Abstract: Objective To observe the inhibitory effects of ⁹⁹Tc-methylenediphosphonate(⁹⁹Tc-MDP) and ¹⁵³Sm-ethylene diamine tetramethylene phosphonic acid(¹⁵³Sm-EDTMP) on bone invasion and osteolysis by Walker 256 carcinoma in rats, and their influence on the implanted tumor cells comparatively. Methods Bone invasion and osteolysis model was induced by Walker 256 carcinoma cells. The animals were divided into four groups: control group, ⁹⁹Tc-MDP treatment group, ¹⁵³Sm-EDTMP treatment group and ⁹⁹Tc-MDP+¹⁵³Sm-EDTMP treatment group. Radionuclide bone scan of ⁹⁹Tc^m-MDP, X-ray and histological examination were used in the experiment to estimate the inhibitory effects of ⁹⁹Tc-MDP or/and ¹⁵³Sm-EDTMP on the bone invasion and osteolysis. Meanwhile, the rate of apoptosis and percentage of each cell cycle phase of the rat-implanted tumor were analyzed by flow cytometry. Results Compared with the control, the rat number of tibia invasion and bone absorption reduced markedly in ⁹⁹Tc-MDP treatment group, ¹⁵³Sm-EDTMP treatment group and DP+¹⁵³Sm-EDTMP treatment group(Fisher's exact test:P<0.05). The rat number of bone absorption in the ⁹⁹Tc-MDP-j-¹⁵³Sm-EDTMP treatment group was lower than that of ⁹⁹Tc-MDP treatment group and ¹⁵³Sm-EDTMP treatment group. However, there was no significant difference. In addition, the rate of cell apoptosis in all the treatment groups was greater than that of the control group. And the cell percentage of DNA synthesis phase(S phase) notably dropped. There was enhancive effect on the transplanted tumor cells when both ⁹⁹Tc-MDP and ¹⁵³Sm-EDTMP were injected into the Walker 256 bearing rats. Conclusions ①⁹⁹Tc-MDP and ¹⁵³Sm-EDTMP can obviously prevent bone invasion and osteolysis induced by Walker 256 carcinoma in rats. ②They also have an effect on inducing the apoptosis of implanted tumor cells and inhibiting the proliferation of the transplanted tumor cells. There is enhancive effect on the implanted tumor cells when both ⁹⁹Tc-MDP and ¹⁵³Sm-EDTMP are applied simultaneously.