High counts of wear particles and activated macrophages are strong predictors of prosthetic loosening in total joint arthroplasty patients. The tissue response, dominated by macrophages, with production of inflammatory mediators and matrix-degrading enzymes, triggers a self-accelerating cycle of osteolysis, ultimately resulting in failure of the arthroplasty, high treatment cost and poor patient outcome. Vitamin D is frequently used as a treatment for osteoporosis, but might also contribute to osteolysis in inflammatory joints. Here, we review the effects of extrarenal vitamin D, activation by macrophages in the joint space. The summarized pathways contribute to increased bone resorption in the setting of the inflammatory micro-environment at the bone-prosthesis interface. If further evidence confirms a role of oral vitamin D, as a risk factor for aseptic loosening, this might influence the current treatment strategies for patients at risk for this condition.