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Keywords:

  • ZOLEDRONATE;
  • LOW DOSE;
  • ANTIRESORPTIVE;
  • BONE DENSITY;
  • BONE TURNOVER

ABSTRACT

  1. Top of page
  2. ABSTRACT
  3. Introduction
  4. Subjects and Methods
  5. Results
  6. Discussion
  7. Disclosures
  8. Acknowledgments
  9. References

Annual intravenous administration of 5 mg zoledronate decreases fracture risk, but the optimal dosing regimen for zoledronate has not been determined. We set out to evaluate the antiresorptive effects of a single administration of lower doses of zoledronate. A total of 180 postmenopausal women with osteopenia enrolled in a double-blind, randomized, placebo-controlled trial over 2 years at an academic research center. Participants were randomized to a single baseline administration of intravenous zoledronate in doses of 1 mg, 2.5 mg, or 5 mg, or placebo. The primary endpoint was change in bone mineral density(BMD) at the lumbar spine. Secondary endpoints were change in BMD at the proximal femur and total body, and changes in biochemical markers of bone turnover. After 2 years, the change in spine BMD was greater in each of the zoledronate groups than in the placebo group; values are mean (95% confidence interval [CI]) difference versus placebo: zoledronate 1 mg 4.4% [2.7% to 6.1%]; 2.5 mg 5.5% [3.9% to 7.2%]; 5 mg 5.3% [3.8% to 6.7%], p < 0.001 for each dose). Change in BMD at the total hip was greater in each of the zoledronate groups than the placebo group (mean [95% CI] difference versus placebo: zoledronate 1 mg 2.6% [1.5% to 3.7%]; 2.5 mg 4.4% [3.5% to 5.3%]; 5 mg 4.7% [3.7% to 5.7%], p < 0.001 for each dose). Each of the bone turnover markers, β-C-terminal telopeptide of type I collagen (β-CTX) and procollagen type-I N-terminal propeptide (P1NP), was lower in each of the 2.5-mg and 5-mg zoledronate groups than the placebo group throughout the trial (p < 0.001 versus placebo for each marker for each dose at each time point). For each endpoint, changes were similar in the 2.5-mg and 5-mg zoledronate groups, whereas those in the 1-mg group were smaller than those in the other zoledronate groups. These data demonstrate that single administrations of zoledronate 1 mg or 2.5 mg produce antiresorptive effects that persist for at least 2 years. Trials assessing the antifracture efficacy of intermittent low doses of zoledronate, in particular the 2.5-mg dose, are justified. © 2014 American Society for Bone and Mineral Research.


Introduction

  1. Top of page
  2. ABSTRACT
  3. Introduction
  4. Subjects and Methods
  5. Results
  6. Discussion
  7. Disclosures
  8. Acknowledgments
  9. References

Annual treatment with 5 mg of intravenous zoledronate reduces fracture risk in people with osteoporosis,[1, 2] and decreases mortality in those who have suffered a hip fracture.[2] However, the optimal dosing regimen for zoledronate is not known. The antiresorptive actions of a single 5-mg dose of zoledronate are stably persistent for at least 5 years,[3] and similar effects on bone mineral density (BMD) and markers of bone turnover were observed after 2 years in a trial comparing a single 5-mg dose of zoledronate with two annual 5-mg doses.[4] Recent evidence suggests that fracture risk reduction 3 years after a single 5-mg dose may be comparable to that observed after three annual doses.[5]

Uncertainty also exists as to the optimal dose of zoledronate. In the 1-year phase II zoledronate trial, intravenous dosing regimens that involved administration of total doses of between 1 mg and 4 mg were demonstrated to be equally effective in decreasing markers of bone turnover and increasing BMD.[6] Recently, we reported that, compared to placebo, single baseline doses of zoledronate of 1 mg and 2.5 mg significantly decreased markers of bone turnover and increased BMD compared to placebo in osteopenic postmenopausal women, after 1 year of follow-up.[7] The effects of the 2.5-mg dose were similar to those of the 5-mg dose. In that trial, the primary endpoint was change in lumbar spine BMD at 1 year, but because of emerging evidence of prolonged antiresorptive activity following single drug administration, the protocol specified 2 years of follow-up. Here, we report the results of analyses conducted at the conclusion of the trial.

Subjects and Methods

  1. Top of page
  2. ABSTRACT
  3. Introduction
  4. Subjects and Methods
  5. Results
  6. Discussion
  7. Disclosures
  8. Acknowledgments
  9. References

Protocol

The trial protocol has previously been reported in detail.[7] In brief, eligible women were as follows: >5 years postmenopausal with BMD T-score between −1 and −2.5 at either lumbar spine or total hip who had not had a hip, clinical vertebral, or postmenopausal forearm fracture, were not taking medications known to affect bone health, and had a baseline serum 25(OH)D level >25 nmol/L. Recruitment occurred between January 2008 and July 2009. The flow of participants through the trial is shown in Fig. 1. Among the 180 women randomized, 8 (2 in each treatment group) withdrew before receiving study medication for personal reasons. Of those who received study medication, 12 participants withdrew during the study: 4 placebo (2 personal reasons, 1 gastroesophageal reflux disease, 1 atrial fibrillation), 3 zoledronate 1 mg (2 personal reasons, 1 brain tumor), 4 zoledronate 2.5 mg (4 personal reasons), and 1 zoledronate 5 mg (personal reasons). The final 2-year study visit occurred in July 2011.

image

Figure 1. Flow of subjects through the study.

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Participants were randomly allocated to receive a single administration of one of three doses of zoledronate 1 mg, 2.5 mg, or 5 mg, given as a 15-minute intravenous infusion in 100 mL of 0.9% NaCl, or placebo (100 mL of 0.9% NaCl, administered in an identical fashion). No other study medication was administered. Treatment allocations were randomized by the study statistician, using a variable block size schedule, based on computer-generated (Excel 2003; Microsoft, Redmond, WA, USA) random numbers. Only the statistician and the staff member who prepared the intravenous infusions had access to treatment allocation, and neither had contact with participants. All the other study personnel and subjects were blinded to treatment allocation throughout. Only the study statistician saw unblinded data. The study received ethical approval from the Northern X Regional Ethics Committee and was registered with the Australian New Zealand Clinical Trials Registry (https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=82391; ACTRN12607000576426, “Low dose zoledronate in postmenopausal women with thin bones,” registration date: 9/11/2007). All participants gave written, informed consent.

Measurements

BMD was measured at baseline, 6, 12, 18, and 24 months at the lumbar spine (L1–L4), dual proximal femur, and total body using a Lunar Prodigy dual-energy x-ray absorptiometer (GE Lunar, Madison WI, USA). Measurements were performed by a technician who is certified by Synarc, the international company that provides bone density oversight for most international osteoporosis drug registration trials. The coefficients of variation for measurement of total hip and lumbar spine BMDs in our laboratory are 1.1% and 1.4%, respectively. During the trial period, the coefficient of variation for measurement of BMD of a spine phantom was 0.4%.

The serum bone turnover markers procollagen type-I N-terminal propeptide (P1NP) and β-C-terminal telopeptide of type I collagen (β-CTX) were measured in samples collected after overnight fast at baseline, 3, 6, 9, 12, 18, and 24 months using the Roche Elecsys 2010 platform (Roche Diagnostics, Indianapolis, IN, USA). Coefficients of variation of these markers are β-CTX, 5.1%, and PINP, 1.9%.

Statistics

Data were analyzed using procedures of SAS (SAS v9.2; SAS Institute, Inc., Cary, NC, USA). All analyses were by intention to treat and were performed on percent change from baseline value. Continuous, normally distributed variables were analyzed with a mixed models analysis of variance. The main effects of time and treatment, and their interaction (treatment*time), were included in a fully saturated model. In the event that the interaction term failed to reach statistical significance, a reduced model was fitted to explore the remaining main effects. Significant main or interaction effects were further explored using the method of Tukey to preserve the overall pairwise error rate. Data from all participants were included in these analyses. Participants who withdrew from the study were encouraged to attend study visits for bone density and bone turnover marker measurement. Where data were missing, the estimation of the study error of the random effects by maximum likelihood (Proc Mixed, SAS v 9.2) produces unbiased estimates of effect size. This approach was adopted in the analysis of each of the BMD and turnover marker endpoints.

In additional analyses we tested whether the treatment response at each skeletal site was influenced by baseline BMD, by constructing an interaction term that included tertile of baseline BMD, treatment allocation, and time. For these analyses the dependent variable was absolute BMD at each time point.

Post hoc equivalence analyses were conducted to compare the effects of the low zoledronate doses with those of the 5-mg dose. We took an approach endorsed by trial methodology experts and regulatory authorities, by calculating the mean +90% confidence interval (CI) between-group differences in percent change from baseline for each BMD and bone turnover variable.[8, 9] This approach ensures that decisions regarding equivalence are made with the same risk of type I error that exists in placebo-controlled trials in which results are reported using 95% CIs.[10] Equivalence between zoledronate doses was evaluated using Schuirmann's two one-sided test (SAS Proc ttest TOST) for equivalence bands of 1.5% and 15% for changes in BMD and bone turnover markers, respectively. The BMD equivalence band examined was that used in equivalence analyses in trials of oral bisphosphonates;[11, 12] the equivalence band examined for bone turnover markers was necessarily pragmatic, because no clinical trials have previously assessed treatment equivalence using bone turnover marker data.

Data are presented as mean ± 95% CI unless otherwise indicated. All tests were two-tailed and p < 0.05 was considered significant.

Results

  1. Top of page
  2. ABSTRACT
  3. Introduction
  4. Subjects and Methods
  5. Results
  6. Discussion
  7. Disclosures
  8. Acknowledgments
  9. References

Table 1 shows the baseline demographic, BMD, and bone turnover data in the treatment groups. There was no difference between treatment groups in the number of participants with normal BMD at the non-osteopenic site (p = 0.75).

Table 1. Baseline Data for Trial Participants
 PlaceboZoledronate 1 mgZoledronate 2.5 mgZoledronate 5 mg
  1. Values are mean (SD) or n (%), as indicated.

  2. 25OHD = serum 25-hydroxyvitamin D; BMD = bone mineral density; P1NP = procollagen type-I N-terminal propeptide; β-CTX = β-C-terminal telopeptide of type I collagen.

n43434343
Age (years), mean (SD)65 (9)64 (8)66 (9)66 (8)
Weight (kg), mean (SD)67 (13)67 (8)66 (10)65 (11)
Current smoker, n (%)0 (0)0 (0)2 (4.7)0
Calcium intake (mg/d), mean (SD)950 (330)960 (340)880 (460)850 (520)
Serum 25OHD (nmol/L), mean (SD)76 (22)71 (17)67 (18)71 (20)
Fracture during adulthood, n (%)8 (19)7 (16)9 (21)6 (14)
Lumbar spine BMD (g/cm2), mean (SD)1.03 (0.10)1.01 (0.08)1.03 (0.11)1.05 (0.12)
T-score, mean (SD)−1.3 (0.8)−1.4 (0.7)−1.2 (0.9)−1.1 (1.0)
Total hip BMD (g/cm2), mean (SD)0.87 (0.08)0.85 (0.08)0.84 (0.07)0.84 (0.09)
T-score, mean (SD)−1.1 (0.7)−1.2 (0.7)−1.3 (0.5)−1.3 (0.7)
Total body BMD (g/cm2), mean (SD)1.08 (0.06)1.05 (0.06)1.06 (0.06)1.06 (0.05)
T-score, mean (SD)−0.6 (0.8)−0.9 (0.7)−0.8 (0.8)−0.8 (0.7)
P1NP (µg/L), mean (SD)53 (21)61 (20)59 (22)58 (19)
β-CTX (ng/L), mean (SD)451 (186)468 (197)516 (232)456 (220)

BMD

Figure 2 shows the BMD data from the lumbar spine, dual total hip, and total body sites. At each site, BMD was higher during the trial in each of the zoledronate groups than in the placebo group (p < 0.0001 for each zoledronate group versus placebo at each time point). The differences in BMD between each of the zoledronate groups and the placebo group at each site at the end of 2 years are summarized in Table 2. At the lumbar spine the mean increases in BMD in the zoledronate groups at the end of the trial were within 1.1% of each other, and were stable during the second year. At the total hip, the mean increases in BMD in the 5-mg and 2.5-mg zoledronate groups at the end of the trial differed by 0.3%, and were stable during the second year, whereas the effect of the 1-mg dose waned during the second year. At the total body, the dose-dependent effect on BMD that was apparent after 12 months persisted during the second year, and tended to become more pronounced.

image

Figure 2. Effects of study treatments on bone mineral density at the lumbar spine (top), total hip (middle), and total body (bottom) over 2 years in osteopenic postmenopausal women. Data are mean percent change from baseline (95% CI). At each skeletal site, bone density was higher in the each of the zoledronate groups than the placebo group throughout the study (p < 0.0001 at each time point).

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Table 2. Summary Data for Change in BMD and Bone Turnover Markers 2 Years After a Single Administration of Zoledronate
 Zoledronate 1 mgZoledronate 2.5 mgZoledronate 5 mg
  1. Data are mean (95% CI) percent difference from values in the placebo group.

  2. BMD = bone mineral density; β-CTX = β-C-terminal telopeptide of type I collagen; P1NP = procollagen type-I N-terminal propeptide.

Lumbar spine BMD4.4% (2.7% to 6.1%)5.5% (3.9% to 7.2%)5.3% (3.8% to 6.7%)
Total hip BMD2.6% (1.5% to 3.7%)4.4% (3.5% to 5.3%)4.7% (3.7% to 5.7%)
Total body BMD1.3% (0.6% to 2.1%)1.9% (1.3% to 2.6%)2.5% (1.9% to 3.1%)
β-CTX−18% (−30% to −7%)−45% (−54% to −35%)−51% (−60% to −42%)
P1NP−15% (−26% to −4%)−28% (−39% to −17%)−29% (−40% to −19%)

Finally, we found no evidence that baseline BMD influenced the treatment response at any skeletal site (all p > 0.50).

Bone turnover markers

The bone turnover marker data are shown in Fig. 3. In the 2.5-mg and 5-mg zoledronate groups, values of each of the turnover markers, β-CTX and P1NP, were significantly lower than those in the placebo group throughout the trial (p < 0.0001 for each marker at each time point). In the 1-mg zoledronate group, values of P1NP were lower than those in the placebo group at each time point (p < 0.0001) except 2 years, and values of β-CTX were below those in the placebo group (p < 0.0001 at each time point) until 18 months. The changes in each marker at the end of 2 years are summarized in Table 2. The pattern of changes observed in the zoledronate groups paralleled those observed for BMD. Thus, mean reductions in each marker in the zoledronate 2.5-mg and 5-mg groups after 2 years differed by only 7% (β-CTX) and 1% (P1NP). In the 1-mg group, changes in each marker after 2 years were clearly intermediate between those of the higher-dose zoledronate groups and the placebo group.

image

Figure 3. Effects of study treatments on markers of bone turnover, β-C-terminal-telopeptide of type I collagen (β-CTX) (top), and procollagen type-I N-terminal propeptide (P1NP) (bottom), over 2 years in osteopenic postmenopausal women. Data are mean percent change from baseline (95% CI). The level of each turnover marker was lower in each of the 2.5-mg and 5-mg zoledronate groups than the placebo group throughout the study (p < 0.0001 at each time point); in the 1-mg zoledronate group, levels of β-CTX and P1NP were lower than the placebo group at each time point (p < 0.0001) until 18 months and 24 months, respectively.

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Comparisons between zoledronate groups

In post hoc analyses, we compared the 2-year change from baseline in BMD at each site and in each of the turnover markers in the 1-mg and 2.5-mg zoledronate groups with those observed in the 5-mg zoledronate group (Table 3). These analyses suggested that the 2.5-mg zoledronate dose produced changes in BMD which fell within ± 1.5% of those observed in the 5-mg group and changes in bone turnover markers which fell within ± 15% of those observed in the 5-mg group. The change in spine BMD was not equivalent between these treatment groups; the CI around the point estimate of the between-group difference overlapped the upper equivalence bound, so a greater increase in the 2.5-mg dose could not be excluded. In contrast, the 1-mg dose was not equivalent to the 5-mg dose using these bounds for any of the BMD or turnover endpoints.

Table 3. Post Hoc Comparisons of the Effects of Low Doses of Zoledronate With Those of the 5-mg Dose on Change in BMD and Bone Turnover After 2 Years
VariableZoledronate 1 mg versus 5 mgZoledronate 2.5 versus 5 mg
  • Data are mean (90% CI) between-group differences in change from baseline in the indicated variable for the indicated zoledronate dose comparisons. For BMD variables, a negative value indicates a smaller increase in the low-dose group; for turnover variables, a positive value indicates a smaller decrease in the low-dose group.

  • BMD = bone mineral density; β-CTX = β-C-terminal telopeptide of type I collagen; P1NP = procollagen type-I N-terminal propeptide.

  • a

    Equivalent using a bound of ± 1.5%.

  • b

    Equivalent using a bound of ± 15%.

Change in lumbar spine BMD−0.9% (−2.2% to 0.5%)0.3% (−1.0% to 1.6%)
Change in total hip BMD−2.1% (−3.0% to −1.2%)−0.3% (−1.1% to 0.5%)a
Change in total body BMD−1.1% (−1.6% to 0.6%)−0.5% (−1.0% to 0%)a
Change in β-CTX32.7% (23.0% to 42.5%)6.5% (−1.8% to 14.7%)b
Change in P1NP14.4% (5.8% to 23.1%)1.3% (−7.6% to 10.2%)b

Adverse events

None of the participants developed osteonecrosis of the jaw or atypical femoral fracture. One participant in the zoledronate 5-mg group developed iritis. Eight fractures occurred in 8 participants: 3 in the placebo group (1 forearm, 2 metatarsal), 1 in the zoledronate 1-mg dose (metatarsal), 2 in the zoledronate 2.5-mg group (1 forearm, 1 metacarpal), and 2 in the zoledronate 5-mg group (1 finger, 1 tibia).

Discussion

  1. Top of page
  2. ABSTRACT
  3. Introduction
  4. Subjects and Methods
  5. Results
  6. Discussion
  7. Disclosures
  8. Acknowledgments
  9. References

Determining the optimum dosing regimens for treatments for chronic diseases has important implications for patient care and pharmacoeconomics. Administering the least amount of treatment that is effective is likely to reduce the incidence of adverse events, improve patient acceptance and adherence, and reduce the cost of treating each patient, which is an important consideration in an environment of limited healthcare budgets.[13]

At present, the optimal strategy for administration of zoledronate is uncertain. Dosing regimens that administer total doses of 1 to 2 mg produce antiresorptive effects after 1 year that match those of a single 4-mg dose.[6] Annual 5-mg doses of zoledronate reduce fracture risk over 3 years at both vertebral and nonvertebral sites in osteoporotic populations.[1, 2] Interruption of annual dosing with 5 mg after 3 years is associated with similar rates of all clinical, nonvertebral, clinical vertebral, and hip fractures, but a higher rate of morphometric vertebral facture than continuing with annual administration, over a further 3 years of follow-up.[14] Post hoc analyses of trials in the phase III zoledronate program suggest that comparable fracture risk reduction might be achieved 3 years after a single zoledronate 5-mg dose to that achieved after three annual 5-mg zoledronate doses.[5] Combined with evidence that the antiresorptive effects of zoledronate doses of 4 or 5 mg persist for up to 5 years,[3, 4, 15] these data suggest that effective fracture risk reduction is possible with less zoledronate drug exposure than 5 mg annually.

The current analyses further support that possibility, by demonstrating that a single administration of doses of zoledronate of either 1 mg or 2.5 mg produces antiresorptive effects that are superior to those observed in the placebo group over 2 years. The effects of the 2.5-mg dose remained similar to those induced by the 5-mg dose for each of the BMD and turnover marker endpoints assessed, throughout the course of the trial. Further, the effects of the 2.5-mg dose on BMD and a marker of bone resorption after 2 years are comparable to those reported after a similar duration of treatment with other bisphosphonates that have been shown to decrease the incidence of fragility fractures at both vertebral and nonvertebral sites.[16, 17] These effects are also greater than those reported in a trial of a bisphosphonate that proved ineffective in reducing fracture risk.[18] These data justify the conduct of trials to carefully define the duration of antiresorptive action of zoledronate doses of 2.5 mg and 5 mg, and to investigate the antifracture efficacy of intermittent treatment with 2.5 mg of zoledronate in populations at high risk of fracture. The current data also suggest that a 1-mg dose of zoledronate produces substantial antiresorptive effects for up to 12 months, after which slow offset is apparent.

In the United States, zoledronate is approved for prevention of bone loss when administered as a 5-mg dose every 2 years. The current data suggest that doses of either 2.5 mg or 1 mg, given at 2-year intervals, also prevent bone loss. The finding that very intermittent treatment with zoledronate effectively reduces bone resorption and maintains BMD suggests that such treatment has the potential, if applied as a preventative strategy, to reduce the fracture burden in postmenopausal women.

A strength of our study is its double-blind, randomized, and placebo-controlled design. The trial also has limitations. The BMD and bone turnover marker endpoints are surrogates for fracture risk, albeit those that are frequently employed in evaluating the effects of skeletal interventions. We recruited osteopenic postmenopausal women, not those with high fracture risk, so the results may not be generalizable to other population groups. However, the effects of antiresorptive agents on bone turnover and BMD in osteopenic populations in phase II trials have consistently been replicated in phase III trials conducted in osteoporotic populations.[1, 6, 19, 20] Finally, the trial was configured to compare the effects of each zoledronate dose with placebo—comparisons between zoledronate groups were conducted post hoc, and should therefore be interpreted with caution.

In summary, the results from this trial suggest that doses of intravenous zoledronate of 1 mg and 2.5 mg produce antiresorptive effects which are apparent for at least 2 years. Two years after administration, the skeletal effects of a single dose of 2.5 mg of zoledronate are similar to those induced by a 5-mg dose. A 1-mg dose produces substantial antiresorptive effects that persist for 12 months, after which slow offset is observed. Trials to assess the antifracture efficacy of annual administration of 1 mg of zoledronate or 2-yearly administration of 2.5 mg of zoledronate are justified.

Disclosures

  1. Top of page
  2. ABSTRACT
  3. Introduction
  4. Subjects and Methods
  5. Results
  6. Discussion
  7. Disclosures
  8. Acknowledgments
  9. References

IRR has received research funding, speaker and consultancy fees from Novartis, Merck, Procter & Gamble, and Amgen. All of the other authors state that they have no conflicts of interest.

Acknowledgments

  1. Top of page
  2. ABSTRACT
  3. Introduction
  4. Subjects and Methods
  5. Results
  6. Discussion
  7. Disclosures
  8. Acknowledgments
  9. References

This work was supported by the Health Research Council of New Zealand and the University of Auckland. The study drug was provided by Novartis.

Authors' roles: Study design: AG, MB, AH, GG, IR. Study conduct: BM, SW, AH. Data analysis: GG. Drafting manuscript: AG. Revising manuscript: AG, MB, GG, IR. Approving final version of manuscript: AG, MB, BM, SW, AH, GG, IR. AG takes responsibility for the integrity of the data analysis.

References

  1. Top of page
  2. ABSTRACT
  3. Introduction
  4. Subjects and Methods
  5. Results
  6. Discussion
  7. Disclosures
  8. Acknowledgments
  9. References
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