Use Of ZOL Research Articles

The effects of zoledronic acid on the progression of experimental periodontitis in rats: histological and microtomographic analyses

PurposePeriodontitis is considered a local risk factor for medication-related osteonecrosis of the jaws (MRONJ). However, little is known about the progression of periodontitis in the presence of zoledronic acid (ZOL). The aim of this study was to evaluate the effects of the systemic use of ZOL on the progression of experimental periodontitis (EP) in rats, as ZOL could modulate the progression of periodontitis and concomitantly cause MRONJ in individuals with periodontitis.MethodsForty-eight male Wistar rats were randomly distributed in 6 groups (n=8 each). To induce EP, ligatures were placed around the right first mandibular molars. Three groups were treated with ZOL (0.15 mg/kg/week, intraperitoneal), and 3 with 0.9% saline solution (controls). In the ZOL/Lig30 and ZOL/Lig 15 groups, after 4 weeks of treatment with ZOL, EP was induced and euthanasia was performed after 30 and 15 days of EP induction, respectively. In both groups, the animals continued to receive ZOL after EP until the end of the experiment. In the Lig/ZOL group, EP was induced first, and 15 days later, ZOL was administered for 8 weeks, with euthanasia 1 week after the last dose. After euthanasia, the mandibles were evaluated using micro-computed microtomography (micro-CT) and histomorphometry. Bone loss was measured, and the presence of osteonecrosis was evaluated histologically. The data were evaluated using the Student t-test and the Mann-Whitney test, with a significance level of 5%.ResultsIn the Lig/ZOL group, micro-CT revealed less alveolar bone resorption in the distal root (P<0.01) than in the control group (Lig/Con). Histomorphometric analysis confirmed less alveolar bone resorption in the Lig/ZOL group (P=0.001). Histologically, osteonecrosis was more common in the ZOL groups.ConclusionZOL decreased alveolar bone resorption in rats with EP. However, it presented a higher risk for MRONJ.

Zoledronic acid exhibits radio-sensitizing activity in human pancreatic cancer cells via inactivation of STAT3/NF-κB signaling.

Background: Although pancreatic cancer is typically radio-sensitive, local treatment failure and metastasis are commonly caused by the development of resistance to radiotherapy. In the current study, the radio-sensitizing actions of zoledronic acid (ZOL) on pancreatic cancer cells were investigated.Materials and methods: Three human pancreatic cancer cell lines were exposed to ZOL, ionizing radiation (IR), or a combination of both, and the effects of the respective drug regimens on cell proliferation and invasion were examined.Results: Combined treatment with low doses of ZOL plus IR efficiently increased cell death and attenuated cell invasion compared with the individual use of ZOL or IR. These effects of ZOL were associated with inactivation of signal transducer and activator of transcription 3 (STAT3) and nuclear factor-κB (NF-κB).Conclusion: Collectively, these data suggest that ZOL in combination with IR is a promising therapeutic strategy for enhancing radio-sensitivity in pancreatic cancer cells via downregulation of the STAT3/NF-κB signaling pathway.

Osteonecrosis of the jaw in patients with cancer receiving zoledronic acid for bone metastases: SWOG S0702, NCT00874211.

11502 Background: Osteonecrosis of the jaw (ONJ) may occur in cancer patients (pts) with metastatic bone disease (MBD) treated with bone modifying agents. No large prospective studies have precisely determined the incidence of ONJ. A better understanding of the true incidence and predictors of ONJ is needed. Methods: SWOG S0702 was a prospective observational study that assessed the cumulative incidence (CI) of ONJ at 3 years in pts with MBD from any malignancy receiving zoledronic acid (Zol). Participants must have had either limited or no prior exposure to bone modifying agents and a clinical care plan that included use of Zol within 30 days of registration. Cancer treatments, bone modifying agents (including Zol), and dental care were administered as clinically indicated and were not directed by S0702. Baseline and every 6 m followup dental exams were recommended. Report forms (medical, dental and pt reported outcomes) were submitted every 6 m but if ONJ was diagnosed, follow up interval became every 3 m. Protocol defined ONJ required exposed bone in the maxillofacial region present 8 weeks or more in a pt who was receiving or had been exposed to a bisphosphonate, and had not had radiation therapy to the craniofacial region. Results: The study enrolled 3,491 evaluable pts (breast 1,120; myeloma 580; prostate 702, lung 666, other 423) between 2009-2013. About 2/3 of pts had a baseline dental exam. Overall, 87 pts had confirmed ONJ. The cumulative incidence of ONJ was 0.8% at year 1 (95% CI: 0.5%-1.1%), 2.0% at year 2 (95% CI: 1.5%-2.5%), and 2.8% at year 3 (95% CI: 2.3-3.5%). Rates of 3-year confirmed ONJ were highest in myeloma pts (4.3%; 95% CI, 2.8%-6.4%). Pts with planned Zol dosing intervals of every 3-4 weeks (n = 3,032, 87.2%) were much more likely to experience ONJ than pts with planned dosing intervals of 5 weeks or greater (n = 447, 12.8%; 3.2% vs 0.7%; HR = 4.80, 95% CI, 1.52-15.18, p = .008). Fewer total number of teeth, the presence of dentures and any oral surgery at baseline were all associated with a higher rate of ONJ. Conclusions: About 1 in 40 patients receiving Zol for MBD developed ONJ. S0702 provides information to guide stratification of risk for developing ONJ in pts with MBD receiving Zol. Cancer type, oral health and frequency of Zol dosing affect risk of ONJ. Clinical trial information: NCT00874211.

The Impact of Bisphosphonates on the Osteoclast Cells of Osteogenesis Imperfecta Patients

Bisphosphonates (BPs) are widely used for treatment of osteogenesis imperfecta (OI). However, prolonged use may be associated with suppression of bone turnover, the exact molecular mechanism of which is poorly understood. The objective of this study was to evaluate the effect of zoledronic acid (ZOL) on precursor osteoclasts by studying caspase 3 activity. A total of 15 children participated in the study (n = 10 OI patients, n= 5 controls). Out of the 10 OI children, 5 had received a cumulative dose of &lt;30 mg and 5 received &gt; 30 mg of ZOL. Isolated mononuclear cells were studied for caspase 3 activity from all study participants. The mean age of study participants was 7 ±1.5 years. Six of them had OI type IV, two had type III and one had types I &amp; II each. Radiographs showed “zebra stripe sign” and dense metaphyses; suggestive of acquired osteosclerosis. Bone turnover markers (PINP and CTx) were suppressed in all OI patients compared to controls. Caspase-3 activity was significantly increased in precursor osteoclasts cells at higher doses of BPs (&gt;30 mg). Overzealous use of ZOL in OI suppresses bone turnover markers (P1NP, CTx) causes osteosclerosis and increased expression of caspase 3 activity in precursor osteoclasts which results in adynamic bone.

Sequential treatment with zoledronic acid followed by teriparatide or vice versa increases bone mineral density and bone strength in ovariectomized rats

Bisphosphonates (BPs) and teriparatide (TPTD) are both effective treatments for osteoporosis, but BP treatment prior to daily TPTD treatment has been shown to impair the effect of TPTD in some clinical studies. In contrast, the loss of bone mineral density (BMD) that occurs after withdrawal of TPTD can be prevented by BP treatment. Although various studies have investigated the combination and/or sequential use of BP and TPTD, there have been no clinical studies investigating sequential treatment with zoledronic acid (ZOL) and TPTD (or vice versa). In this study, we evaluated the effects of sequential treatment with TPTD followed by ZOL, and ZOL followed by TPTD, using ovariectomized (OVX) rats.Two months after OVX, osteopenic rats were treated with ZOL, TPTD, or vehicle for a period of 4months (first treatment period), and then the treatments were switched and administered for another 4months (second treatment period).The group treated with ZOL followed by TPTD showed an immediate increase in BMD of the proximal tibia and greater BMD and bone strength of the lumbar vertebral body, femoral diaphysis, and proximal femur than the group treated with ZOL followed by vehicle. Serum osteocalcin, a marker of bone formation, increased rapidly after switching to TPTD from ZOL.The group treated with TPTD followed by ZOL did not lose BMD in the proximal tibia after TPTD was stopped, while the group treated with TPTD followed by vehicle did lose BMD. The BMD and bone strength of the lumbar vertebral body, femoral diaphysis, and proximal femur were greater in the group treated with TPTD followed by ZOL than in the group treated with TPTD followed by vehicle. The increase in serum osteocalcin and urinary CTX after withdrawal of TPTD was prevented by the switch from TPTD to ZOL.In conclusion, our results demonstrate that switching from ZOL to TPTD resulted in a non-attenuated anabolic response in the lumbar spine and femur of OVX rats. In addition, switching from TPTD to ZOL caused BMD to be maintained or further increased. If these results can be reproduced in a clinical setting, the sequential use of ZOL followed by TPTD or vice versa in the treatment of osteoporosis patients would contribute to increases in BMD that, hopefully, would translate into a corresponding decrease in the incidence of vertebral and non-vertebral fractures.

Evaluation of Mandibular Bone After Dental Extraction in Rats Treated With Antiresorptive Drugs

Zoledronic acid (ZOL) and denosumab (Dmab) are commonly used to treat bone pathologies. Because these drugs suppress bone metabolism, this study sought to compare their effect on bone repair after tooth extraction. Four-week-old male Wistar rats were randomly assigned to 1 of 3 groups: ZOL 0.125mg/kg, Dmab 0.25mg/kg, or saline solution 10mL/kg (control). After 1week of treatment, the first left molar was extracted; the rats were euthanized at 28days. The jaws were removed and photographed for macroscopic analysis of wound healing and then subjected to tomographic and histologic analyses. Immunohistochemistry was carried out against the receptor activator of nuclear factor-κB ligand (RANKL) and osteoprotegerin (OPG). No difference in wound healing, presence of inflammatory infiltrate and bone sequestration, or osteocyte expression of RANKL and OPG was found among groups. Tomographic analysis showed that the ZOL group had less alveolar resorption and more complete alveolar repair compared with the other groups. There was a statistically significant difference in the OPG marker in the control (P=.008) and ZOL (P=.05) groups when comparing the extracted and non-extracted sides. Systemic use of ZOL can improve alveolar bone healing; however, the potential risk for the development of osteonecrosis should be considered. Higher expression of OPG seems to be associated with the control of osteoclastogenesis during bone repair.

Stealth liposomes for the delivery of zoledronic acid into tumors enhance the anticancer activity of the drug

Zoledronic acid (ZOL) is a third generation aminobisphosphonate, commonly used for the treatment of bone metastases. Several studies have shown a direct in vitro antitumor activity of ZOL but a clear evidence of clinical activity is still lacking. Unfortunately, the use of ZOL as an anticancer agent in extraskeletal tissues is limited probably because it is rapidly removed from the blood and tends to accumulate in the bone. On these bases, we developed stealth liposomes encapsulating ZOL (Lipo- ZOL) to improve the pharmacokinetic profile of the drug. Compared to free ZOL, Lipo-ZOL induced a stronger inhibition of growth in two different cancer cell lines H460 and CG5. Moreover, Lipo-ZOL also significantly caused a larger inhibition of tumor growth and increased the overall survival in murine models of human lung and breast cancer, in comparison with free ZOL. These results suggest the use of Lipo-ZOL as a potential anticancer agent in patients with neoplastic disease.

Abstract P1-09-01: Impact of MAF gene amplification on disease recurrence and effects of adjuvant zoledronic acid in early breast cancer

Abstract Background: Meta-analysis of clinical trials has shown that adjuvant bisphosphonates reduce bone metastases and improve survival in postmenopausal (PM) pts1. However, we are unable to select pts most likely to benefit. To address this, the recently identified early breast cancer bone relapse biomarker, 16q23(MAF) gain (MAF+)2, was tested retrospectively in the large prospectively randomized AZURE trial3 of standard adjuvant therapy +/- zoledronic acid (ZOL) to determine the prognostic value of MAF and its potential to predict the effects of ZOL on disease outcomes. Materials and methods: All analyses were performed with ethics approval and consent. The biomarker analysis was completed on TMAs from primary tumors. Quadruplicate cores of breast tumor tissue were arrayed across replicate TMAs. MAF+ was detected using a validated (MAF/D16Z3) FISH test (Inbiomotion SL, Barcelona, Spain). A central laboratory (Targos, Kassel, Germany) validated the assay for analytic and diagnostic performance, established acceptance criteria, included appropriate quality controls for each assay, and performed the analyses in a blinded fashion. A copy number cut-off ≥2.5 was preset for MAF+. Invasive disease free (IDFS), overall (OS) survival and time to bone metastases multivariate analyses were performed in control and ZOL pts separately. Subsequently, interactions between MAF+ and effects of ZOL on disease outcomes by menopausal status were evaluated. Results: 1769 of the 3360 AZURE pts donated primary tumor samples. Median follow-up was 84 months. 865 pts (49%) had 2 FISH evaluable cores and were included in the analysis of which 184 (21%) had MAF+ tumors. Tumors that were MAF+ were more likely to be of higher grade, ER-ve and Her2+. In control pts, MAF was not prognostic for IDFS or OS although there were differences in IDFS by menopause (HR for MAF-/MAF+ in PM=0.47 [95%CI 0.25-0.88]; HR in non-PM=1.58 [0.82-3.03], test for interaction (TFI) by menopause P=0.007). In ZOL pts, MAF was prognostic for IDFS (HR=0.52 [0.36-0.75] and OS (HR=0.48 [0.31-0.75]). There were insufficient bone events (19 MAF+, 73 MAF-) in this sample set to reliably assess the impact of MAF+ on relapse in bone. In pts with MAF- tumors, ZOL was associated with improved IDFS (HR=0.74 [0.56-0.98]) and OS (HR=0.78 [0.55-1.10]). However, the effects of ZOL in MAF+ were profoundly influenced by menopausal status with possibly better outcomes in PM women (HR for IDFS=0.74 [0.35-1.58]) but clearly worse IDFS and OS outcomes in ZOL treated MAF+ pts who were non-PM (HR for IDFS 2.46 [1.23-4.92], TFI by treatment P=0.002 and HR for OS=2.27 [1.04-4.93], TFI by treatment P=0.032). The interactions between disease outcomes, ZOL use and menopause were driven largely by an association between MAF+ and an increased risk of extra-skeletal recurrence with the use of ZOL in women who were not PM. Conclusions: Absence of MAF amplification is associated with improved disease outcomes with adjuvant ZOL. However, the use of adjuvant ZOL in women with MAF+ tumors who are not PM at the start of treatment is associated with extraskeletal spread and worse DFS and OS. 1EBCTCG Lancet 2015;386:1353–1361; 2Pavlovic M et al JNCI 2015;107(12):djv256; 3Coleman RE et al Lancet Oncol 2014;15:997-1006. Citation Format: Coleman R, Hall A, Bell R, Cameron D, Marshall H, Jean-Mairet J, Tercero J, Rojo F, Albanell J, Gomis R. Impact of MAF gene amplification on disease recurrence and effects of adjuvant zoledronic acid in early breast cancer [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P1-09-01.

Radiodensitometric study for evaluation of bone mineral density around dental implants after zoledronic acid treatment in ovariectomized rats

BackgroundThe purpose of this study was to evaluate the effects of intravenous zoledronic acid applied systemically on osseointegration of dental implants and the surrounding bone mineral density (BMD) in the ovariectomized rats.Material and Methods36 rats were divided into three groups: control (CTRL), ovariectomy (OVX), and ovariectomy-zoledronic acid (OVX/ZOL). The rats in the CTRL group underwent sham surgery, while rats in OVX and OVX / ZOL group underwent ovariectomy. After 12 weeks, rats from OVX / ZOL were injected with 0.04 mg/kg ZOL intravenously once a week for 6 weeks. The rats from CTRL and OVX groups were injected with 0.9% NaCl. Implants were placed in the left tibia. After 8 weeks, rats were sacrificed and tibia bones were removed for radiodensitometric examination. Digital radiographs of bones’ lateral surface were taken. The BMD was measured by using radiographic analysis software.ResultsStatistically significant differences were found between all groups (p<0.05). While highest mean BMD values were observed in the CTRL group, the lowest were in the OVX group.ConclusionsThe systemic use of ZOL has increased the bone density around the implants inserted osteoporotic rat tibia. Key words:Bisphosphonate, bone density, dental implants, osteoporosis.

Combination of a third generation bisphosphonate and replication-competent adenoviruses augments the cytotoxicity on mesothelioma

BackgroundApproximately 80 % of mesothelioma specimens have the wild-type p53 gene, whereas they contain homozygous deletions in the INK4A/ARF locus that encodes p14ARF and the 16INK4A genes. Consequently, the majority of mesothelioma is defective of the p53 pathways. We examined whether zoledronic acid (ZOL), a third generation bisphosphonate, and adenoviruses with a deletion of the E1B-55kD gene (Ad-delE1B55), which augments p53 levels in the infected tumors, could produce combinatory anti-tumor effects on human mesothelioma cells bearing the wild-type p53 gene.MethodsCytotoxicity of ZOL and Ad-delE1B55 was assessed with a WST assay. Cell cycle changes were tested with flow cytometry. Expression levels of relevant molecules were examined with western blot analysis to investigate a possible mechanism of cytotoxicity. Furthermore, the expressions of Ad receptors on target cells and infectivity were estimated with flow cytometry. Viral replication was assayed with the tissue culture infection dose method.ResultsA combinatory use of ZOL and Ad-delE1B55 suppressed cell growth and increased sub-G1 or S-phase populations compared with a single agent, depending on cells tested. The combinatory treatment up-regulated p53 levels and subsequently enhanced the cleavage of caspase-3, 8, 9 and poly (ADP-ribose) polymerase, but expression of molecules involved in autophagy pathways were inconsistent. ZOL-treated cells also increased Ad infectivity with a dose-dependent manner and augmented Ad replication although the expression levels of integrin molecules, one of the Ad receptors, were down-regulated.ConclusionsThese findings indicated that ZOL and Ad-delE1B55 achieved combinatory anti-tumor effects through augmented apoptotic pathways or increased viral replication.Electronic supplementary materialThe online version of this article (doi:10.1186/s12885-016-2483-y) contains supplementary material, which is available to authorized users.

Effects of bisphosphonate zoledronic acid in hepatocellular carcinoma, depending on mevalonate pathway.

Zoledronic acid (ZOL) is a nitrogen-containing bisphosphonate and is used to reduce cancer-induced osteolysis. We reported previously that ZOL delayed both the growth and pain progression of bone metastases from hepatocellular carcinoma. The present study was designed to evaluate the effects of ZOL on hepatoma cell lines and the molecular mechanisms of such effects. Cell viability assay, scratch assay, immunohistochemistry, Western blotting, and flow cytometry analysis were performed using Huh7 and HepG2 cells treated with and without ZOL. ZOL reduced cell growth in a dose-dependent manner and prevented cell migration when used at a concentration exceeding 10 μM. Immunohistochemistry showed that the inhibitory effects of ZOL on hepatoma cell progression was not due to the suppression of Ras and RhoA expression but due to inhibition of their translocation from the cytosol to the cell membrane, which terminates mevalonate pathway. Immunoblotting and flow cytometry showed that ZOL inhibited the mitogen-activated protein kinase pathway (MAPK) and induced apoptosis of hepatoma cells. Our results indicated that ZOL prevented cell growth and metastasis based on direct antitumor effects in hepatoma cells. The use of ZOL could not only suppress the progression to bone metastatic lesions but also prevented growth of primary hepatocellular carcinoma.

Zoledronic acid increases bone mineral density and improves health-related quality of life over two years of treatment in Chinese women with postmenopausal osteoporosis.

Osteoporosis is characterised by decreased bone mass and weakened bones, with an increased risk of fractures. Osteoporotic fracture, the most serious complication of osteoporosis, is related not only to lower bone mineral density (BMD), but also falls. Osteoporosis and fractures are associated with a decreased health-related quality of life (HRQL). Zoledronic acid (ZOL) is an intravenous once-yearly bisphosphonate that has been shown to be effective and safe in improving BMD and reducing fracture risk in controlled clinical trials. In this self-controlled, prospective trial, 220 postmenopausal women with osteoporosis (mean age 67 years) received a single infusion of ZOL 5 mg at baseline and month 12. BMD, HRQL and Fall Index (FI) were measured at baseline, and months 12 and 24 (before each use of ZOL). The main outcome measures were the changes in lumbar spine and hip BMD and the changes in HRQL, the Short Form-36 questionnaire (SF-36). Additional comparisons were based on the FI. LSD multiple comparisons were used in the comparisons of BMD, SF-36 domain scores and FI. The patients had significantly higher L1-4, total hip, femoral neck and trochanter BMD (P < 0.05) with improved HRQL (P < 0.05) over two years of treatment of once-yearly ZOL 5mg. FI was reduced (P < 0.05) with oral daily elemental calcium and vitamin D in the treatment course. ZOL improves BMD and HRQL, especially in the physical aspects, over two years of treatment in women with postmenopausal osteoporosis, and can help improve balance ability.

Zoledronic Acid Produces Combinatory Anti-Tumor Effects with Cisplatin on Mesothelioma by Increasing p53 Expression Levels

We examined anti-tumor effects of zoledronic acid (ZOL), one of the bisphosphonates agents clinically used for preventing loss of bone mass, on human mesothelioma cells bearing the wild-type p53 gene. ZOL-treated cells showed activation of caspase-3/7, -8 and -9, and increased sub-G1 phase fractions. A combinatory use of ZOL and cisplatin (CDDP), one of the first-line anti-cancer agents for mesothelioma, synergistically or additively produced the cytotoxicity on mesothelioma cells. Moreover, the combination achieved greater anti-tumor effects on mesothelioma developed in the pleural cavity than administration of either ZOL or CDDP alone. ZOL-treated cells as well as CDDP-treated cells induced p53 phosphorylation at Ser 15, a marker of p53 activation, and up-regulated p53 protein expression levels. Down-regulation of p53 levels with siRNA however did not influence the ZOL-mediated cytotoxicity but negated the combinatory effects by ZOL and CDDP. In addition, ZOL treatments augmented cytotoxicity of adenoviruses expressing the p53 gene on mesothelioma. These data demonstrated that ZOL-mediated augmentation of p53, which was not linked with ZOL-induced cytotoxicity, played a role in the combinatory effects with a p53 up-regulating agent, and suggests a possible clinical use of ZOL to mesothelioma with anti-cancer agents.

Safety and efficacy of a 1-year treatment with zoledronic acid compared with pamidronate in children with osteogenesis imperfecta

Pamidronate (PAM) infusion is the standard treatment in children with osteogenesis imperfecta (OI). Zoledronic acid (ZOL) is a bisphosphonate with higher potency and faster intravenous infusion, but its efficacy and safety has not been established for OI patients. We report an open-label, prospective, and randomized clinical analysis to study the safety and efficacy of ZOL compared with PAM in 23 children with OI. They were selected to receive PAM (PAM group), 1 mg/kg/day, over 2 days or ZOL (ZOL group), 0.025-0.05 mg/kg/day, over 2 days every 3-4 months according to their ages, during a 1-year follow-up. They were observed for clinical and biochemical parameters, side effects, bone mineral density (BMD), and fracture rate. After treatment, the PAM and ZOL groups average lumbar spine (LS) BMD increased by 51.8% (p = 0.053) and 67.6% (p = 0.003), respectively. Parallel improvement was seen in LS Z-score in the PAM and ZOL groups, with scores of -5.3 to -3.8 (p = 0.032) and -4.8 to -2.3 (p = 0.007), respectively. LS Z-score for the ZOL group at the end of treatment was higher compared with the PAM group but only a borderline significance (p = 0.053). The total alkaline phosphatase (AP) in the ZOL group significantly decreased from baseline at third and fourth infusion (p = 0.032). Mild side effects were similar in both groups, but no severe clinical symptoms were reported. In conclusion, the present study shows that the use of ZOL in the dosage and period studied was safe and efficient to promote a clinical and densitometric improvement, similarly to PAM. Further studies are needed to establish optimal dosing and long-term safety.

PCN73 Cost Effectiveness of Zoledronic Acid vs. Pamidronate or No therapy for the Treatment of Bone Metastases Secondary to Prostate Cancer

Zoledronic acid (ZOL) is the only approved bisphosphonate for SRE prevention in hormone-refractory prostate cancer (mHRPC). However, in the UK (UK), 19% and 4% of metastatic, mHRPC patients, do not receive bisphosphonates or receive non-approved/unproven bisphosphonates (i.e., pamidronate [PAM]), respectively for the prevention of skeletal-related events (SREs). This analysis sought to estimate, from a UK payer perspective, the cost effectiveness of providing ZOL to those mHRPC patients not receiving ZOL. This analysis was based on the results of a published randomized phase III clinical trial wherein mHRPC patients received ≤15 months of ZOL or placebo (PBO) (Saad et al, 2002). Since PAM has been shown to be no different than PBO in mHRPC in a pooled analysis of two trials (Small et al 2003) (i.e., 25% of subjects experienced an SRE at 6 months), the PBO cohort data from the ZOL trial was as a surrogate for PAM data in the absence of a direct comparison of ZOL versus PAM (or other bisphosphonates). Costs were estimated using hospital tariffs and published/internet sources. Quality adjusted life years (QALYs) gained were based on a previously published analysis of the Saad et al (2002) data. Survival was assumed to be identical for both groups. Compared with the use of PAM/PBO, treatment with ZOL (at list price of £174.14/infusion vs £80/infusion with PAM) resulted in increased QALYs (+0.03566/pt), fewer SREs (-0.8314/pt, i.e., 0.8315 vs 1.6629), and fewer SRE-related costs (-£1,639/pt, i.e., £2,004 vs. £3,643). Total costs were higher with ZOL (+£702/pt). ZOL cost £19,689/QALY. The use of ZOL for the prevention of SREs in UK patients with bone metastases secondary to mHRPC is cost effective relative to providing no or unapproved bisphosphonates.

Effect of zoledronate acid treatment on osseointegration and fixation of implants in autologous iliac bone grafts in ovariectomized rabbits

One main problem associated with alveolar bone augmentation in implant dentistry is resorption of grafted bone, which may be further compromised by systemic skeletal disorders such as osteoporosis. Zoledronate acid (ZOL) is the most potent bisphosphonate to treat osteoporosis and therefore it is hypothesized to be able to invert the negative effect of osteoporosis on osseointegration and fixation of dental implants in autologous bone grafts. In this study, 56 rabbits received bilateral ovariectomy (OVX) (40 rabbits) or sham operation (16 rabbits). Three months later, 8 animals from each group were sacrificed for bone mineral density (BMD) examination. Then the remaining animals underwent bilateral autologous iliac bone grafting with simultaneous implantation of titanium implants in tibiae and were divided into 5 groups (n=8): Sham, OVX, Loc-ZOL (local treatment), Sys-ZOL (systemic treatment) and Loc+Sys-ZOL (local plus systemic) group. At 3 months after implantation, all animals were sacrificed and specimens were harvested for examinations. Both BMD and histological examinations of femurs showed osteoporotic changes after ovariectomy, while systemic treatment with ZOL restored mineralized bone. Micro-CT examination demonstrated that OVX group showed significant decrease of mineralized bone and implant-bone contact when compared with sham control, whereas both systemic and local treatments of ZOL significantly increased mineralized bone and implant-bone contact in ovariectomized animals. However, the best effects were observed in Loc+Sys-ZOL group (combined use of ZOL) and most of bone indices were similar to (IBCR, p>0.05) or higher than (BV/TV, Conn.D and Tb.N) (p<0.01) those of the sham group, except Tb.Th, which was still significantly lower (p<0.01), and Tb.Sp, which was further decreased (p<0.01). The aforementioned effects were also confirmed by histomorphometric analysis of bone indices on implant-bone contact and mineralized bone. In addition, biomechanical testing further supported the beneficial effect of ZOL treatment and maximal removal torque of titanium implants was observed in Loc+Sys-ZOL group. In conclusion, our study suggests that both systemic and local treatments with ZOL can invert negative effect of osteoporosis and promote osseointegration and fixation of dental implants in autologous bone grafts under osteoporotic condition. Combined systemic and local use of ZOL exerts best effects when compared to their single use.

Are there benefits to long-term bisphosphonate treatment in multiple myeloma (MM)? Insights from temporal analyses of zoledronic acid (ZOL) versus clodronate (CLO) in the MRC Myeloma IX Trial.

8011 Background: The MRC Myeloma IX Study (MMIX) showed significant benefits for zoledronic acid (ZOL) beyond those of clodronate (CLO) for overall survival (OS) in patients (pts) with newly diagnosed multiple myeloma (MM; Lancet 2010). Guidance is needed for the optimal initiation and duration of bisphosphonate therapy for MM. Treatment effects across the duration of MMIX could provide additional insight. Methods: Newly diagnosed MM pts were randomized to antimyeloma therapies plus ZOL (4 mg q 21-28 days) or CLO (1,600 mg q day) at least until disease progression; pts could participate in a subsequent randomization to either maintenance thalidomide (Thal) or no Thal. Exploratory analyses of OS and skeletal-related events (SREs) were performed for time periods within the study to evaluate potential temporal differences. Results: Among the intent-to-treat population (N=1,960; median follow-up, 3.7 yr), 917 died. Median OS was 5.5 mo longer with ZOL vs CLO (hazard ratio [HR]=0.84; 95% CI, 0.736, 0.963; P=.012). The OS benefit first achieved statistical significance during mo 2 and was especially profound during the first 4 mo, wherein ZOL significantly reduced the risk of death by 36% relative to CLO (HR=0.64; P=.004). ZOL consistently reduced the mean number of SREs/pt vs CLO by 26% at 1 yr (D0.11; 95%CI 0.04, 0.18), by 30% at 2 yr (D0.18; 95%CI 0.09, 0.26), by 33% at 3 yr (D0.23; 95%CI 0.12, 0.33), by 38% at 4 yr (D0.30; 95%CI 0.17, 0.44), and by 39% at 5 yr (D0.32; 95%CI 0.18, 0.46). Overall, ZOL reduced the cumulative incidence of SREs vs CLO (HR=0.74; 95%CI, 0.62, 0.87; P=.0004). ZOL continued to significantly reduce SRE risk vs CLO during the maintenance phase in both the Thal (P=.044) and no-Thal (P=.003) groups. Conclusions: In MMIX, the OS benefit from ZOL vs CLO became apparent during the first 4 mo of therapy, supporting early use of ZOL for potential anticancer effects in pts with newly diagnosed MM. ZOL produced significant reductions in SRE risk vs CLO with either Thal maintenance therapy or no Thal, and during each yr of the study, supporting ongoing use to prevent SREs.

Nanotechnologies to use bisphosphonates as potent anticancer agents: the effects of zoledronic acid encapsulated into liposomes

Zoledronic acid (ZOL) is a potent amino-bisphosphonate used for the treatment of bone metastases with recently reported antitumor activity. However, the short plasma half-life and rapid accumulation in bone limits the use of ZOL as an antitumor agent in extraskeletal tissues. Therefore, we developed stealth liposomes encapsulating ZOL (LipoZOL) to increase extraskeletal drug availability. Compared to free ZOL, LipoZOL induced a stronger inhibition of growth of a range of different cancer cell lines in vitro. LipoZOL also caused significantly larger inhibition of tumor growth and increased the overall survival in murine models of human prostate cancer and multiple myeloma, in comparison with ZOL. Moreover, a strong inhibition of vasculogenetic events without evidence of necrosis in the tumor xenografts from prostate cancer was recorded after treatment with LipoZOL. We demonstrated both antitumor activity and tolerability of LipoZOL in preclinical animal models of both solid and hematopoietic malignancies, providing a rationale for early exploration of use of LipoZOL as a potential anticancer agent in cancer patients. From the Clinical EditorThe short plasma half-life and rapid accumulation in bone limits the use of zoledronic acid as an antitumor agent in extraskeletal tissues. Therefore, stealth liposomes encapsulating ZOL (LipoZOL) have been developed to increase extraskeletal drug availability.

Zoledronic acid for prevention and treatment of osteoporosis

Introduction: Osteoporosis (OP) is associated with a high risk of fracture and disability and with substantial medical costs. This paper is a review of the intravenous (i.v.) bisphosphonate zoledronic acid 5 mg (ZOL), used in the treatment and prevention of OP.Areas covered: This is a review of the scientific literature, between 2003 and 2010, on the use of ZOL in patients with low bone mass or OP.Expert opinion: ZOL, given as a single infusion once yearly, has proven efficacy in reducing risk of vertebral and hip fractures in postmenopausal women with OP. In men and women with a recent hip fracture, ZOL has been shown to reduce the incidence of future clinical fractures. Data also demonstrate an increase in bone mineral density in postmenopausal women with osteopenia, in men with OP, and in patients at risk for glucocorticoid-induced osteoporosis. The ZOL clinical program has shown this agent to be safe and generally well tolerated. Acute flu-like symptoms may occur following the first infusion of ZOL, but these are generally mild and transient, and decrease in frequency with subsequent infusions. Patients must have adequate renal function (creatinine clearance ≥ 35 ml/min) and be adequately hydrated prior to infusion. With orally administered bisphosphonates, patient compliance and persistence with weekly or monthly dosing are frequently suboptimal. The ability to administer i.v. ZOL once yearly over 15 min for the treatment of OP provides the advantage of guaranteeing medication compliance for the duration of the dosing interval.

The proapoptotic effect of zoledronic acid is independent of either the bone microenvironment or the intrinsic resistance to bortezomib of myeloma cells and is enhanced by the combination with arsenic trioxide

Multiple myeloma (MM) cells are extremely resistant to drug-induced apoptosis due to both intrinsic- and bone marrow (BM) microenvironment-dependent drug resistance particularly supported by bone cells. Growing evidence suggest that the osteoclast inhibitor zoledronic acid (ZOL) exerts both indirect and direct anti-tumoral effects, including an in vitro proapoptotic effect on MM cells, although this property has not yet been clearly observed in MM patients. In this study, we attempt to better define the cytotoxic effect of ZOL on MM cells in order to identify novel drug combinations able to potentiate its proapoptotic effect. Our data shows that ZOL at concentrations ranging from 10 to 100 μM was able to induce MM cell apoptosis overcoming the prosurvival effect of both stromal cells and osteoclasts and independent of the intrinsic bortezomib resistance of MM cells. Interestingly, we found that the capacity of ZOL to induce apoptosis in bortezomib-resistant cells was associated with a downregulation of the proapoptotic molecule myeloid cell leukemia-1. A transcriptional analysis by microarray was also performed to identify genes specifically modulated by ZOL in bortezomib-resistant MM cells. Finally, we show an additive effect of arsenic trioxide on apoptosis when used in combination with ZOL. Our in vitro data suggest that the use of ZOL at appropriate doses could be explored clinically in bortezomib-resistant MM patients and combined with arsenic trioxide to increase its proapoptotic effect.