Necrotic-cell-activated macrophages drive an ERK-Bcl-xL survival pathway in osteoclasts and confer bisphosphonate resistance.

Nontraumatic osteonecrosis of the femoral head (ONFH) is a progressive disorder marked by ischemic necrosis of subchondral bone, often leading to femoral head collapse. Although bisphosphonates effectively target osteoclasts in osteoporosis and show benefit in ONFH animal models, their effectiveness to prevent bone collapse in patients has been inconsistent. Here, we modeled the necrotic microenvironment in which macrophages were exposed to necrotic cell debris and demonstrate that macrophage-derived soluble factors promoted osteoclast differentiation and protected osteoclasts against bisphosphonate-induced apoptosis. Conditioned medium from necrosis-primed macrophages was sufficient to reduce cleaved caspase-3 and maintain osteoclast numbers under alendronate exposure. Mechanistically, these factors activated ERK and increased the anti-apoptotic protein Bcl-xL at the mRNA and protein levels. Reanalysis of published single-cell transcriptomic data from ONFH patients detected Bcl-xL transcripts within osteoclast clusters, supporting clinical relevance. Collectively, our data indicate that necrosis-primed macrophages drive an ERK-Bcl-xL survival axis in osteoclasts that may underlie the limited therapeutic efficacy of bisphosphonates in ONFH. Targeting macrophage-derived factors or downstream osteoclast survival pathways, potentially in combination with bisphosphonates, may improve therapeutic outcomes.