Fakhrizal Akbar

20190710020

Review Article
Mechanisms of Bone Resorption in Periodontitis
Alveolar bone loss is a hallmark of periodontitis progression and its prevention is a key
clinical challenge in periodontal disease treatment. Bone destruction is mediated by the host
immune and inflammatory response to the microbial challenge. The osteoclast, the principal
bone resorptive cell, differentiates from monocyte/macrophage precursors under the regulation
of the critical cytokines macrophage colony stimulating factor, RANK ligand, and
osteoprotegerin. TNF-α, IL-1, and PGE2 also promote osteoclast activity, particularly in states of
inflammatory osteolysis such as those found in periodontitis. The pathogenic processes of
destructive inflammatory periodontal diseases are instigated by subgingival plaque microflora
and factors such as lipopolysaccharides derived from specific pathogens.
Bone Homeostasis and Maintenance: Bone is a remarkably dynamic and active tissue,
undergoing constant renewal in response to mechanical, nutritional, and hormonal influences. A
balance between the coupled processes of bone resorption by osteoclasts and bone formation by
osteoblasts is required in a healthy adult. bone resorption plays a major role in the homeostasis of
skeletal and serum calcium levels, and the regulated coupling of resorption to new bone
formation by osteoblasts is required for proper growth, remodelling, and skeletal maintenance.
Bone Cells: Preosteoblasts, osteoblasts, osteocytes, and bone lining cells all arise from the
osteogenic line of cells, which, in turn, arise from primitive mesenchymal cells in bone marrow
stroma and from pericytes adjacent to connective tissue blood vessels. Their differentiation
requires activation of the Osf2/Cbfa gene, which activates expression of osteocalcin, (BSP),
(OPN), and collagen synthesis, and is followed by stimulation from (BMP-) 2 and transforming
(TGF-β). Besides their primary role in bone formation, osteoblasts express chemokines,
prostaglandins, and growth factors. Osteoblastic cells have a major influence on the
environmental responsiveness of osteoclasts through localisation, induction, stimulation, and
inhibition of resorption. Osteocytes are mature bone cells that have become entrapped in bone
matrix and mobilise calcium from matrix for transport and exchange with body fluids in response
to systemic demand. Osteoclasts are highly specialised motile migratory bone resorptive cells,
derived from haematopoietic stem cells. In response to key factors, such as M-CSF/CSF-1,
osteoclast differentiation factor (ODF/RANKL), interleukins (IL), tumor necrosis factor (TNF),
and contact with mineralized bone particles containing osteocalcin, haematopoietic precursors
may undergo differentiation into monocyte and macrophage derived colony forming cells,
circulating peripheral blood monocytes and tissue macrophages, and finally fuse into mature
multicellular osteoclasts.
Cellular Mechanisms of Bone Remodelling: Resorption and Formation. The bone
remodelling cycle operates continually as osteoclasts are constantly removing mature bone, with
new bone simultaneously formed by osteoblasts. This occurs throughout the skeleton in focal
units called bone remodelling units (BRU), with each unit of activity lasting three to four
months. This multistep process functions in four distinct phases of activation, resorption,
reversal, and formation. “Activation” is the initiating event that converts a resting bone surface
into a remodelling surface. During the “resorption” phase, osteoclasts work in concert removing
both mineral and organic components of the bone matrix. The resorption phase lasts about 8–10
days, presumably the life span of the osteoclast. Once most of the mineral and organic matrix has
been resolved, there is a “reversal” phase lasting 7–14 days, marking the transition from
destruction to repair. Here, the coupling of resorption to formation takes place. After completion
of one resorption lacuna, the osteoclast can move along the bone surface and restart resorption or
undergo apoptosis. Numerous paracrine and autocrine chemical signaling factors are involved in
all aspects of remodelling, resorption, proliferation, and coupling.
Bone Formation: Formation of new bone, a two-stage process, begins after a short
reversal phase, commencing with the deposition of osteoid. The initial organic matrix consisting
primarily (90%) of type 1 collagen and various other components is subsequently mineralised
over a period of about 20 days. Noncollagenous bone matrix proteins play a key role in matrix
mineralisation, cellular adhesion, and regulation of cell activity during coupling of formation and
resorption. Osteocalcin, one of the most abundant of these proteins, has a vital role in
mineralization, may act as a chemoattractant, and may be essential for osteoclast differentiation.
Degradation of the Mineral and Organic Matrix: Osteoclasts resorb bone in resorption
lacunae by generating a pH gradient between the cell and bone surface, favouring the mineral-
dissolving action of the osteoclast proteinases. Carbonic anhydrase (CA) II is the main
cytoplasmic source of protons for the acidification of the lacuna. The basolateral membrane
exchangers Na+ and Cl−HCO3 + maintain internal pH at physiologic levels. Degradation
products are removed by transcytosis and finally released into the extracellular space. The
specific enzyme TRAP is located in cytoplasmic vesicles, which fuse to the transcytotic vesicles
to destroy the endocytosed material. When the osteoclast moves away from the resorption
lacuna, phagocytes clean up the debri, and osteoblasts move in to begin bone formation anew.
The dissolution of the mineral phase in the acidic microenvironment below the RB exposes
collagen fibrils to the enzymatic attack of cathepsins B, E, K, S, and L. These cysteine proteases
are secreted by osteoclasts to degrade native collagen at an acidic pH of 4,5.
Regulation of Osteoclastic Bone Resorption: The rate of bone resorption can be
regulated either at the level of differentiation of osteoclasts from their hematopoietic precursor
pool or through the regulation of key functional proteins which control the attachment,
migration, and resorptive activities of the mature cell. As emphasised previously, in states of
disease, a disturbance in the homeostatic balance that is essential for functional bone turnover
results in destructive osteolytic processes. Cytokine regulation is likely to be more important for
trabecular bone, which is closer to the cytokine-rich marrow than cortical bone. The
proinflammatory cytokines (IL-1 and IL-6, TNFs) resorption in periodontitis. The functions of
the immunoregulatory cytokines (IL-2 and IL-4, interferon gamma) are less clear, but low levels
of these may contribute to periodontitis.have been implicated in the stimulation of osteoclastic.
Systemic influences on bone resorption may be exerted by several mediators, including PTH, IL-
1, TNF, TGF, and 1,25-dihydroxyvitamin D3. The polypeptide calcitonin increases cellular
calcium and cAMP and disrupts the clear zone cytoskeleton by decreasing the size of the RB and
altering podosome binding ability.
Local Mediators of Bone Resorption: Local formation of osteoclasts and their
stimulation are required for alveolar bone loss. The roles of local inflammatory mediators
generated by macrophages and T lymphocytes in bone resorption have been extensively studied.
The gingival crevicular fluid (GCF) has been shown to contain a complex array of protein
components that not only irrigate the gingival sulcus but also are released into the oral cavity.
Analysis of GCF has identified cell and humoral responses in both healthy individuals and those
with periodontal disease. Although there is no direct evidence of a relationship between GCF
cytokine levels and disease, interleukin-1 alpha (IL-1α) and IL-1β are known to increase the
binding of PMNs and monocytes/macrophages to endothelial cells, stimulate the production of
PGE2 and the release of lysosomal enzymes, and stimulate bone resorption.
Roles of Receptor Activator of Nuclear Factor-κB Ligand (RANKL) and OPG: The
activation and differentiation of osteoclasts are modulated by three members of the TNF ligand
and receptor super- families: the osteoclastogenesis inducers RANKL, RANK, and OPG.
Osteoprotegerin (OPG), its decoy receptor, is a circulating protein, produced by a variety of cell
types including osteoblasts and marrow stromal cells, which inhibits osteoclast formation by
binding mRANKL, thereby preventing the stimulatory cell-to-cell interaction with preosteoclasts
and inhibiting RANKL/RANK interactions. Other resident periodontal cells including ligament
and gingival fibroblasts also participate in the regulation of bone remodelling and resorption. A
key finding of recent studies is that sRANKL in combination with CSF-1/M-CSF stimulates
osteoclast development from peripheral blood cell precursors by binding to its receptor.
Activation of the RANKL receptor increases the expression of TRAP, β3 integrins, cathepsin K,
and calcitonin receptors on preosteoclasts.
Immunopathogenesis of Periodontal Disease: In chronic periodontal disease,
biologically active substances within bacterial plaque induce a local inflammatory response in
the gingival soft tissues and periodontium. In periodontal disease, the cellular inflammatory
infiltrate of T cells, B cells, macrophages, and neutrophils within gingival connective tissue is
increased, with a concurrent increase in the secretion of inflammatory mediators. Gingival
fibroblasts are heterogenic in that they produce OPG in response to LPS and IL-1, suggesting a
protective role to suppress osteoclast formation; however, they may also augment chronic
inflammatory processes through IL-6 and IFN production.
Role of Specific Immune Cells: CD4+ and CD8+ T cells are present in periodontal
lesions, as are memory and activated T lymphocytes, and different T cell subsets appear involved
in either up- or downregulation of RANKL-mediated periodontal bone resorption. Bacterial
Influence: Similar to other polymicrobial diseases, periodontitis is now characterized as a
microbial-shift disease owing to a well characterized change in the microorganisms that are
present during the transition from periodontal health to periodontal disease. The pathogenic
processes of periodontal diseases are primarily due to the host response, which propagates the
destruction initiated by microbes. Harmful pathogenic products and enzymes such as
hyaluronidases, collagenases, and proteases break down extracellular matrix components in order
to produce nutrients for their growth. Bacterial virulence factors are capable of potentiating bone
resorption themselves. Endotoxin from Gram-negative cell walls activates CD4+ T cells to
stimulate resorption via their interaction with macrophages.
The Innate Immune Response, TLRs, and PAMPs: The host response against
periodontopathic bacteria consists of innate and acquired immunity. The innate response meets
the challenge of discriminating among large numbers of pathogens through recognition of
conserved evolutionary molecular motifs called PAMPs (pathogen associated molecular
patterns), which are expressed on pathogens but not by the host. The TLR-PAMP interaction
results in the recruitment of specific adapter molecules, which then bind the IL-1R- associated
kinase. Collective data over the last few years provide evidence that gingival fibroblasts and
periodontal ligament cells are equipped to respond to LPS stimulation through TLR PAMP
recognition and involvement of the RANKL-mediated responses, producing various
inflammatory cytokines, such as IL-1, IL-6, and IL-8, when stimulated by oral bacterial LPS
fractions from pathogens such as Pg, Pi (Prevotella intermedia), or Aa. Osteoblasts, which are
highly sensitive to PAMPS, can also be induced to produce mediators and cytokines that are
involved in bone resorption, as well as inhibition of the protective factor OPG. In addition, LPS
from different periodontopathogens, CPg DNA, and Aa capsular polysaccharide promote
osteoclast differentiation from bone marrow cells. Thus, in summary, LPS induced disease leads
to the initiation of a local host response in gingival tissues that involves recruitment of
inflammatory cells, generation of prostanoids and cytokines, elaboration of lytic enzymes, and
activation of osteoclasts.
Bone resorption via osteoclasts and bone formation via osteoblasts are coupled, and their
dysregulation is associated with numerous diseases of the skeletal system. A wide range of host
and microbial factors contribute to alveolar bone loss in periodontitis. Yet, much remains to be
understood about the complex mechanisms whereby these factors regulate bone resorption in
periodontitis. Recent developments in the area of biological processes and mediators of
osteoclast differentiation and activity have expanded our knowledge of resorption processes and
set the stage for new diagnostic and therapeutic modalities to treat situations of localized bone
loss as seen in periodontal disease.
 Review Article
Prevalence of periodontal disease, its association with systemic diseases and
prevention
Periodontal diseases are prevalent both in developed and developing countries and
affect about 20-50% of global population. High prevalence of periodontal disease in adolescents,
adults, and older individuals makes it a public health concern. Several risk factors such as
smoking, poor oral hygiene, diabetes, medication, age, hereditary, and stress are related to
periodontal diseases. Oral disease prevention strategies should be incorporated in chronic
systemic disease preventive initiatives to curtail the burden of disease in populations. The
reduction in the incidence and prevalence of periodontal disease can reduce its associated
systemic diseases and can also minimize their financial impact on the health-care systems. It is
hoped that medical, dental practitioners, and other health-care professionals will get familiar with
perio-systemic link and risk factors, and need to refer to the specialized dental or periodontal
care.
Periodontal disease is a chronic inflammatory disease of periodontium and its advanced
form is characterized by periodontal ligament loss and destruction of surrounding alveolar bone.
Periodontal disease is the most common oral condition of human population. The prevalence and
incidence statistics of periodontal diseases vary because of bias, case misclassification, and the
number of teeth and the sites examined. WHO has maintained global oral health data bank using
community periodontal index (CPI). This global oral health data from large epidemiological
studies from different countries were gathered to show the distribution of periodontal disease in
adolescents, adults and elderly populations. CPI index score ranges from 0 to 4 and describes the
periodontal condition of individuals at population level. CPI score 0 represents no periodontal
disease; score 1 means gingival bleeding on probing; score 2 shows the presence of calculus and
bleeding; score 3 indicates shallow periodontal pockets of 4-5 mm; score 4 represents deep
periodontal pockets of 6 mm or above.
Modifiable Risk Factors :
 Smoking: Smoking is one of the most important risk factors for periodontitis, and the
reduction in periodontal disease prevalence is related to the drop in smoking rates. The
nicotine has been shown to cause periodontal tissue breakdown, directly or indirectly
through interaction with other factors.
 Poor oral hygiene: Poor oral hygiene is linked with periodontal disease, and lack of
proper tooth brushing and other measures of oral hygiene can encourage bacterial
deposition and build-up of dental plaque on teeth and gums which can set a stage for
inflammatory changes in periodontal tissues.
 Hormonal changes in females: Hormonal changes in women increase the likelihood of
periodontal disease. Females may experience gingival inflammation before menstruation
and during ovulation due to a high level of progesterone which blocks the repair of
collagen fibers and causes the dilatation of blood vessels.
 Diabetes mellitus: Literature consistently shows that diabetes mellitus is one of the
systemic risk factors for periodontal diseases which can play a major role in initiation and
progression of the disease.
 Medications: Vulnerability to infections and periodontal diseases intensifies when there is
diminished salivary flow due to certain medications.
 Stress: It is clear from evidence that stress reduces the flow of salivary secretions which
in turn can enhance dental plaque formation.
Non-modifiable Risk Factors
 Age: The risk of periodontal disease increases with the advancing age that is why the
high prevalence of periodontal disease is seen among elderly population.
 Hereditary: complex interplay of genetic factors with environmental and demographic
factors has been hypothesized to demonstrate wide variations among different racial and
ethnic populations.
 Association of Periodontal Disease with other Medical Conditions:
 Cardiovascular disease
A systematic review identified that periodontitis is a risk factor for coronary heart
disease, and the association is independent of other risk factors such as diabetes,
smoking, and socioeconomic status.
 Metabolic disease
 Adverse pregnancy outcomes: Periodontitis is related to adverse pregnancy outcomes
which include maternal infection, preterm birth, low birth weight, preeclampsia, and
microbiological and immunological factors are implicated in the underlying mechanisms.
 Rheumatoid arthritis (RA): Periodontal disease is prevalent among RA patients, and the
disease is thought to initiate autoimmune response in RA.
 Respiratory diseases: The importance of maintaining optimum oral care among patients
with chronic obstructive pulmonary disease (COPD) has been emphasized due to its
association with periodontitis.
 Chronic kidney disease (CKD)
 Cancers
 Impairment of cognitive function

Prevention of Periodontal Disease:

 Oral hygiene practices: Proper mouth cleaning, regular tooth brushing, and dental
flossing are most effective in preventing oral disease and periodontitis.
 Diet: Although the role of diet in the prevention of dental caries is more significant
compared with preventing periodontal disease; nonetheless, poor diet can negatively
affect periodontal tissues causing rapid progression of disease.
 Use of fluoride: Stannous fluoride has antiplaque and antigingivitis effects and it reduces
the proportion of bacteria and spirochetes in subgingival areas, thus can help to promote
gingival health.
 Use of antimicrobial agents: Chlorhexidine, triclosan, essential oils and zinc in
toothpastes, mouthwashes and gels are used to control specific periodontal bacteria as
well as plaque.
 Smoking cessation: Smoking cessation not only inhibits further progression of
periodontal disease but can also reduce the periodontal tissue destruction.
 Community and high risk approaches

Although periodontal disease is the most prevalent infectious oral condition but is
treatable and preventable. The reduction in the incidence and prevalence of periodontal
disease can result in lowering its associated systemic diseases and complications.
Decreased periodontal disease burden can minimize treatment needs and can reduce
financial impact on health care systems. High prevalence of periodontal disease also
necessitates the establishment of surveillance system for oral diseases in the community.
Preventive programs for periodontal disease should utilize common risk approaches to
reduce the magnitude of other chronic diseases. Cost-effective strategies would also
enhance interdisciplinary collaborations among health-care providers. Health-care
providers should be familiar with perio systemic link and should be able to diagnose and
refer the patients to specialized dental or periodontal care to improve the quality of life of
their patients.
 Review Article
Localized Necrotic Ulceration Gingivitis, in Orthodontic Patient,
Treated with Non- Surgical Periodontal Therapy and with Probiotics (L. Reuteri)
Acute Necrotic Ulcerative Gingivitis constitute a group of aggressive semi-
reversible periodontal disease usually linked to deep microbiome alterations (Treponema
sp., B. melaninogenicus ssp. intermedius and the Fusobacterium sp) and difficult plaque
removal. Patients undergoing in fixed orthodontic treatment could have higher risk in
periodontal/gum disease development. Therapy for resilient and resistant ANUG is
usually represented by pocket debridement and additional systemic therapies.
Orthodontic is set in this way due to its incredible adaptability, wide age range adaptation
and faster results gaining techniques. As orthodontic treatments are widely found to be
effective, careful preventive guidelines need to be provide to dental clinicians and
patients. Periodontal and gum diseases, represent a widespread alteration during
orthodontic fixed treatment due to patients difficult manual debridement and deplaquing
ability. Acute Necrotic Ulcerative Gingivitis constitute a group of aggressive semi-
reversible periodontal disease usually linked to deep microbiome alterations and difficult
plaque removal.
Patients undergoing in fixed orthodontic treatment could have higher risk in
periodontal/gum disease development. ANUG usually show peculiar pathogenic
characteristics. It has an acute clinical presentation with the distinctive characteristics of
rapid onset of interdental gingival necrosis, gingival pain, bleeding, and halitosis.
Systemic symptoms such as lymphadenopathy and general sickness could be also found.
There are various predisposing factors such as stress, nutritional deficiencies, and
immune system dysfunctions (HIV, transplant therapy, immunosuppression). Therapy for
resilient and resistant ANUG is usually represented by causal therapy and chemical
antimicrobial additional systemic therapies (often Metronidazole combined therapy).
The use of topical probiotics in the treatment of gingivitis and ANUG could be
considered a valid alternative to conventional treatments for refractory cases in patients in
orthodontic therapy, for their effectiveness and safety. Further studies, especially
randomized clinical trials, must be performed to confirm this starting result.
 Review Article
Use of Fractal Analysis for the Discrimination of Trabecular Changes Between
Individuals With Healthy Gingiva or Moderate Periodontitis

Accurate assessment of the alveolar bone status is a prerequisite for the diagnosis,
treatment, and prognosis of periodontal disease. Although radiography is one of the most
suitable
methods for periodontal diagnosis, it has proven to be of limited value for early detection
of subtle bone changes. Because two-dimensional images (either film or digital) are
proven to have various drawbacks, such as overlaps, distortion, and magnification of the
size of bone defects. Fractal analysis is an alternative method of quantitatively assessing
trabecular changes of alveolar bone. This is a method for describing complex structural
patterns and is represented numerically as fractal dimension (FD). FD on periapical
radiographs has been used as an identifier of the complex pattern of the alveolar bone
surrounding the dentition. The potential of fractal analysis, which has been proven to be
independent of projection geometry, has been found in numerous applications in several
branches of dental practice related to the evaluation of the trabecular bone.
Many signs and symptoms of periodontitis can be diagnosed both clinically and
with radiographs. However, no diagnostic method is currently available to demonstrate
the initial stages of transition from gingivitis to periodontitis. This discrimination is
essential to the implementation of appropriate treatment. In individuals with periodontitis,
the aim of therapy is to prevent disease progression; the aim of the treatment in patients
with gingivitis is to improve the health of periodontal tissues. Therefore, early detection
of bone breakdown is crucial to prevent major tissue damage.
This preliminary study demonstrates that fractal analysis may be able to discern
changes in the interdental trabecular pattern of patients with moderate periodontitis.
Therefore, as long as digital images are used, fractal analysis is recommended as a
quantitative and objective method in early detection of subtle bone changes associated
with the early stages of periodontal breakdown.