Oral Virtual Presentation (Virtual only) ESA-SRB-ANZBMS 2021

Bisphosphonate drugs have effects outside the skeleton and inhibit the mevalonate pathway in alveolar macrophages in lung (#168)

Emma K Fletcher 1 2 , Oliver P Skinner 1 2 , Julie Jurczyluk 1 2 , Mark P Hodson 3 , Esther Kristianto 3 , Ya Xiao 1 2 , Michael J Rogers 1 2 , Marcia A Munoz 1 2
  1. The Garvan Institute of Medical Research, Sydney, New South Wales, Australia
  2. St Vincent's Clinical School, UNSW Sydney, Sydney, New South Wales, Australia
  3. Victor Chang Cardiac Research Institute Innovation Centre, Sydney, New South Wales, Australia

Nitrogen-containing bisphosphonates (N-BPs) are well-established treatments for post-menopausal osteoporosis, metastatic bone disease and other skeletal disorders. These drugs inhibit bone resorption by blocking the mevalonate pathway in osteoclasts, thereby preventing protein prenylation. The high affinity of N-BPs for bone mineral confers bone-targeting and specificity for osteoclasts, hence, it's widely considered that N-BPs only act in the skeleton. However, accumulating epidemiological data suggest that N‑BPs also have beneficial, pleiotropic effects outside bone, including decreased risk of mortality from pneumonia, but the mechanisms remain unknown.

Like osteoclasts, macrophages in culture and in tumours in vivo efficiently internalise N-BP by endocytosis. Here, we sought to identify whether N-BPs could also act on macrophages in the lung in vivo, and alter immune function. We used fluorescently-labelled N-BP and flow cytometry to detect drug uptake into cells. 24 hours after iv injection, we detected N-BP in >98% of CD11blo/-CD11chiF4/80+ alveolar macrophages in lung, as well as 80% of peritoneal cells (almost entirely CD11b+F4/80+ peritoneal macrophages). Characteristic features of N-BP action – inhibition of protein prenylation and build-up of the metabolite isopentenyl pyrophosphate – were also detected in alveolar and peritoneal macrophages 48 hours after one iv dose of the N‑BP zoledronate. Importantly, a single iv dose of zoledronate significantly enhanced 2.5-5-fold the release of proinflammatory cytokines and chemokines (including IL-1beta, IL-6, TNFalpha, CXCL1, CCL2,3,4,5) into bronchoalveolar lavage fluid after intranasal endotoxin stimulation.

In summary, we present new evidence that N-BP treatment targets tissue resident macrophages in vivo in lung and peritoneum and enhances immune responses, dispelling the long-held dogma that bisphosphonates act only in bone. Given that inhibition of the mevalonate pathway is known to have a variety of anti-microbial effects, we propose that the apparent beneficial effects of N-BPs on pneumonia infection and mortality occur via actions on alveolar macrophages in the lung.