Clinical Drug Investigation

, Volume 33, Issue 3, pp 193–198 | Cite as

Improved Efficacy of Intramuscular Weekly Administration of Clodronate 200 mg (100 mg Twice Weekly) Compared with 100 mg (Once Weekly) for Increasing Bone Mineral Density in Postmenopausal Osteoporosis

  • Bruno Frediani
  • Ilaria Bertoldi
  • Serena Pierguidi
  • Antonella Nicosia
  • Valentina Picerno
  • Georgios Filippou
  • Luca Cantarini
  • Mauro Galeazzi
Original Research Article



Clodronate is a bisphosphonate used for the treatment of postmenopausal osteoporosis and all conditions characterized by excess bone resorption. We have previously reported that intramuscular (IM) therapy with clodronate at a dose of 100 mg/week displays significant effects on bone mineral density (BMD) although a plateau effect is observed after 1 year of treatment. Previous reports indicate that the densitometric effects of bisphosphonates directly correlate with the drug dosage and suggest that using IM clodronate at doses higher than 100 mg/week may result in improved efficacy. However, to the best of our knowledge, this has never been proved.


The primary endpoint of the study was the effect on BMD of IM clodronate 100 mg once weekly or 100 mg twice weekly in patients with postmenopausal osteoporosis. The incidence of non-traumatic vertebral fractures and adverse events was also reported.


The present study was a randomized, open-label, parallel-group trial conducted between January 2007 and December 2009 in the Osteoporosis and Osteoarticular Instrumental Diagnosis Centre (University of Siena, Siena, Italy). The study involved 60 women, aged 57–78 years, with a history of postmenopausal osteoporosis for more than 5 years. Patients were randomized to receive IM clodronate 100 mg once weekly (Group A, 30 patients) or 100 mg twice weekly (Group B, 30 patients), for 2 years.


Significant increases compared with baseline in BMD were observed for both groups at 1 and 2 years, with significantly higher increases for Group B compared with Group A. Group B displayed a BMD increase (±SD) at the lumbar spine of +4.0 % (±2.1) and +5.9 % (±2.0) at 1 and 2 year(s), respectively, compared with +2.8 % (±1.7) and +3.5 % (±2.2), respectively, observed for Group A. Similarly, Group B showed better performance compared with Group A for BMD increase at the femoral neck, with an observed increase of +3.5 % (±1.7) and +5.4 % (±1.8) at 1 and 2 year(s), respectively, compared with a change of +2.3 % (±1.9) and +2.5 % (±1.9), respectively, registered in Group A. Consistently, the BMD increase measured at the total femur was significantly higher for Group B [+3.4 % (±1.9) and +4.9 % (±2.1) at years 1 and 2, respectively] compared with Group A [+1.6 % (±0.9) and +2.4 % (±1.9) at years 1 and 2, respectively]. When the change in BMD from year 1 to year 2 was compared, a significant increase of BMD was seen in Group B in all the analysed regions, contrary to that observed for Group A where a plateau effect resulted in no significant change from year 1 to year 2. Three non-traumatic vertebral fractures occurred during the study: two in Group A and one in Group B.


The present study indicates the superior performance of IM clodronate 200 mg weekly (100 mg twice weekly) compared with 100 mg once weekly in BMD in women with postmenopausal osteoporosis. This work demonstrated that administration of twice the drug dosage in a week significantly improved the efficacy of the treatment without inducing serious adverse events. Therefore, IM clodronate 200 mg weekly may be considered a valid therapeutic choice for the treatment of postmenopausal osteoporosis.



Prof. Frediani wishes to thank his entire group for their important contribution in performing the assessments and in collecting data. The authors declare no conflicts of interest. Editorial assistance was provided by inScience Communications, Springer Healthcare, and funded by Prof. Frediani.


  1. 1.
    Rogers MJ, Gordon S, Benford HL, et al. Cellular and molecular mechanisms of action of bisphosphonates. Cancer. 2000;88(12 Suppl):2961–78.PubMedCrossRefGoogle Scholar
  2. 2.
    Adami S, Bolzicco GP, Rizzo A, et al. The use of dichloromethylene bisphosphonate and aminobutane bisphosphonate in hypercalcemia of malignancy. Bone Miner. 1987;2(5):395–404.PubMedGoogle Scholar
  3. 3.
    Adami S, Guarrera G, Salvagno G, et al. Sequential treatment of Paget’s disease with human calcitonin and dichloromethylene diphosphonate (Cl2MDP). Metab Bone Dis Relat Res. 1984;5(6):265–7.PubMedCrossRefGoogle Scholar
  4. 4.
    Adami S, Salvagno G, Guarrera G, et al. Dichloromethylene-diphosphonate in patients with prostatic carcinoma metastatic to the skeleton. J Urol. 1985;134(6):1152–4.PubMedGoogle Scholar
  5. 5.
    Body JJ, Coleman RE, Piccart M. Use of bisphosphonates in cancer patients. Cancer Treat Rev. 1996;22(4):265–87.PubMedCrossRefGoogle Scholar
  6. 6.
    Kanis JA, Powles T, Paterson AH, et al. Clodronate decreases the frequency of skeletal metastases in women with breast cancer. Bone. 1996;19(6):663–7.PubMedCrossRefGoogle Scholar
  7. 7.
    Kanis JA, McCloskey EV, Sirtori P, et al. Rationale for the use of clodronate in osteoporosis. Osteoporos Int. 1993;3(Suppl 2):S23–8.PubMedCrossRefGoogle Scholar
  8. 8.
    Minaire P, Depassio J, Berard E, et al. Effects of clodronate on immobilization bone loss. Bone. 1987;8(Suppl 1):S63–8.PubMedGoogle Scholar
  9. 9.
    Kaastad TS, Reikeras O, Madsen JE, et al. Effects of clodronate on cortical and trabecular bone in ovariectomized rats on a low calcium diet. Calcif Tissue Int. 1997;61(2):158–64.PubMedCrossRefGoogle Scholar
  10. 10.
    Lepola VT, Hannuniemi R, Kippo K, et al. Long-term effects of clodronate on growing rat bone. Bone. 1996;18(2):191–6.PubMedCrossRefGoogle Scholar
  11. 11.
    Lahtinen R, Laakso M, Palva I, et al. Randomised, placebo-controlled multicentre trial of clodronate in multiple myeloma. Finnish Leukaemia Group. Lancet. 1992;340(8827):1049–52.PubMedCrossRefGoogle Scholar
  12. 12.
    McCloskey EV, Dunn JA, Kanis JA, et al. Long-term follow-up of a prospective, double-blind, placebo-controlled randomized trial of clodronate in multiple myeloma. Br J Haematol. 2001;113(4):1035–43.PubMedCrossRefGoogle Scholar
  13. 13.
    Paterson AH, Powles TJ, Kanis JA, et al. Double-blind controlled trial of oral clodronate in patients with bone metastases from breast cancer. J Clin Oncol. 1993;11(1):59–65.PubMedGoogle Scholar
  14. 14.
    Johnson IS. Use of bisphosphonates for the treatment of metastatic bone pain. A survey of palliative physicians in the UK. Palliat Med. 2001;15(2):141–7.PubMedCrossRefGoogle Scholar
  15. 15.
    Mannix K, Ahmedzai SH, Anderson H, et al. Using bisphosphonates to control the pain of bone metastases: evidence-based guidelines for palliative care. Palliat Med. 2000;14(6):455–61.PubMedCrossRefGoogle Scholar
  16. 16.
    Filipponi P, Cristallini S, Rizzello E, et al. Cyclical intravenous clodronate in postmenopausal osteoporosis: results of a long-term clinical trial. Bone. 1996;18(2):179–84.PubMedCrossRefGoogle Scholar
  17. 17.
    Filipponi P, Pedetti M, Fedeli L, et al. Cyclical clodronate is effective in preventing postmenopausal bone loss: a comparative study with transcutaneous hormone replacement therapy. J Bone Miner Res. 1995;10(5):697–703.PubMedCrossRefGoogle Scholar
  18. 18.
    Giannini S, D’Angelo A, Malvasi L, et al. Effects of one-year cyclical treatment with clodronate on postmenopausal bone loss. Bone. 1993;14(2):137–41.Google Scholar
  19. 19.
    Giannini S, D’Angelo A, Sartori L, et al. Continuous and cyclical clodronate therapies and bone density in postmenopausal bone loss. Obstet Gynecol. 1996;88(3):431–6.PubMedCrossRefGoogle Scholar
  20. 20.
    Heikkinen JE, Selander KS, Laitinen K, et al. Short-term intravenous bisphosphonates in prevention of postmenopausal bone loss. J Bone Miner Res. 1997;12(1):103–10.PubMedCrossRefGoogle Scholar
  21. 21.
    Rossini M, Braga V, Gatti D, et al. Intramuscular clodronate therapy in postmenopausal osteoporosis. Bone. 1999;24(2):125–9.PubMedCrossRefGoogle Scholar
  22. 22.
    Herrala J, Puolijoki H, Liippo K, et al. Clodronate is effective in preventing corticosteroid-induced bone loss among asthmatic patients. Bone. 1998;22(5):577–82.PubMedCrossRefGoogle Scholar
  23. 23.
    Ippoliti G, Pellegrini C, Campana C, et al. Clodronate treatment of established bone loss in cardiac recipients: a randomized study. Transplantation. 2003;75(3):330–4.PubMedCrossRefGoogle Scholar
  24. 24.
    Hilding M, Aspenberg P. Postoperative clodronate decreases prosthetic migration: 4-year follow-up of a randomized radiostereometric study of 50 total knee patients. Acta orthopaedica. 2006;77(6):912–6.PubMedCrossRefGoogle Scholar
  25. 25.
    Chesnut CH 3rd, McClung MR, Ensrud KE, et al. Alendronate treatment of the postmenopausal osteoporotic woman: effect of multiple dosages on bone mass and bone remodeling. Am J Med. 1995;99(2):144–52.PubMedCrossRefGoogle Scholar
  26. 26.
    Miller PD, McClung MR, Macovei L, et al. Monthly oral ibandronate therapy in postmenopausal osteoporosis: 1-year results from the MOBILE study. J Bone Miner Res. 2005;20(8):1315–22.PubMedCrossRefGoogle Scholar
  27. 27.
    Reginster JY, Adami S, Lakatos P, et al. Efficacy and tolerability of once-monthly oral ibandronate in postmenopausal osteoporosis: 2 year results from the MOBILE study. Ann Rheum Dis. 2006;65(5):654–61.PubMedCrossRefGoogle Scholar
  28. 28.
    McCloskey E, Selby P, Davies M, et al. Clodronate reduces vertebral fracture risk in women with postmenopausal or secondary osteoporosis: results of a double-blind, placebo-controlled 3-year study. J Bone Miner Res. 2004;19(5):728–36.PubMedCrossRefGoogle Scholar
  29. 29.
    McCloskey EV, Beneton M, Charlesworth D, et al. Clodronate reduces the incidence of fractures in community-dwelling elderly women unselected for osteoporosis: results of a double-blind, placebo-controlled randomized study. J Bone Miner Res. 2007;22(1):135–41.PubMedCrossRefGoogle Scholar
  30. 30.
    Cummings SR, Black DM, Thompson DE, et al. Effect of alendronate on risk of fracture in women with low bone density but without vertebral fractures: results from the Fracture Intervention Trial. JAMA. 1998;280(24):2077–82.Google Scholar
  31. 31.
    Ettinger B, Black DM, Mitlak BH, et al. Reduction of vertebral fracture risk in postmenopausal women with osteoporosis treated with raloxifene: results from a 3-year randomized clinical trial. Multiple Outcomes of Raloxifene Evaluation (MORE) Investigators. JAMA. 1999;282(7):637–45.PubMedCrossRefGoogle Scholar
  32. 32.
    Reginster J, Minne HW, Sorensen OH, et al. Randomized trial of the effects of risedronate on vertebral fractures in women with established postmenopausal osteoporosis. Vertebral Efficacy with Risedronate Therapy (VERT) Study Group. Osteoporos Int. 2000;11(1):83–91.PubMedCrossRefGoogle Scholar
  33. 33.
    Frediani B, Falsetti P, Baldi F, et al. Effects of 4-year treatment with once-weekly clodronate on prevention of corticosteroid-induced bone loss and fractures in patients with arthritis: evaluation with dual-energy X-ray absorptiometry and quantitative ultrasound. Bone. 2003;33(4):575–81.PubMedCrossRefGoogle Scholar
  34. 34.
    Laitinen K, Patronen A, Harju P, et al. Timing of food intake has a marked effect on the bioavailability of clodronate. Bone. 2000;27(2):293–6.PubMedCrossRefGoogle Scholar
  35. 35.
    Villikka K, Perttunen K, Rosnell J, et al. The absolute bioavailability of clodronate from two different oral doses. Bone. 2002;31(3):418–21.PubMedCrossRefGoogle Scholar
  36. 36.
    Dominguez LJ, Galioto A, Ferlisi A, et al. Intermittent intramuscular clodronate therapy: a valuable option for older osteoporotic women. Age Ageing. 2005;34(6):633–6.PubMedCrossRefGoogle Scholar
  37. 37.
    Frediani B. Effects of two administration schemes of intramuscular clodronic acid on bone mineral density: a randomized, open-label, parallel-group study. Clin Drug Investig. 2011;31(1):43–50.PubMedCrossRefGoogle Scholar
  38. 38.
    Genant HK, Li J, Wu CY, Shepherd JA. Vertebral fractures in osteoporosis: a new method for clinical assessment. J Clin Densitom 2000 Fall;3(3):281–90.Google Scholar
  39. 39.
    Schnitzer T, Bone HG, Crepaldi G, et al. Therapeutic equivalence of alendronate 70 mg once-weekly and alendronate 10 mg daily in the treatment of osteoporosis. Alendronate Once-Weekly Study Group. Aging (Milano). 2000;12(1):1–12.Google Scholar
  40. 40.
    Black DM, Delmas PD, Eastell R, et al. Once-yearly zoledronic acid for treatment of postmenopausal osteoporosis. N Engl J Med. 2007;356(18):1809–22.PubMedCrossRefGoogle Scholar
  41. 41.
    Adami S, Gatti D, Bertoldo F, et al. Intramuscular neridronate in postmenopausal women with low bone mineral density. Calcif Tissue Int. 2008;83(5):301–7.PubMedCrossRefGoogle Scholar
  42. 42.
    Harris ST, Watts NB, Jackson RD, et al. Four-year study of intermittent cyclic etidronate treatment of postmenopausal osteoporosis: three years of blinded therapy followed by one year of open therapy. Am J Med. 1993;95(6):557–67.PubMedCrossRefGoogle Scholar

Copyright information

© Springer International Publishing Switzerland 2013

Authors and Affiliations

  • Bruno Frediani
    • 1
    • 2
  • Ilaria Bertoldi
    • 1
  • Serena Pierguidi
    • 1
  • Antonella Nicosia
    • 1
  • Valentina Picerno
    • 1
  • Georgios Filippou
    • 1
  • Luca Cantarini
    • 1
  • Mauro Galeazzi
    • 1
  1. 1.Rheumatology Department, Osteoporosis and Osteoarticular Instrumental Diagnosis CentreUniversity of SienaSienaItaly
  2. 2.Rheumatology Department, Osteoporosis and Rheumatologic Instrumental Diagnosis Centre, Ospedale ‘Le Scotte’University of SienaSienaItaly

Personalised recommendations