Nitrogen-containing BPs (N-BPs), also termed the second- and third-generation BPs, induce apoptosis in osteoclasts by inhibiting protein prenylation of small G proteins through the inhibition of farnesyl pyrophosphate synthase in the meval- onate pathway

Metastatic and primary bone tumors are malignant tumors affecting the skeleton. Although the prognosis of patients with these tumors has improved with the development of effective chemotherapy, the challenges of local recurrence, subsequent osteolysis, degradation of bone strength and unresectable tumors persist. Local control of these tumors is therefore a key strategy to address these limitations. The third-generation bisphosphonate (BP), zoledronic acid (ZOL), has been demonstrated to reduce osteoclasts and exhibited potent antitumor effects in a number of malignancies. Hydroxyapatite (HA) and polymethyl methacrylate (PMMA) bone cement are used in orthopedic surgery as bone graft substitutes, for implant arthroplasty and bone strengthening, and as a sustained-release system for drugs such as antibiotics. At present, the antitumor effects of ZOL-loaded HA in vitro or in vivo or of ZOL-loaded bone cement in vivo have not been described. Therefore, the present study assessed the effects of ZOL-loaded HA and bone cement in malignant tumor cells. The two materials exerted strong antitumor effects against osteosarcoma, fibrosarcoma, synovial sarcoma, renal cancer, prostate cancer and lung cancer cells upon releasing ZOL. The antitumor effects of ZOL-loaded HA were less potent compared with those of ZOL-loaded bone cement, possibly as BPs exhibit higher affinity to HA. ZOL‐loaded bone cement also exerted antitumor effects against pulmonary metastases and primary lesions, without exhibiting systemic toxicity in vivo. These results demonstrate that these materials may be beneficial for the treatment of malignant bone tumors, including metastatic bone tumors. In addition, as these materials are already in clinical use, such applications may be easily implemented.