Periodontology 2000, Vol. 70, 2016, 26–37 © 2015 John Wiley & Sons A/S.
y & Sons A/S. Published by John Wiley & Sons Ltd
Printed in Singapore. All rights reserved
Personalized medicine: an
update of salivary biomarkers for
periodontal diseases
D I N A L. K O R T E & J A N E T K I N N E Y
For oral health-care clinicians, there can be a level of
uncertainty in predicting successful periodontal
site-specific treatment outcomes and stability. When
using the conventional approach of probing depths
as a measure of disease progression, more than
2 mm of clinical attachment loss must occur before
a site is deemed as having ‘progressed’, making this
method of monitoring disease breakdown an assess-
ment of disease ‘history’ rather than a ‘real time’
appraisal of disease activity (6, 7). Thus, the need
exists for an innovative diagnostic instrument with
the capability of detecting real-time changes in the
periodontium. Oral fluids, such as gingival crevicular
fluid and saliva, have emerged as potential supple-
mental diagnostic tools. Early investigations focusing
on gingival crevicular fluid sought to identify the
presence and functions of proteins, particularly the
enzymes released from damaged periodontal tissue,
and the complex role of neutrophil-mediated host
defense (21). Later investigations began exploring
saliva as a host-derived oral fluid with potential diag-
nostic capabilities. Saliva is a fluid rich in serum
albumin and in antimicrobial and immunomodulary
proteins, which contribute to mucosal lubrication,
tooth-structure buffering and overall maintenance of
the integrity of the oral cavity (66). Studies have
unveiled the potential to identify and measure pan-
els of biomarkers in saliva for diagnosing periodontal
diseases and monitoring progression and health.
Periodontal tissue physiology and periodontal
diseases are very complex, and have provided
challenges along the way toward reaching the goal of
chair-side salivary diagnostics for individualized
treatment and maintaining periodontal health. This
review serves to provide an overview of salivary
biomarkers that demonstrate potential for diagnostic
26
PERIODONTOLOGY 2000
significance, as well as of panels of combined
markers and periodontal pathogens that reveal
increased sensitivity and specificity for obtaining
accurate diagnostic information.
Periodontal disease diagnosis and
monitoring
Fossil evidence of alveolar bone loss surrounding the
root surfaces of teeth demonstrates that periodontal
disease is an ancient disease and yet remains as the
most common cause of tooth loss in the world today
(19). Periodontal diseases are complex, multifactorial
chronic inflammatory infections which affect the
bone and soft tissue that support the teeth (1, 5, 65).
Microorganisms and microbial products in the pla-
que biofilm are the main etiologic factors that lead to
degradation of the supportive periodontal structures.
In addition, the host immune response, as well as
local and systemic factors, play a significant role in
the process of destruction or maintenance of the peri-
odontium. (19, 56).
Periodontal diseases are widely prevalent in the
USA, where over one-half of adults are affected by
some level of the disease (2). A more recent preva-
lence investigation of adult periodontitis in the USA,
with data from the 2009 and 2010 National Health
and Nutrition Examination Survey, revealed that over
47% of the sample had periodontitis, which equates
to 64.7 million adults (23).
Many studies have been published in the past
decade that contribute to the notion that periodontal
diseases may truly influence a number of systemic
diseases, such as diabetes, cardiovascular events and
osteoporosis. One hypothesis is that bacteria from

plaque biofilm enter the bloodstream and cause
infection and inflammation at a distant site. Another
relates to the stimulation and release of proinflam-
matory cytokines or acute-phase proteins at a distant
site that may intensify or initiate a disease process.
More research is needed to elucidate these associa-
tions, but links are being explored and may provide a
more thorough explanation of the oral–systemic links
(27, 67). The role of inflammation appears to be the
common denominator between periodontal diseases
and some systemic diseases, which emphasizes
the importance of utilizing salivary diagnostics for
periodontal diseases and monitoring.
Current clinical assessments used to determine
periodontal disease severity, response to therapy
and disease activity include: pocket depth; clinical
attachment level; bleeding upon probing; gingival
inflammation; plaque presence or level of oral-hy-
giene care; suppuration; and radiographic bone loss.
An important caveat of periodontal disease diagnosis
is that only after the biologic onset of the disease
process will clinical assessments provide a diagnosis
of periodontal disease (42, 53). In addition, measure-
ment errors, such as probing angulation and force,
can interfere with accurate measurements of attach-
ment level and can be significant enough to distort
clinical treatment planning (31, 35). These clinical
measurements are helpful for assessment, but alone
are unable to determine current disease activity or
future risk of structure loss (86).
Utility of salivary diagnostics in
medicine
The vast amount of saliva is produced by the three
pairs of major salivary glands (parotid, submandibu-
lar and sublingual) with lesser quantities of saliva
originating from hundreds of minor glands located in
the buccal, labial and palatal tissues (80). Saliva also
contains nonsalivary elements, such as gingival
crevicular fluid, desquamated cells, nasopharyngeal
discharge, extraneous debris, and bacteria and bacte-
rial by-products (59, 87).
The typical saliva flow rate varies between 800 and
1,500 ml/day, making it a readily available, plentiful
biological fluid. Another advantage of using saliva as
a ‘real time’ diagnostic specimen is the fact that it can
be collected in a comfortable manner. Unlike a blood
draw and the associated fear of the needle, or a urine
sample and the intrusion of privacy, saliva can be
collection in a noninvasive manner. Deviations in
salivary production and flow rates can be influenced
Salivary diagnostics
by factors such as time of day, duration of collection
time, temperature, hydration status of the individual,
systemic health status of the person and emotional
state of the person (13, 37, 38, 45, 62, 64, 81, 82).
Despite these potential limitations, the analysis of
biomarkers in saliva has been shown for disease
detection, monitoring and compliance with
treatment recommendations, in both medicine and
dentistry (68, 69).
The term ‘biomarker’ refers to biologic substances
that can be measured and evaluated to serve as
indicators of biological health, pathogenic pro-
cesses, environmental exposure and pharmacologic
responses to a therapeutic intervention (74, 76). The
study of salivary proteins and the complete human
salivary proteome provides an insight into the
intricate cellular functional interactions that main-
tain oral and general health. Thus, the biologic
parameters (biomarkers) of health and disease can
be better understood and allow better implementa-
tion of appropriate and personalized preventive
and therapeutic strategies to maintain optimal
health (74).
A great deal of work has been dedicated to
cataloging, centralizing the salivary proteome and
annotating identified saliva proteins (74). This large
database is known as the Saliva Proteome Knowledge
Base and is available to the public (http://www.skb.u-
cla.edu). This central database is crucial in identifica-
tion of combinations of biomarker panels that may
provide distinct diagnostic information and thus
serves as a valuable resource for identifying devia-
tions within proteins or peptides that align with oral
and systemic disease and will aid in the development
of saliva-based diagnostic tests (22).
The proteins found in salivary fluid and blood
plasma fluid have been compared (83). Approxi-
mately 27% of proteins found in whole saliva are also
found in plasma. Of particular interest, almost 40% of
proteins that may be biomarkers for cancer,
cardiovascular disease and stroke can be found in
whole saliva (44). This overlap of proteins in both
plasma and saliva could allow for noninvasive, early
detection and monitoring of oral and systemic dis-
eases (Fig. 1).
Salivary diagnostics may become a reality in the
near future with the development of analytical tools
and reproducible biomarkers. For example, Zhang
et al. (85) recently identified, with high sensitivity and
specificity, salivary messenger RNA biomarkers that
are discriminatory for the detection of resectable pan-
creatic cancer without the complication of chronic
pancreatitis. This is a breakthrough proof-of-concept
27
Korte & Kinney
Fig. 1. Biomarker overlap in saliva and blood plasma fluid.
Salivary glands and their internal lobules are highly perme-
able and are surrounded by capillaries. Cells within the
salivary glands absorb protein leaked from blood plasma
investigation for noninvasive detection of a systemic
cancer (85).
In terms of cardiovascular biomarker research, the
feasibility and utility of a programmable bio-nanochip
(P-BNC) to identify biomarkers of acute myocardial
infarction in saliva, was investigated. Interestingly,
this nanotechnology was able to identify saliva-based
biomarker panels that had significant diagnostic capa-
bility when used in conjunction with an electrocardio-
gram, and far exceeded the screening capacity of an
electrocardiogram alone (17).
Saliva HIV tests have demonstrated comparable
accuracy to the traditional blood test (54). Oral HIV
tests can be a powerful tool for high-risk popula-
tions. Several commercial salivary tests are cur-
rently available within and outside the USA to
screen for or diagnose many other conditions and
disease states, including hormone levels, alcohol and
drugs of abuse (55).
Salivary biomarkers involved in
periodontitis
When considering the periodontal pathogenic pro-
cesses, periodontitis can be generally divided into
three phases: inflammation; connective tissue degra-
dation; and bone turnover. During each phase of the
disease, specific host-derived biomarkers have been
identified and therefore provide a general sense of
28
and secrete these proteins as saliva into the oral cavity. This
free exchange of blood-derived protein molecules into the
oral fluid could allow for early detection and monitoring of
oral and systemic diseases.
what stage of pathologic breakdown the patient is
currently experiencing. In the early inflammatory
stage of the disease, numerous cytokines, such as
prostaglandin E2, interleukin-1, interleukin-6 and
tumor necrosis factor-alpha, are released from a vari-
ety of cells, such as junctional epithelia, connective
tissue fibroblasts, macrophages and polymorphonu-
clear neutrophils (Fig. 2). As the disease progresses,
powerful enzymes, such as matrix metalloproteinase-
8, matrix metalloproteinase-9 and matrix metallopro-
teinase-13, are released at the infected site, which
leads to the destruction of connective tissue collagen
and alveolar bone loss. As the disease becomes more
severe, the levels of tumor necrosis factor, inter-
leukin-1 and RANKL are elevated and ultimately
mediate osteoclastogenesis and alveolar bone break-
down. Bone-specific biomarkers, such as pyridinoline
cross-linked carboxyterminal telopeptide of type I
collagen are dispersed into the surrounding tissue
and subsequently transported via the gingival crevic-
ular fluid into the periodontal pocket and finally into
the oral cavity, becoming a component of saliva (12,
84). Table 1 provides details of individual salivary
biomarkers that have been associated with various
stages of periodontal disease. Although individual
biomarkers have been studied as indicators of period-
ontal disease progression, it is unlikely that one stan-
dalone biomarker will present with sufficiently high
sensitivity and specificity level to meet the criteria of
a diagnostic tool. However, evidence points to panels

of salivary biomarkers and putative periodontal
pathogens that may offer promising applications for
differential diagnosis, treatment planning and moni-
toring, as well as for identification of patients at risk
for future tissue destruction (46, 86).
Inflammatory markers
Periodontal destruction is orchestrated by a number
of mediators, including cytokines. Cytokines are
soluble protein ‘messenger’ molecules that transmit
signals to other cells (3, 20, 73). Cytokines play a key
role in initiating and maintaining immune
and inflammatory responses by stimulating the pro-
duction of secondary mediators. These mediators, in
turn, evoke a cascade of events that amplify the
inflammatory response and induce the production of
enzymes that are responsible for the degrada-
tion of connective tissue and for osteoclastic bone
resorption.
Salivary diagnostics
Fig. 2. Role of molecular mediators
in periodontal disease. Pathogenic
processes in periodontal disease are
characterized by the host immune
defense with the release of polymor-
phonuclear neutrophils (PMN) and
the response of inflammatory-phase
markers [interleukin-1beta (IL-1b)
and tumor necrosis factor-alpha
(TNF-a)], connective tissue degrada-
tion markers [matrix metallopro-
teinases (MMPs) and aspartate
aminotransferase (AST)] and bone
turnover markers [osteoprotegerin
(OPG) and carboxyterminal telopep-
tide of type I collagen]. LPS,
lipopolysaccharide; PGE2, prosta-
glandin E2. Adapted with permission
(57).
One proinflammatory cytokine that plays a
paramount role in chronic inflammation is inter-
leukin-1. Interleukin-1 is produced by several cell
types, including monocytes, polymorphonu-
clear neutrophils, fibroblasts, epithelial cells,
endothelial cells and osteoblasts, and is involved
early in the inflammatory response by recruiting
chemotactic cytokines to the infected periodontal
site (32, 41). Interleukin-1 also stimulates enzymes
necessary for the production of prostaglandin E2
and helps to control metalloproteinases and their
inhibitors. Interleukin-1 induces osteoclastogenesis,
which ultimately results in permanent alveolar
bone loss (9, 32, 58). The sum biological activity of
interleukin-1 is composed of two agonists – inter-
leukin-1alpha and interleukin-1beta – and the
interleukin-1 receptor antagonist. In particular, sali-
vary interleukin-1beta has been shown to be
elevated in periodontal diseases (24, 34, 75). Addi-
tional studies have found salivary interleukin-1beta
29
Korte & Kinney

Table 1. Biomarkers and their potentially destructive role in periodontal disease

Type of marker Salivary biomarker Function References

Inflammatory Interleukin-1beta Potent inflammatory stimulator. Strong correlation 16, 24, 34, 75
with periodontal disease progression
Interleukin-6 Regulates immune and inflammatory responses, 18, 26, 41, 43, 60, 63
and stimulates osteoclast differentiation. Increased
levels in periodontal disease
Macrophage inflammatory Synthesis and distribution of proinflammatory 4, 25
protein-1alpha cytokines. Increased salivary concentration
associated with periodontal disease
Tumor necrosis factor- Inhibits bone collagen synthesis. Induces 33, 46, 61
alpha collagenases
Connective tissue Matrix metalloproteinase-8 Degradation of interstitial collagens. Prevalent host 33, 39, 47, 57, 61
degradation proteinase in periodontal disease
Matrix metalloproteinase-9 Degradation of extracellular matrix proteins. 4, 39, 57, 72
Mediator of tissue destruction and immune
responses in periodontal disease
Tissue inhibitor of Inhibitor of matrix metalloproteinase-8 and 33, 34, 72
metalloproteinase-1 collagenolytic activity. Decreased levels in
periodontal disease
Aspartate Released during cell injury or death. Increased levels 15, 46, 50–52, 78, 79
aminotransferase during periodontal disease progression
Alkaline phosphatase Associated with the calcification process. Increased 46, 50, 51, 79
levels in periodontal disease
Alveolar bone Osteoprotegerin Competitively inhibits osteoclast differentiation and 4, 36, 39, 47, 57
turnover/ activity
resorption
Carboxyterminal Collagen degradation. Released during periodontal 4, 33, 39, 48, 57
telopeptide of type I disease progression
collagen
Microbial Aggregatibacter Putative periodontal pathogen associated with 25, 33
periodontal actinomycetemcomitans chronic and aggressive periodontitis. Carriers may
pathogens be at greater risk for periodontal disease
Porphyromonas gingivalis High prevalence in periodontal disease. Significant 34, 39, 50, 57, 71
predictor of periodontal disease progression.
Increased predictability with alkaline
aminotransferase and the inflammatory
biomarkers interleukin-1beta, interleukin-8 and
matrix metalloproteinase-8
Prevotella intermedia Significant predictor of periodontal disease 50, 71
progression
Tannerella forsythia High prevalence in chronic periodontitis. Increased 34, 39, 57, 71
predictability with the inflammatory biomarkers
interleukin-1beta, interleukin-8 and matrix
metalloproteinase-8
Treponema denticola High prevalence in periodontal disease. Significant 39, 57, 71
predictor of periodontal disease progression.
Increased predictability with inflammatory
biomarkers

to be strongly correlated with periodontal disease periodontal sites (16, 34). Salivary interleukin-1beta
progression and considered to be a good biomar- has also been associated, in a dose-dependent
ker for discriminating between active and inactive manner, with advanced periodontitis (34).

30

Interleukin-6 is a pleiotropic cytokine that,
similarly to interleukin-1, affects the activity of mul-
tiple physiologic and pathologic processes (49).
Interleukin-6 plays a critical role in the regulation of
the immune and inflammatory responses (41, 49,
77). It is produced by several cell types, including
macrophages, neutrophils, keratinocytes, fibroblasts
and endothelial cells (49). Increased salivary levels
of interleukin-6 have been correlated with the pres-
ence of gingivitis and are present in individuals with
periodontitis compared with healthy subjects (11,
18, 26, 63). Salivary interleukin-6 has also been
shown to stimulate osteoclast differentiation and
bone resorption, and is associated with tissue
destruction in periodontitis and peri-implant dis-
ease (43, 60).
Macrophage inflammatory protein occurs in two
forms, namely macrophage inflammatory protein-
1alpha and macrophage inflammatory protein-1beta.
Both macrophage inflammatory proteins are
produced by macrophages after stimulation with
bacterial endotoxins. As a whole, macrophage inflam-
matory proteins belong to a branch of cytokines
called chemotactic cytokines or chemokines. As their
name suggests, these signaling proteins induce an
exacerbated inflammatory effect and are implicated
in the synthesis and distribution of other proinflam-
matory cytokines, such as interleukin-1, interleukin-6
and tumor necrosis factor-alpha. Recently, Al-Sab-
bagh et al. (4) shared the results of their cross-sec-
tional study involving salivary concentrations of
macrophage inflammatory protein-1alpha in subjects
with moderate to severe chronic periodontis
compared with sex- and age-matched healthy coun-
terparts. The mean level of macrophage inflamma-
tory protein-1alpha was 18-fold higher in the
periodontal subjects than in the healthy group,
demonstrating the strong ability of macrophage
inflammatory protein-1alpha to distinguish between
periodontal health and disease.
Another important inflammatory and primary
immune mediator is tumor necrosis factor-alpha.
Tumor necrosis factor-alpha is one of two proteins
associated with the parent cytokine, tumor necrosis
factor; lymphotoxin-alpha, also known as tumor
necrosis factor-beta, is the other protein. This key
biomarker is mainly produced by macrophages and
plays a pivotal role in producing a wide range of
systemic inflammatory responses. Specific to peri-
odontal disease, tumor necrosis factor-alpha has the
ability to inhibit bone collagen synthesis and
induce collagenases, much like interleukin-1 (32, 46).
Interestingly, in 1987, Stashenko et al. (75) reported a
Salivary diagnostics
synergistic effect of interleukin-1 and tumor necrosis
factor, and bone resorption. Salivary levels of tumor
necrosis factor-alpha indicate the presence of
generalized chronic periodontitis and have also
demonstrated significant changes after nonsurgical
periodontal therapy (61).
Connective tissue degradation
Matrix metalloproteinase-8 is one of many matrix
metalloproteinases. Subcategories of matrix metallo-
proteinases include collagenases, gelatinases, strome-
lysins, matrilysins, membrane-type and other matrix
metalloproteinases. As a group, matrix metallopro-
teinases are part of a larger family of proteinases that
function in both normal physiologic states, such as
health, tissue repair and remodeling, as well as in
times of pathological disease destruction and
progression. Proteinases are produced by host
keratinocytes, fibroblasts, periodontal ligament cells,
cementoblasts, osteoblasts and osteoclasts, as well as
by inflammatory and immune cells, such as
neutrophils, monocytes, macrophages and plasma
cells. As a family, matrix metalloproteinases are
responsible for remodeling and degradation of matrix
components of the periodontium and also break
down interstitial and basement membrane collagens.
Matrix metalloproteinase-8, also referred to as
collagenase-2, is one of the most prevalent host
proteinases found in diseased periodontal tissues and
is linked to the degradation of interstitial collagens.
Elevated levels of salivary matrix metalloproteinase-8
have repeatedly demonstrated significant, positive
correlations with increased bleeding upon probing,
clinical attachment level and pocket depth (33, 39, 47,
57). Moreover, significant reductions in salivary
matrix metalloproteinase-8 levels have been found
after periodontal scaling and root planing, suggesting
their potential ability to monitor periodontal disease
activity (61).
Matrix metalloproteinase-9, also called gelatinase
B, is a gelatinolytic enzyme capable of breaking down
extracellular matrix proteins, including type IV
collagen. Recently, matrix metalloproteinase-9 has
gained significant attention in medicine and appears
to be associated with cardiovascular disease, cancer,
multiple sclerosis and neuropsychiatric disorders,
such as schizophrenia and bipolar mood disorder.
Regarding periodontal disease, matrix metallopro-
teinase-9 mediates many functions of the periodontal
disease process, including tissue destruction and
immune responses (39, 57, 72). This biomarker has
consistently demonstrated elevated salivary levels in
31
Korte & Kinney
clinically diseased conditions as well as reduced
salivary levels in clinically stable conditions (4, 39).
Tissue inhibitor of metalloproteinase-1 is one of
four endogenous tissue inhibitors referred to as tissue
inhibitor of metalloproteinases. The main function of
tissue inhibitor of metalloproteinase-1 is to prevent
the collagenolytic activities and function of matrix
metalloproteinases 1, 2, 3, 8, 9 and 13. During periods
of periodontal quiescence, a fine balance between
low levels of matrix metalloproteinases and tissue
inhibitor of metalloproteinase exists. However, during
episodes of disease progression, the delicate balance
between these two enzymes is disrupted with levels
of matrix metalloproteinases escalating and causing
extracellular matrix to be destroyed and ultimately
pathologic periodontal lesions to form (34). For exam-
ple, an increase in matrix metalloproteinase levels
and a decrease of tissue inhibitor of metallopro-
teinase levels triggers collagen degradation from both
connective tissue and alveolar bone (72). The salivary
concentrations of tissue inhibitor of metallopro-
teinase-1 consistently differ between patients with
periodontitis and control subjects, suggesting this
marker as a significant marker for periodontal disease
detection and stability, especially in combination
with salivary matrix metalloproteinase-8 and carboxy-
terminal telopeptide of type I collagen (33).
Aspartate aminotransferase is a soluble cytoplasmic
enzyme that naturally occurs within the cell cyto-
plasm. However, during active phases of periodontal
disease, cells die and aspartate aminotransferase is
released into the surrounding tissues, making this
enzyme a viable marker of disease activity (52).
Chambers et al. (15) published one of the first studies
showing a relationship between increased levels of
aspartate aminotransferase in gingival crevicular fluid
and diseased periodontal tissues during an experi-
mental periodontitis model in Beagle dogs. Since that
time, additional studies have explored the relation-
ship between elevated levels of salivary aspartate
aminotransferase and periodontal disease. Findings
from these studies link periodontal disease progres-
sion, as defined by pocket depth, gingival bleeding
and suppuration, with increased levels of salivary
aspartate aminotransferase (78, 79). When consider-
ing the effects of periodontal treatment on aspartate
aminotransferase levels, there appears to be a parallel
between the levels of aspartate aminotransferase and
periodontal disease activity, with a marked decrease
in aspartate aminotransferase levels after scaling (46,
50, 51).
Alkaline phosphatase is one of many host-derived
enzymes studied for its role in the detection, and
32
progression, of periodontal disease. Early studies
exploring the correlation between alkaline
phosphatase and periodontal disease reported
associations between alkaline phosphatase and
pocket-depth measures and alkaline phosphatase and
levels of inflammation. Totan et al. (79) assessed the
levels of alkaline phosphatase in saliva samples from
clinically diagnosed periodontal patients. The findings
of this study showed that periodontal destruction,
assessed by measurement of pocket depth, gingival
bleeding and suppuration, was associated with higher
levels of alkaline phosphatase in saliva. The levels of
salivary alkaline phosphatase were significantly
increased in subjects with periodontal disease com-
pared with controls (46, 50, 51, 79).
Alveolar bone turnover/resorption
Osteoprotegerin plays an essential role in the devel-
opment and maintenance of bone tissues. It is a
glycoprotein that binds with RANKL and competi-
tively inhibits osteoclast differentiation and activity,
resulting in the stimulation of osteoclasts (47). RANK
and RANKL interactions have been shown to activate
the proliferation, differentiation and survival of osteo-
clasts, resulting in bone resorption. Osteoprotegerin
is involved in preventing the bone-resorption pro-
cess, as a neutralizing receptor for RANKL (14). The
ratio of RANKL and osteoprotegerin plays a critical
role in both physiologic bone reconstruction and
pathological bone loss (14, 36). In a cross-sectional
study, the levels of salivary osteoprotegerin were
shown to have a positive correlation in patients with
increased bleeding upon probing and pocket depths,
but not with clinical attachment levels (47). Addition-
ally, osteoprotegerin was not able to distinguish
patients with periodontal disease from control sub-
jects (47). However, in a more recent investigation,
salivary osteoprotegerin was highly correlated with
periodontal disease status, and osteoprotegerin
concentrations were significantly reduced after
periodontal therapy was provided (39). Salivary con-
centrations of osteoprotegerin were significantly
lower within the clinically stable groups. These
finding suggest that osteoprotegerin, along with
connective tissue degradation markers, could
strengthen the predictability for periodontal disease
activity.
Carboxyterminal telopeptide of type I callagen
biomarkers are specific for alveolar bone deteriora-
tion and offer great potential as an indicator differen-
tiating between patients with gingivitis and those
patients undergoing active periodontal bone destruc-

tion. During active periodontal disease progression,
the carboxyterminal telopeptide of type I callagen is
released as a result of collagen degradation. In medi-
cine, the serum concentrations of carboxyterminal
telopeptide of type I collagen are being evaluated for
their utility as biomarkers for monitoring metastatic
bone levels of patients with prostate cancer. In den-
tistry, salivary levels of carboxyterminal telopeptide of
type I collagen have been shown to be strongly corre-
lated with periodontal clinical measures (33). Addi-
tionally, elevated levels of salivary carboxyterminal
telopeptide of type I collagen have been found in sub-
jects with periodontitis compared with control sub-
jects, but a stronger association can be made when
combined with other markers, such as matrix metal-
loproteinase-8 (33, 48).
Robust panels of biomarkers in
periodontitis
Advances in technologies have allowed development
of new methods for evaluating multiple salivary
biomarkers. Recent cross-sectional and longitudinal
studies have identified potential panels of salivary
biomarkers that may be used to identify sites with
active disease, periodontal stability and positive
responses to therapy. The combinatorial markers are
more robust in predicting periodontal disease pro-
gression and stability (39). Recently, a study examined
six salivary protein biomarkers – matrix metallopro-
teinase-8, osteoprotegerin, macrophage inflamma-
tory protein-1alpha, interleukin-1beta, interleukin-8
and tumor necrosis factor-alpha – associated with
chronic periodontitis (61). These biomarkers are
involved in inflammation, connective tissue degrada-
tion and osteoclast-modulated alveolar bone
turnover. This study demonstrated that three of the
proteins – macrophage inflammatory protein-1a,
matrix metalloproteinase-8 and osteoprotegerin – are
potentially useful in monitoring periodontal disease.
Additionally, matrix metalloproteinase-8 was the
stand out as the best biomarker indicative of response
to therapy (61). Similarly, Kinney et al. (39) demon-
strated a panel of markers (namely matrix
metalloproteinase-8, matrix metalloproteinase-9,
osteoprotegerin and interleukin-lbeta) that, in low
concentrations, predicted periodontal stability in
subjects monitored longitudinally.
Other combinations of biomarkers that have been
identified together in significantly greater numbers in
subjects with periodontal disease compared
with healthy controls are matrix metalloproteinase-8,
Salivary diagnostics
tissue inhibitor of metalloproteinase-1 and carboxy-
terminal telopeptide of type I collagen (33). In the
smoker subjects, the accuracy was significantly greater
when evaluated for proportions of matrix metallopro-
teinase-8 with tissue inhibitor of metalloproteinase-1
and combinations of matrix metalloproteinase-8 with
carboxyterminal telopeptide of type I collagen
(P < 0.001) (33). In another cross-sectional investiga-
tion, matrix metalloproteinase-8 and interleukin-1-
beta were found at significantly higher levels in
subjects with periodontitis compared with healthy
controls (47). Additionally, these two markers demon-
strated a positive correlation with periodontal indices,
bleeding upon probing, clinical attachment level and
percentage of sites with pocket depth ≥4 mm (47).
Longitudinal analyses for periodontal pathogens
and host-response biomarkers have been investigated
for the ability to determine periodontal disease pro-
gression (39, 50, 57). The ‘red-complex’ pathogens
(Porphyromonas gingivalis, Treponema denticola and
Tannerella forsythia) were able to predict periodontal
disease progression and demonstrated an association
with the inflammatory biomarkers interleukin-1beta,
interleukin-8 and matrix metalloproteinase-8. Certain
putative periodontal pathogens, when elevated, were
able to predict periodontal disease progression; these
include the aforementioned ‘red-complex’ patho-
gens, as well as Fusobacterium nucleatum, Campy-
lobacter rectis and Prevotella intermedia. When
clustered together, these microbial markers and
inflammatory markers offer a strong relationship to
current disease status (39, 57). Additionally, alkaline
aminotransferase and P. gingivalis demonstrated
high levels of predictive ability for disease progression
(50). The microbial stand-outs in that study were
P. gingivalis and P. intermedia for their ability to
predict periodontal disease progression. A novel diag-
nostic approach was investigated for the combinato-
rial ability of P. gingivalis, interleukin-1beta and
matrix metalloproteinase-8 to detect periodontitis
(34). From data collected in their previous investiga-
tions, the researchers chose each of these markers as
having the greatest potential to identify the periodon-
tal pathogen burden, inflammatory response and
tissue degradation, respectively. This study proposed
to define ranges (high, medium, low) of disease mark-
ers that could be adopted universally for comparing
study populations. They used a unique approach of
dividing risk into three categories based on cumula-
tions of the three markers and used multiplication of
that result in a score. The three markers together
were able to reveal periodontitis more accurately
than each marker was individually (34).
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Korte & Kinney
Additionally, Fine et al. (25) performed a longitudi-
nal evaluation of salivary cytokines in children who
developed localized aggressive periodontitis, and
reported macrophage inflammatory protein-1alpha
as an early detection biomarker. In this report, the
marker was specific and sensitive in advance of
radiographic evidence of bone loss (25). In a case–
control study, macrophage inflammatory protein-1al-
pha and osteoprotegerin were significantly increased
in subjects with periodontitis compared with healthy
subjects (4). Both of these markers demonstrated a
positive correlation with clinical indices of percentage
bleeding upon probing, percentage pocket depth (≥4
and ≥5 mm) and percentage clinical attachment level.
This cross-sectional study is important because the
level of the chemokine macrophage inflammatory
protein-1alpha was 18-fold higher in the periodontal
disease group. The peptide, procalcitonin, is an estab-
lished serum marker for inflammation. It circulates at
very low levels in periodontal health, but increases
dramatically in subjects with systemic infection. Sali-
vary and serum levels of procalcitonin have been
compared in type 2 diabetes patients with periodon-
tal disease to determine its value as a salivary marker
for periodontitis. Higher mean levels of salivary pro-
calcitonin were found for subjects with periodontitis
compared with healthy control subjects. This group
also found that levels of procalcitonin were correlated
with bleeding upon probing and hyperglycemic levels
(glycated hemoglobin) (10).
Point-of-care diagnostics
Investigators are continuously identifying and
testing the complex periodontal disease ‘signatures’
Fig. 3. Salivary diagnostics at point-of-care. Whole saliva is
an easily collected fluid containing microbial, genetic and
protein markers. Rapid point-of-care assays in a chair-side
processing unit could ultimately provide a biomarker
34
that will allow for accurate chair-side diagnostics
and enhance individualized care (28). New tech-
nologies are becoming available that are capable of
measuring salivary biomarker panels for accurate
periodontal disease diagnosis and treatment recom-
mendations. The time is growing to a point where
oral health-care providers will be able to utilize
high-throughput biomarker validation tools for
rapid chair-side testing (Fig. 3). The focus has been
on the development of miniature-sized ‘chemical
processing units’ that process fluids and provide
information that is relevant to the inflammatory,
connective tissue-degradation and bone-loss phases
of periodontitis (28, 46). As the specific biomarkers
for periodontal disease and progression are deter-
mined through longitudinal analysis, it appears the
technology is prepared to meet the scientific
discovery. Both will come together to allow oral
health-care providers to improve prevention and
treatment of periodontal diseases through personal-
ized medicine.
Personalized medicine in
periodontics
Personalized medicine is a medical model that
uses genetic, genomic, environmental and clinical
diagnostic testing to individualize patient care (28,
40). This approach utilizes clinical assessment and
subclinical profiles to develop highly individualized
diagnosis, prognosis and treatment algorithms (28).
Utilization of this model in oral health care, specif-
ically in periodontology, has the potential to
provide discriminating patient-stratification models
to enhance personalized treatment algorithms.
report that is interpreted by the oral health-care provider,
to improve and personalize clinical decision making and
risk assessments for periodontal diseases. Reprinted with
permission (28).

Personalized medicine for periodontal diseases may
soon involve utilization of saliva to develop
subclinical profiles, identifying and measuring
specific genotypes, phenotypes, putative pathogens,
inflammatory markers and collagen-degradation
biomarkers to make informed clinical decisions
about disease susceptibility, site-specific risk and
treatment interventions (29, 30, 70). When consid-
ering the possible utilization of saliva in a person-
alized model for periodontal disease, one can
imagine implementation at multiple levels –
screening, disease detection, monitoring of treat-
ment outcomes and identification of refractory or
progressing cases. During the screening phase, the
use of saliva to identify patients at risk for future
disease activity opens the door for heightened risk-
management strategies, preventive care and/or
behavior change on the part of the patient to
prevent the onset of disease. At the diagnostic
stage, identifying the presence of disease at the
earliest possible stage may allow for less-invasive,
less-costly treatment. Saliva as a simple mechanism
for monitoring treatment outcomes, as well as
identification of refractory sites, additionally pro-
vides both the patient and the clinician with
valuable information regarding the present state of
the disease (76).
Acknowledgments
The authors thank multimedia designers, Ken Rieger
and Stephanie O’Neil, for providing image design. We
acknowledge the administrative support of Karen
Gardner. We appreciate William Giannobile for criti-
cally reading the manuscript.
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