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PubMed2005

Osteonecrosis of jaw in patient with hormone-refractory prostate cancer treated with zoledronic acid.

Intravenous bisphosphonates are widely used in the management of metastatic bone disease, as well as osteoporosis. Recent published reports have documented a possible link between treatment with intravenous bisphosphonates and osteonecrosis of the jaw. We report a case of osteonecrosis of the jaw in 1 patient with prostate cancer receiving both chemotherapy and intravenous zoledronic acid (Zometa). Bisphosphonates have been demonstrated to alter the normal bone microenvironment and appear to have direct effects on tumors as well. These changes may contribute to the development of osteonecrosis of the jaw, particularly after tooth extractions or other invasive dental procedures.

Adenocarcinoma↗
PubMed2006

Anticancer effects of zoledronic acid against human osteosarcoma cells.

Based on neoadjuvant chemotherapy, the prognosis of osteosarcoma patients has improved dramatically. However, due to therapy resistance in patient subgroups, the development of new treatment strategies is still of utmost importance. The aim of our study was to test the effects of the nitrogen-containing bisphosphonate zoledronic acid (ZOL) on osteosarcoma cell lines (N = 9). Exposure to ZOL at low micromolar concentrations induced a dose- and time-dependent block of DNA synthesis and cell cycle progression followed by microfilament breakdown and apoptosis induction. The ZOL-induced cell cycle accumulation in S phase was accompanied by significant changes in the expression of cyclins and cyclin-dependent kinase inhibitors with a prominent loss of cyclin E and D1. ZOL not only inhibited growth but also migration of osteosarcoma cells. The mevalonate pathway intermediary geranyl-geraniol (GGOH) but not farnesol (FOH) significantly inhibited the anticancer effects of ZOL against osteosarcoma cells. Correspondingly, ZOL sensitivity correlated with the blockade of protein geranylgeranylation indicated by unprenylated Rap1. Overexpression of even high levels of P-glycoprotein, as frequently present in therapy-resistant osteosarcomas, did not impair the anticancer activity of ZOL. Summarizing, our data suggest that ZOL, which selectively accumulates in the bone, represents a promising agent to improve osteosarcoma therapy.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed2004

Zoledronic acid up-regulates bone sialoprotein expression in osteoblastic cells through Rho GTPase inhibition.

Clinical practice reveals that osteoporotic women treated with BPs (bisphosphonates) show an increased bone mass density and a reduced risk of fractures. However, the mechanisms leading to these beneficial effects of BPs are still poorly understood. We hypothesized that ZOL (zoledronic acid), a potent third-generation BP, may induce the expression of proteins associated with the bone-forming potential of osteoblastic cells such as BSP (bone sialo-protein). Expression of BSP gene is up-regulated by hormones that promote bone formation and has been associated with de novo bone mineralization. Using real-time reverse transcriptase-PCR and Western-blot analysis, we demonstrated that ZOL increased BSP expression in Saos-2 osteoblast-like cells. Nuclear run-on and mRNA decay assays showed no effect at the transcriptional level but a stabilization of BSP transcripts in ZOL-treated cells. ZOL effect on BSP expression occurred through an interference with the mevalonate pathway since it was reversed by either mevalonate pathway intermediates or a Rho GTPase activator. We showed that ZOL impaired membrane localization of RhoA in Saos-2 cells indicating reduced prenylation of this protein. By the use of small interfering RNAs directed to RhoA and Rac1, we identified both Rho GTPases as negative regulators of BSP expression in Saos-2 cells. Our study demonstrates that ZOL induces BSP expression in osteoblast-like cells through inactivation of Rho GTPases and provides a potential mechanism to explain the favourable effects of ZOL treatment on bone mass and integrity.

Calcification, Physiologic↗
PubMed2005

The bisphosphonate zoledronic acid inhibits the development of plasmacytoma induced in BALB/c mice by intraperitoneal injection of pristane.

OBJECTIVES: Bisphosphonates (BPs) are mostly used in the palliative care of myeloma-associated osteolytic lesions. Recent studies have suggested that BPs may also exert direct antitumor effects on myeloma cells. We have investigated the effect of the potent bisphosphonate, zoledronic acid (ZOL), on the development of pristane (2,6,10,14-tetramethylpentadecane)-induced plasmacytoma (PCT) in six-week-old BALB/c mice. METHODS: Different groups of pristane-treated mice also received ZOL (100 microg/kg) commencing after the development of PCT or ZOL (20 microg/kg) from the first day. Control groups received pristane alone, ZOL alone (20 microg/kg), or phosphate-buffered saline. The study was terminated on day 300, and the remaining mice were autopsied and abdominal tissues were examined histologically for PCT. RESULTS AND CONCLUSIONS: Statistical analysis revealed a significant delay in PCT development in the group receiving pristane plus ZOL (20 microg/kg) from the first day compared to the groups receiving pristane alone and pristane combined with ZOL (100 microg/kg) after the appearance of PCT (Log-rank, P = 0.0001 and 0.0001; respectively). Kaplan-Meier analysis revealed a significant difference in survival between the group treated with pristane alone and the groups receiving pristane plus ZOL (20 microg/kg) from the first day or ZOL (100 microg/kg) after the appearance of PCT (Log-rank, P = 0.016 and 0.023; respectively). These results indicate a direct anti-tumor effect of ZOL in pristane-induced PCT development BALB/c mice, which may contribute to their significantly increased survival. This hypothesis should now be further investigated in clinical trials.

Animals↗
PubMed2006

Assessment of renal toxicity and osteonecrosis of the jaws in patients receiving zoledronic acid for bone metastasis.

BACKGROUND: Bisphosphonates (BP) decrease the incidence of skeletal related events among cancer patients with bone metastases from solid tumors and multiple myeloma. Renal safety and osteonecrosis of the jaws (ONJ) are two major concerns of toxicity. Information about safety of using BP beyond 2 years is scarce. MATERIALS AND METHODS: Patients receiving zoledronic acid (ZA) at the time of the study were reviewed. Serum creatinine levels (SCL) were collected at three different moments: before the start of BP (baseline), at the time of analysis (final), and the highest SCL during the treatment (highest). Oral examination was carried out in every patient. Separated analysis was made for patients on BP for >2 years. Concomitant risk factors for both renal toxicity and ONJ were evaluated. RESULTS: Sixty-seven patients were included. Median time of BP was 22 months, with 22 patients receiving BP for >2 years. Median baseline and final values of SCL were 0.71 mg/dl and 0.70 mg/dl, respectively (P = 0.121). Median highest SCL during treatment was 0.82 mg/dl (P <0.0001). A notable increase in the SCL was observed in six of the 67 patients (9%), four of them receiving BP for >2 years (P = 0.085). ONJ was also diagnosed in six patients, four of them in the group of prolonged BP treatment. CONCLUSION: ZA showed to be safe with a low rate of reversible renal toxicity. Patients receiving BP should be monitored carefully for renal toxicity and ONJ, especially those with exposure to BP beyond 2 years.

Adult↗
PubMed2005

Treatment of Gorham's disease with zoledronic acid.

Gorham's disease (GD) is a rare disorder characterized by spontaneous and progressive osteolysis of one or more bones and thought to belong to lymphangiomatoses spectrum of diseases. Surgical, radiation and medical therapies have been performed with variable and often discouraging outcomes and currently there is no recognized effective treatment. In this paper we describe a 24-year-old girl with GD localized to mandible who was effectively managed with zoledronic acid, a nitrogen-containing high-potency bisphosphonate.

Adult↗
PubMed2006

Administration of zoledronic acid enhances the effects of docetaxel on growth of prostate cancer in the bone environment.

BACKGROUND: After development of hormone-refractory metastatic disease, prostate cancer is incurable. The recent history of chemotherapy has shown that with difficult disease targets, combinatorial therapy frequently offers the best chance of a cure. In this study we have examined the effects of a combination of zoledronic acid (ZOL), a new-generation bisphosphonate, and docetaxel on LuCaP 23.1, a prostate cancer xenograft that stimulates the osteoblastic reaction when grown in the bone environment. METHODS: Intra-tibial injections of LuCaP 23.1 cells were used to generate tumors in the bone environment, and animals were treated with ZOL, docetaxel, or a combination of these. Effects on bone and tumor were evaluated by measurements of bone mineral density and histomorphometrical analysis. RESULTS: ZOL decreased proliferation of LuCaP 23.1 in the bone environment, while docetaxel at a dose that effectively inhibited growth of subcutaneous tumors did not show any effects in the bone environment. The combination of the drugs significantly inhibited the growth of LuCaP 23.1 tumors in the bone. CONCLUSION: In conclusion, the use of the osteolysis-inhibitory agent ZOL in combination with docetaxel inhibits growth of prostate tumors in bone and represents a potential treatment option.

Animals↗
PubMed2006

The use of zoledronic acid for Paget's disease of bone.

Paget's disease of bone is a common skeletal disorder of the elderly that often results in significant morbidity and disability. Although there are a number of oral bisphosphonates currently available for treatment, normalization of biochemical markers of bone turnover with these agents is rarely accomplished due to difficulty with administration, adherence, and possibly resistance to individual bisphosphonates. This paper will focus on zoledronic acid, a potent and easily administered intravenous bisphosphonate that appears to result in a higher percentage of patients with normalization of markers of bone turnover and results in improvements in quality of life in patients with Paget's disease of bone.

Bone Density↗
PubMed2003

The role of intravenous zoledronic acid in the management of high-risk prostate cancer.

PURPOSE OF REVIEW: There are limited effective therapies that would persuade most urologists actively to screen for and treat patients who have developed asymptomatic bone metastases. RECENT FINDINGS: Recently published trials regarding new treatment options for patients with high-risk metastatic prostate cancer are now available, which describe the utility of the intravenous bisphosphonate zoledronic acid. SUMMARY: Prostate cancer is the most common malignancy in men in the United States. Many prostate cancer patients, especially those with aggressive and advanced disease, are at increased risk of developing bone metastases and, subsequently, skeletal-related events. Skeletal-related events may result both from disease and/or treatment of disease, and include bone pain, pathological fractures and spinal cord compressions. Furthermore, bone radiation and surgery to address bone-related pain, prevent pathological fractures and/or spinal cord compression are also considered skeletal-related events. These sequelae of bone metastases are both painful and debilitating, and severely compromise a patient's quality of life.

Animals↗
PubMed2004

Successful treatment of SAPHO syndrome with zoledronic acid.

The SAPHO syndrome (synovitis, acne, pustulosis, hyperostosis, and osteitis) is a chronic, relapsing, inflammatory condition with skin and osteoarticular manifestations. Its etiology remains unclear, and various treatment regimens with steroids and nonsteroidal antiinflammatory drugs frequently fail to control the disease, while exposing patients to the side effects of these drugs. Because the SAPHO syndrome manifests as a destructive inflammatory bone disease, use of bisphosphonates that possess antiosteoclastic and probably antiinflammatory properties has been suggested to be helpful. To our knowledge, this is the first reported case of successful treatment with zoledronic acid of SAPHO syndrome that was resistant to conventional treatment.

Acquired Hyperostosis Syndrome↗
PubMed2004

Zoledronic acid inhibits visceral metastases in the 4T1/luc mouse breast cancer model.

PURPOSE: It is established that bisphosphonates (BPs), specific inhibitors of osteoclasts, have beneficial effects on bone metastases of breast cancer. In addition, recent studies have reported that BPs have anticancer effects and suppress visceral metastases, too. However, the results of clinical studies are still conflicting. In the present study, we examined the effects of the BP zoledronic acid (ZOL), one of the most potent BPs currently available, on visceral metastases of breast cancer using an animal model in which mouse breast cancer cells 4T1/luc implanted at the orthotopic mammary fat pad spontaneously metastasize to multiple organs including bone, lung, and liver in female BALB/c mice. EXPERIMENTAL DESIGN AND RESULTS: The 4T1/luc-bearing mice received single or four i.v. injections of ZOL (0.5 or 5 microg/mouse) during the whole experimental period. Bone metastases were reduced by the ZOL treatment. More importantly, ZOL significantly suppressed lung and liver metastases. Furthermore, ZOL prolonged overall survival of the tumor-bearing mice. Of interest, apoptosis in 4T1/luc cells colonized in bone was increased by ZOL; however, those in lung were not changed. In vitro studies demonstrated that ZOL inhibited cell migration and invasion and promoted apoptosis of 4T1/luc cells. CONCLUSIONS: These results are consistent with the notion that ZOL affects breast cancer metastasis to visceral organs as well as bone. These effects of ZOL may be attributable to inhibition of migration and invasion of breast cancer cells. Clinical relevance of our experimental results needs to be determined in breast cancer patients with visceral metastases.

Animals↗
PubMed2005

In vitro chemosensitivity to gemcitabine, oxaliplatin and zoledronic acid predicts treatment response in metastatic gastric cancer.

Individual response of disseminated cancer to chemotherapy is unpredictable. In vitro chemotherapy-induced apoptosis can be measured and might be a method to evaluate in vivo activity of tested drugs. In this report, tumor cells of a patient with signet cell carcinoma of the stomach and diffuse bone marrow infiltration were cultured and tested for in vitro chemosensitivity. The drugs gemcitabine, oxaliplatin and zoledronic acid were found to induce in vitro tumor cell apoptosis synergistically, and subsequently were used as combination chemotherapy regimen. An initially existing disseminated intravascular coagulopathy quickly resolved and after 6 months of treatment on ongoing complete response was induced, thus confirming the results of in vitro chemosensitivity testing.

Aged↗
PubMed2002

U.S. Food and Drug Administration drug approval summaries: imatinib mesylate, mesna tablets, and zoledronic acid.

The purpose of this report is to summarize information on drugs recently approved by the U.S. Food and Drug Administration. Three drugs have recently been approved: Gleevec (imatinib mesylate) at a starting dose of 400 or 600 mg daily for the treatment of malignant unresectable and/or metastatic gastrointestinal stromal tumors; Mesnex (mesna) tablets as a prophylactic agent to reduce the incidence of ifosfamide-induced hemorrhagic cystitis, and Zometa (zoledronic acid) for the treatment of patients with multiple myeloma and for patients with documented bone metastases from solid tumors, in conjunction with standard antineoplastic therapy. Prostate cancer should have progressed after treatment with at least one hormonal therapy. The recommended dose and schedule is 4 mg infused over 15 minutes every 3-4 weeks. These three drugs represent three different types of drug approval: Gleevec is an accelerated approval and supplemental new drug application (NDA); Mesnex tablets represent an oral formulation of a drug approved 14 years ago as an intravenous formulation, and Zometa represents a standard NDA for a noncytotoxic, supportive-care drug. Information provided includes rationale for drug development, study design, efficacy and safety results, and pertinent literature references.

Antineoplastic Agents↗
PubMed2004

The nitrogen-containing bisphosphonate, zoledronic acid, increases mineralisation of human bone-derived cells in vitro.

Previous studies have attributed the increase in bone mass observed following bisphophonate (BP) therapy to their effects on bone-resorbing osteoclasts (OCs). However, recent evidence suggests that BPs can also act directly on bone forming osteoblasts (OBs) to increase their anabolic activity. Using an established model of in vitro OB differentiation, we found that the potent nitrogen-containing BP, zoledronic acid (ZOL), may enhance the bone forming potential of human adult OB-like cells in vitro by inducing their differentiation. ZOL dose dependently induced both cytostasis and cell death in OB-like cells at concentrations of 0.5 microM or greater. Cells expressing high levels of the osteoprogenitor antigen, STRO-1, exhibited a greater proliferative potential than STRO-1negative/dim cells, and were more susceptible to the cytostatic and apoptotic effects of ZOL. ZOL was also found to promote bone cell differentiation, as evidenced by an increase in the number of cells exhibiting a more differentiated (STRO-1(-)/AP+ and STRO-1(-)/AP-) phenotype. Analysis of gene expression, using semi-quantitative RT-PCR, demonstrated that ZOL treatment resulted in a significant upregulation of osteocalcin (OCN) and bone morphogenetic protein-2 (BMP-2) gene expression. Furthermore, in vitro mineralisation studies revealed that ZOL enhanced mineralised matrix formation at concentrations between 5 and 25 microM. These results show that, in addition to its direct effects on OCs, ZOL also directly affects the proliferation and differentiation of human OB-like cells in vitro and may enhance bone formation in vivo.

Calcification, Physiologic↗
PubMed2006

Zoledronic acid slows down rat primary chondrosarcoma development, recurrent tumor progression after intralesional curretage and increases overall survival.

Chondrosarcoma is a difficult musculoskeletal tumor to treat. Surgical treatment leads to severe disability, with high rates of local recurrence and life threat. No adjuvant therapy is effective in differentiated chondrosarcomas. Bisphosphonates (BPs) are a class of molecules which is effective in malignant bone diseases. The aim of the present study was to determine the effects of zoledronic acid (ZOL) on chondrosarcoma tumor progression. ZOL was tested in vivo (s.c. 100 microg/kg, twice a week) in a rat chondrosarcoma model and in vitro (10(-7)-10(-4) M) on cells derived from this model. Two types of animal models were assessed, the first simulated development after intralesional curettage, the second nonoperative development of the tumor. Cell proliferation, caspase-1, -3 activities and cell cycle analysis were studied. The results revealed that ZOL slows down primary tumor development, tumor progression after intralesional curretage and increases overall survival. ZOL inhibits cell proliferation and increases cell death, with no significant variation of caspase-1 and -3 activities and cell cycle profiles. The present study demonstrates for the first time that in addition to surgery, the therapy of chondrosarcoma with BPs might be beneficial. Because of these first results, new therapeutic approaches of chondrosarcoma must be considered, mainly for low grade chondrosarcoma when disabling operation is planned and when only intralesional resection can be undertaken.

Animals↗
PubMed2005

RAS-blocking bisphosphonate zoledronic acid inhibits the abnormal proliferation and differentiation of juvenile myelomonocytic leukemia cells in vitro.

Juvenile myelomonocytic leukemia (JMML) is a clonal myeloproliferative/myelodysplastic disorder of early childhood with a poor prognosis. JMML cells are characterized by hypersensitivity to granulocyte-macrophage colony-stimulating factor (GM-CSF) caused by a continuously activated GM-CSF receptor-retrovirus-associated sequence (RAS) signal transduction pathway through various molecular mechanisms, resulting in spontaneous GM colony formation in vitro. Bisphosphonate zoledronic acid (ZOL), a RAS-blocking compound, suppressed colony formation from bone marrow (BM) cells of 8 patients with JMML and 5 healthy control subjects without and with GM-CSF (10 ng/mL), respectively, in a dose-dependent manner in clonal culture. At 10 microM ZOL, however, spontaneous GM colony formation from JMML BM cells decreased to 3%, but the formation of G colonies containing granulocytes, but no macrophages, was enhanced, whereas 40% of GM colonies were retained and G colony formation was not affected in culture of normal BM cells with GM-CSF. In suspension culture, cytochemical and flow cytometric analyses showed that 10 microM ZOL also inhibited spontaneous proliferation and differentiation along monocyte/macrophage lineage of JMML BM cells but not the development of normal BM cells by GM-CSF. The inhibitory effect of ZOL on JMML cells was confirmed at a single-clone level and observed even at 3 microM. The current result offers a novel approach to therapy in JMML.

Adolescent↗
PubMed2005

Efficacy of the third-generation bisphosphonate, zoledronic acid alone and combined with anti-cancer agents against small cell lung cancer cell lines.

Small cell lung cancer (SCLC) is one of the most aggressive types of cancers because of its early development of regional and distant metastases. Novel and more effective therapeutic strategies for the treatment of this disease are necessary. Bisphosphonates (BP), originally developed to treat bone disease, have recently been identified as attractive cancer theraptic agents. In this study, we investigated the anti-proliferative effects of zoledronic acid (ZOL) as a single agent and in combination with other agents. ZOL inhibited both farnesylation and geranylgeranylation of RAS related proteins, induced apoptosis and inhibited the growth of eight out of twelve SCLC cell lines examined the in vitro. ZOL also significantly inhibited SCLC tumor growth and SBC-3 cells transplanted subcutaneously into nude mice. Its suppressive effect have not been completed, the addition effect of ZOL with other agents was examined. ZOL augmented the effects of paclitaxel, etoposide, cisplatinum and irinotecan synergistically, and imatinib mesylate additively. These findings indicate that ZOL and combined use of these agents may be promising therapeutic strategies for SCLC.

Animals↗
PubMed2003

The bisphosphonate zoledronic acid induces cytotoxicity in human myeloma cell lines with enhancing effects of dexamethasone and thalidomide.

Bisphosphonates have recently been introduced in the therapeutic armamentarium for long-term treatment of patients with multiple myeloma. These pyrophosphate analogs not only reduce the occurrence of skeletal events but also provide clinical benefit to patients and improve the survival of some of them. The existence of these capabilities raises the possibility that these compounds may have a direct antiproliferative effect on tumor cells. To investigate whether these drugs exert a direct antitumor effect, we exposed human myeloma cell lines ARH-77 and RPMI-8226 to increasing concentrations of zoledronic acid (ZOL) in vitro. A concentration- but not time-dependent cytotoxic effect was detected with drug treatment of ARH-77 and RPMI-8226 cell lines (30% and 60% at 48 hours and 38% and 62% at 72 hours, respectively, for 50 microM of ZOL). Cytotoxicity was not due to ZOL-induced chelation of extracellular calcium as shown by control experiments with the calcium chelator ethylene glycol-bis(beta-aminoethylether)-N,N,N',N'-tetraacetic acid. Addition of the competitive inhibitor of the nitric oxide synthase N omega-nitro-L-arginine methyl ester did not modulate ZOL-induced cytotoxicity. However, a decrease in the number of apoptotic cells was detected when protein kinase C was inhibited by addition of staurosporine to ZOL-containing cultures. Cytotoxicity also was increased by addition of dexamethasone (Dex) and thalidomide (Thal) to ARH-77 and RPMI-8226 cultures. We demonstrated that exposing myeloma cell lines ARH-77 and RPMI-8226 to ZOL inhibits cell growth in a dose-dependent but not a time-dependent manner and that combination of Dex and Thal with ZOL induces apoptotic cell death, providing a rationale for potential applications in vivo.

Antineoplastic Agents↗