The undesired movement of anchor teeth, and relapse of previously moved teeth, are major clinical problems in orthodontics. Dental implants are increasingly used to preserve anchorage, but these are costly and require invasive surgical procedures. An alternative strategy for maintaining anchorage may be the use of biological inhibitors of osteoclastic bone resorption. In the present study, we investigated the relative efficacy of pamidronate vs. osteoprotegerin (OPG) in inhibiting bone resorption and tooth movement, using a new orthodontic model in mice in which maxillary molars are moved for prolonged periods by near-constant, clinically relevant forces. Osteoclast influx to compression sites was initiated on day 3, was maximal on day 4, and persisted until at least day 12 after force application. Tooth movement paralleled osteoclast numbers. Minimal osteoclast apoptosis was observed, suggesting that recruitment, rather than programmed cell death, is a critical regulatory mechanism under conditions of constant force. Osteoclasts were reduced at compression sites by both OPG (95%) and pamidronate (70%); tooth movement was more dramatically inhibited by OPG (77% vs. 34%). Our findings indicate that constant orthodontic force regulates the recruitment, activation, and viability of osteoclasts, and that OPG could have clinical utility in preventing undesired tooth movement.