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Duration of antiresorptive activity of Zoledronate in postmenopausal women with osteopenia

Duration of antiresorptive activity of Zoledronate in postmenopausal women with osteopenia Duration of antiresorptive activity of Zoledronate in postmenopausal women with osteopenia
Duration of antiresorptive activity of Zoledronate in postmenopausal women with osteopenia Duration of antiresorptive activity of Zoledronate in postmenopausal women with osteopenia

Zoledronate is a bisphosphonate administered intravenously to reduce the risk of fractures in osteoporosis.

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Key take away

The antiresorptive activity of single zoledronate doses of 1–5 mg continues for at least three years in postmenopausal women with osteopenia.

Background

Zoledronate is a bisphosphonate administered intravenously to reduce the risk of fractures in osteoporosis. It is approved for preventing bone loss in the management of osteoporosis, to be administered every two years due to its prolonged activity in bone. The dosing regimen of zoledronate is still unclear despite its clinical use for almost a decade. The dose approved for the clinical trial is 5 mg, which is higher than in phase II zoledronate trial. The phase II zoledronate trial determined the effects of total zoledronate doses of 1 mg, 2 mg, and 4 mg, administered at intervals including three months, six months and 12 months and lasted for only one year, but the optimal dose and dosing interval were not identified.  

Bone mineral density (BMD) and biochemical markers of bone turnover were affected by administration of zoledronate and were superior as compared to placebo. These effects were indistinguishable and remain substantial for one year. The less frequent administration of the currently recommended 5-mg dose of zoledronate might reduce fracture risk.  These randomized controlled trials were conducted in postmenopausal women, older women in institutional care and men with HIV infection.  A post hoc analysis indicated similar reductions in fracture risk after three years in response to 3 annual administrations of 5 mg zoledronate and a single baseline administration of 5 mg.

The present situation demonstrated no evidence for the duration of antiresorptive activity of zoledronate at doses below 4 mg. Substantial and sustained effects of zoledronate dose on BMD and bone turnover markers were reported in a 2-year randomized placebo-controlled trial of single baseline doses of zoledronate (1 mg, 2.5 mg or 5 mg) in 180 postmenopausal women with a mild bone loss. The present study was conducted to clarify the duration of action of these doses on markers of bone health.  

 

Rationale behind the research;

The previous studies lack in explaining and clarifying the antiresorptive activity of zoledronate at doses below 4 mg, so this open-label 3-year extension of the core trial was conducted to illuminate the duration of action of  zoledronate doses on biomarkers of bone health.

 

Objective:

This study aimed to elucidate the duration of antiresorptive activity of different doses of zoledronate in postmenopausal women with osteopenia.

Method


Study outcome measures:

  • Primary endpoint: Change in spine BMD
  • Secondary endpoint: Changes in hip BMD and serum markers of bone turnover

 

Time points: Baseline and two years

Result


Study Outcomes:

  • An increase in BMD and reduction in markers of bone turnover was obtained with Zoledronate in a dose-dependent manner
  • An increase of 5.0% (95% confidence interval [CI] 3.0% to 7.0%), 5.7% (95% CI 3.7% to 7.7%) and 5.7% (95% CI 3.7% to 7.6%) was obtained in spine BMD over placebo for the 1 mg, 2.5 mg and 5 mg zoledronate doses respectively, after 2 years
  • Respective increases of 2.0% (95% CI –1.1% to 5.0%), 2.2% (95% CI –1.0% to 5.4%) and 5.1% (95% CI 2.2% to 8.1%)  was obtained in spine BMD over placebo for the 1 mg, 2.5 mg and 5 mg zoledronate doses respectively, after 5 years
  • Zoledronate doses of 1mg, 2.5 mg and 5 mg increased total hip BMD over placebo by 2.6% (95% CI 1.3% to 3.9%), 4.1% (95% CI 2.9% to 5.4%) and 4.7% (95% CI 3.4% to 5.9%), respectively after 2 years and the respective increases were 1.8% (95% CI –0.1% to 3.8%), 2.8% (95% CI 0.8% to 4.8%) and 5.4% (95% CI 3.5% to 7.3%) after 5 years
  • BMD remained above baseline values for 2–3 years in the 1 mg group, 3–4 years in the 2.5 mg group and at least 5 years in the 5 mg group

Conclusion

This open-label clinical trial suggests that 1 mg and 2.5 mg doses of zoledronate have long durations of action. It was found that 1 mg dose prevents bone loss for 30 months and a 2.5 mg dose for at least 42 months, indicating that antiresorptive action of zoledronate is gradual and occurs over several years. The current data establishes the use of a 1 mg dose of zoledronate for 2–3 years bone loss prevention, a 2.5 mg dose for 3–4 years bone loss prevention, and a 5 mg dose bone loss for at least five years bone loss prevention.  Thus, both smaller and less frequent doses of zoledronate for bone loss prevention can be administered than the currently recommended 5 mg dose every two years. A reduction in fracture risk, suppression of bone turnover, and an increase in BMD was also obtained by 1 mg to 5 mg doses of zoledronate for about two years, four years and five years, respectively.

The results are clinically significant. The slow offset of action of zoledronate differentiates with the quicker offset of therapies such as denosumab and parathyroid hormone. A low adherence associated with higher incidence of fracture was reported.  The clinical trials evaluating the effects on fracture risk of less frequent or smaller doses of zoledronate are currently justified because the results would have significant implications on patient care and costs of osteoporosis treatment.

Limitations

  • The participants enrolled in this study were at low fracture risk, so the results of the survey were not applicable to those with established osteoporosis
  • The present trial relies on comparing each dose of zoledronate with placebo, so it does not help in concluding the relative effects of the different doses of zoledronate

Clinical take-away

The antiresorptive activities of single zoledronate doses of 1 to 5 mg were determined in postmenopausal women with osteopenia. The results were clinically significant. The slow offset of antiresorptive action and availability of medication with prolonged activity can mitigate the adverse effects associated with low rates of treatment adherence. The low dose of zoledronate can be preferable for patients with drug toxicity as a concern, for example, patients with impaired renal function.

Source:

CMAJ 2017 September 11;189: E1130-6.

Article:

Duration of antiresorptive activity of zoledronate in postmenopausal women with osteopenia: a randomized, controlled multidose trial

Authors:

Andrew Grey et al.

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