Archives of Osteoporosis

, 13:67 | Cite as

Patient satisfaction and efficacy of switching from weekly bisphosphonates to monthly minodronate for treatment and prevention of glucocorticoid-induced osteoporosis in Japanese patients with systemic rheumatic diseases: a randomized, clinical trial

  • Shin-ya Tamechika
  • Kaneshige Sasaki
  • Yoshihito Hayami
  • Shin-ichiro Ohmura
  • Shinji Maeda
  • Shiho Iwagaitsu
  • Taio NaniwaEmail author
Original Article



The randomized, clinical trial demonstrated that switching to monthly minodronate from weekly alendronate and risedronate provides greater increases in patients’ satisfaction and bone mineral density and more substantial decreases in a bone resorption marker than continuing weekly alendronate and risedronate in patients with systemic rheumatic diseases on glucocorticoid therapy.


Osteoporosis and associated fractures are major concerns for patients with systemic rheumatic diseases on long-term glucocorticoid therapy. Bisphosphonates increase bone mineral density (BMD) and reduce the frequency of vertebral fractures, but they are associated with poor adherence. The effects of monthly oral minodronate on patients’ satisfaction, BMD, and bone turnover markers were investigated in patients with systemic rheumatic diseases on glucocorticoids and weekly oral alendronate or risedronate.


Study patients with systemic rheumatic diseases on oral glucocorticoids and weekly alendronate 35 mg or risedronate 17.5 mg were randomly assigned either to switch to minodronate 50 mg every 4 weeks or to continue the currently taking weekly bisphosphonate for 52 weeks after a 24-week run-in period.Patients were stratified by hospital site, sex, and menopausal status in women at enrollment. The primary endpoint was the difference between the proportions of patients who responded very satisfactory or satisfactory for the current bisphosphonate therapy at weeks 48 and 76 between the two groups. Secondary endpoints included percentage changes in lumbar spine BMD and bone turnover markers from the time of starting allocated treatment.


Monthly minodronate was superior to weekly alendronate or risedronate for patients’ satisfaction, the increase of lumbar spine BMD, and suppression of serum tartrate-resistant acid phosphatase 5b at week 76.


Monthly minodronate is more acceptable and may be more effective than weekly alendronate or risedronate for prevention and treatment of bone loss in patients with systemic rheumatic diseases on glucocorticoid therapy.


Glucocorticoid-induced osteoporosis Glucocorticoid Bisphosphonate Minodronate Alendronate Risedronate 



The authors would like to thank Drs. Jun-ichi Wada (Division of Rheumatology, Department of Internal Medicine, Nagoya City University Hospital), who collected the samples of the patients, and Prof. Akio Niimi (Department of Respiratory Medicine, Allergy and Clinical Immunology, Nagoya City University Graduate School of Medical Sciences), who provided general support as a department chair.

Authors’ roles

Study design: TN. Study conduct and data collection: TN, ST, KS, YH, and SM. Data analysis: TN and ST. Data interpretation: TN and ST. The first draft of the manuscript: ST and TN. Revising manuscript content: TN and ST with assistance in the form of critique and suggestions from all authors. Approving final version of manuscript: all authors. TN takes responsibility for the integrity of the data analysis.


This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.

Compliance with ethical standards

Conflict of interest

TN has received research grants from Ono Pharmaceutical Company Limited, Teijin Pharma Limited, and Eisai Company Limited. TN has received lecture fees (< $5000) from Ono Pharmaceutical Company Limited, Teijin Pharma limited, Eisai Company Limited, and Astellas Pharma Incorporated. ST and SM received lecture fees (< $5000) from Ono Pharmaceutical Company Limited. KS received lecture fees (< $5000) from Eisai Company Limited, Astellas Pharm Incorporated, and Takeda Pharmaceutical Company Limited. YH received lecture fees (< $5000) from Takeda Pharmaceutical Company Limited. The other authors declare no conflicts of interest.

Supplementary material

11657_2018_451_MOESM1_ESM.docx (34 kb)
ESM 1 (DOCX 33 kb)
11657_2018_451_MOESM2_ESM.xlsx (19 kb)
ESM 2 (XLSX 19 kb)


  1. 1.
    Curtis JR, Saag KG (2007) Prevention and treatment of glucocorticoid-induced osteoporosis. Curr Osteoporos Rep 5(1):14–21CrossRefGoogle Scholar
  2. 2.
    van Staa TP (2006) The pathogenesis, epidemiology and management of glucocorticoid-induced osteoporosis. Calcif Tissue Int 79(3):129–137CrossRefGoogle Scholar
  3. 3.
    Lems WF (2007) Bisphosphonates and glucocorticoids: effects on bone quality. Arthritis Rheum 56(11):3518–3522CrossRefGoogle Scholar
  4. 4.
    Saag KG (2003) Glucocorticoid-induced osteoporosis. Endocrinol Metab Clin N Am 32:135–157CrossRefGoogle Scholar
  5. 5.
    van Staa TP, Leufkens HG, Abenhaim L, Zhang B, Cooper C (2000) Use of oral corticosteroids and risk of fractures. J Bone Miner Res 15(6):993–1000CrossRefGoogle Scholar
  6. 6.
    Vestergaard P, Olsen ML, Paaske Johnsen S, Rejnmark L, Sørensen HT, Mosekilde L (2003) Corticosteroid use and risk of hip fracture: a population-based case-control study in Denmark. J Intern Med 254(5):486–493CrossRefGoogle Scholar
  7. 7.
    Soucy E, Bellamy N, Adachi JD, Pope JE, Flynn J, Sutton E, Campbell J (2000 Jun) A Canadian survey on the management of corticosteroid induced osteoporosis by rheumatologists. J Rheumatol 27(6):1506–1512PubMedGoogle Scholar
  8. 8.
    Fardet L, Petersen I, Nazareth I (2011) Prevalence of long-term oral glucocorticoid prescriptions in the UK over the past 20 years. Rheumatology (Oxford) 50(11):1982–1990CrossRefGoogle Scholar
  9. 9.
    Overman RA, Yeh JY, Deal CL (2013) Prevalence of oral glucocorticoid usage in the United States: a general population perspective. Arthritis Care Res (Hoboken) 65(2):294–298CrossRefGoogle Scholar
  10. 10.
    Díez-Pérez A, Hooven FH, Adachi JD, Adami S, Anderson FA, Boonen S, Chapurlat R, Compston JE, Cooper C, Delmas P, Greenspan SL, LaCroix AZ, Lindsay R, Netelenbos JC, Pfeilschifter J, Roux C, Saag KG, Sambrook P, Silverman S, Siris ES, Watts NB, Nika G, Gehlbach SH (2011) Regional differences in treatment for osteoporosis. The global longitudinal study of osteoporosis in women (GLOW). Bone 49(3):493–498CrossRefGoogle Scholar
  11. 11.
    Silverman S, Curtis J, Saag K, Flahive J, Adachi J, Anderson F, Chapurlat R, Cooper C, Diez-Perez A, Greenspan S, Hooven F, le Croix A, March L, Netelenbos JC, Nieves J, Pfeilschifter J, Rossini M, Roux C, Siris E, Watts N, Compston J (2015) International management of bone health in glucocorticoid-exposed individuals in the observational GLOW study. Osteoporos Int 26(1):419–420CrossRefGoogle Scholar
  12. 12.
    Buckley L, Guyatt G, Fink HA et al (2017) 2017 American College of Rheumatology Guideline for the Prevention and Treatment of Glucocorticoid-Induced Osteoporosis. Arthritis Care Res (Hoboken) 69(8):1095–1110CrossRefGoogle Scholar
  13. 13.
    Suzuki Y, Nawata H, Soen S, Fujiwara S, Nakayama H, Tanaka I, Ozono K, Sagawa A, Takayanagi R, Tanaka H, Miki T, Masunari N, Tanaka Y (2014) Guidelines on the management and treatment of glucocorticoid-induced osteoporosis of the Japanese Society for Bone and Mineral Research: 2014 update. J Bone Miner Metab 32(4):337–350CrossRefGoogle Scholar
  14. 14.
    Lekamwasam S, Adachi JD, Agnusdei D et al (2012) A framework for the development of guidelines for the management of glucocorticoid-induced osteoporosis. Osteoporos Int 23(9):2257–2276CrossRefGoogle Scholar
  15. 15.
    Bone HG, Hosking D, Devogelaer JP, Tucci JR, Emkey RD, Tonino RP, Rodriguez-Portales JA, Downs RW, Gupta J, Santora AC, Liberman UA, Alendronate Phase III Osteoporosis Treatment Study Group (2004) Ten years’ experience with alendronate for osteoporosis in postmenopausal women. N Engl J Med 350(12):1189–1199CrossRefGoogle Scholar
  16. 16.
    Wells GA, Cranney A, Peterson J et al (2008) Alendronate for the primary and secondary prevention of osteoporotic fractures in postmenopausal women. Cochrane Database Syst Rev 23(1):CD001155Google Scholar
  17. 17.
    Saag KG, Emkey R, Schnitzer TJ, Brown JP, Hawkins F, Goemaere S, Thamsborg G, Liberman UA, Delmas PD, Malice MP, Czachur M, Daifotis AG, Lane N, Correa-Rotter R, Yanover M, Westhovens R, Epstein S, Adachi JD, Poubelle P, Melo-Gomes J, Rodriguez-Portales JA (1998) Alendronate for the prevention and treatment of glucocorticoid-induced osteoporosis. Glucocorticoid-induced osteoporosis intervention study group. N Engl J Med 339(5):292–299CrossRefGoogle Scholar
  18. 18.
    Adachi JD, Saag KG, Delmas PD, Liberman UA, Emkey RD, Seeman E, Lane NE, Kaufman JM, Poubelle PEE, Hawkins F, Correa-Rotter R, Menkes CJ, Rodriguez-Portales JA, Schnitzer TJ, Block JA, Wing J, McIlwain HH, Westhovens R, Brown J, Melo-Gomes JA, Gruber BL, Yanover MJ, Leite MOR, Siminoski KG, Nevitt MC, Sharp JT, Malice MP, Dumortier T, Czachur M, Carofano W, Daifotis A (2001) Two-year effects of alendronate on bone mineral density and vertebral fracture in patients receiving glucocorticoids: a randomized, double-blind, placebo-controlled extension trial. Arthritis Rheum 44(1):202–211CrossRefGoogle Scholar
  19. 19.
    Cohen S, Levy RM, Keller M, Boling E, Emkey RD, Greenwald M, Zizic TM, Wallach S, Sewell KL, Lukert BP, Axelrod DW, Chines AA (1999) Risedronate therapy prevents corticosteroid-induced bone loss: a twelve-month, multicenter, randomized, double-blind, placebo-controlled, parallel-group study. Arthritis Rheum 42(11):2309–2318CrossRefGoogle Scholar
  20. 20.
    Dunford JE, Thompson K, Coxon FP, Luckman SP, Hahn FM, Poulter CD, Ebetino FH, Rogers MJ (2001) Structure-activity relationships for inhibition of farnesyl diphosphate synthase in vitro and inhibition of bone resorption in vivo by nitrogen-containing bisphosphonates. J Pharmacol Exp Ther 296(2):235–242PubMedGoogle Scholar
  21. 21.
    Matsumoto T, Hagino H, Shiraki M, Fukunaga M, Nakano T, Takaoka K, Morii H, Ohashi Y, Nakamura T (2009) Effect of daily oral minodronate on vertebral fractures in Japanese postmenopausal women with established osteoporosis: a randomized placebo-controlled double-blind study. Osteoporos Int 20(8):1429–1437CrossRefGoogle Scholar
  22. 22.
    Hagino H, Nishizawa Y, Sone T, Morii H, Taketani Y, Nakamura T, Itabashi A, Mizunuma H, Ohashi Y, Shiraki M, Minamide T, Matsumoto T (2009) A double-blinded head-to-head trial of minodronate and alendronate in women with postmenopausal osteoporosis. Bone 44(6):1078–1084CrossRefGoogle Scholar
  23. 23.
    Furuta K, Adachi K, Arima N et al (2008) A study on the recognition of Japanese adults for upper abdominal symptoms. Nippon Shokakibyo Gakkai Zasshi ( J Jpn Soc Gastroenterol) 105:817–824 (in Japanese, Abstract in English)Google Scholar
  24. 24.
    Reginster JY, Rabenda V (2006) Patient preference in the management of postmenopausal osteoporosis with bisphosphonates. Clin Interv Aging 1(4):415–423CrossRefGoogle Scholar
  25. 25.
    Emkey R, Koltun W, Beusterien K, Seidman L, Kivitz A, Devas V, Masanauskaite D (2005) Patient preference for once-monthly ibandronate versus once-weekly alendronate in a randomized, open-label, cross-over trial: the Boniva Alendronate Trial in Osteoporosis (BALTO). Curr Med Res Opin 21(12):1895–1903CrossRefGoogle Scholar
  26. 26.
    Iwamoto J, Okano H, Furuya T, Urano T, Hasegawa M, Hirabayashi H, Kumakubo T, Makita K (2016) Patient preference for monthly bisphosphonate versus weekly bisphosphonate in a cluster-randomized, open-label, crossover trial: Minodroate Alendronate/Risedronate Trial in Osteoporosis (MARTO). J Bone Miner Metab 34(2):201–208CrossRefGoogle Scholar
  27. 27.
    Widler L, Jaeggi KA, Glatt M, Müller K, Bachmann R, Bisping M, Born AR, Cortesi R, Guiglia G, Jeker H, Klein R, Ramseier U, Schmid J, Schreiber G, Seltenmeyer Y, Green JR (2002) Highly potent geminal bisphosphonates. From pamidronate disodium (Aredia) to zoledronic acid (Zometa). J Med Chem 45(17):3721–3738CrossRefGoogle Scholar
  28. 28.
    Sekiguchi M, Kawasaki Y, Kawasaki M, Hirakura Y, Yuda M, Teramura T (2012) Biophysical chemical analysis of bisphosphonates. J New Rem & Clin 61:1683–1688 (in Japanese, Abstract in English)Google Scholar
  29. 29.
    Nancollas GH, Tang R, Phipps RJ, Henneman Z, Gulde S, Wu W, Mangood A, Russell RGG, Ebetino FH (2006) Novel insights into actions of bisphosphonates on bone: differences in interactions with hydroxyapatite. Bone 38(5):617–627CrossRefGoogle Scholar
  30. 30.
    Roelofs AJ, Thompson K, Gordon S, Rogers MJ (2006) Molecular mechanisms of action of bisphosphonates: current status. Clin Cancer Res 12:6222s–6230sCrossRefGoogle Scholar
  31. 31.
    Shimizu E, Tamasi J, Partridge NC (2012) Alendronate affects osteoblast functions by crosstalk through EphrinB1-EphB. J Dent Res 91(3):268–274CrossRefGoogle Scholar
  32. 32.
    Brown JP, Prince RL, Deal C, Recker RR, Kiel DP, de Gregorio LH, Hadji P, Hofbauer LC, Álvaro-Gracia JM, Wang H, Austin M, Wagman RB, Newmark R, Libanati C, San Martin J, Bone HG (2009) Comparison of the effect of denosumab and alendronate on BMD and biochemical markers of bone turnover in postmenopausal women with low bone mass: a randomized, blinded, phase 3 trial. J Bone Miner Res 24(1):153–161CrossRefGoogle Scholar
  33. 33.
    Ebina K, Noguchi T, Hirao M, Hashimoto J, Kaneshiro S, Yukioka M, Yoshikawa H (2016) Effects of switching weekly alendronate or risedronate to monthly minodronate in patients with rheumatoid arthritis: a 12-month prospective study. Osteoporos Int 27(1):351–359CrossRefGoogle Scholar
  34. 34.
    Kamimura M, Nakamura Y, Ikegami S, Komatsu M, Uchiyama S, Kato H (2016) Monthly minodronate inhibits bone resorption to a greater extent than does monthly risedronate. Osteoporos Sarcopenia 2(3):170–174CrossRefGoogle Scholar
  35. 35.
    Gennari L, Bilezikian JP (2009) Glucocorticoid-induced osteoporosis: hope on the HORIZON. Lancet 373(9671):1225–1226CrossRefGoogle Scholar
  36. 36.
    Raggatt LJ, Partridge NC (2010) Cellular and molecular mechanisms of bone remodeling. J Biol Chem 285(33):25103–25108CrossRefGoogle Scholar
  37. 37.
    Hongo H, Sasaki M, Kobayashi S, Hasegawa T, Yamamoto T, Tsuboi K, Tsuchiya E, Nagai T, Khadiza N, Abe M, Kudo A, Oda K, Henrique Luiz de Freitas P, Li M, Yurimoto H, Amizuka N (2016) Localization of Minodronate in mouse femora through isotope microscopy. J Histochem Cytochem 64(10):601–622CrossRefGoogle Scholar
  38. 38.
    Tanishima S, Kishimoto Y, Fukata S, Mizumura H, Hagino H, Teshima R (2007) Minodronic acid influences receptor activator of nuclear factor kappaB ligand expression and suppresses bone resorption by osteoclasts in rats with collagen-induced arthritis. Mod Rheumatol 17(3):198–205CrossRefGoogle Scholar
  39. 39.
    Kim YH, Kim GS, Jeong-Hwa B (2002) Inhibitory action of bisphosphonates on bone resorption does not involve the regulation of RANKL and OPG expression. Exp Mol Med 34(2):145–151CrossRefGoogle Scholar
  40. 40.
    Roux S, Brown JP (2009) Osteoclast apoptosis in rheumatic diseases characterized by a high level of bone resorption (osteoporosis, rheumatoid arthritis, myeloma and Paget’s disease of bone). Curr Rheumatol Rev 5:98–110CrossRefGoogle Scholar
  41. 41.
    Zhang Q, Badell IR, Schwarz EM, Boulukos KE, Yao Z, Boyce BF, Xing L (2005) Tumor necrosis factor prevents alendronate-induced osteoclast apoptosis in vivo by stimulating Bcl-xL expression through Ets-2. Arthritis Rheum 52(9):2708–2718CrossRefGoogle Scholar
  42. 42.
    van Staa TP, Leufkens HG, Cooper C (2002) The epidemiology of corticosteroid-induced osteoporosis: a meta-analysis. Osteoporos Int 13(10):777–787CrossRefGoogle Scholar
  43. 43.
    Hosoi T (2015) On “2015 guidelines for prevention and treatment of osteoporosis”. Diagnostic criteria of primary osteoporosis and the criteria for pharmacological treatment. Clin Calcium 25(9):1279–1283PubMedGoogle Scholar

Copyright information

© International Osteoporosis Foundation and National Osteoporosis Foundation 2018

Authors and Affiliations

  • Shin-ya Tamechika
    • 1
  • Kaneshige Sasaki
    • 2
  • Yoshihito Hayami
    • 3
  • Shin-ichiro Ohmura
    • 1
  • Shinji Maeda
    • 1
  • Shiho Iwagaitsu
    • 1
  • Taio Naniwa
    • 1
    Email author
  1. 1.Division of Rheumatology, Department of Internal Medicine, Nagoya City University Hospital and Department of Respiratory Medicine, Allergy and Clinical ImmunologyNagoya City University Graduate School of Medical SciencesNagoyaJapan
  2. 2.Department of RheumatologyThe Aichi Prefectural Federation of Agricultural Cooperatives for Health and Welfare Kainan HospitalYatomiJapan
  3. 3.Department of RheumatologyNagoya City West Medical CenterNagoyaJapan

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