Nitrogen bisphosphonates (NBPs) are commonly prescribed for osteoporosis but have also been found to induce inflammatory reactions and to delay the progression of breast cancer. The authors showed that intraperitoneal NBP administration in mice caused a rapid influx of neutrophils and monocytes. This response was dependent on the myeloid differentiation primary response gene 88 (MyD88), a mediator of Toll-like receptor (TLR) and IL-1 signaling. In vitro NBPs did not directly stimulate murine bone marrow-derived mononuclear cells or human peripheral blood mononuclear cells. Rather, NBPs primed these cells to produce increased amounts of cytokines when they were exposed to IL-1 or TLR ligands. This activity was mediated by a reduction in IL-1 receptor-associated kinase-M, a negative regulator of MyD88-dependent signaling.