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Aim: Therapeutic agents suppressing bone remodeling have been clinically approved to delay metastatic progression and skeletal-related events in patients with bone metastasis. However, therapeutic agents including zoledronic acid (ZA) are insufficient to regress established bone metastasis. Therefore, new treatment strategies are desired, and unraveling the status of cancer cells during bone metastatic progression will help develop therapeutic strategies. Methods: We developed a unique multiplexed reporter system for bioluminescent imaging (MRS-BLI) using three luciferase reporter genes. This system allows for the noninvasive and quantitative monitoring of tumor growth and activities of nuclear factor-kappa B (NF-κB) and hypoxia-inducible factor (HIF), which are the key transcriptional factors in response to inflammation and hypoxia, respectively. PC-3/MRS-BLI, a human prostate cancer cell line that stably retains the MRS-BLI reporter genes, was applied to the caudal-artery injection model of bone metastasis to observe the status of cancer cells during bone metastasis development and ZA treatment (< 1 month). Results: MRS-BLI reveals key events during the bone metastasis development: NF-κB and HIF are activated in cancer cells after migration to the bone marrow and are transiently reduced, followed by rapid activation before proliferation begins. ZA treatment suppresses the growth of metastasized cancer cells by suppressing NF-κB and HIF activities that may be indirectly induced by osteoclast activation. Conclusion: By visualizing the NF-κB and HIF activities of PC-3/MRS-BLI in bone, MRS-BLI has enabled new discoveries regarding the regulation of bone metastases. Further analysis of the progression of bone metastases using MRS-BLI may provide important information for developing new therapeutic strategies.