Nitrogen-containing bisphosphonates (NBPs) are widely used as anti-bone resorptive drugs; however, NBPs have inflammatory side effects, including osteomyelitis and osteonecrosis of the jaw. In this paper, we review the effects of alendronate, a typical NBP, on cytokine production by mouse and human cells incubated with Porphyromonas gingivalis or lipid A.
Pretreatment of J774.1 cells, a mouse macrophage-like cell line, with alendronate augments P. gingivalis-induced interleukin (IL)-1β production, but decreases the production of Toll-like receptor (TLR) ligand-induced monocyte chemoattractant protein-1 (MCP-1) and macrophage inflammatory protein-1α (MIP-1α). Furthermore, caspase-1, a promoter of IL-1β production, is activated by treatment with alendronate; however, alendronate directly activates Smad3.
Pretreatment of human peripheral blood mononuclear cells (PBMCs) with alendronate promotes P. gingivalis-induced production of IL-1β and IL-6, but decreases P. gingivalis-induced IL-8 and MCP-1 production. We observed similar results in PBMCs treated with alendronate followed by lipid A. Pretreatment with alendronate did not increase NF-κB activation in PBMCs stimulated with lipid A.
In human gingival fibroblasts, alendronate pretreatment increased lipid A-induced production of IL-6 and IL-8. In addition, pretreatment with alendronate increased NF-κB and Smad3 activation in gingival fibroblasts stimulated with lipid A, and SIS3, a specific inhibitor of Smad3, significantly inhibited alendronate-increased IL-6 and IL-8 production.
These results suggest that alendronate-mediated changes in cytokine production by cells occur via regulation of transcriptional activity, including NF-κB and Smad3, and that this agent may exacerbate periodontitis and jaw osteomyelitis, which are chronic inflammatory diseases caused by high levels of oral bacterial components.

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