Abstract
Background
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.
Objective
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.
Methods
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.
Results
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.
Conclusion
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.
Similar content being viewed by others
References
Rogers MJ, Gordon S, Benford HL, et al. Cellular and molecular mechanisms of action of bisphosphonates. Cancer. 2000;88(12 Suppl):2961–78.
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.
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.
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.
Body JJ, Coleman RE, Piccart M. Use of bisphosphonates in cancer patients. Cancer Treat Rev. 1996;22(4):265–87.
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.
Kanis JA, McCloskey EV, Sirtori P, et al. Rationale for the use of clodronate in osteoporosis. Osteoporos Int. 1993;3(Suppl 2):S23–8.
Minaire P, Depassio J, Berard E, et al. Effects of clodronate on immobilization bone loss. Bone. 1987;8(Suppl 1):S63–8.
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.
Lepola VT, Hannuniemi R, Kippo K, et al. Long-term effects of clodronate on growing rat bone. Bone. 1996;18(2):191–6.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
Rossini M, Braga V, Gatti D, et al. Intramuscular clodronate therapy in postmenopausal osteoporosis. Bone. 1999;24(2):125–9.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
Villikka K, Perttunen K, Rosnell J, et al. The absolute bioavailability of clodronate from two different oral doses. Bone. 2002;31(3):418–21.
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.
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.
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.
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.
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.
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.
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.
Acknowledgements
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.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Frediani, B., Bertoldi, I., Pierguidi, S. et al. 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. Clin Drug Investig 33, 193–198 (2013). https://doi.org/10.1007/s40261-013-0062-4
Published:
Issue Date:
DOI: https://doi.org/10.1007/s40261-013-0062-4