PRIMER

a b

Figure 6 | Generalized aggressive periodontitis. a | A 27‑year-old woman had a phobia Nature Reviews
about visiting her| Disease Primers
dentist and
failed to brush her teeth adequately. The periodontal condition around the teeth was untreatable, as the attachment was
destroyed by chronic inflammation and bone loss. The patient eventually lost her teeth and was provided with dentures.
b | The radiographic appearance of a case of less-severe generalized aggressive periodontitis.

antibiotic (or antibiotics) targeting Gram-negative bac­
teria, in the usual adult dose range, for 1–3 weeks98.
Three systematic reviews that evaluated different sys­
temic antibiotic regimens in the treatment of chronic
and aggressive periodontitis concluded that the combin­
ation of amoxicillin and metronidazole seems to be the
most potent and resulted in more-pronounced clinical
improvements in probing depth and clinical attachment
level99–101. A systematic review and meta-analysis of stud­
ies on the use of this antibiotic combination in addition
to non-surgical periodontal therapy concluded that there
is moderate-to-strong evidence to support that this treat­
ment strategy results in significantly superior clinical out­
comes in terms of probing depth reduction, clinical
attachment level gain and bleeding on probing reduction
than s­ caling and root planing alone102. These s­ uperior
outcomes were even more pronounced in sites with
­initially deeper pockets of ≥6 mm. The results of the stud­
ies on adjunctive use of systemic antibiotics are promis­
ing; however, additional research is required to define
specific recommendations on several treatment aspects,
such as drug dosage, duration of adjunctive treatment
and appropriate timing during non-surgical treatment to
initiate antibiotic use. In addition, the potential clinical
improvement needs to be carefully evaluated and out­
weigh the potential risks, which include the emergence
of antibiotic resistance, substantial adverse reactions
and drug interactions98. Furthermore, long-term studies
that include tooth loss as an end point in addition to the
­clinical measurements are needed.
Systemic host response modulation. When used in a
sub-antimicrobial dose, doxycycline targets the host
response. Sub-antimicrobial doses do not have anti­
microbial properties and the mechanism of action of the
drug is exclusively through inhibition of matrix metallo­
proteinases103. A multicentre, randomized controlled
trial104 of daily sub-antimicrobial dose doxycycline in
combination with scaling and root planing provided a
defined but limited improvement in periodontal status,
with compliance as a potential issue and long-term
benefits unknown. Host modulation therapy could
be ­beneficial for patients with increased susceptibility 105.
Limitations of non-surgical therapy
Non-surgical periodontal therapy, with or without
adjunctive therapies, is an effective treatment for chronic
periodontitis: it reduces pocket depth and results in the
formation of some new attachment; however, it also
has several limitations, and surgical therapy might be
required to control inflammation and optimize out­
comes. When used for non-surgical scaling and root
planing, periodontal curettes can reach a mean probing
depth of up to approximately 5.5 mm. The mean prob­
ing depth in which a plaque-free and calculus-free sur­
face can be established is <4 mm (REF. 106). However, in
moderate (4–6 mm) and deep (>6 mm) pockets, curettes
have reduced efficacy, and the possibility of achieving
a calculus-free surface substantially increases with
surgical access for scaling and root planing 107. Several
local anatomical factors can contribute to plaque reten­
tion (BOX 2), and surgical access is frequently required
to elimin­ate plaque and calculus at these sites. Surgical
access is also required when recontouring (reshaping)
of osseous defects is necessary to establish a favourable
osseous architecture or when regenerative procedures
are needed to restore lost periodontal structures108.
Surgical therapy
Several surgical approaches are available. Open flap
debridement is a procedure in which a section of the
­gingiva is surgically separated from the underlying
­tissues to provide visibility and access to the lesion.
Pocket reduction surgery includes resection of soft and
hard tissue using various techniques109,110. Regenerative
surgery includes guided tissue regeneration (the use of
barrier membranes to direct the growth of new perio­
dontium, by preventing the epithelium and connective
tissue from growing in areas where bone and perio­
dontal ligament are desired)111, grafting and the use of

8 | ARTICLE NUMBER 17038 | VOLUME 3 www.nature.com/nrdp

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biologics112. Laser-assisted new attachment procedure
(LANAP)113 has been recently introduced as a con­
servative alternative to surgical therapy. LANAP uses a
Nd:YAG laser for the initial pocket de‑epithelialization
and final fibrin clotting instead of a scalpel and sutures,
and does not include extensive gingival flap elevation.
Treatment outcome
Long-term randomized controlled trials evaluating dif­
ferent modalities of conventional non-surgical and sur­
gical periodontal therapy have shown that all are effective
in improving clinical diagnostic parameters and arrest­
ing disease progression93,114–119. The reported outcomes
have been strikingly consistent among different studies,
independent of location or practice setting (academic or
private). When comparing surgical with non-surgical
therapy, the breakdown rate (disease progression) was
lower for surgical therapy, especially on posterior multi-­
rooted teeth120,121. In fact, surgical access to the diseased
teeth enables a more-accurate determination of progno­
sis; thus, teeth with worse prognosis may be extracted
during the initial surgery, which results in a better long-
term prognosis for the remaining teeth. Appropriate
maintenance and patient compliance with the recom­
mended interval of periodontal maintenance sessions
were key common factors that contributed to long-term
stability of the disease and treatment success93,114–119.
In non-surgical and the majority of surgical perio­
dontal therapies, healing occurs through the formation
of a long junctional epithelium or a new connective
­tissue attachment to the previously diseased root surface.
Regenerative surgical procedures have the potential to
also induce the restoration of lost alveolar bone, perio­
dontal ligament and cementum (the surface layer of the
root), and is the ultimate form of periodontal healing.
A systematic review of guided tissue regeneration con­
cluded that regeneration in intra-bony defects (perio­
dontal defects within the bone surrounded by one, two or
three bony walls) and furcation defects (bone loss at the
base of the root trunk of multi-rooted teeth, where two
or more roots meet) is possible on previously diseased
sites, as evidenced by clinical attachment gain, probing
depth reduction and radiographic bone fill (radiopaque
fill of a previously radiolucent defect in an X‑ray, a find­
ing that on its own, however, does not necessarily mean
that regeneration has taken place); in addition, these
outcomes were significantly better than those obtained
with open flap debridement alone122. Another system­
atic review on periodontal regeneration confirmed these
findings and further added that, for intra-bony defects,
the use of biologics results in clinical improvement that
is generally comparable with that obtained with bone
replacement grafts and guided tissue regeneration, and
that these favourable outcomes can be maintained over
>10 years123,124.
LANAP can induce new attachment and perio­dontal
regeneration113,125 and has the potential to improve clin­
ical outcomes, as shown in a short-term prospective
clinical evaluation126. However, extensive randomized
controlled studies are necessary to evaluate the long-term
efficiency of this procedure compared with the c­ urrent
established non-surgical and surgical approaches.
Periodontal maintenance
Periodontal therapy has the potential to control dis­
ease progression and reduce tooth loss by 10‑fold127–132.
However, the long-term success of periodontal therapy
is strongly dependent on appropriate maintenance after
active treatment has been completed129–133. Periodontal
maintenance consists of the removal of supragingival

Patient with periodontitis

(diagnosed through full-mouth probing and radiographs)

Perform scaling and root planing

Has disease been resolved in all sites?

(Re-evaluation through full-mouth probing)

Yes No

Periodontal maintenance Is unresolved disease localized or generalized?

(full-mouth debridement at regular intervals,
typically every 3 months)

Yes Localized Generalized

No

Is disease controlled in all sites? Scaling and root planing, Systemic antibiotics,
(Evaluation through full-mouth probing local delivery drugs host response modulation
during periodontal maintenance) or periodontal surgery or periodontal surgery

Figure 7 | Decision algorithm for the therapeutic management of chronic periodontitis. Once
Nature diagnosed,
Reviews patients
| Disease Primers
with periodontitis undergo scaling and root planing (deep cleaning), in addition to basic motivation and education on
personal plaque control and reducing modifiable risk factors, such as smoking. If this approach proves successful at
resolving the disease, patients should be offered periodic maintenance therapy comprising debridement (scaling and
root planing). If the disease is not controlled, additional treatment is needed and can comprise antibiotic, host modulation
or surgical therapy.

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PRIMER

Box 2 | Factors that contribute to plaque retention
• Overhanging restoration: iatrogenic extension of a dental restoration into the
interdental space
• Cervical enamel projection: developmental apical extension of enamel, usually
towards a furcation between the roots of molar teeth
• Enamel pearl: developmental focal mass of enamel that forms apical to the
cemento-enamel junction, typically located in the area between the roots of molars
• Distopalatal groove: developmental anomalous groove usually on the palate close
to the root of maxillary (upper teeth) central and lateral incisors
• Root proximity: the closeness of roots of adjacent teeth, typically associated with
inadequate interdental tissue
and subgingival dental plaque, and is performed at
regu­lar intervals for the life of the dentition. In general,
a 3‑month maintenance interval in patients treated
for chronic periodontitis has been shown93,114–119 to be
adequate and appropriate to ensure long-term success
by disturbing the microbial biofilm before it becomes
pathogenic. The maintenance interval can be further
customized depending on patient susceptibility and the
presence or absence of patient-specific risk factors, such
as smoking, diabetes mellitus or the ability to perform
adequate home care.
Supportive periodontal therapy aims at the long-term
maintenance of the periodontium, dentition, occlu­
sion (the contact between the maxillary (upper) and
mandibular (lower) teeth) and oral aesthetics. This is a
challenging phase of therapy as it relies again on patient
motivation and adherence to strict recall intervals and
requires a reasonable investment in time and energy. In a
population of patients treated in a private practice, com­
pliance with the recommended recall interval was erratic
in approximately 50% of those patients treated for chronic
periodontitis, and complete compliance was achieved in
<20% of these patients134. When measures were taken to
improve compliance (for example, reminder phone calls
and postcards, scheduling the following appointment
at the end of each appointment, reinforcement of the
importance of oral hygiene and maintenance, and edu­
cation of dental practice staff members), this percent­
age increased to >30%; however, approximately 20% of
patients never returned for recall, regardless of the efforts
of the practice135. Lack of compliance can substantially
affect long-term prognosis, as the rate of progression
of treated chronic periodontitis without maintenance
­therapy is similar to the rate of untreated disease133.
Management of peri-implant disease
Essentially, the management of peri-implant mucositis
and peri-implantitis is similar to the treatment of conven­
tional periodontal disease, with two main differences. The
first is that the implant is not surrounded by perio­dontal
ligament and, therefore, the blood supply to the tissue
around the implant is somewhat anatomically l­imited.
The second main difference is that titanium implants are
softer than natural teeth and will scratch with conven­
tional mechanical debridement. Thus, cleaning instru­
ments (scalers and curettes) should be coated with softer
materials, such as polytetrafluoroethylene (also known
as Teflon (Chemours, Wilmington, Delaware, USA)
or ­carbon fibre136, or with titanium as well137. Similar
considerations apply to ultrasonic debridement instru­
ments, and tips made of polyether ether ketone are avail­
able. Recently, even less-abrasive instruments, such as
airflow devices, have been shown to be more effective
in vitro in the removal of biofilm with minimal damage
to the implant surface138.
Quality of life
Periodontal disease is a silent disease, often subclinical,
but can negatively affect eating, aesthetics and speaking
in particular 139. Loss of function due to tooth or implant
loss affects mastication and, therefore, digestion and
can greatly affect nutrition and diet 139–141. This effect
on nutrition has the most detrimental consequences
in elderly individuals: studies have suggested that a
non-functioning dentition can severely impair survival
and correlates with hospital visits and morbidity 142.
The considerable aesthetic consequences of bone and
tooth loss and recession of the gingiva can also affect
quality of life. The aesthetic consequences are most
rele­vant to the patient if the anterior periodontium is
­damaged, as the teeth at the back of the mouth are not
readily seen. Halitosis can be a considerable ­problem
in social interactions143. Disrupted dentition with pre­
dom­in­antly aesthetic consequences has been linked
with poor employment prospects144 and marked social
­shyness and inhibitions.
Comorbidities associated with chronic forms of
perio­dontal disease, particularly chronic perio­dontitis,
can also play a part in patient quality of life. Strong evi­
dence from longitudinal studies links chronic perio­
dontitis with diabetes mellitus in a two-way relationship
— that is, chronic periodontitis worsens diabetes melli­
tus and vice versa. Both diseases are thought to adversely
influence the patient’s metabolic balance and overall
inflammatory burden16. Associations between chronic
periodontitis and cardiovascular disease, stress and obe­
sity have also been supported in the literature, but these
associations might be explained by shared risk f­ actors
and comorbidity, rather than being directly causal (FIG. 5).
Periodontal disease has also been associated with poor
pregnancy outcomes (preterm delivery and low birth
weight), but the body of evidence and interventional
studies21 failed to convincingly prove this correlation.
Periodontal disease and pregnancy outcome might be
linked by shared risk factors, comorbidity, inflamma­
tory burden and metabolic syndrome, but the chances
of a causal correlation are low, as the majority of babies
are born to mothers <30 years of age, whereas chronic
periodontitis generally manifests around 35 years of
age4. This temporal discrepancy could be explained
by hypothesizing that chronic gingivitis is associated
with poor pregnancy outcomes, but the mildness of the
extent and severity of chronic gingivitis and the fact that
chronic gingivitis is common in the global population
would suggest that this correlation is also improbable.
Nevertheless, adequate oral hygiene is undoubtedly
important in reducing or preventing chronic gingivitis
and, therefore, any as yet unconfirmed risk145.

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 PRIMER

Outlook human periodontal disease148. Thus, although immuni­

Diagnostics
Clinical measures, such as pocket depth, clinical attach­
ment level and bleeding on probing, are essential for
the diagnosis of periodontal disease79 and have not
been ­b ettered, despite concerted efforts to discover
bio­markers in saliva and gingival crevicular fluid (the
inflammatory exudate that can be collected at the gingi­
val margin or within the gingival crevice). Greater
awareness of periodontal disease and more-sensitive and
speci­fic diagnostic methods will enable general dentists
to prevent and diagnose chronic periodontitis early and
refer patients for specialist treatment rapidly. The use
of multiple biomarkers for screening, diagnosis and
prediction of disease progression has been extensively
studied; however, only one is currently commercially
available (neutrophil collagenase; also known as matrix
­metalloproteinase 8) in some European countries45.
The ratio between the proteins tumour necrosis fac­
tor ligand superfamily member 11 (also known as recep­
tor activator of nuclear factor-κB ligand (RANKL)),
which promotes osteoclast differentiation and activ­
ation, and tumour necrosis factor receptor superfamily
member 11B (also known as osteoprotegerin), which
acts as a decoy receptor for RANKL, thereby neutral­
izing its osteoclastogenesis-promoting function, shows
promise in detecting bone loss and, therefore, cur­
rent chronic periodontitis activity, but cannot predict
future disease. Many other molecules related to tissue
destruction, such as matrix metalloproteinases45, and
periodontal inflammation, such as cytokines, are being
investigated as possible diagnostic biomarkers, but have
still to meet the sensitivity and specificity requirements
to be used as predictors of disease course146. The natural
history and nature of periodontal disease substantially
complicate the discovery of predictive biomarkers, as
periodontal disease progresses episodically with diffi­
cult to define quiescent and active periods. Clinical
attachment loss remains the strongest predictor of
future attachment loss79, and the absence of certain clin­
ical inflammatory signs, such as bleeding on probing,
is an excellent negative predictor of periodontal inflam­
mation147. Although currently of limited use, in the
future, biomarkers could be developed that would over­
come specificity, sensitivity and utility concerns and be
widely used146.
Vaccination against periodontal disease
Vaccination against putative bacteria that are impli­
cated in periodontal disease has been tested in a mouse
model148. The results suggest that it could be possible
to vaccinate against P. gingivalis infection and that the
immunological protection could manifest through alter­
ation of the TH17–Treg cell balance. Many questions and
potential pitfalls remain, most importantly regarding the
effectiveness of a mouse model of periodontal disease,
as mice are generally not susceptible to the disease and
their immune response is markedly different from that
of humans, and there is lack of evidence on the specific
involvement and importance of TH17‑mediated immuno­
logical pathways in the pathogenesis or aetiology of
zation against periodontal disease could be developed
in the future, it is far from clear what manner it will take
and what elements of immunity could be involved.
Management
Tissue engineering. Regenerating lost tissues is the ulti­
mate therapeutic goal. Novel periodontal therapies have
incorporated gene-based, protein-based and cell-based
tissue regeneration approaches coupled with scaffolding
and guiding biomaterials, which can be resorbable or
non-resorbable and conventional or 3D printed149. The
main focus of these approaches is on regenerating bone
to stabilize teeth or implants, but soft tissue regeneration
is also needed, especially for aesthetic purposes. Guided
tissue regeneration has been associated with highly
variable success, and this technique is now only used
in guided bone regeneration, in which the membrane
barrier is placed under the soft tissue (and is, therefore,
less prone to infection) and used as a scaffold or occa­
sionally as a holding device for bone or bone substitute
grafts150. Membranes have now been designed to deliver
antimicrobial or growth-stimulating agents151.
3D printing of biomaterials and inclusion of plasmids,
peptides, proteins and living cells is a rapidly growing
field152. A 3D‑printed bioresorbable scaffold made of
polycaprolactone with compartments to release platelet-­
derived growth factor has been used in one patient in
Italy to repair periodontal defects, and it is still in place
after >1 year 153. However, the long-term use of these
novel methods needs to be addressed in properly con­
ducted randomized controlled trials before ­becoming
standard of care.
Biological mediators used for bone regeneration
include cells, growth factors and gene therapeutics. Stem
cell therapies are in their infancy and ­numerous safety
and regulatory hurdles remain, but sheets of perio­
dontal ligament cells grown from autologous cells have
been implanted into periodontal lesions151. Common
growth factors being researched are platelet-­derived
growth factor, bone morphogenetic proteins and mol­
ecules implicated in vascular and cell growth154. Gene
therapeutics that use plasmids to insert desired genes
into specific cells in specific periodontal sites are being
assessed155 and are considered safer than viral v­ ectors,
which would have long-lasting and unpredict­able
effects as they would insert the genes into a chromo­
some. Adenoviruses and non-integrating lentiviruses
are being researched, and adenoviral vectors contain­
ing bone morphogenetic protein 7 have been used to
enhance attachment and ­differentiation of osteoblasts
to titanium implants155.
Laser therapy. Lasers have been extensively studied
in periodontal therapy and have not demonstrated
superior­ity to existing mechanical debridement pro­
cedures156. A study compared an Er:YAG laser with
an air-abrasive device: both were similarly effective157.
Air-abrasive devices have also been effectively used
in treating peri-implantitis and demonstrated signifi­
cant improvement over conventional carbon curettes

NATURE REVIEWS | DISEASE PRIMERS VOLUME 3 | ARTICLE NUMBER 17038 | 11

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PRIMER

in reducing bleeding on probing 158. Lasers have also
been used in antimicrobial photodynamic therapy to
kill microbial biofilm bacteria; however, although the
outcomes seem promising, studies are conflicting, and
the protocols used are so varied to preclude meaningful
comparisons. Thus, using lasers to debride diseased sur­
faces in periodontal disease, either as a replacement for
mechanical therapy or as antimicrobial agents, is not yet
­recommended as an alternative treatment modality 159.
Host response modulation. As the host-specific inflam­
matory response is considered a key aetiopathogenic
­element (FIG. 3), excessive inflammation and failure of the
resolution of inflammation can affect disease outcome.
Research previously focused on understanding the role
of prostanoids and leukotrienes in the propagation of
the inflammatory response in order to manipulate
it, but recently, attention has turned to enhancing the
resolution of inflammation by enhancing the ‘off signal’
and promoting healing 160. Pro-resolving lipid mediators,
which are produced via the arachidonic acid pathways
and include lipoxins and newly discovered resolvins and
protectins161, are key agonists of resolution pathways
that drive restoration of tissue homeostasis, thereby
­enabling the tissue to heal more effectively and enhanc­
ing the tissue resistance to new or ongoing inflamma­
tion. Experiments in animals and humans on the use
of these agonists to actively regulate the inflammatory
response have been promising 162,163. Resolution agonists
do not work by dampening the inflammatory process,
thereby interfering with crucial host defences, but rather
are physiological agents that accelerate the resolution of
inflammation and might improve bacterial clearance164.
The potential for treating perio­dontal disease with these
lipid mediators is apparent, and future clinical studies
are awaited.

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Acknowledgements
The authors thank M. Benakanakere for assistance in
developing Figure 3.
Author contributions
Introduction (D.F.K.); Epidemiology (P.N.P.); Mechanisms/
pathophysiology (D.F.K.); Diagnosis, screening and prevention
(D.F.K. and P.G.S.); Management (P.G.S.); Quality of life
(D.F.K.); Outlook (D.F.K.); Overview of Primer (D.F.K.).
Competing interests
The authors declare no competing interests.
Publisher’s note
Springer Nature remains neutral with regard to jurisdictional
claims in published maps and institutional affiliations.
How to cite this article
Kinane, D. F., Stathopoulou, P. G. & Papapanou, P. N.
Periodontal diseases. Nat. Rev. Dis. Primers 3, 17038 (2017).

14 | ARTICLE NUMBER 17038 | VOLUME 3 www.nature.com/nrdp

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