LAUSR

We read with great interest the article by Sing and colleagues. The authors conducted a nicely designed cohort study using a nationwide database and concluded that nitrogen-containing bisphosphonates (N-BPs) are protective against pneumonia. Alendronate and other N-BPs significantly reduced the risk of pneumonia (HR 0.76; 95% CI, 0.70 to 0.83) and pneumonia mortality (HR 0.65; 95% CI, 0.56 to 0.75). Confounding by indication, a type of channeling bias, might have altered the findings; however, the authors performed a propensity score matching analysis and several sensitivity analyses to reduce such bias. The authors have proposed several potential mechanisms underpinning the protective role of N-BPs. Herein, we suggest another hypothesis. One possible explanation might reside in a known immunological effect of N-BPs. Administration of N-BPs is frequently associated with an acute phase response (APR), a flu-like syndrome ascribed to the indirect activation of γδ T cells, which results in an excessive release of T helper 1 (Th1)-type cytokines. Indeed, it has already been proved that the amount of circulating γδ T cells is an important determinant of the occurrence of APR, and that γδ T cells are abruptly abated after administration of N-BPs, possibly in relation to a peripheral homing of these lymphocytes into several target tissues. However, the reduction of γδ T cells has been shown to persist for a long time, justifying the expected lower incidence of APRs in patients previously exposed to N-BPs. In this scenario, the chronic reduction of γδ T cells might even attenuate the inflammatory response, as observed in patients with inflammatory rheumatic diseases exposed to N-BPs. In conclusion, the findings by Sing and colleagues have important clinical implications, especially in the current coronavirus disease 2019 (COVID-19) emergency. Indeed, the release of Th1-type cytokines in response to COVID-19 is strictly associated withmore severe clinical manifestations. This immune overstimulation resembles the APR seen after the first administration of N-BPs, and is known as a “cytokine storm.” Could previous exposure to N-BPs mitigate even this “friendly fire”? Author Contributions