Randomized head-to-head comparison of minodronic acid and raloxifene for fracture incidence in postmenopausal Japanese women: the Japanese Osteoporosis Intervention Trial (JOINT)-04

Abstract

Aims

We conducted a head-to-head randomized trial of minodronate, a bisphosphonate, and raloxifene, a selective estrogen receptor modulator, to obtain clinical evidence and information about their efficacy and safety.

Methods

The Japanese Osteoporosis Intervention Trial protocol number 4 (JOINT-04) trial is a multi-center, open-labeled, blinded endpoints, head-to-head randomized trial of minodronate and raloxifene. Ambulatory elderly women with osteoporosis (age, >60 years) were randomly allocated to the raloxifene or minodronate group by central registration. The co-primary endpoints included any one of osteoporotic fractures (vertebral, humeral, femoral, and radial fractures), vertebral fractures, and major osteoporotic fractures (clinical vertebral, humeral, femoral, and radial fractures). The biological effects of each drug, patients’ quality of life, and drug safety were assessed based on the secondary outcomes. This study was registered at the University Hospital Medical Information Network-Clinical Trials Registry (UMIN-CTR) under trial identification number UMIN000005433.

Results

A total of 3896 patients were randomized to the minodronate and raloxifene groups, and drug efficacy assessments were performed for 3247 patients (1623 and 1624 patients, respectively). Among these patients, 1176 and 1187 patients received allocated treatment for 2 years. The incidence rate ratios for osteoporotic, vertebral, and major osteoporotic fractures in the minodronate group were 0.94 (95% CI: 0.78–1.13, p = .494), 0.86 (95% CI: 0.70–1.05, p = .147), and 1.22 (95% CI: 0.86–1.74, p = .274), respectively. Compared to the raloxifene group, the minodronate group showed significantly increased bone mineral density of the lumbar spine for each visit (6 months: p = .007, 12 months: p = .0003, 24 months: p<.0001). Also, serious adverse reactions were observed for four and six patients in the minodronate and raloxifene groups, respectively.

Conclusions

Overall, there were no statistical differences in the incidence rates of osteoporotic, vertebral, or major osteoporotic fractures between the two groups. Serious adverse reactions were rare in both groups.

Keywords:

• Head-to-head randomized trial
• minodronate
• raloxifene
• osteoporotic
• fractures

Transparency

Declaration of funding

This JOINT study was sponsored by the Public Health Research Foundation. This study was also supported in part by funding of the Project Promoting Clinical Trials for Development of New Drugs (19lk0201061t0004) from the AMED to ST.

Declaration of financial/other relationships

YU received a consultancy fee from Teijin Pharma Ltd and Daiichi Sankyo and outsourcing fees from Chugai Pharmaceutical Co. TS received research grants from Asahi Kasei Pharma Corp., Astellas Pharma, Taisho Toyama Pharmaceutical Co. Ltd, Takeda Pharmaceutical Co. Ltd, Pfizer, and Teijin Pharma Ltd, and consulting fees from Kissei pharmaceutical Co. Ltd, Shimadzu Corp., and Takeda Pharmaceutical Co. Ltd. ST has received lecture fee from Amgen Astellas BioPharma, Boehringer Ingelheim, AstraZeneca, Taiho Pharmaceutical, Ono Pharmaceutical Co. Ltd, and JMDC Inc. He has also received consultation fees from the Pharmaceuticals and Medical Devices Agency and DeNA Life Science. TM and MT are employees of the Public Health Research Foundation. AT received consultancy or lecture fees from Asahi Kasei Pharma Corp., Teijin Pharma Ltd, Ono Pharmaceutical Co. Ltd, Chugai Pharmaceutical Co., Takeda Pharmaceutical Company Ltd, and Daiichi Sankyo Pharma. SS received lecture and consultancy fees from Asahi Kasei Pharma Corp., Astellas Pharma, Chugai Pharmaceutical Co., Daiichi Sankyo, Eisai Co. Ltd, Eli Lilly Japan, Ono Pharmaceutical Co., Pfizer, and Takeda Pharmaceutical Company Ltd. HH has received lecture and consultancy fees from Asahi Kasei Pharma Corp., Astellas Pharma Inc., MSD Co., Ltd, Chugai Pharmaceutical Co., Eisai Co., Ltd, Eli Lilly Japan K.K., Pfizer, Mitsubishi Tanabe Pharma Corp., Mochida Pharmaceutical Co., Ltd, Ono Pharmaceutical Co. Ltd, Pfizer, Taisho Toyama Pharmaceutical Co., Ltd, Takeda Pharmaceutical Co., Ltd, and Teijin Pharma Ltd. ToS has received research grants from Astellas Pharma, Eisai Co., Daiichi Sankyo, Chugai Pharmaceutical Co., and Eli Lilly Japan as well as consulting and/or lecture fees from Asahi Kasei Pharma Corp, Daiichi Sankyo, and Pfizer. MF received consulting fees from Asahi Kasei Pharma Corp and lecture fees from Daiichi Sankyo, MSD, and Chugai Pharmaceutical Co. HiO received lecture fee from Pfizer Co., Ltd. MS received lecture and consultancy fees from Asahi Kasei Pharma and Teijin Pharma Ltd. TN has received reports personal fees and other from Asahi Pharma, Teijin Pharma, Daiichi-Sankyo Pharma, UCB Pharma, AMGEN, ASTELAS, Chugai pharma, personal fees and other from MERCK. SM and HO have nothing to disclose. Peer reviewers on this manuscript have received an honorarium from CMRO for their review work but have no other relevant financial relationships to disclose.

Acknowledgements

The authors would like to thank the chairman Dr. Rikushi Morita and the members of the ethics committee, Ms. Mamiko Matsumura, Dr. Tetsuro Inoue, Dr. Isao Yoshimura, Dr. Mitsuyoshi Nakajima, Tooru Ebihara, R.Ph., and Mr. Shinya Hattori. The authors would also like to thank those who participated as clinical investigators in JOINT-04. Lastly, we would like to thank Editage (www.editage.jp) for English language editing.