Advertisement

Osteoporosis International

, Volume 14, Issue 3, pp 225–234 | Cite as

A double-blind dose-ranging study of risedronate in Japanese patients with osteoporosis (a study by the Risedronate Late Phase II Research Group)

  • M. Shiraki
  • M. Fukunaga
  • K. Kushida
  • H. Kishimoto
  • Y. Taketani
  • H. Minaguchi
  • T. Inoue
  • R. Morita
  • H. Morii
  • K. Yamamoto
  • Y. Ohashi
  • H. Orimo
Original Article

Abstract

To determine the clinical recommended dosage regimen of risedronate for the treatment of involutional osteoporosis in Japanese patients, dose-response relationships for the efficacy and safety of this drug were investigated using a multi-center, randomized, double-blind, parallel group comparative design with four dose levels of risedronate (placebo, 1 mg, 2.5 mg and 5 mg per day). A total of 211 patients diagnosed with involutional osteoporosis according to the criteria proposed by the Japanese Society for Bone and Mineral Research were randomized and received one of the four doses once daily for 36 weeks. All patients were supplemented with 200 mg of calcium daily in the form of calcium lactate. The primary efficacy endpoint was the percent change in bone mineral density of the lumbar spine (L2–L4 BMD) determined by dual-energy X-ray absorptiometry (DXA) from baseline to the time of final evaluation. Changes in biochemical markers of bone turnover and safety profile were also compared. Percent changes in L2–L4 BMD at final evaluation in the placebo, and 1-, 2.5-, and 5-mg risedronate groups were 0.79±5.30, 2.71±4.93, 5.29±3.96, and 5.15±4.25% (mean±SD), respectively. A linear dose-response relationship was obtained up to a dose of 2.5 mg, whereas no further increase in BMD was observed at 5 mg. The decrease in bone turnover markers, including N-terminal osteocalcin, phosphorus, and urinary deoxypyridinoline, also showed a linear dose-response relationship up to a dose of 2.5 mg. Alkaline phosphatase level decreased linearly up to a dose of 5 mg. Risedronate was well tolerated in this 36-week study with 1- to 5-mg doses. Neither the overall incidence of adverse events nor the percentage of patients without problem in overall safety assessment differed significantly among the dose groups including the placebo group. Based on these results, a once-daily dose of 2.5 mg of risedronate, which is half that used in Caucasians, is recommended for the treatment of involutional osteoporosis in Japanese patients.

Keywords

Bone mineral density Dose response Osteoporosis Risedronate 

References

  1. 1.
    Harris ST, Watts NB, Genant HK et al. (1999) Effects of risedronate treatment on vertebral and nonvertebral fractures in women with postmenopausal osteoporosis, a randomized, controlled trial. J Am Med Assoc 282:1344–1352Google Scholar
  2. 2.
    Reginster J-Y, Minne HW, Sorensen OH et al. (2000) Randomized trial of the effects of risedronate on vertebral fractures in women with established postmenopausal osteoporosis. Osteoporos Int 11:83–91Google Scholar
  3. 3.
    Liberman UA, Weiss SR, Broll J et al. (1995) Effect of oral alendronate on bone mineral density and the incidence of fracture in postmenopausal osteoporosis. N Engl J Med 333:1437–1443Google Scholar
  4. 4.
    Black DM, Cummings SR, Karpf DB et al. (1996) Randomised trial of effect of alendronate on risk of facture in women with existing vertebral fractures. Lancet 348:1535–1541Google Scholar
  5. 5.
    McClung MR, Geusens P, Miller PD et al. (2001) Effect of risedronate on the risk of hip fracture in elderly women. N Engl J Med 344:333–340Google Scholar
  6. 6.
    Nakamura T, Kushida K, Shiraki M et al. (1998) A placebo-controlled, double blind study to determine the appropriate alendronate dosage in Japanese patients with involutional osteoporosis, and postmenopausal osteopenia or artificially menopausal women. Med Consult New Remedies 35:3–17 [in Japanese]Google Scholar
  7. 7.
    Shiraki M, Kushida K, Fukunaga M et al. (1999) A double-masked multicenter comparative study between alendronate and alfacalcidol in Japanese patients with osteoporosis. Osteoporos Int 10:183–192Google Scholar
  8. 8.
    Kishimoto H, Kushida K, Shiraki M et al. (2002) A clinical trial evaluating the efficacy and safety of risedronate (NE-58095) in patients with involutional osteoporosis or bone mineral content loss associated with lack of ovarian function: early phase II study of NE-58095. Osteoporosis Jpn 10:61–83 [in Japanese]Google Scholar
  9. 9.
    Orimo H, Sugioka Y, Fukunaga M et al. (1995) The Committee of the Japanese Society for Bone and Mineral Research for Development of Diagnostic Criteria of Osteoporosis. Diagnostic criteria of primary osteoporosis. Osteoporosis Jpn 3:669–674 [in Japanese]Google Scholar
  10. 10.
    Brown RC, Aston JP, Weeks I et al. (1987) Circulating intact parathyroid hormone measured by a two-site immunochemiluminometric assay. J Clin Endocrinol Metab 65:407–414Google Scholar
  11. 11.
    Eguchi H, Hosoda K, Kurihara N et al. (1995) Sandwich immunoassay specific for the N-terminal sequence of osteocalcin. J Immunol Methods 184:213–240Google Scholar
  12. 12.
    De Leenheer AP, Bauwens RM (1985) Comparison of a cytosol radioreceptor assay with a radioimmunoassay for 1,25-dihydroxyvitamine D in serum or plasma. Clin Chim Acta 152:143–154Google Scholar
  13. 13.
    Black D, Dunkan A, Robins SP (1988) Quantitative analysis of the pyridinium crosslinks of collagen in urine using ion-paired reverse-phase high-performance liquid chromatography. Anal Biochem 169:197–203Google Scholar
  14. 14.
    Fogelman I, Ribot C, Smith R et al. (2000) Risedronate reverses bone loss in postmenopausal women with low bone mass: results from a multinational, double-blind, placebo-controlled trial. J Clin Endocrinol Metab 85:1895–1900Google Scholar
  15. 15.
    Laboratory of Informatics on Health and Nutrition (1999) Sixth revision of recommended dietary allowances (RDA) for the Japanese: dietary reference intakes. Dai-ichi Shuppan Publishing, Tokyo [in Japanese]Google Scholar
  16. 16.
    Ogura Y, Gonsyo A, Tei M et al. (in press) Phase I clinical trial of risedronate sodium (NE-58095) hydrate: single and multiple oral dose studies. J Bone Miner MetabGoogle Scholar
  17. 17.
    Mitchell DY, Eusebio RA, Sacco-Gibson NA et al. (2000) Dose-proportional pharmacokinetics of risedronate on single-dose oral administration to healthy volunteers. J Clin Pharmacol 40:258–265Google Scholar
  18. 18.
    McClung M, Bensen W, Bolognese M et al. (1998) Risedronate increases bone mineral density at the hip, spine, and radius in postmenopausal women with low bone mass. Osteoporos Int 8 (Suppl 3):111Google Scholar

Copyright information

© International Osteoporosis Foundation and National Osteoporosis Foundation 2003

Authors and Affiliations

  • M. Shiraki
    • 1
  • M. Fukunaga
    • 2
  • K. Kushida
    • 3
  • H. Kishimoto
    • 4
    • 11
  • Y. Taketani
    • 5
    • 12
  • H. Minaguchi
    • 6
    • 13
  • T. Inoue
    • 3
    • 14
  • R. Morita
    • 7
    • 15
  • H. Morii
    • 8
    • 16
  • K. Yamamoto
    • 4
    • 17
  • Y. Ohashi
    • 9
  • H. Orimo
    • 10
    • 18
  1. 1.Research Institute and Practice for Involutional DiseasesMinamiazumi-gun, Nagano PrefectureJapan
  2. 2.Department of Nuclear MedicineKawasaki Medical SchoolOkayamaJapan
  3. 3.Department of Orthopedic SurgeryHamamatsu University School of MedicineShizuokaJapan
  4. 4.Department of Orthopedic Surgery, Faculty of MedicineTottori UniversityTottoriJapan
  5. 5.Department of Obstetrics and Gynecology, Faculty of MedicineThe University of TokyoTokyoJapan
  6. 6.Department of Obstetrics and GynecologyYokohama City University School of MedicineYokohamaJapan
  7. 7.Department of RadiologyShiga University of Medical ScienceShigaJapan
  8. 8.Second Department of Internal MedicineOsaka City University Medical SchoolOsakaJapan
  9. 9.Department of Biostatistics, School of Health Sciences and NursingThe University of TokyoTokyoJapan
  10. 10.Ministry of Finance Tokyo HospitalTokyoJapan
  11. 11.Department of OrthopedicsSan-in Rosai HospitalTottori Japan
  12. 12.The University of Tokyo HospitalTokyoJapan
  13. 13.Minaguchi HospitalTokyo Japan
  14. 14.Houmikai Aoyama General HospitalAichi Japan
  15. 15.Shiga University of Medical Science HospitalShiga Japan
  16. 16.Osaka City University Medical SchoolOsakaJapan
  17. 17.Department of OrthopedicsHakuai HospitalTottori Japan
  18. 18.Tokyo Metropolitan Geriatric HospitalTokyoJapan

Personalised recommendations