Elsevier

Bone

Volume 41, Issue 1, July 2007, Pages 122-128
Bone

Intravenous zoledronic acid 5 mg in the treatment of postmenopausal women with low bone density previously treated with alendronate

https://doi.org/10.1016/j.bone.2007.03.011Get rights and content

Abstract

This randomized, double-blind, double-dummy, multicenter trial assessed safety and efficacy of a single dose of IV zoledronic acid (ZOL) 5 mg vs. oral alendronate (ALN) 70 mg weekly in postmenopausal women with low bone mineral density (BMD) who had previously been treated with ALN. Postmenopausal women who were receiving oral ALN for at least 1 year immediately prior to randomization and with lumbar spine or femoral neck BMD T-score values ≤ − 2.0 prior to initiation of ALN were randomized to one 15-min IV infusion of ZOL 5 mg plus 52 weeks of oral placebo (n = 113) or one IV infusion of placebo plus 52 weeks of oral ALN 70 mg (n = 112). End points included percent change in lumbar spine BMD from baseline to month 12 and relative change from baseline in urine N-telopeptide of type I collagen (NTX), serum C-telopeptide of type I collagen (CTX), amino terminal propeptides of type I collagen (PINP), and bone-specific alkaline phosphatase (bone ALP) over 12 months. Adverse events, bone histomorphometry and microscopic appearance, and patient preference for the 2 treatment regimens were also assessed.

In this study, a single infusion of ZOL 5 mg maintained BMD 12 months following the switch from oral ALN in women with osteoporosis. The mean duration of prior ALN therapy at baseline was 4 years. Mean biomarker levels in the ALN 70-mg group remained at or close to baseline levels for the duration of the study. In the ZOL 5-mg group, mean biomarker levels were reduced from baseline after 3 months, returned to baseline after 6 months, and increased thereafter but remained within the premenopausal range. The overall rates of adverse events were comparable in the 2 groups (ZOL 5 mg, 86.7%; ALN 70 mg, 80.4%). Headache occurred more commonly within the first 3 days after infusion with ZOL 5 mg (12.4%) than with ALN 70 mg (6.3%). Bone biopsies indicate that both treatments decrease excessive remodeling seen in osteoporosis. The majority (78.7%) of patients expressed preference for once yearly infusion over weekly oral therapy.

We conclude that patients can be switched from oral ALN to ZOL 5 mg infusion with maintenance of therapeutic effect for at least 12 months and that patients prefer a once yearly infusion to weekly oral therapy.

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.

Section snippets

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.

References (13)

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