk,
as well as significant clinical implications for treatment. Another issue
encountered with this relationship between periodontal disease and osteoporosis
is the fact that periodontal disease is diagnosed largely in males whereas
osteoporosis is a disorder predominantly diagnosed in females. Detractors may
argue that the relationship is weak because of this fact; however, osteoporosis
is found to be a risk factor for periodontal disease within the female
population. When tested in the general population, no correlation between sex
and the relationship between periodontal disease and osteoporosis was found,
reducing this finding to a mere confounding variable.
Conclusion
Periodontal disease as a risk factor for the development of various systemic
conditions, such as CVD, diabetes, adverse pregnancy outcomes, and
osteoporosis, is a highly researched and debated topic. Although most evidence
in regard to the relationship between periodontal disease and those systemic
conditions is consistently supportive of this notion, the need for more studies
is greatly advocated by physicians and dentists. In general, larger and more
randomized populations and better controlled clinical trials will be required
to substantiate the correlation of periodontal disease to these systemic
conditions.
Each of the specific conditions has its own needs for future research. In the
relationship between periodontal disease and CVD, current studies do not
provide sufficient information to differentiate between the possibilities of
direct infection of the vascular wall versus the stimulation of a
proinflammatory state by periodontitis (or both, simultaneously). The
distinction is crucial, because some treatment strategies for periodontal
disease, such as scaling and root planing, may promote the hematogenous seeding
of bacteria.117 Furthermore, antibiotic and antiinflammatory strategies should
be incorporated into studies to evaluate their effectiveness in preventing
cardiovascular events through the remediation of periodontal disease.
In addition to more controlled studies of the correlation between metabolic
control and periodontal disease, the role of pathogens other than P. gingivalis
(such as C. albicans) should be studied. Also, the current hypothesis that
chronic inflammation caused by periodontal infection contributes to the
pathogenesis of type 2 diabetes needs further clarification. A logical
framework provided by elucidation of the mechanism behind periodontal infection
and CVD would aid in this search, and, possibly, a hypothesis unifying both
these inflammatory diseases could offer a unique opportunity for improving
complications associated with both diseases.
In the relationship between periodontal disease and osteoporosis, detailed
knowledge of the molecular mechanisms involved in RANKL-RANK activation and
downstream signaling could generate new pharmacological principles for the
inhibition of excessive bone resorption in pathological conditions.
Furthermore, additional longitudinal studies may be necessary to explain more
fully the usefulness of osteocalcin, parathyroid hormone, and calcitonin as
diagnostic indicators of periodontal disease activity. In addition to these
research topics, further studies of the mechanism of NO effects on alveolar
bone are needed, in association with an understanding of the indications for
isosorbide in treating periodontal infection.
Lastly, the mechanisms by which periodontal disease may reduce birth weight
have still not been elucidated, but there is evidence that this association has
a biologically feasible basis. Nevertheless, the association between maternal
periodontal disease and low birth weight should be further explored and
clarified to establish whether it is causal or simply associative. Further
research in the area of the role of periodontal pathogens, direct or indirect,
in contributing to PLBW is required. These developments will be of importance
to obstetrics, as periodontal disease may become a modifiable risk factor for
several serious systemic conditions, including the pregnancy complications
encountered in daily practice.
In this era of evidence-based medicine, further work needs to be done to
establish the associations noted above. As greater knowledge becomes available
concerning the etiologic factors and pathology of periodontal disease as it
relates to the systemic conditions described above, the research must shift
towards advances in effective treatment. Most researchers have found
statistically significant connections between these systemic conditions and
moderate to severe periodontal disease; therefore, better awareness of the
effects of oral health on systemic health must be made available to the public.
Simple oral healthcare tasks, such as brushing and flossing, and limiting other
risk factors, such as smoking, may assist in initially decreasing periodontal
pockets and periodontal bacterial flora, consequently decreasing the likelihood
of the progression of periodontal disease in causing these detrimental systemic
diseases.
Jemin Kim, Boston University Goldman School of Dental Medicine, Department of
Periodontology and Oral Biology, Boston, MA, USA.
Salomon Amar, Boston University Medical Center, 700 Albany Street, W201E,
Boston, MA 02118, USA Tel. +1?617?638?4983; Fax +1?617?638?8549 e-mail:
samar@bu.edu .
References
1.
Loesche, WJ; Grossman, NS. Periodontal disease as a specific, albeit chronic,
infection: diagnosis and treatment. Clin Microbiol Rev. 2001;14:727-52.
[PubMed]
2.
Amar, S; Gokce, N; Morgan, S; Loukideli, M; Van Dyke, TE; Vita, JA. Periodontal
disease is associated with brachial artery endothelial dysfunction and systemic
inflammation. Arterioscler Thromb Vasc Biol. 2003;23:1245-9. [PubMed]
3.
Genco, RJ; Grossi, SG. Is estrogen deficiency a risk factor for periodontal
disease? Compend Contin Educ Dent Suppl. 1998;22:S23-9. [PubMed]
4.
Fuster, V; Badimon, L; Badimon, JJ, et al. The pathogenesis of coronary artery
disease and the acute coronary syndromes. N Engl J Med. 1992;326:242-50.
[PubMed]
5.
Angeli, F; Verdecchia, P; Pellegrino, C; Pellegrino, RG; Pellegrino, G;
Prosciutti, L; Giannoni, C; Cianetti, S; Bentivoglio, M. Association between
periodontal disease and left ventricle mass in essential hypertension.
Hypertension. 2003;41:488-92. [PubMed]
6.
Elter, JR; Champagne, CME; Offenbacher, S; Beck, JD. Relationship of
periodontal disease and tooth loss to prevalence of coronary heart disease. J
Periodontol. 2004;75:782-90. [PubMed]
7.
Hujoel, PP; Drangsholt, MT; Spiekerman, C; Derouen, TA. Periodontitis-systemic
disease associations in the presence of smoking: causal or coincidental? J
Periodontol. 2000 2002;30:51-60.
8.
Ebersole, JL; Capelli, D; Steffen, MJ. Longitudinal dynamics of infection and
serum antibody in A. actinomycetemcomitans periodontitis. Oral Dis.
1995;1:129-38. [PubMed]
9.
Hayes, C; Antezak-Bouckoms, A; Burdick, E. Quality assessment and meta-analysis
of systemic tetracycline use in chronic adult periodontitis. J Clin
Periodontol. 1992;19:164-8. [PubMed]
10.
Van Winkelhoff, AJ; Tijhof, CJ; de Graaff, J. Microbiological and clinical
results of metronidazole plus amoxicillin therapy in Actinobacillus
actinomycetemcomitans-associated periodontitis. J Periodontol. 1992;63:52-7.
[PubMed]
11.
Sorsa, T; Ingman, T; Suomalainen, K; Haapasalo, M; Konttinen, YT; Lindy, O;
Saari, H; Uitto, VJ. Identification of proteases from periodontopathogenic
bacteria as activators of latent human neutrophil and fibroblast-type
interstitial collagenases. Infect Immun. 1992;60:4491-5. [PubMed]
12.
Lee, W; Aitken, S; Sodek, J; McCulloch, CA. Evidence of a direct relationship
between neutrophil collagenase activity and periodontal tissue destruction in
vivo: role of active enzyme in human periodontitis. J Periodontal Res.
1995;30:23-33. [PubMed]
13.
Geerts, SO; Legrand, V; Charpentier, J; Albert, A; Rompen, EH. Further evidence
of the association between periodontal conditions and coronary artery disease.
J Periodontol. 2004;75:1274-80. [PubMed]
14.
Page, RC. The role of inflammatory mediators in the pathogenesis of periodontal
disease. J Periodontal Res. 1991;26:230-42. [PubMed]
15.
Loesche, WJ; Gusberti, F; Mettraux, G; Higgins, T; Syed, S. Relationship
between oxygen tension and subgingival bacterial flora in untreated human
periodontal pockets. Infect Immun. 1983;42:659-67. [PubMed]
16.
Amar, S; Han, X. The impact of periodontal infection on systemic diseases. Med
Sci Monit. 2003;9:RA291-9. [PubMed]
17.
Socransky, SS; Haffajee, AD; Cugini, MA; Smith, C; Kent, RL., Jr Microbial
complexes in subgingival plaque. J Clin Periodontol. 1998;25:134-44. [PubMed]
18.
Slots, J; Kamma, JJ; Sugar, C. The herpesvirus-Porphyromonas
gingivalis-periodontitis axis. J Periodont Res. 2003;38:312-23.
19.
Leivadaros, E; van der Velden, U; Bizzarro, S; ten Heggeler, JM; Gerdes, VE;
Hoek, FJ; Nagy, TO; Scholma, J; Bakker, SJ; Gans, RO; ten Cate, H; Loos, BG. A
pilot study into measurements of markers of atherosclerosis in periodontitis. J
Periodontol. 2005;76:121-8. [PubMed]
20.
Prabhu, A; Michalowicz, BS; Mathur, A. Detection of local and systemic
cytokines in adult periodontitis. J Periodontol. 1996;67:515-22. [PubMed]
21.
Lusis, AJ. Atherosclerosis. Nature. 2000;407:233-41. [PubMed]
22.
Beck, J; Garcia, R; Heiss, G; Vokonas, PS; Offenbacher, S. Periodontal disease
and cardiovascular disease. J Periodontol. 1996;67:1123-37. [PubMed]
23.
Haraszthy, VI; Zambon, JJ; Trevisan, M; Zeid, M; Genco, RJ. Identification of
periodontal pathogens in atheromatous plaques. J Periodontol. 2000;71:1554-60.
[PubMed]
24.
Cairo, F; Gaeta, C; Dorigo, W; Oggioni, MR; Pratesi, C; Pini Prato, GP; Pozzi,
G. Periodontal pathogens in atheromatous plaques. A controlled clinical and
laboratory trial. J Periodontal Res. 2004;39:442-6. [PubMed]
25.
Iwai, T; Inoue, Y; Umeda, M; Huang, Y; Kurihara, N; Koike, M; Ishikawa, I. Oral
bacteria in the occluded arteries of patients with Buerger disease. J Vasc
Surg. 2005;42:107-15. [PubMed]
26.
Chun, YH; Chun, KR; Olguin, D; Wang, HL. Biological foundation for
periodontitis as a potential risk factor for atherosclerosis. J Periodontal
Res. 2005;40:87-95. [PubMed]
27.
Zhang, SH; Reddick, RL; Piedrahita, JA, et al. Spontaneous hypercholesterolemia
and arterial lesions in mice lacking apolipoprotein E. Science.
1992;258:468-71. [PubMed]
28.
Plump, AS; Smith, JD; Hayek, T, et al. Severe hypercholesterolemia and
atherosclerosis in apolipoprotein E-deficient mice created by homologous
recombination in ES cells. Cell. 1992;71:343-53. [PubMed]
29.
Gibson, FC, 3rd; Hong, C; Chou, HH; Yumoto, H; Chen, J; Lien, E; Wong, J;
Genco, CA. Innate immune recognition of invasive bacteria accelerates
atherosclerosis in apolipoprotein E-deficient mice. Circulation.
2004;109:2801-6. Epub 2004 May 3. [PubMed]
30.
Loos, BG; Craandijk, J; Hoek, FJ; Wertheim-van Dillen, PM; van der Velden, U.
Elevation of systemic markers related to cardiovascular diseases in the
peripheral blood of periodontitis patients. J Periodontol. 2000;71:1528-34.
[PubMed]
31.
Khlgatian, M; Nassar, H; Chou, HH; Gibson, FC, 3rd; Genco, CA.
Fimbria-dependent activation of cell adhesion molecule expression in
Porphyromonas gingivalis-infected endothelial cells. Infect Immun.
2002;70:257-67. [PubMed]
32.
Schachinger, V; Britten, MB; Zeiher, AM. Prognostic impact of coronary
vasodilator dysfunction on adverse long-term outcome of coronary heart disease.
Circulation. 2000;101:1899-906. [PubMed]
33.
Firatli, E. The relationship between clinical periodontal status and
insulin-dependent diabetes mellitus. Results after 5 years. J Periodontol.
1997;68:136-40. [PubMed]
34.
Hung, HC; Willett, W; Merchant, A; Rosner, BA; Acherio, A; Joshipura, KJ. Oral
health and peripheral arterial disease. Circulation. 2003;107:1152-7. [PubMed]
35.
Joshipura, KJ; Wand, HC; Merchant, AT; Rimm, EB. Periodontal disease and
biomarkers related to cardiovascular disease. J Dent Res. 2004;83:151-5.
[PubMed]
36.
Sinisalo, J; Paronen, J; Mattila, KJ; Syrjala, M; Alfthan, G; Palosuo, T;
Nieminen, MS; Vaarala, O. Relation of inflammation to vascular function in
patients with coronary heart disease. Atherosclerosis. 2000;149:403-11.
[PubMed]
37.
Thompson, SG; Kienast, J; Pyke, SD; Haverkate, F; van de Loo, JC. Hemostatic
factors and the risk of myocardial infarction or sudden death in patients with
angina pectoris. N Engl J Med. 1995;332:635-41. [PubMed]
38.
Skoog, T; Dichtl, W; Boquist, S; Skoglund-Andersson, C; Karpe, F; Tang, et al.
Plasma tumour necrosis factor-alpha and early carotid atherosclerosis in
healthy middle-aged men. Eur Heart J. 2002;23:376-83. [PubMed]
39.
Desvarieux, M; Demmer, RT; Rundek, T; Boden-Albala, B; Jacobs, DR, Jr;
Papapanou, PN; Sacco, RL. Relationship between periodontal disease, tooth loss,
and carotid artery plaque: the Oral Infections and Vascular Disease
Epidemiology Study (INVEST). Stroke. 2003;34:2120-5. [PubMed]
40.
Wang, CH; Li, SH; Weisel, RD, et al. C-reactive protein upregulates angiotensin
type 1 receptors in vascular smooth muscle. Circulation. 2003;107:1783-90.
[PubMed]
41.
Fichtlscherer, S; Breuer, S; Schachinger, V; Dimmeler, S; Zeiher, AM.
C-reactive protein levels determine systemic nitric oxide bioavailability in
patients with coronary artery disease. Eur Heart J. 2004;25:1412-8. [PubMed]
42.
Pussinen, PJ; Viluna-Rautiainen, T; Alfthan, G; Palosuo, T; Jauhiainen, M;
Sundvall, J; Vesanen, M; Mattila, K; Asikainen, S. Severe periodontitis
enhances macrophage activation via increased serum lipopolysaccharide.
Arterioscler Thromb Vasc Biol. 2004;24:2174-80. [PubMed]
43.
Zwaka, TP; Hombach, V; Torzewski, J. C-reactive protein-mediated low density
lipoprotein uptake by macrophages: implications for atherosclerosis.
Circulation. 2001;103:1194-7. [PubMed]
44.
Mattila, KJ; Pussinen, PJ; Paju, S. Dental infections and cardiovascular
diseases: a review. J Periodontol. 2005;76:2085-8. [PubMed]
45.
Pussinen, PJ; Jauhiainen, M; Vilkuna-Rautiainen, T; Sundvall, J; Vesanen, M;
Mattila, K; Palosuo, T; Alfthan, G; Asikainen, S. Periodontitis decreases the
antiatherogenic potency of high density lipoprotein. J Lipid Res.
2004;45:139-47. [PubMed]
46.
Pearson, TA; Mensah, GA; Alexander, RW; Anderson, JL; Cannon, RO, 3rd; Criqui,
M, et al. Markers of inflammation and cardiovascular disease: application to
clinical and public health practice: a statement for healthcare professionals
from the Centers for Disease Control and Prevention and the American Heart
Association. Circulation. 2003;107:499-511. [PubMed]
47.
Pussinen, PJ; Jousilahti, P; Alfthan, G; Palosuo, T; Asikainen, S; Salomaa, V.
Antibodies to periodontal pathogens are associated with coronary heart disease.
Arterioscler Thromb Vasc Biol. 2003;23:1250-4. [PubMed]
48.
Pussinen, PJ; Nyysonen, K; Alfthan, G; Salonen, R; Laukkanen, JA; Salonen, JT.
Serum antibody levels to Actinobacillus actinomycetemcomitans predict the risk
for coronary heart disease. Arterioscler Thromb Vasc Biol. 2005;25:833-8.
[PubMed]
49.
Gilbert, GH; Miller, MK; Duncan, RP; Ringelberg, ML; Dolan, TA; Foerster, U.
Tooth-specific and person-level predictors of 24-month tooth loss among older
adults. Community Dent Oral Epidemiol. 1999;27:372-85. [PubMed]
50.
Chi, H; Messas, E; Levine, RA; Graves, DT; Amar, S. Interleukin-1 receptor
signaling mediates atherosclerosis associated with bacterial exposure and/or a
high-fat diet in a murine apolipoprotein E heterozygote model:
pharmacotherapeutic implications. Circulation. 2004;110:1678-85. [PubMed]
51.
Li, L; Messas, E; Batista, EL, Jr, et al. Porphyromonas gingivalis infection
accelerates the progression of atherosclerosis in a heterozygous apolipoprotein
E-deficient murine model. Circulation. 2002;105:861-7. [PubMed]
52.
Skyler, J; Oddo, C. Diabetes trends in the USA. Diabetes Metab Res Rev.
2002;18:S21-6. [PubMed]
53.
King, H; Aubert, RE; Herman, WH. Global burden of diabetes, 1995-2025:
prevalence, numerical estimates, and projections. Diabetes Care.
1998;21:1414-31. [PubMed]
54.
Matthews, DC. The relationship between diabetes and periodontal disease. J Can
Dent Assoc. 2002;68:161-4. [PubMed]
55.
Tervonen, T; Oliver, RC; Wolff, LF; Bereuter, J; Anderson, LA; Aeppli, DM.
Prevalence of periodontal pathogens with varying metabolic control of diabetes
mellitus. J Clin Periodontol. 1994;21:375-9. [PubMed]
56.
Yuan, K; Chang, CJ; Hsu, PC; Sun, HS; Tseng, CC; Wang, JR. Detection of
putative periodontal pathogens in non-insulin-dependent diabetes mellitus and
non-diabetes mellitus by polymerase chain reaction. J Periodontal Res.
2001;36:18-24. [PubMed]
57.
Teng, YT; Taylor, GW; Scannapieco, F; Kinane, DF; Curtis, M; Beck, JD; Kogon,
S. Periodontal health and systemic disorders. J Can Dent Assoc. 2002;68:188-92.
[PubMed]
58.
Pradhan, AD; Ridker, PM. Do atherosclerosis and type 2 diabetes share a common
inflammatory basis? Eur Heart J. 2002;23:831-4. [PubMed]
59.
Yudkin, JS; Stehouwer, CD; Emeis, JJ; Coppack, SW. C-reactive protein in
healthy subjects: associations with obesity, insulin resistance, and
endothelial dysfunction: a potential role for cytokines originating from
adipose tissue? Arterioscler Thromb Vasc Biol. 1999;19:972-8. [PubMed]
60.
Bluher, M; Fasshauer, M; Tonjes, A; Kratzsch, J; Schon, MR; Paschke, R.
Association of interleukin-6, C-reactive protein, interleukin-10 and
adiponectin plasma concentrations with measures of obesity, insulin sensitivity
and glucose metabolism. Exp Clin Endocrinol Diabetes. 2005;113:534-7. [PubMed]
61.
Thorand, B; Kolb, H; Baumert, J; Koenig, W; Chambless, L; Meisinger, C; Illig,
T; Martin, S; Herder, C. Elevated levels of interleukin-18 predict the
development of type 2 diabetes: results from the MONICA/KORA Augsburg Study,
1984-2002. Diabetes. 2005;54:2932-8. [PubMed]
62.
Grossi, SG; Zambon, JJ; Ho, AW; Koch, G; Dunford, RG; Machtel, EE, et al.
Assessment of risk for periodontal disease. I. Risk indicators for attachment
loss. J Periodontol. 1994;65:260-7. [PubMed]
63.
Christgau, M; Palitzsch, KD; Schmalz, G; Kreiner, U; Frenzel, S. Healing
response to nonsurgical periodontal therapy in patients with diabetes mellitus:
clinical, microbiological, and immunologic results. J Clin Periodontol.
1998;25:112-24. [PubMed]
64.
Stewart, JE; Wager, KA; Friedlander, AH; Zadeh, HH. The effect of periodontal
treatment on glycemic control in patients with type 2 diabetes mellitus. J Clin
Periodontol. 2001;28:306-10. [PubMed]
65.
Offenbacher, S; Salvi, GE. Induction of prostaglandin release from macrophages
by bacterial endotoxin. Clin Infect Dis. 1999;28:505-13. [PubMed]
66.
Lalla, RV; D'Ambrosio, JA. Dental management considerations for the patient
with diabetes mellitus. J Am Dent Assoc. 2001;132:1425-32. [PubMed]
67.
Westfelt, E; Rylander, H; Blohme, G; Jonasson, P; Lindhe, J. The effect of
periodontal therapy in diabetics. Results after 5 years. J Clin Periodontol.
1996;23:92-100. [PubMed]
68.
Strommer, L; Wickbom, M; Wang, F; Herrington, MK; Ostenson, CG; Arnelo, U;
Permert, J. Early impairment of insulin secretion in rats after surgical
trauma. Eur J Endocrinol. 2002;147:825-33. [PubMed]
69.
Tsigos, C; Papanicolaou, DA; Kyrou, I; Defensor, R; Mitsiadis, CS; Chrousos,
GP. Dose-dependent effects of recombinant human interleukin-6 on glucose
regulation. J Clin Endocrinol Metab. 1997;82:4167-70. [PubMed]
70.
Plomgaard, P; Bouzakri, K; Krogh-Madsen, R; Mittendorfer, B; Zierath, JR;
Pedersen, BK. Tumor necrosis factor-alpha induces skeletal muscle insulin
resistance in healthy human subjects via inhibition of Akt substrate 160
phosphorylation. Diabetes. 2005;54:2939-45. [PubMed]
71.
Vendrell, J; Broch, M; Vilarrasa, N, et al. Resistin, adiponectin, ghrelin,
leptin, and proinflammatory cytokines: relationships in obesity. Obes Res.
2004;12:962-71. [PubMed]
72.
Genco, RJ; Grossi, SG; Ho, A; Nishimura, F; Murayama, Y. A proposed model
linking inflammation to obesity, diabetes, and periodontal infections. J
Periodontol. 2005;76:2075-84. [PubMed]
73.
Berkowitz, GS; Papeirnik, E. Epidemiology of preterm birth. Epidemiol Rev.
1993;15:414-43. [PubMed]
74.
Buduneli, N; Baylas, H; Buduneli, E; Turkoglu, O; Kose, T; Dahlen, G.
Periodontal infections and pre-term low birth weight: a case-control study. J
Clin Periodontol. 2005;32:174-81. [PubMed]
75.
McCormick, MC. The contribution of low birth weight to infant mortality and
childhood morbidity. N Engl J Med. 1985;312:82-90. [PubMed]
76.
Davenport, ES; Williams, CE; Sterne, KA; Murad, S; Sivapathasundram, V; Curtis,
MA. Maternal periodontal disease and preterm low birthweight: case-control
study. J Dent Res. 2002;81:313-8. [PubMed]
77.
Offenbacher, S; Lieff, S; Boggess, K; Murtha, A; Madianos, P; Champagne, C, et
al. Maternal periodontitis and prematurity. Part I: obstetric outcome of
prematurity and growth restriction. Ann Periodontol. 2001;6:164-74. [PubMed]
78.
Moreu, G; Tellez, L; Gonzalez-Jaranay, M. Relationship between maternal
periodontal disease and low-birth-weight pre-term infants. J Clin Periodontol.
2005;32:622-7. [PubMed]
79.
Yeo, BK; Lim, LP; Paquette, DW; Williams, RC. Periodontal disease - the
emergence of a risk for systemic conditions: pre-term low birth weight. Ann
Acad Med. 2005;34:111-6.
80.
Ventura, SJ; Martine, JA; Curtin, SC, et al. Births: final data for 1997. Natl
Vital Stat Rep. 1999;47:1-96.
81.
Skuldbol, T; Johansen, KH; Dahlen, G; Stoltze, K; Holmstrup, P. Is pre-term
labour associated with periodontitis in a Danish maternity ward? J Clin
Periodontol. 2006;33:177-83. [PubMed]
82.
Andrews, WW; Goldenberg, RL; Hauth, JC. Preterm labor: emerging role of genital
tract infections. Infect Agents Dis. 1995;4:196-211. [PubMed]
83.
Gibbs, RS; Romero, R; Hillier, SL; Eschenbach, DA; Sweet, RL. A review of
premature birth subclinical infection. Am J Obstet Gynecol. 1992;166:1515-26.
[PubMed]
84.
Minkoff, H; Grunebaum, AN; Schwarz, RH; Feldman, J; Cummings, M; Crombleholme,
W, et al. Risk factors for premature rupture of membranes: a prospective study
of the vagina flora in pregnancy. Am J Obstet Gynecol. 1984;150:965-72.
[PubMed]
85.
Offenbacher, S; Katz, V; Fertik, G, et al. Periodontal infection as a possible
risk factor for preterm low birth weight. J Periodontol. 1996;67:1103-13.
[PubMed]
86.
Slattery, MM; Morrison, JJ. Preterm delivery. Lancet. 2002;360:1489-97.
[PubMed]
87.
Romero, R; Mazor, M. Infection and preterm labor. Clin Obstet Gynecol.
1988;31:553-84. [PubMed]
88.
Madianos, PN; Lieff, S; Murtha, AP; Boggess, KA; Auten, RL, Jr; Beck, JD;
Offenbacher, S. Maternal periodontitis and prematurity. Part II: maternal
infection and fetal exposure. Ann Periodontol. 2001;6:175-82. [PubMed]
89.
Offenbacher, S; Riche, EL; Barros, SP; Bobetsis; Lin, D; Beck, JD. Effects of
maternal Campylobacter rectus infection on murine placenta, fetal and neonatal
survival, and brain development. J Periodontol. 2005;76:2133-43. [PubMed]
90.
Han, YW; Redline, RW; Li, M; Yin, L; Hill, GB; McCormick, TS. Fusobacterium
nucleatum induces premature and term stillbirths in pregnant mice: implication
of oral bacteria in preterm birth. Infect Immun. 2004;72:2272-9. [PubMed]
91.
Boggess, KA; Moss, K; Madianos, P; Murtha, AP; Beck, J; Offenbacher, S. Fetal
immune response to oral pathogens and risk of preterm birth. Am J Obstet
Gynecol. 2005;193:1121-6. [PubMed]
92.
Lopez, NJ; Silva, ID; Ipinza, J; Gutierrez, J. Periodontal therapy reduces the
rate of preterm low birth weight in women with pregnancy-associated gingivitis.
J Periodontol. 2005;76:2144-53. [PubMed]
93.
Wactawski-Wende, J; Grossi, SG; Trevisan, M; Genco, RJ; Tezal, M; Dunford, RG;
Ho, AW; Hausmann, E; Hreshchyshyn, MM. The role of osteopenia in oral bone loss
and periodontal disease. J Periodontol. 1996;67(10 Suppl):1076-84. [PubMed]
94.
Garnero, P. Markers of bone turnover for the prediction of fracture risk.
Osteoporos Int. 2000;11(Suppl 6):S55-65. [PubMed]
95.
Jeffcoat, MK; Chestnut, CH., 3rd Systemic osteoporosis and oral bone loss:
evidence shows increased risk factors. J Am Dent Assoc. 1993;124:49-56.
[PubMed]
96.
Page, RC; Sims, TJ; Geissler, F; Altman, LC; Baab, DA. Defective neutrophil and
monocyte motility in patients with early-onset periodontitis. Infect Immun.
1985;47:169-75. [PubMed]
97.
Lerner, UH. Osteoclast formation and resorption. Matrix Biol. 2000;19:107-20.
[PubMed]
98.
Manabe, H; Kawaguchi, H; Chikuda, H; Miyaura, C; Inada, M; Nagai, R, et al.
Connection between B lymphocyte and ostoclast differentiation pathways. J
Immunol. 2001;167:2625-31. [PubMed]
99.
Taubman, MA; Kawai, T. Involvement of T-lymphocytes in periodontal disease and
in direct and indirect induction of bone resoprtion. Crit Rev Oral Biol Med.
2001;12:125-35. [PubMed]
100.
Liu, D; Xu, JK; Figliomeni, L; Huang, L; Pavlos, NJ; Rogers, M, et al.
Expression of RANKL and OPG mRnNA in periodontal disease. Possible involvement
in bone destruction. Int J Mol Med. 2003;11:17-21. [PubMed]
101.
Nagasawa, T; Kobayashi, H; Kiji, M; Aramaki, M; Mahanoda, R; Kojima, T, et al.
LPS-stimulated human gingival fibroblast inhibits the differentiation of
monocytes into osteoclasts through the production of osteoprotegerin. Clin Exp
Immunol. 2002;130:338-44. [PubMed]
102.
Teng, YTA; Nguyen, H; Gao, X; Kong, YY; Gorczynski, RM; Singh, B, et al.
Functional human T-cell immunity and osteoprotegerin ligand control alveolar
bone destruction in periodontal infection. J Clin Invest. 2000;106:R59-67.
[PubMed]
103.
Jiang, Y; Mehta, CK; Hsu, TY; Alsulaimani, FFH. Bacteria induce
osteoclastogenesis via an osteoblast-independent pathway. Infect Immun.
2002;70:3143-8. [PubMed]
104.
Jacobs, R; Ghyselen, J; Konincks, P; van Steeberghe, D. Long-term bone mass
evaluation of mandible and lumbar spine in a group of women receiving hormone
replacement therapy. Eur J Oral Sci. 1996;104:10-6. [PubMed]
105.
Pacifici, R. Cytokines, estrogen, and postmenopausal osteoporosis - the second
decade. Endocrinology. 1998;139:2659-61. [PubMed]
106.
Gemmell, E; Marshall, RI; Seymour, GJ. Cytokines and prostaglandins in immune
homeostasis and tissue destruction in periodontal disease. J Periodontol.
2000;1997:14:112-43.
107.
Baker, PJ. The role of immune responses in bone loss during periodontal
disease. Microbes Infect. 2000;2:1181-92. [PubMed]
108.
Tezal, M; Wactawaki-Wende, J; Grossi, SG; Ho, AW; Dunford, R; Genco, RJ. The
relationship between bone mineral density and periodontitis in postmenopausal
women. J Periodontol. 2000;71:1492-8. [PubMed]
109.
Inagaki, K; Kurosu, Y; Yoshinari, N; Noguchi, T; Krall, EA; Garcia, RI.
Efficacy of periodontal disease and tooth loss to screen for low bone mineral
density in Japanese women. Calcif Tissue Int. 2005;77:9-14. Epub 2005 Jul 14.
[PubMed]
110.
Wactawski-Wende, J; Hausmann, E; Hovey, K; Trevisan, M; Grossi, S; Genco, RJ.
The association between osteoporosis and alveolar crestal height in
postmenopausal women. J Periodontol. 2005;76:2116-24. [PubMed]
111.
Marques, MR; da Silva, MAD; Manzi, FR; Cesar-Neto, JB; Nociti, FH, Jr; Barros,
SP. Effect of intermittent PTH administration in the periodontitis-associated
bone loss in ovariectomized rats. Arch Oral Biol. 2005;50:421-9. [PubMed]
112.
Jeffcoat, M. The association between osteoporosis and oral bone loss. J
Periodontol. 2005;76:2125-32. [PubMed]
113.
Brandi, ML; Hukkanen, M; Umeda, T, et al. Bidirectional regulation of
osteoclast function by nitric oxide synthase isoforms. Proc Natl Acad Sci USA.
1995;92:2954-8. [PubMed]
114.
Lohinai, Z; Stachlewitz, R; Virag, L; Szekely, AD; Hasko, G; Szabo, C. Evidence
for reactive nitrogen species formation in gingivomucosal tissue. J Dent Res.
2001;80:470-5. [PubMed]
115.
Gyurko, R; Boustany, G; Huang, PL, et al. Mice lacking inducible nitric oxide
synthase demonstrate impaired killing of Porphyromonas gingivalis. Infect
Immun. 2003;18:39-46.
116.
Leitao, RFC; Rocha, FAC; Chaves, HV; Lima, V; Cunha, FQ; Ribeiro, RA; Brito,
GAC. Locally applied isosorbide decreases bone resorption in experimental
periodontitis in rats. J Periodontol. 2004;75:1227-32. [PubMed]
117.
American Academy of Periodontology. Systemic antibiotics in peridontics. J
Periodontol. 1996;67:831-8. [PubMed]
Odontology. 2006 September; 94(1): 10-21.
doi: 10.1007/s10266-006-0060-6.PMCID: PMC2443711
NIHMSID: NIHMS13055
see
http://www.pubmedcentral.nih.gov:80/articlerender.fcgi?tool=pubmed&pubmedid=16998613
Copyright notice and Disclaimer