Abstract
We have previously demonstrated that intravenous ibandronate produces high initial response rates in Paget’s disease, but the durability of this effect is unknown. It might be expected to be short lived because ibandronate has a low affinity for bone. Here we report long-term follow-up (up to 14 years) of patients from that trial. Twenty-five patients with active Paget’s disease [baseline serum total alkaline phosphatase (ALP) ~3 times the upper limit of normal] received either 6 or 12 mg intravenous ibandronate at baseline. There were prompt reductions in ALP following treatment, with normalization in 88%. ALP remained in the normal range in most patients for 20–30 months, but some subjects then showed gradual increases. Three years after ibandronate, before any patients had received additional treatment, ALP was normal in 61%. Six patients maintained normal ALP beyond 6 years without further intervention. Responses to 6 and 12 mg were similar. These results indicate that long-term remissions in Paget’s disease can be achieved with bolus delivery of a potent bisphosphonate, even if the drug has a low affinity for bone. Therefore, bisphosphonate retention in bone might not be the only factor determining duration of remission. Intravenous bisphosphonates are likely to produce high drug concentrations within pagetic lesions which might result in cytotoxicity to the pagetic cells, leading to long durations of remission. These findings strengthen the evidence that potent bisphosphonates delivered in a single intravenous dose are a very efficient way to manage this condition.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
Frijlink WB, te Velde J, Bijvoet OLM et al (1979) Treatment of Paget’s disease with (3-amino-1-hydoxypropylidene)-1,1-bisphosphonate (APD). Lancet 313:799–803
Reid IR, Miller P, Lyles K et al (2005) Comparison of a single infusion of zoledronic acid with risedronate for Paget’s disease. N Engl J Med 353:898–908
Dunford JE, Thompson K, Coxon FP et al (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
Black DM, Delmas PD, Eastell R et al (2007) Once-yearly zoledronic acid for treatment of postmenopausal osteoporosis. N Engl J Med 356:1809–1822
Grey A, Bolland MJ, Horne A et al (2012) Five years of anti-resorptive activity after a single dose of zoledronate: results from a randomized double-blind placebo-controlled trial. Bone 50:1389–1393
Reid IR, Lyles K, Su GQ et al (2011) A single infusion of zoledronic acid produces sustained remissions in Paget disease: data to 6.5 years. J Bone Miner Res 26:2261–2270
Nancollas GH, Tang R, Phipps RJ et al (2006) Novel insights into actions of bisphosphonates on bone: differences in interactions with hydroxyapatite. Bone 38:617–627
Reid IR, Davidson JS, Wattie D et al (2004) Comparative responses of bone turnover markers to bisphosphonate therapy in Paget’s disease of bone. Bone 35:224–230
Recker R, Stakkestad JA, Chesnut CH et al (2004) Insufficiently dosed intravenous ibandronate injections are associated with suboptimal antifracture efficacy in postmenopausal osteoporosis. Bone 34:890–899
Thiebaud D, Burckhardt P, Kriegbaum H et al (1997) Three monthly intravenous injections of ibandronate in the treatment of postmenopausal osteoporosis. Am J Med 103:298–307
Grauer A, Heichel S, Knaus J et al (1999) Ibandronate treatment in Paget’s disease of bone. Bone 24:87S–89S
Reid IR, Nicholson GC, Weinstein RS et al (1996) Biochemical and radiologic improvement in Paget’s disease of bone treated with alendronate: a randomized, placebo-controlled trial. Am J Med 101:341–348
Siris E, Weinstein RS, Altman R et al (1996) Comparative study of alendronate versus etidronate for the treatment of Paget’s disease of bone. J Clin Endocrinol Metab 81:961–967
Harinck HIJ, Bijvoet OLM, Blanksma HJ et al (1987) Efficacious management with aminobisphosphonate (APD) in Paget’s disease of bone. Clin Orthop 217:79–98
Fisher JE, Rosenberg E, Santora AC et al (2013) In vitro and in vivo responses to high and low doses of nitrogen-containing bisphosphonates suggest engagement of different mechanisms for inhibition of osteoclastic bone resorption. Calcif Tissue Int 92:531–538
Reid IR, Sharma S, Kalluru R et al (2016) Treatment of Paget’s disease of bone with denosumab: case report and literature review. Calcif Tissue Int 99:322–325
Acknowledgements
The original study and this follow-up analysis were supported by the Health Research Council of New Zealand.
Author Contributions
IRR involved in design, analysis, and interpretation and drafted the manuscript; DW contributed to design, data acquisition, and critical revision of manuscript; GDG and TC participated in design, analysis, interpretation, and critical revision of manuscript; RK involved in data acquisition and critical revision of manuscript;. The final version has been approved by all authors who agree to be accountable for it. IRR accepts responsibility for the integrity of the data analysis.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Conflict of interest
Ian Reid has received honoraria or research support from Amgen, Novartis, and Merck. Diana Wattie, Gregory Gamble, Ramanamma Kalluru, and Tim Cundy have no conflicts of interest to declare.
Human and Animal Rights and Informed Consent
The study was approved by the local ethics committee, and each subject gave written informed consent.
Additional information
The medication for the original study was donated by Roche.
Rights and permissions
About this article
Cite this article
Reid, I.R., Wattie, D., Gamble, G.D. et al. Long-Term Effects of Intravenous Ibandronate in Paget’s Disease of Bone. Calcif Tissue Int 100, 250–254 (2017). https://doi.org/10.1007/s00223-016-0214-7
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00223-016-0214-7