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PubMed2006

In vitro synergistic cytoreductive effects of zoledronic acid and radiation on breast cancer cells.

INTRODUCTION: Bisphosphonates are mostly used in the treatment of bone metastases. They have been shown to act synergistically with other chemotherapeutic agents. It is not known, however, whether similar synergistic effects exist with radiation on breast cancer cells. METHODS: Human MCF-7 breast cancer cells were treated with up to 100 microM zoledronic acid, were irradiated with up to 800 cGy or were exposed to combinations of both treatments to determine the antiproliferative effects of zoledronic acid and radiation. RESULTS: Zoledronic acid and radiation caused a dose-dependent and time-dependent decrease in cell viability (approximate 50% growth inhibition values were 48 microM and 20 microM for 24 hours and 72 hours, respectively, for zoledronic acid and 500 cGy for radiation). A synergistic cytotoxic effect of the combination of zoledronic acid and radiation was confirmed by isobologram analysis. CONCLUSION: These data constitute the first in vitro evidence for synergistic effects between zoledronic acid and radiation. This combination therapy might thus be expected to be more effective than either treatment alone in patients with metastatic breast carcinoma.

Antineoplastic Agents↗
PubMed2006

Zoledronic acid (Zometa) enhances the cytotoxic effect of gemcitabine and fluvastatin: in vitro isobologram studies with conventional and nonconventional cytotoxic agents.

OBJECTIVES: To identify synergistic combinations of clinically available agents with zoledronic acid which would enhance antitumor activity as measured by median effect isobologram analysis and apoptosis assays in vitro. METHODS: The interaction of zoledronic acid as a doublet with either carboplatin, cisplatin, 5'DFUR, docetaxel, epirubicin, fluvastatin, gemcitabine, imatinib, paclitaxel, trastuzumab, or vinorelbine was studied in a 72-hour in vitro system using defined human cancer cell lines grown as a monolayer in exponential phase. Drug effect on growth was measured by a standard MTT assay. Median effect isobologram analysis was applied to the results to determine the presence of synergism, additive effects, or antagonism of drug combinations. Synergistic combinations were also assayed by a cytoplasmic histone-associated DNA fragmentation apoptosis assay to verify that the effect was not cytostatic. RESULTS: Zoledronic acid with gemcitabine demonstrated global cytotoxic synergy across 7 of 8 cell lines. Clinically achievable concentrations of fluvastatin with zoledronic acid also demonstrated synergy in 7 of 8 cell lines. All the breast cancer cell lines were sensitive. Zoledronic acid and epirubicin were antagonistic in all 4 breast cell lines studied. CONCLUSIONS: Combinations of zoledronic acid with either gemcitabine or fluvastatin may have a therapeutic role in treatment of bone metastasis of selected malignancies.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed2003

The pharmacokinetics and pharmacodynamics of zoledronic acid in cancer patients with varying degrees of renal function.

An open-label pharmacokinetic and pharmacodynamic study of zoledronic acid (Zometa) was performed in 19 cancer patients with bone metastases and known, varying levels of renal function. Patients were stratified according to creatinine clearance (CLcr) into different groups of normal (CLcr > 80 mL/min), mildly (CLcr = 50-80 mL/min), or moderately/severely impaired (CLcr = 10-50 mL/min) renal function. Three intravenous infusions of 4 mg zoledronic acid were administered at 1-month intervals between doses. Plasma concentrations and amounts excreted in urine were determined in all subjects, and 4 patients were administered 14C-labeled zoledronic acid to assess excretion and distribution of drug in whole blood. In general, the drug was well tolerated by the patients. Mean area under the plasma concentration versus time curve and mean concentration immediately after cessation of drug infusion were lower, and mean amounts excreted in urine over 24 hours from start of infusion were higher in normal subjects than in those with impaired renal function (36% vs. 28% of excreted dose), although the differences were not significant. Furthermore, with repeated doses, there was no evidence of drug accumulation in plasma or changes in drug exposure in any of the groups, nor was there any evidence of changes in renal function status. Serum levels of markers of bone resorption (serum C-telopeptide and N-telopeptide) were noticeably reduced after each dose of zoledronic acid across all three renal groups. It was concluded that in patients with mildly to moderately reduced renal function, dosage adjustment of zoledronic acid is likely not necessary.

Adult↗
PubMed2005

Weekly docetaxel and zoledronic acid every 4 weeks in hormone-refractory prostate cancer patients.

OBJECTIVES: To investigate the safety and efficacy of docetaxel and zoledronic acid in patients with hormone-refractory prostate cancer (HRPC), based on preclinical evidence of synergism between taxanes and bisphosphonates. METHODS: Twenty-five patients with advanced HRPC received weekly docetaxel 30 mg/m2: in 18 patients with symptomatic bone metastases and normal renal function, docetaxel was combined with zoledronic acid, 4 mg i.v. every 4 weeks. Premedication consisted of intravenous dexamethasone before docetaxel. No oral steroids were given. RESULTS: Overall, 12 patients (48%) had a PSA response (reduction of 50% or more compared to baseline). A PSA response was achieved in 8/18 patients (44%) receiving concomitant docetaxel and zoledronic acid, and in 7/12 patients (58%) receiving docetaxel and zoledronic acid as first-line therapy. The weekly schedule of docetaxel resulted in a mean received dose intensity of 26 mg/m2/week, or 87% of the planned dose intensity. Toxicity was mild and as expected for docetaxel. The median time to progression was 7 months, and the median overall survival was 16 months. CONCLUSIONS: Concomitant treatment with docetaxel and zoledronic acid is safe and has encouraging activity in HRPC. The combination should be evaluated in randomised clinical trials.

Aged↗
PubMed2003

Randomized controlled trial of zoledronic acid to prevent bone loss in men receiving androgen deprivation therapy for nonmetastatic prostate cancer.

PURPOSE: A multicenter double-blind, randomized, placebo controlled clinical trial was performed to assess the effect of zoledronic acid, a potent new bisphosphonate, on bone mineral density during androgen deprivation therapy for nonmetastatic prostate cancer. MATERIALS AND METHODS: Men with M0 (no distant metastases) prostate cancer beginning androgen deprivation therapy were randomly assigned to receive 4 mg. zoledronic acid or placebo intravenously every 3 months for 1 year. The primary efficacy variable was the percent change from baseline to 1 year in bone mineral density of the lumbar spine as measured by dual energy x-ray absorptiometry. RESULTS: A total of 106 men were enrolled in the trial. Mean bone mineral density in the lumbar spine increased by 5.6% in men receiving zoledronic acid and decreased by 2.2% in those given placebo (mean difference 7.8%, 95% confidence interval 5.6%-10.0%, p <0.001). Mean bone mineral density of the femoral neck, trochanter and total hip also increased in the zoledronic acid group and decreased in the placebo group. Zoledronic acid was well tolerated. CONCLUSIONS: Zoledronic acid increases bone mineral density in the hip and spine during androgen deprivation therapy for nonmetastatic prostate cancer.

Aged↗
PubMed2001

Zoledronic acid is superior to pamidronate in the treatment of hypercalcemia of malignancy: a pooled analysis of two randomized, controlled clinical trials.

PURPOSE: Two identical, concurrent, parallel, multicenter, randomized, double-blind, double-dummy trials were conducted to compare the efficacy and safety of zoledronic acid and pamidronate for treating hypercalcemia of malignancy (HCM). PATIENTS AND METHODS: Patients with moderate to severe HCM (corrected serum calcium [CSC] > or = 3.00 mmol/L [12.0 mg/dL]) were treated with a single dose of zoledronic acid (4 or 8 mg) via 5-minute infusion or pamidronate (90 mg) via 2-hour infusion. A protocol-specified pooled analysis of the two parallel trials was performed. Clinical end points included rate of complete response by day 10, response duration, and time to relapse. RESULTS: Two hundred eighty-seven patients were randomized and evaluated for safety; 275 were evaluated for efficacy. Both doses of zoledronic acid were superior to pamidronate in the treatment of HCM. The complete response rates by day 10 were 88.4% (P = .002), 86.7% (P = .015), and 69.7% for zoledronic acid 4 mg and 8 mg and pamidronate 90 mg, respectively. Normalization of CSC occurred by day 4 in approximately 50% of patients treated with zoledronic acid and in only 33.3% of the pamidronate-treated patients. The median duration of complete response favored zoledronic acid 4 and 8 mg over pamidronate 90 mg with response durations of 32, 43, and 18 days, respectively. CONCLUSION: Zoledronic acid is superior to pamidronate; 4 mg is the dose recommended for initial treatment of HCM and 8 mg for relapsed or refractory hypercalcemia.

Adult↗
PubMed2002

Novel antiangiogenic effects of the bisphosphonate compound zoledronic acid.

Bisphosphonate drugs inhibit osteoclastic bone resorption and are widely used to treat skeletal complications in patients with tumor-induced osteolysis. We now show that zoledronic acid, a new generation bisphosphonate with a heterocyclic imidazole substituent, is also a potent inhibitor of angiogenesis. In vitro, zoledronic acid inhibits proliferation of human endothelial cells stimulated with fetal calf serum, basic fibroblast growth factor (bFGF), and vascular endothelial growth factor (IC(50) values 4.1, 4.2, and 6.9 microM, respectively), and modulates endothelial cell adhesion and migration. In cultured aortic rings and in the chicken egg chorioallantoic membrane assay, zoledronic acid reduces vessel sprouting. When administered systemically to mice, zoledronic acid potently inhibits the angiogenesis induced by subcutaneous implants impregnated with bFGF [ED(50), 3 microg/kg (7.5 nmol/kg) s.c.]. These findings indicate that zoledronic acid has marked antiangiogenic properties that could augment its efficacy in the treatment of malignant bone disease and extend its potential clinical use to other diseases with an angiogenic component.

Angiogenesis Inhibitors↗
PubMed2001

The role of zoledronic acid in cancer: clinical studies in the treatment and prevention of bone metastases.

Preclinical studies with zoledronic acid (Zometa; Novartis Pharmaceuticals Corp, East Hanover, NJ) have shown its potential in malignant bone disease. Clinical studies in the treatment of hypercalcemia of malignancy have been completed, as have phase I and II trials in patients with cancer and pre-existing bone metastases. Three randomized, double-blind, controlled phase III trials are ongoing to establish the efficacy and safety of zoledronic acid in the treatment of osteolytic and osteoblastic bone metastases. In one study, 4 mg zoledronic acid is compared with the standard therapy, 90 mg pamidronate, in treatment of osteolytic lesions in patients with breast cancer and multiple myeloma. Two other studies, one in patients with prostate cancer and bone metastases and another in patients with non-small cell lung cancer and other tumor types, are placebo-controlled. The primary end point in all three studies is the frequency of skeletal complications resulting from bone metastases. Adjuvant trials that assess the ability of zoledronic acid to prevent or reduce the incidence of bone metastases in patients at high risk for future skeletal metastasis are also planned or ongoing. The rationale and design of these ongoing and planned studies is discussed.

Antineoplastic Agents↗
PubMed2004

Clinical benefit of zoledronic acid in patients with lung cancer and other solid tumors: analysis based on history of skeletal complications.

The results of a retrospective exploratory analysis of a phase III trial of zoledronic acid in patients with bone metastases secondary to lung cancer or other solid tumors are reported herein to assess the risk of skeletal-related events (SREs) and the efficacy of 4 mg zoledronic acid compared with placebo. The study is based on patient SRE history before study entry. Patients were stratified based on SRE history (eg, pathologic fracture, spinal cord compression, radiation therapy or surgery to bone, or hypercalcemia) before study entry, and SRE incidence over 21 months was analyzed. Of 507 patients randomized to 4 mg zoledronic acid or placebo, 131 completed the 9-month core phase and 69 entered the 12-month extension phase. Before study entry, 347 of 503 patients who were evaluable for efficacy (69%) experienced >/= 1 SRE; these patients had a higher risk of developing an SRE on study than patients with no prior SRE (odds ratio, 1.41). Among patients with an SRE before study entry, zoledronic acid reduced the risk of SREs by 31% (P = 0.009), reduced the mean skeletal morbidity rate (1.96 vs. 2.81 SREs per year for placebo; P = 0.030), and prolonged the median time to first SRE by nearly 4 months (215 days vs. 106 days for placebo; P = 0.011). Among patients with no SRE before study entry (n = 156), zoledronic acid reduced the risk of SREs by 23% (P = 0.308), reduced the mean skeletal morbidity rate (1.34 vs. 2.53 SREs per year for placebo; P = 0.332), and prolonged the median time to first SRE by 2.5 months (P = 0.534). This exploratory analysis demonstrates that patients with a history of SREs are at high risk for subsequent SREs, but zoledronic acid reduces skeletal morbidity regardless of SRE history.

Antineoplastic Agents↗
PubMed2005

Economic evaluation of zoledronic acid versus pamidronate for the prevention of skeletal-related events in metastatic breast cancer and multiple myeloma.

Skeletal complications of cancer decrease health-related quality of life. Bisphosphonates can prevent skeletal-related events. We collected resource use data prospectively for 930 patients alongside a multinational trial of zoledronic acid versus pamidronate for patients with metastatic multiple myeloma or breast cancer and > or =1 bone lesion. Country-specific unit costs were assigned to counts of resource use from randomization through last trial visit. Total costs were calculated by summing costs for medical resources, plus costs of institutional care and study medications and administration. Resource use was similar for both groups. Approximately half of the patients were hospitalized at least once during the mean follow-up of 10 months (52.8% for zoledronic acid versus 52.6% for pamidronate; P = 0.9504). The average number of hospital days was 8.9 for zoledronic acid versus 9.2 for pamidronate (P = 0.728). The mean total cost was 16,434 dollars for zoledronic acid and 15,735 dollars for pamidronate, an incremental cost of 699 dollars (95% confidence interval [CI], -1047 to 2163). Mean total costs for patients with multiple myeloma were 1982 dollars (95% CI, -1491 to 5335) higher for zoledronic acid (17,958 dollars) than for pamidronate (15,976 dollars). However, among patients with breast cancer, total costs in both groups were approximately equal (15,703 dollars for zoledronic acid versus 15,680 dollars for pamidronate; 95% CI for the difference: -1875 to 2012). There were no significant cost differences between patients receiving zoledronic acid and those receiving pamidronate.

Ambulatory Care↗
PubMed2003

Long-term efficacy and safety of zoledronic acid compared with pamidronate disodium in the treatment of skeletal complications in patients with advanced multiple myeloma or breast carcinoma: a randomized, double-blind, multicenter, comparative trial.

BACKGROUND: The goal of the current study was to compare the long-term (25-month) safety and efficacy of zoledronic acid with pamidronate in patients with bone lesions secondary to advanced breast carcinoma or multiple myeloma. METHODS: Patients (n = 1648) were randomized to receive 4 mg or 8 mg (reduced to 4 mg) zoledronic acid as a 15-minute infusion or to receive 90 mg pamidronate as a 2-hour infusion every 3-4 weeks for 24 months. The primary endpoint was the proportion of patients with at least 1 skeletal-related event (SRE), defined as pathologic fracture, spinal cord compression, radiation therapy, or surgery to bone. Secondary analyses included time to first SRE, skeletal morbidity rate, and multiple-event analysis. Hypercalcemia of malignancy (HCM) was included as an SRE in some secondary analyses. RESULTS: After 25 months of follow-up, zoledronic acid reduced the overall proportion of patients with an SRE and reduced the skeletal morbidity rate similar to pamidronate. Compared with pamidronate, zoledronic acid (4 mg) reduced the overall risk of developing skeletal complications (including HCM) by an additional 16% (P = 0.030). In patients with breast carcinoma, zoledronic acid (4 mg) was significantly more effective than pamidronate, reducing the risk of SREs by an additional 20% (P = 0.025) compared with pamidronate and by an additional 30% in patients receiving hormonal therapy (P = 0.009). Zoledronic acid (4 mg) and pamidronate were tolerated equally well. The most common adverse events included bone pain, nausea, and fatigue. CONCLUSIONS: Long-term follow-up data confirm that zoledronic acid was more effective than pamidronate in reducing the risk of skeletal complications in patients with bone metastases from breast carcinoma and was of similar efficacy in patients with multiple myeloma.

Bone Diseases↗
PubMed2006

Growth inhibition and sensitization to cisplatin by zoledronic acid in osteosarcoma cells.

Since osteosarcoma is a drug-resistant disease, the aim of the present study was to explore the possible interest of therapeutic approaches including nitrogen-containing biphosphonate zoledronic acid using osteosarcoma cell lines with different genetic backgrounds. Parental p53+/pRb+ U2-OS, p53-mutant U2-OS (U2-OS/175) and p53-/pRb- SAOS were sensitive to zoledronic acid with no significant differences in IC50 values. Analysis of cell cycle distribution revealed a time-dependent shifting of U2-OS cells towards G2 phase with cell cycle arrest in G2 phase at 96 h of exposure to the compound. Conversely, U2-OS/175 and SAOS cells responded to treatment with transient cell accumulation in S phase up to 48-72 h, respectively. Cell lines were exposed to increasing concentrations of cisplatin alone or combined with sub-toxic doses of zoledronic acid. A growth inhibitory effect was seen after combined treatment in U2-OS, otherwise resistant to cisplatin up to 100 ng/ml. Zoledronic acid did not efficiently sensitized U2-OS/175 and SAOS to cisplatin, thereby suggesting that different behavior may depend on p53 mutation. This data was confirmed in U2-OS cells where p53 expression was downregulated by RNA interference. Present findings indicate occurrence of sensitization to cisplatin by zoledronic acid in wild-type p53 osteosarcoma cells but not in p53-null cells nor in cells expressing a dominant-negative form of p53, supporting that wild-type p53 is required for synergistic interaction of cisplatin and zoledronic acid.

Antineoplastic Agents↗
PubMed2005

Effect of zoledronic acid on incorporation of a bioceramic bone graft substitute.

Many osteoporotic fracture patients are candidates for concurrent treatment with bisphosphonates and bioceramic bone graft substitutes. Osteopromotive silica-based bioactive glasses are known to induce accelerated local bone turnover and adjunct antiresorptive agents, such as zoledronic acid, may affect the process. The current study examined the effect of adjunct zoledronic acid therapy on bioactive glass incorporation. In Harlan Sprague-Dawley rats (n = 80), a standardized region of the proximal tibia was subjected to ablation of local bone marrow and filled with bioactive glass (BG) microspheres. Experimental animals received zoledronic acid (1.5 mug/kg, s.c., once a week, started 1 week before surgery) or doxycycline (a metalloproteinase inhibitor) (33 mg/kg, daily gavage) as a control agent. BG incorporation and geometric bone properties were followed by sequential pQCT imaging. The final outcome at 8 weeks was analyzed by digital radiography, histomorphometry, BEI-SEM, EDXA and muCT. The mRNA levels of markers for bone resorption (cathepsin K, TRACP, MMP-9, MMP-13) and synthesis (type I, II, III collagens, osteocalcin, osteonectin, osteopontin) were measured for determination of local bone turnover. Bones filled with BG microspheres produced 2.5-fold more intramedullary new bone than controls with bone marrow ablation only, but the BG filling delayed the recovery of pQCT strength strain index (SSI) of the bones. Adjunct therapy with zoledronic acid enhanced new bone formation on BG microspheres and particularly improved the SSI values of the BG-filled bones (P < 0.05). The zoledronic acid therapy alone (without BG filling) produced the highest amount of intramedullary new bone (6-fold more than in unfilled controls, P < 0.001) but did not show a similar benefit in SSI. The analyses of mRNA expression confirmed high local bone turnover in all bones with BG filling. At the 9th week of zoledronic acid treatment, bones with and without BG filling showed increased mRNA levels of bone resorption markers and decreased mRNA levels of markers for synthesis, indicating that a corrective resorption process was already in progress in response to massive accumulation of medullary new bone at earlier stages of the therapy. Adjunct antiresorptive therapy seems to be beneficial for incorporation of bioactive glass microspheres and does not block local natural remodeling processes. In the current model, the therapy even resulted in favorable remodeling of the tubular bone structure.

Absorptiometry, Photon↗
PubMed2002

Intravenous zoledronic acid in postmenopausal women with low bone mineral density.

BACKGROUND: Bisphosphonates are effective agents for the management of osteoporosis. Their low bioavailability and low potency necessitate frequent administration on an empty stomach, which may reduce compliance. Gastrointestinal intolerance limits maximal dosing. Although intermittent intravenous treatments have been used, the optimal doses and dosing interval have not been systematically explored. METHODS: We studied the effects of five regimens of zoledronic acid, the most potent bisphosphonate, on bone turnover and density in 351 postmenopausal women with low bone mineral density in a one-year, randomized, double-blind, placebo-controlled trial. Women received placebo or intravenous zoledronic acid in doses of 0.25 mg, 0.5 mg, or 1 mg at three-month intervals. In addition, one group received a total annual dose of 4 mg as a single dose, and another received two doses of 2 mg each, six months apart. Lumbar-spine bone mineral density was the primary end point. RESULTS: There were similar increases in bone mineral density in all the zoledronic acid groups to values for the spine that were 4.3 to 5.1 percent higher than those in the placebo group (P<0.001) and values for the femoral neck that were 3.1 to 3.5 percent higher than those in the placebo group (P<0.001). Biochemical markers of bone resorption were significantly suppressed throughout the study in all zoledronic acid groups. Myalgia and pyrexia occurred more commonly in the zoledronic acid groups, but treatment-related dropout rates were similar to that in the placebo group. CONCLUSIONS: Zoledronic acid infusions given at intervals of up to one year produce effects on bone turnover and bone density as great as those achieved with daily oral dosing with bisphosphonates with proven efficacy against fractures, suggesting that an annual infusion of zoledronic acid might be an effective treatment for postmenopausal osteoporosis.

Aged↗
PubMed2005

Additive/synergistic antitumoral effects on prostate cancer cells in vitro following treatment with a combination of docetaxel and zoledronic acid.

Once bone metastasized and androgen independent, prostate cancer is often associated with skeletal morbidity and disability. New treatment modalities that can palliate symptoms from the skeleton and inhibit further progression are warranted. In this study, the antitumoral effects following treatment with a combination of docetaxel and the new generation bisphosphonate, zoledronic acid, were investigated on two hormone-refractory prostate cancer cell lines: PC3 and DU145. The prostate cancer cells were treated with increasing concentrations of zoledronic acid in the absence or presence of docetaxel. Toxicity was measured using fluorometric microculture cytotoxic assay technique. A concentration of 25 microM, zoledronic acid reduced the viable cell number to 68% and 98% for PC3 and DU145 cells respectively. Docetaxel, on the other hand, at a concentration of 0.1 ng/ml, had no effect on the viability. However, a combination of zoledronic acid and docetaxel reduced the cell number to 60% and 81% respectively. Furthermore, zoledronic acid in the concentration range 12.5 microM-50 microM enhanced the antitumoral effects of docetaxel (0.01-1 ng/ml) in an additive and/or synergistic manner for both cell lines. These data support the hypothesis that zoledronic acid, in addition to having bone resorption inhibiting properties, also exhibits anti-tumoral effects. It also appears that combined treatment with docetaxel causes additive and/or synergistic cytostatic effects on prostate cancer cells.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed2003

Zoledronic acid treatment of 5T2MM-bearing mice inhibits the development of myeloma bone disease: evidence for decreased osteolysis, tumor burden and angiogenesis, and increased survival.

Multiple myeloma is characterized by the growth of plasma cells in the bone marrow and the development of osteolytic bone disease. Myeloma cells are found closely associated with bone, and targeting this environment may therefore affect both the bone disease and the growth of myeloma cells. We have investigated the effect of the potent bisphosphonate, zoledronic acid, on the development of bone disease, tumor burden, and disease-free survival in the 5T2MM model of myeloma. 5T2MM murine myeloma cells were injected intravenously into C57BL/KaLwRij mice. After 8 weeks, all animals had a paraprotein. Animals were treated with zoledronic acid (120 microg/kg, subcutaneously, twice weekly) or vehicle, from the time of tumor cell injection or from paraprotein detection for 12 or 4 weeks, respectively. All animals injected with tumor cells developed osteolytic lesions, a decrease in cancellous bone volume, an increase in osteoclast perimeter, and a decrease in bone mineral density. Zoledronic acid prevented the formation of lesions, prevented cancellous bone loss and loss of bone mineral density, and reduced osteoclast perimeter. Zoledronic acid also decreased paraprotein concentration, decreased tumor burden, and reduced angiogenesis. In separate experiments, Kaplan-Meier analysis demonstrated a significant increase in survival after treatment with zoledronic acid when compared with control (47 vs. 35 days). A single dose of zoledronic acid was also shown to be effective in preventing the development of osteolytic bone disease. These data show that zoledronic acid is able to prevent the development of osteolytic bone disease, decrease tumor burden in bone, and increase survival in a model of established myeloma.

Animals↗
PubMed2002

The use of zoledronic acid, a novel, highly potent bisphosphonate, for the treatment of hypercalcemia of malignancy.

BACKGROUND: Hypercalcemia of malignancy is a serious complication of cancer that affects patients with and without bone metastases. A single infusion of pamidronate disodium, a nitrogen-containing bisphosphonate, effectively normalizes serum calcium in the majority of patients treated for up to 1 month. Zoledronic acid is a new-generation, heterocyclic nitrogen-containing bisphosphonate and the most potent inhibitor of bone resorption identified to date. METHODS: The natural history, clinical presentation, and treatment of hypercalcemia of malignancy are reviewed, with a focus on the mechanisms of action and relative efficacy and safety of bisphosphonate therapies. RESULTS: The improved efficacy of zoledronic acid compared with pamidronate disodium has been demonstrated in a pooled analysis of two randomized clinical trials in patients with hypercalcemia of malignancy. In these trials, both zoledronic acid and pamidronate disodium were safe and well tolerated; however, zoledronic acid treatment resulted in a significantly higher number of complete responses, more rapid calcium normalization, and more durable responses compared with pamidronate disodium. CONCLUSIONS: Given the superior efficacy and comparable safety profile of zoledronic acid compared with pamidronate disodium, zoledronic acid is likely to become the treatment of choice for hypercalcemia of malignancy.

Anti-Inflammatory Agents↗
PubMed2005

In vitro comparison of clodronate, pamidronate and zoledronic acid effects on rat osteoclasts and human stem cell-derived osteoblasts.

In the present study we compared the first generation non-nitrogen-containing bisphosphonate, clodronate with second and third generation nitrogen-containing bisphosphonates, pamidronate and zoledronic acid in dynamic rat osteoclast resorption and apoptosis assays and in human mesenchymal stem cell-derived osteoblast assay. We found that due to high bisphosphonate-bone binding affinity, bone surface exposure to clodronate for 3 min. had maximal resorption inhibition. The mechanism of action of both clodronate and zoledronic acid involved osteoclast apoptosis, whereas pamidronate had only minor apoptotic effect at dosages, which readily inhibited resorption. Zoledronic acid was not metabolised into an intracellular ATP-analogue in vitro in contrast to clodronate. All bisphosphonates had a dose-dependent inhibitory effect on the human bone marrow mesenchymal stem cell (hMSC)-derived osteoblast calcium deposition. None of the compounds had inhibitory effect on hMSC differentiation. Zoledronic acid was the most potent of all three bisphosphonates in terms of both apoptosis induction and resorption inhibition. Zoledronic acid efficacy might thus use its capacity to trigger osteoclast apoptosis in an unknown, but similar manner to that of the non-nitrogen-containing bisphosphonates. It appears that zoledronic acid has properties of both bisphosphonate classes and could well be the first member of a new class of bisphosphonates, by definition.

Animals↗