Use Of Zoledronic Acid Research Articles

104. Zoledronic acid decreases infection burden in mouse model of spine implant Infection

BACKGROUND CONTEXT Bisphosphonates are commonly used in the orthopedic patient population to manage osteoporosis and other metabolic bone diseases. There is also increasing support for bisphosphonate use in the perioperative setting, to minimize osteolysis and bone loss. Additionally, bisphosphonates are known to affect the host immune system; however, their effect on implant infections, which are notoriously difficult to treat, remains largely unknown. PURPOSE The purpose of this study was to assess the effect of zoledronic acid (ZA) on spinal implant infection in our validated mouse model. METHODS Twenty-six 8-week-old C57BL/6 mice were included in the study. Twelve were treated with 250 ug/kg of ZA,12 with normal saline via retro-orbital injection on the day of surgery, and the remaining 2 were sterile controls. A stainless steel pin was then placed into the L4 spinous processes of all mice and site was inoculated with 1E+3 CFUs of bioluminescent Xen36 Staphylococcus aureus in experimental groups. Infection burden was monitored with in vivo bioluminescence imaging at pre-determined intervals. RESULTS Following an initial similar increase after surgery and inoculation, mice treated with ZA showed a decreased bacterial burden as compared to infected control group (p CONCLUSIONS The indications for ZA use continue to expand, and it is often used in the perioperative setting. In our validated mouse model of spine implant infection, ZA decreases bacterial burden as compared to controls. Further investigation is required to determine the effects of dosing, location of infection and to explore possible mechanisms by which ZA exerts this effect. These findings may suggest a further benefit to bisphosphonate use in the perioperative setting. FDA DEVICE/DRUG STATUS Unavailable from authors at time of publication.

SAT-539 The Utility of Prophylactic Zoledronic Acid in Patients Undergoing Lung Transplantation: A Retrospective Analysis

Purpose Osteoporosis is prevalent among lung transplant candidates and exacerbated post-transplant by immunosuppressive therapy (glucocorticoids and calcineurin inhibitors). Many groups, ours included, prophylactically treat lung transplant recipients with bisphosphonate therapy to prevent bone mineral density (BMD) loss and reduce fracture rates. However, no documented national or international consensus protocols exist to date. Given the early and dose-related fracture increase seen with glucocorticoids, our protocol comprises 6-monthly intravenous zoledronic acid (ZA) from wait-listing to 1 year post-transplant, with interval reassessment to guide ongoing treatment. Use of ZA to protect bone health in transplant recipients has been tested and proven efficacious in liver and bone marrow transplantation, however, its effect in the lung transplant population has not previously been described in the literature. The purpose of our study is to audit the impact of this protocol on BMD and fracture occurrence in lung transplant patients. Methods A retrospective analysis was performed on all adult lung transplant recipients between April 2012 and October 2014. 60 of 142 met inclusion criteria, which included a 3-year follow up period post-transplant with BMD assessment 1) within 24 months pre-transplant and 2) 36-60 months post-transplant. Those who received ZA within 6 months of their transplant as per protocol (n=37) were compared to those who did not (n=23). The outcome measures were change in BMD at the lumbar spine and hip (primary), and fracture occurrence (secondary). Results Primarily due to a non-uniform referral system, 61.7% of patients received ZA as per protocol. The median baseline BMD (g/cm2) in this group was 0.99 (IQR: 0.90-1.08) at the spine and 0.80 (IQR: 0.71-0.93) at the femur, while the non-protocol group had a baseline BMD of 1.08 (IQR:0.99-1.13) and 0.88 (IQR:0.81-0.92), respectively. The protocol treated group experienced a median change in BMD of 8.1% (IQR:-2.8%-10.8%) at the spine and 1.4% (IQR:-4.1%-7.4%) at the femur, compared to -1.2% (IQR:-5.2%-5.9%) and -3.9% (IQR:-8.6%-2.8%), respectively, in the non-protocol group (p=0.003). In the protocol treated group, 6 (16.2%) patients suffered an atraumatic fracture, compared to 7 (30.4%) in the non-protocol group (p=0.22). Fractures in traditional osteoporotic sites accounted for 3 (8.1%) and 5 (21.7%) of these, in the two groups respectively (p=0.24). Despite improvement in BMD there was no significant difference seen in fracture rates, likely due to cohort size. Conclusion Our results suggest that prophylactic ZA in the lung transplant cohort is effective in reducing BMD loss and may reduce fracture rates. Proven benefit of this protocol may influence clinical practice not only at our center but may contribute to an international consensus on the best management of bone health in lung transplant patients.

Outcomes following intravenous bisphosphonate infusion in pediatric patients: A 7-year retrospective chart review.

Intravenous bisphosphonates (IV BP) have been used to treat children with osteoporosis for many years. Favorable side effect profile and improvements in bone mineral density (BMD) have been demonstrated in patients with osteogenesis imperfecta (OI), a primary form of osteoporosis in pediatrics. Less is known about the safety of IV BP in children with secondary osteoporosis or glucocorticoid-induced osteoporosis (GIO). We aimed to determine the prevalence of both acute and long-term side effects and assess the efficacy of IV BP treatment to increase bone mineral density in pediatric patients with varying presentations of compromised bone health. We conducted a retrospective chart review of pediatric patients (<21 years old) treated for osteoporosis with intravenous pamidronate (PAM) or zoledronic acid (ZA) at Cincinnati Children's Hospital Medical Center from 2010 to 2017. Patient demographics, diagnosis, infusion type and dose, acute phase reactions (APR), electrolyte abnormalities, and bone density measurements were collected from the electronic medical records. Diagnoses were grouped into 3 categories: primary osteoporosis, secondary osteoporosis, and GIO. Descriptive characteristics and adverse events were compared among categories. Change in bone mineral density (BMD) over time was compared among groups. 123 patients (56% male) received 942 infusions (83% PAM and 17% ZA). APR was reported in 7% of all infusions and more common in secondary osteoporosis (16%, p < 0.0001). There was a higher percentage of acute adverse events after the first infusion (27% vs 5%, p < 0.0001). Hypocalcemia following IV BP infusions occurred in 7% (27/379) of infusions and was significantly associated with ZA use (p = 0.04). Severity of hypocalcemia was generally mild, requiring intravenous calcium in 3% (13/379) of infusions. Hypophosphatemia occurred frequently, however rarely required intravenous supplementation. In 468 patient years of IV BP exposure, there were no reports of osteonecrosis of the jaw (ONJ) nor atypical femoral fracture (AFF). Lumbar spine (LS) aBMD Z-score 1 year after IV BP initiation increased overall for all groups (p < 0.0001) but did not significantly differ for those who did or did not fracture following IV BP treatment. APR due to intravenous BP treatment for pediatric osteoporosis were infrequent and generally mild. APR were more likely to occur in patients with secondary osteoporosis, a group who may require closer monitoring. A higher proportion of hypophosphatemia occurred in the patients with GIO. Long-term serious adverse events including ONJ and AFF were not identified in our patient population. LS aBMD Z-score increased following initiation of IV BP. However, the change in BMD was not associated with risk of fracture during the follow-up interval. These data provide reassurance and suggest that IV BP can be safely used in pediatric patients with osteoporosis.

Zoledronic acid renders human M1 and M2 macrophages susceptible to V\u03b42+ \u03b3\u03b4 T cell cytotoxicity in a perforin-dependent manner

Vδ2+ T cells are a subpopulation of γδ T cells in humans that are cytotoxic towards cells which accumulate isopentenyl pyrophosphate. The nitrogen-containing bisphosphonate, zoledronic acid (ZA), can induce tumour cell lines to accumulate isopentenyl pyrophosphate, thus rendering them more susceptible to Vδ2+ T cell cytotoxicity. However, little is known about whether ZA renders other, non-malignant cell types susceptible. In this study we focussed on macrophages (Mϕs), as these cells have been shown to take up ZA. We differentiated peripheral blood monocytes from healthy donors into Mϕs and then treated them with IFN-γ or IL-4 to generate M1 and M2 Mϕs, respectively. We characterised these Mϕs based on their phenotype and cytokine production and then tested whether ZA rendered them susceptible to Vδ2+ T cell cytotoxicity. Consistent with the literature, IFN-γ-treated Mϕs expressed higher levels of the M1 markers CD64 and IL-12p70, whereas IL-4-treated Mϕs expressed higher levels of the M2 markers CD206 and chemokine (C–C motif) ligand 18. When treated with ZA, both M1 and M2 Mϕs became susceptible to Vδ2+ T cell cytotoxicity. Vδ2+ T cells expressed perforin and degranulated in response to ZA-treated Mϕs as shown by mobilisation of CD107a and CD107b to the cell surface. Furthermore, cytotoxicity towards ZA-treated Mϕs was sensitive—at least in part—to the perforin inhibitor concanamycin A. These findings suggest that ZA can render M1 and M2 Mϕs susceptible to Vδ2+ T cell cytotoxicity in a perforin-dependent manner, which has important implications regarding the use of ZA in cancer immunotherapy.

Yearly Long-Acting Zoledronic Acid (Reclast) Is Safe and Effective for Treatment of Bone Loss after Hematopoietic Stem Cell Transplantation

Background:With growing numbers of hematopoietic stem cell transplantation (HSCT) survivors due to more widespread use and better long-term outcomes, recognition and treatment of long-term complications of HSCT is important. Bone demineralization with resultant osteopenia and osteoporosis is one such common long-term complication with reported incidence of up to 50% of allogeneic HSCT survivors. Known risk factors include large cumulative doses of glucocorticoids, total body irradiation, calcineurin inhibitors and graft versus host disease, placing them at higher risk of developing bone demineralization compared to the general population. Zoledronic acid (ZA) is a long acting bisphosphonate which has not been well studied in the HSCT population for the treatment of bone loss. We hypothesize that the use of ZA in the post-HSCT setting is safe and effective in preserving bone density.Methods:We performed a retrospective IRB approved study evaluating patients after allogeneic HSCT at Vanderbilt University Medical Center (VUMC) from January 1, 2000 to December 31, 2015 who had evidence of bone demineralization and were treated with ZA. The patients who survived more than a year and who had surveillance dual-energy X-ray absorptiometry (DXA) scans following HSCT were selected for analysis. ZA (Reclast, 5 mg intravenous, Norvatis Pharmaceuticals Corp., Basel, Switzerland) was administered once yearly when the BMD from the DXA scan showed evidence of osteopenia (T-score -1 to -2.5) or osteoporosis (T-score < -2.5). BMD measurements, Z-scores, and T-scores were obtained for the lumbar spine and femur neck within 1 year after transplant and then every 2 to 3 years thereafter for surveillance. Stabilization was determined to be minimal change in the bone mineral density pre and post ZA ± 0.010.Results:A total of 564 patients were analyzed with 132 patients receiving ZA in the designated time frame. Of those patients, 56 patients had received surveillance DXA monitoring pre and post administration of ZA. Patients received between one to six doses of ZA with median three doses. In this patient population, 27 (48.2%) patients had improvement in BMD over the course of surveillance. 22 (39.3%) patients had stabilization in BMD and only 7 (12.5%) had had progressive bone loss despite being on ZA at a median of two years after starting ZA. All patients with progressive bone loss have been on two or more immunosuppressive therapy regimens including daily steroids for chronic GVHD. The average BMD of the lumbar spine prior to ZA was 1.036 ± 0.119 (Z-score -1.11 ± 1.07, T-score -1.46 ± 0.89) and after was 1.094 ± 0.114 (Z-score -0.46 ± 1.14; p = 0.01, T-score -0.94 ± 0.91; p = 0.02). The average BMD of the femur prior to ZA was 0.795 ± 0.106 (Z-score -1.10 ± 0.97, T-score -1.93 ± 0.89) and after was 0.791 ± 0.116 (Z-score -0.5 ± 1.11; p = 0.06, T-score -0.97 ± 0.90; p = 0.05). This shows that there was on average an improvement of BMD in the lumbar spine and stabilization of the femur hip BMD. ZA was generally well tolerated with one (0.8%) patient developing dyspepsia, one (0.8%) developing jaw pain without evidence of osteonecrosis of the jaw, and one (0.8%) patient developing bone pain after ZA administration. No patients developed renal dysfunction or osteonecrosis of the jaw as a result of ZA. Two patients did develop asymptomatic compression fractures while on treatment with ZA that were monitored and did not require surgical management.Conclusions:Yearly administration of a single dose of ZA is a safe and convenient intervention for the treatment of bone loss after HSCT. The majority of patients experienced either improvement or stabilization of their bone loss after receiving ZA. Prospective large-scale studies are needed to evaluate the efficacy of ZA for the prevention and treatment of bone loss in the HSCT population. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

TRAPEZE: a randomised controlled trial of the clinical effectiveness and cost-effectiveness of chemotherapy with zoledronic acid, strontium-89, or both, in men with bony metastatic castration-refractory prostate cancer

Bony metastatic castration-refractory prostate cancer is associated with a poor prognosis and high morbidity. TRAPEZE was a two-by-two factorial randomised controlled trial of zoledronic acid (ZA) and strontium-89 (Sr-89), each combined with docetaxel. All have palliative benefits, are used to control bone symptoms and are used with docetaxel to prolong survival. ZA, approved on the basis of reducing skeletal-related events (SREs), is commonly combined with docetaxel in practice, although evidence of efficacy and cost-effectiveness is lacking. Sr-89, approved for controlling metastatic pain and reducing need for subsequent bone treatments, is generally palliatively used in patients unfit for chemotherapy. Phase II analysis confirmed the safety and feasibility of combining these agents. TRAPEZE aimed to determine the clinical effectiveness and cost-effectiveness of each agent. Patients were randomised to receive six cycles of docetaxel plus prednisolone: alone, with ZA, with a single Sr-89 dose after cycle 6, or with both. Primary outcomes were clinical progression-free survival (CPFS: time to pain progression, SRE or death) and cost-effectiveness. Secondary outcomes were SRE-free interval (SREFI), total SREs, overall survival (OS) and quality of life (QoL). Log-rank test and Cox regression modelling were used to determine clinical effectiveness. Cost-effectiveness was assessed from the NHS perspective and expressed as cost per additional quality-adjusted life-year (QALY). An additional analysis was carried out for ZA to reflect the availability of generic ZA. 757 randomised (median age 68.7 years; Eastern Cooperative Oncology Group scale score 0, 40%; 1, 52%; 2, 8%; prior radiotherapy, 45%); median prostate-specific antigen 143.78 ng/ml (interquartile range 50.8-353.9 ng/ml). Stratified log-rank analysis of CPFS was statistically non-significant for either agent (Sr-89, p = 0.11; ZA, p = 0.45). Cox regression analysis adjusted for stratification variables showed CPFS benefit for Sr-89 [hazard ratio (HR) 0.845, 95% confidence interval (CI) 0.72 to 0.99; p = 0.036] and confirmed no effect of ZA (p = 0.46). ZA showed a significant SREFI effect (HR 0.76; 95% CI 0.63 to 0.93; p = 0.008). Neither agent affected OS (Sr-89, p = 0.74; ZA, p = 0.91), but both increased total cost (vs. no ZA and no Sr-89, respectively); decreased post-trial therapies partly offset costs [net difference: Sr-89 £1341; proprietary ZA (Zometa(®), East Hanover, NJ, USA) £1319; generic ZA £251]. QoL was maintained in all trial arms; Sr-89 (0.08 additional QALYs) and ZA (0.03 additional QALYs) showed slight improvements. The resulting incremental cost-effectiveness ratio (ICER) for Sr-89 was £16,590, with £42,047 per QALY for Zometa and £8005 per QALY for generic ZA. Strontium-89 improved CPFS, but not OS. ZA did not improve CPFS or OS but significantly improved SREFI, mostly post progression, suggesting a role as post-chemotherapy maintenance therapy. QoL was well maintained in all treatment arms, with differing patterns of care resulting from the effects of Sr-89 on time to progression and ZA on SREFI and total SREs. The addition of Sr-89 resulted in additional cost and a small positive increase in QALYs, with an ICER below the £20,000 ceiling per QALY. The additional costs and small positive QALY changes in favour of ZA resulted in ICERs of £42,047 (Zometa) and £8005 for the generic alternative; thus, generic ZA represents a cost-effective option. Additional analyses on the basis of data from the Hospital Episode Statistics data set would allow corroborating the findings of this study. Further research into the use of ZA (and other bone-targeting therapies) with newer prostate cancer therapies would be desirable. Current Controlled Trials ISRCTN12808747. This project was funded by the NIHR Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 20, No. 53. See the NIHR Journals Library website for further project information.

The miR-21/PTEN/Akt signaling pathway is involved in the anti-tumoral effects of zoledronic acid in human breast cancer cell lines.

Preclinical data indicate a direct anti-tumor effect of zoledronic acid (ZA) outside the skeleton, but its molecular mechanism is still not completely clarified. The aim of this study was to investigate the anti-cancer effects of ZA in human breast cancer cell lines, suggesting that they may in part be mediated via the miR-21/PTEN/Akt signaling pathway. The effect of ZA on cell viability was measured by MTT assay, and cell death induction was analyzed using either a double AO/EtBr staining and M30 ELISA assay. A Proteome Profiler Human Apoptosis Array was executed to evaluate the molecular basis of ZA-induced apoptosis. Cell cycle analysis was executed by flow cytometry. The effect of ZA on miR-21 expression was quantified by qRT-PCR, and the amount of PTEN protein and its targets were analyzed by Western blot. ZA inhibited cell growth in a concentration- and time-dependent manner, through the activation of cell death pathways and arrest of cell cycle progression. ZA downregulated the expression of miR-21, resulting in dephosphorilation of Akt and Bad and in a significant increase of p21 and p27 proteins expression. These results were observed also in MDA-MB-231 cells, commonly used as an experimental model of bone metastasis of breast cancer. This study revealed, for the first time, an involvement of the miR-21/PTEN/Akt signaling pathway in the mechanism of ZA anti-cancer actions in breast cancer cells. We would like to underline that this pathway is present both in the hormone responsive BC cell line (MCF-7) as well as in a triple negative cell line (MDA-MB-231). Taken together these results reinforce the use of ZA in clinical practice, suggesting the role of miR-21 as a possible mediator of its therapeutic efficacy.

Zoledronic acid induces dose-dependent increase of antigen-specific CD8 T-cell responses in combination with peptide/poly-IC vaccine

Zoledronic acid (ZA) is used for treating osteoporosis and for preventing skeletal fractures in cancer patients suffering from myeloma and prostate cancer. It is also reported to directly induce cancer cell apoptosis and indirectly modulate T-cell immune response as an antitumor agent. In this study, the effect of ZA following peptide/polyinosinic–polycytidylic acid (poly-IC) vaccination was investigated in a murine tumor model. The combination of ZA with peptide/poly-IC vaccine showed a synergistic effect on the induction of antigen-specific CD8 T-cell response. Three consecutive intravenous administrations of ZA was defined to induce the highest CD8 T-cell response. Further, total splenocyte counts and antigen-specific CD8 T-cell response gradually increased depending on the dose of ZA. In tumor-bearing mice, ZA showed a dose-dependent decrease of growth and prolonged survival. Treatment with ZA only decreased the number of CD11b+Gr1+ myeloid cells in blood. Our results demonstrate that the use of ZA could improve antitumor immune responses induced by the peptide/poly-IC vaccine.

A Case of Severe, Prolonged, Refractory Hypophosphatemia After Zoledronic Acid Administration

Zoledronic acid (ZA) administration has been associated with electrolyte abnormalities, including hypocalcemia, hypomagnesemia, hypokalemia, and hypophosphatemia. We describe a case of severe, refractory hypophosphatemia in a patient who received ZA for hypercalcemia of malignancy (HCM). Little data are available that describe the incidence or degree of severity of hypophosphatemia that can occur following ZA administration. In addition, no formal recommendations exist to guide monitoring for or management of electrolyte derangements in the setting of bisphosphonate use. Our patient required daily, high-dose phosphorus replacement beginning day 4 following ZA administration. The average daily dose of phosphorus, including both intravenous and enteral administration, was highest in the first 2 weeks after ZA, averaging 77 mmol/d days 4 through 15, and does not include sources of phosphorus from the patient’s nutrition support. Despite this high amount of supplementation, which was well beyond what meets normal daily requirements and the amount expected to treat “usual” hypophosphatemia, the patient did not achieve sustained normal serum phosphorus levels for over 30 days after ZA. ZA is a favorable option for treating HCM because of its longer duration of action, potent serum calcium-lowering effects, and favorable safety profile. The risk of hypophosphatemia with ZA use is reviewed.

Dose-dependent inhibitory effects of zoledronic acid on osteoblast viability and function in vitro

Zoledronic acid (ZA), which is one of the most potent and efficacious bisphosphonates, has been commonly used in clinical practice for the treatment of various bone disorders. The extensive use of ZA has been associated with increasing occurrence of jaw complications, now known as bisphosphonate-associated osteonecrosis of the jaw (BRONJ). However, the mechanism underlying BRONJ remains to be fully elucidated. The aim of the present study was to investigate the effects of different concentrations of ZA on the MC3T3-E1 murine preosteoblast cell line cells and examine the possible pathogenesis of BRONJ. In the present study, the effect of ZA on the viability, apoptosis, differentiation and maturation of MC3T3-E1 cells, as well as its relevant molecular mechanism, were examined The results of a Cell Counting Kit 8 assay, a flow cytometric Annexin-V/propidium iodide assay and western blot analysis demonstrated that ZA exhibited a significant inhibition of cell viability and induction of apoptosis at concentrations >10 µM. Subsequently, the effect of ZA on cell differentiation at concentrations <1 µM were investigated. In this condition, ZA inhibited bone nodule formation and decreased the activity of alkaline phosphatase. The results of reverse transcription-quantitative polymerase chain reaction and western blot analyses indicated that ZA downregulated the expression levels of the marker genes and proteins associated with osteogenic differentiation. Further investigation revealed that the suppression of differentiation by ZA was associated with decreased expression of bone morphogenetic protein-2 (BMP-2) and downregulation of the phosphorylation levels in the downstream extracellular signal-regulated kinase 1/2 and p38 pathways. These adverse effects of ZA were observed to be concentration-dependent. The results from the present study suggested that ZA at higher concentrations induces cytotoxicity towards osteoblasts, and ZA at lower concentrations suppresses osteoblast differentiation by downregulation of BMP-2. These results assist in further understanding the mechanisms of BRONJ.

Osteoporosis treatment with zoledronic acid in pediatric population at a university hospital in Western Saudi Arabia. A 13-year experience.

Objectives:To highlight the clinical benefit, efficacy, and safety of zoledronic acid (ZA) therapy in children and adolescents with primary and secondary osteoporosis.Methods:This is a retrospective observational study of 131 children and adolescents visiting the Pediatric Endocrine Clinic at King Abdulaziz University Hospital, Jeddah, Kingdom of Saudi Arabia, between January 2002 and January 2015. Clinical and laboratory data were collected for each patient and adverse events were evaluated.Results:The mean patient age was 11.43 years. There was a significant decrease in the number of fractures after ZA treatment for primary osteoporosis (p=0.000) and in secondary osteoporosis (p=0.005). There was a significant decrease in both osteocalcin (p=0.001) and C-terminal telopeptide (p=0.003) in patients with primary osteoporosis, as well as osteocalcin (p=0.003) and C-terminal telopeptide (p=0.008) in patients with secondary osteoporosis after treatment.Conclusion:The use of ZA in children and adolescent appears to have favorable effects on fracture rate and quality of life, including pain and mobility in symptomatic individuals. Intravenous ZA is comparable to other bisphosphonate agents in its efficacy and safety and features a more convenient infusion protocol with no documented long-term complications, thus, we advise its use in pediatric population.

Changes in cortical bone channels network and osteocyte organization after the use of zoledronic acid.

The aim of this study was to evaluate the effects of zoledronic acid (ZA) on the cortical bone channels network (CBCN) and osteocyte organization in relation to the bone channels. Eighteen male Wistar rats were divided into control (CG) and test groups (TG). Twelve animals from TG received 3 ZA doses (7.5 µg/kg), and 6 animals from CG did not receive any medication. TG animals were euthanized at 14 (n = 6) and 75 (n = 6) dadys after drug injection. CBCN was analyzed in mandibles and tibias using computational routines. The osteocyte organization was qualitatively evaluated in tibias using a three-dimensional reconstruction of images from serial histological sections. Significant differences in CBCN of tibia were found between the treated and untreated rats, with a wider range of sizes and shapes of the channels after the use of ZA (channels area p = 0.0063, channels area SD p = 0.0276) and less bone matrix (bone volume p = 0.0388). The alterations in the channels' morphology were more evident at 75 days after the drug injection (channels perimeter p = 0.0286). No differences were found in mandibles CBCN. The osteocyte distribution revealed more variable patterns of cell distribution in ZA groups, with non-homogeneous distribution of cells in relation to the bone channels. Zoledronic acid induces structural changes in CBCN and modifies the osteocyte arrangement in cortical bone in the tibia; also, the variability in the morphology of bone channels became more evident after a certain time of the use of the drug.

A phase III, multicenter, randomized, controlled study of maximum androgen blockade with versus without zoledronic acid in treatment-naïve prostate cancer patients with bone metastases: Results of ZAPCA study.

150 Background: Zoledronic acid (ZA) is proved to be useful for the prevention of skeletal-related events (SREs) in men with castration-resistant prostate cancer and bone metastases, but its early use combined with androgen deprivation therapy (ADT) in men with hormonal treatment-naïve prostate cancer and bone metastases is controversial. Methods: A total of 227 men with hormonal treatment-naïve prostate cancer and bone metastases were randomly assigned in a 1:1 ratio to receive zoledronic acid (4mg intravenously every 4 weeks up to 2 years) along with ADT (LH-RH analogue + bicalutamide, MZ group) or ADT alone (MAB group). Stratification factors were PSA (&lt;200ng/ml vs. ≥200ng/ml), EOD (extent of diseases) grade (1,2 vs. 3,4) and Gleason score (&lt;7 vs. ≥8). The primary end point was time to treatment failure (TTTF), defined as 3 consecutive rise of PSA from the nadir, clinical progression, SRE, death or cessation of protocol therapy for any reason. Results: The median follow-up was 41.1 months. The median TTTF was 12.4 months in MZ group (95% CI, 10.6 to 16.6) and 9.7 months in MAB group (95% CI, 8.9 to 12.6; hazard ratio, 0.754; 95% CI, 0.567 to 1.003; log-rank P= .051). In a subset of men with baseline PSA levels &lt;200ng/mL, the median TTTF was 23.7 months in MZ group (95% CI, 15.2 to 31.3) and 9.8 months in MAB group (95% CI, 6.6 to 17.0; hazard ratio, 0.575; 95% CI, 0.354 to 0.933; log-rank P= .023). An exploratory multivariate analysis using Cox proportional hazards model identified MZ group, age less than 80, and EOD ≤2 as independent factors associated with better TTTF. Conclusions: In men with hormonal treatment naïve prostate cancer with bone metastases, concurrent use of ZA with ADT did not show a significant advantage over ADT alone regarding TTTF. However, in a subgroup of men with lower baseline PSA levels, ZA significantly prolonged TTTF, compared with ADT alone. Clinical trial information: NCT00685646.

Bisphosphonate-adsorbed ceramic nanoparticles increase bone formation in an injectable carrier for bone tissue engineering

Sucrose acetate isobutyrate (SAIB) is a sugar-based carrier. We have previously applied SAIB as a minimally invasive system for the co-delivery of recombinant human bone morphogenetic protein-2 (rhBMP-2) and found synergy when co-delivering zoledronic acid (ZA) and hydroxyapatite (HA) nanoparticles. Alternative bioceramics were investigated in a murine SAIB/rhBMP-2 injection model. Neither beta-tricalcium phosphate (TCP) nor Bioglass (BG) 45S5 had a significant effect on bone volume (BV) alone or in combination with the ZA. 14C-labelled ZA binding assays showed particle size and ceramic composition affected binding with nano-HA > micro-HA > TCP > BG. Micro-HA and nano-HA increased BV in a rat model of rhBMP-2/SAIB injection (+278% and +337%), and BV was further increased with ZA–adsorbed micro-HA and nano-HA (+530% and +889%). These data support the use of ZA–adsorbed nanoparticle-sized HA as an optimal additive for the SAIB/rhBMP-2 injectable system for bone tissue engineering.

Zoledronic acid causes γδ T cells to target monocytes and down‐modulate inflammatory homing

Zoledronic acid (ZA) is a potential immunotherapy for cancer because it can induce potent γδ T-cell-mediated anti-tumour responses. Clinical trials are testing the efficacy of intravenous ZA in cancer patients; however, the effects of systemic ZA on the activation and migration of peripheral γδ T cells remain poorly understood. We found that γδ T cells within ZA-treated peripheral blood mononuclear cells were degranulating, as shown by up-regulated expression of CD107a/b. Degranulation was monocyte dependent because CD107a/b expression was markedly reduced in the absence of CD14(+) cells. Consistent with monocyte-induced degranulation, we observed γδ T-cell-dependent induction of monocyte apoptosis, as shown by phosphatidylserine expression on monocytes and decreased percentages of monocytes in culture. Despite the prevailing paradigm that ZA promotes tumour homing in γδ T cells, we observed down-modulation of their tumour homing capacity, as shown by decreased expression of the inflammatory chemokine receptors CCR5 and CXCR3, and reduced migration towards the inflammatory chemokine CCL5. Taken together our data suggest that ZA causes γδ T cells to target monocytes and down-modulate the migratory programme required for inflammatory homing. This study provides novel insight into how γδ T cells interact with monocytes and the possible implications of systemic use of ZA in cancer.

Efficacy of combined androgen blockade with zoledronic acid treatment in prostate cancer with bone metastasis: The Zoledronic Acid/Androgen Blockade Trial on Prostate Cancer (Zabton-PC) study.

207 Background: Zoledronic acid (ZA) reduces the onset risk of skeletal-related events (SRE) caused by bone metastasis in prostate cancer (PCa) patients and improves the QOL. Therefore ZA has become a standard supportive therapy for PCa with bone metastasis. However, it remains unclear when the physicians should start ZA treatment. In the present study, we investigated whether combination of ZA could delay PSA relapse of PCa and prevent SREs. Methods: The patients were randomly classified in two groups (combined androgen blockade (CAB) alone group and CAB + ZA treatment group). In the CAB + ZA group, 4 mg ZA was intravenously administered every 4 weeks with the start of treatment. The first end point was a period to PSA relapse, and the secondary end point was SREs rate. Results: Untreated 60 PCa patients with bone metastasis were enrolled by 2011 from 2006. Thirty one patients were treated with CAB alone and 29 patients were treated with CAB + ZA. There were no significant differences in the baseline characteristics in the both groups, and the mean observation period was 27.4 months and 32.1 months, respectively. Although there was no significant difference in progression free survival (PFS) (p=0.073), tendency that CAB + ZA shows better PFS than CAB alone group was observed (time to 50% PFS was extended 11.6 months than CAB alone group). Moreover, the sub analysis using the patients with more than Gleason score 7, CAB +ZA group showed significantly longer PFS than the CAB group (p=0.021). And statistically significant difference was recognized in SRE rate between the two groups (p=0.019), ZA tended to delay the occurrence of SRE in PCa patients. Conclusions: This result indicates that the use of ZA at the beginning of hormonal therapy have not only a preventive effect on the occurrence of SREs but also a relapse-delaying effect, especially in the patients with high Gleason score and severe bone metastasis. Though careful observation is essential, since the long-term use of ZA may increase the incidence of adverse effects, CAB-ZA treatment may be recommended for the treatment of PCa patients with bone metastasis.

Survival benefit of zoledronic Acid in postmenopausal breast cancer patients receiving aromatase inhibitors.

PurposeA growing body of evidence indicates that zoledronic acid (ZA) can improve the clinical outcome in patients with breast cancer and low estrogen levels. In the present study, we aimed to investigate the survival benefit of ZA administration in postmenopausal Korean women with breast cancer who were also receiving aromatase inhibitors.MethodsBetween January 2004 and December 2010, 235 postmenopausal breast cancer patients undergoing aromatase inhibitor therapy were investigated. All patients were postmenopausal, as confirmed by laboratory tests. Of these patients, 77 received adjuvant upfront ZA for at least 1 year in addition to conventional adjuvant treatment. The remaining 158 patients never received ZA and were treated according to the St. Gallen guidelines.ResultsThe baseline characteristics for ZA treatment were not different between the two groups. The median follow-up time was 62 months, and the patients who received ZA in addition to aromatase inhibitors showed a better recurrence-free survival compared to those who received aromatase inhibitors alone (p=0.035). On multivariate analysis, the patients who received ZA showed a better recurrence-free survival independent of the tumor size, nodal status, progesterone receptor, and histological grade. For this model, Harrell c index was 0.743. The hazard ratio of ZA use for recurrence-free survival was 0.12 (95% confidence interval, 0.01-0.99).ConclusionOur findings suggest that upfront use of ZA as part of adjuvant treatment can offer a survival benefit to postmenopausal breast cancer patients receiving aromatase inhibitor treatment.

Abstract P6-07-12: Should adjuvant zoledronic acid be used in early-stage, endocrine-sensitive breast cancer?

Abstract Introduction: Adjuvant zoledronic acid (ZA) appears to improve disease-free survival (DFS) in women with endocrine-sensitive breast cancer and low estrogen levels (LEL) including post-menopausal women, and pre-menopausal women treated with LHRH agonists. ZA, however, is also associated with potential adverse events and incremental drug acquisition costs. An overall assessment of the long-term clinical and economic impacts of adjuvant ZA may therefore help guide the decision to adopt this novel therapeutic option. We examined the incremental quality-adjusted life-years (QALY) and costs per QALY associated with adjuvant treatment including ZA relative to treatment without ZA in women with endocrine-sensitive breast cancer and LEL. Methods: A Markov model was developed to compute cumulative costs, from a Canadian perspective, and QALY associated with and without adjuvant ZA over a 25-year horizon. Costs, utilities, DFS and adverse events were derived from relevant clinical trials, the literature and local resources. One-way and probabilistic sensitivity analyses were conducted for key model parameters. Results: Adjuvant ZA was associated with incremental QALY gains of 0.62 and 0.42 and resultant CU estimates of $12,617 and $19,775 per QALY gained in pre- and post-menopausal women, respectively. CU estimates were robust across reasonable uncertainty ranges in all parameters. Conclusions: Adjuvant ZA appears to be associated with long-term QALY gains in women with endocrine-sensitive breast cancer and LEL as well as CU estimates that are below commonly accepted North American thresholds. The favourable long-term clinical and economic impacts observed in this study further support the use of adjuvant ZA in this setting. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P6-07-12.

Impact of zoledronic acid (ZA) versus pamidronate (P) on overall survival (OS) in multiple myeloma (MM).

e17546 Background: Nitrogen-containing bisphosphonates (BPs) have been shown to improve OS compared to non-nitrogen containing BPs in MM (Morgan et al. Lancet 2010). Treatment guidelines recommend use of ZA or P (both nitrogen-containing) in MM patients with bone disease. No study has compared the effect of these two drugs on OS. We compared the impact of ZA versus P on OS in United States Veterans with MM. Methods: We retrospectively identified patients diagnosed with MM from 10/2002-2/2009 within the Veterans Heath Administration Central Cancer Registry who received ZA (n=482) or P (n=757) by linking registry data to pharmacy records. Cox multivariable analysis was used to estimate the association between choice of BP and OS while controlling for potential confounders: body mass index (BMI), age, race, Charlson comorbidity index, year, treatment, hemoglobin (Hgb), creatinine (Cr), and albumin. Results: The median OS in patients receiving ZA was 34.5 months, compared to 26.4 months in the P group. After adjusting for confounders, ZA reduced the risk of death by 24% compared to P (hazard ratio [HR] 0.76; 95% confidence interval [CI]: 0.66-0.88) at 5 years (Table). A sensitivity analysis that compared ZA only (n=482) versus all patients who received P, regardless if they later received ZA (n=1117) continued to show decreased mortality (HR 0.82; 95% CI: 0.71-0.94) after controlling for the same potential confounders. Conclusions: In this, the largest study to evaluate the association between ZA versus P on OS in MM, we found decreased mortality associated with ZA. Given the similar toxicity profiles, this study supports preferential use of ZA over P and may serve as evidence for re-evaluation of current guidelines for BP use in MM. [Table: see text]

Should adjuvant zoledronic acid be used in early-stage, endocrine-sensitive breast cancer?

e17564 Background: Adjuvant zoledronic acid (ZA) appears to improve disease-free survival (DFS) in women with endocrine-sensitive breast cancer and low estrogen levels (LEL) including post-menopausal women, and pre-menopausal women treated with LHRH agonists. ZA, however, is also associated with potential adverse events and incremental drug acquisition costs. An overall assessment of the long-term clinical and economic impacts of adjuvant ZA may therefore help guide the decision to adopt this novel therapeutic option. We examined the incremental quality-adjusted life-years (QALY) and costs per QALY associated with adjuvant endocrine treatment plus ZA relative to endocrine treatment without ZA in women with endocrine-sensitive breast cancer and LEL. Methods: A generic state-transition model was developed to compute cumulative costs, from a Canadian perspective, and QALY associated with and without adjuvant ZA (4 mg IV qM*3→ q3M*8 → q6M*5) over a 25-year horizon for women with endocrine-sensitive breast cancer and LEL. Costs, utilities, DFS and adverse events were derived from relevant clinical trials, the literature and local resources. One-way and probabilistic sensitivity analyses were conducted for key model parameters. Results: Adjuvant ZA was associated with incremental QALY gains of 0.80 and 0.52 and resultant CU estimates of $3,571 and $7,683 per QALY gained in pre- and post-menopausal women, respectively. CU estimates were robust across reasonable uncertainty ranges in all parameters. Conclusions: Adjuvant ZA appears to be associated with long-term QALY gains in women with endocrine-sensitive breast cancer and LEL as well as CU estimates that are well below commonly accepted North American thresholds. The favourable long-term clinical and economic impacts observed in this study further support the use of adjuvant ZA in this setting.