Intratibial injection in nude rats of 1 x 10(6) OHS, MHMX, and LOX human tumor cells resulted in each case in progressively growing bone tumors. When the diameter of the affected leg had increased by 2-3 mm, the animals were examined for uptake of 99mTc-methylenediphosphonate. The OHS osteosarcoma tumors caused sclerotic lesions with high and uniform isotope uptake, and the MHMX unclassified sarcoma showed a mixed pattern with both sclerotic and lytic areas, whereas the LOX melanoma caused lytic bone lesions with low uptake of the radionuclide. These findings were compared with the results of analogous investigations previously performed in the patients from whom the tumor lines originated. Striking similarities in both the morphology and the scintigraphic images were observed between corresponding tumors in rats and humans, with results supporting the clinical relevance of the model systems. When the LOX model was used for therapy experiments, doxorubicin had no effect on the growth of the tibial tumors, which in the control group appeared after a latency of 13.5 days. The alkylating agent mitozolomide increased the median tumor-free latency to 47 days in 7 rats, and 5 animals did not develop tumors within the observation period of 60 days. Doxorubicin was ineffective also against the OHS tumor, whereas ifosfamide and the radionuclide 89Sr-chloride showed significant antitumor activity. The disease-free latency increased from 20 days, in the control animals, to 45 and 28.5 days, respectively, in the 2 treated groups, in which 2 of 7 and 2 of 10 rats were without tumors at 60 days. The data demonstrate that the tibial models discriminated between the action of the different therapeutic agents, and suggest that they may be useful in selecting compounds with clinical activity against skeletal tumors.