For many years, medical and dental researchers have been focusing on their own fields of study, conducting researches in medicine related to the general well-being and the health of the oral cavity, respectively. However, the strong relationship between oral disease and systemic conditions has been increasingly studied and proved through the past few decades. Recent studies have provided obvious proof that oral hygiene and systemic well-being are directly related.

The recent findings are strongly suggestive of the presence of an association between periodontal disease and systemic diseases such as osteoporosis, cardiac disease, low birth weight, poor control of diabetes mellitus, and pregnancy complications. The numerous efforts of the researchers from both fields have brought about many breakthroughs in our understanding of the etiological and patho-physiological mechanisms underlying the link between the chronic inflammation present in dental disease and other systemic conditions.
Consequently, there is hope that the important findings from these researches may help dentists to greatly improve the current guidelines in treatment of periodontal disease, to prevent the negative consequences of oral disease on systemic health. Therefore, researchers must continue to not only establish the link between oral health and systemic conditions but also to recognize the positive effects of eliminating periodontal infections on the success of the treatment of systemic disease.

Chronic Periodontitis
Periodontal disease is the condition resulting from accumulation of bacteria in the tissues around the teeth which trigger a chronic inflammatory response from the body. The chronic invasion of the gums by bacteria results in bone destruction and weak attachment between the teeth and the gum. There are several types of periodontal disease, from gingivitis which is the mildest form to periodontitis which is severe and difficult to treat.Several risk factors predispose to the development of periodontitis, such as stress, alcohol consumption, smoking, the normal process of aging and conditions that affect the immune system response such as diabetes and (HIV) infection.

Gingivitis is the most common form which affects 75 percent of adults in the United States. It involves red inflamed gums with frequent bleeding. There are more severe types that affect about 40 percent of the population in the United States. In these types, there are more accumulations of pathogens which lead to stronger inflammatory process and more severe symptoms.The diagnosis of periodontal disease depends on probing depth as an accurate measurement of the grade of inflammation. A depth less than 2 mm of the periodontal pocket is not considered periodontitis.

If the depth of periodontal pockets is 4 mm or more, periodontitis is confirmed. Periodontal pocket depths of 6 mm or more refers to severe periodontitis.The treatment of periodontal disease is usually effective. Such treatments are aimed at eliminating the invading bacteria from the body, ameliorating the inflammatory process, and removing the predisposing factors to prevent further recurrences of the same condition in the future.The main line of treatment of periodontitis is antibiotics that are usually broad spectrum to target most types of bacteria. Antibiotic therapy together with maintaining good oral hygiene, is usually successful in eliminating the infection. However, If the periodontal pockets are not removed, then surgical treatment is indicated to protect against further bone destruction and teeth loss.

Periodontal disease and osteoporosis
Bone loss occurs in both osteoporosis and periodontitis. A decrease in bone mass occurs because of the increased resorption of bone compared to bone formation, leading to demineralization of bone and finally osteoporosis.
Similarly, in addition to weakened attachment of the soft tissue to the teeth, resorption of bone is a feature of periodontal disease: specifically, the alveolar bone.
Because of this common pathological mechanism that is shared between periodontal disease and osteoporosis, researchers have tried to establish the links between the two diseases to recognize the possible effect of having one as a predisposition to the other.
The underlying pathology in the case of increased resorption of bone may be explained by increased local and systemic osteoclastic activity, or by the local action of inflammatory cytokine on the bone tissue. Increased resorption by osteoclasts is characteristic to chronic inflammations as in periodontitis.

In chronic inflammation, the T-lymphocytes express Receptor Activator of Nuclear Factor-kB Ligand and hence it is possible that direct contact between T-lymphocytes and precursor cells to monocytes is involved in the formation of osteoclasts.Osteoprotegerin (OPG) released by stromal cells and osteoblasts inhibits the activation of mature osteoclasts. B-lymphocytes also have a role in formation of osteoclast, either by working as osteoclast progenitor cells or by expressing RANKL.

Nagasawa et al., stated that OPG mRNA was stimulated by P. gingivalis and A.actinomyecetemcomitans, indicating that OPG released by the action of LPS might have a role in the process of osteoclast formation in periodontal disease. The findings linking OPG and periodontitis is supported by other studies involving gram negative bacteria. Because the infection due to these pathogens is usually transient, exposure to periodontal infection may stimulate the activation of RANKL and the activity of osteoclasts, leading to development of osteoporosis in patients with chronic periodontitis.Another major mechanism of osteoporosis in women is oestrogen deficiency. Oestrogen, whether directly or indirectly, has a modulatory action on cytokines that work as regulators of bone metabolism and also modulators of the host inflammatory reaction, such as IL-1 alpha and beta, TNF-alpha, and macrophage colony-stimulating factor (M-CSF). Therefore, oestrogen deficiency leads to an increased number of osteoclasts, because of the same cytokines which inhibit formation of osteoblasts. The disturbed balance of bone metabolism will result in decreased bone mineral density (BMD).

Chronic periodontitis also triggers the host inflammatory reaction, thereby recruiting cytokines and leading to formation of osteoclasts and therefore stimulating absorption of bone. High levels of some of these cytokines, such as IL-1 beta, TNF-alpha, and IL-8, were found in the inflamed gingival tissue in patients with periodontal disease, with concentrations that can cause absorption of alveolar bone.Therefore, numerous studies have found a significant positive link between chronic periodontitis and oestrogen deficiency.

Another research study in Japan focused on the link between oral health and bone mineral density; these findings proved that chronic periodontitis and teeth loss after menopause are directly related to decreased BMD in post-menopausal females, and the deficiency in oestrogen is the suggested underlying mechanism.In a related study, Wactawski-Wende et al., stated that “a strong and consistent association between alveolar crestal height (ACH) and osteoporosis was found through measurements of bone density and ACH in postmenopausal women, with icreasing age as an important modifier of that association”.

Despite the big achievements made in understanding the relationship between periodontal disease and osteoporosis, more efforts are required to clarify the link.
The recognition of this link might provide useful warnings for the risk of osteoporosis, as well as important applications in treatment.Chronic periodontitis and diabetes mellitus
The relationship between periodontal disease anddiabetes mellitus is bidirectional. As it was proved that patients with diabetes are more liable to develop one or more types of periodontal disease, recent datasuggests that periodontal disease can lead to the increased probability of suffering from endocrinal disturbance, including diabetes mellitus.

Chronic periodontitis could lead to bacterial spread to blood and various body organs, and thereby activate cells of the immune system. The stimulated cells trigger inflammatory active substances (cytokines) which have a catabolic action all over body systems.Moreover, the chronically elevated levels of inflammatory cytokines in the body can lead to damage of the beta cells of the pancreas, leading to a decrease in the secretion of insulin. This process can lead to development of diabetes in patients with no family history, obesity, hypercholesterolemia or other risk factors.Due to the possible effect of periodontal disease on the development of insulin resistance and glucose intolerance and finally overt diabetes mellitus, studies have suggested that preventive dental and diabetes measures, in addition to regular dental and diabetes evaluation and follow up, are necessary to break this link between the two conditions.

Chronic periodontitis and malignancy
Many research studies have indicated that chronic periodontitis plays a key role as an independent factor for the development of head and neck squamous cell carcinoma (HNSCC), with specific characteristic site in the oral cavity. Also, it was found that periodontitis predisposes to carcinoma of the oropharynx and the larynx.Michaud et al., 34 found a strong relationship between the chronic presence of periodontal disease and high risk of being diagnosed with lung, renal, pancreatic, and haematological tumours. These relations are the results of a prospective cohort study and they were confirmed in various studies with modification of risk factors, including cigarette smoking and patients’ socioeconomic status.

However, the strongest evidence was found in the research studies of the relationship between oral and oesophageal cancers and chronic periodontal disease.A relationship was proven between gastric and pancreatic cancers and periodontal disease in vast majority of the reviewed papers, although tumours of the lungs and the blood and other tumours were less proven or there were insufficient studies to establish a strong connection.

Moreover, Tezal et al. concluded that having periodontal disease can affect the pathologic type of cancers. The study found that patients with periodontal disease are more liable to have poorly-differentiated types of squamous cell carcinoma of the oral cavity than patients without chronic periodontitis.These results were said to have applications in clinical and preventive measures, diagnosis, and treatment of head and neck squamous cell carcinoma. The possible connection between chronic periodontitis and malignancy is not obvious, but chronic infection exposure is being studied.

Chronic periodontitis and pregnancy
Numerous research studies have focused on the possible relationship between periodontal disease and poor pregnancy outcomes, pregnancy complications and defective health status of the new-born. Recently, many studies have confirmed the presence of a link between low birth weight and preterm babies and chronic periodontal disease regardless of the paternal health status, race, and the age of the mother.
There is also evidence that periodontal disease may be an independent factor for increased susceptibility to pregnancy complications. Primary evidence indicates that treatment of periodontal infection might lead to a decrease in pregnancy-related complications. The underlying mechanism is not clear yet. However, some studies suggest that the presence of bacterial infection leads to stimulation of cell-mediated immunity and then the production of various cytokines including interleukins, prostaglandins, which is important during the process of delivery, and tumour necrosis factor.

The newly-suggested mechanism of labour states that the levels of these cytokines increase significantly within the intra-amniotic through all phases of pregnancy, until a certain high level is reached which induces the process of labour. Therefore, it is quite reasonable to suppose that the presence of any type of infection, for example periodontitis, could lead to increased levels of the normal mediators of delivery leading to preterm birth and possibly low birth weight.

Researchers also suppose that overt infections such as periodontitis can lead to preterm birth and low birth weight through the invading microorganisms or the byproducts and toxins of the bacteria including lipopolysaccharide (LPS), which invade the uterus through blood stream, stimulating cytokine production in the uterus and placenta or in the amniotic fluid, leading to elevated prostaglandin, which stimulates the contraction of the uterine muscles.Moreover, it was indicated that pregnant women who suffer from some degree of periodontal disease are more liable to gestational diabetes mellitus than pregnant women who are free of periodontitis. However, more research studies are needed in the coming years to have a strong statistically significant correlation between periodontal disease and endocrinal disorders including diabetes, as well as the link with poor pregnancy outcomes.

The relationship between periodontal disease and the development of various systemic diseases, such as diabetes mellitus (DM), osteoporosis, pregnancy complications, and coronary vascular disease, is the topic of many research studies.Although most studies have provided evidence suggesting the presence of a positive relationship between periodontal disease and various systemic diseases, many physicians and dentists greatly advocate the need for more studies to confirm these conclusions. In general, more controlled clinical trials and more randomized samples are needed to confirm the relationship between periodontal disease and these systemic diseases.Studies on each of the systemic conditions have their own defects that prompt further research.

Current studies of the relationship between periodontal disease and coronary vascular disease should provide more data to differentiate between the stimulation of inflammatory cytokines by periodontitis as opposed to the possibility of a direct infection of the endothelium
(or both).Furthermore, anti-inflammatory and antibiotic therapy as a treatment strategy for periodontal disease should be incorporated in the studies to assess their role in preventing the deterioration of cardiovascular disease.Regarding diabetes mellitus, the current notion that chronic inflammation associated with periodontal disease may result in the metabolic disturbances associated with DM needs further evidence to clarify the underlying mechanisms. Also, elucidation of the mechanism underlying the relationship between periodontal infection and coronary vascular disease may provide a hypothesis that unifies both diseases, which may aid in the prevention of complications associated with both diseases.

Regarding the relationship between periodontal disease and osteoporosis, more information about the molecular mechanisms involved in the activation of RANKL/RANK system could help in the development of new pharmacological methods for the inhibition of excessive bone resorption. Also, larger studies are needed to assess the value of osteocalcin, calcitonin, and parathyroid hormones as laboratory indicators of periodontal disease activity.Furthermore, more studies are needed to clarify the mechanisms by which periodontal disease may lead to malignancy, low birth weight, and pregnancy complications. It is of specific importance to differentiate between the presence of a causative relationship and a simple association.

These findings will be of importance to dentists as well as clinicians, as periodontal infection could become a modifiable risk factor for the development of several systemic diseases, and this may result in advances in the prevention of those conditions.Lastly, oral health has direct and/or indirect effects on the individual’s general health. Both dentists and physicians should recognize the increasing significance of this relationship in modern health care. Dentists should increase their awareness and their clinical exposure to relevant systemic diseases to be able to interact meaningfully about these issues with their medical colleagues. Team approach is strongly advocated for the management of severe periodontal disease associated with relevant systemic conditions.

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