Many clinical studies up to now have demonstrated the efficacy of the annual intravenous infusion of zoledronic acid with respect to the treatment of postmenopausal osteoporosis.
The indication for postmenopausal osteoporosis was based on the HORIZON Pivotal Fracture Trial (Black et al 2007
). This trial included 7765 patients (mean age, 73 years) who were randomly assigned to receive either a single 15-minute infusion of zoledronic acid (5 mg) or placebo at baseline, at 12 months, and at 24 months. The patients were followed until 36 months. Inclusion criteria were lumbar spine BMD T-score less than or equal to −1.5 and at least 2 mild or moderate existing vertebral fracture(s) or a femoral neck BMD T-score less than or equal to −2.5 with or without evidence of existing vertebral fracture(s). Treatment with zoledronic acid reduced the risk of morphometric vertebral fracture by 70% during a 3-year period, compared to placebo (3.3% incidence of morphometric vertebral fracture in the zoledronic acid group compared to 10.9% in the placebo group, relative risk = 0.30, 95% confidence interval [CI] = 0.24–0.38). Additionally, there was a reduction in the risk of hip fracture by 41% (1.4% incidence of hip fracture in the zoledronic acid group and 2.5% in the placebo group, hazard ratio = 0.59, 95% CI = 0.42–0.83). Nonvertebral fractures, clinical fractures, and clinical vertebral fractures were reduced by 25%, 33%, and 77%, respectively (p < 0.001 for all comparisons). Patients receiving zoledronic acid had also a significant improvement in BMD and bone metabolism markers. The results of this trial indicate that a once-yearly infusion of zoledronic acid during a 3-year period significantly reduces the risk of vertebral, hip, and other fractures in patients with postmenopausal osteoporosis. However, it should be taken into account that the HORIZON trial recruited patients who had already sustained a vertebral fracture and were, therefore, a selected high risk population, who might have shown higher rates of fracture reduction compared to patients without prevalent fractures.
A randomized, double-blind, double-dummy, multicenter trial was conducted in order to assess the safety and the efficacy of a single dose of IV zoledronic acid 5 mg compared to oral alendronate 70 mg weekly in postmenopausal women with low BMD who had previously been treated with alendronate (McClung et al 2007
). In this trial, a single infusion of zoledronic acid 5 mg maintained BMD 12 months following the switch from oral alendronate in women with osteoporosis. In the zoledronic acid 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. On the contrary, mean biomarker levels in the alendronate group remained at or close to baseline levels for the duration of the study. The overall rates of adverse events were comparable in both groups. Additionally, bone biopsies indicated that both treatments decrease excessive remodeling seen in osteoporosis. More specifically, 23 specimens with comparable baseline characteristics had adequate tissue for examination. All the specimens had normal appearance and contained adequate double tetracycline label, indicating that remodeling continued with both treating options. There was no evidence of marrow fibrosis and bone tissue appeared normal with no excess accumulation of unmineralized osteoid. The two treatments resulted in almost identical effects on static and dynamic histomorphometric measures. The median point estimates of activation frequency for the groups treated with zoledronic acid and alendronate were 0.08 and 0.09, respectively. This confirms the fact that bone turnover is not excessively reduced with zoledronic acid treatment. As for the preference expressed by the participants, 78.7% of the patients preferred the once-yearly infusion to weekly oral therapy. According to the above, patients can be safely switched from oral alendronate to zoledronic acid 5 mg infusion with maintenance of therapeutic effect for at least 12 months.
In a substudy of the HORIZON pivotal fracture trial (Recker et al 2008
) 152 patients receiving intravenous zoledronic acid 5 mg once-yearly underwent bone biopsy in order to determine effects on bone remodelling and bone architecture. According to this study, the zoledronic acid group exhibited higher trabecular bone volume (p = 0.020), higher trabecular numbers (p = 0.008), decreased trabecular separation (p = 0.011), and a trend toward improvement in connectivity density (p = 0.062) compared to the placebo group, all indicating better preservation of trabecular structure after treatment with zoledronic acid. Bone biopsies also indicate that zoledronic acid is associated with reduced bone turnover due to the fact that it causes reduction in activation frequency and also in mineralizing surface and volume referent bone formation rate versus placebo. Additionally, mineral appositional rate was improved in the zoledronic acid group (p = 0.0002) suggesting improved osteoblast function. Finally, zoledronic acid is associated with normal osteoid formation and mineralization of newly formed bone as indicated by the similar mineralization lag time in both groups and the lower osteoid volume (p < 0.0001) and osteoid thickness (p = 0.0094) in zoledronic acid-treated patients. According to the above, zoledronic acid favors the reduction of bone turnover and the preservation of bone structure and mass without any signs of adynamic bone.
A randomized, double-blind, double-dummy, multi-center, 24-week trial (Saag et al 2007
) evaluated the onset of action for both zoledronic acid and alendronate comparing a single infusion of zoledronic acid 5 mg (n = 69) to weekly oral alendronate 70 mg (n = 59) in postmenopausal women with low BMD (T-score ≤−2 by DXA) as assessed by reductions in urine N-telopeptide of type I collagen (NTX) at week 1. Zoledronic acid resulted in a significantly greater reduction in urine NTX levels at week 1 compared to alendronate, suggesting a more rapid onset of action (p < 0.0001).
At week 1, 6 patients receiving zoledronic acid and 0 patients receiving alendronate had NTX levels below the limit of detection. The zoledronic acid group had significantly lower mean urine NTX values throughout the 24-week study, compared to the alendronate group. The lowest levels of mean urine NTX was at 1 week in the zoledronic group. Levels gradually increased thereafter, and remained stable within the study reference range for premenopausal women from week 12 to study end. In the alendronate group, mean urine NTX levels showed a more gradual reduction, reaching the lowest levels by week 12. At week 24, 1 patient in the zoledronic acid group and 0 patients in the alendronate group had NTX below the limit of detection. Reductions in serum C-terminal telopeptide of type I collagen (β-CTX) levels over time were similar to those observed for urine NTX. Zoledronic acid resulted in significantly greater reductions in serum β-CTX levels at all post-baseline time points compared to aledronate. At week 24, mean β-CTX was within the premenopausal reference range in the alendronate group and slightly below the reference range in the zoledronic acid group. Additionaly, the decline of serum beta-C-telopeptide of type I collagen (β-CTX) levels was greater for zoledronic acid in comparison with aledronate throughout the 24-week study, with levels remaining in the premenopausal range from week 12 to the end of the study. Additionally, bone-specific alkaline phosphatase (BSAP) levels showed a more gradual reduction in both groups, reaching premenopausal range by week 12. According to this trial, a single infusion of zoledronic acid 5 mg leads to a greater and more rapid reduction in bone resorption markers compared to oral alendronate 70 mg, although they both have similar effects on bone formation.
A 1-year, randomized, double-blind, placebo-controlled trial by Reid et al included 351 postmenopausal women with low BMD who received placebo or 5 regimens of intravenous zoledronic acid (0.25 mg, 0.5 mg, or 1 mg at 3-month intervals or a total annual dose of 4 mg or 2 doses of 2 mg each, 6 months apart) (Reid et al 2002
). The aim was to assess the effect of zoledronic acid on bone turnover and BMD. The increase in BMD was similar in all the zoledronic acid groups and ranged between 4.3% and 5.1% and between 3.1% and 3.5% for the femoral neck compared to placebo. Biochemical markers of bone resorption were significantly suppressed throughout the study in all zoledronic acid groups. According to this trial, annual infusions of zoledronic acid might be an effective treatment for postmenopausal osteoporosis, as they produce effects on bone turnover and bone density as great as those achieved with daily oral bisphosphonates with proven efficacy against fractures.
A 5-year study by Devogelaer et al assessed the long-term efficacy and safety of prolonged use of zoledronic acid 4 mg for over 5 years (Devogelaer et al 2007
). A single infusion of zoledronic acid 4 mg given once-yearly for 2, 3 or 5 years was well tolerated with no evidence of excessive bone turnover reduction or any safety signals. Moreover, BMD increased significantly, while bone turnover markers decreased from baseline and were maintained within premenopausal reference ranges.
The HORIZON recurrent fracture trial evaluated the fracture recurrence and mortality in patients receiving zoledronic acid (Lyles et al 2007
). In this trial 1065 patients were assigned to receive yearly 5 mg of intravenous zoledronic acid, and 1062 patients were assigned to receive placebo. The infusions were first administered within 90 days after surgical repair of a hip fracture. The aim was to evaluate the impact of zoledronic acid on new clinical fractures and the mortality after hip fracture. The rates of any new clinical fracture were 8.6% in the zoledronic acid group and 13.9% in the placebo group, indicating a 35% risk reduction with zoledronic acid. The respective rates of a new clinical vertebral fracture were 1.7% and 3.8%, and the respective rates of new nonvertebral fractures were 7.6% and 10.7%. Concerning mortality there was a 28% reduction in deaths from any cause in the zoledronic acid group (p = 0.01). According to this study an annual infusion of zoledronic acid within 90 days after repair of a low-trauma hip fracture was associated with a reduction in the rate of new clinical fractures and with improved survival.