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RCT
ACE Report #6019

Effects of 2.5mg zoledronate are long-lasting and similar to 5mg dose in osteopenic women


Study Type:Therapy
OE Level Evidence:1
Journal Level of Evidence:N/A

Duration of Antiresorptive Effects of Low‐Dose Zoledronate in Osteopenic Postmenopausal Women: A Randomized, Placebo‐Controlled Trial

J Bone Miner Res. 2014 Jan;29(1):166-72. doi: 10.1002/jbmr.2009.

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Synopsis

180 postmenopausal women with osteopenia were randomly allocated to receive either 1mg, 2.5 mg, or 5 mg intravenous infusion of zoledronate or a placebo. The purpose of this trial was to determine the optimal dosing regimen of zoledronate. Results indicated that a single administration of a 1 mg or 2.5 mg dose of intravenous zoledronate produces antiresorptive effects for at least two years, although the 1 mg antiresorptive effects appear to slow after 12 months. At 2 years post-intervention, the change in bone mineral density (BMD) and bone turnover markers in the 2.5 mg dose group were similar to effects induced by 5 mg.

Publication Funding Details +
Funding:
Industry funded
Sponsor:
Health Research Council of New Zealand, University of Auckland, Novartis
Conflicts:
Consultant

Risk of Bias

8/10

Reporting Criteria

18/20

Fragility Index

N/A

Was the allocation sequence adequately generated?

Was allocation adequately concealed?

Blinding Treatment Providers: Was knowledge of the allocated interventions adequately prevented?

Blinding Outcome Assessors: Was knowledge of the allocated interventions adequately prevented?

Blinding Patients: Was knowledge of the allocated interventions adequately prevented?

Was loss to follow-up (missing outcome data) infrequent?

Are reports of the study free of suggestion of selective outcome reporting?

Were outcomes objective, patient-important and assessed in a manner to limit bias (ie. duplicate assessors, Independent assessors)?

Was the sample size sufficiently large to assure a balance of prognosis and sufficiently large number of outcome events?

Was investigator expertise/experience with both treatment and control techniques likely the same (ie.were criteria for surgeon participation/expertise provided)?

Yes = 1

Uncertain = 0.5

Not Relevant = 0

No = 0

The Reporting Criteria Assessment evaluates the transparency with which authors report the methodological and trial characteristics of the trial within the publication. The assessment is divided into five categories which are presented below.

4/4

Randomization

4/4

Outcome Measurements

3/4

Inclusion / Exclusion

4/4

Therapy Description

3/4

Statistics

Detsky AS, Naylor CD, O'Rourke K, McGeer AJ, L'Abbé KA. J Clin Epidemiol. 1992;45:255-65

The Fragility Index is a tool that aids in the interpretation of significant findings, providing a measure of strength for a result. The Fragility Index represents the number of consecutive events that need to be added to a dichotomous outcome to make the finding no longer significant. A small number represents a weaker finding and a large number represents a stronger finding.

Why was this study needed now?

While it has been observed that annual intravenous administration of 5 mg of zoledronate may reduce the risk of fractures in osteoporosis patients and decrease mortality in hip fracture patients, the optimal dosing regimen of zoledronate remains ambiguous. Previously, it was found that a single administration of 1 mg and 2.5 mg zoledronate significantly decreased markers of bone turnover and increased bone mineral density after 1 year. Due to recent insight regarding potential long-term antiresorptive effects following single dose drug administration, the aim of this study was to investigate this topic at a follow-up of 2 years post-intervention.

What was the principal research question?

What are the effects of a single intravenous administration of either 1 mg, 2.5 mg, or 5 mg zoledronate on bone mineral density and bone turnover markers after 2 years?

Study Characteristics -
Population:
180 women (>5 years postmenopausal) with a bone mineral density T-score of -1 to -2.5 at the total hip or lumbar spine. Participants did not have hip, clinical vertebral, or postmenopausal forearm fractures and did not report taking medications specific to bone health.
Intervention:
Zoledronate Group: Participants received a single administration of one of three different zoledronate doses intravenously (over 15 minutes) in 100 mL of 0.9% NaCl. Doses: 1 mg zoledronate (Mean age: 64 +/- 8; n=45, 40 completed follow-up), 2.5 mg zoledronate (Mean age: 66 +/-9; n=45, 39 completed follow up), or 5 mg zoledronate (Mean age: 66 +/- 8; n=45, 42 completed follow up).
Comparison:
Placebo group: Placebo administration consisted of an infusion of 100 mL of 0.9% NaCl. The procedure was performed in the same manner as the one in the zoledronate group (Mean age 65 +/- 9; n=45, 39 completed follow-up).
Outcomes:
The primary outcome measured change in bone mineral density (BMD) at the lumbar spine, while secondary outcomes measured change in proximal femur and total body BMD, and biochemical markers of bone turnover (type-I N-terminal propeptide (P1NP) and Beta-C-terminal telopeptide of type I collagen (Beta-CTX). BMD was measured with a Lunar Prodigy dual-energy x-ray absorptiometer, and serum bone turnover markers were measured using the Roche Elecsys 2010 platform.
Methods:
RCT; Single Centre; Double-blinded (patients & assessors)
Time:
Bone mineral density was measured at baseline, 6, 12, 18, and 24 months. Serum bone turnover markers were measured at baseline, 3, 6, 9, 12, and 18 months.

What were the important findings?

  • Bone mineral density (BMD) was higher in the zoledronate groups than the placebo group at each site and each time point during the trial (all p<0.0001).
  • Change in lumbar spine BMD 2 years after a single administration of zoledronate was greater in the zoledronate groups than the placebo group, data expressed as mean (95% CI) percent difference than values in the placebo group [4.4% (2.7% to 6.1%) with 1 mg, 5.5% (3.9% to 7.2%) with 2.5 mg, and 5.3% (3.8% to 6.7%) with 5 mg] (for each dose, p<0.001).
  • Change in total hip BMD 2 years after a single administration of zoledronate was greater in the zoledronate groups than the placebo group [2.6% (1.5% to 3.7%) with 1 mg, 4.4% (3.5% to 5.3%) with 2.5 mg; 4.7% (3.7% to 5.7%) with 5 mg] (for each dose, p<0.001).
  • Change in the bone turnover marker Beta-CTX 2 years after a single administration of zoledronate was [-18% (-30% to -7%) with 1 mg, -45% (-54% to -35%) with 2.5 mg, and -51% (-60% to -42%) with 5 mg]. Throughout the trial the value of Beta-CTX in the 2.5 and 5 mg dose groups was significantly lower than the placebo group (p<0.0001). In the 1 mg dose group, the values of Beta-CTX were lower than placebo group values until 18 months.
  • Change in the bone turnover marker P1NP 2 years after a single administration of zoledronate was [-15% (-26% to -4%) with 1 mg, -28% (-39% to -17%) with 2.5 mg, and -29% (-40% to -19%) with 5 mg]. Throughout the trial the value of P1NP in the 2.5 and 5 mg dose groups was significantly lower than the placebo group (p<0.0001). In the 1 mg dose group, P1NP values were lower than the placebo group, except at the two year time point.
  • Comparison between zoledronate groups suggests the 2.5 mg zoledronate group produced changes in BMD and bone turnover markers which fell within +/- 1.5%, and +/- 15% of those observed in the 5 mg group, respectively. Contrarily, the 1-mg dose was not equivalent to the 5-mg dose for any of the BMD or turnover endpoints.
  • In the zoledronate group, 1 participant developed iritis (with 5 mg), and 5 developed fractures (1 with 1 mg dose, 2 with 2.5 mg dose, 2 with 5 mg dose). In the placebo group, 3 participants developed fractures. No patient developed osteonecrosis of the jaw or suffered an atypical femoral fracture.

What should I remember most?

A single administration of 1 mg and 2.5 mg doses of intravenous zoledronate produced antiresorptive effects for at least two years, although the 1 mg antiresorptive effects appear to slow after 12 months. At 2 years post-intervention, the change in bone mineral density (BMD) and bone turnover markers in the 2.5 mg dose group were similar to effects induced by 5 mg.

How will this affect the care of my patients?

Results from this study suggest that a single administration of 2.5 mg zoledronate may be equally effective in increasing total bone mineral density and decreasing bone turnover markers as a 5 mg dose. Caution must be exercised when considering comparative efficacy between these doses however; the study compared doses to placebo and not direct comparisons between doses. Direct comparisons are thus needed in future trials.

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