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PubMedDate not supplied

Comparative evaluation of safety and efficacy of pamidronate and zoledronic acid in multiple myeloma patients (single center experience).

Osteolytic bone destruction, caused by the aberrant production and activation of osteoclasts, results in significant morbidity for patients with multiple myeloma (MM). Pamidronate [(3-amino-1-hydroxypropylidene)-1,1-bis-phosphonate] inhibits osteoclastic activity and reduces bone resorption. A potency of zoledronic acid (2-[imidazol-1-yl]-1-hydroxyethylidene-1,1-bisphosphonic acid, a new third generation bisphosphonate, as inhibitor of resorption was 850-fold greater than pamidronate, as was shown in preclinical models of bone resorption. Randomized, double-blind study was conducted to compare the efficacy and safety of zoledronic acid and pamidronate for treating myeloma bone disease. Since March 1999 the efficacy and safety of pamidronate and zoledronic acid is evaluated in MM patients all receiving anti-myeloma chemotherapy acc. to VMCP/VBAP alternating regimen. Nine patients with stage III myeloma and osteolytic lesions (3 female, 6 male, median age 57 years, range 52-67, with monoclonal protein: IgG-7, IgA-2) were randomly assigned (1:1:1 ratio) to treatment with either 4 or 8 mg of zoledronic acid via 15-minute intravenous infusion or 90 mg of pamidronate via 2-hour intravenous infusion every 3 to 4 weeks for 12 months. All patients have received 500 mg of calcium supplements and 500 IU of vit.D, orally, once daily, for the duration of administration of study medication. In extension phase of the study (June 2000-April 2002) patients did not received bisphosphonates. In 7 patients 18 cycles of assessed treatment was administered to each of them and one patient received 16 cycles. One patient died after receiving of 12 pamidronate therapy cycles at 11 month of the trial duration (and at 49 month since MM diagnosis and anti-tumour treatment). The patient's death occurred during the progression of plasma cell proliferation due to acute left ventricle cardiac failure. During the 12-month-period of bisphosphonate treatment skeletal related events (SRE) and progression of osteolysis occurred with the same frequency in 3 treatment groups. One patient experienced spinal cord compression and received radiation to bone and 2 patients experienced vertebral fracture. Time from study entry to the first SRE was 304 days in pamidronate and 366 and 392 days in 4 and 8 mg zoledronic acid group, respectively. The skeletal morbidity rate was identical in all treatment groups. Single hypocalcemic events occurred in 2 patients, mild hypertransaminasemia was observed in 3, worsening of renal function parameters in 2 patients (transient in one of them). Muscular pain and fever up to 39 degrees C (transient and self-limiting "flu-like" symptoms) occurred in 6 patients after several or some dozens of hours from study drug administration. Adverse events were similar in nature and frequency with zoledronic acid and pamidronate and were experienced by a similar proportion of patients in each treatment group. Median time of patient's observation duration after completing of administered treatment with zoledronic acid and pamidronate amounts to 20 months. At present actual median survival time of analysed patients since MM diagnosis is 42 months, since the beginning of treatment with pamidronate and zoledronic acid--33 months, and since completing treatment--20 months and is similar in 3 treatment groups. As was shown in our single center study in MM patients the safety and efficacy of pamidronate 90 mg and zoledronic acid 4 mg and 8 mg in monthly i.v. infusion are comparable. Thus the recommended dosage of zoledronic acid is 4 mg administered as a 15 minute i.v. infusion at intervals of 3 to 4 weeks.

Aged↗
PubMed2006

Zoledronic acid initiated during the first year of androgen deprivation therapy increases bone mineral density in patients with prostate cancer.

PURPOSE: Androgen deprivation therapy in patients with prostate cancer is associated with bone loss and an increased risk of fractures. Zoledronic acid protects against bone mineral density loss when initiated concurrently with androgen deprivation therapy. We evaluated the effect of zoledronic acid initiated subsequent to androgen deprivation therapy on bone mineral density and biochemical markers of bone turnover. MATERIALS AND METHODS: Patients with prostate cancer without bone metastases who had received androgen deprivation therapy for 12 months or less were randomized to 4 mg zoledronic acid or placebo intravenously every 3 months for 1 year. Patients were stratified according to androgen deprivation therapy duration (less than 6 vs 6 to 12 months). The primary end point was the change in femoral neck and lumbar spine bone mineral density in the 2 groups. The secondary end point was the change in serum bone specific alkaline phosphatase and urine N-telopeptide levels. Total hip bone mineral density was also measured. RESULTS: The 120 patients with prostate cancer received zoledronic acid (61) or placebo (59). Compared with placebo, zoledronic acid increased femoral neck, total hip and lumbar spine bone mineral density yearly by 3.6% (p = 0.0004), 3.8% (p <0.0001) and 6.7% (p <0.0001), respectively. The effects of zoledronic acid on bone mineral density at these 3 sites were not differentiated according to androgen deprivation therapy duration. Additionally, mean bone specific alkaline phosphatase and N-telopeptide levels were decreased in the zoledronic acid group (each p <0.0001) and were increased in the placebo group (p <0.0001 and p = 0.004, respectively). CONCLUSIONS: Zoledronic acid increased bone mineral density and suppressed bone turnover markers in patients with prostate cancer without bone metastases when initiated during year 1 of androgen deprivation therapy.

Adenocarcinoma↗
PubMed2005

[Zoledronic acid in the treatment of prostate cancer].

Zoledronic acid is the most biologically active of all bisphosphonates. Clinical evidence suggests that it acts not only on osteoclasts and bone resorption but that it also displays antitumoral activity, proaptotic activity in synergy with antineoplastic drugs and antiangiogenic activity. Moreover, studies on zoledronic acid have reported that the agent is the only biphosphonate of demonstrated efficacy (vs. placebo) in the treatment of prostate cancer, both at a late stage of disease following bone metastasis (over 5-month delay of first skeletal event and 36% reduction in global risk of skeletal complications) and at bone demineralization in subjects receiving androgenic depletion (overall improvement of 8% in bone mineral density).

Bone Density Conservation Agents↗
PubMed2005

Stimulation of bone formation by zoledronic acid in particle-induced osteolysis.

We investigated the effect of a single subcutaneous dose of zoledronic acid on particle-induced osteolysis and observed excessive regional new bone formation. We utilized the murine calvarial osteolysis model and polyethylene particles in C57BL/J6 mice. Twenty-eight mice were used, seven per group. Specimens were stained with Giemsa dye. The osteoid tissue area was determined. Bone thickness was measured as an indicator of bone growth. Net bone growth was significantly increased in animals with zoledronic acid treatment: 0.02 mm(2)+/-0.03 mm(2) in animals with particle implantation only (group 2), 0.25 mm(2)+/-0.08 mm(2) with particle implantation and zoledronic acid treatment directly after surgery (group 3; p=0.0018), and 0.21 mm(2)+/-0.11 mm(2) with particle implantation and zoledronic acid treatment on the fourth postoperative day (group 4; p=0.0042). The mean bone thickness was 0.2 mm+/-0.04 mm (range 0.17 mm-0.31 mm) in group 1 (sham controls) and 0.16 mm+/-0.02 mm (range 0.14 mm-0.19 mm) in group 2, 0.31 mm+/-0.04 mm (range 0.28 mm-0.39 mm) in group 3, and 0.29 mm+/-0.02 mm (range 0.28 mm-0.34 mm) in group 4. Student's t-test revealed a statistically significant difference between groups 2 and 3 (p=0.00042), and groups 2 and 4 (p=0.0019). In conclusion, our observational study suggests that zoledronic acid may stimulate bone apposition locally in the process of particle-induced osteolysis.

Animals↗
PubMed2001

A microcosting analysis of zoledronic acid and pamidronate therapy in patients with metastatic bone disease.

Our goal was to calculate resource use associated with administration of zoledronic acid, compared with pamidronate, as palliative care for patients with metastatic bone lesions. We conducted a time-and-motion study of therapy administration at each of three outpatient chemotherapy infusion sites participating in clinical trials of zoledronic acid and pamidronate. We developed a data-collection instrument to record all staff effort and patient resource use in drug administration. The main outcome measures were (a) direct costs of therapy administration per patient and (b) opportunity benefits expressed as the availability of resources gained per year. The average visit time for patients receiving the study dose of zoledronic acid, 4 mg, was 1 h, 6 min, compared to 2 h, 52 min for patients receiving a 90-mg dose of pamidronate. Infusion time accounted for much of the difference. In the base-case analysis, total direct costs per patient were $728 for zoledronic acid and $776 for pamidronate. The opportunity benefit for infusion of zoledronic acid vs pamidronate in the base case was 1.8 chairs per day, or 426 chairs per 240-workday year. Results were sensitive to changes in infusion facility size, days of operation, and average number of patients treated. Shorter infusion time associated with the administration of zoledronic acid, compared with pamidronate, yields substantial time savings for patients, as well as opportunity benefits for outpatient oncology facilities.

Antineoplastic Agents↗
PubMedDate not supplied

Zoledronic acid versus pamidronate in the treatment of skeletal metastases in patients with breast cancer or osteolytic lesions of multiple myeloma: a phase III, double-blind, comparative trial.

PURPOSE: Zoledronic acid, a new and more potent bisphosphonate, was compared with pamidronate, the current standard treatment for patients with osteolytic or mixed bone metastases/lesions. PATIENTS AND METHODS: A total of 1,648 patients with either Durie-Salmon stage III multiple myeloma or advanced breast cancer and at least one bone lesion were randomly assigned to treatment with either 4 or 8 mg of zoledronic acid via 15-minute intravenous infusion or 90 mg of pamidronate via 2-hour intravenous infusion every 3 to 4 weeks for 12 months. The primary efficacy endpoint was the proportion of patients experiencing at least one skeletal-related event over 13 months. RESULTS: The proportion of patients with at least one skeletal-related event was similar in all treatment groups. Median time to the first skeletal-related eventwas approximately 1 year in each treatment group. The skeletal morbidity rate was slightly lower in patients treated with zoledronic acid than in those treated with pamidronate, and zoledronic acid (4 mg) significantly decreased the incidence and event rate for radiation therapy to bone, both overall and in breast cancer patients receiving hormonal therapy. Pain scores decreased in all treatment groups in the presence of stable or decreased analgesic use. Zoledronic acid (4 mg) and pamidronate were equally well tolerated; the most common adverse events were bone pain, nausea, fatigue, and fever and < 5% of serious adverse events were related to the study drug. The incidence of renal impairment among patients treated with 4 mg of zoledronic acid via 15-minute infusion was similar to that among patients treated with pamidronate. CONCLUSIONS: Zoledronic acid (4 mg) via 15-minute intravenous infusion was as effective and well tolerated as 90 mg of pamidronate in the treatment of osteolytic and mixed bone metastases/lesions in patients with advanced breast cancer or multiple myeloma. (Can-

Antineoplastic Agents↗
PubMed2005

Pilot studies of the effect of zoledronic acid (Zometa) on tumor-derived cells ex vivo in the ATP-based tumor chemosensitivity assay.

There is debate regarding the direct effect of bisphosphonates against visceral metastases from solid tumors, despite their proven efficacy against the skeletal complications of metastasis. The aim of this study was to determine whether zoledronic acid showed direct activity against five ovarian cell lines and tumor-derived cells, and whether addition of zoledronic acid to cytotoxic agents increased their cytotoxicity. In this study we used a standardized ATP-based tumor chemosensitivity assay (ATP-TCA) to measure the activity of alendronate, clodronate and zoledronic acid in five ovarian carcinoma cell lines and human solid tumors (breast, lung, ovarian, unknown primary carcinoma, and cutaneous and uveal melanoma) (n=34). We also tested the combination of zoledronic acid with paclitaxel and cisplatin in tumor-derived cells. All five cell lines exhibited greater sensitivity to bisphosphonates than the tumor-derived cells and in all five the IC50 for zoledronic acid was less than 4 muM. In the tumor-derived cells, zoledronic acid showed concentration-dependent inhibition with a median IC50 for all tumors tested of 17 muM and evidence of apoptosis (caspase activation). Simultaneous addition of zoledronic acid to cisplatin or paclitaxel showed no major increase in cytotoxicity. We conclude that the activity of bisphosphonates was greater in cell lines than in tumor-derived cells. However, the pattern of activity of bisphosphonates was the same in cell lines and tumor derived cells. This study suggests a direct, or possibly an indirect, effect of zoledronic acid and other nitrogen-containing bisphosphonates against neoplastic cells, but simultaneous addition with cisplatin or paclitaxel does not substantially increase the activity of the cytotoxic agent.

Adenosine Triphosphate↗
PubMed2007

Long-term control of bone turnover in Paget's disease with zoledronic acid and risedronate.

UNLABELLED: A single 5-mg infusion of zoledronic acid restores biochemical markers of bone turnover into the reference range in the majority of patients with Paget's disease and maintains biochemical remission for at least 2 years. This effect is largely independent of pretreatment disease activity and prior bisphosphonate therapy. INTRODUCTION: Zoledronic acid (ZOL) is a potent bisphosphonate that produces a rapid and complete control of the increased bone turnover of Paget's disease. Long-term control of disease activity is an important aim of treatment in the hope that this will reduce the risk of complications such as deformity, fracture, and degenerative joint disease. MATERIALS AND METHODS: This study compares the ability of ZOL 5 mg given as a 15-minute intravenous infusion with risedronate (RIS) 30 mg daily by mouth for 60 days to maintain long-term control of bone turnover. No bisphosphonate was given during the extension study. All patients (n = 296) who achieved a therapeutic response, defined as normalization or a >75% reduction in the total alkaline phosphatase (total ALP) excess above the midpoint of the reference range, were eligible for inclusion. RESULTS: ZOL maintained the mean level of total ALP at the middle of the reference range, whereas those treated with risedronate showed a linear increase in total ALP from the 6-month post-treatment time-point. Both treatments resulted in a linear relationship between the 6-month nadir and 24-month total ALP. The relationship for RIS was shifted upward, showing that for a given level of post-treatment biochemical activity, bone turnover increased with time. This was in contrast to the ZOL-treated patients where total ALP generally remained unchanged over this 18-month extension period. A similar pattern of response was seen with the other bone turnover markers. CONCLUSIONS: ZOL maintains bone turnover within the reference range over 24 months from the initiation of treatment. A reduction in the incidence and severity of long-term complications may require persistent normalization of bone turnover over many years, and this now seems a realistic possibility with ZOL.

Administration, Oral↗
PubMed2006

Combined therapy of Sr-89 and zoledronic acid in patients with painful bone metastases.

PURPOSE: We evaluated the pain response and daily discomfort in patients with painful bone metastases treated by merging 89Sr-chloride and zoledronic acid. The results were compared with those of patients who received 89Sr-chloride or zoledronic acid separately. METHODS: 25 patients (12 women; mean age 65+/-13 years) chronically treated with zoledronic acid underwent bone pain palliation with 150 MBq of 89Sr-chloride at least 6 months later that bisphoshonate therapy started (group A). 13 patients (6 women; mean age 70+/-12 years) received 89Sr-chloride alone (group B) and 11 patients (5 women; mean age 69+/-12 years) were chronically treated and continued to receive only zoledronic acid therapy (group C), both constituted the control groups. Patients kept a daily pain diary assessing both their discomfort and the pain of specific sites by using a visual analog scale (VAS), rating from 0 (no d iscomfort-no pain) to 10 (worst discomfort-pain). These diaries were reviewed weekly for 2 months and three different physicians rated the pain response on a scale of -2 (considerable deterioration) to +2 (considerable improvement). RESULTS: Baseline characteristics were similar in the three groups. The reduction of total discomfort and of bone pain in the group A was significantly greater as compared to group B (P<0.01) and group C (P<0.01). During the monitored period, a significant improvement of clinical conditions was observed in the group A, varying the rate from -1 to 1 as compared to both groups B and C in which the rate changed from -1 to 0. CONCLUSION: Our findings indicate that combined therapy of 89Sr-chloride and zoledronic acid in patients with painful bone metastases is more effective in treating pain and improving clinical conditions than 89Sr-chloride or zoledronic acid used separately.

Aged↗
PubMed2001

The bisphosphonate, zoledronic acid, induces apoptosis of breast cancer cells: evidence for synergy with paclitaxel.

Bisphosphonates are well established in the management of breast-cancer-induced bone disease. Recent studies have suggested that these compounds are effective in preventing the development of bone metastases. However, it is unclear whether this reflects an indirect effect via an inhibition of bone resorption or a direct anti-tumour effect. The breast cancer cell lines, MCF-7 and MDA-MB-231 cells were treated with increasing concentrations of the bisphosphonate, zoledronic acid, for varying time periods, in the presence or absence of paclitaxel. The effects of zoledronic acid were determined by assessing cell number and rate of apoptosis by evaluating changes in nuclear morphology and using a fluorescence nick translation assay. Zoledronic acid caused a dose- and time-dependent decrease in cell number (P< 0.001) and a concomitant increase in tumour cell apoptosis (P< 0.005). Short-term exposure to zoledronic acid was sufficient to cause a significant reduction in cell number and increase in apoptosis (P< 0.05). These effects could be prevented by incubation with geranyl geraniol, suggesting that zoledronic acid-induced apoptosis is mediated by inhibiting the mevalonate pathway. Treatment with zoledronic acid and clinically achievable concentrations of paclitaxel resulted in a 4-5-fold increase in tumour cell apoptosis (P< 0.02). Isobologram analysis revealed synergistic effects on tumour cell number and apoptosis when zoledronic acid and paclitaxel were combined. Short-term treatment with zoledronic acid, which closely resembles the clinical setting, has a clear anti-tumour effect on breast cancer cells. Importantly, the commonly used anti-neoplastic agent, paclitaxel, potentiates the anti-tumour effects of zoledronic acid. These data suggest that, in addition to inhibiting bone resorption, zoledronic acid has a direct anti-tumour activity on breast cancer cells in vitro.

Antineoplastic Agents, Phytogenic↗
PubMed2004

[Separation of zoledronic acid and its related substances by ion-pair reversed-phase high performance liquid chromatography].

A rapid and simple ion-pair reversed-phase high performance liquid chromatographic method (HPLC) has been established for the routine analysis of zoledronic acid and its related substances. The chromatographic conditions were optimized based on the satisfactory separation of zoledronic acid from imidazol-1-ylacetic acid, their retention times and peak shape. The excellent separation of zoledronic acid from its related substances, including the remaining imidazol-1-ylacetic acid used in the synthesis of zoledronic acid and other impurities of oxidation and decomposition, was achieved within 9 min on a Hypersil C8 column with UV detection at 220 nm. The mobile phase was a mixture of methanol (20%) and 5 mmo/L phosphate buffer (80%) that contains 6 mmol/L tetrabutylammonium bromide. The resolution factor of zoledronic acid from its adjacent peak was more than 2.5. This is a simple and rapid method for the routine assay of zoledronic acid.

Chromatography, High Pressure Liquid↗
PubMed2005

The use of zoledronic acid in patients with bone metastases from prostate carcinoma: effect on analgesic response and bone metabolism biomarkers.

Zoledronic acid is a bisphosphonate that is effective in the treatment of complications of metastatic bone disease. We have carried out a perspective study on 24 consecutive patients with prostate cancer metastatic to bone to verify the effect of zoledronic acid on analgesic response and a possible relationship with the levels of bone metabolism biomarkers. Eligibility for this study required prostate cancer patients with metastatic bone disease and pain not controlled by analgesics. Patients were excluded from the study if they were receiving cytotoxic chemotherapy or radiation therapy within three months. Eighteen patients (75%) were considered responder to acid zoledronic, only 6 patients did not respond. Before starting treatment (T0) mean Visual Analogue Scale was 7.8 (SE +/- 0.29), after 1 month therapy (T1) was 3.6 (SE +/- 0.3) and after three months (T2) was 3.1 (SE +/- 0.4) with a significant difference between T0 and T1 (p<0.0005) and between T0 and T2 (p<0.0005). Visual Analogue Scale improvement was positively correlated with decrease of C-telopeptide and bone phosphatase alkaline (p<0.05) serum levels.

Aged↗
PubMed2001

A phase I dose-ranging trial of monthly infusions of zoledronic acid for the treatment of osteolytic bone metastases.

Bisphosphonates are potent inhibitors of bone resorption and provide a therapeutic benefit for patients with bone metastases. Zoledronic acid is a highly potent, nitrogen-containing bisphosphonate. In the present trial, we assessed the safety and tolerability of increasing doses of zoledronic acid and its effects on urinary markers of bone resorption in cancer patients with bone metastases. Fifty-nine cancer patients with bone metastases were enrolled sequentially into one of 8 treatment groups in the core protocol. Each patient received a 5-min i.v. infusion of 0.1, 0.2, 0.4, 0.8, 1.5, 2, 4, or 8 mg zoledronic acid monthly for 3 months. Patients were monitored for clinical findings, adverse events, electrocardiograms, markers of bone resorption, as well as routine hematology, blood chemistries, and urinalysis. Thirty patients who demonstrated a radiographic response to treatment or stable disease in the core protocol were enrolled in a humanitarian extension protocol and continued to receive monthly infusions. Zoledronic acid was well tolerated at all dose levels. Adverse events reported by >10% of patients included skeletal pain, nausea, fatigue, upper respiratory tract infection, constipation, headache, diarrhea, and fever. Three patients in the core protocol and one patient in the extension protocol experienced grade 3 skeletal pain, "flu-like" symptoms, or hypophosphatemia, which were possibly related to treatment; all recovered completely. Adverse events were reported with similar frequency across all of the dosage groups. Zoledronic acid resulted in sustained, dose-dependent decreases in urinary markers of bone resorption. Zoledronic acid was safe and well tolerated and demonstrated potent inhibition of bone resorption.

Adult↗
PubMed2004

Long-term efficacy and safety of zoledronic acid in the treatment of skeletal metastases in patients with nonsmall cell lung carcinoma and other solid tumors: a randomized, Phase III, double-blind, placebo-controlled trial.

BACKGROUND: The authors previously reported the efficacy of a dose of 4 mg of zoledronic acid in reducing skeletal complications in patients with bone metastases secondary to lung carcinoma and other solid tumors (except carcinomas of the breast and prostate). In the current study, they update these results and report the long-term efficacy and safety of 21 months of treatment with zoledronic acid in a randomized, placebo-controlled trial. METHODS: A total of 773 patients were randomized to receive zoledronic acid (4 mg or 8 mg) or placebo via a 15-minute infusion every 3 weeks for 21 months. The 8-mg dose later was reduced to 4 mg (8/4-mg group). The primary efficacy endpoint was the percentage of patients at 21 months with >/= 1 skeletal-related event (SRE) (pathologic fracture, spinal cord compression, radiation therapy to bone, or surgery to bone). Secondary analyses (time to first SRE, annual incidence of SREs, and multiple-event analysis) included hypercalcemia of malignancy. RESULTS: Fewer patients treated with zoledronic acid developed at least 1 SRE at 21 months compared with patients treated with placebo (39% of those treated at the 4-mg dose [P =0.127] and 36% of those treated at the 8/4-mg dose [P = 0.023], compared with 46% of those treated with placebo). Furthermore, 4 mg of zoledronic acid significantly delayed the median time to first SRE (236 days with 4 mg vs. 155 days with placebo; P = 0.009) and significantly reduced the annual incidence of SREs (1.74 per year with the 4-mg dose vs. 2.71 per year with placebo; P = 0.012). Moreover, the 4-mg dose of zoledronic acid was found to reduce the risk of developing a skeletal event by 31% (hazard ratio of 0.693; P = 0.003). Zoledronic acid was found to be well tolerated with long-term use; the most commonly reported adverse events in all treatment groups included bone pain and the transient, acute-phase reactions of nausea, anemia, and emesis. CONCLUSIONS: To the authors' knowledge, zoledronic acid is the first bisphosphonate to demonstrate long-term safety and efficacy in this patient population.

Antineoplastic Agents↗
PubMed2004

Zoledronic acid induces apoptosis and inhibits adhesion to mineralized matrix in prostate cancer cells via inhibition of protein prenylation.

OBJECTIVE: To investigate effects of zoledronic acid on apoptosis and adhesion to mineralized matrix in prostate cancer cells, to quantify these actions, and to elucidate some of the underlying molecular mechanisms, in terms of dependence on caspase activation and involvement of protein prenylation. MATERIALS AND METHODS: DU145 and PC-3 prostate cancer cell lines were used; cells were treated with zoledronic acid, with or without several other reagents, to investigate its mechanism of action. Apoptosis was detected using a cell-death detection enzyme-linked immunosorbent assay. Adhesion was measured by seeding cells onto mineralized dentine inserts for 24 h, and counting cells after washing. RESULTS: Apoptosis depended on time and dose; there was significant apoptosis with higher concentrations of zoledronic acid (100 micromol/L) after 24 h of exposure, and in DU145 cells with concentrations as low as 1 micromol/L after 72 h of exposure. The apoptotic effect was diminished by co-treating with a broad-spectrum caspase inhibitor, Z-VAD-FMK. Zoledronic acid at 1 micromol/L also significantly inhibited cell adhesion to the mineralized matrix. The lipid isoprenoid analogue geranylgeraniol reduced the apoptotic and anti-adhesive effects of zoledronic acid to a greater degree than farnesol. There was also apoptosis and inhibition of adhesion with direct inhibitors of prenylation, e.g. manumycin A and GGTI-298. C3 exoenzyme, an inhibitor of RhoA, inhibited adhesion but did not cause apoptosis. CONCLUSION: Zoledronic acid induces apoptosis in prostate cancer cells via a caspase-dependent mechanism, and at concentrations as low as 1 micromol/L it also inhibits adhesion of cells to mineralized matrix. These effects appear to be exerted via inhibiting G-protein prenylation and in particular geranylgeranylation.

Apoptosis↗
PubMed2002

The effect of bone remodeling inhibition by zoledronic acid in an animal model of cartilage matrix damage.

OBJECTIVE: The purpose of this work was to test the effect of inhibition of bone remodeling, through the use of the bisphosphonate, zoledronic acid, on cartilage matrix damage in an animal model of cartilage matrix damage. DESIGN: New Zealand white rabbits were divided into four groups for treatment purposes: (1) untreated controls; (2) injected into one knee joint with the cartilage matrix degradation enzyme, chymopapain; (3) injected into one knee joint with chymopapain and also given subcutaneous injections of the bisphosphonate, zoledronic acid, three times per week until sacrifice at either day 28 or 56 post-chymopapain-injection; (4) received only the zoledronic acid injections. At sacrifice, the knee joints were examined grossly and histologically, and biochemically for proteoglycan content. Urine samples were analysed, at intervals, for levels of collagen cross-links which are biochemical markers of cartilage and bone. RESULTS: Animals receiving both intraarticular chymopapain injections and subcutaneous zoledronic acid injections displayed a significantly lower degree of grossly and histologically detectable cartilage degeneration on the tibial articular surfaces (the articular surface displaying the greatest degree of degeneration) than did animals only receiving the chymopapain injections. In addition, urinary levels of collagen cross-links for bone and cartilage were significantly higher in those animals only receiving chymopapain injections. CONCLUSION: The bone resorption observed after chymopapain injection into the rabbit knee joint can be inhibited through the use of the bisphosphonate, zoledronic acid. Furthermore, zoledronic acid does not increase the level of cartilage degeneration and appears to provide some level of chondroprotection in this model.

Animals↗
PubMed2005

Zoledronic acid causes enhancement of bone growth into porous implants.

The effect of zoledronic acid on bone ingrowth was examined in an animal model in which porous tantalum implants were placed bilaterally within the ulnae of seven dogs. Zoledronic acid in saline was administered via a single post-operative intravenous injection at a dose of 0.1 mg/kg. The ulnae were harvested six weeks after surgery. Undecalcified transverse histological sections of the implant-bone interfaces were imaged with backscattered scanning electron microscopy and the percentage of available pore space that was filled with new bone was calculated. The mean extent of bone ingrowth was 6.6% for the control implants and 12.2% for the zoledronic acid-treated implants, an absolute difference of 5.6% (95% confidence interval, 1.2 to 10.1) and a relative difference of 85% which was statistically significant. Individual islands of new bone formation within the implant pores were similar in number in both groups but were 69% larger in the zoledronic acid-treated group. The bisphosphonate zoledronic acid should be further investigated for use in accelerating or enhancing the biological fixation of implants to bone.

Animals↗
PubMed2006

[Osteonecrosis of the jaw in patients with multiple myeloma during and after treatment with zoledronic acid].

BACKGROUND AND OBJECTIVE: To analyze the incidence, the clinical features, and the factors associated with the development of osteonecrosis of the jaw (ONJ) in patients with multiple myeloma (MM) treated with zoledronic acid. PATIENTS AND METHODS: Sixty-four patients diagnosed with MM and treated with zoledronic acid between August 1996 and March 2006 were included. Demographic data, predisposing factors, the type of antineoplastic therapy received and the infusions of biophosphonate were recorded. The main characteristics of the seven patients with ONJ, including clinical and physical examinations data, diagnostic methods and treatment established were reported. RESULTS: The overall incidence of ONJ was 7 out of 64 patients (10.93%). A recent oral surgical procedure has been associated with the ONJ (p < 0.0001). The mean of infusions of zoledronic acid before onset of osteonecrosis (standard deviation) was 30 (7.04) in contrast to 19.5 (11.8) cycles (p = 0.03) in the patients who did not present this complication. The cumulative risk increased from 6.7% after 20 treatments with zoledronic acid up to 31.7% at 36 infusions. Three patients exhibited ONJ after discounting zoledronic acid. CONCLUSIONS: The ONJ in patients with MM who underwent dental or oral surgery appears to be associated with long term exposure to zoledronic acid. The long-lasting bone effect of biophosphonate could explain the appearance of osteonecrotic lesions after discontinuing treatment with biphosphonate.

Aged↗