Skip to main content
SpringerLink
Log in

Effect of Intermittent and Daily Regimens of Minodronic Acid on Bone Metabolism in an Ovariectomized Rat Model of Osteoporosis

  • Original Research
  • Published:
Calcified Tissue International Aims and scope Submit manuscript

Abstract

The goal of the study was to compare the effects of minodronic acid on bone mineral density (BMD) and bone turnover in a rat ovariectomized (OVX) osteoporosis model, using two intermittent treatment regimens (weekly and 4 continuous days every 4 weeks) and a daily regimen. Female F344 rats (age 14 weeks) underwent ovariectomy or a sham operation. Minodronic acid was orally administered at 0.042, 0.21, and 1.05 mg/kg in the intermittent regimens, and at 0.03 and 0.15 mg/kg in the daily regimen for 12 weeks from the day after surgery. Minodronic acid dose-dependently ameliorated the decreases in areal BMD of the lumbar vertebrae and femur, and volumetric BMD of total and trabecular bone in the distal femur. Minodronic acid also suppressed the increase in urinary deoxypyridinoline levels and reduced serum osteocalcin levels. In bone histomorphometry, all three minodronic acid regimens suppressed OVX-induced increases in bone turnover at the tissue level and ameliorated all structural indices, except that an effect on trabecular thickness only occurred with daily treatment. In conclusion, minodronic acid administered weekly or for 4 continuous days every 4 weeks suppressed increased bone resorption and BMD to a similar extent to that of a similar total dose given daily in a rat OVX model.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

Similar content being viewed by others

References

  1. Black DM, Cummings SR, Karpf DB, Cauley JA, DE Thompson, Nevitt MC, Bauer DC, Genant HK, Haskell WL, Marcus R, Ott SM, Torner JC, Quandt SA, Reiss TF, Ensrud KE, Fracture Intervention Trial Research Group (1996) Randomised trial of effect of alendronate on risk of fracture in women with existing vertebral fractures. Lancet 348:1535–1541. doi:10.1016/S0140-6736(96)07088-2

    Article  CAS  PubMed  Google Scholar 

  2. Reginster J, Minne HW, Sorensen OH, Hooper M, Roux C, Brandi ML, Lund B, Ethgen D, Pack S, Roumagnac I, Eastell R, Vertebral Efficacy with Risedronate Therapy (VERT) Study Group (2000) (2000) Randomized trial of the effects of risedronate on vertebral fractures in women with established postmenopausal osteoporosis. Osteoporos Int 11:83–91. doi:10.1007/s001980050010

    Article  CAS  PubMed  Google Scholar 

  3. Delmas PD, Recker RR, Chesnut CH 3rd, Skag A, Stakkestad JA, Emkey R, Gilbride J, Schimmer RC, Christiansen C (2004) Daily and intermittent oral ibandronate normalize bone turnover and provide significant reduction in vertebral fracture risk: results from the BONE study. Osteoporos Int 15:792–798. doi:10.1007/s00198-004-1602-9

    Article  CAS  PubMed  Google Scholar 

  4. Black DM, Kelly MP, Genant HK, Palermo L, Eastell R, Bucci-Rechtweg C, Cauley J, Leung PC, Boonen S, Santora A, de Papp A, Bauer DC, Fracture Intervention Trial Steering Committee; HORIZON Pivotal Fracture Trial Steering Committee (2010) Bisphosphonates and fractures of the subtrochanteric or diaphyseal femur. N Engl J Med 362:1761–1771. doi:10.1056/NEJMoa1001086

    Article  CAS  PubMed  Google Scholar 

  5. 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 20:1429–1437. doi:10.1007/s00198-008-0816-7

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  6. Fleisch H (1998) Bisphosphonates: mechanisms of action. Endocr Rev 19:80–100

    Article  CAS  PubMed  Google Scholar 

  7. Ebetino FH, Hogan AM, Sun S, Tsoumpra MK, Duan X, Triffitt JT, Kwaasi AA, Dunford JE, Barnett BL, Oppermann U, Lundy MW, Boyde A, Kashemirov BA, McKenna CE, Russell RG (2011) The relationship between the chemistry and biological activity of the bisphosphonates. Bone 49:20–33. doi:10.1016/j.bone.2011.03.774

    Article  CAS  PubMed  Google Scholar 

  8. Takeuchi M, Sakamoto S, Kawamuki K, Kurihara H, Nakahara H, Isomura Y (1998) Studies on novel bone resorption inhibitors. II. Synthesis and pharmacological activities of fused aza-heteroarylbisphosphonate derivatives. Chem Pharm Bull 46:1703–1709

    Article  CAS  PubMed  Google Scholar 

  9. 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 296:235–242

    CAS  PubMed  Google Scholar 

  10. Ohno K, Mori K, Orita M, Takeuchi M (2011) Computational insights into binding of bisphosphates to farnesyl pyrophosphate synthase. Curr Med Chem 18:220–233. doi:10.2174/192986711794088335

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  11. Rizzoli R, Greenspan SL, Bone G III, Schnitzer TJ, Watts NB, Adami S, Foldes AJ, Roux C, Levine MA, Uebelhart B, Santora AC 2nd, Kaur A, Peverly CA, Orloff JJ, Alendronate Once-Weekly Study Group (2002) Two-year results of once-weekly administration of alendronate 70 mg for the treatment of postmenopausal osteoporosis. J Bone Miner Res 17:1988–1996. doi:10.1359/jbmr.2002.17.11.1988

    Article  CAS  PubMed  Google Scholar 

  12. Brown JP, Kendler DL, McClung MR, Emkey RD, Adachi JD, Bolognese MA, Li Z, Balske A, Lindsay R (2002) The efficacy and tolerability of risedronate once a week for the treatment of postmenopausal osteoporosis. Calcif Tissue Int 71:103–111. doi:10.1007/s00223-002-2011-8

    Article  CAS  PubMed  Google Scholar 

  13. Miller PD, McClung MR, Macovei L, Stakkestad JA, Luckey M, Bonvoisin B, Reginster JY, Recker RR, Hughes C, Lewiecki EM, Felsenberg D, Delmas PD, Kendler DL, Bolognese MA, Mairon N, Cooper C (2005) Monthly oral ibandronate therapy in postmenopausal osteoporosis: 1-year results from the MOBILE study. J Bone Miner Res 20:1315–1322. doi:10.1359/JBMR.050313

    Article  CAS  PubMed  Google Scholar 

  14. 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 44:1078–1084. doi:10.1016/j.bone.2009.02.016

    Article  CAS  PubMed  Google Scholar 

  15. Cotté FE, Fardellone P, Mercier F, Gaudin AF, Roux C (2010) Adherence to monthly and weekly oral bisphosphonates in women with osteoporosis. Osteoporos Int 21:145–155. doi:10.1007/s00198-009-0930-1

    Article  PubMed Central  PubMed  Google Scholar 

  16. Roerholt C, Eiken P, Abrahamsen B (2009) Initiation of anti-osteoporotic therapy in patients with recent fractures: a nationwide analysis of prescription rates and persistence. Osteoporos Int 20:299–307. doi:10.1007/s00198-008-0651-x

    Article  CAS  PubMed  Google Scholar 

  17. Okazaki R, Hagino H, Ito M, Sone T, Nakamura T, Mizunuma H, Fukunaga M, Shiraki M, Nishizawa Y, Ohashi Y, Matsumoto T (2012) Efficacy and safety of monthly oral minodronate in patients with involutional osteoporosis. Osteoporos Int 23:1737–1745. doi:10.1007/s00198-011-1782-z

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  18. Usui T, Kawakami R, Watanabe T, Higuchi S (1994) Sensitive determination of a novel bisphosphonate, YM529, in plasma, urine and bone by high-performance liquid chromatography with fluorescence detection. J Chromatogr. 652:67–72

    Article  CAS  PubMed  Google Scholar 

  19. Kimoto A, Tanaka M, Nozaki K, Mori M, Fukushima S, Mori H, Shiroya T, Nakamura T (2013) Intermittent minodronic acid treatment with sufficient bone resorption inhibition prevents reduction in bone mass and strength in ovariectomized rats with established osteopenia comparable with daily treatment. Bone 55:189–197. doi:10.1016/j.bone.2008.07.242

    Article  CAS  PubMed  Google Scholar 

  20. Tanaka M, Mori H, Kayasuga R, Ochi Y, Kawada N, Yamada H, Kishikawa K (2008) Long-term minodronic acid (ONO-5920/YM529) treatment suppresses increased bone turnover, plus prevents reduction in bone mass and bone strength in ovariectomized rats with established osteopenia. Bone. 43(5):894–900. doi:10.1016/j.bone.2008.07.002

    Article  CAS  PubMed  Google Scholar 

  21. Monma Y, Funayama H, Mayanagi H, Endo Y (2004) Effects of weekly administrations of alendronate + clodronate on young mouse tibia: localized action at the proximal growth plate. Calcif Tissue Int 74:115–121. doi:10.1007/s00223-002-2156-5

    Article  CAS  PubMed  Google Scholar 

  22. Christiansen C, Tankó LB, Warming L, Moelgaard A, Christgau S, Qvist P, Baumann M, Wieczorek L, Hoyle N (2003) Dose dependent effects on bone resorption and formation of intermittently administered intravenous ibandronate. Osteoporos Int. 14:609–613. doi:10.1007/s00198-003-1409-0

    Article  CAS  PubMed  Google Scholar 

  23. Wronski TJ, Cintrón M, Dann LM (1988) Temporal relationship between bone loss and increased bone turnover in ovariectomized rats. Calcif Tissue Int 43:179–183

    Article  CAS  PubMed  Google Scholar 

  24. Engelke K, Kemmler W, Lauber D, Beeskow C, Pintag R, Kalender WA (2006) Exercise maintains bone density at spine and hip EFOPS: a 3-year longitudinal study in early postmenopausal women. Osteoporos Int. 17(1):133–142

    Article  CAS  PubMed  Google Scholar 

  25. Usui T, Kamimura H (2008) Pharmacokinetics of minodronic acid hydrate, a novel bisphonate, in rats and dogs. Clin Pharmacol Ther (Japansese) 18:S-129–S-142

    Google Scholar 

  26. Fleisch H (2000) Bisphosphonates in bone disease from the laboratory to the patient. Academic Press, San Diego

    Google Scholar 

Download references

Acknowledgments

We thank H. Tsusaki (Shin Nippon Biomedical Laboratories, Ltd.) for their expertise and technical support in animal care and a BMD assessments, and staff of SkeleTech Inc. for performing histomorphometric analysis.

Human and Animal Rights and Informed Consent

This study was ethically approved by the Institutional Animal Care and Use Committee of Shin Nippon Biomedical Laboratories, Ltd. (Kagoshima, Japan) and performed in accordance with the criteria defined by the rules of the committee.

Author information

Authors and Affiliations

  1. Research Promotion, Ono Pharmaceutical Co., Ltd., 3-1-1, Sakurai, Shimamoto-cho, Mishima-gun, Osaka, 618-8585, Japan

    Makoto Tanaka

  2. Discovery Research Laboratories, Ono Pharmaceutical Co., Ltd., Shimamoto-cho, Mishima-gun, Osaka, 618-8585, Japan

    Hiroshi Mori, Ryoji Kayasuga, Yasuo Ochi, Hiroyuki Yamada, Naoki Kawada & Kazuhito Kawabata

Authors
  1. Makoto Tanaka
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Hiroshi Mori
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Ryoji Kayasuga
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Yasuo Ochi
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Hiroyuki Yamada
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Naoki Kawada
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Kazuhito Kawabata
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Makoto Tanaka.

Additional information

All authors are research scientists at Ono Pharmaceutical Co., Ltd. Minodronic acid was launched by Ono Pharmaceutical Co., Ltd. and Astellas Pharma Inc. in Japan. MT and HM are applicants for use patent of intermittent regimen.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Tanaka, M., Mori, H., Kayasuga, R. et al. Effect of Intermittent and Daily Regimens of Minodronic Acid on Bone Metabolism in an Ovariectomized Rat Model of Osteoporosis. Calcif Tissue Int 95, 166–173 (2014). https://doi.org/10.1007/s00223-014-9876-1

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00223-014-9876-1

Keywords

Search

Navigation