Synovitis and subchondral bone turnover are associated with pain in osteoarthritis. Bisphosphonates provide tools for investigating these pathogenic mechanisms and also may have therapeutic potential. Translating preclinical findings into new treatments for human osteoarthritis requires a critical appraisal and refinement of animal models, identification of those pathogenic mechanisms that are amenable to intervention, and pharmacological targeting of those mechanisms in the right people at the right time.