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PubMed2001

Zoledronic acid in the treatment of hypercalcemia of malignancy: results of the international clinical development program.

This report summarizes results of the clinical development program evaluating zoledronic acid (Zometa; Novartis Pharmaceuticals Corp, East Hanover, NJ) in the treatment of hypercalcemia of malignancy (HCM). In addition to a phase I dose escalation trial, two randomized, double-blind, double-dummy studies were conducted in parallel to investigate the clinical efficacy and safety of 4 mg and 8 mg zoledronic acid in patients with moderate to severe HCM. Patients were treated with a single dose of zoledronic acid (4 or 8 mg) via 5-minute infusion or a control treatment, 90 mg pamidronate via 2-hour infusion. Patients who relapsed or had refractory HCM after initial treatment could be re-treated with 8 mg zoledronic acid. End points included rate of complete response, defined as normalization of corrected serum calcium by day 10, change in corrected serum calcium, time to relapse, duration of response, and bone biochemical markers. Doses of > or =0.02 mg/kg were effective and nontoxic in the phase I study. In the controlled studies, 287 patients were randomized and evaluated for safety and 275 patients were evaluable for efficacy. The proportions of patients with a complete response by day 10 were 88.4% and 86.7% in the 4 mg and 8 mg zoledronic acid groups, respectively, compared with 69.7% in the 90 mg pamidronate group. Corrected serum calcium normalization occurred by day 4 in 45.3% of patients treated with 4 mg zoledronic acid, 55.6% of patients treated with 8 mg zoledronic acid, and 33.3% of patients treated with pamidronate. Mean change from baseline in corrected serum calcium also was greater with zoledronic acid than with pamidronate. Median times to relapse were significantly longer in both the zoledronic acid 4 mg and 8 mg groups compared with the pamidronate group. There were no significant differences in efficacy between the 4 mg and 8 mg zoledronic acid doses. Retreatment in 69 patients with relapsing or refractory hypercalcemia with 8 mg zoledronic acid resulted in a 52% complete response rate. Fever, hypophosphatemia, and asymptomatic hypocalcemia were the most common drug-related adverse events. These studies have shown that a short single intravenous dose of 4 mg or 8 mg zoledronic acid is effective in treating moderate to severe HCM. Zoledronic acid produced a higher rate of calcium normalization, faster onset of action, and longer time to relapse than pamidronate, while maintaining an excellent safety profile. The lower dose of 4 mg is recommended as initial therapy, with the 8 mg dose reserved for patients requiring retreatment.

Bone Neoplasms↗
PubMed2005

Sequence- and schedule-dependent enhancement of zoledronic acid induced apoptosis by doxorubicin in breast and prostate cancer cells.

We investigated whether the combination of zoledronic acid and doxorubicin induced apoptosis of breast and prostate cancer cell lines, and if synergistic interaction was present. We investigated whether the levels of cell death altered depending on the sequence in which the drugs were administered and the possible mechanism of action responsible for the increased cell death following combined treatments. Breast and prostate cancer cells were treated with zoledronic acid alone, doxorubicin alone, or drugs in sequence (doxorubicin before, after, or with zoledronic acid), and the levels of apoptotic death were determined by evaluation of nuclear morphology. We found that clinically relevant concentrations of doxorubicin and zoledronic acid induced sequence- and schedule-dependent apoptosis of breast and prostate cancer cells. For maximal apoptosis, cells had to be pretreated for 24 hr with doxorubicin before immediate treatment with zoledronic acid for 1 hr. This observation is a characteristic feature of cell cycle phase-specific synergistic effect. Replacing zoledronic acid with the nonnitrogen-containing bisphosphonate clodronate did not induce increased apoptosis. Induction of apoptosis was mainly via inhibition of the mevalonate (MVA) pathway, as addition of the MVA pathway intermediary geranylgeraniol inhibited the induction of apoptosis by doxorubicin followed by zoledronic acid. In conclusion, combined treatment of breast and prostate cancer cell lines with clinically relevant doses of doxorubicin and zoledronic acid induces apoptosis in a synergistic fashion. These findings may have relevance for the clinical setting, particularly breast cancer patients receiving these drugs in the adjuvant setting.

Antibiotics, Antineoplastic↗
PubMed2001

Zoledronic acid reduces skeletal-related events in patients with osteolytic metastases.

BACKGROUND: This study evaluated the dose-response relation for zoledronic acid, a new generation high potency bisphosphonate, given as a 5-minute infusion in patients with malignant osteolytic disease. METHODS: Two-hundred eighty patients with osteolytic lesions due to metastatic breast carcinoma or multiple myeloma were randomized to double-blind treatment with either 0.4, 2.0, or 4.0 mg of zoledronic acid or 90 mg pamidronate. The primary efficacy endpoint was the proportion of patients receiving radiation to bone. Other skeletal-related events, bone mineral density (BMD), bone markers, Eastern Cooperative Oncology Group performance status, pain and analgesic scores, and safety also were evaluated. RESULTS: Zoledronic acid at doses of 2.0 and 4.0 mg and pamidronate at a dose of 90 mg each significantly reduced the need for radiation therapy to bone (P < 0.05) in contrast with 0.4 mg zoledronic acid, which did not. Skeletal-related events of any kind, pathologic fractures, and hypercalcemia also occurred less frequently in patients treated with 2.0 or 4.0 mg zoledronic acid or pamidronate than with 0.4 mg zoledronic acid. Increases in lumbar spine BMD (6.2-9.6%) and decreases in the bone resorption marker N-telopeptide (range, -37.1 to -60.8%) were observed for all treatment groups. Skeletal pain, fatigue, nausea, vomiting, and headache were the most commonly reported adverse events. Adverse events were similar in nature and frequency with zoledronic acid and pamidronate. CONCLUSIONS: A 5-minute infusion of 2.0-4.0 mg zoledronic acid was at least as effective as a 2-hour 90-mg pamidronate infusion in treatment of osteolytic metastases. A 0.4-mg dose of zoledronic acid was significantly less effective. Both zoledronic acid and pamidronate were well tolerated.

Antineoplastic Agents↗
PubMed2004

Bone microenvironment-related growth factors modulate differentially the anticancer actions of zoledronic acid and doxorubicin on PC-3 prostate cancer cells.

OBJECTIVES: We analyzed the actions of zoledronic acid (10-250 microM) and doxorubicin (10-250 nM) on PC-3 prostate cancer cells using both continuous (48-96 hr) and pulsatile exposures (15 min/day for up to three consecutive days). RESULTS: The proliferation of PC-3 cells was inhibited by either continuous or pulsatile exposures of zoledronic acid in a dose-dependent manner. In contrast, pulsatile exposures of doxorubicin failed to inhibit the growth of PC-3 cells. In addition, the inhibition of PC-3 cells by zoledronic acid was partially neutralized by exogenous administration of geranylgeranyl pyrophosphate (GGPP), however, not by farnesyl pyrophosphate (FPP). Furthermore, exogenous administration of transforming growth factor beta 1 (TGF-beta1), interleukin 6 (IL-6), basic fibroblast growth factor (bFGF), and more potently, insulin-like growth factor 1 (IGF-1) inhibited the doxorubicin-induced apoptosis of PC-3 cells. Under identical experimental conditions, these growth factors failed to alter the cytotoxicity of PC-3 cells induced by zoledronic acid. CONCLUSIONS: These data suggest that (i) repetitive and pulsatile (15 min/day) exposure to zoledronic acid inhibited the growth of PC-3 cells, (ii) this anticancer action of zoledronic acid was partially mediated by the attenuation of GGPP production, and (iii) bone microenvironment-related growth factors do not alter the anticancer actions of zoledronic acid on PC-3 cells.

Antibiotics, Antineoplastic↗
PubMed2002

Development and validation of a highly sensitive RIA for zoledronic acid, a new potent heterocyclic bisphosphonate, in human serum, plasma and urine.

Zoledronic acid is a new, highly potent bisphosphonate drug under clinical evaluation. A radioimmunoassay has been developed to determine zoledronic acid concentration in human serum, plasma, and urine. The assay utilizes rabbit polyclonal antisera against a zoledronic acid-BSA conjugate and a [125I]zoledronic acid derivative as tracer in a competitive format adapted to microtiter plates. The assay shows a LLOQ 0.4 ng/ml in serum or plasma (interassay%CV=17%, accuracy 97%), 5 ng/ml in urine (21%, 98%). In 23 patients receiving 4, 8 or 16 mg of zoledronic acid, drug concentrations in plasma were dose proportional and showed a multiphasic profile, followed by a prolonged gradual decline to concentrations near the LLOQ. Zoledronic acid disposition in plasma and the recovery of only 40-50% of the dose in urine are consistent with the rapid and extensive uptake by and slow release from bone in parallel with renal clearance, typically shown by bisphosphonates.

Adult↗
PubMed2005

Recommendations for zoledronic acid treatment of patients with bone metastases.

The introduction of zoledronic acid, a new-generation bisphosphonate, has greatly extended the use of bisphosphonates in the treatment of patients with bone metastases. On the basis of results from three large, randomized, phase III clinical trials enrolling more than 3,000 patients, zoledronic acid (4 mg via 15-minute infusion) was approved in the United States for the treatment of patients with documented bone metastases from solid tumors in conjunction with standard antineoplastic therapy and patients with multiple myeloma. Zoledronic acid is also approved in Europe for the prevention of skeletal-related events in patients with advanced malignancies involving bone. Current treatment guidelines published by the American Society of Clinical Oncology recommend the use of intravenous bisphosphonates at first radiographic evidence of osteopenia in patients with multiple myeloma or osteolytic bone lesions in patients with breast cancer to significantly reduce the occurrence and delay the onset of skeletal complications. Zoledronic acid has also demonstrated efficacy in the treatment of bone metastases in patients with prostate cancer, lung cancer, and other solid tumors. Bisphosphonate therapy is generally well tolerated but can be associated with increases in serum creatinine. Therefore, monitoring renal function is required for all patients receiving bisphosphonate therapy. Serum creatinine should be monitored before each dose and treatment withheld until any serum creatinine elevations have resolved to baseline levels. Caution should be exercised when treating patients who are receiving other potentially nephrotoxic therapies. With these simple precautions, intravenous bisphosphonate therapy is safe for long-term use and provides durable treatment benefits.

Bone Diseases, Metabolic↗
PubMed2004

Hypocalcemia and azotemia associated with zoledronic acid and interferon alfa.

OBJECTIVE: To describe severe hypocalcemia and acute renal failure associated with zoledronic acid and interferon alfa in a patient with metastatic carcinoid tumors. CASE SUMMARY: A 39-year-old white man with metastatic carcinoid tumor tolerated treatment with subcutaneous long-acting octreotide monthly and interferon alfa 6 million units 3 times weekly for 6 months. Due to multiple bony metastases, zoledronic acid was prescribed as a monthly 4-mg intravenous infusion over 30 minutes to prevent skeletal-related events. Although the first infusion went well, the patient developed severe hypocalcemia and acute renal failure after the second zoledronic infusion. DISCUSSION: Bisphosphonates may infrequently cause symptomatic hypocalcemia, especially among patients who have vitamin D deficiency or hypoparathyroidism or receive treatment with an aminoglycoside. Our literature review suggests that zoledronic acid and interferon alfa may exert additive effects on the inhibition of osteoclasts, thus potentially precipitating hypocalcemia. Renal dysfunction may not be a direct consequence of interferon alfa. However, altered mental function due to hypocalcemia may lead to dehydration and further exacerbate renal dysfunction, a known adverse effect of zoledronic acid. Since therapeutic indications of both interferon alfa and zoledronic acid continue to expand, clinicians should be aware of these serious adverse reactions and potential interaction. Supportive treatment with hydration, calcium supplement, and oral calcitriol resulted in resolution of hypocalcemia, but only partial improvement of azotemia. CONCLUSIONS: In our patient with metastatic carcinoid tumor, treatment with zoledronic acid and interferon alfa was associated with symptomatic hypocalcemia and acute renal failure.

Adult↗
PubMed2003

Zoledronic acid delays the onset of skeletal-related events and progression of skeletal disease in patients with advanced renal cell carcinoma.

BACKGROUND: The objective of this study was to assess the efficacy and safety of zoledronic acid in patients with bone metastases secondary to renal cell carcinoma (RCC). METHODS: A retrospective subset analysis of patients with RCC enrolled in a multicenter, randomized, placebo-controlled study of zoledronic acid was performed. Patients were randomized to receive zoledronic acid (4 or 8 mg as a 15-minute infusion) or placebo with concomitant antineoplastic therapy every 3 weeks for 9 months. The primary efficacy analysis was the proportion of patients with one or more skeletal-related events (SREs), which were defined as pathologic fracture, spinal cord compression, radiation therapy, or surgery to bone. Secondary analyses included time to first SRE, skeletal morbidity rate (events per year), disease progression, and multiple event analysis. RESULTS: In this subset of 74 patients with RCC, zoledronic acid (4 mg) was found to significantly reduce the proportion of patients with an SRE (37% vs. 74% for placebo; P = 0.015). Similarly, zoledronic acid significantly reduced the mean skeletal morbidity rate (2.68 vs. 3.38 for placebo; P = 0.014) and extended the time to the first event (median not reached vs. 72 days for placebo; P = 0.006). A multiple event analysis demonstrated that the risk of developing an SRE was reduced by 61% compared with placebo (hazard ratio of 0.394; P = 0.008). The median time to progression of bone lesions was significantly longer for patients who were treated with zoledronic acid (P = 0.014 vs. placebo). Zoledronic acid appeared to be well tolerated; the most common adverse events in all treatment groups included bone pain, nausea, anemia, and emesis. CONCLUSIONS: Zoledronic acid (4 mg as a 15-minute infusion) demonstrated significant clinical benefit in patients with bone metastases from RCC, suggesting that further investigation of zoledronic acid in this patient population is warranted.

Aged↗
PubMed2005

Comparison of a single infusion of zoledronic acid with risedronate for Paget's disease.

BACKGROUND: The advent of bisphosphonates advanced therapy for Paget's disease, but more effective and convenient agents are needed to increase adherence. Zoledronic acid, a bisphosphonate administered as a single intravenous infusion, might meet these needs. METHODS: In two identical, randomized, double-blind, actively controlled trials of 6 months' duration, we compared one 15-minute infusion of 5 mg of zoledronic acid with 60 days of oral risedronate (30 mg per day). The primary efficacy end point was the rate of therapeutic response at six months, defined as a normalization of alkaline phosphatase levels or a reduction of at least 75 percent in the total alkaline phosphatase excess. The results of the studies were pooled. RESULTS: At six months, 96.0 percent of patients receiving zoledronic acid had a therapeutic response (169 of 176), as compared with 74.3 percent of patients receiving risedronate (127 of 171, P<0.001). Alkaline phosphatase levels normalized in 88.6 percent of patients in the zoledronic acid group and 57.9 percent of patients in the risedronate group (P<0.001). Zoledronic acid was associated with a shorter median time to a first therapeutic response (64 vs. 89 days, P<0.001). Higher response rates in the zoledronic acid group were consistent across all demographic, disease-severity, and treatment-history subgroups and with changes in other bone-turnover markers. The physical-component summary score of the Medical Outcomes Study 36-item Short-Form General Health Survey, a measure of the quality of life, increased significantly from baseline at both three and six months in the zoledronic acid group and differed significantly from those in the risedronate group at three months. Pain scores improved in both groups. During post-trial follow-up (median, 190 days), 21 of 82 patients in the risedronate group had a loss of therapeutic response, as compared with 1 of 113 patients in the zoledronic acid group (P<0.001). CONCLUSIONS: A single infusion of zoledronic acid produces more rapid, more complete, and more sustained responses in Paget's disease than does daily treatment with risedronate.

Administration, Oral↗
PubMed2003

Zoledronic acid induces significant and long-lasting modifications of circulating angiogenic factors in cancer patients.

PURPOSE: The commercial availability of zoledronic acid, a third generation bisphosphonate, prompted us to evaluate the modifications in angiogenic cytokines levels after a single i.v. infusion of this drug. EXPERIMENTAL DESIGN: Thirty consecutive cancer patients with scintigraphic and radiographic evidence of bone metastases were treated with a single infusion of 4 mg of zoledronic acid before any chemotherapy. The patients were prospectively evaluated for circulating levels of vascular endothelial growth factor (VEGF) and platelet-derived growth factor (PDGF) just before and at 1, 2, 7, and 21 days after zoledronic acid infusion. RESULTS: Basal serum VEGF median levels were significantly decreased at days 2 (-23%), 7 (-28%), and 21 (-34%) after zoledronic acid infusion (P = 0.0498, 0.0090, and 0.0011, respectively). Serum PDGF levels were significantly decreased by 25% 1 day after zoledronic acid infusion (P = 0.0032). This effect on circulating PDGF levels persisted for 2 days after bisphosphonate infusion (P = 0.0050). PDGF levels had returned to values similar to the median basal value at 7 and 21 days. Moreover, a linear regression model with variance analysis showed a significant positive correlation between basal VEGF and PDGF values but not at the following time points. No significant differences were recorded in platelet levels, WBC count, or hemoglobin concentration before and after zoledronic acid single infusion. CONCLUSIONS: This study confirms that zoledronic acid could have an in vivo antiangiogenic property through a significant and long-lasting reduction in serum VEGF levels.

Adult↗
PubMed2005

Costs and consequences of using pamidronate compared with zoledronic acid in the management of breast cancer patients in the UK.

OBJECTIVE: To estimate the costs and consequences of using pamidronate compared to zoledronic acid in the prophylactic management of skeletal morbidity among breast cancer patients in the UK. DESIGN AND SETTING: This was a modelling study performed from the perspective of the UK's National Health Service (NHS). METHODS: Published clinical outcomes from a comparative study were combined with resource utilisation estimates derived from a panel of clinicians. This enabled the construction of a decision model depicting the management of patients with breast cancer receiving antineoplastic therapy who are 18 years of age or above and who have at least one bone metastasis (lytic or mixed). There are no significant differences in outcome between using pamidronate and zoledronic acid in breast cancer patients. Therefore, a cost minimisation analysis was performed to identify the treatment strategy that achieves the same outcome for least cost. The expected time attributable to a pamidronate and zoledronic acid infusion was also estimated. MAIN OUTCOME MEASURES AND RESULTS: Starting treatment with pamidronate among patients receiving chemotherapy is expected to lead to a healthcare cost of 6046 pounds over 12 months compared to 6981 pounds with zoledronic acid. In comparison, for patients receiving hormonal therapy, starting treatment with pamidronate is expected to lead to a healthcare cost of 5401 pounds over 12 months compared to 6043 pounds with zoledronic acid. This cost difference is primarily due to the lower acquisition cost of pamidronate and fewer tests among pamidronate-treated patients. Accordingly, pamidronate affords a less expensive management modality. Multivariate analysis showed the expected time attributable to a pamidronate infusion to be 110 to 277 minutes compared with 136 to 296 minutes for a zoledronic acid infusion. CONCLUSION: Use of pamidronate instead of zoledronic acid affords an economic benefit to the NHS. Moreover, published clinical trials show no statistical difference between pamidronate and zoledronic acid at 1 year. Hence, within the limitations of our model and the published evidence, pamidronate is the preferred first-line intravenous bisphosphonate for use in breast cancer patients receiving antineoplastic therapy who are 18 years of age or above and who have at least one bone metastasis (lytic or mixed).

Adolescent↗
PubMed2002

Efficacy of zoledronic acid and pamidronate in breast cancer patients: a comparative analysis of randomized phase III trials.

Results of a large, randomized, comparative phase III trial involving 1,130 breast cancer patients demonstrated that 4 mg zoledronic acid and 90 mg pamidronate were equally effective at reducing the occurrence and delaying the onset of skeletal-related events in patients with bone metastases secondary to breast cancer. However, zoledronic acid has demonstrated a treatment advantage over pamidronate with respect to the proportion of patients receiving radiation therapy to bone. Moreover, among patients with at least one osteolytic lesion (N = 352), zoledronic acid achieved a 17% reduction in the proportion of patients with a skeletal-related event compared with pamidronate and significantly prolonged the time to first event. In general, zoledronic acid and pamidronate had comparable effects on time to progression of bone metastases, overall disease progression, pain and analgesia scores, and overall survival. Both zoledronic acid and pamidronate effectively suppressed markers of bone resorption. However, zoledronic acid demonstrated a greater and more sustained suppressive effect. Zoledronic acid (4 mg via 15-minute infusion) also demonstrated a safety profile similar to that of pamidronate (90 mg via 2-hour infusion). In summary, the increased efficacy of zoledronic acid in specific patient subsets and the convenience of a 15-minute infusion suggest that 4 mg zoledronic acid has advantages over 90 mg pamidronate for treatment of bone metastases in patients with breast cancer.

Bone Neoplasms↗
PubMed2004

Skeletal complications in patients with bone metastases from renal cell carcinoma and therapeutic benefits of zoledronic acid.

Bone metastases in patients with renal cell carcinoma are associated with a high risk of skeletal complications. Therefore, a subset analysis of a larger clinical trial was performed to determine the efficacy of zoledronic acid in renal cell carcinoma patients. Patients with bone metastases from solid tumors other than breast or prostate cancer (n=773) were randomized to receive zoledronic acid or placebo via 15-minute infusion every 3 weeks for 9 months. Patients were monitored for skeletal-related events, which were defined as pathological fracture, spinal cord compression, radiotherapy, or surgery to bone. Among the subset of 74 patients with renal cell carcinoma, 46 patients were treated with 4 mg of zoledronic acid or placebo. Significantly fewer patients treated with 4 mg zoledronic acid had a skeletal-related event (37% versus 74% for placebo, P=0.015), and zoledronic acid significantly prolonged the time to first skeletal-related event (median not reached at 9 months versus 72 days for placebo; P=0.006). Zoledronic acid significantly reduced the annual incidence of skeletal-related events by approximately 21% (mean 2.68 versus 3.38 events per year for placebo, P=0.014) and significantly reduced the risk of developing a skeletal-related event by 61% compared with placebo (risk ratio=0.394, P=0.008) by multiple event analysis. Median time to progression of bone lesions was also significantly extended with zoledronic acid treatment (P=0.014). Zoledronic acid is the first bisphosphonate to significantly reduce skeletal morbidity and significantly prolong time to bone lesion progression in patients with bone metastases from renal cell carcinoma.

Bone Diseases↗
PubMed2004

Long-term efficacy of zoledronic acid for the prevention of skeletal complications in patients with metastatic hormone-refractory prostate cancer.

In a placebo-controlled randomized clinical trial, zoledronic acid (4 mg via a 15-minute infusion every 3 weeks for 15 months) reduced the incidence of skeletal-related events (SREs) in men with hormone-refractory metastatic prostate cancer. Among 122 patients who completed a total of 24 months on study, fewer patients in the 4-mg zoledronic acid group than in the placebo group had at least one SRE (38% versus 49%, difference = -11.0%, 95% confidence interval [CI] = -20.2% to -1.3%; P =.028), and the annual incidence of SREs was 0.77 for the 4-mg zoledronic acid group versus 1.47 for the placebo group (P=.005). The median time to the first SRE was 488 days for the 4-mg zoledronic acid group versus 321 days for the placebo group (P =.009). Compared with placebo, 4 mg of zoledronic acid reduced the ongoing risk of SREs by 36% (risk ratio = 0.64, 95% CI = 0.485 to 0.845; P =.002). Patients in the 4-mg zoledronic acid group had a lower incidence of SREs than did patients in the placebo group, regardless of whether they had an SRE prior to entry in the study. Long-term treatment with 4 mg of zoledronic acid is safe and provides sustained clinical benefits for men with metastatic hormone-refractory prostate cancer.

Aged↗
PubMed2005

Zoledronic acid significantly reduces skeletal complications compared with placebo in Japanese women with bone metastases from breast cancer: a randomized, placebo-controlled trial.

PURPOSE: To investigate the efficacy and safety of zoledronic acid for the treatment of bone metastases from breast cancer. PATIENTS AND METHODS: Women with bone metastases (N = 228) were randomly assigned to receive 4 mg zoledronic acid (n = 114) or placebo (n = 114) via 15-minute infusions every 4 weeks for 1 year. The primary efficacy end point was the skeletal-related event (SRE) rate ratio between treatment groups. An SRE was defined as pathologic fracture, spinal cord compression, and radiation or surgery to bone. Secondary end points included percentage of patients with at least one SRE, time-to-first SRE, and Andersen-Gill multiple-event analysis. RESULTS: The SRE rate ratio at 1 year (excluding HCM and adjusted for prior fracture) was 0.61 (permutation test; P = .027), indicating that zoledronic acid reduced the rate of SRE by 39% compared with placebo. The percentage of patients with at least one SRE (excluding HCM) was significantly reduced by 20% by zoledronic acid (29.8% v 49.6% for placebo; P = .003). Zoledronic acid significantly delayed time-to-first SRE (median not reached v 364 days; Cox regression; P = .007) and reduced the risk of SREs by 41% in multiple event analysis (risk ratio = 0.59; P = .019) compared with placebo. Zoledronic acid was well tolerated with a safety profile similar to placebo. No patient treated with zoledronic acid had grade 3 or 4 serum creatinine increase. CONCLUSION: Zoledronic acid significantly reduced skeletal complications compared with placebo across multiple end points in Japanese women with bone metastases from breast cancer.

Adult↗
PubMed2006

Preliminary evidence for a structural benefit of the new bisphosphonate zoledronic acid in early rheumatoid arthritis.

OBJECTIVE: Bisphosphonates inhibit osteoclast activity, which is central to the development of bone damage in rheumatoid arthritis (RA). The aim of this study was to assess whether treatment with zoledronic acid, compared with placebo, could achieve a > or = 50% reduction in the development of new erosions on magnetic resonance imaging (MRI) in patients with early RA. METHODS: In this proof-of-concept study, 39 patients with early RA and clinical synovitis of the hand/wrist were randomized to receive infusions with either zoledronic acid (5 mg) or placebo, administered at baseline and week 13. Patients in both groups received methotrexate (MTX) at a dosage of 7.5-20 mg/week. MRI and plain radiography were performed at baseline and week 26. RESULTS: At week 26, the mean +/- SD change in MRI hand and wrist erosions was 61% lower in the zoledronic acid group compared with the placebo group (0.9 +/- 1.63 versus 2.3 +/- 3.09; P = 0.176). The mean +/- SD increase in the number of hand and wrist bones with erosions was 0.3 +/- 0.75 for zoledronic acid compared with 1.4 +/- 1.77 for placebo (P = 0.029). The proportion of patients in whom new MRI-visualized bone edema developed was smaller in the zoledronic acid group compared with the placebo group (33% versus 58%; P = 0.121). The zoledronic acid group had a mean change in the number of radiographic erosions of 0.1 compared with 0.5 for the placebo group (P = 0.677). The safety profile of zoledronic acid was similar to that of placebo. CONCLUSION: The results of this study suggest a structural benefit associated with zoledronic acid therapy in patients with RA, as demonstrated by consistent results in structural end points in favor of zoledronic acid plus MTX compared with MTX alone.

Adult↗
PubMed2006

Effect of zoledronic acid in an L6-L7 rabbit spine fusion model.

Previous studies have shown that zoledronic acid administration can increase mineral content and strength in distraction osteogenesis. Of the few studies that have examined the use of bisphosphonates in spinal arthrodesis, none have assessed the effect of single dose treatment. The objective of this study was to evaluate the feasibility of enhancing spinal fusion rate using single dose zoledronic acid (ZA) to increase fusion-mass size and mineral density. Forty-eight New Zealand white rabbits underwent an L6-L7 intertransverse process fusion. The L6-L7 model is more challenging than the more commonly used level of L5-L6. Animals were randomly allocated to one of three groups, one received iliac crest bone graft alone, one group received iliac crest bone graft with locally administered zoledronic acid, 20 microg, and one group received iliac crest bone graft with a single dose of systemically administered zoledronic acid, 0.1 mg/kg. ZA doses were administered at the time of surgery. Twenty-four rabbits were culled at 6 weeks and 24 rabbits were culled at 12 weeks. Success of spinal fusion was determined by manual palpation. Specimens were evaluated radiographically, underwent quantitative computerised tomography analysis and were tested biomechanically in flexion and extension. In the six-week group, only five of the 24 spines fused with no noticeable trend with respect to treatment. In the 12-week group there was a trend toward increased fusion in the systemically administered ZA group (63%) versus the other two groups (25%) but was not statistically significant (p = 0.15). Radiographically, the local ZA treatment group showed a delay in remodelling with the presence of unremodelled bone chips. The 12-week systemic ZA group exhibited an 86% increase in BMC, a 31% increase in vBMD and a 41% increase in the volume of the fusion-mass (p < 0.05). The 12-week local ZA group also showed significant increases in BMC (69%), vBMD (31%) and total fusion-mass volume (29%) (p < 0.05). Biomechanical testing showed that the range of motion in flexion decreased to 4.5 (+/-2.5) degrees and 4.8 (+/-4.7) degrees for the local and systemic groups respectively compared to 9.6 (+/-4.9) degrees for the control group (p < 0.05). This study has shown that zoledronic acid increased fusion-mass size and bone mineral content. Systemic ZA led to an increased fusion rate; however the fusion rate remained below 100%. We suggest that bisphosphonate treatment may require an anabolic conjunctive therapy to ensure enhanced successful fusion.

Animals↗
PubMed2004

Cost-effectiveness of zoledronic acid for the prevention of skeletal complications in patients with prostate cancer.

PURPOSE: We estimated the cost-effectiveness of zoledronic acid vs placebo for decreasing skeletal complications in men with prostate cancer. MATERIALS AND METHODS: We performed a cost-effectiveness analysis alongside a multinational clinical trial of zoledronic acid. Cost estimation was based on prospectively collected resource use data for 85.3% of enrolled patients. Cost-effectiveness ratios were based on within-trial data on clinical outcomes, quality of life and study medication cost. RESULTS: Patients receiving zoledronic acid experienced fewer hospital days during a mean followup of 9 months (average 5.6 vs 8.0 days; p = 0.1910). Mean direct costs excluding study medication were US dollars 5365 for patients receiving zoledronic acid and US dollars 5689 for patients receiving placebo, a difference of US dollars 324 (95% CI US dollars 1781 to US dollars 1146). The global average cost of zoledronic acid plus its administration during the trial was US dollars 5677 (US dollars 450 per dose). The nominal cost per skeletal complication avoided was US dollars 112300 (95% CI US dollars 6900 to US dollars 48700) and the cost per additional patient free of skeletal complications was US dollars 51400 (95% CI US dollars 26900 to US dollars 243700). Nominal within-trial cost per quality adjusted life-year was US dollars 159200, which varied widely in sensitivity analyses. CONCLUSIONS: The nominal base case estimate of the cost per quality adjusted life-year for zoledronic acid in the prevention of skeletal complications of prostate cancer is consistent with that of bisphosphonates in breast cancer. However, the cost-effectiveness ratios for bisphosphonates are higher than commonly cited thresholds for conferring cost-effectiveness.

Aged↗