2013 John Wiley & Sons A/S

Periodontology 2000, Vol. 62, 2013, 5994

Printed in Singapore. All rights reserved

PERIODONTOLOGY 2000

Risk factors for periodontal

disease
R O B E R T J. G E N C O & W E N C H E S. B O R G N A K K E

Extensive epidemiologic and experimental evidence

exists for the role of several risk factors in the initiation, progression, and severity of periodontal disease.
The goal of this article is to provide a clear analysis of
the evidence supporting the important role of risk
factors in determining the differences between individuals in susceptibility to periodontal disease. The
paper is written so that clinicians can gain a deeper
understanding of the role of risk factors in periodontal disease in order to incorporate risk-factor
modification in the management of periodontal disease. There are systemic conditions and factors that
are probably protective, but we have less information
on these and therefore, the emphasis in this article is
on risk factors that increase susceptibility to periodontal infections.
A search for papers relating to risk factors revealed more than 3,000 citations as of July 2012; of
these, over 700 publications were reviews. Therefore, this review will focus specifically on systemic
risk factors for susceptibility for periodontal disease
that are relatively common in the population and
are likely to have a substantial population-attributable risk. Hence, topics such as local risk factors
or etiopathogenesis of periodontal disease, as well
as periodontal disease as a risk factor for other
conditions, are outside the scope of this paper.
Comprehensive, systematic reviews and meta-analyses will be summarized when available, and selected other relevant key reports will be cited.
Apologies are made in advance to those authors
whose contributions to understanding the role of
risk factors in periodontal disease are not directly
quoted.
Fitting with the theme of this volume of Periodontology 2000, the goal of this paper was to clarify
new concepts we have learned about risk factors in
the past few decades, and to critically analyze past
and present evidence supporting the management

of risk factors as an essential component in the

prevention and the treatment of periodontal disease
in susceptible individuals.

Periodontal disease as an infection,

and the overall role and definition
of periodontal risk factors
It is now well established that periodontal disease is
predominantly a bacterial infection involving the
dental biofilm or dental plaque. Some of the principal
periodontal pathogens of the subgingival microbiome have been identified to have virulence potential
and are associated strongly with the etiology and the
pathogenesis of periodontal disease. Studies of the
total subgingival microbiome are ongoing, and
identification of previously undescribed periodontal
pathogens is likely to result from current human
microbiome studies. We now understand that biofilms which cause gingivitis and periodontitis are
site-specific, complex polymicrobial communities
that are resistant to antimicrobial agents and hostdefense mechanisms (15). However, the concept that
the rate of progression, age at onset, and severity of
periodontal disease in an individual are often determined by systemic risk factors in the host is a fairly
recent concept made possible by our understanding
of the epidemiology of periodontal disease and the
role of risk factors.
Before we could study risk factors for periodontal
disease, we had to undergo a fundamental change
in our understanding of periodontal diseases. As
recently as the 1960s, the prevailing concept was
that all individuals were equally susceptible to
periodontal disease (28, 145, 231). This notion of
equal susceptibility to periodontal disease probably
came from the misconception that most adults
suffered from periodontal disease as they grew

59

Genco & Borgnakke

older (i.e., that eventually periodontal disease

would affect most individuals if they lived long
enough).
A key methodologic advance in the measurement
of periodontitis was made by assessing clinical
attachment loss as well as pocket depth (29, 224),
in addition to gingival inflammation. When this
method was applied to determine the prevalence
and incidence of periodontitis in populations, it
was found that only a subset of adults suffered
from severe periodontitis, defined by loss of clinical
attachment and periodontal pocket formation (205,
278, 289). This is in contrast to the earlier misconception that periodontal disease was universal,
which was based mainly on assessment of gingival
inflammation.
The realization that there were individuals who
suffered from severe periodontitis and others who
remained healthy throughout life presented the
important question: What are the factors that
determine an individuals susceptibility or resistance to periodontal disease?. In other words,
what are the risk factors for periodontitis? This
question was not addressed rigorously until the
1980s.
Our concept of risk factors and mechanisms involved in the initiation and progression of periodontitis has developed dramatically in the last few
decades, from a simplistic view of microbes directly
causing clinical signs and symptoms of periodontitis,
through understanding the importance of the immune system and the inflammatory response of the
host, to our current (still developing) view of periodontitis as a multifactorial disease that also is
influenced by genetic and environmental risk factors
(142, 207).
Several important developments came into play
to make the study of risk factors possible. First, the
development of several national databases in
the USA and other countries, such as the US
National Health and Nutrition Examination Survey
(NHANES), where a comprehensive analysis of
underlying systemic factors, habits and demographic factors, plus measures of dental disease,
including periodontal disease, were assessed. There
was also a National Institute of Dental and
Craniofacial Research-sponsored program for
Periodontal Disease Research Centers, which
allowed for long-term, stable funding necessary for
large epidemiologic studies of risk factors for
periodontal disease.
Finally, increasingly powerful computers and
more sophisticated and refined statistical tech-

60

niques, such as multivariate logistic and linear

regression, were developed. These multivariate statistical procedures are used to analyze epidemiologic studies of risk factors by adjusting for confounding variables or covariants to help isolate and
identify specific independent risk factors in large
population databases.
The lack of standard, globally accepted and applied case definitions was addressed by several
authors (8, 15, 166, 206, 238, 282). When assessing
scientific evidence and results from population
surveys, it should be borne in mind that studies
often use unique definitions of periodontitis cases
based on a myriad of periodontal parameters that
may be clinical, radiographic, serologic, or salivary
assessments of various aspects of periodontal disease. Therefore, studies are difficult to compare.
Useful case definitions for moderate and severe
periodontitis have been developed by a collaboration between the Centers for Disease Control and
Prevention and the American Academy of Periodontology (65, 66, 206), and they have been applied
in a number of studies of risk factors, as well as in
studies of prevalence and incidence of periodontal
diseases.
A recent study suggests that previous NHANES
examinations may have underestimated the prevalence of periodontal disease by 50% or more as a
result of the use of partial-mouth recordings (67).
However, even with full-mouth probing providing a
more accurate and higher prevalence of periodontal
disease, only a subset of adults is found to suffer
from severe periodontitis. For example, the periodontitis case definitions (65) can be used to better
estimate the true prevalence of periodontitis in the
current NHANES 20092014 protocol. Data from the
first two years, 20092010, show that among people
30 years of age, almost half (47.2%) have periodontitis with 8.7% having mild, 30.0% moderate, and
8.5% severe (64, 65). It appears that those with severe periodontitis constitute a subgroup especially
susceptible to periodontal infection. This notion that
severe periodontitis is clustered in a subset of subjects is in accordance with what was learned from
earlier epidemiologic studies in the 1980s (1922).
There may be individuals among those with no or
mild periodontal disease who are resistant to periodontal disease, but few studies have focused on
possible protective factors found in such individuals.
The current concept is that adults vary widely in
their susceptibility to periodontitis, and that not
everyone is universally susceptible to periodontitis,
regardless how long they live.

Risk factors for periodontal diseases

Strength of evidence for risk factors

Upon reviewing the body of evidence, recommendations of risk-factor modification as a public health
measure may be made. The strength of the contribution from each scientific report to the body of
epidemiologic evidence is determined not only by the
quality of the conduct of the study, but is limited by
its design and methods that determine which conclusions about causality can be inferred from the
results. Causality factors relevant in human health
issues can be defined as: a factor is a cause of a
disease or health-related condition if its operation
increases the frequency of the disease or condition
(70). In order to establish causality, stringent criteria
must be satisfied (106), such as the condition needs
to occur before the disease outcome (temporality)
and it needs to be biologically plausible. From the
results of epidemiologic studies, potential risk factors
can be identified for further studies, which subsequently yield evidence that elucidates etiology and
mechanisms by which risk factors operate at the
basic molecular, cellular, and genetic levels. If a
condition does not fulfill the causality criteria, but is
frequently observed to be associated with the studied
outcome, it can still be considered as a risk factor
which increases susceptibility to the periodontal
infection. However, for simplicity and for conveying
concepts in this review, only risk factors for which
causality is likely as well as those that increase the
susceptibility of a patient, will be considered. An
important concept is the extent to which any risk
factor contributes to periodontitis, namely the
attributable risk. Currently, we only have estimates of
attributable risk for most periodontal risk factors and
therefore, future studies are necessary to establish
attributable risk so that priorities can be made to
determine which risk factors are of most importance
in the management of periodontal disease.

Analytical observational study designs:

cross-sectional, casecontrol, and cohort
studies
There are three main types of analytic, nonexperimental studies that are observational in nature: (i)
cross-sectional studies, which provide a snapshot at a
given time point; (ii) casecontrol studies, in which
there are two groups, one with and one without the
outcome studied, and you go back in time to elucidate any differences in their past exposure to potential putative (assumed alleged) risk factors;
and (iii) cohort (longitudinal) studies, in which study

participants are followed over time to compare

groups of individuals exposed to a putative risk factor
with those who are not exposed. Cross-sectional and
casecontrol studies are able to provide evidence
only regarding associations (relationships and correlations), whereas longitudinal studies include
temporal sequence and thus may infer causality,
provided that all other criteria therefore are satisfied.

Intervention studies
The next level of evidence is provided by experimental (intervention or treatment) studies in which
there are at least two groups of participants who are
as similar as possible in all of their relevant characteristics, and in which the risk factor is modified in
the test group but not in the control group. The
highest level of this type of evidence is provided by a
randomized controlled trial design, which is most
extensively used in comparing methods of treatment:
each participant is allocated to a group receiving
treatment or to a control group by chance assignment (i.e., random allocation) and, when possible,
neither the participants nor the investigators are
aware of which is the treated or the control group
(double-blinding or masking), thus guarding against
bias. However, in some instances, it is not feasible to
carry out such studies for ethical or practical reasons,
and an approximation to randomized controlled trials can be made using propensity score analysis,
where the treated and control groups are made similar in distribution of background variables, which
may influence the outcome (e.g., age, gender, habits
and socio-economic status (230).

Systematic reviews and

meta-analyses
The highest level of evidence for a causal relationship
is a systematic review and meta-analysis of randomized controlled trials of high quality. All evidence
is located and reviewed by at least two different
reviewers, according to predetermined, stringent
criteria regarding inclusion of each study. Pooling
participants and analyzing the findings in studies of
sufficient quality and similarity is called a metaanalysis; because of the combined number of participants it has much greater statistical power than any
individual study. The quality of meta-analyses
depends on many factors, including the thoroughness
of the literature search, the validity of inclusion and
exclusion criteria for study selection, and the quality
of each study.

61

Genco & Borgnakke

The search for periodontal disease

risk factors in multifactorial
epidemiologic studies using
contemporary statistical
methodologies
A powerful approach to identify risk factors is through
large epidemiologic studies where subjects with
periodontal disease are compared with those who
have little or no periodontal disease in order to
determine which factors differentiate the two. Those
factors that are increased in patients with periodontal
disease compared with patients with periodontal
health are then termed risk factors. They probably
increase susceptibility to periodontal disease. Factors
found at lower levels in subjects with periodontal
disease may be protective and are associated with
resistance. From the 1990s to the present time, a
series of epidemiologic studies have been carried out
that measured a large battery of potential risk factors
in large populations and identified those associated
with periodontal disease. In most of these studies, the
results are statistically adjusted for confounding
factors or correlations and isolate those that are likely
to be true risk factors (39). Common confounding
factors for periodontal disease include age, gender,
and race ethnic origin, with older, male, and nonwhite people having more periodontitis. Examples of
such population-based studies include urban and
suburban communities in Western New York (91, 92),
a racially diverse urban population in Minnesota (10);
Australian Arboriginal young adults (121); older Japanese (204), Norwegians (197), and Americans (155);
NHANES representative of the US population 30 years
and older (64) and subsets representative of African
Americans (269) and employed persons (7, 116), in
addition to studies of adults in Denmark (146), Sweden (114, 123, 197, 199), Norway (198), Germany (108,
109, 140), Australia (256), and Brazil (264, 265).
To illustrate the design and some of the findings of
these studies, the two studies by Grossi et al. (91, 92)
will be used. In these studies, adults 2575 years of
age were recruited and stratified using census tracks
from different socio-economic populations to help
ensure a wide distribution among various socioeconomic strata in the urban and suburban communities in Erie County, New York. The population
was also stratified by age to ensure equal numbers of
participants in each decade. Over 500 characteristics
were assessed, including demographics; health measurements; diseases; habit history; stress, distress,
and coping behaviors; as well as local factors, such

62

as caries and oral mucous membrane lesions.

Periodontal disease was measured by assessment of
full-mouth periodontal probing at six sites per tooth,
reported as probing depth and clinical attachment
level, gingival inflammation, and calculus formation.
In addition, the Gingival Index, Plaque Index, Calculus Index, and subgingival flora were assessed. As
an additional measure of periodontal disease, standardized radiographs were exposed and digitized,
and measurement of alveolar crest height was made
for each interproximal site.
In the first paper, a series of independent risk factors was revealed after adjustment for confounding
factors (92), which included smoking, infection with
Porphyromonas gingivalis and Tannerella forsythia,
diabetes, age, and male gender (Fig. 1). Anemia,
increasing levels of education, and infection with
Capnocytophaga were found to be correlated with
healthy periodontal status and appear to be protective. In this study, periodontal outcome was assessed
by attachment loss and pocket depth. The study used
multiple adjustments, and all the risk factors shown
in Fig. 1 were independent and survived correction
by multiple logistic regression. In the second study
(91), a similar set of risk factors was found using
alveolar crest height, an independent, but related,
radiographic measure of periodontitis.
Large-scale epidemiologic surveys assessing multiple potential risk factors support the conclusions of
the Erie County studies (91, 92). These studies include age and gender (64, 97); smoking, gender, low
educational level (64, 140), and diabetes (133); and
age, gender, and ethnicity (64, 108). A meta-analysis of 18 epidemiologic studies concluded that low

Capnocytophaga species

Anemia
Educaon
Allergy
Male sex
P. gingivalis
Age (decade increase)
Diabetes
T. forsythia
Moderate smoking
0

2
3
Esmated odds rao (95% confidence interval)

Fig. 1. Potential risk indicators for periodontal disease.

The error bars represent the 95% confidence intervals.
None of the 95% confidence intervals cross the odds ratio
1.0, and hence they are all statistically significant at
P 0.05. Odds ratios >1 can be considered to increase
risk for periodontal clinical attachment loss, and may be
risk factors; odds ratios <1 are associated with less
attachment loss, and may be protective factors. From
Grossi et al. (91).

Risk factors for periodontal diseases

educational attainment was associated with an

increased risk of periodontitis in people 35 years and
older (35). Furthermore, Kocher et al. (140) found
that higher education level, consumption of antiallergic medications, and regular dental check-ups
proved to be protective for periodontal disease.
We will now look at each of the major risk factors
separately and assess the association according to the
strength of evidence outlined earlier.

Individual risk factors

Risk factors for periodontal disease will be placed in
the following groups for ease of understanding and
presentation.
Gender, smoking, and alcohol (lifestyle)
Diabetes
Obesity and metabolic syndrome
Osteoporosis, dietary calcium, and vitamin D
Stress
Genetic factors.

Gender, smoking, and alcohol (lifestyle)

Gender as a risk factor for periodontal disease
The most prevalent risk factor for periodontal disease
is being of male sex. Even though ones biological sex
is genetically determined, there does not seem to be
any inherent difference between the two sexes in
susceptibility to periodontal disease. Rather, the societal gender difference presumably is a consequence
of lifestyle and thus will be mentioned here and not
in the section on genetic factors. For decades, it has
been recognized that men of all ages, race ethnic
groups, and geographic locations (64, 91, 97) have
significantly more periodontal disease than women,
assessed by prevalence, extent, and severity, as well
as by any parameter and case definition of periodontitis. From the recently published, first analyzes of
the NHANES 20092010 data collected by the gold
standard, full mouth periodontal probing at six sites
per tooth, it can be calculated that overall, men had
about 50% higher prevalence of periodontitis (64),
using the CDC AAP case definitions (65, 206). Men
had 33% more mild, 28% more moderate and 180%
more severe periodontitis than women, with over half
the men affected (56.4%): 10.0% had mild, 33.8%
moderate, and 12.6% severe periodontitis (64). It
should be borne in mind that being male greatly
increases the risk for periodontal disease and
therefore, men could potentially benefit from being

preferentially targeted for preventive measures and

more aggressive interventions.
Smoking as a risk factor for periodontal disease
Cigarette smoking has long been associated with
periodontal disease and tooth loss. A large body of
evidence shows that smoking cigarettes, the source of
more than 4,000 toxins, is a major risk factor for allcause mortality, cardiovascular disease, various
cancers, and several chronic diseases. The finding
that smoking is associated with periodontal disease
suggests that it is probably a major risk factor for
subsequent tooth loss. An association between acute
necrotizing ulcerative gingivitis and tobacco smoking
was reported in 1947 (217). Over the next several
decades, many studies showed an association of cigarette smoking with periodontal measures, and these
studies are reviewed by Bergstrom & Preber (31).
Most of the studies showed poorer oral hygiene in
smokers compared with nonsmokers, and this probably accounts for the prevailing concept at the time,
that smoking was not a risk factor for periodontitis
and that oral hygiene alone would account for the
differences in the levels of periodontal disease between smokers and nonsmokers. This was shown to
be an incorrect understanding, based upon multivariate studies with adjustment for confounders,
including plaque levels. For example, in the Erie
County Study (91, 92) when adjustments for confounding and correlations were made, smoking was
one of the major risk factors, with odds ratios for
moderate smoking of 45, both for periodontal
attachment loss as well as for alveolar crest bone loss.
Studies relating smoking to periodontal disease,
which show that smoking is an independent risk
factor, are reviewed by Tonetti (284). Cigar and pipe
smoking seem to have effects on the periodontium
similar to smoking of cigarettes (6, 143).
Analysis of epidemiologic studies implicating smoking
as a risk factor for periodontal disease. The importance of cigarette smoking as a risk factor for periodontal disease is supported by: (i) consistency of
results across many studies; (ii) strength of the
association; (iii) doseresponse of the association; (iv)
temporal sequence of smoking and periodontal disease; and (v) biologic plausibility. A meta-analysis of
six studies (209) with a total of 2,361 subjects showed
consistency in the findings. For all six studies included in this meta-analysis, an overall estimated
odds ratio of 2.82 (95% confidence interval: 2.36
3.39) was found. Several studies have shown a dose
response (100). For example, Grossi and colleagues

63

No. of pack years ( standare error)

Genco & Borgnakke

40
30
20
10
0
Healthy

High
Low
Moderate
Level of clinical attachment loss

Severe

Fig. 2. There is a positive relation between prevalence of

periodontal disease of increasing severity and number of
pack-years smoked (4.3, 7.2, 15.3, 24.9 and 28.3 packyears). From Grossi et al. (92).

(92) showed that as the number of pack years increased, the amount of attachment loss was greater
(Fig. 2). These authors also found that the amount of
alveolar crest height loss was positively correlated
with the number of pack years of smoking, showing a
clear dose response (91), Studies of the association of
cigarette smoking and tooth loss have also been
consistent, even among diverse populations in Australia (16), Brazil (97), India (32), and Thailand (287),
as well as in the USA (6, 143), and Europe.
There are few longitudinal studies of smoking and
periodontal disease (158). Smoking was not a significant risk factor for incidence of periodontal attachment loss over 5 years among South Australians
aged 60 years and over (279). However, there are
numerous studies of the effect of smoking on periodontal treatment response, which suggest that
smoking has a causal effect, at least in impairing
healing of the periodontal wound. This evidence was
been reviewed by Heasman et al. (102), and their
analysis shows that smoking cessation is beneficial to
healing following periodontal treatment. Following
non-surgical periodontal therapy and smoking cessation, the subgingival microbiome is recolonized by
a greater number of health-associated species along
with a significantly lower prevalence and abundance
of putative periodontal pathogens (59). Furthermore,
Jin et al. (127) showed significantly greater reductions in probing depth, of 1.0 mm, in nonsmokers
compared with smokers following nonsurgical periodontal therapy. A recent systematic review by Patel
et al. (210) of ten studies also found smoking to negatively affect bone regeneration after periodontal
treatment. Also, one study reported significantly
higher incidence of membrane exposure in smokers
(285). Papantonopoulos (208) showed that signifi-

64

cantly more smokers (42.8%) than nonsmokers

(11.5%) required further treatment between 6 and
8 weeks after initial therapy. Not all studies agree; for
example, Pucher et al. (222) and Zuabi et al. (304)
reported no difference in post-treatment clinical
attachment level between smokers and nonsmokers.
However, these studies may have been confounded
by the increased level of plaque found in smokers and
the greater initial pocket depth seen in smokers
compared with nonsmokers.
Enhanced healing after treatment in nonsmokers
as compared with smokers has been shown for various other periodontal treatments, including surgical
treatment (4, 210, 219) and guided tissue regeneration (210, 284). In addition, superior clinical outcomes in smokers as compared with nonsmokers
have been reported, with nonsurgical treatment using
adjunctive systemic or locally applied antimicrobial
agents (137, 257, 283).
Longitudinal evidence for the benefits of smoking
cessation on periodontal disease. Emerging evidence
is available for the long-term effects of smoking
cessation on the periodontium. One 12-month study
(220) showed that 10 subjects with periodontitis who
had continuously refrained from smoking for the
entire study period had a significant reduction in
probing depths compared with smokers. An earlier
study, by Bolin et al. (36), reported the results of a 10year radiographic follow-up, showing that progression of alveolar bone loss was significantly reduced in
those who had quit smoking during the study compared with continual smokers.
There is a need for long-term follow-up of nonsmokers and those who have quit smoking to determine
more clearly the effects of smoking cessation on the
periodontium. However, existing studies of smoking
cessation, or of nonsmokers vs. smokers, strongly suggest that part of the management of periodontal disease
should involve an attempt at smoking cessation.
Smoking as a risk factor for periodontal disease:
pathogenic mechanisms. Cigarette smoke contains
more than 4,000 reported toxic substances, such as
carbon monoxide, oxidizing radicals, carcinogens
(such as nitrosamine) and nicotine (which is
addictive). An extensive body of evidence exists to
implicate several mechanisms by which tobacco
smoke may exert adverse effects on the periodontium, and these are reviewed in Heasman et al.
(102). These adverse effects fall into several
categories regarding the effect of cigarette smoking
on:

Risk factors for periodontal diseases

microbiology (microbiota periodontal pathogens)

gingival blood flow
polymorphonuclear neutrophil phagocytosis
cytokine production (e.g., interleukin-1)
CD3, CD4 and CD8+ T-cell subsets
periodontal healing.
Smoking was found to select for specific periodontal
pathogens, including P. gingivalis, Treponema
denticola and T. forsythia, and this was proposed to
increase the risk for development and progression of
periodontal disease (301). This was confirmed by
Kazor et al. (134) and Haffajee & Socransky (99).
Another line of evidence suggests that smoking
leads to peripheral vasoconstriction, probably associated with low doses of nicotine (30, 159, 187).
Vasoconstriction can lead to reduced gingival bleeding and hence can cause the observation of less
gingivitis and reduced gingival bleeding in smokers
compared with nonsmokers. This also could explain,
to some extent, the compromised microvascular response, which could lead to reduced oxygen tension in
the periodontal pocket and thus favor the overgrowth
of anaerobes, such as P. gingivalis and T. denticola.
A third line of evidence linking smoking to the
etiopathogenesis of periodontal disease is that
smoking alters neutrophil function, mainly through
the effects of nicotine. Nicotine also enhances the
degranulation of neutrophils, making the neutrophils
more sensitive to bacterial challenge (257). Macrophages have also been implicated in the increased
levels of tumor necrosis factor-a found in the gingival
crevicular fluid of smokers, probably in response to
the presence of nicotine. Tumor necrosis factor-a
may also be expressed by peripheral neutrophils
found in the periodontium, and increased levels of
tumor necrosis factor-a may contribute to connective
tissue and periodontal bone destruction. Proliferation, chemotaxis, and attachment of fibroblasts from
the periodontium are inhibited by nicotine (54, 120).
These effects could be enhanced by nicotine bound
to the root surface, which could inhibit periodontal
regeneration. Smoking also leads to increased numbers of CD3, CD4 and CD8+ T-cell subsets in the
periodontal tissue, changes associated with greater
periodontal breakdown (162).
Several studies show that the levels of interleukin1b in gingival crevicular fluid are reduced in periodontally diseased sites in smokers, but are enhanced in
smokers who are periodontally healthy. This raises
the possibility of an imbalance in cytokine production that may affect the pathogenesis of periodontal
disease in smokers. This is supported by Petropoulos
et al. (215) who also found an interleukin-1 genotype

that may result in a reduced level of interleukin-1 in

gingival crevicular fluid.
Although there are several possible mechanisms
that could explain the higher levels of periodontal
disease and reduced healing seen in smokers, there is
no clear evidence that points to one particular
mechanism as being of greater importance. The response to smoking is likely to be mediated through a
number of different pathways, including a shift toward a more pathogenic subgingival flora, reduced
microcirculation, dysfunction of neutrophils, production of proinflammatory cytokines, and increased
levels of pathogenic T-cells.
Smoking is clearly a major risk factor for cardiovascular disease as well as for periodontal disease.
Hence, in studies showing associations between
cardiovascular disease and periodontal disease,
there is a risk for confounding by smoking. However, most studies have carefully adjusted for
smoking and still show that periodontal disease is a
risk factor for cardiovascular disease, independent of
smoking (158). Perhaps the most rigorous design to
demonstrate this independence is to compare the
increased risk for cardiovascular disease in both
smokers with periodontitis and nonsmokers with
periodontitis, by stratifying the population. This has
been carried out in two studies. Andriankaja et al.
(13) found that among nonsmokers, those with
periodontal disease had an increased risk of cardiovascular disease. The finding of an increased risk
of cardiovascular disease in nonsmokers with periodontal disease strongly suggests that smoking
alone does not account for the increased risk of
cardiovascular disease seen in individuals with
periodontal disease. Further evidence is provided by
a longitudinal component of the same study (63)
that showed similar findings (i.e., the recurrence of
myocardial infarction or other cardiovascular events
during the follow-up period showed that this
recurrence was related to periodontal disease levels
in nonsmokers as well as in smokers).
Similarly, at the immunologic level, Beck and
co-workers (27) found that the systemic antibody
response to periodontal pathogens was associated
with coronary heart disease in both smokers and
never smokers among participants in the Atherosclerosis Risk in Communities (ARIC) study. Smoking
is clearly an important risk factor for periodontal
disease, as well as for many other chronic diseases
and events in humans, including heart disease,
stroke, and cancer. Therefore, it is imperative for
dentists to actively encourage their patients to engage
in smoking-cessation activities, a major key to

65

Genco & Borgnakke

Alcohol consumption as a risk factor for periodontal

disease
Alcohol consumption may be associated, in a dosedependent manner, with increased severity of clinical
attachment loss (276). In a study of data from
NHANES III from 13,198 employed adults 20 years
and older, there was a significant, linear relationship
between number of alcoholic drinks per week and
log clinical attachment loss (P = 0.0001). Odds ratios
(95% confidence interval) for the risk of attachment
loss, using 5, 10, 15, and 20 alcoholic drinks per
week as cut-off points, were 1.22 (1.021.47), 1.39
(1.131.71), 1.54 (1.221.93), and 1.67 (1.252.23),
respectively. Further studies are necessary to
understand more fully the association between
alcohol consumption and periodontal disease.

Diabetes
Diabetes mellitus as a risk factor for periodontal
disease
Diabetes mellitus is a metabolic disorder that occurs
in several forms; however, all forms of diabetes
mellitus are characterized by hyperglycemia. The
abnormal glucose metabolism results from defects in
insulin action or in insulin production (or in both in
severe cases). In the USA in 2010, diabetes mellitus
was estimated to affect 8.3% of the entire population,
or 25.8 million people, of whom about 7 million are
undiagnosed (46). The prevalence of diabetes increases sharply after age 45. For example, among
seniors over 65 years of age, the prevalence of diabetes is about 27%. Diabetes is a growing public
health concern globally and leads to significant
mortality and morbidity associated with its major
complications, such as cardiovascular disease and
end-stage renal disease. Diabetes is also the leading
cause of loss of limbs and new cases of blindness in
the USA (46). Diabetes mellitus and periodontal disease are both chronic, common diseases in the
population, especially in those over 65 years of age,
and are related.
Two-way relationship between diabetes and periodontal disease. For decades, it has been suspected that
diabetes contributes to poorer oral health because
more people with diabetes have periodontal infections than do those without diabetes. In the late
1990s, evidence that periodontal infection could

66

adversely affect glycemic control in patients with

diabetes was presented (84, 270). Because the interrelationship between diabetes and periodontal
disease applies in both directions it is called a bidirectional (two-way) relationship (154, 271). As this
review concerns risk factors that influence or cause
periodontal disease, the effects of diabetes on periodontal disease will be described. Only a brief
description of the evidence for the effects of periodontal disease on diabetes will be provided. But
because of the importance of dental care professionals in potentially breaking the vicious cycle of the
two conditions mutually having adverse effects on
each other, the effect of periodontal treatment in
controlling diabetes will be discussed.
Cross-sectional studies. The relationship between
diabetes and periodontitis has appeared in the literature for over 70 years. However, the data were conflicting and confusing. Clarification of these conflicting data has been based mainly on a large study of the
Pima Indians, who have an extremely high prevalence
of type 2 diabetes, of 4050% (71, 191, 251). It is clear,
from these studies, that the severity of periodontal
disease is higher in individuals with mostly uncontrolled diabetes than in those with no diabetes
from the same population (Fig. 3). Also, the severity
of periodontitis is greater in all age groups among
those with diabetes and increases with age.
Numerous studies in various other populations
have shown higher prevalence and severity of periodontal disease in patients with type 1 (107) as well
as type 2 diabetes, especially in certain subgroups,
such as African Americans (80, 273), compared with
people without diabetes. Chavarry and coworkers
(49) carried out a systematic review of these studies.
5

Mean Clinical
Attachment Loss (mm)

improving their oral health as well as their overall

health.

Diabetes
3

No Diabetes
1

1524

2534

3544

4554

Age (years)

Fig. 3. Severity of periodontal disease among diabetic and

nondiabetic Pima Indians. Adapted from Emrich et al. (71).

Risk factors for periodontal diseases

Meta-analyses indicated a statistically significantly

higher mean clinical attachment loss of 1 mm (95%
confidence interval: 0.151.84; P = 0.021) and a
greater mean periodontal probing depth of 0.46 mm
(95% confidence interval: 0.010.91; P = 0.046) in
individuals suffering from type 2 diabetes mellitus
compared with control subjects. Important case
control studies of children and adolescents with type
1 diabetes showed that periodontal disease was more
prevalent and severe in subjects with type 1 diabetes,
especially in those 1218 years of age (51, 149151).
Longitudinal studies. A two-year follow-up radiographic study of Pima Indians with type 2 diabetes
demonstrated that poorer glycemic control leads to
both an increased risk for alveolar bone loss and
more severe progression of periodontal disease than
among those without type 2 diabetes. Additionally, it
was shown that there may be a gradient, with less risk
for bone-loss progression for those with better controlled type 2 diabetes mellitus than for those with
poor control (272). Overall, however, there was an
increased rate of alveolar bone-loss progression in
individuals with type 2 diabetes compared with those
without diabetes.
Two important longitudinal studies were not included in the review by Chavarry and co-workers (49)
and the results of both support the findings of accelerated periodontal disease in patients with diabetes.
Nelson and colleagues (191) reported an adjusted relative risk of incident (i.e., development of new cases)
periodontal disease of 2.6 (95% confidence interval:
1.06.6) in patients with type 2 diabetes compared with
people without diabetes. This study also showed that
diabetes mellitus precedes periodontal disease, a finding supporting causality (191). The second longitudinal
study, carried out in African Americans with type 2
diabetes mellitus, showed an accelerated progression
of periodontal disease in patients with poor metabolic
control (glycated hemoglobin 7%) compared with
patients who had good metabolic control (24).
Prediabetes (impaired fasting glucose or glucose
intolerance) as a risk factor for periodontal disease
Of the 8.3% of US adults who have manifest diabetes mellitus (46), over one-quarter are undiagnosed. In addition, about 30% of the adult population has prediabetes or alternatively termed, are at
high risk for diabetes, as measured by elevated
glycated hemoglobin, impaired fasting glucose or
impaired glucose tolerance. Prediabetes often leads
to diabetes and is associated with major risk factors
for cardiovascular disease and other diabetic com-

plications (53). Thus, an astounding 38% of the US

population 20 years of age suffers from diabetes or
prediabetes.
A series of studies show that the prevalence of
periodontal disease is increased in patients with prediabetes. For example, in an age- and sex-matched
casecontrol study, subjects with prediabetes had
moderate periodontal disease. All study subjects were
between 50 and 60 years of age and systemically
healthy, according to their medical history (164). Despite not having diabetes, the blood glucose levels
were significantly higher in those with prediabetes
than in the controls (85 25 mg dl vs. 73 17 mg dl;
P < 0.02). Similar findings were reported from a crosssectional study of 815 male military personnel (mean
age 38.17.0 years) who did not have diabetes (300). A
total of 55 (6.7%) had alveolar bone loss of 6 mm,
with a statistically significant higher prevalence
among individuals with impaired fasting glucose
(100 mg dl, but <126 mg dl) than among individuals without impaired fasting glucose (P = 0.032).
Among 535 adult dental patients who had at least
one self-reported risk factor for diabetes, but had never
been told that they had prediabetes or diabetes, more
than one-third (36.0%) had abnormally high glucose
levels (152). In those with hyperglycemia, a larger
proportion of sites had pathologic probing depths
(5 mm) than in subjects with normal glucose levels
(14% vs. 9%). Also, more teeth were missing in patients with hyperglycemia than in subjects with normal glucose levels (nine teeth vs. six teeth).
In NHANES III, participants who had never been
told that they have diabetes, and individuals with a
self-reported family history of diabetes, hypertension,
high cholesterol levels and clinical evidence of periodontal disease have a probability of 2753% of
having undiagnosed diabetes or prediabetes (38).
Of 962 Uygur adults (mean age standard deviation = 48.9 13.7 years) from Xinjiang, China, 47.1%
had periodontitis, 9.5% had type 2 diabetes and
11.4% had impaired fasting glucose (i.e., more than
one in five of those with periodontitis also suffered
from hyperglycemia) (18). In those with impaired
fasting glucose, 71.3% had periodontitis, about the
same prevalence of periodontitis as in those with
manifest diabetes (75.6%).
Two-directional (reciprocal) relationships are
suggested in two cross-sectional studies, carried out
by Katz and colleagues, in the same population of
10,590 military servicemen and servicewomen in
Israel (131, 132). Those with abnormally high bloodglucose levels were significantly more likely to have
severe periodontal conditions (132). Periodontal

67

Genco & Borgnakke

conditions were assessed using the World Health

Organizations Community Periodontal Index of
Treatment Needs as a proxy for periodontal health
status (5). The Community Periodontal Index score
for an individual is the highest of the scores for each
dental sextant. Moreover, there was a significant
association between elevated blood-glucose levels
(120 mg dl) and severe periodontal conditions.
Compared with those with normal glucose levels,
participants with hyperglycemia had more than
double the risk (odds ratio = 2.46) for having severe
periodontal conditions (131). Thus, Katz concludes:
The present study supports the existence of a twoway relationship between periodontal disease and
elevated glucose level in a large population (131).
In a study using a cross-sectional, retrospective
cohort design, the current data were supplemented
with knowledge of the cohorts glycemic control status, but not periodontal status, 10 years earlier (232).
Significant associations were found between deep
pockets and impaired glucose tolerance. The findings
from these studies suggest that people who do not
suffer from diabetes, but have abnormally high blood
glucose levels (prediabetes), may be at increased risk
for periodontal disease.
This question of the effect of glycemia on periodontal disease was addressed in a longitudinal study
in 30- to 69-year-old Japanese employees (183).
Among 5,856 individuals without any periodontal
pockets of 4 mm at baseline, those with a baseline
glycated hemoglobin level of 6.5% had a 17% higher
risk of developing such pathologic pockets after
5 years than did those with a baseline glycated
hemoglobin level of <6.5% (P = 0.038). This difference was seen after controlling for confounders,
including age, gender, smoking, and body mass index. This longitudinal study confirmed that the incidence of periodontal disease was associated with
elevated baseline levels of glycated hemoglobin (183).
In conclusion, there is evidence for hyperglycemia
(elevated glucose level) being a risk factor for developing periodontal disease.
Gestational diabetes as a risk factor for periodontal
disease
Several studies using different analysis methodologies
show a strong relationship between gestational diabetes and periodontal disease. Two studies report on
the NHANES III data from over 4,000 women in the
USA. One report included women 1544 years of age
(n = 4,490) (296) and the other report included
women 2059 years of age (n = 4,244) (202). In both
reports, women with a history of gestational diabetes

68

had a higher risk of having periodontal disease. One

study found the prevalence of periodontitis to be
30.5% among women with a history of gestational
diabetes vs. 4.8% for those without any history of any
form of diabetes (202). The other study found that in
pregnant women, the prevalence of periodontitis was
44.8% in those with gestational diabetes vs. 13.2% in
those with no evidence of diabetes. In nonpregnant
women, the prevalence of periodontitis was 40.3% in
those with type 1 or type 2 diabetes, 25.0% in those
with a history of gestational diabetes and 13.9% in
those without diabetes, and the differences were statistically significant. In a casecontrol study, periodontitis was found in 77.4% of women with gestational diabetes and in 57.5% of women without
gestational diabetes, with an adjusted odds ratio of 2.6
(95% confidence interval: 1.16.1) (297). It is important to note that nonsurgical periodontal treatment of
pregnant women is probably safe for both the mother
and the child (177, 193), and hence management of
periodontal disease during pregnancy may be an option to modify the increased risk of worsening periodontal disease in pregnant women.
Effects of periodontal disease on the incidence
(initiation of new cases) of diabetes mellitus
Four longitudinal studies evaluated the effects of
periodontal disease on the future development of
type 2 diabetes. Analyses of data from NHANES I
found that baseline periodontal disease independently predicts incident diabetes over a mean of
17 years of follow-up (61). Comparisons were made
for 9,296 (7,168 dentate) 25- to 74-year-old participants who did not have diabetes at baseline in 1971
1976 and their follow-up in 19821992. Nine per cent
developed diabetes. Compared with those with no or
mild periodontitis, individuals with increasingly
more severe periodontitis had odds ratios of developing diabetes of 1.50 (95% confidence interval:
0.992.27), 1.71 (95% confidence interval: 1.02.69)
and 2.26 (95% confidence interval: 1.563.27). Additionally, dentate participants missing 2531 teeth had
a 70% higher risk of developing diabetes (odds ratio = 1.70; P < 0.05) relative to those with 08 teeth
missing (61). These results were adjusted for confounders, including age, gender, obesity, and smoking, and the results were statistically significant.
Hence, it is suggested that periodontal health is an
independent risk factor for the development of type 2
diabetes. Consistent with this study is a German
population-based cohort study (60), including 2,973
initially diabetes-free participants of 2081 years of
age. This study found that those with the highest level

Risk factors for periodontal diseases

Table 1. Effect of nonsurgical periodontal treatment on glycemic control in people with type 2 diabetes: a summary
of four meta-analyses.
Author
(Reference Number)

Janket et al. (122)

Darre et al. (58)

Diabetes Pooled
Glycated
95% confidence
No. of
No. of
type
n
hemoglobin
interval for
studies randomized
change
change
analyzed controlled
trials
5

1*

2
2

264

)0.66%

)2.2; 0.9

n.s.#

485

)0.46%

)0.82; )0.11

0.01

Teeuw et al. (274)

180

)0.40%

)0.77; )0.04

0.03

Simpson et al. (255) (Cochrane review)

244

)0.40%

)0.78; )0.01

0.04

*Nonrandomized controlled trials were clinical controlled trials.

Standardized mean difference.
#n.s.: Not significant.

of baseline periodontal disease experienced a fivefold

increase in glycated hemoglobin level 5 years later
when compared with those with the lowest level of
periodontal disease. Similar findings were reported
among Japanese 40-79 years old employees at 10
years follow-up (232).
In contrast, a 7-year study of 5,848 Japanese individuals without diabetes mellitus at baseline, found
no statistically significant association of incident
diabetes with periodontal disease (118). However, the
major shortcomings of this study were that the participants were young Japanese with an average age of
43 years (range: 3059 years). Furthermore, they were
classified as no, moderate (Community Periodontal
Index = 3) or severe (Community Periodontal Index = 4) periodontitis, using the 1982 Community
Periodontal Index of Treatment Needs (5) only as a
proxy indicator for periodontal disease (118). Finally,
there may be a difference related to race and ethnic
group studied. Hence, the effect of pre-existing
periodontal disease on the development of incident
diabetes is unclear, and further studies of this
important question are needed.
Periodontal treatment and glycemic control
Several meta-analyses have been published of the
effects on glycemic control of nonsurgical periodontal treatment in people with type 2 diabetes
(58, 122, 255, 274). Their results are displayed in
Table 1.
Despite the variation in the studies included, the
results of the meta-analyses are remarkably similar,
with a significant decrease in glycated hemoglobin level of 0.40.7% in the periodontally treated group. The
Cochrane reviewers conclude that there is evidence of
improvement in glycemic metabolic control in people
with type 2 diabetes after treating periodontal disease.

They also noted a lack of sufficient data for such an

effect in people with type 1 diabetes (255).
In summary, there is emerging evidence that periodontal treatment improves glycemic control in patients with type 2 diabetes, i.e., causes a significant
decrease in level of glycated hemoglobin, also referred to as glycosylated hemoglobin, hemoglobin
A1c, HbA1c, or simply A1c. However, there is no
consensus regarding such treatment in patients with
type 1 diabetes or the potential benefits of adjunct
local or systemic antibiotics. Improving periodontal
health is an important objective in itself. However, in
order to understand more fully the potential of
treatment to improve glycemic control among people
with diabetes, larger, carefully conducted and reported studies are needed, especially of type 1 diabetes.
Importance and clinical significance of reduction in
glycated hemoglobin levels
It is reasonable to hypothesize that treatment of
periodontal infections, with a subsequent reduction
of inflammation, could explain, in part, glycemic
control in patients with diabetes. This is based on
evidence that infection and inflammation can lead to
insulin resistance (112, 138, 252).
The importance of controlling hyperglycemia in
reducing especially the microvascular complications
of diabetes (retinopathy and nephropathy) is clear, as
demonstrated in The UK Prospective Diabetes Study
of Type 2 Diabetes (288). Over 10 years, an absolute
reduction of 0.9% in glycated hemoglobin, from 7.9%
to 7.0%, decreased diabetes-related deaths by 10%
and all-cause mortality by 6%. Furthermore, each
percentage point decrease in the level of glycated
hemoglobin, results in a reduction in risk of microvascular complications of about 35% (262). More-

69

Genco & Borgnakke

over, studies in the general population show an that

average reduction in glycated hemoglobin of 0.20% is
associated with a reduction in mortality of approximately 10% (136). Therefore, it is reasonable to expect that the reduction in glycated hemoglobin of
approximately 0.4%, found to be associated with
nonsurgical periodontal treatment in patients with
diabetes, has clinically significant effects on systemic
health, especially in patients with poorly controlled
diabetes. This, of course, has to be studied.
Remaining questions include the following. What
is the effect of the pretreatment levels of glycated
hemoglobin? Is the reduction found only in patients
with severe periodontitis, maybe only in patients with
severely uncontrolled diabetes or maybe only in patients with type 2 diabetes? What is the effect of
treatment of gingivitis? To what extent does periodontal disease need to be resolved before a glycated
hemoglobin effect is seen? Also, in those studies
where systemic antibiotics are used, there is a question of whether the systemic antibiotics have affected
other infections as well as periodontal disease, and to
what extent does that result in reduction of glycated
hemoglobin? Therefore, trials of the effect of periodontal therapy on diabetic complications and
overall mortality are needed and justified.
It should also be pointed out that in randomized
controlled trials of periodontal intervention, there
may be a Hawthorne effect (40) (i.e., an effect of
enrollment in the study that would encourage the
patient to seek more intense medical care and in
general be more attentive to his or her conditions
and diseases). In fact, a differential Hawthorne effect
seems to have occurred in the study by Jones et al.
(129), where, after therapy, the patients in the control
arm had increased use of insulin compared with
patients in the test arm, although the insulin use in
both arms was comparable immediately after randomization. In this study, there was a reduction of
glycated hemoglobin, at 4 months, of 0.65% in the
intervention group and of 0.51% in the control
group. The difference between the two groups was
not statistically significant, although the difference
between baseline and 4 months was statistically
different in both treatment and control arms,
respectively.
The increased hyperglycemia associated with
periodontal disease in patients with diabetes, and the
reduction in glycated hemoglobin found after periodontal treatment, suggest that control of periodontal infection is not only important for oral health, but
may also improve the overall health of patients with
diabetes.

70

Mechanisms
Mechanisms to explain the role of diabetes mellitus in
periodontitis. Inflammation is a central feature of
both diabetes and periodontal disease, and inflammatory processes are up-regulated in the periodontal tissues of patients with diabetes. The levels of
interleukin-1b and prostaglandin E2 are higher in
the gingival fluid of patients with type 1 diabetes
than in the gingival fluid of diabetes free individuals
with the same level of periodontal disease (235).
Similar findings were made in patients with type 2
diabetes, where elevated concentrations of interleukin-1b in the gingival crevicular fluid were correlated with elevated levels of glycated hemoglobin
and periodontitis (74). In addition, monocytes from
patients with type 1 diabetes produce significantly
higher levels of tumor necrosis factor-a, interleukin1b and prostaglandin E2 compared with monocytes
from nondiabetic individuals (74, 234, 235). Both
type 1 and type 2 diabetes mellitus are also associated with elevated levels of systemic markers of
inflammation (56). Many of the complications of
diabetes may be associated with elevation of
inflammatory pathways. Hyperglycemia can result
in increased inflammation, oxidative stress, and
apoptosis, and hence contribute to enhanced periodontal destruction (45).
Another line of evidence suggests that a hyperreactive inflammatory response to bacterial challenge
is responsible for enhanced severity of periodontal
disease in patients with diabetes mellitus. For
example, in the gingival tissue of mice with diabetes
mellitus, vascular permeability is increased and
neutrophils exhibit impaired chemotaxis, both of
which can lead to more severe periodontitis given a
similar bacterial challenge (96, 253).
It does not appear that the microbial flora of people with diabetes differs markedly from the microbial
flora of those with no diabetes (79, 201, 242, 280, 302).
However, definitive studies of the composition of the
microbial flora by deep sequencing of the oral microbiomes of these two conditions using emerging
technologies that can identify and quantify the entire
microbiome associated with periodontal disease are
necessary.
The increased levels of proinflammatory mediators
in patients with diabetes contribute to more severe
periodontal disease, and the elevated levels of proinflammatory mediators associated with periodontal
disease contribute to poor diabetes metabolic control, probably explaining, in part, the bidirectional
relationship of these two diseases.

Risk factors for periodontal diseases

Role of advanced glycation end-products and of

receptors for advanced glycation end-products. The
receptors for advanced glycation end-products are
elevated in patients with diabetes. This is important
because the interaction of these receptors with advanced glycation end-products, which are elevated in
patients with diabetes, plays a role in the development of diabetic complications such as cardiovascular disease and kidney disease (298). In humans,
the levels of advanced glycation end-products in
serum are also associated with the extent of periodontitis in adults with type 2 diabetes mellitus (268).
In a mouse model of infection with P. gingivalis,
diabetic animals exhibit increased expression of
receptors for advanced glycation end-products, and
subsequent treatment with soluble receptors for advanced glycation end-products decreased the levels
of cytokines, such as interleukin-6 and tumor
necrosis factor-a, in gingival tissues, and suppressed
alveolar bone loss in a dose-dependent manner (153).
Hence, there is strong evidence for a role of advanced
glycation end-products and receptors for advanced
glycation end-products in the exaggerated inflammatory response to bacterial challenge and subsequent
tissue destruction seen in patients with diabetes who
also suffer from periodontal disease.
Alteration and capacity for repair in periodontitis
associated with diabetes. Patients with diabetes have
increased apoptosis, which is associated with delayed
wound healing (57). It is likely that apoptosis plays a
role in the increased severity of periodontitis in patients with diabetes. For example, in diabetic mice
infected with P. gingivalis, fibroblast apoptosis was
significantly increased compared with nondiabetic
mice (157). Hence, periodontal organisms interfere
with the capacity for repair in inflamed periodontal
tissues in patients with diabetes by enhancing the
death of matrix-producing cells.
Altered native immune responses in patients with
diabetes. Patients with diabetes have been shown to
have impaired neutrophil chemotaxis (95, 190). Patients with type 2 diabetes have also been shown to
have impaired neutrophil adherence and phagocytosis (23, 170). In a study of patients with severe
periodontitis it was found that patients with diabetes
and severe periodontitis have depressed neutrophil
chemotaxis compared with nondiabetic subjects with
periodontitis or with diabetic subjects with mild
periodontitis (33, 167). Furthermore, diabetes may
lead to increased severity of periodontal disease as a
result of defective neutrophil apoptosis (90, 275).

This, in turn, could lead to increased retention of

neutrophils in the periodontium, resulting in increased tissue destruction as a result of the release of
reactive oxygen species and histiolytic enzymes from
neutrophils.
Effects of periodontitis on the levels of glycated
hemoglobin and on diabetes complications: possible
mechanisms. Periodontitis increases the levels of
proinflammatory and prothrombotic mediators in
serum (135, 161). Hence, it is possible that systemic
inflammation associated with the local inflammatory
response triggered by periodontal microflora leads to
insulin resistance. For example, tumor necrosis factor-a, which is elevated in the plasma of patients with
periodontitis (73), is known to promote insulin
resistance by interfering with insulin signaling (1, 94,
111, 216). Periodontal therapy appears to be able to
reduce systemic inflammatory mediators, such as Creactive protein, tumor necrosis factor-a, interleukin6, and others, as well as to increase adiponectins in
individuals with diabetes (52, 172, 203, 263). The
reduction of these inflammatory mediators by periodontal treatment may result in increased insulin
sensitivity with improved control of glycated hemoglobin. In turn, this improvement in glycated hemoglobin can lead to a reduction in the complications of
diabetes mellitus that are associated with periodontitis, including cardiovascular and renal complications (237). However, there is as yet little or no
evidence that treatment of periodontal disease has an
effect on the complications of diabetes, although as
noted above, there is mounting evidence that periodontal treatment will result in a reduction of glycated hemoglobin in patients with poorly controlled
diabetes and that the level of reduction may be
clinically significant.
Conclusions regarding diabetes and periodontal
disease
Considerable evidence has been presented to support
the concept that diabetes mellitus (types 1 and 2, and
gestational) is a risk factor for periodontitis by
increasing the prevalence, severity, extent, progression, and possibly the initiation (incidence) of periodontal disease. There is also evidence that worsened
glycemic control is associated with more periodontal
disease, and that diabetes patients with good glycemic control may suffer from little or no periodontal
disease. It appears that this is a bidirectional relationship (i.e., patients with periodontal disease and
diabetes mellitus suffer from worsened glycemic
control as evidenced by elevated glycated hemoglo-

71

Genco & Borgnakke

poses a serious risk to general health (294). Overweight and obesity have effects on general health,
including insulin resistance and a state of chronic
systemic inflammation (77, 141). Several chronic
diseases, including diabetes, cardiovascular disease,
and cancer that are major causes of death, are associated with overweight. Also, liver disease and gallbladder disease, as well as periodontal disease, are
associated with obesity (141).
The current age-adjusted prevalence of obesity in
US adults is estimated to be 36%, while obesity in US
children and adolescents is estimated to be 17.7%
(81). The prevalence of obesity has increased
between 1980 and 1990; however, it appears to be
plateauing in 2010. Although the trend in the USA
appears to be to stabilizing, the absolute rates are still
unacceptably high, with over one-third of the adult
population and almost one-fifth of children and
adolescents classified as obese. The prevalence of
obesity in other countries is also high, but in general,
not as high as in the USA. For example, it is 22.1% in
England (101) and appears to be plateauing. Similarly, studies of obesity in Sweden, Switzerland, and
Spain have also suggested a possible degree of plateauing, although the absolute rates are still high (75,
76, 83, 196).
The association of obesity with several chronic
diseases, including periodontal disease, has been
hypothesized to result from the chronic systemic
inflammation associated with obesity, affecting susceptibility to these diseases (77, 84, 218).

bin) and that patients with severe periodontitis and

diabetes mellitus suffer from more cardiorenal mortality and microalbuminuria than do patients with
diabetes who have little or no periodontal disease.
Evidence is accumulating that treatment of periodontal disease results in consistent reduction in
glycated hemoglobin in the short term. This is
probably a clinically significant reduction; however,
further studies are needed to determine the optimal
periodontal treatment and secondary prevention to
achieve and sustain better glycemic control. Finally,
studies are needed to determine if prevention or
treatment of periodontal disease will result in the
reduction of diabetes complications, such as cardiovascular disease and renal disease.
Given the increase in prevalence of diabetes in the
population, the dental care professionals may be of
great value in the management of periodontal disease
in patients with diabetes. Conversely, it is very
important for the dental team to be aware of diagnosed and undiagnosed diabetes and partner with
the medical team to identify and control diabetes
(152, 156), which in turn will help to reduce periodontal disease and possibly the other complications
of diabetes (273) and need for any medical care (117,
188, 273).

Obesity and metabolic syndrome

Obesity as a risk factor for periodontal disease
Obesity is an emerging major public health problem,
as the prevalence of obesity and overweight has trebled since the 1980s (295). Overweight and obesity
are defined by measures such as body mass index,
waist:hip ratio, waist circumference, body weight,
and body-weight changes. Abnormal or excessive fat
accumulation associated with overweight and obesity
Study
ID

Evidence for association of obesity with periodontal

disease. Numerous studies over the last decade show
an association of being overweight or obese with
increased levels of periodontitis, and available studies
are summarized in two recent systematic reviews
(48, 266). Suvan et al. (266) reviewed cross-sectional

(95% confidence %
Odds ratio interval) Weight

Buhlin 2003

(n = 96)

4.54 (1.59, 13.00) 9.58

Genco 2005

(n = 12,367)

1.48 (1.13, 1.93)

21.18

Nishida 2005

(n = 372)

3.17 (1.79, 5.61)

16.31

Saito 2005

(n = 584)

4.30 (2.10, 8.90)

13.87

Kushiyama 2009

(n = 1,070)

1.09 (0.77, 1.53)

20.09

Han 2009 (males)

(n = 96)

2.50 (0.85, 7.38)

9.27

Han 2009 (females)

(n = 102)

1.47 (0.52, 4.16)

9.70

2.13 (1.40, 3.26)

100.00

Overall (I2 = 73.0%, P < 0.001)

NOTE: Weights are from random effects analysis

Odds ratio

72

0.25

0.5

16

Fig. 4. Forest plot of studies of

periodontal disease in overweight
and obese subjects compared with
those with a normal body mass index. From Suvan et al. (266).

Risk factors for periodontal diseases

studies, most of which show greater severity and or

prevalence of periodontal disease in individuals who
are either overweight or obese. Figure 4 summarizes
seven studies and presents a Forest plot that compares the periodontal status of individuals who are
overweight and obese (based upon body mass index)
with those of normal weight (also based upon body
mass index). The overall odds ratio of having
periodontal disease in obese or overweight individuals is 2.13 (95% confidence interval: 1.403.26;
P < 0.0001) (266) (Fig. 4).
In another meta-analysis of 57 independent study
populations, an approximate increase of one-third in
the prevalence of obesity was found among subjects
with periodontal disease and a greater mean attachment loss was found among obese individuals (48).
Several studies show a dose response effect, relating
risk for periodontitis with increasing body mass index
(195). These odds ratios were adjusted for age,
gender, smoking, alcohol consumption, and frequency of toothbrushing. Hence, it appears from
the association studies that there is consistency in the
association of obesity with periodontal disease. The
strength of association is reasonable, with odds ratios
ranging from 1.88 to 4.40, and the dose response
is clear.
These cross-sectional studies are supported by results from two important, recent, longitudinal studies
of up to 40 years duration of men in the Veterans
Administration Dental Longitudinal Study. Not only
were both overall obesity and central adiposity associated with an increased hazard of periodontal
disease progression (88), but those who were overweight at baseline and gained weight most rapidly
had significantly more such progression (89). Other
recent longitudinal studies of the incidence of periodontal disease, as related to body mass (126, 184,
241) and waist:hip ratio (126), also support these

findings. The longitudinal study by Morita et al. (184)

shows a direct doseresponse relationship between
body mass index and the subsequent development of
periodontal disease in a population of Japanese
individuals (2,787 men and 803 women) followed
over 5 years (Table 2). Similar findings were reported
among 36,910 healthy males in the Health Professionals Follow-Up Study (HPFS) who were free of
periodontal disease at baseline and followed up to 20
years. Importantly, the associations were significant
even among individuals free of diabetes and never
smokers (126). A smaller study of 396 Finnish adults,
however, did not provide evidence for overweight and
obesity in the development of periodontal infections
(241). Clearly, more longitudinal studies are necessary before the temporal sequence of obesity and
periodontal disease can be definitively clarified.
Mechanisms by which obesity may lead to increased
periodontal disease. There are few studies of the oral
microbiome in obese and nonobese subjects. Haffajee & Socransky (98) compared periodontally healthy
and gingivitis subjects with chronic periodontitis
subjects. They found that the numbers of T. forsythia
were significantly higher in obese individuals suffering from gingivitis, but who were otherwise periodontally healthy, compared with the other groups.
They hypothesized that overgrowth of T. forsythia
may occur in periodontally healthy individuals who
are obese, putting them at risk for the initiation and
progression of periodontitis.
In another study, Goodson et al. (87) found that in
the saliva of overweight women, Selenomonas noxia
was present at higher levels than in nonobese women. The relationship to periodontal disease was not
described in this study; however, the study may
provide a clue as to the possible effect of the
endogenous oral flora in obesity.

Table 2. Risk of developing new periodontal disease during 5 years in men and women by body mass index.
Men (N = 2,787)

Women (N = 803)

Adjusted
hazard
ratio

95%
confidence
interval

Adjusted
hazard
ratio

95%
confidence
interval

Reference

Reference

Reference

Reference

22 to <25

1.04

0.901.21

0.575

1.19

0.881.62

0.264

25 to <30

1.30

1.111.53

0.002

1.70

1.152.55

0.007

>30

1.44

0.972.14

0.072

3.24

1.327.94

0.010

Body mass
index
<22

*From Morita et al. (184).

Adjusted for age, smoking status, and diabetes mellitus.

73

Genco & Borgnakke

Further studies of the oral and gut microbiome in

overweight and obese subjects compared with normal-weight individuals, with and without periodontal
disease, are needed to fully understand the extent to
which differences in these flora can explain the increased periodontal disease in obese individuals
(115).
Role of the immune and inflammatory response in
periodontal disease seen in obese and overweight
individuals. Some studies suggest that obese individuals develop infections of various types (including
postoperative and nosocomial infections) more often
than do people of normal weight (77). The mechanisms by which obese people are predisposed to
infection include the participation of adipose tissue
in inflammation and immunity. A variety of proinflammatory and anti-inflammatory factors are produced by adipose tissue (78).
A heightened inflammatory response is regularly
observed in individuals in who are obese (252). The
adipocytes in centrally located adipose tissue act as
critical sites for the generation of inflammatory responses and mediators. In addition, careful examination of adipose tissue during obesity reveals the
presence of increased numbers of macrophages,
which may also contribute to the inflammatory
mediators produced by adipose tissue (110). Demonstration of increased inflammatory mediators in
patients with periodontal disease, with and without
obesity, comes from at least two human studies (84,
233). In the study by Genco et al. (84), 1,221 individuals were categorized as having a high body mass
index or a low body mass index, with and without
periodontal disease. The levels of tumor necrosis
factor-a and soluble tumor necrosis factor-a receptor
1 and receptor 2 were assessed and it was found that
overweight individuals had elevated levels of soluble
tumor necrosis factor-a receptor 1 and receptor 2.
They also found that individuals who were lean but
suffered from periodontal disease had elevated levels
of these mediators. In addition, obese subjects with
high insulin resistance appeared to have the most
severe periodontitis, suggesting that proinflammatory mediators produced by adipose tissue and
or periodontal inflammation may contribute to
insulin resistance. Recently, Saxlin and collaborators
(240, 241) demonstrated associations between obesity, serum lipid levels, and the cytokines tumor necrosis factor-a and interleukin-6. Physical activity
may protect against excessive inflammatory response
in periodontitis by decreasing the risk of elevated
interleukin-1 and C-reactive protein (236). In the

74

study by Saito et al. (233), adiponectin was found to

be increased in middle-aged Japanese with periodontitis. These changes also occur in obesity.
The findings in humans are supported by a study of
obese Zucker rats and their lean littermates (72).
Periodontal disease was induced, and the level of
tumor necrosis factor-a was found to be significantly
higher in the periodontitis and obesity group of rats
compared with the control group. It was concluded
that systemic low-grade inflammation combined
with increased gene expression for hepatic levels of
tumor necrosis factor-a and C-reactive protein, and
elevated adipose interleukin-6 and C-reactive protein
in obese rats, combined to make the obese rats more
susceptible to periodontal disease. In a study of dietinduced obesity in mice, impaired immune response
to P. gingivalis infection was found (12). The authors
suggested that this immune dysregulation leads to
increased alveolar bone loss after uncontrolled bacterial infection in obese mice.
In the first such human study, by Perri et al. (212),
microRNA from gingival biopsies was compared
among obese and nonobese subjects, with and
without periodontal disease. They found that specific
microRNA species were observed in obese subjects,
which could modulate cytokine mRNA (messenger
RNA). These epigenetic changes may very well
modify periodontal inflammation, increasing the
susceptibility of obese individuals to periodontal
disease.
There is evidence suggesting that changes in the
proinflammatory and immune responses associated
with obesity may contribute to their increased susceptibility to periodontal disease. However, the specific molecular and cellular mechanisms are not yet
clear and further studies are needed to unravel the
mechanisms, which may provide targets for prevention or treatment.
Metabolic syndrome as a risk factor for periodontal
disease
Metabolic syndrome is a cluster of disorders,
including increased blood pressure, elevated plasma
glucose, excess body fat around the waist and
abdominal area, and altered cholesterol levels, which
occur in certain individuals. Metabolic syndrome
increases the risk of heart disease, stroke, and diabetes. Having metabolic syndrome is defined as
having three or more of these disorders related to an
individuals metabolism at the same time. Obesity in
this context is defined as a waist circumference of 40
(100 cm) or more in men and 35 (90 cm) or more
in women in the US Caucasian population. The cir-

Risk factors for periodontal diseases

cumference cut-off can vary by race. Increased blood

pressure is defined as a systolic pressure measurement of 130 mmHg, and a diastolic pressure of
85 mmHg. Elevated blood glucose is defined as a
fasting blood glucose level of 100 mg dl but
<126 mg dl. The altered blood lipid levels are defined as levels of triglycerides of 150 mg dl and or
a level of high-density lipoprotein of <40 mg dl for
men or <50 mg dl for women.
The cause of metabolic syndrome, although not
completely known, appears to be associated with
insulin resistance. Risk factors for metabolic syndrome include age, race, obesity, a history of diabetes
and other diseases, including hypertension, cardiovascular disease and polycystic ovary syndrome.
Metabolic syndrome itself is an important risk factor
for type 2 diabetes and cardiovascular disease, and it
increases total mortality (93). Other complications
include kidney disease, nonalcoholic fatty liver disease, peripheral artery disease, and stroke (9, 229).
There is recent concern on whether metabolic
syndrome, as a whole, predicts clinical outcomes,
such as atheromatous disease or type 2 diabetes,
more than is predicted by the effects of its components (9, 254).
Evidence for the association of metabolic syndrome
with periodontal disease. Several cross-sectional
studies demonstrate an association of periodontal
disease with metabolic syndrome. One of the first
studies by Shimazaki and coworkers (249), of 984
Japanese women, showed that metabolic syndrome
increases the risk of periodontitis. They examined the
relationship between periodontitis and five components of metabolic syndrome, including abdominal
obesity, triglyceride level, high-density lipoprotein
cholesterol level, blood pressure, and fasting plasma
glucose. The odds ratio for subjects who had four or
five of these components was 6.6 (95% confidence
interval: 2.616.4) for greater pocket depth. Highdensity lipoprotein cholesterol and fasting plasma
glucose had the highest effects of the five components.
There is also some evidence for a greater prevalence of metabolic syndrome in individuals with
periodontitis. A study of Brazilians of Japanese descent (37) found that the prevalence of metabolic
syndrome was 54.3% in patients with periodontitis
compared with a prevalence of metabolic syndrome
of 48.8% in those who had little or no periodontitis.
This difference was not found to be statistically significant, however.
In a study of the US population from the NHANES
III database, DAiuto et al. (55) found that severe

periodontitis was associated with the metabolic syndrome in middle-aged individuals. The prevalence of
metabolic syndrome was 18% (95% confidence
interval: 1619) in subjects with no or mild periodontitis, compared with 37% (95% confidence
interval: 2848) in subjects with severe periodontitis.
After adjusting for confounders, individuals 45 years
of age suffering from periodontits were 2.3 times more
likely to have metabolic syndrome than were individuals with little or no periodontal disease (95%
confidence interval: 1.134.47). Figure 5 shows the
association of gingival bleeding and pockets with each
of the five components of metabolic syndrome, and it
can be seen that both gingival disease measures are

A
Metabolic
syndrome
Obesity
High triglycerides
Low high-density
lipoprotein cholesterol
Hypertension
High glucose

1.00

1.10

1.20

1.30

B
Metabolic
syndrome
Obesity
High triglycerides
Low high-density
lipoprotein cholesterol
Hypertension
High glucose

1.00

1.10

1.20

1.30

1.40

Fig. 5. Odds ratios for having metabolic syndrome overall

and for each individual component, respectively, in groups
with two clinical measures of periodontal disease: (A) Gingival Bleeding and (B) Gingival Pockets. Odds ratios are
marked as boxes with their 95% confidence interval indicated as horizontal lines. The odds ratios are adjusted for
age, sex, years of education, poverty ratio, ethnicity, general
conditions, and smoking. Odds ratios for having metabolic
syndrome overall show increases of 12% and 13% in the
two groups, respectively: (A) 1.12 (95% confidence interval
1.071.18, P < 0.001); (B) 1.13 (95% confidence interval
1.031.24, P < 0.05). From DAiuto et al. (55).

75

Genco & Borgnakke

associated with elevated risks for having metabolic

syndrome overall, as well as with each of its components, although the risk of having high triglycerides is
not statistically significant. The latter finding is in
accord with a large Finnish population study that
suggested the association between body weight and
periodontal infection was mainly mediated through a
mechanism other than serum lipids (239). A limitation of using NHANES data is that many other factors,
including genetics and oral hygiene, were not assessed and the strong effects of smoking may not have
been adequately controlled. A second analysis of the
NHANES III study by Andriankaja et al. (14) analyzed
data from the same survey, but calculated odds ratios
for the opposite direction, finding that those with
metabolic syndrome were more likely to have periodontitis after adjustment for possible confounders.
Other cross-sectional studies also showed a positive
association of periodontitis with metabolic syndrome.
Increased periodontal disease in subjects with metabolic syndrome was seen in a study of 2,478 adult
employees of a single Japanese company (185) and in
another study of 1,070 Japanese individuals, 40
70 years of age (147). In addition, a study of 112 men
and 78 women in the USA found greater alveolar bone
loss in those with metabolic syndrome compared with
those who did not have metabolic syndrome (192). A
study of 2,050 individuals, 3064 years of age, from
Finland shows not only an association of metabolic
syndrome with greater periodontal disease, but also a
greater number of carious teeth in those with metabolic syndrome (281).

It appears then that evidence exists from studies

conducted in different countries, such as the USA,
Japan, Brazil, and Finland and the majority
demonstrates an association of periodontal disease
and metabolic syndrome. Most studies found a
greater risk for periodontal disease in those with
metabolic syndrome. The studies are summarized in
Table 3.
Because the studies summarized in Table 3 are
cross-sectional, a temporal sequence cannot be
determined. However, a longitudinal study by Morita
and coworkers (186) shows that periodontal disease
affects the components of the metabolic syndrome.
The odds ratios (95% confidence interval) were: 1.7
(1.03.0; P < 0.05) for obesity; 1.5 (1.02.3; P < 0.05)
for hypertension; 1.9 (1.13.2; P < 0.05) for lipid
abnormality; and 1.4 (1.02.1) for hyperglycemia.
There appears then to be a reciprocal relationship
between periodontal disease and metabolic syndrome; however confirmatory studies in other populations, and studies to explain the mechanisms of
these effects, are needed.
There is also an unanswered question of which of
the multiple components of metabolic syndrome are
more strongly associated with periodontal disease. It
is reasonable to expect that obesity and diabetes or
prediabetes would affect periodontal disease as there
is strong, independent evidence for the association of
both factors with a greater risk for periodontal disease. However, although the roles of elevated blood
pressure, dyslipidemia involving elevated triglycerides, and lower high-density lipoprotein cholesterol,

Table 3. Cross-sectional, epidemiologic studies evaluating the risk for periodontal disease in people with metabolic
syndrome.
Author (Reference Number)

Population (n)

Odds ratio (95% confidence interval) for greater risk for

periodontitis

Shimazaki et al. (249)

Japanese women (585)

6.5 (2.616.4) in those with four or five components

DAiuto et al. (55)

US NHANES III (13,994)

2.31 (1.134.73) in those with metabolic syndrome

Morita et al. (185)

Japanese (2,478)

1.8 (1.42.3) with two metabolic syndrome components

2.4 (1.72.7) with three or four metabolic syndrome
components

Kushiyama et al. (147)

Japanese (1,070)

2.13 (1.223.70) with three metabolic syndrome components

2.34 (1.085.08) with four or five metabolic syndrome
components

Andriankaja et al. (14)

US NHANES III (7,431)

5.6 (2.214.4) for two or more components of metabolic

syndrome

Nesbitt et al. (192)

USA (112 men; 78 women)

2.61 (1.16.1) for alveolar bone loss

Timonen et al. (281)

Finnish (2,050)

1.50 (0.962.36) for pockets 6 mm

1.25 (0.931.70) for carious teeth

76

Risk factors for periodontal diseases

are of great interest, it is less clear as to how they may

affect periodontal disease.
Mechanisms to explain the association between periodontal disease and metabolic syndrome. There is a
heightened, chronic systemic inflammatory response
seen in subjects who have some of the components
that define metabolic syndrome, including subjects
with hyperglycemia, reduced high-density lipoprotein cholesterol and obesity. The cytokines elevated
in these conditions include interleukin-6, interleukin1b and the acute-phase proteins, C-reactive protein,
and fibrinogen. It may be, as suggested for patients
with diabetes, that the elevated systemic inflammatory response seen in individuals who are obese increases the destructive immunopathologic response
of these individuals to the periodontal microflora,
resulting in greater tissue destruction.
Intervention trials. Investigation of the effect of
periodontal therapy on one or another of the components or biomarkers in metabolic syndrome has
begun (125). Intervention to reduce the components
of metabolic syndrome in patients with both metabolic syndrome and periodontal disease resulted in
reduction of the concentration of interleukin-1b and
interleukin-6 in gingivo-crevicular fluid. There was
also a reduction in gingival inflammation and pocket
depth. It is unclear whether the changes were associated with diet, as this was an uncontrolled study. It
may well have been that the reduction in inflammation seen was caused by the placebo effect and that,
in turn, resulted in a reduction in proinflammatory
cytokines. A more recent study showed that with
periodontal therapy in patients who suffered from
metabolic syndrome and chronic periodontitis, there
was a significant decrease in C-reactive protein, total
leukocyte counts and serum triglycerides, concomitant with a rise in serum high-density lipoprotein (3).
These changes were seen only after periodontal
therapy in the group with metabolic syndrome, but
not in those of the control group who were systemically healthy.
A parallel-arm, double-blind, randomized clinical
trial of 1-year duration of patients with metabolic
syndrome and periodontitis found that the experimental treatment group who received root planing,
amoxicillin
and
metronidazole,
experienced
significantly greater improvement in periodontal
status compared with the control group (163).
Fibrinogen levels were significantly decreased in the
active treatment group at 12 months, but not in the
control group, while C-reactive protein was

decreased in both groups. The authors conclude that

reducing periodontal inflammation significantly reduces C-reactive protein levels, as well as fibrinogen,
in patients with metabolic syndrome suffering from
periodontal disease, with the potential to moderate
the effects of metabolic syndrome. It is clear that
more studies are needed to answer well-formulated
questions regarding the effect of periodontal therapy
on one or another of the components of metabolic
syndrome. In addition, if it turns out that metabolic
syndrome is indeed a risk factor for periodontal disease, or there is a two-way relationship, testing the
effects of intervention by modifying metabolic syndrome on the periodontal status is needed to justify
incorporation of modification of metabolic syndrome
as a goal of risk reduction for periodontal disease.

Osteoporosis, dietary calcium, and

vitamin D
Osteoporosis as a risk factors for periodontal
disease
Osteoporosis is a systemic disorder characterized by
reduced bone-mineral density throughout the skeletal system, including the jaws. Osteoporosis increases
the risk for fracture, particularly hip fractures, which
in the elderly doubles the risk of death in the first
12 years after fracture (2). Data from the NHANES III
estimate that 1318%, or 46 million, women have
osteoporosis, and another 3750%, or 1317 million,
have osteopenia (160). In men, the estimate is that 3
6%, or 12 million, have osteoporosis, and 2847%,
or 813 million, have osteopenia.
The main risk factor for osteoporosis in women is
menopause, which is associated with reduced estrogen production that results in increased bone
resorption (226). In addition, there is also a decrease in
calcium absorption and an increase in calcium
excretion, which increases the calcium requirement
(200). This process has a significant impact on mortality and morbidity. Also, because menopause is
associated with increased bone resorption, other disease processes that involve bone loss, including periodontal disease and tooth loss, are probably affected.
A systematic review of the relationship of osteoporosis to periodontitis, tooth loss, and mandibular
atrophy has recently been published by MartinezMaestre and coworkers (171). They report that most
studies showed that systemic osteoporosis was
associated with mandibular osteoporosis, and that
systemic osteoporosis was associated also with increased tooth loss. In addition, they report that the

77

Genco & Borgnakke

Table 4. Studies assessing the relationship between systemic bone loss and periodontitis.
Author (Reference Number)

Periodontal measurement

Systemic bone measurement

Correlation

Elders et al. (68)

Alveolar bone height

Dual-photon absorptiometry, L2L4,

metacarpal thickness

No

Klemetti et al. (139)

Community periodontal
index of treatment needs

Dual-energy X-ray absorptiometry

of spine and hip

No

Mohammad &
Brunsvold (180)

Clinical attachment loss

Dual-photon absorptiometry
of spine and hip

Yes

Hildebolt et al. (104)

Clinical attachment loss

Dual-energy X-ray absorptiometry

of spine and hip

No

Mohammad et al. (179)

Clinical attachment loss

Dual-energy X-ray absorptiometry

of spine and hip

Yes

Tezal et al. (277)

Clinical attachment loss

Alveolar crest height

Dual-energy X-ray absorptiometry

of lumbar spine and hip

No
Yes

Lundstrom et al. (165)

Alveolar crest height

Dual-energy X-ray absorptiometry

of hip

No

Mohammad et al. (181)

Clinical attachment loss

Dual-energy X-ray absorptiometry

of spine

Yes

Taguchi et al. (267)

Alveolar crest height

Dual-energy X-ray absorptiometry

of spine and femoral neck

No

Ishii et al. (119)

Alveolar crest height

Dual-energy X-ray absorptiometry

of femoral neck

No

Brennan et al. (43)

Clinical attachment loss

Dual-energy X-ray absorptiometry

of spine, hip and forearm

Yes

Brennan-Calanan
et al. (44)

Alveolar crest height

(<70 years)

Dual-energy X-ray absorptiometry

of spine, hip and forearm

Yes

Wactawski-Wende
et al. (292)

Alveolar crest height

Dual-energy X-ray absorptiometry

of spine, hip and forearm

Yes

Payne et al. (211)

Alveolar crest height

Dual-energy X-ray absorptiometry

Yes

Yoshihara et al. (299)

Clinical attachment loss

Dual-energy X-ray absorptiometry

No

*Adapted from Martinez-Maestre et al. (171) and Rios & Giannobile (227).

majority of studies showed that osteoporotic fracture

was associated with mandibular osteoporosis with
less strong evidence for associations of osteoporotic
fracture with tooth loss. Studies of the association of
osteoporosis with periodontitis are summarized in
Table 4.
In the 15 studies in Table 4, some assess periodontitis by measurements of alveolar crest height or
alveolar bone height, and others assess periodontitis
on the basis of clinical attachment loss. Approximately half of the studies that assessed periodontitis
on the basis of alveolar crest height or alveolar bone
height found a positive association with systemic
bone loss, while the other half found no correlation.
Similarly, of those studies that used clinical attachment loss to assess periodontitis, about half showed a
positive association with systemic bone loss.

78

These studies vary in size, periodontal measurement method, and also in the systemic bone measurement. Most use dual-energy X-ray absorptiometry of
the spine, but some use X-ray absorptiometry of the
femoral neck only, while others use metacarpal
thickness. Hence, the variability in these studies
could explain this lack of consensus. In spite of this
lack of consensus, there is suggestive evidence of an
association of osteoporosis and periodontal disease,
especially for the larger and better-controlled studies
in Table 4. Further studies with larger populations
and standardized measurements of systemic bone
and periodontal disease are needed to definitively
address the question of whether or not osteoporosis
is a risk factor for periodontal disease and, if so, to
what extent it contributes to the overall risk of periodontal disease.

Risk factors for periodontal diseases

An excellent overview of periodontal disease and

osteoporosis is found in Rios & Giannobile (227),
where the mechanisms of bone resorption functional
in osteoporosis, as well as the interaction with dietary
calcium, are outlined.
Dietary calcium and vitamin D as risk factors for
periodontal disease
The role of dietary calcium in periodontal disease has
also been studied and an inverse relationship was
found. Nishida et al. (194) reported from the NHANES
III data that individuals, especially women, with a low
intake of dietary calcium (less than half of the recommended dietary allowance, for example) had more
severe periodontal disease. The same was true for men,
but it was a more modest effect. Similar findings of low
dietary calcium intake being associated with greater
risk for and severity of periodontal disease were made
by Al-Zahrani (11) and Shimazaki et al. (250), although
the latter found effect only with intake of lactic acid
foods, such as yoghurt, not with milk.
Several studies show that calcium and vitamin D
supplements used to prevent or treat osteoporosis
also appear to have beneficial effects on tooth
retention (144). More recently, Miley et al. (178)
showed, in a randomized controlled trial over 5 years,
that subjects taking calcium and vitamin D lost fewer
teeth than subjects in the control group.
The effects of bisphosphonates, which are commonly used to treat osteoporosis, have been studied
for their ability to inhibit periodontal bone loss. In
one study (124), bisphosphonates were effective in
reducing alveolar bone loss in those patients who had
low baseline bone mineral density. Other studies also
show an effect of bisphosphonates in reducing alveolar bone loss (47, 173).
The association of bisphosphonates (especially
those administered intravenously) with oral osteonecrosis is a cause for concern and has dampened
enthusiasm for the use of bisphosphonates to manage periodontal disease. A meta-analysis of studies
describing the adverse effects of orally administered
antiresorptive agents estimates that the prevalence of
osteonecrosis of the jaw occurs in 0.1%; however, it
causes considerable morbidity and mortality when it
occurs. They conclude that a sound oral health program may be the optimal approach to lower the risk
of antiresorptive agent-induced osteonecrosis of the
jaw (103).
There appears to be limited evidence to indicate
that altered bone biology leading to osteoporosis has
effects on tooth loss and possibly periodontal status.
It also appears that there is no evidence to suggest

that osteoporotic patients with periodontitis should

be treated any differently from those who do not
suffer from osteoporosis. However, the negative role
of osteoporosis in risk for implant failure appears to
be clear.
Two studies of treatment with teriparatide (also
known as recombinant human parathyroid hormone), which stimulates osteoblasts, have shown this
agent to be effective in modulating periodontitis (25).
Studies with this and other bone-sparing agents used
in periodontitis may show that they are protective
against periodontitis, especially in target groups with
high levels of osteoporosis and osteopenia, such as
postmenopausal women.
In summary, further critical studies are needed to
unravel the mechanisms by which systemic osteoporosis, low dietary calcium, and low vitamin D levels
may influence periodontitis and associated tooth
loss. Meanwhile, knowledge of the dental patients
systemic bone health, as well as intake of calcium
and vitamin D, may be important in understanding
their periodontal status and provide direction for
modification of these factors.

Stress
Stress, distress, and coping skills as risk factors for
periodontal disease
The association of psychological stress with periodontal disease was postulated in early studies of
acute necrotizing ulcerative gingivitis (128). More
recently, many studies have addressed the role of
psychological stress, distress and coping as they affect the more common adult chronic periodontal
disease (85, 213).
Evidence for the role of psychological stress, distress
and
coping
as
affecting
periodontal
disease. Controlled cross-sectional studies and a randomized controlled trial have suggested a correlation
between chronic periodontal disease and the psychosocial stress status of patients. These studies have
been summarized in a systematic review (213). Table 5 summarizes studies that have used cross-sectional epidemiologic methodologies to assess the
association of stress, distress, and psychiatric symptoms with periodontal disease.
Four out of five studies show a positive relationship
(i.e., the more severe the stress in patients, the greater
the intensity of periodontal disease). In two of these
studies by Genco et al. (85) and Hugoson et al. (113),
respectively, the effects of stress were modified by the

79

Genco & Borgnakke

Table 5. Cross-sectional, epidemiologic studies calculating the risks of having periodontal disease in population
groups experiencing stress, distress, and psychiatric symptoms.
Author (Reference Number)

Condition (Possible Risk Factor)

Odds ratio (95%

confidence interval)
(measure of periodontal disease)

Moss et al. (189)

Depression
Strain stress

6.75 (1.2536.5)
2.84 (1.087.46)

Genco et al. (85)

Strain stress

2.24 (1.153.17) (clinical attachment loss)

1.91 (1.153.17) (alveolar crestal height)

Hugoson et al. (113)

Strain stress

2.69 (1.285.64)

Solis et al. (258)

Psychiatric symptoms

1.24 (0.334.78)

Chiou et al. (50)

Psychosocial factors

1.69 (1.012.77)

ability to cope. For example, in a cross-sectional

study of 1,426 subjects between 25 and 74 years of
age, financial strain (a measure of chronic stress) was
found to be associated with a greater severity of
periodontal disease, measured either as periodontal
attachment loss or alveolar bone loss (85). The levels
of periodontal disease in individuals who had high
levels of financial strain, but were effective copers
(i.e., had a high level of problem-focused coping),
were no different from subjects who were not stressed. High levels of coping modified the effects of
stress on periodontal disease, probably by nullifying
the adverse effects of financial stress among those
with periodontitis (85). This is illustrated in Fig. 6.
Similar findings were reported by Hugoson et al.
(113). They concluded that traumatic life events, such
as loss of a spouse, increased the risk of periodontal
disease, but individuals with the ability to cope with

Financial strain
All subjects
Emotion-focused copers
High
Low
Problem-focused copers
High
Low
0

Adjusted odds ratio (95% confidence interval)

Periodontal attachement loss
Alveolar bone loss

Fig. 6. Association between severity of periodontal

attachment loss and alveolar bone loss in those reporting
financial strain and different coping behaviors, adjusted
for age, gender and smoking. High problem-focused
coping is considered to be effective, and the risk for
financial strain on periodontal disease is nullified in this
group. From Genco et al. (85).

80

this stressful stimulus had reduced the role of the

traumatic life event in the progression of periodontal
disease.
Based on this review of published studies, it is
reasonable to propose that stress psychological
factors are risk factors for periodontal disease, and
that the effects can be modified or abrogated by
adequate coping behaviors. To date, there is one
randomized controlled trial that addresses the
important issue of the effects of modification of stress
in modifying periodontal disease (293). In this trial,
the influence of coping behavior was assessed over a
24-month period. It was found that passive coping
strategies resulted in more pronounced periodontal
disease, whereas patients with active coping strategies (presumably a more effective form of coping)
had a milder disease level and more favorable course
of treatment. Clearly, more intervention studies are
needed before psychological stress can be firmly
established as being important in the treatment or
prevention of periodontal disease.
The biologic plausibility for an association between
psychosocial conditions and infectious disease is well
established as exposure to psychological stresses may
affect the host immune response as well as encourage
unhealthy behaviors. Dysregulation of the host immune response can be brought about by psychologic
stress in several ways. Exposure to stress can induce
the release of noradrenaline through the sympathetic
nervous system by activation of the adrenal medulla,
which can have immunosuppressive effects (247).
Such immunosuppressive effect can enhance periodontal tissue destruction (41). Stress can promote
the production of corticotropin-releasing hormone
by the pituitary gland and the production of glucocorticoid hormones from the adrenal cortex (42, 82,
169, 182). Stress can also result in a decrease in the
production of proinflammatory cytokines as a result

Risk factors for periodontal diseases

of the release of neuropeptides from sensory nerve

fibers. These neuropeptides can modulate the activity
of the immune system, leading to more tissue
destruction (26).
Another effect of stress is on behavior. Stress may
modify behaviors that are harmful to periodontal
health, such as poor oral hygiene, increased smoking,
fewer dental visits, and changes in eating habits.
These behaviors may have effects on periodontal
disease, by affecting plaque control, increasing the
adverse effects of smoking on periodontal disease,
and also may result in suppression of the immunologic system (86).
There are mechanism studies which point to
biologic plausibility for the role of stress in periodontal disease. For example, Hilgert et al. (105)
showed that cortisol levels were positively associated with the extent and severity of periodontitis;
that is, higher levels were indicative of stress and
were associated with higher levels of periodontal
disease. A more recent, but smaller, study showed
that salivary cortisol and beta-endorphins were
statistically significantly associated with tooth loss
and clinical parameters of periodontal disease (223).
A third study, of 45 periodontal patients, suggested
that salivary cortisol was a significant predictor of
the number of missing teeth and also of the number of teeth with clinical attachment loss of 5 mm
(228).
Clearly, more studies are needed to be able to
firmly establish that psychological stress is a significant risk factor for periodontal disease and that its
modification can make a clinically meaningful
impact on periodontal therapy or response to
periodontal therapy. However, there is emerging
evidence that stress and inadequate coping skills may
explain some of the risk for periodontal disease in
some patients. Therefore, recognizing that patients
suffer from stress suggests that more definitive
management of their periodontal disease may be
necessary.

Genetics
Genetic factors as risk factors for periodontal
disease
Periodontal disease is initiated by microorganisms in
the subgingival biofilm, and lifestyle risk factors, as
well as systemic diseases, play a role in modifying the
disease, as discussed above. In addition, it has been
hypothesized that some genes may also modify
periodontal disease. It also is clear that other genetic

factors, such as genegene interactions and gene

environmental interactions (epigenetic factors) may
be important in the development of periodontal
disease.
Familial aggregation and twin studies. Familial
aggregation studies carried out by Marazita and coworkers (168) suggest that early-onset, or aggressive,
periodontitis is inherited as an autosomal-dominant
trait in Black families. Also, Rapp et al. (225) have
shown familial aggregation of periodontal disease in
three generations of Brazilian families. Genetic
studies of families affected with aggressive periodontitis were reviewed by Meng and co-workers
(174). Their review of the literature shows that the
familial aggregation of aggressive periodontitis is often very high among certain families, with the percentage of affected siblings and affected pedigree
members reaching 4050%, suggesting that genetic
factors may be important in susceptibility to aggressive periodontitis. In fact, subtypes of aggressive
periodontitis have been proposed to be inherited in a
Mendelian manner as X-linked-dominant, autosomal-recessive or autosomal-dominant characteristics; however, this is controversial. It should be
pointed out that it is commonly reported that the
underlying cause of localized aggressive periodontitis
is related to leukocyte dysfunction in certain races,
and the basis of this dysfunction may be genetic.
Familial aggregation studies in chronic periodontitis are less common. However, a study by Shearer
et al. (248), of a probandparent group of 625
individuals, concluded that parents with poor
periodontal health tend to have offspring with poor
periodontal health. They also found that family
history is a valid representation of shared genetic and
also shared environmental factors that contribute to
an individuals periodontal status. Their analysis,
however, could not distinguish between the genetic
and the environmental factors. Other studies,
including one of an Indonesian population (290) and
epidemiologic studies of a Dutch population (214,
291) suggest that periodontitis in adults may aggregate in families. Again, there is no clear indication of
the relative importance of shared environmental
factors compared with genetic factors that may be
operative in these families.
It is possible to estimate, from twin studies, a role
for genetic factors in chronic periodontal disease.
Michalowicz and co-workers (175, 176) estimate that
a substantial portion of the expression of periodontitis in adult chronic periodontitis in twins could be
attributed to genetic factors. However, a recent study

81

Genco & Borgnakke

comparing monozygotic and dizygotic twins (286)

found a lack of concordance between both monozygotic and dizygotic twin pairs regarding the severity of
attachment loss or alveolar bone loss. In the dizygotic
twins, 45.6% of the discordance could be explained
by smoking. This suggests that the role of genetics in
chronic periodontitis may have been overestimated.
It is clear, however, that the familial aggregation
phenomenon of periodontal disease is more apparent
among young individuals with periodontitis and
therefore, it may be that this form of periodontitis
(aggressive periodontitis) has a stronger genetic
background than does adult chronic periodontitis.
Polymorphisms in chronic periodontitis
Studies attempting to differentiate aggressive periodontitis from chronic periodontitis based upon
gene polymorphisms were reviewed by Stabholz et
al. (259). For the most part, gene-polymorphism
studies have not been able to distinguish between
chronic periodontitis and aggressive periodontitis.
However, patients with aggressive periodontitis do
show a positive association with human leukocyte
antigen-A9, and a negative association with human
leukocyte antigen-A2 and human leukocyte antigenA5 (260). It may well be that genetic factors can
distinguish aggressive periodontitis from chronic
periodontitis; however, there is limited evidence for
this distinction.
An extensive review of gene polymorphisms in
chronic periodontitis has been carried out by Laine
et al. (148). They present a comprehensive literature
search up to 2009 and have analyzed studies looking
at polymorphisms in the following: the interleukin-1
gene cluster; the tumor necrosis factor-a gene cluster;
the interleukin-4 and interleukin-4RA genes; the
interleukin-6 and interleukin-6R genes; the interleukin-10 genes; the FcR genes; the vitamin D receptor
genes; pattern recognition receptor genes such as
CD-14; and a series of miscellaneous genes. Often the
associations found are restricted to specific racial or
ethnic groups. Overall, the evidence points to polymorphisms in the interleukin-1, interleukin-6, interleukin-10, vitamin D receptor, and CD-14 genes as
playing a role in chronic periodontitis, but most find
that these associations are restricted to certain populations. They conclude that there is as yet no gene
polymorphism that has definitively been shown to be
a risk factor for chronic periodontitis susceptibility in
a broad representation of the population.
A particularly active area of investigation deals with
interleukin-1 polymorphisms. These studies were
reviewed by Karimbux and co-workers (130). They

82

found significant effects for two individual gene

variations interleukin-1A (odds ratio = 1.48) and
interleukin-1B (odds ratio = 1.54) and for a composite genotype that combines minor alleles at each
locus (odds ratio = 1.51). Significant heterogeneity
was found that could not be explained. They conclude that interleukin-1A and interleukin-1B genetic
variations are significant contributors to chronic
periodontitis; however, like other polymorphisms,
the association is found mainly in Caucasians. There
is presently a commercially available test to assess
interleukin-1 genetic polymorphisms in periodontal
disease.
It is clear that there is considerable controversy
regarding the role of genetic polymorphisms based
upon casecontrol studies of candidate gene associations. These gene polymorphism studies have a
variety of potential methodologic flaws. There is
concern with the definition of the phenotype,
including defining the most severe cases of chronic
periodontitis, selection of controls, control of the
diversity of the racial and ethnic backgrounds, and
sample size. Finally, genetic polymorphisms generally also have other effects, including interactions of
genes with each other and with the environment, and
these are not often taken into account.
Genome-wide association studies
Genome-wide association studies of chronic diseases
appeared in the literature in 2000 and were based
upon technological advances which allowed
hypothesis-free testing of 500,000 to 1,000,000
polymorphisms spread across the whole genome for
genes associated with disease. These studies were
applied to large-population casecontrol panels, often of 1,000 well-defined cases and at least that many
well-defined controls, to identify genetic risk variants
of a minor allele frequency of 20% (245). These
studies have yielded most of the common genetic risk
factors for coronary heart disease and type 2 diabetes
and for other chronic diseases of humans. There are
at least 11 genetic risk factors for coronary heart
disease (246) and 1824 for type 2 diabetes (221, 261).
Many of these genes had not previously been seriously considered as likely candidate genes, and their
discovery has led to new awareness of pathways in
patients with these diseases.
This genome-wide association study approach has
only just started to be used to assess the genetics of
periodontal disease. A genome-wide association of
1,020 adults with a range of periodontal disease from
healthy to severe (62) found that 13 loci provided
suggestive evidence of an association with peri-

Risk factors for periodontal diseases

odontal pathogen colonization. However, none of

these polymorphisms was statistically significantly
associated with the periodontal disease status
(presumably chronic periodontitis). The lack of
genetic loci associated with chronic periodontitis
may be related to the small sample size, the heterogeneity of the study population, and weak phenotypes. In chronic periodontitis, the contribution of
the subgingival microflora and of risk factors (such as
smoking and obesity) to the disease may be much
more dominant than the contribution of genetic
factors as the chronicity increases. There may be
common gene variants that have weak effects, or rare
variants with major effects that are difficult to uncover by genome-wide association studies. Clearly,
more genome-wide association studies with larger
populations with well-defined levels of health and
chronic periodontitis are needed to clarify this issue.
Genome-wide association studies for aggressive
periodontitis have revealed more clear associations
with disease. For example, in a study of generalized
aggressive periodontitis, Schaefer and coworkers
(244) found one single-nucleotide polymorphism
associated with intron 2 of glucosyltransferase-6
domain containing 1 (Gene ID 360203). This was
replicated also on a panel of Dutch patients with
generalized and localized aggressive periodontitis.
Further studies of tissue-specific expression analysis
of glucosyltransferase-6 domain containing one
indicated high transcript levels in the leukocytes, the
gingiva, and the testes. Expression of a genetic transcription factor-binding protein suggested that it was
an important potential signaling component in the
pathophysiology of aggressive periodontitis.
It is clear that further adequately powered genomewide association studies of both chronic and
aggressive forms of periodontitis are needed to better
understand the genetic factors operative in periodontal disease.
Epigenetics in periodontal disease
Evidence is emerging for a role of epigenetic phenomena, including post-translational methylation of
genes, in periodontal disease. It is therefore reasonable to expect that these effects will have significance,
especially in contributing to the chronicity of periodontal disease. For example, the methylation status
of genes affecting levels of prostaglandins was
changed in tissues from periodontal disease, suggesting an epigenetic contribution to the periodontal
disease inflammatory response (303). The evidence in
other diseases suggests that epigenetic regulatory
mechanisms can modulate inflammatory responses,

and the finding that periodontal pathogens can promote DNA hypermethylation (34) suggests that this
may occur in periodontal disease.
Sharing genetic risk factors between periodontal
disease and other associated chronic diseases
Genetic risk factors may increase susceptibility not
only to periodontal disease, but also to other associated chronic diseases such as cancer, heart disease
and diabetes. A study of shared genetic risk factors
between periodontal disease and cancer, based upon
twin studies, is described to illustrate the potential of
this approach to understand not only the risk for
periodontal disease, but also for associated systemic
conditions (17). These investigators studied 15,333
Swedish twins and used a co-twin analysis to control
for familial factors. They restricted their analysis to
monozygotic twins to further control for confounding
genetic factors. Between 1963 and 2004, they observed 4,361 cancer cases over 548,913 person years.
They report an association between periodontal disease and increased risk for several cancers, ranging
from 15% for total cancer to 120% for uterine cancer.
They also found that periodontal disease was associated with increased risk for colorectal cancer and
prostate cancer.
In another study (69), co-twin analysis using dizygotic twins with baseline periodontal disease showed
a 50% increase in total cancer risk, but in monozygotic twins this association was markedly attenuated.
The association of periodontal disease with total as
well as digestive tract cancers was stronger in dizygotic twins than in monozygotic twins and this supports the hypothesis of shared genetic factors that
may affect the association between periodontal disease and cancer. It is hypothesized that inflammation
may underlie this association and that interleukin-1
gene polymorphisms associated with increased levels
of periodontal disease may also be associated with
the increased risk of gastric cancer.
Schaefer et al. (243) have shown that three of the
genetic variant single-nucleotide polymorphisms
found in coronary heart disease are also associated
with aggressive periodontitis. The possible genes include CDKN2A 2B, which encode inhibitors believed
to play a role in cell proliferation and tumor suppression. Also included is MTAP, a tumor-suppressor
gene that plays a role in interferon sensitivity and
hence may modulate the immune response. These
genes are embedded in ANRIL, a class of genes
thought to regulate the transcriptome. There may be
an overlap between aggressive periodontitis and
coronary heart disease, related to the function of

83

Genco & Borgnakke

these genes in cell proliferation, but at present the

detailed mechanism for these overlapping genetic
effects is not clear. In addition, there are no studies
relating aggressive periodontitis, per se, to coronary
heart disease, although such a relationship is reasonable.
Genetic studies of periodontal disease have the
potential to lead to a better understanding of the
etiopathogenesis of periodontal disease and its
association with other chronic diseases of humans.
Periodontal disease risk is clearly associated with
genetic factors; however, the genes involved, and
their mechanisms of action, are as yet unclear.

Summary and conclusions

Table 7. US prevalence of risk factors for periodontal

disease.
Factor indicator

Prevalence in the US

Cigarette smoking

19.3% of adults in 2010

Diabetes mellitus

8.3% all ages (2.37% undiagnosed)

12.9% of adults
(25.6 million), including 5.0%
(10 million) undiagnosed

Pre-diabetes

35% of adults

Osteoporosis

7.9% of women

Dietary calcium
deficiency

1 3 below 50% of the

recommended dietary
allowance

Stress work related 3040%

Obesity

Overgrowth of biofilms, especially in the subgingival

area, with the emergence of periodontal pathogens is
a necessary, but often insufficient, condition for the
development of periodontal disease. Risk factors
work to change the susceptibility or resistance of
individuals to the disease.
Risk factors for periodontal disease can be systemic
or local, and those that are systemic include behaviors,
such as smoking; medical conditions, such as poorly
controlled diabetes, possibly obesity, stress, osteopenia, and inadequate dietary consumption of calcium
and vitamin D. It is reasonable to talk of eliminating
or modifying these risk factors as part of the management of periodontal disease. Other risk factors,
such as race or genetic factors, cannot be changed;
however, identifying people at risk for adverse outcomes by race or genetic make-up provides a means
for targeting interventions. Table 6 lists the periodontal risk factors for which modification is possible
and Table 7 displays their prevalence in the USA.
Table 6. Modifiable risk factors for periodontal disease.
Risk factor

Modification

Smoking

Smoking cessation

Poorly controlled diabetes

Improved glycemic
control

Obesity

Diet and exercise

Osteoporosis

Bone-sparing agents,
calcium and vitamin
D supplementation

Low dietary calcium

and vitamin D

Calcium and vitamin

D supplementation

Stress and
inadequate coping

Stress-reduction
measures

84

36% of US adults
18% of US children
35.7% (78 million) of adults
(men : 35.5%; women : 35.8%)
http://www.cdc.gov/obesity/data/
adult.html

From Table 7 it can be seen that most patients with

periodontal disease in the US will probably be affected by one or more of these modifiable systemic
risk factors. Hence, they should be candidates for
risk-factor modification as part of the management of
periodontal disease.
In conclusion, it is imperative that the clinician
looks beyond the oral cavity for factors of which to
potentially recommend modification in order to help
their patients reach their common goal of prevention
or management of periodontal disease and thereby
possibly improve general health as well.

Acknowledgments
The authors thank Rose Parkhill for her expert
assistance in all aspects of preparation of this manuscript. They also thank Denise Lewis for assistance
in obtaining the references for this review, Robert
Dunford for help in preparing the figures, and Dr.
Nastassia Vlasava for providing proofreading assistance. The authors have no real or potential conflicts
of interest and no funding was available for this work.

References
1. Abbatecola AM, Ferrucci L, Grella R, Bandinelli S, Bonafe
M, Barbieri M, Corsi AM, Laurentani F, Franceschi C,
Paolisso G. Diverse effect of inflammatory markers on

Risk factors for periodontal diseases

2.

3.

4.

5.

6.

7.
8.
9.

10.

11.

12.

13.

14.

15.

16.

17.

18.

insulin resistance and insulin-resistance syndrome in the

elderly. J Am Geriatr Soc 2004: 52: 399404.
Abrahamsen B, Van Staa T, Ariely R, Olson M, Cooper C.
Excess mortality following hip fracture: a systematic epidemiological review. Osteoporos Int 2009: 20: 16331650.
Acharya A, Bhavsar N, Jadav B, Parikh H. Cardioprotective
effect of periodontal therapy in metabolic syndrome: a
pilot study in Indian subjects. Metab Syndr Relat Disord
2010: 8: 335341.
Ah MK, Johnson GK, Kaldahl WB, Patil KB, Kalkwarf KL.
The effect of smoking on the response to periodontal
therapy. J Clin Periodontol 1994: 21: 9197.
Ainamo J, Barmes D, Beagrie G, Cutress T, Martin J, SardoInfirri J. Development of the World Health Organization
(WHO) community periodontal index of treatment needs
(CPITN). Int Dent J 1982: 32: 281291.
Albandar JM, Streckfus CF, Adesanya MR, Winn DM. Cigar, pipe, and cigarette smoking as risk factors for periodontal disease and tooth loss. J Periodontol 2000: 71:
18741881.
Albandar JM. Global risk factors and risk indicators for
periodontal diseases. Periodontol 2000 2002: 29: 177206.
Albandar JM. Periodontal disease surveillance. J Periodontol 2007: 78: 11791181.
Alberti KG, Eckel RH, Grundy SM. Harmonizing the metabolic syndrome: a joint interim statement of the International Diabetes Federation Task Force on Epidemiology
and Prevention; National Heart, Lung, and Blood Institute;
American Heart Association; World Heart Federation;
International Atherosclerosis Society; and International
Association for the Study of Obesity. Circulation 2009: 120:
16401645.
Alpagot T, Wolff LF, Smith QT, Tran SD. Risk indicators for
periodontal disease in a racially diverse urban population.
J Clin Periodontol 1996: 23: 982988.
Al-Zahrani MS. Increased intake of dairy products is related to lower periodontitis prevalence. J Periodontol 2006:
77: 289294.
Amar S, Zhou Q, Shaik-Dasthagirisheb Y, Leeman S. Dietinduced obesity in mice causes changes in immune response and bone loss manifested by bacterial challenge.
PNAS 2007: 104: 2046620471.
Andriankaja OM, Genco RJ, Dorn J, Dmochowski J, Hovey
K, Falkner KL, Trevisan M. Periodontal disease and risk of
myocardial infarction. The role of gender and smoking.
Eur J Epidemiol 2007: 22: 699705.
Andriankaja OM, Sreenivasa S, Dunford R, DeNardin E.
Association between metabolic syndrome and periodontal
disease. Austr Dent J 2010: 55: 252259.
Armitage GC, Robertson PB. The biology, prevention,
diagnosis and treatment of periodontal diseases: scientific
advances in the United States. J Am Dent Assoc 2009:
140(Suppl. 1): 36S43S.
Arora M, Schwarz E, Sivaneswaran S, Banks E. Cigarette
smoking and tooth loss in a cohort of older Australians. The
45 and up study. J Am Dent Assoc 2010: 141: 12421249.
Arora M, Weuve J, Fall K, Pedersen NL, Mucci LA. An
exploration of shared genetic risk factors between periodontal disease and cancers: a prospective co-twin study.
Am J Epidemiol 2010: 171: 253259.
Awuti G, Younusi K, Li L, Upur H, Ren J. Epidemiological
survey on the prevalence of periodontitis and diabetes

19.
20.

21.
22.

23.

24.

25.

26.

27.

28.
29.

30.

31.
32.

33.

34.

35.

36.

37.

mellitus in Uyghur adults from rural Hotan area in Xinjiang. Exp Diabetes Res 2012: 2012: 758921.
Baelum V. Pattern of periodontal breakdown in adult
Tanzanians. Scand J Dent Res 1987: 95: 221228.
Baelum V, Fejerskov O, Karring T. Oral hygiene, gingivitis,
and periodontal breakdown in adult Tanzanians. J Periodontal Res 1986: 21: 221232.
Baelum V, Fejerskov O, Manji F. Periodontal diseases in
adult Kenyans. J Clin Periodontol 1988: 15: 445452.
Baelum V, Wen-Min L, Fejerskov O, Xia C. Tooth mortality
and periodontal conditions in 60- to 80-year-old Chinese.
Scand J Dent Res 1988: 96: 99107.
Bagdade JD, Stewart M, Walters E. Impaired granulocyte
adherence. A reversible defect in host defense in patients
with poorly controlled diabetes. Diabetes 1978: 27: 677
681.
Bandyopadhyay D, Marlow NM, Fernandes JK, Leite RS.
Periodontal disease progression and glycaemic control
among Gullah African Americans with type-2 diabetes.
J Clin Periodontol 2010: 37: 501509.
Barros SP, Silva MA, Somerman MJ, Nociti FH Jr. Parathyroid hormone protects against periodontitis-associated
bone loss. J Dent Res 2003: 82: 791795.
Bartold PM, Kylstra A, Lawson R. Substance-P: an immunohistochemical and biochemical study in human gingival tissue. A role for neurogenic inflammation?. J
Periodontol 1994: 65: 11131121.
Beck JD, Eke P, Heiss G, Madianos P, Couper D, Lin D,
Moss K, Elter J, Offenbacher S. Periodontal disease and
coronary heart disease: a reappraisal of the exposure.
Circulation 2005: 112: 1924.
Belting CM. A review of the epidemiology of periodontal
diseases. J Periodontol 1957: 28: 3746.
Beltran-Aguilar ED, Eke PI, Thornton-Evans G, Petersen
PE. Recording and surveillance systems for periodontal
diseases. Periodontol 2000 2012: 60: 4053.
Bergstrom J, Bostrom L. Tobacco smoking and periodontal
hemorrhagic responsiveness. J Clin Periodontol 2001: 28:
680685.
Bergstrom J, Preber H. Tobacco use as a risk factor. J Periodontol 1994: 65(Suppl): 545550.
Bhagyajyothi CS, Pushpanjali K. Assessment and comparison of periodontal status among young smokers and
nonsmokers of Bangalore, India. A cross sectional study.
Commun Dent Health 2011: 28: 8994.
Bissada NF, Manouchehr-Pour M, Haddow M, Spagnuolo
PJ. Neutrophil functional activity in juvenile and adult
onset diabetic patients with mold and severe periodontitis. J Periodontal Res 1982: 17: 500502.
Bobetsis YA, Barros SP, Lin DM, Weidman JR, Dolinoy DC,
Jirtle RL, Boggess KA, Beck JD, Offenbacher S. Bacterial
infection promotes DNA hypermethylation. J Dent Res
2007: 86: 169174.
Boillot A, El Halabi B, Batty GD, Range H, Czernichow S,
Bouchard P. Education as a predictor of chronic periodontitis: a systematic review with meta-analysis population-based studies. PLoS One 2011: 6: e21508.
Bolin A, Eklund G, Frithiof L, Lavstedt S. The effect of
changed smoking habits on marginal alveolar bone loss. A
longitudinal study. Swed Dent J 1993: 17: 211216.
Borges PK, Gimeno SG, Tomita NE, Ferreira SR. Prevalence and characteristics associated with metabolic syn-

85

Genco & Borgnakke

38.

39.

40.

41.

42.

43.

44.

45.
46.

47.

48.

49.

50.

51.

52.

53.

86

drome in Japanese-Brazilians with and without periodontal disease. Cad Saude Publica 2007: 23: 657668.
Borrell LN, Kunzel C, Lamster I, Lalla E. Diabetes in the
dental office: using NHANES III to estimate the probability
of undiagnosed disease. J Periodontal Res 2007: 42: 559
565.
Borrell LN, Papapanou PN. Analytical epidemiology of
periodontitis. J Clin Periodontol 2005: 32 (Suppl. 6): 132
158.
Braunholtz DA, Edwards SJ, Lilford RJ. Are randomized
clinical trials good for us (in the short term)? Evidence for
a trial effect. J Clin Epidemiol 2001: 54: 217224.
Breivik T, Thrane OS. Psychonuroimmune interactions in
periodontal disease. in: Ader R, Felten DL, Cohen N III
editors. Psychoneuroimmunology, vol 63. New York: Academic Press, 2011: 627644.
Breivik T, Thrane OS, Murison R, Gjermo P. Emotional
stress effects on immunity, gingivitis and periodontitis.
Eur J Oral Sci 1996: 104: 327334.
Brennan RM, Genco RJ, Hovey KM, Trevisan M, Wactawski-Wende J. Clinical attachment loss, systemic bone
density, and subgingival calculus in postmenopausal
women. J Periodontol 2007: 78: 21042111.
Brennan-Calanan RM, Genco RJ, Wilding GE, Hovey KM,
Trevisan M, Wactawski-Wende J. Osteoporosis and oral
infection: independent risk factors for oral bone loss.
J Dent Res 2008: 87: 323327.
Brownlee M. The pathobiology of diabetic complications:
a unifying mechanism. Diabetes 2005: 54: 16151625.
Centers for Disease Control and Prevention. National diabetes fact sheet: national estimated and general information
on diabetes and prediabetes in the United States, 2011.
Atlanta, GA: U.S. Department of Health and Human Services, Centers for Disease Control and Prevention, 2011,
http://www.cdc.gov/diabetes/pubs/estimates11.htm#7.
Cetinkaya BO, Keles GC, Ayas B, Gurgor P. Effects of
risedronate on alveolar bone loss and angiogenesis: a stereologic study in rats. J Periodontol 2008: 79: 19501961.
Chaffee BW, Weston SJ. Association between chronic
periodontal disease and obesity: a systematic review and
meta-analysis. J Periodontol 2010: 81: 17081724.
Chavarry NG, Vettore MV, Sansone C, Sheiham A. The
relationship between diabetes mellitus and destructive
periodontal disease. Oral Health Prev Dent 2009: 7: 107127.
Chiou LJ, Yang YH, Hung HC, Tsai CC, Shieh TY, Wu YM,
Wang WC, Hsu TC. The association of psychosocial factors
and smoking with periodontal health in a community
population. J Periodontal Res 2010: 45: 1622.
Cianciola LJ, Park BH, Bruck E, Mosovich L, Genco RJ.
Prevalence of periodontal disease in insulin dependent
diabetes mellitus (juvenile diabetes). J Am Dent Assoc
1982: 104: 653660.
Correa FO, Goncalves D, Figueredo CM, Bastos AS, Gustafsson A, Orrico SR. Effect of periodontal treatment on
metabolic control, systemic inflammation and cytokines
in patients with type 2 diabetes. J Clin Periodontol 2010:
37: 5358.
Cowie CC, Rust KF, Ford ES, Eberhardt MS, Byrd-Holt DD,
Li C, Williams DE, Gregg EW, Bainbridge KE, Saydah SH,
Geiss LS. Full accounting of diabetes and pre-diabetes in
the U.S. population in 19881994 and 20052006. Diabetes
Care 2009: 32: 287294.

54. Cuff MJ, McQuade MJ, Scheidt MJ, Sutherland DE, Van
Dyke TE. The presence of nicotine on root surfaces of
periodontally diseased teeth in smokers. J Periodontol
1989: 60: 564569.
55. DAiuto F, Sabbah W, Netuveli G, Donos N, Hingorani AD,
Deanfield J, Tsakos G. Association of the metabolic syndrome with severe periodontitis in a large U.S. populationbased survey. J Clin Endocrinol Metab 2008: 93: 39893994.
56. Dandona P, Aljada A, Bandyopadhyay A. Inflammation:
the link between insulin resistance, obesity and diabetes.
Trends Immunol 2004: 25: 47.
57. Darby IA, Bisucci T, Hewitson RD, MacLellan DG. Apoptosis is increased in a model of diabetes-impaired wound
healing in genetically diabetic mice. Int J Biochem Cell Biol
1997: 29: 191200.
58. Darre L, Vergnes JN, Gourdy P, Sixou M. Efficacy of periodontal treatment on glycaemic control in diabetic patients: a meta-analysis of interventional studies. Diabetes
Metab 2008: 34: 497506.
59. Delima SL, McBride RK, Preshaw PM, Heasman PA, Kumar PS. Response of subgingival bacteria to smoking
cessation. J Clin Microbiol 2010: 48: 23442349.
60. Demmer RT, Desvarieux M, Holtfreter B, Jacobs DR Jr,
Wallaschofski H, Nauck M, Volzke H, Kocher T. Periodontal status and A1C change: longitudinal results from
the study of health in Pomerania (SHIP). Diabetes Care
2010: 33: 10371043.
61. Demmer RT, Jacobs DR Jr, Desvarieux M. Periodontal
disease and incident type 2 diabetes: results from the First
National Health and Nutrition Examination Survey and its
epidemiologic follow-up study. Diabetes Care 2008: 31:
13731379.
62. Divaris K, Monda KL, North KE, Olshan AF, Lange EM,
Moss K, Barros SP, Beck JD, Offenbacher S. Genome-wide
association study of periodontal pathogen colonization.
J Dent Res 2012: 91(Suppl 1): 21S26S.
63. Dorn JM, Genco RJ, Grossi SG, Falkner KL, Hovey KM,
Iacoviello L, Trevisan M. Periodontal disease and recurrent cardiovascular events in survivors of myocardial
infarction (MI): the Western New York Acute MI Study.
J Periodontol 2010: 8: 502511.
64. Eke PI, Dye BA, Wei L, Thornton-Evans GO, Genco RJ; on
behalf of the participating members of the CDC Periodontal Disease Surveillance workgroup: James Beck (University of North Carolina CH, USA), Gordon Douglass
(Past President, American Academy of Periodontology),
Roy Page (University of Washington, Seattle, USA), Gary
Slade (University of North Carolina, Chapel Hill, USA),
George W. Taylor (University of Michigan, Ann Arbor,
USA), Wenche S. Borgnakke (University of Michigan, Ann
Arbor, USA), and representatives of the American Academy of Periodontology. Prevalence of periodontitis in
adults in the United States: 2009 and 2010. J Dent Res 2012:
91: 914920.
65. Eke PI, Page RC, Wei L, Thornton-Evans G, Genco RJ.
Update of the case definitions for population-based
surveillance of periodontitis. J Periodontol 2012: 83:
14491454.
66. Eke PI, Thornton-Evans G, Dye B, Genco R. Advances in
surveillance of periodontitis: the Centers for Disease
Control and Prevention Periodontal Disease Surveillance
Project. J Periodontol 2012: 83: 13371342.

Risk factors for periodontal diseases

67. Eke PI, Thornton-Evans GO, Wei L, Borgnakke WS, Dye
BA. Accuracy of NHANES periodontal examination protocols. J Dent Res 2010: 89: 12081213.
68. Elders PJ, Habets LL, Netelenbos JC, van der Linder LW,
van der Stelt PF. The relation between periodontitis and
systemic bone mass in women between 46 and 55 years of
age. J Clin Periodontol 1992: 19: 492496.
69. El-Omar EM, Carrington M, Chow WH, McColl KE, Bream
JH, Young HA, Herrera J, Lissowska J, Yuan CC, Rothman
N, Lanyon G, Martin M, Fraumeni JF Jr, Rabkin CS.
Interleukin-1 polymorphisms associated with increased
risk of gastric cancer. Nature 2000: 404: 102132.
70. Elwood J. Critical appraisal of epidemiological studies and
clinical trials, 2nd edn. Oxford; New York: Oxford University Press, 1998.
71. Emrich LJ, Shlossman M, Genco RJ. Periodontal disease in
non-insulin dependent diabetes mellitus. J Periodontol
1991: 62: 123130.
72. Endo Y, Tomofuji T, Ekuni D, Irie K, Azuma T, Tamaki N,
Yamamoto T, Morita M. Experimental periodontitis induces gene expression of proinflammatory cytokines in
liver and white adipose tissues in obesity. J Periodontol
2010: 81: 520526.
73. Engebretson S, Chertog R, Nichols A, Hey-Hadavi J, Celenti R, Grbic J. Plasma levels of tumour necrosis factoralpha in patients with chronic periodontitis and type 2
diabetes. J Clin Periodontol 2007: 34: 1824.
74. Engebretson SP, Hey-Hadavi J, Ehrhardt FJ, Hsu D, Celenti
RS, Brbic JT, Lamster IB. Gingival crevicular fluid levels of
interleukin-1b and glycemic control in patients with
chronic periodontitis and type 2 diabetes. J Periodontol
2004: 75: 12031208.
75. Eriksson M, Holmgren L, Janlert U, Jansson JH, Lundblad
D, Stegmayr B, Soderberg S, Eliasson M. Large improvements in major cardiovascular risk factors in the population of northern Sweden: the MONICA study 19862009.
J Intern Med 2011: 269: 219231.
76. Faeh D, Bopp M. Excess weight in the canton of Zurich,
19922009: harbinger of a trend reversal in Switzerland?
Swiss Med Wkly 2010: 140: w13090.
77. Falagas ME, Kompoti M. Obesity and infection. Lancet
Infect Dis 2006: 6: 438446.
78. Fantuzzi G. Adipose tissue, adipokines, and inflammation.
J Allergy Clin Immunol 2005: 115: 911919.
79. Feitosa AC, de Uzeda M, Novaes AB Jr. Actinobacillus
actinomycetemcomitans in Brazilian insulin-dependent
individuals with diabetes mellitus. Braz Dent J 1992: 3: 25
31.
80. Fernandes JK, Wiegand RE, Salinas CF, Grossi SG,
Sanders JJ, Lopes-Virella MF, Slate EH. Periodontal disease status in gullah african americans with type 2
diabetes living in South Carolina. J Periodontol 2009: 80:
10621068.
81. Flegal KM, Carroll MD, Kit BK, Ogden CL. Prevalence of
obesity and trends in the distribution of body mass index
among US adults, 19992010. J Am Med Assoc 2012: 307:
491497.
82. Freeman R, Goss S. Stress measures as predictors of
periodontal disease a preliminary communication.
Community Dent Oral Epidemiol 1993: 21: 176177.
83. Garcia-Alvarez A, Serra-Majem L, Ribas-Barba L, Castell C,
Foz M, Uauy R, Plasencia A, Salleras L. Obesity and

84.

85.

86.

87.
88.

89.

90.

91.

92.

93.
94.

95.

96.

97.

98.

99.

100.

overweight trends in Catalonia, Spain (19922003): gender

and socio-economic determinants. Public Health Nutr
2007: 10: 13681378.
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(Suppl):
20752084.
Genco RJ, Ho AW, Grossi SG, Dunford RG, Tedesco LA. Relationship of stress, distress, and inadequate coping behaviors to
periodontal disease. J Periodontol 1999: 70: 711723.
Genco RJ, Ho AW, Kopman J, Grossi SG, Dunford RG,
Tedesco LA. Models to evaluate the role of stress in periodontal disease. Ann Periodontol 1998: 3: 288305.
Goodson JM, Groppo D, Halem S, Carpino E. Is obesity an
oral bacterial disease? J Dent Res 2009: 88: 519523.
Gorman A, Kaye EK, Apovian C, Fung TT, Nunn M, Garcia
RI. Overweight and obesity predict time to periodontal
disease progression in men. J Clin Periodontol 2012: 39:
107114.
Gorman A, Kaye EK, Nunn M, Garcia RI. Changes in
body weight and adiposity predict periodontitis progression in men. J Dent Res 2012: 91: 921926.
Graves DT, Liu R, Alikhani M, Al-Mashat H, Trackman PC.
Diabetes enhanced inflammation and apoptosis impact on periodontal pathology. J Dent Res 2006: 85: 1521.
Grossi SG, Genco RJ, Machtei EE, Ho AW, Koch G, Dunford R, Zambon JJ, Hausmann E. Assessment of risk for
periodontal disease. II. Risk indicators for alveolar bone
loss. J Periodontol 1995: 66: 2329.
Grossi SG, Zambon JJ, Ho AW, Koch G, Dunford RG,
Machtei EE, Norderyd OM, Genco RJ. Assessment of risk
for periodontal disease. I. Risk indicators for attachment
loss. J Periodontol 1994: 65: 260267.
Grundy SM. A constellation of complications: the Metabolic Syndrome. Clin Cornerstone 2005: 7: 3645.
Gupta A, Ten S, Anhalt H. Serum levels of soluble tumor
necrosis factor-alpha receptor 2 are linked to insulin
resistance and glucose intolerance in children. J Pediatr
Endocrinol Metab 2005: 18: 7582.
Gustke CJ, Stein SH, Hart TC, Hoffman WH, Hanes PJ,
Russell CM, Schuster GS, Watson SC. HLA-DR alleles
are associated with IDDM, but not with impaired neutrophil chemotaxis in IDDM. J Dent Res 1998: 77: 1497
1503.
Gyurko R, Siqueira CC, Caldon N, Gao L, Kantarci A, Van
Dyke TE. Chronic hyperglycemia predisposes to exaggerated inflammatory response and leukocyte dysfunction in
Akita mice. J Immunol 2006: 177: 72507256.
Haas AN, Gaio EJ, Oppermann RV, Rosing CK, Albandar
JM, Susin C. Pattern and rate of progression of periodontal
attachment loss in an urban population of South Brazil: a
5-years population-based prospective study. J Clin Periodontol 2012: 39: 19.
Haffajee AD, Socransky SS. Relationship of cigarette
smoking to attachment level profiles. J Clin Periodontol
2001: 28: 283295.
Haffajee AD, Socransky SS. Relation of body mass index,
periodontitis and Tannerella forsythia. J Clin Periodontol
2009: 36: 8999.
Han DH, Lim S, Kim JB. The association of smoking and
diabetes with periodontitis in Koreans. J Periodontol 2012:
83: 13971406.

87

Genco & Borgnakke

101. Health Survey for England: Trend tables. National Health
Service Information Center. http://www.ic.nhs.uk/statistics-and-data-collections/health-and-lifestyles-relatedsurveys/health-survey-for-england/health-survey-forengland2009-trend-tables, 2009.
102. Heasman L, Stacey F, Preshaw PM, McCracken GI, Hepburn S, Heasman PA. The effect of smoking on periodontal
treatment response: a review of clinical evidence. J Clin
Periodontol 2006: 33: 241253.
103. Hellstein JW, Adler RA, Edwards B, Jacobsen PL, Kalmar
JR, Koka S, Migliorati CA, Ristic H. Managing the care of
patients receiving antiresorptive therapy for prevention
and treatment of osteoporosis: executive summary of
recommendations for the American Dental Association
Council on Scientific Affairs. J Am Dent Assoc 2011: 142:
12431251.
104. Hildebolt CF, Pilgram TK, Dotson M, Yokoyama-Crothers
N, Muckerman J, Hauser J, Cohen S, Kardaris E, Vannier
MW, Hanes P, Shrout MK, Civitelli R. Attachment loss with
postmenopausal age and smoking. J Periodontal Res 1997:
32: 610625.
105. Hilgert JB, Hugo FN, Bandeira DR, Bozzetti MC. Stress,
cortisol, and periodontitis in a population aged 50 years
and over. J Dent Res 2006: 85: 324328.
106. Hill AB. The environment and disease: association or
causation? Proc R Soc Med 1965: 58: 295300.
107. Hodge PJ, Robertson D, Paterson K, Smith GLF, Creanor S,
Sherriff A. Periodontitis in non-smoking type 1 diabetic
adults: a cross-sectional study. J Clin Periodontol 2012: 39:
2029.
108. Holtfreter B, Kocher T, Hoffmann T, Desvarieux M,
Micheelis W. Prevalence of periodontal disease and
treatment demands based on a German dental survey
(DMS IV). J Clin Periodontol 2010: 37: 211219.
109. Holtfreter B, Schwahn C, Biffar R, Kocher T. Epidemiology
of periodontal diseases in the Study of Health in Pomerania. J Clin Periodontol 2009: 36: 114123.
110. Hotamisligil GS. Inflammation and metabolic disorders.
Insight Review 2006: 444: 860867.
111. Hotamisligil GS, Shargill NS, Spiegelman BM. Adipose
expression of tumor necrosis factor-alpha: direct role in
obesity-linked insulin resistance. Science 1993: 259: 8791.
112. Hu FB, Meigs JB, Li TY, Rifai N, Manson JE. Inflammatory
markers and risk of developing type 2 diabetes in women.
Diabetes 2004: 53: 693700.
113. Hugoson A, Ljungquist B, Breivik T. The relationship of
some negative events and psychological factors to
periodontal disease in adult Swedish population 50 to
80 years of age. J Clin Periodontol 2002: 29: 247253.
114. Hugoson A, Norderyd O, Slotte C, Thorstensson H. Distribution of periodontal disease in a Swedish adult population 1973, 1983 and 1993. J Clin Periodontol 1998: 25:
542548.
115. Human Microbiome Project Consortium. Structure,
function and diversity of the healthy human microbiome.
Nature 2012: 486: 207214.
116. Hyman JJ, Reid BC. Epidemiologic risk factors for periodontal attachment loss among adults in the United
States. J Clin Periodontol 2003: 30: 230237.
117. Ide R, Hoshuyama T, Takahashi K. The effect of periodontal disease on medical and dental costs in a middle-

88

118.

119.

120.

121.

122.

123.

124.

125.

126.

127.

128.

129.

130.

131.

132.

aged Japanese population: a longitudinal worksite study. J

Periodontol 2007: 78: 21202126.
Ide R, Hoshuyama T, Wilson D, Takahashi K, Higashi T.
Periodontal disease and incident diabetes: a seven-year
study. J Dent Res 2011: 90: 4146.
Ishii K, Taguchi A, Nakamoto T, Ohtsuka M, Sutthiprapaporn P, Tsuda M, Kodama I, Kudo Y, Sumida H, Suei Y,
Tanimoto K. Diagnostic efficacy of alveolar bone loss of
the mandible for identifying postmenopausal women with
femoral osteoporosis. Dentomaxillofac Radiol 2007: 36:
2833.
James JA, Sayers NM, Drucker DB, Hull PS. Effects of tobacco products on the attachment and growth of periodontal ligament fibroblasts. J Periodontol 1999: 70: 518
525.
Jamieson LM, Sayers SM, Roberts-Thomson KF. Clinical
oral health outcomes in young Australian Aboriginal
adults compared with national-level counterparts. Med J
Aust 2010: 192: 558561.
Janket SJ, Wightman A, Baird AE, Van Dyke TE, Jones JA.
Does periodontal treatment improve glycemic control in
diabetic patients? A meta-analysis of intervention studies.
J Dent Res 2005: 84: 11541159.
Jansson H. Studies on periodontitis and analyses of individuals at risk for periodontal diseases. Swed Dent J Suppl
2006: 180: 549.
Jeffcoat MK, Cizza G, Shih WJ, Genco R, Lombardi A.
Efficacy of bisphosphonates for the control of alveolar
bone loss in periodontitis. J Int Acad Periodontol 2007: 9:
7076.
Jenzsch A, Eick S, Rassoul F, Purschwitz R, Jentsch H.
Nutrtional intervention in patients with periodontal disease: clinical, immunological and microbiological variables during 12 months. Br J Nutr 2009: 101: 879885.
Jamieson LM, Sayers SM, Roberts-Thomson KF. Clinical
oral health outcomes in young Australian Aboriginal
adults compared with national-level counterparts. Med J
Aust 2010: 192: 558561.
Jin L, Wong KY, Leung WK, Corbet EF. Comparison of
treatment response patterns following scaling and root
planing in smokers and non-smokers with untreated adult
periodontitis. J Clin Dent 2000: 11: 3541.
Johnson BD, Engel D. Acute necrotizing ulcerative gingivitis. A review of diagnosis, etiology and treatment. J Periodontol 1986: 57: 141150.
Jones JA, Miller DR, Wehler CJ, Rich S, Krall E, Christiansen CL, Torhendler JA, Garcia RI. Does periodontal care
improve glycemic control? The Department of Veterans
Affairs Dental Diabetes Study. J Clin Periodontol 2007: 34:
4652.
Karimbux NY, Saraiya VM, Elangovan S, Allareddy V,
Kinnunen T, Kornman KS, Duff GW. Interleukin-1 gene
polymorphisms and chronic periodontitis in adult whites:
a systematic review and meta-analysis. J Periodontol 2012:
83: 14071419.
Katz J. Elevated blood glucose levels in patients with severe periodontal disease. J Clin Periodontol 2001: 28: 710
712.
Katz J, Chaushu G, Sgan-Cohen HD. Relationship of
blood glucose level to community periodontal index of
treatment needs and body mass index in a permanent

Risk factors for periodontal diseases

133.

134.

135.

136.

137.

138.

139.

140.

141.
142.
143.

144.

145.
146.

147.

148.

149.

150.

151.

Israeli military population. J Periodontol 2000: 71: 1521

1527.
Kaur G, Holtfreter B, Rathmann W, Schwahn C, Wallaschofski H, Schipf S, Nauck M, Kocher T. Association between type 1 and type 2 diabetes with periodontal disease
and tooth loss. J Clin Periodontol 2009: 36: 765774.
Kazor C, Taylor GW, Loesche WJ. The prevalence of BANAhydrolyzing periodontopathic bacteria in smokers. J Clin
Periodontol 1999: 26: 814821.
Kebschull M, Demmer RT, Papapanou PN. Gum bug,
leave my heart alone! epidemiologic and mechanistic
evidence linking periodontal infections and atherosclerosis. J Dent Res 2010: 89: 879902.
Khaw KT, Wareham N, Bingham S, Luben R, Welch A, Day
N. Association of hemoglobin A1c with cardiovascular
disease and mortality in adults: the European prospective
investigation into cancer in Norfolk. Ann Intern Med 2004:
141: 413420.
Kinane DF, Radvar M. The effect of smoking on
mechanical and antimicrobial periodontal therapy. J Periodontol 1997: 68: 467472.
King GL. The role of inflammatory cytokines in diabetes
and its complications. J Periodontol 2008: 79(Suppl):
15271534.
Klemetti E, Collin HL, Forss H, Markkanen H, Lassila V.
Mineral status of skeleton and advanced periodontal disease. J Clin Periodontol 1994: 21: 184188.
Kocher T, Schwahn C, Gesch D, Bernhardt O, John U,
Meisel P, Baelum V. Risk determinants of periodontal
disease an analysis of the Study of Health in Pomerania
(SHIP 0). J Clin Periodontol 2005: 32: 5967.
Kopelman P. Health risks associated with overweight and
obesity. Obes Rev 2007: 8(Suppl): 1317.
Kornman KS. Mapping the pathogenesis of periodontitis: a
new look. J Periodontol 2008: 79(Suppl): 15601568.
Krall EA, Dietrich T, Nunn ME, Garcia RI. Risk of tooth loss
after cigarette smoking cessation. Prev Chronic Dis 2006: 3:
A115.
Krall EA, Garcia RI, Dawson-Hughes B. Increased risk of
tooth loss is related to bone loss at the whole body, hip,
and spine. Calcif Tissue Int 1996: 59: 433437.
Kreshover SJ, Russell AL. Periodontal disease. J Am Dent
Assoc 1958: 56: 625629.
Krustrup U, Petersen PE. Periodontal conditions in 3544
and 6574-year-old adults in Denmark. Acta Odontol
Scand 2006: 64: 6573.
Kushiyama M, Shimazaki Y, Yamashita Y. Relationship
between metabolic syndrome and periodontal disease in
Japanese adults. J Periodontol 2009: 80: 16101615.
Laine ML, Loos BG, Crielaard W. Gene polymorphisms in
chronic periodontitis. Int J Dent 2010: 324719. PMID:
20339487. PMCID: PMC2844543.
Lalla E, Cheng B, Lal S, Kaplan S, Softness B, Greenberg E,
Goland RS, Lamster IB. Diabetes mellitus promotes periodontal destruction in children. J Clin Periodontol 2007:
34: 294298.
Lalla E, Cheng B, Lal S, Kaplan S, Softness B, Greenberg E,
Goland RS, Lamster IB. Diabetes-related parameters and
periodontal conditions in children. J Periodontal Res 2007:
42: 345349.
Lalla E, Cheng B, Lal S, Tucker S, Greenberg E, Goland R,
Lamster IB. Periodontal changes in children and adoles-

152.

153.

154.

155.

156.

157.

158.

159.
160.

161.
162.

163.

164.

165.

166.

167.

cents with diabetes: a casecontrol study. Diabetes Care

2006: 29: 295299.
Lalla E, Kunzel C, Burkett S, Cheng B, Lamster IB. Identification of unrecognized diabetes and pre-diabetes in a
dental setting. J Dent Res 2011: 90: 855860.
Lalla E, Lamster IB, Feit M, Huang L, Spessot A, Qu W,
Kislinger T, Lu Y, Stern DM, Schmidt AM. Blockade of
RAGE suppresses periodontitis-associated bone loss in
diabetic mice. J Clin Invest 2000: 105: 11171124.
Lalla E, Papapanou PN. Diabetes mellitus and periodontitis: a tale of two common interrelated diseases. Nat
Rev Endocrinol 2011: 7: 738748.
LaMonte MJ, Hovey KM, Genco RJ, Millen AE, Trevisan M,
Wactawski-Wende J. Five year changes in periodontal
disease measures among postmenopausal women; the
Buffalo OsteoPerio Study. J Periodontol. Epub 2012 July 19.
PMID: 22813344.
Li S, Williams PL, Douglass CW. Development of a clinical
guideline to predict undiagnosed diabetes in dental patients. J Am Dent Assoc 2011: 142: 2837.
Liu R, Desta T, He H, Graves DT. Diabetes alters the response to bacteria by enhancing fibroblast apoptosis.
Endocrinology 2004: 145: 29973003.
Lockhart PB, Bolger AF, Papapanou PN, Osinbowale O,
Trevisan M, Levison ME, Taubert KA, Newburger JW,
Gornik HL, Gewitz MH, Wilson WR, Smith SC Jr, Baddour
LM; on behalf of the American Heart Association Rheumatic Fever, Endocarditis, and Kawasaki Disease Committee of the Council on Cardiovascular Disease in the
Young, Council on Epidemiology and Prevention, Council
on Peripheral Vascular Disease, and Council on Clinical
Cardiology. Periodontal disease and atherosclerotic vascular disease: does the evidence support an independent
association?: a scientific statement from the American
Heart Association. Circulation 2012: 125: 25202544.
Loesche WJ. Periodontal disease as a risk factor for heart
disease. Compendium 1994: 15: 976991.
Looker AC, Orwoll ES, Johnston CC Jr, Lindsay RL, Wahner
HW, Dunn WL, Calvo MS, Harris TB, Heyse SP. Prevalence
of low femoral bone density in older U.S. adults from
NHANES III. J Bone Miner Res 1997: 12: 17611768.
Loos BG. Systemic markers of inflammation in periodontitis. J Periodontol 2005: 76(Suppl): 21062115.
Loos BG, Roos MT, Schellekens PT, van der Velden U,
Miedema F. Lymphocyte numbers and function in relation to periodontitis and smoking. J Periodontol 2004: 75:
557564.
Lopez NJ, Quintero A, Casanova PA, Ibieta CI, Baelum V,
Lopez R. Effects of periodontal therapy on systemic markers
of inflammation in patients with metabolic syndrome: a
controlled clinical trial. J Periodontol 2012: 83: 267278.
Losche W, Karapetow F, Pohl A, Pohl C, Kocher T. Plasma
lipid and blood glucose levels in patients with destructive
periodontal disease. J Clin Periodontol 2000: 27: 537541.
Lundstrom A, Jendle J, Stenstrom B, Toss G, Ravald N.
Periodontal conditions in 70 year old women with osteoporosis. Swed Dent J 2001: 25: 8996.
Manau C, Echeverria A, Agueda A, Guerrero A, Echeverria
JJ. Periodontal disease definition may determine the
association between periodontitis and pregnancy outcomes. J Clin Periodontol 2008: 35: 385397.
Manouchehr-Pour M, Spagnuolo PJ, Rodman HM, Bissada

89

Genco & Borgnakke

168.

169.

170.

171.

172.

173.

174.

175.

176.

177.

178.

179.

180.

181.

182.

183.

90

NF. Impaired neutrophil chemotaxis in diabetic patients

with severe periodontitis. J Dent Res 1981: 60: 729730.
Marazita ML, Burmeister JA, Gunsolley JC, Koertge TE,
Lake K, Schenkein HA. Evidence for autosomal dominant
inheritance and race-specific heterogeneity in early-onset
periodontitis. J Periodontol 1994: 65: 623630.
Marcenes WS, Sheiham A. The relationship between work
stress and oral health status. Soc Sci Med 1992: 35: 1511
1520.
Marhoffer W, Stein M, Maeser E, Federlin K. Impairment
of polymorphonuclear leukocyte function and metabolic
control of diabetes. Diabetes Care 1992: 15: 256260.
Martinez-Maestre MA, Gonzalez-Cejudo C, Machuca G,
Torrejon R, Castelo-Branco C. Periodontitis and osteoporosis: a systematic review. Climacteric 2010: 13: 523529.
Matsumoto S, Ogawa H, Soda S, Hirayama S, Amarasena
N, Aizawa Y, Miyazaki H. Effect of antimicrobial periodontal treatment and maintenance on serum adiponectin in type 2 diabetes mellitus. J Clin Periodontol 2009: 36:
142148.
Menezes AMA, Rocha FAC, Chaves HV, Carvalho CBM,
Ribeiro RA, Brito GAC. Effect of sodium alendronate on
alveolar bone resorption in experimental periodontitis in
rats. J Periodontol 2005: 76: 19011909.
Meng H, Ren X, Tian Y, Feng X, Xu L, Zhang Li, Lu R, Shi D,
Chen Z. Genetic study of families affected with aggressive
periodontitis. Periodontol 2000 2011: 56: 87101.
Michalowicz BS, Aeppli D, Virag JG, Klymp DG, Hinrichs
JE, Segal NL, Bouchard TJ Jr, Pihlstrom BL. Periodontal
findings in adult twins. J Periodontol 1991: 62: 293299.
Michalowicz BS, Diehl SRR, Gunsolley JC, Sparks BS, Brooks
CN, Koertge TE, Califano JV, Burmeister JA, Schenkein HA.
Evidence of a substantial genetic basis for risk of adult
periodontitis. J Periodontol 2000: 71: 16991707.
Michalowicz BS, Hodges JS, DiAngelis AJ, Lupo VR, Novak
MJ, Ferguson JE, Buchanan W, Bofill J, Papapanou PN,
Mitchell DA, Matseoane S, Tschida PA, OPT Study.
Treatment of periodontal disease and the risk of preterm
birth. N Engl J Med 2006: 355: 18851894.
Miley D, Garcia MN, Hildebolt CF, Shannon WD, Couture
RA, Anderson SpearieCL, Dixon DA, Langenwalter EM,
Mueller C, Civitelli R. Cross-sectional study of vitamin D
and calcium supplementation effects on chronic periodontitis. J Periodontol 2009: 80: 14331439.
Mohammad AR, Bauer RL, Yeh CK. Spinal bone density
and tooth loss in a cohort of postmenopausal women. Int
J Prosthodont 1997: 10: 381385.
Mohammad AR, Brunsvold M. The strength of association
between systemic postmenopausal osteoporosis and
periodontal disease. Int J Prosthodont 1996: 9: 479483.
Mohammad AR, Hooper DA, Vermilyea SG, Mariotti A,
Preshaw PM. An investigation of the relationship between
systemic bone density and clinical periodontal status in
postmenopausal Asian-American women. Int Dent J 2003:
53: 121125.
Monteiro da Silva AM, Newman HN, Oakley DA. Psychosocial factors in inflammatory periodontal diseases. A review. J Clin Periodontol 1995: 22: 516526.
Morita I, Inagaki K, Nakamura F, Noguchi T, Matsubara T,
Yoshii S, Nakagaki H, Mizuno K, Sheiham A, Sabbah W.
Relationship between periodontal status and levels of
glycated hemoglobin. J Dent Res 2012: 91: 161166.

184. Morita I, Okamoto Y, Yoshii S, Nakagaki H, Mizuno K,

Sheiham A, Sabbah W. Five-year incidence of periodontal
disease is related to body mass index. J Dent Res 2011: 90:
199202.
185. Morita T, Ogawa Y, Takada K, Nishinoue N, Sasaki Y,
Motohashi M, Maeno M. Association between periodontal
disease and metabolic syndrome. J Public Health Dent
2009: 69: 248253.
186. Morita T, Yamazaki Y, Mita A, Takada K, Seto M, Nishinoue N, Sasaki Y, Motohashi M, Maeno M. A cohort study
on the association between periodontal disease and the
development of metabolic syndrome. J Periodontol 2010:
81: 512519.
187. Morozumi T, Kubota T, Sato T, Okuda K, yhoshie H.
Smoking cessation increases gingival blood flow and
gingival crevicular fluid. J Clin Periodontol 2004: 31: 267
272.
188. Mosen DM, Pihlstrom DJ, Snyder JJ, Shuster E. Assessing
the association between receipt of dental care, diabetes
control measures and health care utilization. J Am Dent
Assoc 2012: 143: 2030.
189. Moss ME, Beck JD, Kaplan BH, Offenbacher S, Weintraub
JA, Koch GG, Genco RJ, Machtei EE, Tedesco LA. Exploratory casecontrol analysis of psychosocial factors and
adult periodontitis. J Periodontol 1996: 67: 10601069.
190. Mowat A, Baum J. Chemotaxis of polymorphonuclear
leukocytes from patients with diabetes mellitus. N Engl J
Med 1971: 284: 621627.
191. Nelson RG, Shlossman M, Budding LM, Pettitt DJ, Saad
MF, Genco RJ, Knowler WC. Periodontal disease and noninsulin-dependent diabetes mellitus in Pima Indians.
Diabetes Care 1990: 13: 836840.
192. Nesbitt MJ, Reynolds MA, Shiau H, Choe K, Simonsick EM,
Ferrucci L. Association of periodontitis and metabolic
syndrome in the Baltimore Longitudinal Study of Aging.
Aging Clin Exp Res 2010: 22: 238242.
193. Newnham JP, Newnham IA, Ball CM, Wright M, Pennell
CE, Swain J, Doherty DA. Treatment of periodontal disease
during pregnancy: a randomized controlled trial. Obstet
Gynecol 2009: 114: 12391248.
194. Nishida M, Grossi SG, Dunford RG, Ho AW, Trevisan M,
Genco RJ. Calcium and the risk for periodontal disease.
J Periodontol 2000: 71: 10571066.
195. Nishida N, Tanaka M, Hayashi N, Nagata H, Takeshita T,
Nakayama K, Morimoto K, Shizukuishi S. Determination
of smoking and obesity as periodontitis risks using the
classification and regression tree method. J Periodontol
2005: 76: 923928.
196. Norberg M, Lindvall K, Stenlund H, Lindahl B. The obesity
epidemic slows among the middle-aged population in
Sweden while the socioeconomic gap widens. Glob Health
Action 2010 Dec 10; 3. doi:10.3402/gha.v3i0.5149 PMID:
21160918.
197. Norderyd O. Risk for periodontal disease in a Swedish
adult population. Cross-sectional and longitudinal studies
over two decades. Swed Dent J Suppl 1998: 132: 167.
198. Norderyd O, Henriksen BM, Jansson H. Periodontal disease in Norwegian old-age pensioners. Gerodontology
2012: 29: 48.
199. Norderyd O, Hugoson A, Grusovin G. Risk of severe periodontal disease in a Swedish adult population. A longitudinal study. J Clin Periodontol 1999: 26: 608615.

Risk factors for periodontal diseases

200. Nordin BEC, Wishart JM, Clifton PM, McArthur R,
Scopacasa F, Need AG, Morris HA, OLoughlin PD, Horowitz M. A longitudinal study of bone-related biochemical
changes at the menopause. Clin Endocrinol 2004: 61: 123
130.
201. Novaes AB Jr, Gonzalez Gutierrez F, Grisi MF, Novaes AB.
Periodontal disease progression in type 2 non-insulindependent diabetes mellitus patients (NIDDM). Part II.
Microbiological analysis using the BANA test. Braz Dent
J 1997: 8: 2733.
202. Novak KF, Taylor GW, Dawson DR, Ferguson JE II, Novak
MJ. Periodontitis and gestational diabetes mellitus:
exploring the link in NHANES III. J Public Health Dent
2006: 66: 163168.
203. OConnell PA, Taba M, Nomizo A, Foss Freitas MC, Suaid
FA, Uyemura SA, Trevisan Gl, Novaes AV, Souza SL,
Palioto DB, Grisi MF. Effects of periodontal therapy on
glycemic control and inflammatory markers. J Periodontol
2008: 79: 774783.
204. Ogawa H, Yoshihara A, Hirotomi T, Ando Y, Miyazaki H.
Risk factors for periodontal disease progression among
elderly people. J Clin Periodontol 2002: 29: 592597.
205. Oliver RC, Brown LJ, Loe H. Periodontal diseases in the
United States population. J Periodontol 1998: 69: 269278.
206. Page RC, Eke PI. Case definitions for use in populationbased surveillance of periodontitis. J Periodontol 2007:
78(7 Suppl.): 13871399.
207. Page RC, Kornman KS. The pathogenesis of human periodontitis: an introduction. Periodontol 2000 1997: 14: 9
11.
208. Papantonopoulos GH. Smoking influences decision making in periodontal therapy: a retrospective clinical study. J
Periodontol 1999: 70: 11661173.
209. Papapanou P. Periodontal diseases: epidemiology. Ann
Periodontol 1996: 1: 136.
210. Patel RA, Wilson RF, Palmer RM. The effect of smoking on
periodontal bone regeneration: a systematic review and
meta-analysis. J Periodontol 2012: 83: 143155.
211. Payne JB, Reinhardt RA, Nummikoski PV, Dunning DG,
Patil KD. The association of cigarette smoking with alveolar bone loss in postmenopausal females. J Clin Periodontol 2000: 27: 658664.
212. Perri R, Nares S, Zhang S, Barros SP, Offenbacher S.
MicroRNA modulation in obesity and periodontitis. J Dent
Res 2012: 91: 3338.
213. Peruzzo DC, Benatti BB, Ambrosano GM, Nogueira-Filho
GR, Sallum EA, Casati MZ, Nociti FH Jr. A systematic review of stress and psychological factors as possible risk
factors for periodontal disease. J Periodontol 2007: 78:
14911504.
214. Petit MD, van Steenbergen TJ, Timmerman MF, de Graff J,
van der Velden U. Prevalence of periodontitis and suspected periodontal pathogens in families of adult periodontitis patients. J Clin Periodontol 1994: 21: 7685.
215. Petropoulos G, McKay IJ, Hughes FJ. The association between neutrophil numbers and interleukin-1-alpha concentrations in gingival crevicular fluid of smokers and
nonsmokers with periodontal disease. J Clin Periodontol
2004: 31: 390395.
216. Pickup JC. Inflammation and activated innate immunity
in the pathogenesis of type 2 diabetes. Diabetes Care 2004:
27: 813823.

217. Pindborg JJ. Tobacco and gingivitis (I). J Dent Res 1947: 26:
261264.
218. Pradhan A. Obesity, metabolic syndrome, and type 2
diabetes: inflammatory basis of glucose metabolic disorders. Nutr Rev 2007: 65: S152S156.
219. Preber H, Bergstrom J. Effect of cigarette smoking on
periodontal healing following surgical therapy. J Clin
Periodontol 1990: 17: 324328.
220. Preshaw PM, Heasman L, Stacey F, Steen N, McCracken
GI, Heasman PA. The effect of quitting smoking on
chronic periodontitis. J Clin Periodontol 2005: 32: 869879.
221. Prokopenko I, McCarthy MI, Lindgren CM. Type 2 diabetes:
new genes, new understanding. Trends Genet 2008: 24: 613
621.
222. Pucher JJ, Shibley O, Dentino AR, Ciancio SG. Results of
limited initial periodontal therapy in smokers and nonsmokers. J Periodontol 1997: 68: 851856.
223. Rai B, Kaur J, Anand SC, Jacobs R. Salivary stress markers,
stress and periodontitis: a pilot study. J Periodontol 2011:
82: 287292.
224. Ramfjord SP. Indices for prevalence and incidence of
periodontal disease. J Periodontol 1959: 30: 5159.
225. Rapp GE. Genetic power of a Brazilian three-generation
family with generalized aggressive periodontitis. II. Braz
Dent J 2011: 22: 6873.
226. Recker R, Lappe J, Davies KM, Heaney R. Bone remodeling
increases substantially in the years after menopause and
remains increased in older osteoporosis patients. J Bone
Miner Res 2004: 19: 16281633.
227. Rios HF, Giannobile WV. Ch. 11. Periodontal disease and
osteoporosis. In: Genco RJ, Williams RC, editors. Periodontal disease and overall health: a clinicians guide.
Yardley, PA: Professional Audience Communication; 2010:
162178, http://www.colgateprofessional.com/professional
education/Periodontal-Disease-and-Overall-Health-AClinicians-Guide/.
228. Rosania AE, Low KG, McCormich CM, Rosania DA. Stress,
depression, cortisol, and periodontal disease. J Periodontol
2009: 80: 260266.
229. Rosenzweig JL, Ferrannini E, Grundy SM, Haffner SM,
Heine RJ, Horton ES, Kawamori R, Endocrine Society.
Primary prevention of cardiovascular disease and type 2
diabetes in patients at metabolic risk: an Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab
2008: 93: 36713689.
230. Rubin DB. The design versus the analysis of observational
studies for causal effects: parallels with the design of
randomized trials. Statis Med 2007: 26: 2036.
231. Russell AL. Epidemiology of periodontal disease. Intl Dent
J 1967: 17: 282296.
232. Saito T, Shimazaki Y, Kiyohara Y, Kato I, Kubo M, Iida M,
Koga T. The severity of periodontal disease is associated
with the development of glucose intolerance in non-diabetics: the Hisayama study. J Dent Res 2004: 83: 485490.
233. Saito T, Yamaguchi N, Shimazaki Y, Hayashida H, Yonemoto K, Doi Y, Kiyohara Y, Iida M, Yamashita Y. Serum levels
of resistin and adiponectin in women with periodontitis:
the Hisayama study. J Dent Res 2008: 87: 319322.
234. Salvi GE, Collins JG, Yalda B, Arnold RR, Lang NP, Offenbacher S. Monocytic TNF-a secretion patterns in IDDM
patients with periodontal diseases. J Clin Periodontol 1997:
24: 816.

91

Genco & Borgnakke

235. Salvi GE, Yalda B, Collins JG, Jones BH, Smith FW, Arnold
RR, Offenbacher S. Inflammatory mediator response as a
potential risk marker for periodontal diseases in insulindependent diabetes mellitus populations. J Periodontol
1997: 68: 127135.
236. Sanders AE, Slade GD, Fitzsimmons TR, Bartold PM.
Physical activity, inflammatory biomarkers in gingival
crevicular fluid and periodontitis. J Clin Periodontol 2009:
36: 388395.
237. Saremi A, Nelson RG, Tulloch-Reid M, Hanson RL, Sievers
ML, Taylor GW, Shlossman M, Bennett PH, Genco R,
Knowler WC. Periodontal disease and mortality in type 2
diabetes. Diabetes Care 2005: 28: 2732.
238. Savage A, Eaton KA, Moles DR, Needleman I. A systematic
review of definitions of periodontitis and methods that
have been used to identify this disease. J Clin Periodontol
2009: 36: 458467.
239. Saxlin T, Suominen-Taipale L, Kattainen A, Marniemi J,
Knuuttila M, Ylostalo P. Association between serum lipid
levels and periodontal infection. J Clin Periodontol 2008:
35: 10401047.
240. Saxlin T, Suominen-Taipale L, Leiviska J, Knuuttila M,
Ylostalo P. Role of serum cytokines tumour necrosis factor-alpha and interleukin-6 in the association between
body weight and periodontal infection. J Clin Periodontol
2009: 36: 100105.
241. Saxlin T, Ylostalo P, Suominen-Taipale L, Aromaa A,
Knuuttila M. Overweight and obesity weakly predict the
development of periodontal infection. J Clin Periodontol
2010: 37: 10591067.
242. Sbordonne L, Ramaglia L, Barone A, Ciaglia RN, Iacono VJ.
Periodontal status and subgingival microbiota of insulindependent juvenile diabetics: a 3-year longitudinal study.
J Periodontol 1998: 69: 120128.
243. Schaefer AS, Richter GM, Groessner-Schreiber B, Noack B,
Nothnagel M, El Mokhtari N-E, Loos BG, Jepsen S,
Schreiber S. Identification of a shared genetic susceptibility locus for coronary heart disease and periodontitis.
PLoS Genet 2009: 5: e1000378.
244. Schaefer AS, Richter GM, Nothnagel M, Manke T, Dommisch H, Jacobs G, Arit A, Rosenstiel P, Noack B, GroessnerSchreiber B, Jepsen S, Loos BG, Schreiber S. A genome-wide
association study identifies GLT6D1 as a susceptibility locus
for periodontitis. Human Molec Genet 2010: 19: 553562.
245. Schafer AS, Jepsen S, Loos BG. Periodontal genetics: a
decade of genetic association studies mandates better
study designs. J Clin Periodontol 2011: 38: 103107.
246. Schunkert H, Erdmann J, Samani NJ. Genetics of myocardial infarction: a progress report. Eur Heart J 2010: 31:
918925.
247. Seiffert K, Hosoi J, Torii H, Ozawa H, Ding W, Campton K,
Wagner JA, Granstein RD. Catecholamines inhibit the
antigen-presenting capability of epidermal Langerhans
cells. J Immunol 2002: 168: 61286135.
248. Shearer DM, Thomson WM, Caspi A, Moffitt TE, Broadbent JM, Poulton R. Inter-generational continuity in
periodontal health: findings from the Dunedin Family
History Study. J Clin Periodontol 2011: 38: 301309.
249. Shimazaki Y, Saito T, Yonemoto K, Kiyahara Y, Iida M,
Yamashita Y. Relationship of metabolic syndrome to
periodontal disease in Japanese Women: the Hisayama
Study. J Dent Res 2007: 86: 271275.

92

250. Shimazaki Y, Shirota T, Uchida K, Yonemoto K, Kiyohara

Y, Iida M, Saito T, Yamashita Y. Intake of dairy products
and periodontal disease: the Hisayama study. J Periodontol 2008: 79: 131137.
251. Shlossman M, Knowler WC, Pettitt DJ, Genco RJ. Type 2
diabetes and periodontal disease. J Am Dent Assoc 1990:
121: 532536.
252. Shoelson SE, Lee J, Goldfine AB. Inflammation and insulin
resistance. J Clin Invest 2006: 116: 17931801.
253. Sima C, Rhourida K, Van Dyke TE, Gyurko R. type 2 diabetes predisposes to enhanced gingival leukocyte margination and macromolecule extravasation in vivo.
J Periodontal Res 2010: 45: 748756.
254. Simmons RK, Alberti KG, Gale EA. The metabolic syndrome: useful concept or clinical tool? Report of a WHO
Expert Consultation. Diabetol 2009: 53: 600605.
255. Simpson TC, Needleman I, Wild SH, Moles DR, Mills EJ.
Treatment of periodontal disease for glycaemic control in
people with diabetes. Cochrane Database Syst Rev 2010: 5:
CD004714.
256. Slade GD, Spencer AJ, Roberts-Thomson KF, eds. Australias dental generations: the National Survey of Adult
Oral Health 200406. AIHW cat. no. DEN 165. Canberra:
Australian Institute of Health and Welfare (Dental Statistics and Research Series No. 34), 2007.
257. Soder B, Nedlich U, Jin LJ. Longitudinal effect of nonsurgical treatment and systemic metronidazole for 1 week
in smokers and nonsmokers with refractory periodontitis:
a 5-year study. J Periodontol 1999: 70: 761771.
258. Solis ACO, Lotufo RFM, Pannuti CM, Brunheiro EC,
Marques AH, Lotufo-Neto F. Association of periodontal
disease to anxiety and depression symptoms, and
psychosocial stress factors. J Clin Periodontol 2004: 31:
633638.
259. Stabholz A, Soskolne WA, Shapira L. Genetic and environmental risk factors for chronic periodontitis and aggressive
periodontitis. Periodontol 2000 2010: 53: 138153.
260. Stein JM, Machulla HK, Smeets R, Lampert F, Reichert S.
Human leukocyte antigen polymorphisms in chronic and
aggressive periodontitis among Caucasians: a meta-analysis. J Clin Periodontol 2008: 35: 183192.
261. Stolerman ES, Florez JC. Genomics of type 2 diabetes
mellitus: implications for the clinician. Nat Rev Endocrinol
2009: 5: 429436.
262. Stratton IM, Adler AI, Neil HA, Matthews DR, Manley SE,
Cull CA, Hadden D, Turner RC, Holman RR. Association of
glycaemia with macrovascular and microvascular complications of type 2 diabetes (UKPDS 35): prospective
observational study. Br Med J 2000: 321: 405412.
263. Sun WI, Chen LL, Zhang SZ, Ren YZ, Qin GM. Changes of
adiponectin and inflammatory cytokines after periodontal
intervention in type 2 diabetes patients with periodontitis.
Arch Oral Biol 2010: 55: 970974.
264. Susin C, Della Vecchia CF, Opperman RV, Haugejorden O,
Albandar JM. Periodontal attachment loss in an urban
population of Brazilian adults: effect of demographic,
behavioral, and environmental risk indicators. J Periodontol 2004: 75: 10331041.
265. Susin C, Haas AN, Valle PM, Oppermann RV, Albandar JM.
Prevalence and risk indicators for chronic periodontitis in
adolescents and young adults in south Brazil. J Clin Periodontol 2011: 38: 326333.

Risk factors for periodontal diseases

266. Suvan J, DAiuto F, Moles DR, Petrie A, Donos N. Association between overweight obesity and periodontitis in
adults. A systematic review. Obes Rev 2011: 12: e381e404.
267. Taguchi A, Ohtsuka M, Nakamoto T, Naito K, Tsuda M,
Kudo Y, Motoyama E, Suei Y, Tanimoto K. Identification of
post-menopausal women at risk of osteoporosis by trained
general dental practitioners using panoramic radiographs.
Dentomaxillofac Radiol 2007: 36: 149154.
268. Takeda M, Ojima M, Yoshioka H, Inaba H, Kogo M,
Shizukuishi S, Nomura M, Amano A. Relationship of serum advanced glycation end products with deterioration of
periodontitis in type 2 diabetes patients. J Periodontol
2006: 77: 1520.
269. Taylor GW. Exploring interrelationships between diabetes
and periodontal disease in African Americans. Compend
Contin Educ Dent 2001: 22 (3 Spec No): 4248.
270. Taylor GW, Borgnakke WS. Periodontal disease: associations with diabetes, glycemic control and complications.
Oral Dis 2008: 14: 191203.
271. Taylor GW, Borgnakke WS, Graves DT. Ch.6. Association
between periodontal diseases and diabetes mellitus. In:
Genco RJ, Williams RC, editors. Periodontal disease and
overall health; a clinicians guide. Yardley, PA: Professional
Audience Communication, 2010: 83104. http://www.
colgateprofessional.com/professionaleducation/PeriodontalDisease-and-Overall-Health-A-Clinicians-Guide/.
272. Taylor GW, Burt BA, Becker MP, Genco RJ, Shlossman M.
Glycemic control and alveolar bone loss progression in
type 2 diabetes. Ann Periodontol 1998: 3: 3039.
273. Taylor GW, Nahra T, Manz M, Braun T, Herman W,
Borgnakke W, Wheeler JR. Periodontal treatment and
medical care costs in people with diabetes. J Dent Res
2009: 88 (Sp Iss A): 254. Available at: http://iadr.confex.com/iadr/2009miami/webprogram/Paper121343.htm
274. Teeuw WJ, Gerdes VE, Loos BG. Effect of periodontal
treatment on glycemic control of diabetic patients: a systematic review and meta-analysis. Diabetes Care 2010: 33:
421427.
275. Tennenberg SD, Finkenauer R, Dwivedi A. Absence of lipopolysaccharide-induced inhibition of neutrophil apoptosis
in patients with diabetes. Arch Surg 1999: 134: 12291233.
276. Tezal M, Grossi SG, Ho AW, Genco RJ. Alcohol consumption and periodontal disease. The Third National
Health and Nutrition Examination Survey. J Clin Periodontol 2004: 31: 484488.
277. Tezal M, Wactawski-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: 14921498.
278 Third National Health and Nutrition Examination Survey,
198894. Hyattsville, MD: Centers for Disease Control
1997: Public use data file no. 7-0627.
279. Thomson WM, Slade GD, Beck JD, Elter JR, Spencer AJ,
Chalmers JM. Incidence of periodontal attachment loss
over 5 years among older South Australians. J Clin Periodontol 2004: 31: 119125.
280. Thorstensson H, Dahlen G, Hugoson A. Some suspected
periodontopathogens and serum antibody response in
adult long-duration insulin-dependent diabetics. J Clin
Periodontol 1995: 22: 449458.
281. Timonen P, Niskanen M, Suominen-Taipale L, Jula A,
Knuuttila M, Ylostalo P. Metabolic syndrome, periodon-

282.

283.

284.

285.

286.
287.

288.

289.

290.

291.

292.

293.

294.
295.

296.

297.

tal infection, and dental caries. J Dent Res 2010: 89: 1068
1073.
Tomas I, Diz P, Tobias A, Scully C, Donos N. Periodontal
health status and bacteraemia from daily oral activities:
systematic review meta-analysis. J Clin Periodontol 2012:
39: 213228.
Tomasi C, Wennstrom JL. Locally delivered doxycycline
improves the healing following non-surgical periodontal
therapy in smokers. J Clin Periodontol 2004: 31: 589595.
Tonetti MS. Cigarette smoking and periodontal diseases:
etiology and management of disease. Ann Periodontol
1998: 3: 88101.
Tonetti MS, Pini Prato G, Cortellini P. Effect of cigarette
smoking on periodontal healing following GTR in infrabony defects. A preliminary retrospective study. J Clin Periodontol 1995: 22: 229234.
Torres de Heens GL. Monozygotic twins are discordant for
chronic periodontitis. J Clin Periodontol 2010: 37: 120128.
Torrungruang K, Gongsakdi V, Laohaviraphab L, Likittanasombat K, Ratanachaiwong W. Association between
cigarette smoking and the intraoral distribution of periodontal disease in Thai men over 50 years of age. J Investig
Clin Dent 2012: 3: 135141.
UK Prospective Diabetes Study Group. Intensive bloodglucose control with sulphonylureas or insulin compared
with conventional treatment and risk of complications in
patients with type 2 diabetes (UKPDS 33). Lancet 1998:
352: 837853.
U.S. Public Health Service, National Institute of Dental
Research. Oral Health of United States Adults: National
Findings. Bethesda, MD: National Institute of Dental Research, 1987: NIH publication number 87-2868.
van der Velden U, Abbas F, Armand S, de Graaff J,
Timmerman MF, van der Weijden GA, van Winkelhoff AJ,
Winkel EG. The effect of sibling relationship on the
periodontal condition. J Clin Periodontol 1993: 20: 683
690.
Van der Velden U, Abbas F, van Steenbergen TJ, De Doete
OJ, Hesse M, De Ruyter C, De Laat VH, de Graaff J. Prevalence of periodontal breakdown in adolescents and presence of Actinobacillus actinomycetemcomitans in subjects
with attachment loss. J Periodontol 1989: 60: 604610.
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: 21162124.
Wimmer G, Kohldorfer G, Mischak I, Lorenzoni M, Kallus
KW. Coping with stress: its influence on periodontal
therapy. J Periodontol 2005: 76: 9098.
World Health Organization. Obesity and overweight. Fact
sheet No. 311, 2006.
World Health Organization. Obesity: preventing and
managing the global epidemic. Report of a WHO consultation. World Health Organ Tech Rep Ser 2000: 894: ixii,
1253.
Xiong X, Buekens P, Bastardis S, Pridjian G. Periodontal
disease and gestational diabetes mellitus. Am J Obstet
Gynecol 2006: 195: 10861089.
Xiong X, Elkind-Hirsch KE, Vastardis S, Delarosa RL,
Pridjian G, Buekens P. Periodontal disease is associated
with gestational diabetes mellitus: a casecontrol study.
J Periodontol 2009: 80: 17421749.

93

Genco & Borgnakke

298. Yan SF, Ramasamy R, Schmidt AM. Receptor for AGE
(RAGE) and its ligands cast into leading roles in diabetes and
the inflammatory response. J Mol Med 2009: 87: 235247.
299. Yoshihara A, Seida Y, Hanada N, Miyazaki H. A longitudinal study of the relationship between periodontal
disease and bone mineral density in community-dwelling
older adults. J Clin Periodontol 2004: 31: 680684.
300. Zadik Y, Bechor R, Galor S, Levin L. Periodontal disease
might be associated even with impaired fasting glucose. Br
Dent J 2010: 208: E20.
301. Zambon JJ, Grossi SG, Machtei EE, Ho AW, Dunford R,
Genco RJ. Cigarette smoking increases the risk for subgingival infection with periodontal pathogens. J Periodontol 1996: 67: 10501054.

94

302. Zambon JJ, Reynolds H, Fisher J, Shlossman M, Dunford

R, Genco RJ. Microbiological and immunological studies
of adult periodontitis in patients with noninsulindependent diabetes mellitus. J Periodontol 1988: 59:
2331.
303. Zhang S, Barros SP, Niculescu MD, Moretti AJ, Preisser
JS, Offenbacher S. Alternation of PTGS2 promoter methylation in chronic periodontitis. J Dent Res 2010: 89:
133137.
304. Zuabi O, Machtei EE, Ben-Aryeh H, Ardekian L, Peled M,
Laufer D. The effect of smoking and periodontal treatment
on salivary composition in patients with established
periodontitis. J Periodontol 1999: 70: 12401246.