Rheumatoid arthritis is an autoimmune disease that affects ~1% of the global population and leads to joint inflammation, local bone erosions and systemic bone loss. The disability and immobility caused by inflammatory bone loss, joint destruction and fractures in rheumatoid arthritis present a clinical challenge and impose a considerable socioeconomical burden. Osteoclasts have the unique ability to resorb bone and cause bone loss. A comprehensive understanding of the regulatory mechanisms of osteoclasts and their crosstalk with stromal cells, such as osteoblasts, or immune cells during inflammation is essential for the development of targeted therapies to prevent and treat bone loss. The objective of this Review is to present a comprehensive overview of the current knowledge of osteoclast regulation at different levels: from systemic pathways to changes in the bone microenvironment, including the involvement of local cells, to osteoclast-intrinsic regulation such as metabolic adaptations. We also discuss some of the current and emerging therapies that can counteract inflammatory bone loss.