Intravenous zoledronic acid 5 mg in the treatment of postmenopausal women with low bone density previously treated with alendronate
Introduction
Bisphosphonates provide effective therapy for osteoporotic patients at high risk of fracture. In vitro, zoledronic acid (ZOL) is the most potent bisphosphonate available. In a variety of assays of bone metabolism, ZOL has demonstrated inhibition of bone resorption in vitro at concentrations of 0.002 μmol and in vivo at doses of 0.072 μg/kg without exerting any untoward effects on either bone formation or mineralization [1]. An intravenous (IV) formulation of ZOL (4 mg) is used to treat skeletal-related events in patients with cancer, and a 5-mg IV dose is approved in many countries to treat Paget's disease [2]. A recent study in postmenopausal women with low bone mineral density (BMD) or osteoporosis demonstrated that an infusion of ZOL 5 mg has a more rapid onset of action on bone turnover markers than oral alendronate (ALN) 70 mg once weekly [3].
The present study was designed to demonstrate the non-inferiority of IV ZOL 5 mg to oral ALN 70 mg once weekly in maintaining the BMD of the lumbar spine in women with postmenopausal osteoporosis (PMO) who were previously treated with ALN for at least 1 year. Secondary objectives were to compare biochemical markers of bone turnover over 12 months in women with PMO who were switched from ALN therapy to a single infusion of ZOL 5 mg vs. women with PMO who remained on ALN 70 mg once weekly, to evaluate safety and tolerability, to assess bone remodeling by performing bone biopsies in a subset of patients, and to determine patient preference for annual IV therapy vs. weekly oral therapy.
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Patients
Women 45–79 years of age who were postmenopausal (cessation of menses for 18 months in those less than 50 years of age or for 12 months in those 50 years of age or older; or documented bilateral oophorectomy at least 1 year previously) were eligible if they had been treated with ALN for at least 1 year immediately prior to randomization and had a documented T-score of ≤ − 2.0 at the lumbar spine or femoral neck prior to initiation of ALN therapy. All patients provided signed informed consent
Study design
The randomized, multicenter (13 sites), double-blind, double-dummy, active-controlled trial had a 12-month treatment period and was conducted in accordance with the International Conference on Harmonisation Guidelines for Good Clinical Practice and the Declaration of Helsinki.
Treatment
Patients (n = 225) were randomized to either one 15-min IV infusion of ZOL 5 mg plus 52 weeks of oral placebo or one IV infusion of placebo plus 52 weeks of oral ALN 70 mg. All patients also received elemental calcium
Statistical analysis
The primary end point was percent change from baseline at month 12 in lumbar spine BMD. The secondary end points were relative change from baseline at months 3, 6, 9, and 12 in the 4 markers of bone turnover and patient preference for treatment regimen.
The sample size was calculated to show non-inferiority of ZOL 5 mg relative to ALN 70 mg for percent change from baseline to month 12 in lumbar spine BMD. Assuming a standard deviation of 3.3%, approximately 100 patients per group would provide
Patients
Of the 446 patients who were screened for the study, 225 were randomized to double-blind treatment. Nine (4.0%) discontinued from the study prematurely: 7 who received ZOL 5 mg and 2 who received ALN 70 mg. Four patients in the ZOL 5-mg group and 1 in the ALN 70-mg group discontinued the study due to adverse events.
Baseline demographic and disease characteristics were comparable between treatment groups (Table 1, Table 2). Almost all patients (97.3%) were Caucasian and 66.2% were ≥ 65 years of
Safety and tolerability
Overall, the percentages of patients reporting adverse events were similar in the 2 groups (ZOL 5 mg, 86.7%; ALN 70 mg, 80.4%, see Table 4). In the ZOL 5-mg group, 36.3% of patients reported adverse events within the first 3 days after infusion compared with 21.4% in the ALN 70-mg group. The most commonly reported adverse events in the first 3 days in ZOL 5-mg group were headache (12.4%), arthralgia (5.3%), and fatigue (5.3%). After 3 days, the overall incidence of adverse events was comparable
Discussion
In this study, BMD values remained stable for 12 months following the switch from oral ALN to a single infusion of ZOL 5 mg. The small increase in lumbar spine BMD in subjects who continued on alendronate therapy is consistent with previous observations [6], [7]. Different patterns of the changes in biochemical indices of bone turnover were observed in the two treatment groups. The modest but significant decreases in CTX and PINP values in the ALN group from baseline to subsequent time points
Conclusions
Patients can be safely switched from oral ALN to an infusion of ZOL 5 mg with maintenance of therapeutic effect for at least 12 months. A once yearly IV infusion may be preferable to patients and ensures adherence over 12 months.
Acknowledgments
This research was supported by Novartis Pharma AG, Basel, Switzerland. The authors would like to thank Peggy Millstone and Joe Hirsch of BioScience Communications, who provided editorial assistance in the development of this manuscript.
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