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Design of a randomized clinical trial of concurrent treatment with vitamin K2 and risedronate compared to risedronate alone in osteoporotic patients: Japanese Osteoporosis Intervention Trial-03 (JOINT-03)

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Abstract

Concurrent treatments with bisphosphonates and vitamin K are promising given that bisphosphonates possibly interfere with vitamin K activation. This is a prospective, multi-center, open-labeled, randomized trial of the efficacy of concurrent treatment with vitamin K2 and risedronate compared with risedronate alone and to explore subsets of patients for which concurrent treatment is particularly efficacious (trial identification number UMIN000000991). Inclusion criteria are women who meet the criteria for pharmacological therapy for osteoporosis, aged ≥65 years, have any of pre-specified risk factors, can walk unassisted, and are able to answer questionnaires. Exclusion criteria are prior warfarin use, secondary osteoporosis or non-osteoporotic metabolic bone diseases, contraindication for vitamin K2 and risedronate, hyper- or hypoparathyroidism, mental disorders, prevalent vertebral fracture at ≥6 sites, severe degenerative spinal deformation between T4 and L4, serious heart, liver, or kidney disease, or bisphosphonate use within the previous 6 months. Patients were recruited from 123 institutes between January 2008 and February 2010, and allocated to vitamin K2 (45 mg/day) and risedronate (2.5 mg/day or 17.5 mg/week) or risedronate alone (2.5 mg/day or 17.5 mg/week) groups. Primary endpoint is a vertebral or non-vertebral fracture. Secondary endpoints are bone mineral density, height, undercarboxylated osteocalcin, JOQOL, EQ-5D and safety. A sample size of 910 subjects per group and 2-year follow-up will provide 80 % power to detect 35 % risk reduction for fracture, with a two-sided significance level of 5 %. Subgroup analysis stratified to adjustment factors for random allocation, body mass index, 25-hydroxyvitamin D, estimated glomerular filtration rate, grade of vertebral fracture, JOQOL, EQ-5D, and co-morbidity is pre-specified.

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Acknowledgments

The authors express thanks to 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., Mr. Shinya Hattori and Mr. Kousaku Uchida. This JOINT study was sponsored by the Public Health Research Foundation. The authors would like to thank those who participated as clinical investigators in JOINT-03. The authors also thank the Japan Arteriosclerosis Prevention Fund, Teijin Pharma Limited, Asahi Kasei Corporation, Takeda Pharmaceutical Company Limited, GE Healthcare Japan, Toyo Medic Co., Ltd., MSD Co., Ltd., and Dainippon Sumitomo Pharma Co., Ltd., for their generous donations.

Conflict of interest

T.M. is an employee of the Public Health Research Foundation. The other authors declare that there is no conflict of interest associated with this manuscript.

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Authors and Affiliations

  1. Department of Pharmacoepidemiology, Graduate School of Medicine and Public Health, Kyoto University, Kyoto, Japan

    Shiro Tanaka

  2. Public Health Research Foundation, Tokyo, Japan

    Teruhiko Miyazaki, Tatsuhiko Kuroda & Nobuaki Miyakawa

  3. Department of Biostatistics, School of Public Health, University of Tokyo, Tokyo, Japan

    Yukari Uemura & Yasuo Ohashi

  4. Department of Orthopedic Surgery, University of Occupational and Environmental Health School of Medicine, Fukuoka, Japan

    Toshitaka Nakamura

  5. Kawasaki Medical School, Okayama, Japan

    Masao Fukunaga

  6. Department of Obstetrics and Gynecology, International University of Health and Welfare, Tokyo, Japan

    Hiroaki Ohta

  7. Bone and Joint Surgery, Seirei Hamamatu General Hospital, Shizuoka, Japan

    Satoshi Mori

  8. School of Health Science, Tottori University Faculty of Medicine, Tottori, Japan

    Hiroshi Hagino

  9. Department of Clinical Research and Development, National Center for Geriartics and Gerontology, Aichi, Japan

    Takayuki Hosoi

  10. Internal Medicine 1, Shimane University Faculty of Medicine, Shimane, Japan

    Toshitsugu Sugimoto

  11. Department of Orthopaedic Surgery, Tohoku University School of Medicine, Sendai, Japan

    Eiji Itoi

  12. Japan Osteoporosis Foundation, Tokyo, Japan

    Hajime Orimo

  13. Department of Internal Medicine, Research Institute and Practice for Involutional Diseases, Nagano, Japan

    Masataka Shiraki

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  1. Shiro Tanaka
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  2. Teruhiko Miyazaki
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  3. Yukari Uemura
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  7. Masao Fukunaga
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  8. Yasuo Ohashi
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  9. Hiroaki Ohta
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  10. Satoshi Mori
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  11. Hiroshi Hagino
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  13. Toshitsugu Sugimoto
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  14. Eiji Itoi
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  15. Hajime Orimo
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  16. Masataka Shiraki
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Correspondence to Shiro Tanaka.

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Tanaka, S., Miyazaki, T., Uemura, Y. et al. Design of a randomized clinical trial of concurrent treatment with vitamin K2 and risedronate compared to risedronate alone in osteoporotic patients: Japanese Osteoporosis Intervention Trial-03 (JOINT-03). J Bone Miner Metab 32, 298–304 (2014). https://doi.org/10.1007/s00774-013-0491-4

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  • DOI: https://doi.org/10.1007/s00774-013-0491-4

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