Pharmacological Therapies for the Management of Inflammatory Bone Resorption in Periodontal Disease: A Review of Preclinical Studies

Abstract

Periodontitis, a highly prevalent multicausal chronic inflammatory and destructive disease, develops as a result of complex host-parasite interactions. Dysbiotic bacterial biofilm in contact with the gingival tissues initiates a cascade of inflammatory events, mediated and modulated by the host's immune response, which is characterized by increased expression of several inflammatory mediators such as cytokines and chemokines in the connective tissue. If periodontal disease (PD) is left untreated, it results in the destruction of the supporting tissues around the teeth, including periodontal ligament, cementum, and alveolar bone, which lead to a wide range of disabilities and poor quality of life, thus imposing significant burdens. This process depends on the differentiation and activity of osteoclasts, the cells responsible for reabsorbing the bone tissue. Therefore, the inhibition of differentiation or activity of these cells is a promising strategy for controlling bone resorption. Several pharmacological drugs that target osteoclasts and inflammatory cells with immunomodulatory and anti-inflammatory effects, such as bisphosphonates, anti-RANK-L antibody, strontium ranelate, cathepsin inhibitors, curcumin, flavonoids, specialized proresolving mediators, and probiotics, were already described to manage inflammatory bone resorption during experimental PD progression in preclinical studies. Meantime, a growing number of studies have described the beneficial effects of herbal products in inhibiting bone resorption in experimental PD. Therefore, this review summarizes the role of several pharmacological drugs used for PD prevention and treatment and highlights the targeted action of all those drugs with antiresorptive properties. In addition, our review provides a timely and critical appraisal for the scientific rationale use of the antiresorptive and immunomodulatory medications in preclinical studies, which will help to understand the basis for its clinical application.

Figure 1

The pathogenesis of PD. The bacteria that compose the dental biofilm trigger the process of local inflammation generated by the increase of cytokines such as IL-1, IL-6, IL-8, TNF-alpha, and PGE2 by the immune cells and inflammatory cells, such as neutrophils and macrophages. Such inflammatory environment ultimately leads to the activation of osteoclasts, the cells responsible to resorb the bone tissue. Consequently, the signs and symptoms of PD (gingival inflammation, epithelial downgrowth, pocket formation, and alveolar bone destruction) occur.

Figure 2

Denosumab acts similarly to OPG, which is RANKL's natural decoy receptor; denosumab binds to RANKL, preventing the binding of RANKL to its receptor, RANK, on the surface of osteoclasts and also on osteoclast precursors. Thus, the RANK signaling pathway is not activated, resulting in impaired osteoclast precursor differentiation and function and possibly osteoclast apoptosis. All these effects lead to inhibition of bone resorption. Bisphosphonates act on osteoclasts, but not on their precursors. Bisphosphonates are internalized into osteoclasts possibly by endocytosis. Subsequently, bisphosphonates inhibit FPP synthase, a key enzyme in the mevalonate signaling pathway. This leads to impaired intracellular protein prenylation impairing osteoclast function and apoptosis. Thus, bone resorption is inhibited.

Figure 3

Resolvins (RvE1) act to reduce ADP-stimulated platelet aggregation. In macrophages, RvE1 increases S6K (ribosomal protein S6 kinase) phosphorylation and phagocytosis. In monocytes, MAPK (mitogen-activated protein kinase) activation occurs. RvE1 acts on osteoclasts decreasing their growth and differentiation. In dendritic cells, there is a decrease in their migration and in the production of IL-12. In vitro, RvE1 reduced calcium mobilization and activation of NF-kB, and in vivo, there was a lower infiltration of PMN (polymorphonuclear cell/neutrophil). In the blood, there is a decrease in L-selectin and CD18 in PMN and monocytes.