ZOL Group Research Articles

Safety of zoledronic acid and incidence of osteonecrosis of the jaw (ONJ) during adjuvant therapy in a randomised phase III trial (AZURE: BIG 01–04) for women with stage II/III breast cancer

The AZURE trial is an ongoing phase III, academic, multi-centre, randomised trial designed to evaluate the role of zoledronic acid (ZOL) in the adjuvant therapy of women with stage II/III breast cancer. Here, we report the safety and tolerability profile of ZOL in this setting. Eligible patients received (neo)adjuvant chemotherapy and/or endocrine therapy and were randomised to receive neither additional treatment nor intravenous ZOL 4 mg. ZOL was administered after each chemotherapy cycle to exploit potential sequence-dependent synergy. ZOL was continued for 60 months post-randomisation (six doses in the first 6 months, eight doses in the following 24 months and five doses in the final 30 months). Serious (SAE) and non-serious adverse event (AE) data generated during the first 36 months on study were analysed for the safety population. 3,360 patients were recruited to the AZURE trial. The safety population comprised 3,340 patients (ZOL 1,665; control 1,675). The addition of ZOL to standard treatment did not significantly impact on chemotherapy delivery. SAE were similar in both treatment arms. No significant safety differences were seen apart from the occurrence of osteonecrosis of the jaw (ONJ) in the ZOL group (11 confirmed cases; 0.7%; 95% confidence interval 0.3-1.1%). ZOL in the adjuvant setting is well tolerated, and can be safely administered in addition to adjuvant therapy including chemotherapy. The adverse events were consistent with the known safety profile of ZOL, with a low incidence of ONJ.

Intravenous zoledronic acid and oral alendronate in patients with a low trauma fracture: experience from an osteoporosis clinic

Oral bisphosphonates have been shown to be effective in treating osteoporosis. However, there has been a significant problem with compliance. Newer intravenous bisphosphonates are available for osteoporosis management, but have not been compared with oral bisphosphonates in a clinical setting. The aim of this study was to compare the safety and effectiveness of intravenous zoledronic acid (ZOL) and oral alendronate (ALN) in osteoporotic patients following a low trauma fracture. A non-randomized, retrospective cohort study was conducted of 169 patients with a low trauma fracture and reduced bone mineral density (BMD). Patients were treated with either an infusion of 4 mg ZOL or ALN 70 mg weekly. The outcomes measured were change in BMD after 12 months of treatment with either bisphosphonate, and new osteoporotic fractures. All adverse events were documented. Lumbar spine BMD (L2-L4) improved 5.6% in the ZOL group (P < 0.001) and 5.5% in the ALN group (P < 0.001). Total hip BMD improved 2% in the ZOL group (P < 0.01) and 2.5% in the ALN group (P < 0.001). There was no significant difference in BMD change between the groups. There were significantly more new fractures (P < 0.001) in the ZOL group (7.2%) than the ALN group (1%). The ZOL group were significantly older (P < 0.01) and had a significantly higher proportion of males (P < 0.05) at baseline. There were no serious adverse reactions in either group. ZOL and ALN both produce a significant increase in BMD and are well tolerated in patients with osteoporotic, low trauma fractures. Yearly ZOL provides a safe, convenient alternative to weekly oral bisphosphonates.

Zoledronic acid results in better health-related quality of life following hip fracture: the HORIZON–Recurrent Fracture Trial

This study evaluated the benefits of ZOL versus placebo on health-related quality of life (HRQoL) among patients from HORIZON-RFT. At month 24 and end of the study visit, ZOL significantly improved patients' overall health state compared to placebo as assessed by the EQ-5D VAS. To evaluate the benefits of zoledronic acid (ZOL) versus placebo on health-related quality of life (HRQoL) among patients from The Health Outcomes and Reduced Incidence With Zoledronic Acid Once Yearly Recurrent Fracture Trial (HORIZON-RFT). In this randomized, double-blind, placebo-controlled trial, 2,127 patients were randomized to receive annual infusion of ZOL 5 mg (n = 1,065) or placebo (n = 1,062) within 90 days after surgical repair of low-trauma hip fracture. HRQoL was measured using EQ-5D Visual Analogue Scale (VAS) and utility scores (EuroQol instrument) at months 6, 12, 24, 36, and end of the study visit. Analysis of covariance model included baseline EQ-5D value, region, and treatment as explanatory variables. At baseline, patients (mean age 75 years; 24% men and 76% women) were well matched between treatment groups with mean EQ-5D VAS of 65.82 in ZOL and 65.70 in placebo group. At the end of the study, mean change from baseline in EQ-5D VAS was greater for ZOL vs. placebo in all patients (7.67 ± 0.56 vs. 5.42 ± 0.56), and in subgroups of patients experiencing clinical vertebral fractures (8.86 ± 4.91 vs. -1.69 ± 3.42), non-vertebral fractures (5.03 ± 2.48 vs. -1.07 ± 2.16), and clinical fractures (5.19 ± 2.25 vs. -0.72 ± 1.82) with treatment difference significantly in favor of ZOL. EQ-5D utility scores were comparable for ZOL and placebo groups, but more patients on placebo consistently had extreme difficulty in mobility (1.74% for ZOL vs. 2.13% for placebo; p = 0.6238), self-care (4.92% vs. 6.69%; p = 0.1013), and usual activities (10.28% vs. 12.91%; p = 0.0775). ZOL significantly improves HRQoL in patients with low-trauma hip fracture.

Effects of intravenous zoledronic acid and oral ibandronate on early changes in markers of bone turnover in patients with bone metastases from non-small cell lung cancer

The aim of this study was to assess the early effects of zoledronic acid (ZOL) and oral ibandronate (IBA) on the bone resorption marker s-CTX (serum C-telopeptide of collagen type I) and the bone formation marker B-ALP (bone-alkaline phosphatase) in patients with bone metastases from non-small cell lung cancer (NSCLC). Fifty-five patients with at least one site of bone metastasis secondary to NSCLC were randomly assigned to receive intravenous ZOL 4 mg every 4 weeks, or oral IBA 50 mg/day. At 1 month of treatment, s-CTX was reduced by 54.8% (95% CI 40.4-59.8%) in the ZOL group (26 evaluable patients) compared with 38.2% (95% CI 29.8-48.7%) in the oral IBA group (27 evaluable patients) (p = 0.03). At 3 months, s-CTX was reduced by 72.6% (95% CI 58.6-71.3%) in the ZOL group, compared with 66.4% (95% CI 54.3-79.5%) in the oral IBA group (p = 0.22). Both bisphosphonates similarly decreased the bone marker B-ALP at 1 month (ZOL 24.7%, 95% CI 3.6-39.5%, and IBA 24.2%, 95% CI 2.8-43.4%) and 3 months (ZOL 28.6%, 95% CI +2.8-43.3%, and IBA 24.2%, 95% CI 3.2-47.4%). Both bisphosphonates were well tolerated. Considering the changes in bone markers, ZOL and oral IBA show comparable efficacy in patients with NSCLC and bone metastases.

Optimising Bone Disease In Myeloma; Zoledronic Acid Plus Thalidomide Combinations Improves Survival and Bone Endpoints: Results of the MRC Myeloma IX Trial

AbstractAbstract 311 Introduction:MRC Myeloma IX (N = 1,960) included intensive and non-intensive pathways and 2 bisphosphonates (BPs; zoledronic acid [ZOL] and clodronate [CLO]) in patients (pts) with newly diagnosed multiple myeloma. The trial is unique in having investigated both overall survival (OS) and bone endpoints in the context of BP treatment and a thalidomide (Thal), alkylating agent, and steroid induction regimen; and maintenance Thal. We have shown that ZOL significantly reduces skeletal-related events (SREs) and improves OS independent of its effect on SREs, suggesting potential antimyeloma activity (Morgan et al. ASCO 2010, #8021). Early comparisons between antimyeloma regimens demonstrated superiority of Thal-containing regimens for induction (Morgan et al. ASH 2009, #352) and maintenance. Here we present important new data on interactions between BPs, Thal, and standard induction regimens used in terms of response, progression-free survival (PFS), OS, and on the bone endpoints included in SREs. Methods:The intensive pathway randomized pts to 4 to 6, 3-wk cycles of CVAD (cyclophosphamide, vincristine, doxorubicin, dexamethasone) or CTD (cyclophosphamide, Thal, dexamethasone) as induction therapy, followed by high-dose melphalan treatment and ASCT. The non-intensive pathway randomized pts to 4-wk cycles of melphalan and prednisolone (MP) or attenuated CTD (CTDa). Each treatment arm also was randomized to ZOL (4 mg IV q 3–4 wk, dose-adjusted based on renal function) or CLO (1600 mg/d) continued at least until disease progression. After induction, pts in both pathways were offered entry to a maintenance Thal or no maintenance randomization. Endpoints included PFS, OS, and response. SREs include fractures, spinal cord compression, radiation or surgery to bone, and new osteolytic lesions at disease progression. Time to first SRE was assessed using cumulative incidence function, and OS was estimated using the Kaplan-Meier method. Cox analysis was used to assess hazard ratio (HR) and associated 95% CI for SRE risk, adjusting for effects of treatment regimen, minimization factors, and SRE history at baseline (stratified by pathway). Diagnosis of bone lesions was not a study-entry requirement; BP use may be off-label outside the UK in some pts. Results:With a median follow-up of 3.7 yr and 1,960 evaluable pts, ZOL and Thal-containing regimens produced multiple treatment benefits. Overall, there was a trend for more pts with complete response (CR; P = .15), fewer early deaths (within 60 days of randomization; P = .06), and improved OS for ZOL vs CLO (P = .04). SRE risk was significantly reduced with ZOL vs CLO (HR = 0.74, P = .0004), and—for the first time—SRE risk also proved lower for CTDa vs MP (HR = 0.74, P = .021), but was similar for CTD vs CVAD (HR = 1.03; P = .80). In the intensive pathway (n = 1,111; median age 59 yr), CR or very-good-partial response (VGPR) was achieved after induction therapy by 43.2% of pts with CTD and 27.5% of pts with CVAD. Similar proportions of pts achieved CR/VGPR with ZOL and CLO (36.0% vs 34.7%). OS and PFS were slightly better for ZOL vs CLO (OS: HR = 0.84; 95% CI, 0.68–1.03; PFS: HR = 0.90; 95% CI, 0.78–1.05; P > .05 for both). In both the CVAD and CTD arms, fewer ZOL- vs CLO-treated pts had SREs (overall intensive: 27.9% vs 36.3%; log-rank P = .034). In the nonintensive pathway (n = 849; median age 73 yr), pts randomized to CTDa had a significantly higher CR rate (13.1% vs 2.4%; P < .0001) and CR/VGPR (30.0% vs 4.0%; P < .0001) vs MP. In each treatment arm, the ZOL group had higher rates of CR/VGPR vs CLO (MP: 6% vs 2%; CTDa: 34% vs 26%, respectively; P = .03 overall). ZOL significantly reduced risk of death by 17% vs CLO (HR = 0.83; P = .049). Time to first SRE was significantly longer for CTDa vs MP (P = .021) and ZOL vs CLO (log-rank P = .008). In modeling analyses we show that the impact of achieving a CR and of CTDa on SREs may not be independent, suggesting that the improved response is important in reducing bone disease. ZOL prolonged the median time to first SRE vs CLO in both the MP and CTDa arms. In the maintenance randomization (n = 820), ZOL significantly reduced SREs compared with CLO. Conclusions:We demonstrate that ZOL provided benefits beyond CLO, improving OS and response status, and preventing potentially debilitating SREs. Pts receiving regimens containing Thal and ZOL had the best clinical outcomes, being associated with better response, survival, and lower SRE risk. Disclosures:Morgan:Celgene: Honoraria, Research Funding; Ortho Biotech: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Boehringer Ingelheim: Research Funding; Pharmion: Research Funding; Chugai: Research Funding. Off Label Use: Diagnosis of bone lesions was not a study-entry requirement; Therefore bisphosphonate use may be off-label outside the UK in some patients. Davies:Celgene: Honoraria; Ortho Biotech: Honoraria; Novartis: Honoraria. Cook:Orthobiotec: Consultancy, Speakers Bureau. Jackson:Celgene: Honoraria; Janssen-Cilag: Honoraria.

Short‐term zoledronic acid reduces trabecular bone remodeling in dogs

The effects of zoledronic acid, a bisphosphonate, on the trabecular bone remodeling (TBR) of the mandibular condyle are unknown. The objectives of this study were to quantify and compare TBR in the mandibular condyle and vertebrae of 2- to 3-yr-old dogs and to evaluate the effects of short-term zoledronic acid on TBR. Bone samples from two, age-matched groups of dogs [seven dogs were given no treatment (NT group) and seven dogs were treated with four total infusions of zoledronic acid administered monthly (ZOL group)] were analyzed using histomorphometry. Trabecular bone remodeling and microarchitecture were quantified and analyzed statistically. Physiologic TBR, quantified in the NT group, was significantly higher (more than sixfold) in the vertebrae than in the mandibular condyle. Trabecular bone remodeling in the vertebrae of dogs of the ZOL group was 96% lower than in dogs of the NT group. By contrast, TBR in the mandibular condyle of dogs in the ZOL group was statistically equivalent to that of dogs in the NT group. Our results demonstrate that the physiological TBR in aged dogs is vastly different in the mandibular condyle compared to that in the vertebra. A higher level of physiologic TBR in the vertebra than in the mandibular condyle results in greater reduction of TBR in response to short-term treatment with zoledronic acid.

Increased prevalence of bisphosphonate-related osteonecrosis of the jaw with vitamin D deficiency in rats

Necrotic bone exposure in the oral cavity has recently been reported in patients treated with nitrogen-containing bisphosphonates as part of their therapeutic regimen for multiple myeloma or metastatic cancers to bone. It has been postulated that systemic conditions associated with cancer patients combined with tooth extraction may increase the risk of osteonecrosis of the jaw (ONJ). The objective of this study was to establish an animal model of bisphosphonate-related ONJ by testing the combination of these risk factors. The generation of ONJ lesions in rats resembling human disease was achieved under the confluence of intravenous injection of zoledronate (ZOL; 35 µg/kg every 2 weeks), maxillary molar extraction, and vitamin D deficiency [VitD(−)]. The prevalence of ONJ in the VitD(−)/ZOL group was 66.7%, which was significantly higher (p < .05, Fisher exact test) than the control (0%), VitD(−) (0%), and ZOL alone (14.3%) groups. Similar to human patients, rat ONJ lesions prolonged the oral exposure of necrotic bone sequestra and were uniquely associated with pseudoepitheliomatous hyperplasia. The number of terminal deoxynucleotidyl transferase–mediated deoxyuridine triphosphate–biotin nick-end label–positive (TUNEL+) osteoclasts significantly increased on the surface of post–tooth extraction alveolar bone of the VitD(−)/ZOL group, where sustained inflammation was depicted by [18F]fluorodeoxyglucose micro-positron emission tomography (µPET). ONJ lesions were found to be associated with dense accumulation of mixed inflammatory/immune cells. These cells, composed of neutrophils and lymphocytes, appeared to juxtapose apoptotic osteoclasts. It is suggested that the pathophysiologic mechanism(s) underpinning ONJ may involve the interaction between bisphosphonates and compromised vitamin D functions in the realm of skeletal homeostasis and innate immunity. © 2010 American Society for Bone and Mineral Research.

The impact of zoledronic acid therapy in survival of bladder cancer patients with bone metastasis.

e15096 Background: Bone metastases occur in almost 40% of patients with bladder cancer. M-VAC chemotherapy to bone metastasis has been done and median survival time is 10 months. (Bajorin, JCO 17, 3173, 1999). Recent studies demonstrate a direct antiproliferative effect of 3rd generation bisphosphonates (BPs) on bladder tumors, which may influence the survival. Therefore, we examined the clinical impact of zoledronic acid (ZOL; Zometa), a 3rd generation BP, with a focus on the survival, time to progression and pain effect in bladder cancer patients with bone metastases. Methods: Bladder cancer patients (n = 30, Stage IV) with evidence of metastasis bone scan were included. Fifteen patients of 30 experienced bone pain and received ZOL, 4 mg i.v. every 28 days (Group A), whereas the other 15 patients received no ZOL (Group B). All patients were treated with a combination chemotherapy consisted of gemcitabine 1000 mg/m(2) and carboplatin AUC = 6. Results: It was found that Group A had a statistically significant longer survival (p =0.003) when compared to Group B. Median survival time of Group A and Group B was 16 months and 7 months, respectively. A statistically significant positive correlation was found between the number of cycles of therapy with ZOL and total patient survival (p < 0.01, Pearson correlation) and time to progression (p < 0.01). Pain effect of ZOL had no significant difference between the 2 groups of patients (p > 0.05). Urine N-telopeptide of type I collagen (NTx) levels decreased in patients with NTx < or = 29 nM BCE/mM creatinine at baseline after treatment with ZOL. Conclusions: The results of our study suggest that the addition of ZOL increases overall survival in bladder cancer patients with bone metastases. The longer period of receiving ZOL, the better effect on survival and time to progression. Further clinical investigation is warranted. No significant financial relationships to disclose.

Efficacy and safety of a once-yearly i.v. Infusion of zoledronic acid 5 mg versus a once-weekly 70-mg oral alendronate in the treatment of male osteoporosis: A randomized, multicenter, double-blind, active-controlled study

Zoledronic acid (ZOL) has shown beneficial effects on bone turnover and bone mineral density (BMD) in postmenopausal osteoporosis. This study compared the efficacy and safety of a once-yearly i.v. infusion of ZOL with weekly oral alendronate (ALN) in men with osteoporosis. In this multicenter, double-blind, active-controlled, parallel-group study, participants (n = 302) were randomized to receive either once-yearly ZOL 5 mg i.v. or weekly oral ALN 70 mg for 24 months. Changes in BMD and bone marker levels were assessed. ZOL increased BMD at the lumbar spine, total hip, femoral neck, and trochanter and was not inferior to ALN at 24 months [least squares mean estimates of the percentage increases in lumbar spine BMD of 6.1% and 6.2%; difference approximately 0.13; 95% confidence interval (CI) 1.12-0.85 in the ZOL and ALN groups, respectively]. At month 12, the median change from baseline of markers for bone resorption [serum β-C-terminal telopeptide of type I collagen (β-CTx) and urine N-terminal telopeptide of type I collagen (NTx)] and formation [serum N-terminal propeptide of type I collagen (P1NP) and serum bone-specific alkaline phosphatase (BSAP)] were comparable between ZOL and ALN groups. Most men preferred i.v. ZOL over oral ALN. The incidence of adverse events and serious adverse events was similar in the treatment groups. It is concluded that a once-yearly i.v. infusion of ZOL 5 mg increased bone density and decreased bone turnover markers similarly to once-weekly oral ALN 70 mg in men with low bone density.

Abstract 5394: Sequential treatment with zoledronic acid and doxorubicin has no additive effects in an established mouse model of bone metastasis

Abstract Bone metastases still present an unmet need for effective treatment. One preclinical study has suggested a beneficial effect with sequential treatment of doxorubicin (DOX) and zoledronic acid (ZOL). Furthermore, bisphosphonates are used as adjuvant therapy, but controversy of their anti-tumor effects remains. We tested clinically relevant doses of DOX, ZOL and their sequential combination in a treatment setting in a widely used nude mouse model of breast cancer bone metastasis. GFP-transfected MDA-MB-231(SA) human breast cancer cells were inoculated into five-week-old female nude mice via left cardiac ventricle. Subsequent tumor growth and development of osteolytic bone lesions were quantitated by fluorescence imaging and radiography, respectively, on days 14 and 25. The mice were randomized to four groups (n=8/group) on day 14 according to body weight and the presence of osteolytic lesions. Starting on day 15, groups received either weekly dose of vehicle (control group), DOX 2.5 mg/kg i.p. weekly, ZOL 0.1 mg/kg s.c. on day 15 and vehicle weekly, or weekly dose of DOX and a single injection of ZOL 24 hrs after the first dose of DOX (combination group). Bone resorption marker tartrate-resistant acid phosphatase 5b (TRACP 5b) was determined in serum samples collected on days 1, 9, 17 and 24. Bone samples were collected on day 25, and tumor area, trabecular bone area and apoptotic index (TUNEL and apoptotic morphology) were quantitated by histomorphometry. Statistical analysis was performed using One-way ANOVA followed by Dunnett's test or Kruskal-Wallis test followed by Mann-Whitney U-test. All animals in the control and DOX groups had lesions at sacrifice, whereas 12.5% of the mice in the ZOL group and 42.9% in the combination group had lesions. Osteolytic lesion area at sacrifice was significantly lower in both groups treated with ZOL compared to the control group, with no increase from day 14. Lesion area in the DOX-treated group was not different from control. Whole body tumor burden or the tumor area in hind limbs did not differ between the groups, indicating no inhibition on tumor growth. Apoptotic index was increased in groups treated with DOX. ZOL inhibited the increase in serum TRACP 5b, although less effectively in the combination group. Taken together, clinically relevant doses of DOX, ZOL or a sequential combination treatment of these two were not able to inhibit tumor growth in the established disease in this aggressive model of breast cancer bone metastasis. However, DOX increased the apoptosis of cancer cells and ZOL potently inhibited cancer-induced osteolysis, but the sequential treatment did not have additive affects on either tumor growth or osteolytic lesion area. Note: This abstract was not presented at the AACR 101st Annual Meeting 2010 because the presenter was unable to attend. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 5394.

Efficacy and Safety of a Once‐Yearly Intravenous Zoledronic Acid 5 mg for Fracture Prevention in Elderly Postmenopausal Women with Osteoporosis Aged 75 and Older

To determine the efficacy of once-yearly intravenous zoledronic acid (ZOL) 5 mg in reducing risk of clinical vertebral, nonvertebral, and any clinical fractures in elderly osteoporotic postmenopausal women. A post hoc subgroup analysis of pooled data from the Health Outcome and Reduced Incidence with Zoledronic Acid One Yearly (HORIZON) Pivotal Fracture Trial and the HORIZON Recurrent Fracture Trial. Multicenter, randomized, double-blind, placebo-controlled trials. Postmenopausal women (aged > or =75) with documented osteoporosis (T-score < or =-2.5 at femoral neck or >/=1 prevalent vertebral or hip fracture) or a recent hip fracture. Patients were randomized to receive an intravenous infusion of ZOL 5 mg (n=1,961) or placebo (n=1,926) at baseline and 12 and 24 months. Primary endpoints were incidence of clinical vertebral and nonvertebral and any clinical fracture after treatment. At 3 years, incidence of any clinical, clinical vertebral, and nonvertebral fracture were significantly lower in the ZOL group than in the placebo group (10.8% vs 16.6%, 1.1% vs 3.7%, and 9.9% vs 13.7%, respectively) (hazard ratio (HR)=0.65, 95% confidence interval (CI)=0.54-0.78, P<.001; HR=0.34, 95% CI=0.21-0.55, P<.001; and HR=0.73, 95% CI=0.60-0.90, P=.002, respectively). The incidence of hip fracture was lower with ZOL but did not reach statistical significance. The incidence rate of postdose adverse events were higher with ZOL, although the rate of serious adverse events and deaths was comparable between the two groups. Once-yearly intravenous ZOL 5 mg was associated with a significant reduction in the risk of new clinical fractures (vertebral and nonvertebral) in elderly postmenopausal women with osteroporosis.

A single dose of zoledronic acid reverses the deleterious effects of glucocorticoids on titanium implant osseointegration

This study evaluates the effect of zoledronic acid (ZOL) on the osseointegration of titanium implants in rabbits with glucocorticoid (GC)-induced bone loss, and our findings demonstrated that a single dose of ZOL is able to reverse the detrimental effects of GCs on the osseointegration of titanium implants. The purpose of this study is to evaluate the effect of ZOL on the osseointegration of titanium implants in rabbits with GC-induced bone loss. Three groups of six NZW rabbits were treated for 18 weeks with saline (SALINE), GC (methylprednisolone, 0.35 mg/kg three times a week), or GC + ZOL (methylprednisolone + single dose of ZOL, 0.1 mg/kg). The animals received a titanium implant in the left tibia after 6 weeks and were killed at the 18th week. Bone mineral density (BMD) was measured with dual-energy X-ray absorptiometry at baseline, eighth week (W8), and 18th week (W18) after treatment to determine the change upon treatment (BMD). Histomorphometric and serum bone alkaline phosphatase analysis (BAP) were also performed. At W8, GC group had a significant reduction in lumbar spine and tibia BMD compared with SALINE (p = 0.003 and p = 0.000), as also observed for GC + ZOL group (p = 0.014 and p = 0.003) just 2 weeks after ZOL treatment. In contrast, at W18, the GC + ZOL had an evident BMD rescue with similar lumbar spine and tibia BMD compared with SALINE (0.043 +/- 0.006 vs. 0.055 +/- 0.009 g/cm(2), p = 0.457 and 0.027 +/- 0.003 vs. 0.041 +/- 0.011 g/cm(2), p = 0.232) and a significantly higher BMD compared with the GC (p = 0.024 and p = 0.001). Histomorphometry revealed that osseointegration was significantly reduced in GC (tibia cortical thickness and diameter, bone-implant contact, total and peri-implant bone area) whereas GC + ZOL had these parameters similar to SALINE (p > 0.05). Likewise, ZOL reversed the BAP alteration induced by GC. Our findings demonstrated that a single dose of ZOL is able to reverse the detrimental effects of glucocorticoids on the osseointegration of titanium implants, suggesting that ZOL therapy may improve the outcome of bone implants in patients with glucocorticoid-induced osteoporosis.

Retrospective Database Analysis of the Effect of Zoledronic Acid (ZOL) On Skeletal-Related Events (SREs) in Patients (Patients) with Multiple Myeloma (MM).

Abstract 3881Poster Board III-817 BackgroundFor MM patients with malignant bone lesions (BM), SREs including pathologic fracture, spinal cord compression, hypercalcemia of malignancy, and radiotherapy and/or surgery to bone are associated with significant morbidity and mortality and reduced quality of life. ZOL is an IV bisphosphonate (BP) proven to reduce and delay incidence of SREs in several tumor types. This study was designed to assess the benefit of long-term ZOL use in a real-life setting. MethodsClaims-based analysis of commercial and Medicare data from a large US managed care plan and a 45 health-plan database was used to evaluate SRE rates, time from BM to 1st SRE, and mortality in patients treated with ZOL or no IV BP therapy. Patients older than 18 years with MM and BM diagnosed between Jan 2001 and Dec 2006 were included. Treatment Persistency was defined as the absence of a >45 day gap between ZOL administrations. Continuous enrollment in the health plan for 6 months before and no prior evidence of BM or IV BP use were required. When assessing mortality, patients with a date of death less than 30 days following index date were excluded. Patients were followed until they disenrolled from the plan or to the end of the study's follow-up period. In this study, SREs were defined as evidence of pathologic fracture, spinal cord compression, and radiotherapy and/or surgery to bone. ResultsThe study sample included 1,655 Patients with a mean age of 61.7 ± 11.9 years; approx. 64% were treated with ZOL and 36% with no IV BP. Incidences of SREs and mortality rates were both greater in the no IV BP group (incidence rate ratio [IRR] = 1.58; p-value<0.001 and mortality rate = 1.71; p-value=0.0234) vs. the ZOL groups. Longer persistency with ZOL was associated with a lower risks of first SRE compared with no IV BP (trend test p-value=0.0025) [TABLE 1]. ConclusionsThis study showed that in MM Patients with BM, ZOL use was associated with a lower risk of SREs, including fractures, and lower mortality rates. In addition, longer persistence was found to be associated with lower risk of SRE.TABLE 1Risk of ≥ 1 Event per 100-Person Years by ZOL PersistencyPersistency Category (days)SREFractureNo IV BP32.1816.9091-18024.6414.03181-36523.2313.21365-54622.4511.58547+18.799.18P-value: Test for Trend0.00250.0037 Disclosures:Kaura:Novartis: Employment, Equity Ownership. Perez:Novartis: Employment, Equity Ownership.

The impact of zoledronic acid therapy in survival of lung cancer patients with bone metastasis

Bone metastases occur in 20-40% of patients with lung cancer. Recent studies demonstrate a direct antiproliferative effect of 3rd generation bisphosphonates (BPs) on lung tumors, which may influence the survival. Therefore, we examined the clinical impact of zoledronic acid (ZOL; Zometa), a 3rd generation BP, with a focus on the survival, time to progression and pain effect in lung cancer patients with bone metastases. Lung cancer patients (n = 144, Stage IV) with evidence of metastasis bone scan were included. Eighty-seven of 144 experienced bone pain and received ZOL, 4 mg i.v. every 21 days (Group A), whereas the other 57 patients received no ZOL (Group B). All patients were treated with a combination chemotherapy consisted of docetaxel 100 mg/m(2) and carboplatin AUC = 6. It was found that Group A had a statistically significant longer survival (p < 0.01) when compared to Group B. A statistically significant positive correlation was found between the number of cycles of therapy with ZOL and total patient survival (p < 0.01, Pearson correlation) and time to progression (p < 0.01). Pain effect of ZOL had no significant difference between the 2 groups of patients (p > 0.05). Urine N-telopeptide of type I collagen (NTx) levels decreased in patients with NTx < or = 29 nM BCE/mM creatinine at baseline after treatment with ZOL. The results of our study suggest that the addition of ZOL increases overall survival in lung cancer patients with bone metastases. The longer period of receiving ZOL, the better effect on survival and time to progression.

Influence of zoledronic acid on disseminated tumor cells (DTC) in primary breast cancer patients.

Abstract Abstract #2048 Background: The presence of disseminated tumor cells (DTC) in the bone marrow is associated with an increased risk for subsequent bone metastases. Bisphosphonates reduce the occurence of bone metastases in patients (pts) with primary breast cancer (BC) with DTC. The aim of this trial was to evaluate the effect of adjuvant zoledronic acid (ZOL) on DTC in the bone marrow and the Patients and methods: Eligibilty criteria for this prospective, randomized multicenter trial were primary BC pts (pT1-4, N1-2, M0) with positive bone marrow status as determined by a standardized immunocytochemistry staining procedure. Ninety-eight pts were enrolled between April 2002 and January 2006. Randomization and medication had to be started within 28 days of primary surgery. Consenting pts were randomized to the treatment arm (ZOL 4mg i.v. q 4 weekly) or control arm. During the study, all pts received adjuvant treatment in the form of chemotherapy ± hormonal therapy or hormonal therapy alone. Bone marrow aspirations were performed to analyze the presence of DTC at surgery (baseline) and 12 months later. Efficacy and tolerability of intravenous ZOL in pts with primary Result: Bone marrow status was available for 76 patients both at baseline and 12 months after surgery. At baseline a median of 2.0 / range 1-6 (mean 2.1±1.1) DTC were detected in the ZOL group and a median of 2.0 / range 1-35 (mean 2.9±5.5) DTC in the control group. In both groups the number of detected tumor cells decreased during the 12 months follow-up with 0.5±0.8 (median 0.0; 0-2) DTC in the ZOL group and 0.9±0.8 (median 1.0; 0-2) DTC in the control group. By ANCOVA analysis a trend was seen towards a reduction of the number of DTC in the ZOL group compared with the control group (p=0.066). In addition, bone marrow-positive pts treated with ZOL were more likely to become bone marrow negative after 12 months (66.7% versus 35.1%, (p=0.009) compared to the control group. Most frequently reported AEs were musculoskeletal,arthralgia and myalgia in Conclusions: In this first prospective, randomized, multicenter trial we were able to show, that both treatment groups have a reduction in the number of DTC after 12 months as compared to baseline. There is a tendency to more reduction of DTC in the ZOL group. More pts under ZOL achieved a change from positive to negative bone marrow status than controls (p=0.009). Treatment with ZOL was safe and well tolerated. Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 2048.

Effect of combined local treatment with zoledronic acid and basic fibroblast growth factor on implant fixation in ovariectomized rats

Osteoporosis is a skeletal disorder characterized by low bone mass and deterioration of bone microarchitecture resulting in bone fragility, which impairs fixation of the implants. Zoledronic acid (ZOL) is a potential inhibitor of osteoclast-mediated bone resorption and basic fibroblast growth factor (bFGF) is a growth factor that stimulates osteoblast-mediated bone formation, and these drugs could enhance fixation of implants under osteoporotic conditions. In this study, 40 ovariectomized (OVX) rats were randomly divided into 4 groups ( n = 10 for each group) and underwent bilateral tibiae implantation using hydroxyapatite (HA)-coated titanium implant: Control group (distilled water immersing before implantation), ZOL group (1 mg/ml of ZOL immersing), bFGF group (20 μg/ml of bFGF immersing), and ZOL + bFGF group (1 mg/ml of ZOL and 20 μg/ml of bFGF immersing). At 3 months after implantation, all animal were sacrificed and the tibiae were harvested for histology, micro-CT examinations and biomechanical testing. Bone area and contact, determined by histomorphometric analysis, were 2.7-fold and 1.8-fold in the ZOL-treated implants, 1.9-fold and 1.8-fold in the bFGF-treated implants, 3.6-fold and 2.3-fold in the both-treated implants compared with controls ( p < 0.01). Such significant effects were further confirmed by microstructure parameters, the bone volume ratio and the percentage osteointegration were significantly increased by ZOL treatment (3.0-fold and 1.8-fold), bFGF treatment (1.2-fold and 1.9-fold) and ZOL + bFGF treatment (3.3-fold and 2.7-fold) ( p < 0.001). In addition, push-out test showed that the maximum force and the corresponding interfacial shear strength of the implants treated by ZOL, bFGF and ZOL + bFGF was 8.4-fold and 8.6-fold, 3.8-fold and 3.7-fold, 10.8-fold and 10.7-fold of the control levels, respectively ( p < 0.05). The combined treatment was better than either treatment alone for force, but was not different from ZOL alone for interfacial strength. The significant correlation between biomechanical and micro-CT parameters demonstrates the role of microstructure assessments in predicting mechanical fixation of implants ( p < 0.01). Our study suggests that locally applied ZOL or bFGF may improve implant fixation in the ovariectomized rats, and that combined treatment has more beneficial effects on osseointegration, peri-implant bone formation and maximum force than either intervention alone.

Influence of Early and Late Zoledronic Acid Administration on Vertebral Structure and Strength in Ovariectomized Rats

An annual infusion of zoledronic acid (ZOL) reduces fracture risk in osteoporotic patients. Previously, we showed that a single ZOL injection inhibited changes in bone microstructure and strength in rat tibiae after ovariectomy. Here, we determined the effects of a single ZOL injection as preventive and restorative treatment on the bone microstructure and strength in lumbar and caudal vertebrae of ovariectomized (OVX) rats. Twenty-nine female 35-week-old Wistar rats were divided into four groups: SHAM-OVX (n = 9), OVX (n = 5), OVX and early ZOL (n = 8), and OVX and late ZOL (n = 7). ZOL was given once (20 microg/kg body weight s.c.) at OVX in the early ZOL group and 8 weeks later in the late ZOL group; rats were killed 16 weeks after OVX. Trabecular and cortical bone microarchitecture were measured in lumbar (L3) and caudal (Cd6) vertebrae using micro-computed tomography, and compressive mechanical properties were determined in L3 vertebrae. Compared to SHAM-OVX, OVX rats had significantly lower BV/TV; SMI, Tb.N, Tb.Sp, and Conn.D tended to be deteriorated in lumbar vertebrae, while both ZOL groups did not differ from the SHAM-OVX group. Both ZOL groups had significantly higher BV/TV than OVX; the early ZOL group also had significantly lower SMI and higher Tb.Th. OVX tended to decrease mechanical properties, while early and late ZOL treatment inhibited OVX-induced degeneration. Neither OVX nor ZOL induced changes in the trabecular microarchitecture of caudal vertebrae. In summary, in adult rats a single ZOL injection inhibited OVX-induced changes in lumbar vertebral bone microarchitecture and strength.

Zoledronic Acid and Survival in Patients with Metastatic Bone Disease from Lung Cancer and Elevated Markers of Osteoclast Activity

Bone metastases from non-small cell lung cancer (NSCLC) are associated with skeletal-related events (SREs) and elevated levels of N-telopeptide of type I collagen (NTX) in some patients. Zoledronic acid (ZOL) reduces SRE risk and NTX levels. To assess effects of baseline variables, including NTX levels (normal = NTX < 64 nmol/mmol creatinine; high = NTX > or = 64 nmol/mmol creatinine), on treatment effects in NSCLC patients, a retrospective analysis was performed in NSCLC patients with bone metastases (N = 382) treated with ZOL or placebo every 3 weeks in a 21-month randomized clinical trial in patients with NSCLC or other solid tumors. Cox proportional hazards models assessed relative risks (RRs) of SREs, bone lesion progression, and death. Multivariate models analyzed covariate effects on survival. For both placebo- and ZOL-treated patients, high baseline NTX correlated with increased SRE risk (p = 0.068 and 0.012, respectively). Although high versus normal baseline NTX correlated with more than twofold increased risks of bone lesion progression and death in the placebo group (p = 0.039 and 0.001, respectively), correlations were weaker in the ZOL group (RR = 1.38; p = 0.0186 and RR = 1.27; p = 0.142, respectively), suggesting an interaction effect of ZOL and baseline NTX. Among patients with high baseline NTX, ZOL significantly reduced the RR of death by 35% versus placebo (p = 0.024). Per multivariate analysis, ZOL treatment (p = 0.005), higher lymphocyte count (p = 0.011), performance status 0 to 1 (p = 0.012), and absence of narcotic use (p = 0.016) correlated with improved survival. This retrospective analysis revealed statistically significant correlations between ZOL and increased survival versus placebo in NSCLC patients and high baseline NTX levels.

Bone Degeneration and Recovery after Early and Late Bisphosphonate Treatment of Ovariectomized Wistar Rats Assessed by In Vivo Micro-Computed Tomography

Bisphosphonates are antiresorptive drugs commonly used to treat osteoporosis. It is not clear, however, what the influence of the time point of treatment is. Recently developed in vivo micro-computed tomographic (CT) scanners offer the possibility to study such effects on bone microstructure in rats. The aim of this study was to determine the influence of early and late zoledronic acid treatment on bone in ovariectomized rats, using in vivo micro-CT. Twenty-nine female Wistar rats were divided into the following groups: ovariectomy (OVX, n = 5), OVX and zoledronic acid (ZOL) at week 0 (n = 8), OVX and ZOL at week 8 (n = 7), and sham (n = 9). CT scans were made of the proximal tibia at weeks 0, 2, 4, 8, 12, and 16; and bone structural parameters were determined in the metaphysis. Two fluorescent labels were administered to calculate dynamic histomorphometric parameters. At week 16, all groups were significantly different from each other in bone volume fraction (BV/TV), connectivity density, and trabecular number (Tb.N), except for the early ZOL and control groups which were not significantly different for any structural parameter. After ZOL treatment at week 8, BV/TV, structure model index, Tb.N, and trabecular thickness significantly improved in the late ZOL group. The OVX and ZOL groups showed, respectively, higher and lower bone formation rates than the control group. Early ZOL treatment inhibited all bone microstructural changes seen after OVX. Late ZOL treatment significantly improved bone microstructure, although the structure did not recover to original levels. Early ZOL treatment resulted in a significantly better microstructure than late treatment. However, late treatment was still significantly better than no treatment.

Prophylactic Bisphosphonate Treatment Prevents Bone Fractures After Liver Transplantation

A randomized controlled prospective open-label single center trial was performed. At the time of transplantation patients were randomly assigned to one of two treatment arms: The study group of 47 patients received zoledronic acid (ZOL, 8 infusions at 4 mg during the first 12 months after LT), calcium (1000 mg/d) and vitamin D (800 IE/d). The control group consisted of 49 patients who received calcium and vitamin D at same doses (CON). The incidence of bone fractures or death was predefined as the primary endpoint. Secondary endpoints included bone mineral density (BMD), serum biochemical markers of bone metabolism, parameters of trabecular bone histomorphometry and mineralization density distribution (BMDD). Patients were followed up for 24 months. Analysis was performed on an intention-to-treat basis. The primary endpoint fracture or death was reached in 26% of patients in the ZOL group and 46% in the CON group (p = 0.047, log rank test). Densitometry results were different between the groups at the femoral neck at 6 months after LT (mean+/-SD BMD ZOL: 0.80 +/- 0.19 g/cm2 vs. CON: 0.73 +/- 0.14 g/cm2, p = 0.036). Mixed linear models of biochemical bone markers showed less increase of osteocalcin in the ZOL group and histomorphometry and BMDD indicated a reduction in bone turnover. Prophylactic treatment with the bisphosphonate zoledronic acid reduces bone turnover and fractures after liver transplantation.