Effects of alendronate plus alfacalcidol in osteoporosis patients with a high risk of fracture: the Japanese Osteoporosis Intervention Trial (JOINT) – 02

Abstract

Objectives:

The authors conducted a randomized controlled trial to clarify the efficacy and safety of alendronate plus alfacalcidol versus alendronate alone in a clinical setting.

Research design and methods:

Eligible patients were postmenopausal women with severe osteoporosis who were aged 70 years or older and had several risk factors for incident fractures. The primary endpoint was prevention of incident fractures, and the anti-fracture efficacy was evaluated in relation to the baseline serum 25(OH)D level.

Results:

A total of 2164 patients were randomized to alendronate plus alfacalcidol (combination therapy) or alendronate alone (monotherapy). Although the overall difference in the incidence of vertebral fracture between the two groups was not significant, the combination therapy group had a significantly reduced risk of vertebral fractures after the first 6 months (HR, 0.53). In subgroup analyses, the combination therapy group was superior in the strata of number of prevalent vertebral fractures of ≥2 (HR, 0.51) and grade 3 of prevalent vertebral fractures (HR, 0.55). The rate of non-vertebral weight-bearing bone fractures was significantly lower in the combination therapy group than in the monotherapy group during the follow-up period (HR, 0.31). A lower baseline 25(OH)D level was associated with a higher incidence of non-vertebral weight-bearing bone fractures (HR, 3.42) despite alendronate use. Although one patient given the combination therapy had mild hypercalcemia, serious hypercalcemia and unknown adverse events were not encountered. Because of the limitations presented in this study, these results may not apply to female patients with longer than 2 years of treatments, and to male osteoporosis patients.

Conclusions:

The combination therapy was no more effective for overall vertebral fracture prevention. However, subgroup analysis has shown that it was more effective for fracture prevention in patients with severe vertebral deformity, multiple prevalent vertebral fractures, and for non-vertebral weight-bearing bone fracture prevention.

Key words::

• Alendronate
• Alfacalcidol
• Drug therapy
• Osteoporosis
• Vertebral fracture

Transparency

Declaration of funding

The JOINT study was sponsored by the Public Health Research Foundation. The authors would like to thank those who participated as clinical investigators in JOINT-02. The authors would also thank the Japan Arteriosclerosis Prevention Fund, Teijin Pharma Ltd, Asahi Kasei Corporation, Takeda Pharmaceutical Company Ltd, GE Healthcare Japan, Toyo Medic Co. Ltd, Banyu Pharmaceutical Co. Ltd and Dainippon Sumitomo Pharma Co. Ltd for their unlimited donations.

Declaration of financial/other relationships

The authors of the present study belong to different independent institutions and at the same time they were voluntary members of the A-TOP research group without any financial support.

CMRO peer reviewers may have received honoraria for their review work. The peer reviewers on this manuscript have disclosed that they have no relevant financial relationships.

Acknowledgement

The authors thank all investigators involved in this study at the following medical facilities: Yoshida Orthopaedic Clinic, Mie Memorial Hospital, JA Gifu Tohno Kosei Hospital, Sapporo Kiyota Orthopedic Hospital, Yasue Hospital, Research Institute and Practice for Involutional Disease, Yamane Hospital, Haramoto Clinic, Kujukuri Home Hospital, Shibayama Orthopedic Clinic, Yoshimura Clinic, Miyabe Clinic, Kurosawa Hospital, Kotake Orthopedic Clinic, Fujiwara Memorial Hospital, Sanada Clinic, Tokyo Women’s Medical University, Takahashi Orthopaedic Clinic, Matsui Orthopaedic Clinic, Saint Martin’s Hospital, Hanazono Hospital, Katsuga Orthopedic Clinic, Hakodate Redcross Hospital, Suzuki Orthopaedic Clinic, Togi Hospital, Gyotoku Flower Street Clinic, Omachi City Yasaka National Health Insurance Clinic, Orito Orthopedic Clinic, Toyokawa City Hospital, Hakodate Medical Association Hospital, Hara Orthopaedic Clinic, Wada Women’s Clinic, Yamauchi Hospital, Shimonoseki City Central Hospital, Mitaka Pain Clinic, Sato Orthopaedic Clinic, Nishimura Orthopaedic Clinic, Wada Hospital, Saiseikai Kawaguchi General Hospital, Kobe 100Years Memorial Hospital, Nara Medical University, Kodama Clinic, Fukase Orthopaedic Clinic, Kurihara Orthopaedic Clinic, Yanagibashi Hospital, Tiida Ohimachi Orthopaedic Surgery Clinic, Kyoto Katsura Hospital, National Hospital Organization Utano Hospital, Tamaru Orthopedic Clinic, Kumagawa Hospital, Makino Obstetrics and Gynecology Clinic, Meijo Hospital, Matsui Orthopedic Clinic, Akiyoshi Orthopedic Clinic, Soejima Orthopedic Clinic, Oji General Hospital, Kamiyouga Setagaya Street Clinic, Konno Orthopaedic Clinic, Kasama Orthopaedic Clinic, Japanese Red Cross Kobe Hospital, Sugata Clinic, National Hospital Organization Miyazaki Higashi Hospital, Shin Sapporo Orthopaedic Hospital, Kuromatsunaicho National Health Insurance Hospital, Sakusabe Clinic, Hoten Clinic, Tanaka Neurosurgical Hospital, Ikai Clinic, Musashino Clinic, Murayama Orthopaedic Clinic, Nagano National Hospital, Nagoya Daini Red Cross Hospital, Edashige Orthopedic Clinic, Showa Hospital, Sakamoto Medicine Clinic, Hakodate Central General Hospital, Gyoda General Hospital, Okumura Orthopaedic Clinic, Mejiro Orthopedics and Internal Medicine Clinic, Tanizawa Orthopaedic Clinic, Keiju Medical Center, Mitsubishi Kyoto Hospital, Morishita Seikeigeka, Ogihara Misaki Hospital, Murakami Orthopedic Clinic, Kagawa Prefectural Central Hospital, East Hokkaido Hospital, Shimura Hospital, Matsumura Surgery & Orthopaedic Clinic, Chiba Prefectural Togane Hospital, Kaihin Orthopaedic Clinic, Inokuchi Hospital, Senkawa-Shinoda Orthopaedic Clinic, Matsue Orthopaedic Clinic, Kagurazaka Clinic, Kitasato University School of Medicine, Nagasu Clinic, Nakamachidai Saito Orthopaedic Clinic, Fujita Health University School of Medicine, Aichi Saiseikai Hospital, Hilltop Iryou Clinic, Kamada Orthopedic Clinic, Hachimine Clinic, Higashiyodogawa Byouin, Ito Orthopaedic Clinic, Yamaguchi Clinic, Kamura Orthopedic Clinic, Noguchi Orthopedic Clinic, Tahara Orthopedic Clinic, Iwate Prefectural Ninohe Hospital, Chousei Hospital, Ui Orthopaedic Clinic, Jikei University School of Medicine, Ishin Clinic, Konishi Clinic, Machiya Orthopaedic Clinic, Matsuura Orthopaedic Clinic, Koenji Orthopaedic Clinic, Mizue Clinic, Hyakunincho Orthopaedic Clinic, Setagayaicchoume Orthopaedic Clinic, Oshiro Clinic, Kumaki Orthopaedic Rheumatology Clinic, Tokita Genki Clinic, Nagoya University School of Medicine, Tsujino Hospital, Hayaishi Hospital, Ryu Orthopedics Clinic, Japanese Red Cross Suma Clinic, Ogihara Orthopedic Hospital, Ota Orthopedic Clinic, Ehime Seikyo Hospital, Kenai Kinen Hospital, Mikami Surgical Orthopedic, Onozawa Orthopaedic Clinic, K&A Clinic, Dainohara Orthopaedic Clinic, Joto Orthopaedic Clinic, Hasuda Hospital, Saitama Seikeikai Hospital, Heiwadai Hospital, Waku Orthopaedic Clinic, Tokyo Rosai Hospital, Shinagawa East One Medical Clinic, Saneshige Clinic, Kenkokan Suzuki Clinic, Technoport Clinic, Yonekawa Surgery Clinic, Kobayashi Surgical Gastroenterological Clinic, Date Surgery Clinic, Kumagai Orthopaedic Clinic, Furuya Orthopaedic Clinic, Kameda Orthopaedic Clinic, Okubo Clinic, Suga Surgical Orthopedic Clinic, Watanabe Orthopaedic Clinic, Fujita Clinic, Kokubunji Minamicho Clinic, Wada Orthopaedic Clinic, Human Trust Clinic Suzuki, Yoshikawa Orthopaedic Clinic, Tanabe Orthopaedic Clinic, Katayama Orthopaedic Clinic, Miyazaki Orthopaedic Clinic, Amemiya Hospital, Sakudaira Orthopedic Clinic, Kawamura Orthopedic Clinic, Ozeki Orthopedic Clinic, Kaitoh Clinic, Ameno Clinic, Mine Clinic, Fuji Internal Medicine Clinic, Saiseikai Chuwa Hospital, Dongo Hospital, Kaikeonsen Hospital, Sakamoto Orthopedic Clinic, Ishida Clinic, Tanaka Orthopedic Clinic, Nakamura Orthopedic Clinic, Kikunan Hospital, Kawashima Orthopaedic Hospital, Akeno Neurosurgical Clinic.

The authors also express special thanks to the member of A-TOP ethical committee, Ms. Mamiko Matsumura, Dr. Tetsuro Inoue, Dr. Isao Yoshimura, Dr. Mitsuyoshi Nakajima, Tooru Ebihara RPh, Mr. Shinya Hattori, Mr. Kousaku Uchida and Dr. Rikushi Morita (Chairman).

The authors also express sincere thanks to the member of A-TOP research group, Dr. Shiro Tanaka (Division of Clinical Trial Design and Management, Translational Research Center, Kyoto University), Dr. Eiji Itoi (Department of Orthopaedic Surgery, Tohoku University School of Medicine), Dr. Shigeto Morimoto (Geriatric Medicine, Kanazawa Medical University), Dr. Akira Itabashi (Saitama Center for Bone Research, Kubojima Clinic), Dr. Toshitsugu Sugimoto (Department of Endocrinology and Metabolism, Faculty of Medicine, Shimane University), Dr. Toshihiko Yamashita (Department of Orthopaedic Surgery, Sapporo Medical University School of Medicine), Dr. Itsuo Gorai (Department of Obstetrics and Gynecology, International University of Health and Welfare Atami Hospital), Dr. Satoshi Mori (Bone and Joint Surgery, Seirei Hamamatsu General Hospital), Dr. Hideaki Kishimoto (Department of Orthopedic Surgery, San-in Rosai Hospital), Dr. Hideki Mizunuma (Department of Obstetrics and Gynecology, Hirosaki University School of Medicine), Dr. Naoto Endo (Division of Orthopedic Surgery, Niigata University Medical and Dental Hospital), Dr. Yoshiki Nishizawa (Department of Metabolism, Endocrinology and Molecular Medicine, Osaka City University Graduate School of Medicine), Dr. Kunio Takaoka (Department of Orthopaedic Surgery, Osaka City University Medical School) for their help to establish study design, Mr. Naoto Fujinawa (I’cros Co., Ltd), Mr. Kazumasa Tanzawa (ING Corporation) and Ms. Akiko Ishizuka (Japan Clinical Research Support Unit) for their contribution of data management, Mr. Kanji Arima (Arpa-Liaison, Inc.) who edited the English of the manuscript.