Preventing fragility fractures, especially those of the hip and spine, is an important public health objective. Because these fractures are associated with increased morbidity and mortality, an effective fracture prevention strategy would have a major impact on morbidity and a smaller but important impact on mortality in older adults.1–3 In the United States, approximately 10 million women have osteoporosis and another 34 million have low bone mass (osteopenia).4 Although women with low bone mass have a lower fracture risk compared with women of the same age with osteoporosis, they are at risk for developing osteoporosis unless bone loss is prevented. Moreover, it is in patients with low bone mass that the majority of fragility fractures occur.5 Recent guidelines recommend pharmacological therapy for postmenopausal women with low bone mass and moderate or high fracture risk based on validated risk prediction tools such as FRAX.6
Oral bisphosphonate therapy prevents bone loss in both younger and older postmenopausal women.7–9 However, in clinical practice, many patients are poorly compliant with their treatment and commonly do not take their therapy for more than several months.10 An effective treatment that ensures adherence would be an attractive management option to prevent bone loss in postmenopausal women with low bone mass.
Once-yearly infusion of zoledronic acid 5 mg has been proven to reduce the risk of vertebral, hip and nonvertebral fractures and to increase lumbar spine and total hip bone mineral density (BMD) over 3 years in postmenopausal women with osteoporosis.11 This treatment has also been shown to reduce the risk of new clinical fractures in men and women with a recent low trauma hip fracture.12
The objective of this study was to evaluate the effectiveness and tolerability of intravenous zoledronic acid 5 mg in postmenopausal women with low bone mass. Both the annual dosing regimen approved for treating osteoporosis and a single dose were evaluated in this 2-year study to determine whether the prevention of bone loss could be achieved with less frequent dosing.
MATERIALS AND METHODS
The randomized, multicenter (25 centers), double-blind, placebo-controlled trial had a 4-week screening period followed by a 24-month treatment period and was conducted in full conformance with the International Conference on Harmonisation Guidelines for Good Clinical Practice and the Declaration of Helsinki. A patient randomization list was produced by the IVRS provider using a validated system that automated the random assignment of patient numbers to randomization numbers. A separate medication randomization list was produced under the responsibility of Novartis Drug Supply Management using a validated system that automates the random assignment of medication numbers to medication packs containing each of the study drugs. The randomization scheme for patients was reviewed and approved by a member of the Novartis Biostatistics Quality Assurance Group. To ensure 1:1:1 ratio of assignment of the treatment groups, treatment assignment was blocked by the site. Randomization was stratified; Stratum I included women less than 5 years from menopause and Stratum II included women greater than or equal to 5 years from menopause. Eligible participants were randomized to receive either 1) zoledronic acid 5 mg infusion at randomization and at month 12 (once-yearly regimen or ZOL2×5 mg group), 2) zoledronic acid 5 mg infusion at randomization and placebo at month 12 (single infusion or ZOL1×5 mg group), or 3) placebo at randomization and at month 12 (placebo group).
The placebo and zoledronic acid-infusion preparations were indistinguishable, and both the participants and staff at the research centers were blinded to treatment allocation and to efficacy endpoints during the study. Bone mineral density was measured at months 6, 12 and 24. The safety and other efficacy variables were assessed at month 1 (visit 4) and month 3 (visit 5) after the baseline visit. The assessment was continued every 3 months until month 18, with a study completion visit at month 24 (visit 11). Starting at screening, all participants received a daily dose of 500-mg to 1,200-mg elemental calcium and vitamin D 400–800 international units orally throughout the study.
The protocol was approved by either local or central Institutional Review Boards, and all patients provided signed informed consent before initiation of any study procedure.
Women aged 45 years and older who were postmenopausal (cessation of menses for 18 months in those younger than 50 years or for 12 months in those 50 years or older or documented bilateral oophorectomy at least 1 year previously) were eligible if they had low bone mass, defined as BMD T-score less than –1.0 and more than –2.5 at the lumbar spine and a BMD T-score greater than –2.5 at the femoral neck. Participants with more than one grade 1 vertebral facture or with any grade 2 or 3 vertebral fracture,12 vitamin D level less than 15 ng/mL before randomization, renal insufficiency (calculated creatinine clearance less than 30.0 mL/min), hypercalcemia (serum calcium 2.75 mmol/L or more) or hypocalcemia (serum calcium 2.0 mmol/L or less) at visit 1 were excluded from the study. Other major exclusion criteria included use of oral bisphosphonates, calcitonin, SERMs, estrogen, or tibolone (except according to specified washout schedule) or any prior treatment with intravenous bisphosphonates, strontium, or sodium fluoride. To ensure study balance, randomization was stratified by duration of time since menopause (less than 5 years, 5 years or more).
The primary efficacy endpoint was the percentage change in the lumbar spine (L1–L4) BMD at month 24 relative to baseline. Secondary efficacy endpoints included the percentage change in lumbar spine BMD at month 12 and total hip, femoral neck, trochanter, and distal radius at months 12 and 24, and changes in markers of bone resorption (serum C-terminal telopeptides of type I collagen) and formation (serum procollagen type I N-terminal propeptide and serum bone-specific alkaline phosphatase) at months 1, 3, 6, 9, 12, 15, 18, and 24. Measurements of BMD were assessed at screening and postrandomization visits using either Hologic (Bedford, MA) or GE Lunar (Madison, WI) dual-energy X-ray absorptiometry (DXA) machines. Standardization of DXA scan procedures, analysis of all DXA scans and DXA instrument quality control were performed by a central laboratory (Synarc, Portland, OR). Lateral X-rays of the thoracic and lumbar spine, obtained at the screening visit, were reviewed by the central expert reader at the central laboratory (Synarc) who determined the presence of vertebral fracture according to the criteria of Genant.13 Measurement of bone turnover markers in fasting samples of blood was performed by Synarc (Lyon, France). To minimize the assay variability within and between the patients, all samples were shipped in batches from a central laboratory (Covance Central Labs, Indianapolis, IN) for analysis at the end of the study.
Safety was assessed by regular monitoring of adverse events and serious adverse events with their severity and relationship to study drug. These assessments included scheduled measurements of hematology, blood chemistry and urine values and regular assessments of vital signs, physical condition and body weight. Renal safety and clinical fracture events were continuously monitored throughout the trial.
All adverse events and serious adverse events were recorded for safety assessment. This also included physical examination, regular measurement of vital signs, hematology, blood chemistry and urinalysis, assessments of renal abnormalities (predose and postdose administration), postdose symptoms, cardiovascular and cerebrovascular events. The Medical Dictionary for Regulatory Activities was used for adverse events coding.
The primary efficacy variable was the percentage change in lumbar spine BMD at month 24 relative to baseline. The primary efficacy variable was analyzed using an analysis of variance model with treatment (placebo, ZOL2×5 mg, and ZOL1×5 mg), strata (less than 5 years since menopause, 5 years or more since menopause), and geographic region (North America, Europe) as explanatory variables. All analyses presented were performed on the intent-to-treat patient population. A closed testing procedure14,15 was used to adjust for the multiple testing (the comparison of ZOL2×5 mg compared with placebo was performed first, if a statistically significant difference was observed, then the comparison of ZOL1×5 mg compared with placebo was performed). The pair-wise comparisons between treatment groups were computed on least squares mean differences. In addition, the comparison between ZOL2×5 mg and ZOL1×5 mg was performed to explore the efficacy profile of the two zoledronic acid dose regimens. Last observation carried forward algorithm was utilized to impute missing BMD measurements. If a patient did not provide postbaseline measurements, the baseline measurement was carried forward for use in efficacy analyses.
The secondary BMD efficacy variables were analyzed identically as the primary efficacy variable. The analyses of biochemical markers of bone turnover were performed at each time-point on the ratio of the postbaseline value relative to baseline using a loge transformation using an analysis of covariance model with treatment, strata, geographic region, and loge (baseline value) as explanatory variables.
The required sample size was determined assuming that zoledronic acid given only at randomization (ZOL1×5 mg) would provide a 3.5% increase in lumbar spine BMD relative to baseline compared with placebo. Given a standard deviation of 6.0%, and assuming a dropout rate of 20% approximately 98 patients per treatment group would be required to give 95% power for the comparison of each individual zoledronic acid regimen relative to placebo and overall power of approximately 95%. Note that in the regulatory analyses performed, evaluation was stratified by duration of time since menopause (within 5 years, 5 years or more); hence the need for 294 participants in each strata and 588 participants overall for the study. Because the changes in BMD were similar across strata, the two strata have been combined for analysis.
The intent-to-treat population included all participants who were randomized at the start of the study. The safety population included all randomized participants who were exposed to the study drug. The participants in the intent-to-treat population with no major protocol deviations were considered as per protocol population.
A total of 1,140 participants were screened in the study, and 581 were assigned randomly to ZOL2×5 mg (n=198), ZOL1×5 mg (n=181), or placebo (n=202). The proportion of participants who completed the study was similar in the three groups with 91%, 85%, and 93% in ZOL2×5 mg, ZOL1×5 mg, and placebo, respectively (Fig. 1). Demographic and baseline characteristics were comparable between groups. Baseline BMD at different sites and bone turnover marker levels (serum C-terminal telopeptides of type I collagen, serum procollagen type I N-terminal propeptide, and serum bone-specific alkaline phosphatase) at baseline were well-matched in the three groups (Table 1).
Participants receiving either ZOL2×5 mg or ZOL1×5 mg demonstrated greater least squares mean increases (last observation carried forward) in lumbar spine BMD at month 24 relative to baseline compared with participants receiving placebo. The increases at month 24 were 5.18% (95% confidence interval [CI] 4.64, 5.71) and 4.42% (95% CI 3.87, 4.97) in women receiving ZOL2×5 mg and ZOL1×5 mg, respectively compared with −1.32% (95% CI −1.85 to −0.80) in women receiving placebo (all P<.001). Significant increases in lumbar spine BMD were also observed at months 12 and 24 relative to baseline in both zoledronic acid treatment groups compared with placebo (all P<.001). Significant increases from baseline relative to placebo were shown at all proximal femur sites (total hip, trochanter and femoral neck) at month 12 and month 24 in women receiving either ZOL2×5 mg or ZOL1×5 mg groups (Table 2).
Levels of serum C-terminal telopeptides of type I collagen, serum procollagen type I N-terminal propeptide, and serum bone-specific alkaline phosphatase were significantly decreased relative to baseline in both zoledronic acid treatment groups relative to placebo at all timepoints (all P<.001). By comparing zoledronic acid treatment groups, the reduction of bone marker levels showed similar patterns from baseline to month 12. The greatest reductions were observed at month 1 with serum C-terminal telopeptides of type I collagen and at month 3 with serum procollagen type I N-terminal propeptide and serum bone-specific alkaline phosphatase, with mean decreases of 86%, 80%, and 45% for participants receiving ZOL1×5 mg and 85%, 78%, and 48% for those receiving ZOL2×5 mg. Levels remained within the premenopausal reference range at months 6 and 12. In general, participants receiving placebo remained close to their baseline levels throughout the study.
After the second infusion at month 12, bone turnover marker levels decreased significantly in the ZOL2×5 mg, whereas they continued to increase slowly within the premenopausal reference range for ZOL1×5 mg participants (Fig. 2). Additional analyses of BTM changes during the second year of the study showed that levels of all three markers remained significantly reduced in ZOL2×5 mg compared with ZOL1×5 mg and placebo groups at all timepoints (months 15, 18 and 24). Evaluating the changes in time between month 12 and month 24 demonstrated that there were significant increases relative to month 12 for all biomarkers in the ZOL1×5 mg group only.
Both zoledronic acid regimens were well-tolerated, and the incidence rate of adverse events was similar across all groups (93.9%, 95.6%, and 92.1% in ZOL1×5 mg, ZOL2×5 mg, and placebo, respectively) (Table 3). As reported in other studies with intravenous bisphosphonate therapy, the most common postdose symptom adverse events were pain, pyrexia, chills, myalgia and nausea. These symptoms occurred in 8–20% of zoledronic acid–treated participants and in about 2% of participants receiving placebo. Symptoms were generally mild to moderate in intensity, occurred within 3 days of the first study drug infusion, were of short duration (the majority lasting 3 days or less) and most were well tolerated. The incidence of these adverse events was much lower (1–7%) after the second zoledronic acid infusion in the ZOL2×5 mg, confirming previous findings by Black et al (Table 4).8
The overall incidence of serious adverse events was similar across all treatment groups (10.6%, 9.4%, and 11.4% in ZOL1×5 mg, ZOL2×5 mg and placebo, respectively). One death due to sepsis and not suspected to be related to the study drug was reported in ZOL2×5 mg treatment group. A total of 19 patients reported fracture adverse events (six in ZOL2×5 mg, four in ZOL1×5 mg, and nine in placebo). No atrial fibrillation, osteonecrosis of the jaw or any long-term effects on renal function was reported.
These data demonstrate that zoledronic acid 5 mg given either once yearly or as a single infusion is effective in preventing bone loss at the lumbar spine and proximal femur in postmenopausal women with low BMD. This result was proven by significant increases in BMD at all spine and hip locations at month 12 and month 24 relative to baseline and compared with placebo (all P<.001). Increases in BMD observed at month 24 in participants who received zoledronic acid once yearly confirm previous results seen in postmenopausal women with osteoporosis11,16 and in patients after a low-trauma hip fractures12 treated with this annual regimen. As previously reported,9,11,16 the current study confirmed that the average BMD decreased slightly at all sites in participants receiving placebo.
Previous studies reported that fracture risk increases as BMD decreases in untreated participants,17,18 and bisphosphonates are known to prevent bone loss and preserve trabecular architecture in postmenopausal women.19 In the Os des Femmes de Lyon study, of the 158 fractures that occurred during the trial, 76 (48%) occurred in the 48% of women with low bone mass and only 8% of fractures occurred in the 31% of the study population with normal BMD.20 In a prospective study of American women aged 65 and older, only 46% of incident hip fractures occurred in women with osteoporosis by BMD criteria whereas 54% occurred in women with higher BMD values.21 Furthermore, Siris et al (2001) reported in the National Osteoporosis Risk Assessment study that women with low bone density had a 73% higher risk of fracture than women with normal BMD.5
Recently updated guidelines by national and professional societies recommend that pharmacological therapy be considered for postmenopausal women with osteoporosis and for those women without osteoporosis at moderate to high fracture risk, based on a combination of BMD and clinical risk factors.22 Participants were eligible to participate in this study if they simply had low bone mass. Many of the participants in this trial would not meet the new criteria for pharmacological therapy. However, neither FRAX nor the current risk-based guidelines were available when this study began. Furthermore, BMD response to treatment is not affected by age or baseline BMD values,23 providing confidence that women with low bone mass who are candidates for therapy would have responses similar to those observed in our study.
As has been observed in other zoledronic acid 5 mg treatment trials, bone resorption and formation marker levels were significantly reduced at the end of the 12-month dosing interval. After the second infusion at month 12, BTM reduction in participants who received the active treatment (ZOL2×5 mg group) followed a similar pattern to that shown throughout the first year of the trial. Conversely, BTM levels continued to slowly increase in patients who switched from zoledronic acid to placebo at month 12 (ZOL1×5 mg group). Several studies have shown that increases in BTM levels correlate with BMD loss at some skeletal sites20–27 and were predictive of fracture risk independent of BMD.28
During the last decade, the appropriateness and cost-effectiveness of initiating pharmacologic therapy in postmenopausal women for the management of low bone mass has been extensively debated.29–33 The identification of risk factors for fracture is an important step in assessing the need for osteoporosis therapy.5,34,35 Low bone mass is a risk factor for developing osteoporosis, and preventing future bone loss may be associated with a decrease in fracture risk over time.36
In conclusion, with either dosing once yearly or a single infusion, our findings showed that zoledronic acid 5 mg is a well-tolerated and effective drug in the prevention of bone loss in postmenopausal women with low bone mass.
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