Total joint replacements are highly successful in relieving pain and restoring movement of damaged joints. However, the lifespan of the implants is limited. The implant’s long-term stability depends largely on the preservation of periprosthetic bone. Debris-wear particulates were first identified as the factor inducing periprosthetic bone loss. However, it was later shown that the resorption process starts before the particulates reach the periprosthetic bone. Thus a mechanical factor, interface micromotions, has been suspected to be the initiator of the early bone loss. In this work, we then investigated the response of bone cells to micromotions. Using an ex vivo setup, we applied micromotions on fresh human bone cores and showed that micromotions could indirectly activate osteoclasts after only 1 hour of stimulation. Thus micromotion-related osteoclastic activity could be the initiator of periprosthetic bone loss.