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PubMed2002

The IL-6 receptor super-antagonist Sant7 enhances antiproliferative and apoptotic effects induced by dexamethasone and zoledronic acid on multiple myeloma cells.

Interleukin-6 (IL-6) is the major growth and survival factor for multiple myeloma (MM), and has been shown to protect MM cells from apoptosis induced by a variety of agents. IL-6 receptor antagonists, which prevent the assembly of functional IL-6 receptor complexes, inhibit cell proliferation and induce apoptosis in MM cells. We have investigated whether the IL-6 receptor super-antagonist Sant7 might enhance the antiproliferative and apoptotic effects induced by the combination of dexamethasone (Dex) and zoledronic acid (Zln) on human MM cell lines and primary cells from MM patients. Here we show that each of these compounds individually induced detectable antiproliferative effects on MM cells. Sant7 significantly enhanced growth inhibition and apoptosis induced by Dex and Zln on both MM cell lines and primary MM cells. These results indicate that overcoming IL-6 mediated cell resistance by Sant7 potentiates the effect of glucocorticoides and bisphosphonates on MM cell growth and survival, providing a rationale for therapies including IL-6 antagonists in MM.

Antineoplastic Agents, Hormonal↗

PubMed2002

Bisphosphonates pamidronate and zoledronic acid stimulate osteoprotegerin production by primary human osteoblasts.

Bisphosphonates are potent antiresorptive drugs commonly employed in the treatment of metabolic bone diseases. Despite their frequent use, the mechanisms of bisphosphonates on bone cells have largely remained unclear. Receptor activator of nuclear factor-kappaB ligand (RANKL) is essential for osteoclast formation and activation, whereas osteoprotegerin (OPG) neutralizes RANKL. Various osteotropic drugs have been demonstrated to modulate osteoblastic production of RANKL and OPG. In this study, we assessed the effects of the bisphosphonates pamidronate (PAM) and zoledronic acid (ZOL) on OPG mRNA steady-state levels (by semiquantitative RT-PCR) and protein production (by ELISA) in primary human osteoblasts (hOB). PAM increased OPG mRNA levels and protein secretion by hOB by up to 2- to 3-fold in a dose-dependent fashion with a maximum effect at 10(-6) M (P < 0.001) after 72 h. Similarly, ZOL enhanced OPG gene expression and protein secretion by hOB in a dose-dependent fashion with a maximum effect at 10(-8) M after 72 h, consistent with the higher biological potency of ZOL. Time course experiments indicated a stimulatory effect of PAM and ZOL on osteoblastic OPG protein secretion by 6-fold, respectively (P < 0.001). Pretreatment with PAM and ZOL prevented the inhibitory effects of the glucocorticoid dexamethasone on OPG mRNA and protein production. Analysis of cellular markers of osteoblastic differentiation revealed that PAM and ZOL induced type I collagen secretion and alkaline phosphatase activity by 2- and 4-fold, respectively (P < 0.0001 by ANOVA). In conclusion, our data suggest that bisphosphonates modulate OPG production by normal human osteoblasts, which may contribute to the inhibition of osteoclastic bone resorption. Since, OPG production increases with osteoblastic cell maturation, enhancement of OPG by bisphosphonates could be related to their stimulatory effects on osteoblastic differentiation.

Biomarkers↗

PubMed2005

Osteoclasts but not osteoblasts are affected by a calcified surface treated with zoledronic acid in vitro.

Bisphosphonates are potent inhibitors of osteoclast-mediated bone resorption. Recent interest has centered on the effects of bisphosphonates on osteoblasts. Chronic dosing of osteoblasts with solubilized bisphosphonates has been reported to enhance osteogenesis and mineralization in vitro. However, this methodology poorly reflects the in vivo situation, where free bisphosphonate becomes rapidly bound to mineralized bone surfaces. To establish a more clinically relevant cell culture model, we cultured bone cells on calcium phosphate coated quartz discs pre-treated with the potent nitrogen-containing bisphosphonate, zoledronic acid (ZA). Binding studies utilizing [(14)C]-labeled ZA confirmed that the bisphosphonate bound in a concentration-dependent manner over the 1-50microM dose range. When grown on ZA-treated discs, the viability of bone-marrow derived osteoclasts was greatly reduced, while the viability and mineralization of the osteoblastic MC3T3-E1 cell line were largely unaffected. This suggests that only bone resorbing cells are affected by bound bisphosphonate. However, this system does not account for transient exposure to unbound bisphosphonate in the hours following a clinical dosing. To model this event, we transiently treated osteoblasts with ZA in the absence of a calcified surface. Osteoblasts proved highly resistant to all transitory treatment regimes, even when utilizing ZA concentrations that prevented mineralization and/or induced cell death when dosed chronically. This study represents a pharmacologically more relevant approach to modeling bisphosphonate treatment on cultured bone cells and implies that bisphosphonate therapies may not directly affect osteoblasts at bone surfaces.

3T3 Cells↗

PubMed2004

Health-related quality of life among patients with breast cancer receiving zoledronic acid or pamidronate disodium for metastatic bone lesions.

BACKGROUND: Research on individual differences in health-related quality of life (HRQOL) can identify intervention targets and important covariates in analyses of treatment outcomes. OBJECTIVES: The objectives of this study were to describe HRQOL trajectories for women with metastatic breast cancer in a randomized trial of bisphosphonates and to identify characteristics associated with variations in HRQOL. RESEARCH DESIGN: We conducted a prospective quality-of-life study within a randomized, controlled trial. SUBJECTS: We studied women with metastatic breast cancer receiving zoledronic acid or pamidronate disodium to reduce the incidence of skeletal-related events (SREs). MAIN OUTCOME MEASURES: HRQOL was measured at fixed time points during the trial. Individual growth-curve modeling was used to describe longitudinal trajectories and to identify predictors of trajectories. RESULTS: For most domains of HRQOL, the mean trajectory reflected a mild increase, which leveled off later in the trial. Older age and full-time employment were associated with higher baseline HRQOL. Longer time from cancer diagnosis to randomization, lower Eastern Cooperative Oncology Group (ECOG) status (score of 2 ["inactive"]), and a history of SREs were associated with lower baseline HRQOL. Significant differences across geographic regions were observed for all domains. Active ECOG status (score of 0-1) at baseline was predictive of greater increases in all domains of HRQOL except Social/Family Well-Being. Age, geographic region, and time from first bone metastases to randomization were associated with longitudinal changes in some domains. CONCLUSIONS: Women with metastatic breast cancer receiving bisphosphonates for prevention of SREs experienced an overall increase in HRQOL. Variations among women's experiences are explained partly by such characteristics as a history of SREs.

Bone Neoplasms↗

PubMed2006

Treatment of skeletal Erdheim-Chester disease with zoledronic acid: case report and proposed mechanisms of action.

Erdheim-Chester disease (ECD) is a rare non-Langerhans cell histiocytosis characterized by tissue infiltration of lipid-laden macrophages, multinucleated giant cells, and inflammatory infiltrate of lymphocytes and histiocytes. The disease typically involves long bone, but may also affect the central nervous system, the orbit, retroperitoneal organs, and the lungs. Patients with visceral involvement tend to have poorer outcome. There is no proven effective treatment for ECD to date. However, recent data suggested the potential use of bisphosphonates for the treatment of this rare disease. Here we report a case of biopsy-proven skeletal ECD, who received treatment with zoledronic acid, an aminobisphosphonate, with remarkable clinical improvement. We also discuss possible mechanisms of action of bisphosphonates in this disorder, especially their roles in inhibition of inflammatory cytokines and macrophage infiltration.

Bone Density Conservation Agents↗

PubMed2006

The effect of zoledronic acid on the function and differentiation of myeloid cells.

BACKGROUND AND OBJECTIVES: Bisphosphonates are widely used for treatment of osteoporosis and metastases of the skeletal system. Recent data suggest that bisphosphonates may not only reduce bone loss but also exert direct anti-tumor, anti-angiogenic and E inverted exclamation markE not T-cell activating effects, properties which depend at least partially on their affinity to phagocytosing and antigen-presenting cells (i.e. osteoclasts and monocytes). The latter represent the major source of dendritic cells (DC). Thus, we determined the immunomodulatory properties of zoledronic acid (ZA), a member of the latest generation of bisphosphonates. DESIGN AND METHODS: Primary human monocytes, macrophages, immature and mature dendritic cells were incubated with increasing doses of ZA for subsequent analysis of cell surface marker expression and cytokine production. In addition, phagocytic and allo-stimulatory properties, differentiation capacity, and NF-kB activation were determined. RESULTS: Therapeutic doses of ZA inhibited the in vitro generation of DC from monocytes, as shown by an impaired up-regulation of maturation markers. In parallel, ZA also impaired lipopolysaccharide-induced activation of NF-kB, which represents a critical factor for DC differentiation. Accordingly, the activation of allogeneic T cells by ZA-treated DC in a mixed-lymphocyte reaction was significantly reduced. Finally, ZA inhibited the production of tumor necrosis factor-a in monocyte-derived cells and impaired the phagocytic capacity of macrophages and immature DC. INTERPRETATION AND CONCLUSIONS: Therapeutic doses of ZA modulate monocyte, macrophage and DC function and might thereby modulate immune function.

Antigens, CD↗

PubMed2006

The effect of zoledronic acid and osteoprotegerin on growth of human lung cancer in the tibias of nude mice.

The pathogenesis of bone metastases may require the activation of osteoclasts by tumor-secreted factors, which promote important interactions with the bone microenvironment. We utilized an intratibial model of bone metastasis with bioluminescent imaging (BLI) to measure the effect of osteoclast inhibition on the interaction of human lung cancer cells with bone, and on tumor growth. Mice were injected with luciferase-transduced tumor cells (HARA, human pulmonary squamous carcinoma) and divided into three groups: (1) untreated, (2) twice weekly treatment with the bisphosphonate zoledronic acid (ZOL), or (3) osteoprotegerin (OPG). Histomorphometry and imaging were used to evaluate tumor burden, and parameters of osteoclast activity. Mice in the treated groups had increased bone density and decreased osteoclast numbers in nontumor-bearing tibiae. There was greater than 60% reduction in mean tumor volume in both treatment groups when evaluated by histomorphometry (P = 0.06 [OPG], P = 0.07 [ZOL]). However, bioluminescent imaging failed to show a reduction in tumor burden due to wide variability in the data. Osteoclast numbers along tumor-associated bone were significantly increased compared to tumor-free bone, and were not reduced by either treatment. Plasma calcium concentration was increased in all groups. Plasma tartrate-resistant acid phosphatase 5b was reduced in both treatment groups. Plasma PTHrP was significantly increased in the untreated tumor-bearing group, but was not significantly different in the two treatment groups compared to normal mice. OPG or ZOL did not change tumor cell proliferation, but ZOL increased HARA cell apoptosis. OPG and ZOL reduced tumor growth in the tibiae of treated mice, however, PTHrP production by HARA cells may have resulted in a high concentration in the bone microenvironment, partially overriding the antiosteoclast effects of both OPG and ZOL.

Animals↗

PubMed2006

Zoledronic acid in the management of metastatic bone disease.

Bisphosphonate therapy has become a standard of therapy for patients with malignant bone disease. Moreover, in vivo preclinical and preliminary clinical data suggest that bisphosphonates may prevent cancer treatment-induced bone loss and the onset of malignant bone disease in patients with early-stage cancer. This comprehensive review critically reports the several preclinical evidences of action of bisphosphonates on osteoclasts, lymphocytes and tumour cells. In addition, all the clinical trials evaluating the effects of principal bisphosphonates on skeletal disease progression in patients with breast cancer, prostate cancer, non-small cell lung cancer and other cancers have been reported. Of the available bisphosphonates, intravenous zoledronic acid has demonstrated the broadest clinical activity and is actually approved for the treatment of bone metastases from any solid tumour in many countries. Renal safety is an important consideration for oncologists who are treating patients with bisphosphonates. This issue and the other topics relating to the safety of bisphosphonates are discussed in this review.

Animals↗

PubMed2006

[Treatment of Paget's disease of bone: importance of the zoledronic acid].

Paget's disease is a localised monostotic or polyostotic bone disease of unknown origin. It may be caused by a slow viral infection and/or genetic factors. It is characterised by increased bone remodelling and an initially excessive osteoclastic bone resorption, followed by a secondary increase in osteoblastic activity, leading to replacement of the normal bone by a disorganized, enlarged, and weakened osseous structure prone to deformities and fractures. The disease may be diagnosed by radiography, scintigraphy and biochemical tests. The primary aim of treatment is to reduce pain and risk of developing long-term complications. Potent antiresorptive drugs are now available, which control the increased bone remodelling and have led to a dramatic improvement in treatment. Zoledronic acid, a new generation of bisphosphonates, has the advantage of great potency and long duration of remission and a short infusion time.

Adult↗

PubMed2005

Zoledronic acid exerts its antitumor effect in multiple myeloma interfering with the bone marrow microenvironment.

Multiple myeloma (MM) is a B-cell malignancy characterized by an excess of monotypic plasma cells which localize almost exclusively in the bone marrow provoking bone destruction via the activation of the osteoclasts. The bone marrow microenvironment, mainly through stromal cells, is strictly involved in the evolution of the disease supporting MM cell growth and survival [1]. MM plasma cells reside in the bone marrow by binding to adhesion molecule of extracellular matrix (ECM) and stromal cells. The activation of some signaling pathways within the stromal cells increases the production of several cytokines which in turn favors the myeloma cell proliferation and survival [2-6], and enhance the drug resistance by anti-apoptotic mechanisms [1,7-9]. Novel therapeutic agents target not only the myeloma cells but also the interaction between MM cells and the bone marrow microenvironment [8]. Bisphosphonates (Bps) interfere as well with bone microenvironment inhibiting the survival of stromal cells and hampering the contact between plasma and stromal cells. In this review we will revise preclinical evidences, and the potential mechanisms of the antitumor activity of zoledronic acid.

Animals↗

PubMed2002

The new bisphosphonate, Zometa (zoledronic acid), decreases skeletal complications in both osteolytic and osteoblastic lesions: a comparison to pamidronate.

Bisphosphonates are the treatment of choice for lytic bone lesions associated with breast cancer. In contrast, bone lesions associated with prostate cancer are predominately osteoblastic. Zoledonic acid (Zol) is a new-generation bisphosphonate that is approximately 2-3 orders of magnitude more potent than pamidronate (Pam) in preclinical models and has demonstrated clinical efficacy in patients with both lytic and blastic lesions. Zoledonic acid (4 mg via 15 min infusion) every 3-4 weeks was directly compared to Pam (90 mg via 2 hr infusion) in 767 patients with breast cancer and bone metastases. The primary endpoint was the proportion of patients experiencing a skeletal-related event (SRE) over 13 months. Zoledonic acid was as effective as Pam, and the proportion of Zol-treated patients with an SRE (42% in the hormonal therapy strata and 44% in the chemotherapy strata) was comparable to the original studies comparing Pam to placebo. Among 371 breast cancer patients receiving hormonal therapy, the proportion of patients with an SRE was 47% for Pam vs. 57% for placebo (P = 0.057), and among 380 patients treated with chemotherapy, the proportions with an SRE were 43% for Pam vs. 56% for placebo (P = 0.008) at 12 months. Zoledronic acid (4 mg) has been compared to placebo in a randomized Phase III trial involving 422 men with hormone-refractory prostate cancer metastatic to bone. Zoledonic acid demonstrated a significant advantage over placebo for median time to first SRE (median not reached for Zol vs. 321 days for placebo; P = 0.011), the proportion of patients with an SRE over 15 months (33 vs. 44% for placebo; P = 0.021), and mean skeletal morbidity rate (number of SREs/time, 0.08 vs. 1.49 for placebo; P = 0.006). In addition, the effects of Zol were apparent early. At 3 months, only 12% of Zol-treated patients had an SRE vs. 23% for placebo (P = 0.003), and at 6 months, the proportions were 21 vs. 31% for placebo (P = 0.025). In contrast, a previous study of Pam in 236 prostate cancer patients found that Pam was no more effective than placebo in reducing bone pain or SREs over 6 months. In these studies, Zol was well tolerated with a safety profile similar to other IV bisphosphonates. In conclusion, Zol is the first bisphosphonate to demonstrate efficacy in both lytic and blastic disease. The unique properties of this novel agent should be further explored in future clinical trials.

Adenocarcinoma↗

PubMed2003

Effects of oral UFT combined with or without zoledronic acid on bone metastasis in the 4T1/luc mouse breast cancer.

Bone metastasis is one of the major causes of increased morbidity and eventual mortality in breast cancer patients. Therefore, intervention of bone metastases is one of the important targets in the management of breast cancer. In the present study, we examined the effects of the orally administrable chemotherapeutic agent UFT (a combination of tegafur and uracil at a molar ratio of 1:4) on bone metastases using an animal model of the 4T1/luc mouse breast cancer. The 4T1/luc cells developed spontaneous metastases to bone following orthotopic cell inoculation. Oral daily administration of UFT (20 mg/kg/day) significantly reduced the orthotopic tumor burden; however, the lower dose (15 mg/kg/day) did not. In contrast, histologic examination showed that both doses of UFT significantly suppressed bone metastases in a dose-dependent manner. Since clinical studies have demonstrated that bisphosphonates (BPs), specific inhibitors of osteoclastic bone resorption, are beneficial for breast cancer patients with bone metastases, we next examined the effects of UFT combined with the BP zoledronic acid (ZOL) on established bone metastases. The combination of UFT (20 mg/kg/day) with ZOL (250 microg/kg) caused an enhanced reduction of bone metastases compared with UFT alone. In vitro studies showed that 5-fluorouracil (5-FU), an active metabolite of UFT, and ZOL increased apoptosis in 4T1/luc cells and inhibited osteoclast-like cell formation in an additive fashion. Our results suggest that oral UFT is an effective chemotherapeutic agent for advanced breast cancer accompanying bone metastases and that the combination with BP increases its benefits for bone metastases.

Administration, Oral↗

PubMed2001

Early detection of bone metastases in a murine model using fluorescent human breast cancer cells: application to the use of the bisphosphonate zoledronic acid in the treatment of osteolytic lesions.

A very common metastatic site for human breast cancer is bone. The traditional bone metastasis model requires human MDA-MB-231 breast carcinoma cell inoculation into the left heart ventricle of nude mice. MDA-MB-231 cells usually develop osteolytic lesions 3-4 weeks after intracardiac inoculation in these animals. Here, we report a new approach to study the formation of bone metastasis in animals using breast carcinoma cells expressing the bioluminescent jellyfish protein (green fluorescent protein [GFP]). We first established a subclone of MDA-MB-231 cells by repeated in vivo passages in bone using the heart injection model. On stable transfection of this subclone with an expression vector for GFP and subsequent inoculation of GFP-expressing tumor cells (B02/GFP.2) in the mouse tail vein, B02/GFP.2 cells displayed a unique predilection for dissemination to bone. Externally fluorescence imaging of live animals allowed the detection of fluorescent bone metastases approximately 1 week before the occurrence of radiologically distinctive osteolytic lesions. The number, size, and intensity of fluorescent bone metastases increased progressively with time and was indicative of breast cancer cell progression within bone. Histological examination of fluorescent long bones from B02/GFP.2-bearing mice revealed the occurrence of profound bone destruction. Treatment of B02/GFP.2-bearing mice with the bisphosphonate zoledronic acid markedly inhibited the progression of established osteolytic lesions and the expansion of breast cancer cells within bone. Overall, this new bone metastasis model of breast cancer combining both fluorescence imaging and radiography should provide an invaluable tool to study the effectiveness of pharmaceutical agents that could suppress cancer colonization in bone.

Animals↗

PubMed2006