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Zoledronic Acid

A Review of its Use in the Treatment of Paget’s Disease of Bone

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Summary

Abstract

The third-generation, nitrogen-containing bisphosphonate zoledronic acid (Aclasta®) is approved in the EU for the treatment of Paget’s disease of bone. Results of well designed trials show that a single intravenous dose of zoledronic acid 5mg is effective and well tolerated in the treatment of Paget’s disease of bone. A single intravenous dose of zoledronic acid was associated with a significantly higher therapeutic response rate and a more rapid reduction in bone turnover than that achieved with 60 days of oral risedronic acid. Moreover, biochemical remission was sustained after 24 months of follow-up in zoledronic acid recipients. Preliminary results suggest that zoledronic acid is a cost-effective option in Paget’s disease of bone. Thus, zoledronic acid is an important first-line treatment for Paget’s disease of bone.

Pharmacological Properties

The high affinity of zoledronic acid for hydroxyapatite means that it is rapidly and preferentially taken up by bone tissue, particularly in areas of high bone turnover. Zoledronic acid is retained in bone until it is internalised into osteoclasts during bone resorption. The primary action of zoledronic acid is the inhibition of farnesyl pyrophosphate synthase in osteoclasts, resulting in the loss of prenylated proteins, inhibition of osteoclastic bone resorption and osteoclast apoptosis. Zoledronic acid showed beneficial effects on bone density and architecture in animal studies, and was not associated with impairment of bone mineralisation or adynamic bone.

Plasma concentrations of zoledronic acid declined to <1% of peak 24 hours after administration of an intravenous dose. Following rapid biphasic elimination of zoledronic acid from the systemic circulation, there is a long elimination phase, with a terminal elimination half-life of 146 hours. Zoledronic acid does not undergo systemic metabolism but is excreted unchanged by the kidney.

Clinical Efficacy

The Pooled results of two well designed trials (the HORIZON-TOP trials) revealed that a single dose of intravenous zoledronic acid 5mg was significantly more effective than 60 days of therapy with oral risedronic acid 30 mg/day in the treatment of Paget’s disease of bone. At 6 months, the therapeutic response rate (primary endpoint) was significantly higher in zoledronic acid than in risedronic acid recipients, and the median time to a first therapeutic response was significantly shorter. Levels of markers of bone turnover were significantly lower with zoledronic acid than with risedronic acid from day 10 onwards, with significantly more zoledronic acid recipients than risedronic acid recipients having normalisation of alkaline phosphatase (ALP) levels at 6 months.

Zoledronic acid improved aspects of health-related quality of life in patients with Paget’s disease, as assessed by the Medical Outcomes Study 36-item Short-Form General Health Survey. For example, significantly more zoledronic acid than risedronic acid recipients had a clinically significant improvement from baseline in bodily pain domain scores at 6 months.

Patients with a therapeutic response at 6 months entered an 18-month extension study (no bisphosphonates were administered during this extension phase). At the end of the extension phase, a therapeutic response was maintained in 98% of zoledronic acid recipients and in 57% of risedronic acid recipients. Mean total serum ALP levels were maintained within the reference range throughout the 18-month extended observation period in zoledronic acid recipients, whereas in risedronic acid recipients, the mean ALP level exceeded the upper limit of the reference range within the first 6 months of follow-up in the extended-observation period (and remained elevated through to the end of the 18-month extension phase).

Safety and Tolerability

Intravenous zoledronic acid was generally well tolerated in patients with Paget’s disease of bone, according to the results of the HORIZON-TOP trials. Significantly more zoledronic acid than risedronic acid recipients experienced adverse events (mainly influenza-like symptoms) during the first 3 days of the initial study (53.7% vs 25.0%). Influenza-like symptoms were generally of mild to moderate severity and mostly resolved within 4 days. After study day 3, there was no significant between-group difference in the overall incidence of adverse events or in the incidence of individual adverse events. No cases of osteonecrosis of the jaw were reported during 24 months of follow-up.

Pharmacoeconomic Considerations

Zoledronic acid is a cost-effective option in the treatment of Paget’s disease of bone, according to the preliminary results of German and Belgian modelling studies. Zoledronic acid dominated risedronic acid in the German analysis and dominated all comparators (risedronic acid, tiludronic acid, pamidronic acid [Aredia®] and generic pamidronic acid) in the Belgian analysis.

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Notes

  1. The use of trade names is for product identification purposes only and does not imply endorsement.

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Author information

Authors and Affiliations

  1. Wolters Kluwer Health / Adis, 41 Centorian Drive, Private Bag 65901, Mairangi Bay, Auckland, 1311, New Zealand

    Gillian M. Keating & Lesley J. Scott

  2. Wolters Kluwer Health, Conshohocken, Pennsylvania, USA

    Gillian M. Keating & Lesley J. Scott

Authors
  1. Gillian M. Keating
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  2. Lesley J. Scott
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Corresponding author

Correspondence to Gillian M. Keating.

Additional information

Various sections of the manuscript reviewed by: S. Adami, University of Verona, Verona, Italy; M.W. Davie, Charles Salt Centre, Robert Jones and Agnes Hunt Hospital, Oswestry, Shropshire, England; J.-P. Devogelaer, Unité de Rhumatologie et de Métabolisme Phosphocalcique, Université Catholique de Louvain, Brussels, Belgium; P. Garnero, INSERM, Hopital E Herriot, Lyon, France; D.J. Hosking, Nottingham City Hospital, Nottingham, England; S.H. Ralston, Molecular Medicine Centre, Western General Hospital, Edinburgh, Scotland; J.-Y. Reginster, Université de Liège, Liège, Belgium.

Data Selection

Sources: Medical literature published in any language since 1980 on ‘zoledronic acid’, identified using MEDLINE and EMBASE, supplemented by AdisBase (a proprietary database of Wolters Kluwer Health | Adis). Additional references were identified from the reference lists of published articles. Bibliographical information, including contributory unpublished data, was also requested from the company developing the drug.

Search strategy: MEDLINE, EMBASE and AdisBase search terms were (‘zoledronic acid’ or ‘zoledronate’) and ‘paget’s disease’. Searches were last updated 12 March 2007.

Selection: Studies in patients with Paget’s disease who received zoledronic acid. Inclusion of studies was based mainly on the methods section of the trials. When available, large, well controlled trials with appropriate statistical methodology were preferred. Relevant pharmacodynamic and pharmacokinetic data are also included.

Index terms: Zoledronic acid, Paget’s disease, pharmacodynamics, pharmacokinetics, therapeutic use.

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Keating, G.M., Scott, L.J. Zoledronic Acid. Drugs 67, 793–804 (2007). https://doi.org/10.2165/00003495-200767050-00011

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