In order to elucidate the uptake and localization of bone-seeking agents in early and advanced osteoarthritis, bone scintigraphy and contact autoradiography were employed in experimental rabbit osteoarthritis, induced by joint instability of the knee. 42 adult rabbits were examined after administration of 99mTc-methylene diphosphonate given intravenously 1, 2, 4, 6, 12, 26 weeks and 1 1/2-2 years postoperatively, 6 animals at each interval. The scintimetric ratio between uptake in the unstable joint vs. control joint had P6creased as early as one week postoperatively and was highest within the first 3 months. The autoradiograms revealed two localizations of increased 99mTc-MDP uptake during different stages in osteoarthritic development: early uptake in growing osteophytes and late uptake in subchondral bone. The uptake in the osteophytes was localized to the provisional calcifications of enchondral ossification and could be observed as early as one week postoperatively, before there was any radiographic sign of osteophytes. The osteophytic uptake was responsible for the highest scintimetric ratios registered, but in the advanced state most osteophytes had lost their earlier increased uptake. The late subchondral uptake was seen mostly in the medial compartment of the joint under denuded or eburnated articular surfaces. The results provide a better understanding of the topography of bone scintigraphic uptake in osteoarthritis and indicate that early osteophytic growth is the cause of increased bone scintigraphic uptake in joints free from radiographic signs of osteoarthritis.