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Periodontology 2000, Vol. 64, 2014, 198210 Printed in Singapore.

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2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd

PERIODONTOLOGY 2000

Systemic medication and the inammatory cascade


AWS ALANI & ROBIN SEYMOUR

Inammation plays a signicant role in the pathogenesis and expression of plaque-induced periodontal disease. The mechanisms whereby inammatory mediators contribute to the various processes of periodontal breakdown are discussed elsewhere in this volume of Periodontology 2000. It is widely recognized that our patients are living for longer and are retaining their teeth into old age. Part of this increase in life expectancy must be attributed to improved methods of disease diagnosis and control. The latter is most frequently mediated via systemic drug therapy. The range of drugs available to treat diseases is increasing, and this provides an opportunity to investigate the effects of such drugs on the periodontium and on processes involved in the periodontal diseases. The nature and the pathogenesis of periodontal disease can be affected by a variety of drugs, especially those that interact with immune and inammatory responses. Obvious examples include anti-inammatory agents and immunosuppressants. Early studies, which will be discussed later, observed the effects of such systemic medication on the periodontium and on the responses of the tissues to bacterial plaque. Nonsteroidal anti-inammatory drugs, which inhibit eicosanoid synthesis by blocking the cyclooxygenase-1 enzyme system, were particularly relevant in this respect, with an early study showing that patients on long-term nonsteroidal anti-inammatory drug therapy were afforded some degree of protection against periodontal breakdown (62). This did indicate that eicosanoids, especially prostaglandins of the E-series, may be important in the development and progression of periodontal disease. In other words, drugs such as nonsteroidal anti-inammatory drugs with a known mode of action could be used as a tool to provide further insight into the role of inammatory mediators in the expression of periodontal disease. Consideration was

then given to whether nonsteroidal anti-inammatory drugs have a therapeutic role to play in the management of periodontal disease. In this review, the following categories of medicines are discussed and evidence evaluated regarding their effect on the inammatory cascades and how this relates to periodontal disease: corticosteroids. cyclooxygenase-1 and cyclooxygenase-2 inhibitors. immunosuppressants. bisphosphonates. anti-cytokines. statins. omega-3. The topic of host-modulating agents would also be applicable to this review. However, as it has been discussed in a recent volume of Periodontology 2000, it will not be considered further here (44). In addition to reviewing the evidence of such drugs on the periodontium, we will also consider their unwanted effects and, where appropriate, the costrisk benet.

Corticosteroids
Corticosteroids are a group of drugs that are structurally and pharmacologically related to the endogenous hormone cortisol. There are several corticosteroids, each with different potencies and applications. A list of those widely prescribed in medical practice is given in Table 1. Corticosteroids are extensively used in many aspects of medicine. They can be applied topically, by inhalation, orally and parenterally.

Pharmacological properties
Therapeutic usage of corticosteroids relates mainly to their anti-inammatory and immunosuppressive

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Table 1. List of corticosteroids commonly used in medical practice and their indications
Corticosteroid Hydrocortisone Cortisone acetate Betamethasone Deazacort Dexamethasone Prednisolone Methylprednisone Triamcinalone Indication Adrenocortical insufciency, shock, hypersensitivity reaction, asthma, inammatory bowel disease, skin disorders, rheumatic diseases Steroid replacement therapy Suppression of inammatory and allergic disorders, congenital adrenal hyperplasia, oral ulceration Suppression of inammatory and allergic disorders Suppression of inammatory and allergic disorders, cerebral edema, nausea and vomiting from chemotherapy, rheumatic diseases Suppression of inammatory and allergic disorders, asthma, immunosuppression, rheumatic diseases Suppression of inammatory and allergic disorders, inammatory bowel disease, rheumatic diseases Suppression of inammatory and allergic disorders, skin conditions

actions. The main anti-inammatory action is mediated via their ability to stimulate the production of a protein known as lipocortin-1 (annexin A1) (42). Lipocortin suppresses the enzyme phopholipase A2, which acts on cell membranes to produce the various eicosanoids that are discussed elsewhere in this volume of Periodontology 2000. Thus, corticosteroids, via stimulation of lipocortin, block production of prostaglandins and leukotrienes. In addition to this action, corticosteroids also suppress the enzymes cyclooxygenase-1 and cyclooxygenase-2, further reducing eicosanoid synthesis. Corticosteroid-induced immunosuppression has many applications in the treatment of a variety of diseases. Corticosteroids suppress the cell-mediated response by inhibiting the genes that code for cytokines interleukin-1 to -6, interleukin-8 and interferon-c. Suppression of these cytokines leads to reduced T-cell proliferation. Humoral immunity is also suppressed by corticosteroids, resulting in reductions of B-cells, interleukin-2 synthesis and expression of interleukin-2 receptors. The outcome of this suppression is a reduction in B-cell-clone expansion and antibody synthesis and reduced activation of T-lymphocytes (27). Corticosteroids also affect T-cell apoptosis, which is more marked for immature T-cells that are still present in the thymus. The actions of corticosteroids on both inammatory and immune responses are mediated by activation of the glucocorticoid receptor. Once activated, the glucocorticoid receptor up-regulates the expression of anti-inammatory proteins and suppresses the expression of proinammatory proteins (35).

Corticosteroids and the periodontium


Early animal studies showed that systemic cortisone injections have a signicant effect on periodontal tissues (53), including induction of alveolar bone loss and reduction in the numbers of osteoblasts and broblasts and of the intercellular matrix. This condition is virtually identical to the bone status seen in osteoporosis and has been conrmed in further animal studies, which demonstrated that anti-osteoporotic drugs (calcitonin and alendronate) prevented corticosteroid-induced osteoporosis (13). Other animal studies also showed that systemic cortisone could attenuate the plaque-induced inammatory responses in the periodontal tissues. Human studies on the effects of corticosteroids on periodontal tissues and disease progression have, for the most part, been derived from data collected from patients who have been on long-term steroid therapy for medical conditions. These very early studies did demonstrate some anti-inammatory effects of corticosteroids on the gingival tissues, but not necessarily a reduction in the rate of periodontal breakdown. In other words, it is equivocal whether systemic corticosteroid treatment afforded that patient any protection against periodontal disease progression (53). More recently, there has been interest in the role of stress and its effect upon the hypothalamicpituitaryadrenal axis. Stress would have a direct effect on the hypothalamicpituitaryadrenal axis and this would be mediated by the production of cortisol. Again, animal studies have provided some insight into the relationship among stress, cortisol production and periodontal breakdown (6). In this study,

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rats that showed a low response to stress developed signicantly less periodontal breakdown than those that showed a high response. The authors concluded that hypothalamicpituitaryadrenal axis hyperactivation is one mechanism by which periodontal disease susceptibility may be increased. Further conrmation of the possible role of hypothalamic pituitaryadrenal axis hyperactivation has come from the same group who subsequently demonstrated that a glucocorticoid receptor antagonist reduced periodontal breakdown in ligature-induced periodontitis in rats (5). They also demonstrated that neonatal injection of dexamethasone, which permanently down-regulates the hypothalamicpituitaryadrenal axis, inhibits periodontal disease progression in a similar manner to the study cited above (4). The authors further emphasized that central nervous system regulation of inammatory responses to dental plaque may modulate periodontal disease susceptibility and progression. Clinical studies have in part conrmed this nding. Stress and salivary cortisol have been measured in an adult population suffering from periodontitis (24). Salivary cortisol levels were positively associated with an increase in psychological stress and in the extent and severity of periodontitis. However, it is difcult to ascertain what role salivary cortisol could play in the periodontal tissues and in their response to bacterial plaque. A more recent investigation has conrmed the equivocal effects of corticosteroids on the periodontal
Table 2. Unwanted effects of systemic corticosteroids
Target Carbohydrate metabolism Protein Bone Gastric mucosa Adrenal cortex Fat Skin Wound healing Immune system Cardiovascular system Neurological Blood vessels Effect

tissues and their responses to plaque (48). A randomized trial was completed to evaluate the shortterm effects of a combination of dipyridamole (an anti-platelet drug) and prednisolone on a variety of serum proinammatory markers and clinical signs of periodontal disease. The ndings showed that this drug combination did reduce the concentrations of various proinammatory cytokines, but had no effect on the periodontal parameters of bleeding on probing or probing pocket depth. The short-term exposure of the patients to this drug combination may have contributed to the minimal impact on these periodontal measures. Corticosteroids are a very potent and valuable group of drugs that are used to treat a variety of medical conditions. Their interest, in periodontal terms, is on their anti-inammatory actions and whether such actions can provide an insight into the pathogenesis of plaque-induced gingival inammation and periodontal disease expression. Therefore, such drugs have been used as a pharmacological tool and do not have a place in the management of periodontal disease.

Unwanted effects of corticosteroids


Steroids have a range of unwanted effects, which are listed in Table 2. Of particular concern to the periodontist are the unwanted effects of steroidinduced osteoporosis and the risk of adrenocortical suppression.

Decreased uptake of glucose and increased gluconeogenesis, leading to an increased riskof diabetes Decreased protein synthesis and increased protein breakdown, especially in muscles, causing muscle wasting Osteoporosis Increased risk of peptic ulceration Suppression leading to an increased risk of an adrenocortical crisis Redistribution of body fat causing so-called moon faces and Buffalo hump Thinning of skin and an increased risk of acne Impaired Immunosuppression, increased risk of opportunistic infections Hypertension Mood changes and insomnia Easy bruising

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Corticosteroid-induced osteoporosis
Corticosteroids have a signicant effect upon bone metabolism. They increase bone resorption, inhibit bone formation, decrease the intestinal absorption of calcium ions and modify vitamin D metabolism. The net result is an increased risk of osteoporosis, which is considered a risk factor for periodontal disease, especially an increased risk of tooth loss (36). It has been estimated that 2030% of patients on long-term steroid therapy will develop osteoporosis (29). The risk is higher in patients >60 years of age and also in women. Corticosteroid-induced osteoporosis can be managed by dietary supplements of calcium and vitamin D and also by bisphosphonates. Issues relating to the use of bisphosphonates and their unwanted effects are discussed later.

Corticosteroid-induced adrenal suppression


Production of cortisol from the adrenal cortex is under the control of the hypothalamicpituitary axis. Under normal circumstances, the adrenal cortex produces 25 mg of cortisol per day. If the levels of this hormone are increased either from an underlying disease (Addisons disease) or from exogenous steroid medication, then a negative-feedback mechanism is activated. The consequence of this activation is a reduction in the release of corticotrophin-release factor from the hypothalamus, which in turn brings about a reduction in the release of adrenocorticotrophic hormone. The nal outcome is a reduction in cortisol secretion, and if this is maintained long-term there will be atrophy of the adrenal cortex. In such an event, a patient will be unable to respond to any form of stress, or will show only a poor response, and this could lead to an adrenocortical crisis. Such a crisis is characterized by a signicant drop in blood pressure, and if not treated this will lead to cardiovascular collapse. The extent of atrophy of the adrenal cortex will be dependent upon the dose, the duration and the potency of steroid prescribed. An adrenal crisis is prevented by either increasing the dose of medicated steroids or by providing supplementary steroids before the stressful event. Case reports have identied that the stress anxiety arising from dental treatment can induce an adrenocortical crisis in patients on long-term steroid medication. However, current evidence suggests that this problem is very much overstated in the dental setting. Two studies have shown that both organtransplant patients and orthopedic patients on long-

term steroids did not require any steroid supplementation before signicant surgical interventions (7, 18). Of more relevance to dentistry is the placebocontrolled crossover study on organ-transplant patients who required two episodes of gingival surgery and therefore acted as their own controls (55). Blood pressure and pulse-rate measurements were practically identical throughout the surgical procedure and for 2 h afterwards when patients received either 50 mg of intravenous hydrocortisone or placebo. Subsequently, our center has completed well in excess of 3000 various dental interventions, including surgery and extractions, on a diverse group of organtransplant patients. During this period there has not been even a single episode of hypotension that would indicate the onset of an adrenocortical crisis. We would advocate that all patients on long-term steroid therapy, irrespective of their underlying medical condition, should have their blood pressure monitored before, during and for up to 30 min postoperatively. If the diastolic pressure falls below 60 mm or more than 25% from baseline then 100 mg of intravenous hydrocortisone should be administered.

Cyclooxygenase-1 and cyclooxygenase-2 inhibitors


As their name suggests, these drugs inhibit two important enzymes involved in the inammatory cascade. In brief, cyclooxygenase-1 and cyclooxygenase-2 act on arachidonic acid to produce the eicosanoids (prostaglandins, thromboxane and prostacyclin). The role of the eicosanoids in the inammatory cascade is discussed elsewhere in this volume of Periodontology 2000. The cyclooxygenase enzyme system is found in two forms in humans: cyclooxygenase-1 is a constitutive enzyme that is responsible for the secretion of mucous in the gastrointestinal mucosa; and cyclo-oxygenase-2, which is activated by tissue damage, is regarded as an inducible enzyme because it is present only during injury. For many years, it has been recognized that drugs such as aspirin and other nonsteroidal anti-inammatory agents inhibit the cyclooxygenase enzyme system. Such inhibition not only accounts for their pharmacological properties, but also for their unwanted effects, in particular gastrointestinal irritation and ulceration. In the late 1990s, both cyclooxygenase-1 and cyclooxygenase-2 were identied, which led to the evolution of a new range of nonsteroidal anti-

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inammatory drugs that selectively blocked cyclooxygenase-2 with little or no action on cyclooxygenase-1. Such drugs (known as cyclooxygenase-2 inhibitors) had, in theory, all the efcacy of conventional nonsteroidal anti-inammatory drugs without the unwanted effects (17).

Aspirin and nonsteroidal anti-inammatory drugs


As mentioned previously, aspirin and nonsteroidal anti-inammatory drugs inhibit both cyclooxygenase-1 and cyclooxygenase-2 enzyme systems. The pharmacological properties of these agents are discussed below.

which promotes platelet aggregation, and prostacyclin, which inhibits aggregation. This action reduces both thromboxane A2 synthesis in platelets and prostacyclin synthesis in endothelial cells. The action of aspirin on platelets is irreversible and synthesis does not recover until the platelet population has been replaced (usually 710 days). By contrast, many nonsteroidal anti-inammatory drugs are reversible inhibitors of platelet thromboxane and their action only lasts for up to 8 h. The antiplatelet action of aspirin accounts for its widespread use in the prevention of a variety of thromboembolic disorders.

Cyclooxygenase-1 and cyclooxygenase-2 inhibitors and the periodontium


Animal studies
As with other drugs, evidence for the possible therapeutic use of anti-inammatory agents on the periodontium has come from animal studies. For example, systemic indomethacin has been shown to reduce the inammatory responses and also to inhibit alveolar bone loss in a ligature-induced periodontitis model in both beagles and squirrel monkeys (37, 63). Flurbiprofen (both systemic and in the form of a topical gel) is a further nonsteroidal anti-inammatory drug that has been evaluated in animal studies in the management of periodontal disease. Whilst there are some inconsistencies in the ndings from these animal studies, this may be attributed to different dosing regimens of the drug (38, 65). Animal models have also provided opportunities to compare cyclooxygenase-1 and cyclooxygenase-2 inhibitors on periodontal disease progression in rats (45). Local and systemic administration of the cyclooxygenase-2 inhibitor resulted in a signicant reduction in the loss of ber attachment and alveolar bone loss in the ligature-induced periodontitis model. The cyclooxygenase-1 inhibitor had a similar outcome on ber loss in this model, but did not prevent alveolar bone loss. This outcome suggests that cyclooxygenase-2 inhibitors may have a more signicant application in the control of periodontal disease than do cyclooxygenase-1 inhibitors.

Analgesia
Both aspirin and nonsteroidal anti-inammatory drugs are effective analgesics, especially if the pain has a signicant inammatory component. Targeting cyclooxygenase-2 reduces the production of prostaglandins, especially those of the E series (e.g. prostaglandin E2). Such prostaglandins sensitize free nerve-endings to the nociceptive actions of further inammatory mediators, such as bradykinin and histamine.

Antipyretic
Aspirin and nonsteroidal anti-inammatory drugs will reduce body temperature arising from an infection. Bacterial or viral infections induce the release of interleukin-1 from macrophages. Interleukin-1 stimulates the generation of prostaglandin E2 in the hypothalamus, which results in the elevation of body temperature. Both drugs block prostaglandin E2 synthesis and hence reduce the body temperature. These drugs have no action on reducing body temperature if it is raised by exercise or ambient heat.

Anti-inammatory
Again, this action is mediated by the inhibition of both prostaglandin E2 and prostacyclin. Such inhibition results in less vasodilatation and less edema formation.

Antiplatelet
The cyclooxygenase-1 action of aspirin alters the balance between platelet-derived thromboxane A2,

Clinical studies
An early indication that nonsteroidal anti-inammatory drugs may attenuate periodontal disease

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progression came from a cross-sectional study of patients taking these drugs for the control of musculoskeletal disorders (62). Subjects who had been taking nonsteroidal anti-inammatory drugs for 12 months or more had less gingival inammation and shallower probing pocket depths than did control subjects. Other studies of similar design have likewise conrmed the potentially protective effect of nonsteroidal anti-inammatory drugs on the periodontium (15, 47, 61). It has also been demonstrated, in a group of patients with rheumatoid arthritis taking a range of anti-inammatory agents, that their gingival crevicular uid levels of interleukin-1beta, interleukin-18 and total elastase were signicantly lower than those of a control group (31, 32). Again, this study illustrates the effect of such medication on a range of inammatory mediators, which can inuence the response of the periodontal tissues to bacterial plaque. Animal studies have already demonstrated the potential benets of urbiprofen on the periodontium. The rst clinical study evaluated the efcacy of systemic urbiprofen (50 mg, twice daily for 24 months) in a cohort of patients suffering from chronic periodontitis (65). After 12 and 18 months of medication, those treated with systemic urbiprofen exhibited signicantly less alveolar bone loss than those treated with placebo. At 24 months there was no difference between the groups and this was attributed to poor compliance. Various topical (local) preparations of urbiprofen have also been investigated in the management of various aspects of periodontal inammation. For example, topical urbiprofen was applied via an irrigation method in an experimental gingivitis model (23). In this crossover, placebo-controlled trial, the local irrigation with urbiprofen had little or no effect on the development of gingivitis when compared with the placebo solution. However, this may have been caused by the systemic absorption of urbiprofen from the oral mucosa. A further study incorporated urbiprofen into a toothpaste (1% weight by weight) and the paste was used an adjunct to nonsurgical management in patients with chronic periodontitis (22). After 12 months of use, there was some benet from the active paste in terms of sites showing bone gain. However, this benet was concluded as small. The advent of the cyclooxygenase-2 inhibitors has renewed interest in this group of drugs as possible adjunctive treatment in the management of periodontal disease. For example, systemic dosing with the cyclooxygenase-2 inhibitor loxoprofen was shown to be a useful adjunct to nonsurgical treatment in

patients with chronic periodontitis (43). Loxoprofen was used for 28 days following a course of scaling and root planing. Those sites exhibiting deeper probing depths (>7 mm) appeared to benet more from this adjunctive treatment than the shallower sites. This group of nonsteroidal anti-inammatory drugs has also been evaluated in the management of aggressive periodontitis (2). A short course of etoricoxib (120 mg per day for 7 days) was shown to provide no additional benets when used as an adjunct to scaling and root planing. However, a reduction in the levels of prostaglandin E2 in gingival crevicular uid was observed. This apparent failure of treatment may be related to the nature of the periodontal disease being treated or the short-term course of adjunctive treatment. Later in this article the application of omega-3 fatty acids in the management of periodontal diseases will be discussed. A study in rats showed that a combination of a cyclooxygenase-2 inhibitor (celecoxib) and an omega-3 fatty acid signicantly inhibited the expression of matrix metalloproteinase-8. Furthermore, rats treated with omega-3 only showed an increase in expression of tissue inhibitor of metalloproteinase-1 (59). A similar combination (low-dose aspirin with a dietary supplementation of omega-3 fatty acids) has been utilized as an adjunct to conventional nonsurgical management in a group of patients with chronic periodontitis (12). At 3 and 6 months after scaling and root planing, patients receiving the adjunctive therapy showed a signicant reduction in probing pocket depths and attachment gain when compared with baseline measurements and with the control group. The application of dual agents to modify the response of the periodontal tissues to bacterial plaque does open up new vistas in the management of periodontal disease.

Immunosuppressants
Immunosuppressant drugs, as their name suggests, are a group of compounds that target the immune system and suppress various aspects of this system. They have three main indications in medicine: to suppress rejection in organ-transplant patients. in the treatment of a variety of chronic inammatory conditions, where suppression of the immune response may help to alleviate symptoms. in the management of autoimmune diseases. There are several drugs that can affect the immune system and which have therapeutic applications.

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Table 3. List of immunosuppressants used in medical practice and their indications


Immunosuppressant Azathioprine Mycophenolate mofetil Prednisolone Cyclosporine Sirolimus Tacrolimus Indication Transplant patients, inammatory bowel disease, rheumatoid arthritis, severe refractory eczema Prophylaxis of acute renal, hepatic and cardiac transplant rejection Prevention of graft rejection Prevention of graft rejection, treatment of graft-vs.-host disease, severe ulcerative colitis, rheumatoid arthritis, severe skin disorders Prophylaxis of organ rejection in kidney allograft recipients Prophylaxis of organ graft rejection in liver, kidney and heart allograft recipients and for allograft rejection resistant to conventional immunosuppressant regimens, moderate to severe eczema

Those in common usage are shown in Table 3, together with their particular application.

Antiproliferative immunosuppressants
The two main examples of this category of immunosuppressants are azathioprine and mycophenolate mofetil. Azathioprine Azathioprine is a purine derivative that is not directly an immunosuppressant, but can be considered as a prodrug. Azathioprine is rst metabolized to 6-mercaptopurine and further metabolized by the enzyme thiopurine methyltransferase to the pharmacologically active 6-thioguanine nucleotide. The latter suppresses the immune system by inhibiting DNA synthesis in lymphocytes. The most common route of administration of azathioprine is the oral route and the normal dose for suppression of transplant rejection is 15 mg kg of body weight. For autoimmune conditions, the dosage is slightly lower (13 mg kg). An intravenous preparation of azathioprine exists; however, this is an alkaline solution and is irritable to the vasculature and therefore this preparation is only considered if the patient is unable to take the drug by mouth. Unwanted effects. Azathioprine has a range of unwanted effects. Of particular concern to the dental team is the increased susceptibility to infections, especially opportunistic infections, and bone marrow suppression. The latter could have signicant oral manifestations or produce lesions on exposed skin, which could be easily identied. A drug-induced depression of platelets could lead to petechial hemorrhages and also to profuse bleeding from the gingival tissues, especially upon any form of gingival

manipulation. A reduction in the white cell count will increase the risk of oral ulceration and periodontal breakdown. There is a cohort of patients who are particularly susceptible to azathioprine-induced myelosuppression and such individuals manifest thiopurine methyltransferase deciency. Ideally, all patients medicated with azathioprine should have their thiopurine methyltransferase activity assessed before dosing. Azathioprine-induced myelosuppression is most likely to manifest in the early stages of treatment and is managed by reducing the dose. Mycophenolate mofetil As with azathioprine, mycophenolate mofetil is considered a prodrug and is hydrolyzed to mycophenolic acid. Mycophenolic acid reduces both B- and T-cell proliferation by inhibiting the production of guanine nucleotide. As both T- and B-cells are inhibited, it has been suggested that mycophenolate mofetil may be effective against both acute and chronic organ rejection (21). Mycophenolate mofetil is available as an oral preparation, and a dosage of 11.5 g, twice daily, is used to prevent rejection in organ-transplant patients. An intravenous preparation is available and this is mainly used in the early stages of liver transplantation. As with azathioprine, the most signicant unwanted effect of mycophenolate mofetil is myelosuppression. Platelets seem to be particularly sensitive to mycophenolate mofetil and the subsequent thrombocytopenia will have an oral manifestation that has been described previously. Patients on this drug will undergo regular hematological screening and if any form of periodontal surgery is planned then a blood test should be requested before the procedure, with specic attention given to the platelet count. Mycophenolate mofetil is also associated with a high prevalence of gastrointestinal

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problems, especially vomiting. This can readily lead to dental erosion, and preventative measures need to be put into place to avoid the outcome of this unwanted effect.

Calcineurin inhibitors
Calcineurin is a protein phophatase that activates T-cells of the immune system. It is the target of drugs such as cyclosporine and tacrolimus.

Cyclosporine
Cyclosporine has had a dramatic effect on patients undergoing organ-transplant surgery, on subsequent graft survival and on quality of life. The main mode of action of cyclosporine is its selective inhibitory effect on transcription of the interleukin-2 gene. As a consequence of this action, there is decreased clonal proliferation of T-cells, reduced induction of, and clonal proliferation of, cytotoxic cells from CD8+ precursor T-cells, reduced function of the effector Tcells and some reduction in T-cell-dependent B-cell responses. From the periodontal perspective, the main interest in cyclosporine is the unwanted effect of gingival overgrowth. This was rst reported in the early 1980s and has been the subject of extensive research. The topic of drug-induced gingival overgrowth has been covered in a previous volume of Periodontology 2000 and the reader is referred to this article (52). Other unwanted effects of cyclosporine include nephrotoxicity, hypertension and an increased risk of skin malignancies.

plaque. These early studies, in the 1970s and 1980s, showed that patients on long-term immunosuppressants (usually azathioprine and prednisolone) were afforded some degree of protection against periodontal breakdown. The more selective immunosuppressants (cyclosporine and tacrolimus) may not afford the same degree of protection against periodontal breakdown. However, with cyclosporine, the unwanted effect of gingival overgrowth will inhibit plaque removal and thus create a somewhat different environment for periodontal disease. Animal studies have suggested that cyclosporine can have an adverse effect on alveolar bone homeostasis, resulting in increased osteoclasia and a decrease in bone formation (19). The mechanism of such bone loss is unclear, but it may be mediated by cyclosporine attenuating some aspect of the inammatory response, which can lead to osteoclast activation. Whilst this adverse effect has not been widely recognized in human studies, it has been subsequently demonstrated that simvastatin therapy will signicantly reduce cyclosporine-induced alveolar bone loss in rats (34). The benecial effects of simvastatin in this model may be mediated by downregulation of interleukin-1beta and prostaglandin E2 production. As with other categories of systemic medication, there is little or no therapeutic indication for the use of immunosuppressants in the management of periodontal disease. As with other anti-inammatory agents, the main interest in these drugs is what their pharmacodynamics can tell us about the pathogenesis of periodontal disease and periodontal breakdown. Their unwanted effects would exclude any indication for their use in the management of periodontal disease.

Tacrolimus
Tacrolimus is a macrolide antibiotic that also inhibits calcineurin. It is more potent than cyclosporine, and is now replacing cyclosporine as the treatment of choice to prevent graft rejection in organ transplantation. Unwanted effects of tacrolimus include gastrointestinal disturbances, hypertension, nephrotoxicity and metabolic disturbances.

Cytokine modulators
A variety of drugs have now been licenced under this category (for example, adalimumab, etranercept and iniximab) for the management of rheumatoid arthritis and other immune-modulated diseases. These drugs inhibit the activity of tumor necrosis factor-a, which is now recognized as an important cytokine in the pathogenesis of periodontal breakdown. Animal studies have shown that the systemic administration of recombinant interleukin-11 reduced bone loss in a dog model of periodontitis (30), and etanercept reduced inammation, tissue injury and neutrophil inltration in a rat model of experimental periodontitis (10). Clinical evidence for a

Immunosuppressants and the periodontium


Before the advent of cyclosporine, there was an interest on the effect of immunosuppressant therapy on the periodontal tissues and their response to

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possible periodontal benet of these drugs has come from investigations of the periodontal status of cohorts of patients who are receiving such medication for the management of their rheumatoid arthritis. An initial study showed that inxiimab tended to exacerbate gingival inammation in the presence of existing periodontitis, but paradoxically, these patients had less attachment loss when compared with controls (41). The authors suggested that tumor necrosis factor-a blockade could be benecial in the treatment of periodontitis. Other studies of similar design have conrmed the benet of tumor necrosis factor-a blockade in patients with rheumatoid arthritis who also suffer from periodontitis (30, 39). Whilst such ndings tell us more about the role of tumor necrosis factor-a in the pathogenesis of periodontal breakdown, it is unlikely, owing to their adverse-effect prole, that the systemic administration of such drugs would ever have a role in the management of periodontal disease. Side effects from these drugs include an increased risk of infection, gastrointestinal complaints and bone marrow suppression. As with nonsteroidal anti-inammatory drugs, a topical or local-delivery application may be of benet.

Blockage of this pathway inhibits a process known as protein prenylation, which may affect proteins in osteoclasts, leading to osteoclast death (57).

Bisphosphonates and the periodontium


The mode of action of the bisphosphonates indicates that they may be of benet in the management of periodontal disease, especially with an impact on rates of alveolar bone loss. Initial studies, which were reviewed by Rocha et al. (49), showed a degree of promise, with patients on bisphosphonate therapy exhibiting signicantly less alveolar bone loss compared with nonmedicated controls. However, a subsequent systematic review concluded no meaningful conclusion can be reached about the benets of bisphosphonates in the management of periodontal disease (46). A more recent study (25), of 335 patients who were medicated with either alendronate or placebo, showed that there were no differences in alveolar bone levels after 2 years of medication. It would therefore seem that the benets of systemic administration of bisphosphonates in preventing alveolar bone loss or as an adjunct to periodontal therapy are somewhat limited. More signicant, however, are the unwanted effects of these drugs, such as inammation and erosion of the esophagus, and more importantly, in dental practice, the risk of osteonecrosis of the jaws. There have been several professional guidelines issued on the prevention and management of bisphosphonate-induced osteonecrosis of the jaws, and readers are referred to these regarding management of their own patients. These guidelines have also been reviewed and again readers may nd the article of interest (40).

Bisphosphonates
Bisphosphonates are pyrophosphate analogs that have a common phosphorous-carbon-phosphorous chemical core. Their potency is partly related to the existence of a nitrogen side chain. Parenteral and oral preparations are available with differing potencies. These drugs have a major impact upon bone turnover. In brief, they inhibit the digestion of bone by encouraging osteoclasts to undergo apoptosis or cell death, thereby slowing bone loss. Bisphosphonates are widely used in the management of osteoporosis, in Pagets disease and in the treatment of secondary bone cancer arising from malignant disease. The non-nitrogen bisphosphonates are metabolized in the cell to compounds that replace the terminal pyrophosphate moiety of adenosine triphosphate, forming a nonfunctional molecule that competes with adenosine triphosphate in cellular energy metabolism. The osteoclast initiates apoptosis and this leads to an overall decrease in the breakdown of bone (16). Nitrogenous bisphosphonates act on bone metabolism by binding and blocking the enzyme farnesyl disphosphate synthetase in the hydroxymethylglutaryl-coenzyme-A reductase pathway.

Statins
Statins are a group of drugs used to decrease lipid levels by inhibiting the enzyme hydroxymethylglutaryl-coenzyme-A reductase, which plays a role in the production of cholesterol in the liver. A raised cholesterol level has been associated with cardiovascular diseases, and statins are therefore utilized in the prevention of this group of conditions. The mode of action by which statins achieve this is thought to be multifactorial, one of which is modulation of the inammatory response (54, 56, 64). In addition to their primary mode of decreasing lipid levels, statins modulate bone metabolism and decrease T-cell activation. Statins may directly stimulate the

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expression of bone morphogenetic protein-2 and increase osteoblast differentiation. There is also some evidence that they inhibit osteoclast activity and osteoblast apoptosis (20, 33). This ability to have a positive effect on the inammatory cascade as well as an anabolic effect on bone formation has been investigated for its effects on the periodontium and supporting tissues. Seto et al. (51) examined the topical effect of simvastatin on alveolar bone recovery in rodents. This study illustrated the ability of topical simvastatin to recover ligature-induced bone loss (51). They illustrated the maintenance of high levels of alkaline phosphatase and increased bone-nodule formation. It was shown that this effect was dose dependent and was also linked to high levels of osteoblastic activity (51). Indeed, topically applied statins have also shown potential in reducing periodontal tissue breakdown in rats when compared with controls, although this was not found to be statistically signicant (60). Retrospective studies examining the effect of statins in human cohorts have shown some positive results. Lindy et al. (28) examined 100 (three of whom did not meet the inclusion criteria) consecutive chronic periodontitis patients of whom 21 were taking statin medication. They found that patients on statin medication were less likely to present with moderate (46 mm) or advanced (>6 mm) periodontal pocket depths than were those who were not medicated. The authors felt that this decrease in periodontal inammation was attributed to the antiinammatory pleiotropic effect of statins. In a retrospective study examining 1021 patients, statin use was attributed to a decreased rate of tooth loss in patients with chronic periodontitis, although this was nonsignicant (9). The authors highlighted the difculties in examining this patient cohort owing to the confounding variables with which statin users may present, including smoking and diabetes (9). In contrast, a retrospective study of 12,631 patients diagnosed with chronic periodontal disease found that statin use was associated with increased tooth loss. Once the results were adjusted for potential confounders, there was no decreased or increased association for tooth loss in statin users (50). The authors felt that a large-scale, long-term, randomized controlled trial would be required to provide more denitive evidence about the possible relationship between statin use and the course of periodontal disease (50). A subsequent randomized controlled double-blind study of 38 patients with chronic periodontitis investigated the effect of atrovastatin (14). Patients were given either a placebo or 20 mg of

atrovastatin, daily, for 3 months, mechanical periodontal treatment was instigated at baseline and patients were reviewed for indices at 3 months (14). Despite improvements in the majority of parameters in both cohorts, signicant improvements in the test group were only detected in mobility and in the distance between the crestal alveolar bone level and the cementoenamel junction (14). It would seem pertinent that further investigation into the effect of statin medication on periodontal tissues is required.

Omega 3
Fish oil is a main source of omega-3 fatty acids, where the major polyunsaturated fatty-acid components are eicosapentaenoic acid and docohexaenoic acid. As mentioned previously, cyclooxygenase-2 inhibitors reduce inammation by preventing the synthesis of arachidonic acid metabolites via the cyclooxygenase2 pathway. Eicosapentaenoic acid and docohexaenoic acid compete with arachidonic acid for the cyclooxygenase and lipoxygenase pathways, which result in the reduced synthesis of highly active arachidonicacid metabolites. As a result of this ability to reduce the synthesis of arachidonic-acid metabolites, omega3 has anti-inammatory, antithrombotic and vasodilator effects. Indeed, Alam and co-workers (1) demonstrated reductions in the levels of arachidonic acid, prostaglandin E2 and leukotrienes in the gingival tissue of rats given a diet rich in omega-3. Similar results were found in humans with experimental gingivitis (8). Animal studies examining the effects of omega-3 on experimental periodontitis showed a reduction in the levels of arachidonic-acid metabolites in gingival tissues compared with those in healthy tissue (58). When rats were infected with Porphyromonas gingivalis, those fed omega-3 sh oil showed decreased levels of proinammatory mediators in the gingival tissues (26). This observation was supported by the nding that experimental omega-3-fed groups of rats had less alveolar bone loss than controls when infected with periodontal pathogens (3). More recent evidence shows favorable responses in humans. A recent clinical study of 80 patients revealed interesting results. The control group was treated with scaling and root planing and a placebo, whereas the experimental group had the placebo substituted for sh oil and aspirin, daily, for 26 weeks (12). Signicant reduction in pocket depths and attachment gain were recorded after 3 and 6 months (12). These results were mirrored when evaluating clinical parameters for Class II furcation defects

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treated with decalcied freeze-dried bone allograft. One group received a placebo whilst the other received aspirin and sh oil on a daily basis for 6 months after the regenerative procedure (11). The experimental group showed reduced levels of proinammatory mediators, reduction of pocket depth and attachment-level gain (11).

3.

4.

Conclusions
This review has primarily focused on those drugs that affect the inammatory cascade and on the impact, if any of such medication on plaque-induced inammation of the periodontal tissues and disease progression. For the most part, some categories of drugs do affect periodontal disease progression and can afford the patient some degree of protection against periodontal breakdown. This information has led to various developments to explore whether such drugs could have a therapeutic indication in the management of periodontal disease. Apart from host-modulating agents, the only group that has received serious development is the group of nonsteroidal anti-inammatory drugs. Of these agents, the selective cyclooxygenase-2 inhibitors appear to offer the most promise in terms of adjunctive benet. A new indication for a drug to manage periodontal disease should include a balance between any potential benet of the drug vs. its adverse-effect prole. What is clear for many of the agents discussed are their unwanted effects, which may outweigh any periodontal benet. This should not rule out any particular drug for future development. However, it is the unique anatomy of periodontal destruction that could perhaps open a way forward for further development. Local or controlled drug delivery does especially lend itself to the periodontal situation. This mode of therapy has been dominated by antimicrobial agents. Perhaps a way forward is to utilize some of the drugs cited in a local delivery model. This does offer exciting opportunities for the future management of periodontal diseases.

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15.

References
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