Introduction
More than one fourth of women in their 70s suffer from at least one osteoporotic vertebral fracture [
1,
2]. Incidence of new fractures rises with increasing number of preexisting fractures [
3], and not only morbidity but also mortality rate rises with increasing number of fractures [
4,
5]. Thus, osteoporosis has become a significant socioeconomic burden in aged societies.
Bisphosphonates have been shown to have potent anti-fracture efficacy by inhibiting bone resorption, with a reduction in bone turnover and an increase in bone mineral density (BMD). Minodronate (ONO-5920/YM529) is a nitrogen-containing bisphosphonate with potent inhibitory effect on bone resorption [
6]. Previous in vitro and in vivo preclinical studies demonstrated that minodronate is about ten times as potent as alendronate in inhibiting bone resorption [
7]. A randomized placebo-controlled double-blind trial revealed that daily oral administration of 0.5, 1.0, and 1.5 mg minodronate to Japanese women with postmenopausal osteoporosis for 9 months caused an increase in lumbar BMD by 4.9%, 5.7%, and 5.2%, respectively, compared with the placebo group [
8]. Because the incidence of adverse gastrointestinal events did not increase in a dose-dependent manner (0%, 12.6%, 6.3%, and 11.1% by placebo, 0.5, 1.0, and 1.5 mg minodronate treatment, respectively), minodronate was shown to be well tolerated with excellent effect in increasing BMD. In addition, a head-to-head comparison of the effects of daily oral 1 mg minodronate with 5 mg alendronate revealed that the effect of 12-month treatment with 1 mg minodronate on lumbar and total hip BMD was similar to those of 5 mg alendronate and that minodronate was generally well tolerated with similar safety profiles to alendronate (Hagino et al., submitted for publication). These data suggest that minodronate can become a new treatment choice as a potent bisphosphonate for patients with established osteoporosis. However, its efficacy in reducing osteoporotic fractures has not been evaluated. The present phase III clinical trial was conducted to examine the effect of daily oral 1 mg minodronate on the prevention of vertebral fractures in Japanese women with postmenopausal osteoporosis.
Discussion
The present study demonstrated that daily oral administration of 1 mg minodronate for 24 months reduced the risk of new vertebral fractures by 59% compared with that in the placebo group. The effect of minodronate on vertebral fracture was observed within 12 months, and there was also a significant decrease in height loss at 12 months. The overall safety profile including gastrointestinal safety was similar between the two groups.
In the present study, a large number of vertebral fractures occurred during the first 6 months in both groups (20 and 27 in minodronate and placebo groups, respectively). In our previous study, to compare the effect of minodronate on lumbar BMD and bone markers with that of alendronate (Hagino et al., submitted for publication), bone resorption markers were suppressed within 1 month, and lumbar BMD was significantly increased after 3 months of minodronate treatment. It should be noted that the assessment of vertebral fractures at baseline was performed within 2 months before the start of study drug administration. Therefore, a part of vertebral fractures identified after 6 months of drug administration might have occurred before drug administration was started. Although the exact reason why a large number of vertebral fractures occurred during the early period in both groups remains unclear, minodronate showed a marked anti-fracture efficacy from 6 to 24 months of treatment (Table
2).
In contrast to the robust inhibitory effect on vertebral fractures, the present study did not show a significant effect of minodronate in reducing non-vertebral fractures. This is a major limitation of the present study. Because the study was aimed to examine the ability of minodronate to reduce the risk of vertebral fractures, the study did not have enough power in terms of the number of study subjects and the length of study period to examine the effect of minodronate on non-vertebral fractures. Thus, although the study included patients with established osteoporosis having at least one prevalent vertebral fracture, the number of non-vertebral fractures developed in long bones during the 24-month study period was too small to draw any conclusions.
With regard to the safety profile of minodronate, no significant difference was observed between the minodronate and placebo groups in any AEs including drug-related or serious AEs. Although the most common AEs were gastrointestinal AEs, the incidence of gastrointestinal AEs, as well as those that caused discontinuation from the study, was very similar between the minodronate and placebo groups. These results suggest that minodronate does not cause any serious disturbance in osteoporotic patients, and daily administration of minodronate can be well-tolerated in patients with osteoporosis.
Minodronate exhibits very similar antiresorptive potency to zoledronic acid in pre-clinical studies [
7], and intermittent oral administration of ibandronate [
15] as well as yearly intravenous administration of zoledronic acid [
16] demonstrated potent anti-fracture efficacy. Therefore, further studies are warranted to examine the effect of intermittent oral and intravenous minodronate on vertebral and non-vertebral fractures in osteoporotic patients.
In conclusion, daily oral minodronate is safe, well-tolerated, and is effective in reducing vertebral fracture risk in postmenopausal women with established osteoporosis. Because the dose of minodronate in reducing fracture incidence was low, further studies are warranted to evaluate the efficacy of intermittent administration of higher doses of minodronate on osteporotic fractures.
Acknowledgments
We thank Mr. T. Minamide and Mr. T. Matsuoka, ONO Pharmaceutical Co., Ltd., for their scientific and technical support, Astellas Pharmaceutical, for providing supportive data, and the following investigators and clinical sites in Japan that participated in this study: T. Ota, Ota Orthopedic Clinic; M. Kokaji, M. Tsuji, S. Kawamura, Kobayashi Hospital; T. Hashimoto, Hakodate Koseiin Hakodate Central General Hospital; S. Sato, Eniwa Hospital; G. Katahira, Sapporo Kiyota Orthopeadic Hospital; Y. Saito, Hokuei Orthopedics; S. Nabeshima, Nabeshima Clinic; T. Fukunaga, Ainosato Orthopedics; T. Chiba, Kikusui Orthopedics; H. Yamamoto, Toyohira Orthopedics; H. Koga, Koga Orthopedic Clinic; T. Ando, Morioka Hospital; S. Tsukikawa, Tsukikawa Lady’s Clinic; S. Harada, Tsukuba Gakuen Hospital; N. Tajima, Tajima Geka Ichouka; K. Ogata, Seiwakai Shoda Hospital; T. Michimata, Uchibori Seikeigeka Iin; H. Inoue, Inoue Hospital; M. Inuzuka, Chousei Hospital; S. Ichikawa, Cardiovascular Hospital of Center Japan; K. Toba, Toba Orthopedic Clinic; H. Sato, Saiseikai Kawaguchi General Hospital; Y. Kaneda, Kaneda Orthopedics; K. Inoue, Tokyo Women`s Medical University Medical Center East; S. Yamada, Kyoai Clinic; K. Fukuda, Shiratori Clinic; S. Sano, Sanraku Hospital; A. Yamaguchi, Yamaguchi Hospital; T. Nakamura, Abe Clinic; K. Maruyama, Gate Town Hospital; T. Nakagawa, Senpo Tokyo Takanawa Hospital; T. Takemoto, Misyuku Hospital; K. Kamada, Kumegawa Hospital; H. Mizuguchi, T. Ryu, Y. Sakamoto, S. Katayama, Mizuguchi Hospital; R. Kimura, Hideshima Hospital; S. Yamaguchi, Gonohashi Clinic; C. Nokubo, Nokubo Orthopedic Clinic; M. Takemoto, Takemoto Orthopedics; T. Ishihara, Shirahigebashi Hospital; Y. Tsuruta, Tsuruta Clinic; S. Yamazaki, Sengoku Hospital; T. Ishibashi, T. Okubo, Oguchi East Hospital; K. Suzuki, A. Okazaki, Shonan Daiichi Hospital; H. Machida, Kanto Rosai Hospital; S. Yamashita, Hayama Orthopedics; Y. Mikami, Yokohama Rosai Hospital; I. Miyata, Aoba Orthopedics Clinic; M. Kasuga, Kasuga Orthopedics; M. Tsuboi, Yokohama Minoru Clinic; N. Nagata, Nagata Orthopedics; N. Endo, Niigata University Medical & Dental Hospital; Y. Murai, Murai Orthopedic Iin; S. Noto, Noto Orthopedics; M. Katsumi, Katsumi Orthopedics; H. Morishita, T. Takino, Kanazawa Social Insurance Hospital; N. Hachisuka, Hachisuka Orthopedics; M. Takimori, Nirasaki Mutual Hospital; Y. Nagasaka, Nagasaka Orthopedics; M. Suzuki, Suzuki Orthopedic Iin; S. Kumaki, Hokushin General Hospital; S. Kobayashi, Shinsyu University Hospital; T. Hanaoka, Yamabe Spa Hanaoka Orthopedics; H. Misawa, Yodakubo Hospital; M. Shiraki, Research Institute and Practice for Involutional Diseases; S. Tsuboi, Shizuoka Kosei Hospital; K. Yamazaki, Hamamatsu University School of Medicine University Hospital; M. Taniguchi, Taniguchi Orthopedic Iin; M. Fukuchi, Aobadai Fukuchi Orthopedics & Gastroenterology Clinic; M. Denda, Denda Orthopedics; Y. Nishijima, Nishijima Hospital; T. Kitakoji, Nagoya University Hospital; Y. Hachiya, Hachiya Orthopedic Hospital; Y. Osaka, Minamiosaka Hospital; A. Tei, Kishiwada Tokushukai Hospital; Y. Honda, Baba Memorial Hospital; N. Sha, Kanebo Memorial Hospital; T. Noda, C. Terada, Ako Central Hospital; J. Sako, Irie Hospital; Y. Higashi, Himeji Central Hospital; T. Onishi, Onishi Orthopedics; T. Matsubara, Matsubara Clinic; Y. Koyama, Matsubara Mayflower Hospital; S. Soen, Kinki University School of Medicine, Nara Hospital; M. Ozaki, Kitade Hospital; M. Ohama, Yonago East Hospital; T. Nishiyama, Tamashima Daiichi Hospital; H. Sanada, Sanada Hospital; K. Sanuki, Sanuki Orth & Rheumatic Clinic; T. Taguchi, Yamaguchi University Hospital; S. Yamagata, Yamagata Iin; K. Nobutani, Sea Side Hospital; H. Yamazaki, H. Ueno, Mine City Hospital; S. Ono, Marugame Ono Clinic; A. Kuge, S. Morita, Izumino Hospital; T. Ogata, Ogata Orthopedic Hospital; H. Ikematsu, Haradoi Hospital; A. Iwaki, K. Domen, Okabe Hospital; Y. Ishibashi, Ishibashi Orthopedics; T. Tsuruta, Tsuruta Orthopaedic Clinic; H. Shibata, Shibata Chokodo Hospital; T. Segata, Kumamoto Saishunso National Hospital; T. Naono, Oita Oka Hospital; E. Nakamura, Nakamura Hospital; S. Okamoto, Sanyo Osteoporosis Research Foundation Okamoto Naika Clinic; S. Nagai, Kagoshima Red Cross Hospital; H. Sakamoto, Sakamoto Medical Clinic. The present study was sponsored by ONO Pharmaceutical Co., Ltd. and Astellas Pharmaceutical.