Host modulation is a relatively new term that has been incorporated into our dental jargon, but it has not been well defined. Host can be defined as “the organism from which a parasite obtains its nourishment,” or in the transplantation of tissue, “the individual who receives the graft.” Modulation is defined as “the alteration of function or status of something in response to a stimulus or an altered chemical or physical environment” (Taber’s Medical Dictionary, 2004). In diseases of the periodontium that are initiated by bacteria, the “host” clearly is the individual who harbors these pathogens; however, it was not clear for many years whether it was possible to modulate the host response to these pathogens and other stimuli leading to the breakdown of the attachment apparatus. Host modulation with chemotherapeutic agents or drugs is the latest adjunctive therapeutic option for the management of periodontal diseases. The concept of host modulation is fairly new to the field of dentistry but is universally understood by most physicians who routinely apply the principles of host modulation to the management of a number of chronic progressive disorders such as arthritis and osteoporosis. The concept of host modulation was first introduced to dentistry by Williams¹⁰¹ and Golub et al³⁵ and then expanded on by many other scholars in the dental profession. In 1990, Williams concluded “there are compelling data from studies in animals and human trials indicating that pharmacologic agents, that modulate the host responses believed to be involved in the pathogenesis of periodontal destruction, may be efficacious in slowing the progression of periodontitis.”¹⁰¹ In 1992, Golub and colleagues discussed “host modulation with tetracyclines and their chemically modified analogues.”³⁵ The future that these authors described has arrived, and to better understand this new era in disease management, we must first look to the pathogenesis of periodontitis.

Many clinicians previously believed that periodontal disease was an inevitable consequence of aging and was uniformly distributed in the population. They thought that disease severity was directly correlated with plaque levels (i.e., the worse the oral hygiene, the worse the periodontal disease) and that disease progression occurred in a continuous, linear manner throughout life. Now, as a result of better epidemiologic data, there has been a paradigm shift in how clinicians and scientists view the prevalence and progression of this common disease. It has been well established that periodontal disease is not a natural consequence of aging and disease severity is not necessarily correlated with plaque levels. Theories about the pathogenesis of periodontitis have evolved from a purely plaque-associated disease to the more recent hypotheses that place considerable emphasis on the host’s response to the bacteria.¹⁰ The first Surgeon General’s report on “Oral Health in America,” published in 2000, recognized the importance of dental health in the overall general health and well-being of a patient.⁹³ Recent research findings indicate possible associations between chronic oral infections, such as periodontitis, and systemic disorders, such as diabetes, cardiovascular and lung diseases, stroke, osteoporosis, and rheumatoid arthritis. The Surgeon General’s report assesses these emerging associations and explores factors that may underlie oral-systemic disease connections. Along with these findings and the emergence of the discipline of periodontal medicine, there have been many developments in therapeutic approaches to the management of periodontitis. The development of the chemotherapeutic approach known as “host modulation” required a thorough understanding of the host response and the impact of a variety of risk factors.

Anecdotally, many dentists have identified patients with abundant plaque and calculus deposits which may manifest itself as gingivitis with shallow pocketing. By contrast, other patients, despite maintaining a high standard of plaque control, succumb to aggressive forms of periodontitis, with deep pocketing, tooth mobility, and early tooth loss. The former group of patients is periodontal disease resistant, whereas the latter group is periodontal disease susceptible. Clearly, the response of the periodontal tissues to plaque is different in these two types of patients, and certain patients undergo advanced periodontal breakdown even though they achieve a high standard of oral hygiene. The previous observations led researchers to realize that the host response to the bacterial challenge presented by subgingival plaque is perhaps the most important determinant of disease severity, progression, and even response to therapy. Although plaque bacteria are capable of causing direct damage to the periodontal tissues (e.g., by release of H₂S, butyric acid, and other enzymes and mediators), it is now recognized that the great majority of the destructive events occurring in the periodontal tissues result from activation of destructive processes that occur as part of the host immune-inflammatory response to plaque bacteria. The host response is essentially protective by intent but paradoxically can also result in significant tissue damage, including breakdown of connective tissue fibers in the periodontal ligament and resorption of alveolar bone.

In 1985, research began to focus on bacterial-host interactions.⁵⁸ It had been recognized that although bacterial pathogens initiate the periodontal inflammation, the host response to these pathogens is equally, if not more, important in mediating connective tissue breakdown, including bone loss. It has become clear that the host-derived enzymes known as the matrix metalloproteinases (MMPs), as well as changes in osteoclast activity driven by cytokines and prostanoids, cause most of the tissue destruction in the periodontium.⁶⁸ This shift in paradigms, with a focus on the host response, led to the development of host modulatory therapies to improve therapeutic outcomes, slow the progression of disease, and allow for more predictable management of patients with periodontitis. This therapeutic strategy not only may be relevant to individuals at greater risk for periodontal disease but also may be important in the management of those at risk for a number of related systemic conditions. To better understand the host factors that clinicians are attempting to modulate, we need a more detailed assessment of the role of the host response in periodontal pathogenesis (Figure 49-1). After the accumulation of subgingival plaque bacteria, a variety of microbial substances, including chemotactic factors such as lipopolysaccharide (LPS), microbial peptides, and other bacterial antigens, diffuse across the junctional epithelium into the gingival connective tissues. The periodontium is anatomically unique in that the junctional epithelium ends on the tooth surface, which is nonliving tissue; there is no other such discontinuous lining over the entire surface of the body. The dentogingival junction indicates a priori vulnerability to bacterial attack. Epithelial and connective tissue cells are thus stimulated to produce inflammatory mediators that result in an inflammatory response in the tissues. The gingival vasculature dilates (vasodilation) and becomes increasingly permeable to fluid and cells. Fluid accumulates in the tissues, and defense cells migrate from the circulation toward the source of the chemotactic stimulus (bacteria and their products) in the gingival crevice. Neutrophils, or polymorphonuclear leukocytes (PMNs), predominate in the early stages of gingival inflammation to phagocytose and kill plaque bacteria. Bacterial killing by PMNs involves both intracellular mechanisms (after phagocytosis of bacteria within membrane-bound structures inside the cell) and extracellular mechanisms (by release of PMN enzymes and oxygen radicals outside the cell). As bacterial products enter the circulation, committed lymphocytes return to the site of infection, and B lymphocytes are transformed to plasma cells, which produce antibodies against specific bacterial antigens. Antibodies are released in the gingival tissues and, in the presence of complement, facilitate and enhance PMN phagocytosis and bacterial killing.

Thus a host immune-inflammatory response is established in the gingival tissues, and the clinical signs of gingivitis develop as the tissues become more edematous and erythematous. This response is essentially protective in intent, to combat the bacterial infection and prevent ingress of bacteria into the tissues. In persons who are not susceptible to periodontitis (disease resistant), these primary defense mechanisms control the infection, and chronic inflammation (i.e., chronic gingivitis) may persist indefinitely. In disease-susceptible individuals, however, inflammatory events extend apically and laterally to involve deeper connective tissues and alveolar bone. There is proliferation of the junctional epithelium, which becomes increasingly permeable and ulcerated, thus accelerating the ingress of bacterial products, and the inflammation worsens. Further defense cells are recruited to the area, including macrophages and lymphocytes. Large numbers of PMNs migrate into the tissues, secreting excessive quantities of destructive enzymes and inflammatory mediators indiscriminately into the tissues. These enzymes include the MMPs, such as collagenase and gelatinase, which break down collagen fibers in the gingival and periodontal tissues. The infiltrating inflammatory and immune cells are accommodated by the breakdown of structural components of the periodontium. MMPs are a primary target for host modulation. Pharmacologic agents or chemotherapeutics can be administered to suppress excessive levels of MMPs.

Macrophages are recruited to the area and are activated (by binding to LPS) to produce prostaglandins (e.g., prostaglandin E₂ [PGE₂]), interleukins (e.g., IL-1α, IL-1β, IL-6), tumor necrosis factor alpha (TNF-α), and MMPs. The cytokines (interleukins and TNF-α) and prostanoids are additional targets for host modulatory therapeutics. Interleukins and TNF-α bind to fibroblasts, which are stimulated to produce additional quantities of PGE₂, interleukins, TNF-α, and MMPs in positive-feedback cycles. The concentration of these enzymes and inflammatory mediators becomes pathologically high in the periodontal tissues. Host modulatory therapy (HMT) can be used to interrupt these positive-feedback loops and ultimately reduce the excessive levels of cytokines, prostanoids, and enzymes resulting in tissue destruction. MMPs break down collagen fibers, disrupting the normal anatomy of the gingival tissues ultimately resulting in destruction of the periodontal ligament. The inflammation extends apically, and osteoclasts are stimulated to resorb alveolar bone by the high levels of prostaglandins, interleukins, and TNF-α in the tissues. The osteoclasts themselves are targets for host modulation. Drugs can be administered to downregulate osteoclastic activity and ultimately to inhibit bone resorption by these cells.

The elevations in the proinflammatory or destructive mediators in response to bacterial challenge are counterbalanced by elevations in antiinflammatory or protective mediators such as the cytokines IL-4 and IL-10, as well as other mediators, such as IL-1ra (receptor antagonist), and tissue inhibitors of metalloproteinases (TIMPs) (Figure 49-2). Under conditions of health, the antiinflammatory or protective mediators serve to control tissue destruction. If there are adequate levels of these antiinflammatory or protective mediators to keep the host response to the bacterial challenge in check, the individual will be disease resistant. If an imbalance occurs, with excessive levels of the proinflammatory or destructive mediators present in the host tissues, tissue destruction will ensue in the susceptible host. Another potential target for host modulation could entail the use of pharmacologic agents, which either mimic or result in elevations of endogenous antiinflammatory or protective mediators.

Thus plaque bacteria initiate the disease, and bacterial antigens that cross the junctional epithelium drive the inflammatory process. Therefore bacteria are essential for periodontitis to occur, but they are insufficient by themselves to cause disease. For periodontitis to develop, a susceptible host is also required. The majority of periodontal breakdown (bone loss, attachment loss) is caused by host-derived destructive enzymes (MMPs) and inflammatory mediators (prostaglandins, interleukins) that are released during the cascade of destructive events that occur as part of the inflammatory response⁷¹ (see Figure 49-1). Paradoxically, the inflammatory response, which is essentially protective in design, is responsible for much of the breakdown of the soft and hard periodontal tissues. Periodontal disease is characterized by high concentrations of MMPs, cytokines, and prostanoids in the periodontal tissues, whereas periodontal health is characterized by the opposite.⁷⁰ The purpose of HMT is to restore the balance of proinflammatory or destructive mediators and antiinflammatory or protective mediators to that seen in healthy individuals. Pocket formation occurs as coronal junctional epithelium is broken down and restored at a more apical location. Plaque bacteria then migrate apically along the root surface deeper into the pocket, where the physical conditions favor the proliferation of gram-negative anaerobic species. Bacterial products continue to challenge the host, and the host continues its frustrated response against these bacteria and their products. Inflammation extends further and further apically, more bone is resorbed, and periodontal ligament (PDL) is broken down. The pocket deepens, and the associated attachment and bone loss result in clinical and radiographic signs of periodontitis. Intervention is required to prevent eventual tooth loss and other sequelae of the disease.

The nature of the host response to the presence of plaque is modified by genetic factors (helping to explain why aggressive periodontitis tends to have a familial aggregation) and systemic and environmental factors (e.g., smoking, diabetes, stress). These risk factors may lead to the imbalance between the proinflammatory and antiinflammatory mediators seen in susceptible individuals (see Figure 49-2). Risk factors can affect onset, rate of progression, and severity of periodontal disease, as well as response to therapy^24,41,86 (Box 49-1). Risk assessment is extremely important as we now recognize that some of these risk factors can be modified to reduce a patient’s susceptibility to periodontitis. Risk reduction strategies may include smoking cessation, improved control of diabetes, nutritional supplementation, improved oral hygiene, changes in medication, stress management, weight loss, and more frequent dental visits (Box 49-2). The use of chemotherapeutic agents or drugs specifically designed to treat periodontal diseases is emerging to aid as a risk reduction strategy. Intervention in periodontal disease can now include HMT as one of the available adjunctive treatment options. The term adjunctive is meant to imply “in addition to conventional therapies” or “in addition to other established therapies.” For the management of periodontal diseases, conventional approaches were initially mechanical in nature, that is, surgery, as well as scaling and root planing (SRP). Initially, adjunctive therapies were solely antimicrobial such as the use of antiseptics and antibiotics (local and/or systemic). New adjunctive approaches involve modulation of the host response. Researchers are also investigating HMTs, which aim to modify or reduce destructive aspects of the host response so that the immune-inflammatory response to plaque is less damaging to the periodontal tissues. Removal of plaque by SRP targets one aspect of the pathogenic process by reducing the bacterial burden and therefore the antigenic challenge that drives the inflammatory response in the host tissues. However, the bacterial challenge is never completely eliminated after SRP, and recolonization by bacterial species occurs. HMTs offer the potential for downregulating destructive aspects and upregulating protective aspects of the host response so that, in combination with conventional treatments to reduce the bacterial burden, the balance between health (resolution of inflammation and wound healing) and disease progression (continued proinflammatory events) is tipped in the direction of a healing response.

HMT is a means of treating the host side of the host-bacteria interaction. The host response is responsible for most of the tissue breakdown that occurs, leading to the clinical signs of periodontitis (i.e., loss of connective tissue attachment and bone). HMTs offer the opportunity for modulating or reducing this destruction by treating aspects of the chronic inflammatory response. HMTs do not “switch off” normal defense mechanisms or inflammation; instead, they ameliorate excessive or pathologically elevated inflammatory processes to enhance the opportunities for wound healing and periodontal stability.

HMT can be used to reduce excessive levels of enzymes, cytokines, and prostanoids and should not reduce levels below constitutive levels. HMTs can also modulate osteoclast and osteoblast function (Figure 49-3) but should not impact normal tissue turnover. HMT is key to addressing many of the risk factors that have adverse effects on the host response, which are either not easily managed (e.g., smoking, diabetes) or cannot be changed (e.g., genetic susceptibility). In addition, host modulatory agents might be used to increase the levels of a person’s own protective or antiinflammatory mediators. Use of systemic HMTs for treatment of a patient’s periodontal condition may also provide benefits for other inflammatory disorders such as arthritis, cardiovascular disease, dermatologic conditions, diabetes, rheumatoid arthritis, and osteoporosis. Also, patients who are currently taking host modulatory agents, such as nonsteroidal antiinflammatory drugs (NSAIDs), bisphosphonates, or tetracyclines, as well as newer agents targeting specific cytokines for the management of medical conditions, may be experiencing periodontal benefits from these systemic medications prescribed for the management of other chronic inflammatory conditions.

A variety of different drug classes have been evaluated as host modulation agents, including the NSAIDs, bisphosphonates, tetracyclines, enamel matrix proteins, growth factors, and bone morphogenetic proteins. This section discusses chemotherapeutics developed as HMTs researched as adjuncts to treat periodontitis to date, use of HMTs in clinical practice, and what the future might hold for HMTs.