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Bisphosphonates

Bones are living tissues which are constantly being remodelled (old bone tissue is broken down and removed by cells called osteoclasts - whilst cells called osteoblasts form new bone). Cancer can disrupt the normal balance and speed up the breakdown of bone. This may weaken the bones and release extra calcium from the bones into the blood.

Bisphosphonates are a class of drugs which slow down the breakdown of bones and strengthen bones. They are used to treat a range of medical conditions, including osteoporosis. In relation to cancer they may be used to:

  • relieve bone pain caused by multiple myeloma or bone metastases
  • reduce high levels of calcium in the blood (hypercalcemia)
  • help strengthen bone and reduce the risk of fractures caused by cancer and bone metastases

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Information for Patients and the Public
Information for Health Professionals / Researchers
Latest Research Publications (Biphosphonates and Bone Metastases)
Pamidronate (Aredia)
Zoledronic acid (Zometa)
Secondary Bone Cancer (bone metastasis)

Information Patients and the Public (4 links)


Information for Health Professionals / Researchers (4 links)


Latest Research Publications (Biphosphonates and Bone Metastases)

Himelstein AL, Foster JC, Khatcheressian JL, et al.
Effect of Longer-Interval vs Standard Dosing of Zoledronic Acid on Skeletal Events in Patients With Bone Metastases: A Randomized Clinical Trial.
JAMA. 2017; 317(1):48-58 [PubMed] Article available free on PMC after 03/07/2017 Related Publications
Importance: Zoledronic acid, a third-generation aminobisphosphonate, reduces the incidence of skeletal-related events and pain in patients with bone metastases. The optimal dosing interval for zoledronic acid is uncertain.
Objective: To determine whether zoledronic acid administered every 12 weeks is noninferior to zoledronic acid administered every 4 weeks.
Design, Setting, Participants: Randomized, open-label clinical trial conducted at 269 academic and community sites in the United States. Patients (n = 1822) with metastatic breast cancer, metastatic prostate cancer, or multiple myeloma who had at least 1 site of bone involvement were enrolled between May 2009 and April 2012; follow-up concluded in April 2014.
Interventions: Patients were randomized to receive zoledronic acid administered intravenously every 4 weeks (n = 911) vs every 12 weeks (n = 911) for 2 years.
Main Outcomes and Measures: The primary end point was the proportion of patients having at least 1 skeletal-related event (defined as clinical fracture, spinal cord compression, radiation to bone, or surgery involving bone) within 2 years after randomization and a between-group absolute difference of 7% as the noninferiority margin. Secondary end points included the proportion of patients with at least 1 skeletal-related event by disease type, pain as assessed by the Brief Pain Inventory (range, 0-10; higher scores indicate worse pain), Eastern Cooperative Oncology Group performance status (range, 0-4; higher scores indicate worse disability), incidence of osteonecrosis of the jaw, kidney dysfunction, skeletal morbidity rate (mean number of skeletal-related events per year), and, in a subset of 553 patients, suppression of bone turnover (assessed by C-terminal telopeptide levels).
Results: Among 1822 patients who were randomized (median age, 65 years; 980 [53.8%] women; 855 with breast cancer, 689 with prostate cancer, and 278 with multiple myeloma), 795 completed the study at 2 years. A total of 260 patients (29.5%) in the zoledronic acid every 4-week dosing group and 253 patients (28.6%) in the every 12-week dosing group experienced at least 1 skeletal-related event within 2 years of randomization (risk difference of -0.3% [1-sided 95% CI, -4% to ∞]; P < .001 for noninferiority). The proportions of skeletal-related events did not differ significantly between the every 4-week dosing group vs the every 12-week dosing group for patients with breast cancer, prostate cancer, or multiple myeloma. Pain scores, performance status scores, incidence of jaw osteonecrosis, and kidney dysfunction did not differ significantly between the treatment groups. Skeletal morbidity rates were numerically identical in both groups, but bone turnover was greater (C-terminal telopeptide levels were higher) among patients who received zoledronic acid every 12 weeks.
Conclusions and Relevance: Among patients with bone metastases due to breast cancer, prostate cancer, or multiple myeloma, the use of zoledronic acid every 12 weeks compared with the standard dosing interval of every 4 weeks did not result in an increased risk of skeletal events over 2 years. This longer interval may be an acceptable treatment option.
Trial Registration: clinicaltrials.gov Identifier: NCT00869206.

Thellenberg-Karlsson C, Nyman C, Nilsson S, et al.
Bone-targeted Novel Cytotoxic Polybisphosphonate Conjugate in Castration-resistant Prostate Cancer: A Multicenter Phase 1 Study.
Anticancer Res. 2016; 36(12):6499-6504 [PubMed] Related Publications
BACKGROUND: Osteodex (ODX) is a cytotoxic bone-targeting polybisphosphonate, intended for treatment of bone metastasis from castration-resistant prostate cancer (CRPC). The primary objective of this study was to describe the tolerability and toxicity of such treatment by defining its maximum tolerated dose (MTD) and dose-limiting toxicity (DLT).
PATIENTS AND METHODS: Twenty-eight patients with castration-resistant prostate cancer and confirmed bone metastasis were assigned to seven infusions of ODX every third week, divided in seven ascending dose cohorts.
RESULTS: No DLT's were observed and as pre-specified, the highest dose administered was defined as MTD. In total, 206 adverse events (AE) were recorded and 13,6% were classified as treatment-related, while none were serious or severe (SAE). No cumulative toxicity and no renal toxicity were recorded.
CONCLUSION: ODX was well tolerated, with few and mild side-effects and with apparent treatment efficacy in the highest dose cohort. Further clinical development is currently in progress.

Kamba T, Kamoto T, Maruo S, et al.
A phase III multicenter, randomized, controlled study of combined androgen blockade with versus without zoledronic acid in prostate cancer patients with metastatic bone disease: results of the ZAPCA trial.
Int J Clin Oncol. 2017; 22(1):166-173 [PubMed] Related Publications
OBJECTIVE: To examine the antitumor activity of zoledronic acid (ZA) combined with androgen deprivation therapy (ADT) for men with treatment-naive prostate cancer and bone metastasis.
METHODS: We enrolled 227 men with treatment-naive prostate cancer and bone metastasis. Participants were randomly assigned (1:1 ratio) to receive combined androgen blockade alone (CAB group) or ZA with combined androgen blockade (CZ group). Time to treatment failure (TTTF), time to the first skeletal-related event (TTfSRE), and overall survival (OS) rates were estimated using the Kaplan-Meier method. Hazard ratios (HRs) were calculated using the Cox proportional hazards model. Median follow-up duration was 41.5 months.
RESULTS: Median TTTFs were 12.4 and 9.7 months for the CZ and CAB groups, respectively (HR 0.75; 95 % CI 0.57-1.00; p = 0.051). For men with baseline prostate-specific antigen levels <200 ng/mL, median TTTFs were 23.7 and 9.8 months for the CZ and CAB groups, respectively (HR 0.58; 95 % CI 0.35-0.93; p = 0.023). Median TTfSREs were 64.7 and 45.9 months for the CZ and CAB groups, respectively (HR 0.58; 95 % CI 0.38-0.88; p = 0.009). OS was similar between the groups.
CONCLUSIONS: This study failed to demonstrate that combined use of ZA and ADT significantly prolonged TTTF in men with treatment-naive prostate cancer and bone metastasis. However, it generates a new hypothesis that the combined therapy could delay the development of castration resistance in a subgroup of patients with low baseline prostate-specific antigen values <200 ng/mL. The treatment also significantly prolonged TTfSRE but did not affect OS.

Raje N, Vadhan-Raj S, Willenbacher W, et al.
Evaluating results from the multiple myeloma patient subset treated with denosumab or zoledronic acid in a randomized phase 3 trial.
Blood Cancer J. 2016; 6:e378 [PubMed] Article available free on PMC after 03/07/2017 Related Publications
In a phase 3 trial of denosumab vs zoledronic acid in patients (n=1776) with bone metastases and solid tumors or multiple myeloma, denosumab was superior to zoledronic acid for the primary end point of prevention of skeletal-related events. There was no difference in overall survival between the two groups; however, an ad hoc overall survival analysis in the multiple myeloma subset of patients (n=180) favored zoledronic acid (hazard ratio (HR) 2.26; 95% confidence interval (CI) 1.13-4.50; P=0.014). In the present analysis, we found imbalances between the groups with respect to baseline risk characteristics. HRs with two-sided 95% CIs were estimated using the Cox model. After adjustment in a covariate analysis, the CI crossed unity (HR 1.86; 95% CI 0.90-3.84; P=0.0954). Furthermore, we found a higher rate of early withdrawals for the reasons of lost to follow-up and withdrawal of consent in the zoledronic acid group; after accounting for these, the HR was 1.31 (95% CI 0.80-2.15; P=0.278). In conclusion, the survival results in multiple myeloma patients in this trial were confounded and will eventually be resolved by an ongoing phase 3 trial.

Lipton A, Fizazi K, Stopeck AT, et al.
Effect of denosumab versus zoledronic acid in preventing skeletal-related events in patients with bone metastases by baseline characteristics.
Eur J Cancer. 2016; 53:75-83 [PubMed] Related Publications
BACKGROUND: Analyses of phase III trials showed that denosumab was superior to zoledronic acid (ZA) in preventing skeletal-related events (SREs) irrespective of age, history of SREs, or baseline pain status. This analysis assessed the risk of SREs across additional baseline characteristics.
PATIENTS AND METHODS: Patients (N = 5543) from three phase III trials who had breast cancer, prostate cancer, or other solid tumours and one or more bone metastasis were included. Superiority of denosumab versus ZA in reducing risk of first SRE and first and subsequent SREs was assessed in subgroups defined by the Eastern Cooperative Oncology Group performance status (ECOG PS), bone metastasis location, bone metastasis number, visceral metastasis presence/absence, and urinary N-telopeptide (uNTx) level using Cox proportional hazards and Anderson-Gill models. Subgroups except bone metastasis location were also assessed for each solid tumour type.
RESULTS: Compared with ZA, denosumab significantly reduced the risk of first SRE across all subgroups (hazard ratio [HR] ranges: ECOG PS, 0.79-0.84; bone metastasis location, 0.78-0.83; bone metastasis number, 0.78-0.84; visceral metastasis presence/absence, 0.80-0.82; uNTx level, 0.73-0.86) and reduced the risk of first and subsequent SREs in all subgroups (HR ranges: ECOG PS, 0.76-0.83; bone metastasis location, 0.78-0.84; bone metastasis number, 0.79-0.81; visceral metastasis presence/absence, 0.79-0.81; uNTx level, 0.74-0.83). Similar results were observed in subgroups across tumour types.
CONCLUSION: Denosumab was superior to ZA in preventing SREs in patients with bone metastases from advanced cancer, regardless of ECOG PS, bone metastasis number, baseline visceral metastasis presence/absence, and uNTx level.

Jacobs C, Kuchuk I, Bouganim N, et al.
A randomized, double-blind, phase II, exploratory trial evaluating the palliative benefit of either continuing pamidronate or switching to zoledronic acid in patients with high-risk bone metastases from breast cancer.
Breast Cancer Res Treat. 2016; 155(1):77-84 [PubMed] Related Publications
Previous studies suggest switching from pamidronate to a more potent bone-targeted agent is associated with biomarker and palliative response in breast cancer patients with bone metastases. Until now, this has not been addressed in a double-blind, randomized trial. Breast cancer patients with high-risk bone metastases, despite >3 months of pamidronate, were randomized to either continue pamidronate or switch to zoledronic acid every 4 weeks for 12 weeks. Primary outcome was the proportion of patients achieving a fall in serum C-telopeptide (sCTx) at 12 weeks. Secondary outcomes included difference in mean sCTx, pain scores, quality of life, toxicity, and skeletal-related events (SREs). Seventy-three patients entered the study; median age 61 years (range 37-87). Proportion of patients achieving a fall in sCTx over the 12-week evaluation period was 26/32 (81 %) with zoledronic acid and 18/29 (62 %) with pamidronate (p = 0.095). Mean decrease in sCTx (mean difference between groups = 50 ng/L, 95 % CI 18-84; p = 0.003) was significantly greater in patients who received zoledronic acid. Quality of life, pain scores, toxicity, and frequency of new SREs were comparable between the two arms. While a switch from pamidronate to zoledronic acid resulted in reduction in mean sCTx, there were no significant differences between the arms for proportion of patients achieving a reduction in sCTx, quality of life, pain scores, toxicity or SREs. Given the lack of palliative improvement, the current data do not support a switching strategy.

von Moos R, Body JJ, Egerdie B, et al.
Pain and analgesic use associated with skeletal-related events in patients with advanced cancer and bone metastases.
Support Care Cancer. 2016; 24(3):1327-37 [PubMed] Article available free on PMC after 03/07/2017 Related Publications
PURPOSE: Bone metastases secondary to solid tumors increase the risk of skeletal-related events (SREs), including the occurrence of pathological fracture (PF), radiation to bone (RB), surgery to bone (SB), and spinal cord compression (SCC). The aim of this study was to evaluate the impact of SREs on patients' pain, analgesic use, and pain interference with daily functioning.
METHODS: Data were combined from patients with solid tumors and bone metastases who received denosumab or zoledronic acid across three identically designed phase 3 trials (N = 5543). Pain severity (worst pain) and pain interference were assessed using the Brief Pain Inventory at baseline and each monthly visit. Analgesic use was quantified using the Analgesic Quantification Algorithm.
RESULTS: The proportion of patients with moderate/severe pain and strong opioid use generally increased in the 6 months preceding an SRE and remained elevated, while they remained relatively consistent over time in patients without an SRE. Regression analysis indicated that all SRE types were significantly associated with an increased risk of progression to moderate/severe pain and strong opioid use. PF, RB, and SCC were associated with significantly greater risk of pain interference overall. Results were similar for pain interference with emotional well-being. All SRE types were associated with significantly greater risk of pain interference with physical function.
CONCLUSIONS: SREs are associated with increased pain and analgesic use in patients with bone metastases. Treatments that prevent SREs may decrease pain and the need for opioid analgesics and reduce the impact of pain on daily functioning.

Hoskin P, Sundar S, Reczko K, et al.
A Multicenter Randomized Trial of Ibandronate Compared With Single-Dose Radiotherapy for Localized Metastatic Bone Pain in Prostate Cancer.
J Natl Cancer Inst. 2015; 107(10) [PubMed] Related Publications
BACKGROUND: The radiotherapy or ibandronate (RIB) trial was a randomized multicenter nonblind two-arm trial to compare intravenous ibandronate given as a single infusion with single-dose radiotherapy for metastatic bone pain.
METHODS: Four hundred seventy prostate cancer patients with metastatic bone pain who were suitable for local radiotherapy were randomly assigned to radiotherapy (single dose, 8 Gy) or intravenous infusion of ibandronate (6mg) in a noninferiority trial. Pain was measured using the Brief Pain Inventory at baseline and four, eight, 12, 26, and 52 weeks. Pain response was assessed using World Health Organization (WHO) criteria and the Effective Analgesic Score (EAS); the maximum allowable difference was ±15%. Patients failing to respond at four weeks were offered retreatment with the alternative treatment. Quality of life (QoL) was assessed at baseline and four and 12 weeks. Because the trial was designed with a 5% one-sided test, we provide 90% confidence intervals (two-sided) for differences in pain response.
RESULTS: Overall, pain response was not statistically different at four or 12 weeks (WHO: -3.7%, 90% confidence interval [CI] = -12.4% to 5.0%; and 6.7%, 90% CI = -2.6 to 16.0%, respectively). Corresponding differences using the EAS were -7.5% and -3.5%. However, a more rapid initial response with radiotherapy was observed. There was no overall difference in toxicity, although each treatment had different side effects. QoL was similar at four and 12 weeks. Overall survival was similar between the two groups but was better among patients having retreatment than those who did not.
CONCLUSIONS: A single infusion of ibandronate had outcomes similar to a single dose of radiotherapy for metastatic prostate bone pain. Ibandronate could be considered when radiotherapy is not available.

Luedders DW, Steinhoff J, Thill M, et al.
Lack of difference in acute nephrotoxicity of intravenous bisphosphonates zoledronic acid and ibandronate in women with breast cancer and bone metastases.
Anticancer Res. 2015; 35(3):1797-802 [PubMed] Related Publications
BACKGROUND: More than 50% of patients with advanced breast cancer develop bone metastases that may lead to multiple complications such as pathological fractures, bone pain or hypercalcaemia. The standard treatment, besides endocrine, targeted-therapy or chemotherapy, is the use of bisphosphonates. However, one of their main adverse side-effects is bisphosphonate-induced nephrotoxicity. The mechanism by which the latter occurs is not well-understood, although emerging evidence suggests that the effect of bisphosphonates on the kidney may differ between agents.
PATIENTS AND METHODS: The aim of this evaluation was to compare the renal toxicity of 6 mg ibandronate i.v. versus 4 mg zoledronic acid i.v. over a period of six months in women with breast cancer and bone metastases. A prospective randomized trial was carried out to examine specific kidney and other parameters (α1- and β2-microglobulin, albumin, α2-macroglobulin, IgG and C-reactive protein (CRP) generated from spontaneous urine samples from 17 patients of each group.
RESULTS: We were unable to find any significant difference between the two treatment groups with regard to renal toxicity. All patients, independently of the applied bisphosphonate, experienced only temporary renal dysfunction without any evidence of irreversible damage in terms of acute nephrotoxicity during the study period. α1-Microglobulin, a marker for proximal tubular damage, in particular, was not differently elevated in either group.
CONCLUSION: Both applied bisphosphonates were found to be well-tolerated and safe with regard to renal toxicity during a six-month treatment period in patients with otherwise healthy kidneys having advanced breast cancer and bone metastases.

Wu J, Zheng W, Tan Y, et al.
Zoledronic Acid may reduce intraoperative bleeding in spinal tumors: a prospective cohort study.
Biomed Res Int. 2015; 2015:936307 [PubMed] Article available free on PMC after 03/07/2017 Related Publications
Between June 2010 and June 2011, 176 patients were divided into 2 groups: a group with spinal metastasis of solid tumors (n = 157) and a group with multiple myeloma (n = 19). Both groups were further divided into 2 subgroups: a group receiving zoledronic acid before surgery and a control group. The zoledronic acid subgroup of the solid tumors group was group A (n = 81), the control subgroup of the solid tumors group was group B (n = 76), the zoledronic acid subgroup of the multiple myeloma group was group C (n = 10), and the control subgroup of the multiple myeloma group was group D (n = 9). The average intraoperative blood loss during spinal surgery was as follows: 1311 ± 691 mL in group A and 1752 ± 740 mL in group B (P = 0.000) and 1994 ± 810 mL in group C and 3134 ± 795 mL in group D (P = 0.000). Patients receiving zoledronic acid before surgery had significantly less intraoperative bleeding than those who did not receive it. Preoperative use of zoledronic acid can effectively reduce intraoperative bleeding during surgery for the treatment of spinal tumors.

Macpherson IR, Bray C, Hopkins C, et al.
Loading dose ibandronate versus standard oral ibandronate in patients with bone metastases from breast cancer.
Clin Breast Cancer. 2015; 15(2):117-27 [PubMed] Related Publications
INTRODUCTION: In this phase II trial, the efficacy and safety of loading-dose I.V. ibandronate in patients with breast cancer with bone metastases were evaluated.
PATIENTS AND METHODS: Thirty-four patients were randomized to receive a loading dose of 12 mg I.V. ibandronate on day 1 then oral ibandronate 50 mg daily (arm A), or standard oral therapy of 50 mg ibandronate daily from day 1 (arm B). The primary end point was percentage change in serum C-terminal crosslinking telopeptide of type I collagen (S-CTX) from baseline by day 5 of study. Secondary/exploratory end points included percentage change in other bone turnover markers (N-terminal cross-linking telopeptides of type I collagen [NTX], procollagen type I N propeptide, bone alkaline phosphatase) and change in average bone pain score.
RESULTS: There was a significantly greater reduction in S-CTX at day 5 in arm A compared with arm B (median difference, 15.82%; P = .005). There was also a significantly greater reduction in urine NTX/creatinine at day 5 (P = .009) and at the end of weeks 1 to 8 (averaged; P = .006). Average bone pain score was lower in arm A at the end of 8 weeks (P = .012). There were no additional adverse events after administration of 12 mg I.V. loading dose of ibandronate.
CONCLUSION: A 12-mg dose of I.V. ibandronate rapidly reduced markers of bone turnover and can be administered without additional toxicity.

Gierloff M, Reutemann M, Gülses A, et al.
Effects of zoledronate on the radiation-induced collagen breakdown: a prospective randomized clinical trial.
Clin Transl Oncol. 2015; 17(6):454-61 [PubMed] Related Publications
BACKGROUND: A negative side effect of therapeutic irradiation is the radiation-induced bone loss which can lead, in long term, to pathological fractures. Until today, the detailed mechanism is unknown. If osteoclasts would mainly contribute to the pathological bone loss, bisphosphonates could potentially counteract the osteolytic process and possibly help to prevent long-term complications. The aim of this study was to evaluate the effect of zoledronic acid on the early radiation-induced degradation of bone collagen fibrils by monitoring the urinary excretion of hydroxylysylpyridinoline and lysylpyridinoline under radiotherapy.
PATIENTS AND METHODS: A total of 40 patients with skeletal metastases were assigned for a local radiotherapy and bisphosphonate treatment. The patients were prospectively randomized into two treatment groups: group A (n = 20) received the first zoledronate administration after and group B (n = 20) prior to the radiotherapy. Urine samples were collected from each patient on the first day, in the middle, and on the last day of the radiation therapy. Measurement of the bone metabolites hydroxylysylpyridinoline and lysylpyridinoline was performed by high-performance liquid chromatography. Statistical analysis was performed using the Mann-Whitney U test.
RESULTS: The hydroxylysylpyridinoline and lysylpyridinoline excretion decreased significantly in the combined bisphosphonate and radiotherapy group (p = 0.02, p = 0.08). No significant change of the hydroxylysylpyridinoline and lysylpyridinoline excretion was determined in the patients that received solely irradiation.
CONCLUSION: The results indicate the ability of zoledronate to prevent the early radiation-induced bone collagen degradation suggesting that the radiation-induced bone loss is mainly caused by osteoclastic bone resorption rather than by a direct radiation-induced damage.

Nozawa M, Hara I, Matsuyama H, et al.
Significance of baseline bone markers on disease progression and survival in hormone-sensitive prostate cancer with bone metastasis.
World J Urol. 2015; 33(9):1263-8 [PubMed] Related Publications
PURPOSE: This study evaluated the baseline patient characteristics associated with the time to biochemical progression and overall survival in patients who participated in a phase II trial on zoledronic acid combined with the initial androgen-deprivation therapy for treatment-naïve bone-metastatic prostate cancer.
METHODS: Patients received zoledronic acid 4 mg intravenously every 4 weeks for up to 24 months, concomitantly started with bicalutamide 80 mg orally every day and goserelin acetate 10.8 mg subcutaneously every 12 weeks.
RESULTS: A total of 53 Japanese patients were enrolled between July 2008 and April 2010, and 52 patients were evaluable. Median follow-up period was 41.6 months. Updated median time to biochemical progression was 25.9 months (95 % confidence interval 14.5-49.9). Higher serum bone-specific alkaline phosphatase was an independent risk factor for time to biochemical progression based on multivariate analysis (hazard ratio 6.51; 95 % confidence interval 2.71-15.62; P < 0.001). Median time to biochemical progression for patients with serum bone-specific alkaline phosphatase level higher than 26 μg/L was 12.7 months. Multivariate analysis indicated that higher serum C-terminal telopeptide of type I collagen independently increased the risk of death (hazard ratio 9.62; 95 % confidence interval 2.11-43.89; P = 0.003). Median overall survival for patients with serum C-terminal telopeptide of type I collagen level higher than 8.0 ng/ml was 31.1 months.
CONCLUSIONS: Baseline bone markers can be useful as predictors for disease progression and survival time in patients with bone metastasis from treatment-naïve prostate cancer treated with upfront zoledronic acid concomitantly started with androgen-deprivation therapy.

Pan Y, Jin H, Chen W, et al.
Docetaxel with or without zoledronic acid for castration-resistant prostate cancer.
Int Urol Nephrol. 2014; 46(12):2319-26 [PubMed] Related Publications
PURPOSE: The aim of this study was to evaluate the efficacy and safety of zoledronic acid (ZA) in the combination of docetaxel-based chemotherapy for castration-resistant prostate cancer with bone metastases.
METHODS: We conducted a prospective study in recruiting 105 prostate cancer patients with bone metastases from 2008 to 2010. Patients were randomly divided into two groups, 53 in the docetaxel-based chemotherapy + ZA(Group A) and 52 in the docetaxel-based chemotherapy + placebo(Group B). The different outcome between patients treated with chemotherapy combined with ZA and those with chemotherapy alone was evaluated. The Cox multivariate analyses of clinical features and different treatment methods of the 105 patients were conducted.
RESULTS: There was a response of prostate-specific antigen (PSA) in 33 (62.3 %) in Group A and 28 (53.8 %) in Group B (P = 0.20). The combined approach group had better bone progression-free survival (BPFS) (9.0 vs. 6.0 months, P < 0.05) and overall survival (OS) (19.0 vs. 15.0 months, P = 0.02), but no statistical evidence of benefit was observed in terms of PSA response. Cox multivariate analysis identified the following independent prognostic factors: received ZA, high Hb level and more than 6 cycles of chemotherapy. There were no clinical relevant differences in the frequencies of adverse events between these two groups.
CONCLUSIONS: Zoledronic acid treatment combined with docetaxel-based chemotherapy could have a better bone pain control and improve BPFS and OS for prostate cancer patients with bone metastases. The PSA response and SREs rate are similar.

Yeh DC, Chen DR, Chao TY, et al.
EORTC QLQ-BM22 quality of life evaluation and pain outcome in patients with bone metastases from breast cancer treated with zoledronic acid.
In Vivo. 2014 Sep-Oct; 28(5):1001-4 [PubMed] Related Publications
BACKGROUND: We assessed the effect of zoledronic acid on quality of life (QOL) and pain outcome in breast cancer patients with bone metastases using the European Organization for Research and Treatment of Cancer bone metastases module (EORTC QLQ-BM22).
PATIENTS AND METHODS: Three hundred sixty-six breast cancer patients receiving zoledronic acid for bone metastases from 13 Centers were prospectively enrolled. QOL was evaluated using the EORTC QLQ-BM22 and pain outcome were measured monthly with a Visual Analog Scale (VAS) score for 24 months.
RESULTS: No significant change of functional scale (functional interference and psychosocial aspects) of the EORTC QLQ-BM22 was reported. Significant reduction of the symptom scale was noted after treatment compared with the baseline. The painful site subscale was significantly reduced during the first 12 months, with the exception the 6-month follow-up of point. Pain characteristics subscale was also significantly lower from the 2-month time point onwards. VAS scores indicated a significant reduction in pain over the course of the study to the 22-month time point follow-up compared to the baseline.
CONCLUSION: Zoledronic acid treatment improved QOL of breast cancer patients with bone metastases by relieving bone pain.

Broom RJ, Hinder V, Sharples K, et al.
Everolimus and zoledronic acid in patients with renal cell carcinoma with bone metastases: a randomized first-line phase II trial.
Clin Genitourin Cancer. 2015; 13(1):50-8 [PubMed] Related Publications
BACKGROUND: Bone metastases from renal cell carcinoma (RCC) are a major cause of morbidity. Post hoc analysis has suggested that bone turnover markers can identify patients at risk of skeletal-related events (SREs) among those receiving zoledronic acid. This study sought to evaluate the effect on bone metastases of everolimus alone compared with everolimus plus zoledronic acid.
PATIENTS AND METHODS: Thirty treatment-naive patients with RCC and ≥ 1 bone metastases were randomized 1:1 to everolimus (10 mg daily) versus everolimus plus zoledronic acid (4 mg intravenously 4-weekly). Bone-specific assessments were performed at baseline and at weeks 1, 4, 8, and 12. Treatment was continued on allocated arm until progression per RECIST 1.1 (Response Evaluation Criteria in Solid Tumors, version 1.1). The primary outcome measure was urine N-telopeptide (uNTX) level, with secondary measures of plasma C-telopeptide (CTX), quality of life (Functional Assessment of Cancer Therapy-Bone Pain [FACT-BP], Brief Pain Inventory [BPI]), progression-free survival (PFS), SREs, and safety.
RESULTS: After 12 weeks, reduction in mean uNTX and CTX on everolimus plus zoledronic acid relative to everolimus was 68.4% (95% CI, 60.1%-74.9%; P < .0001) and 76.2% (95% CI, 67.3%-82.7%; P < .0001), respectively. There was no evidence of a difference for FACT-BP (P = .5), but evidence was favorable for BPI Severity (P = .05) and BPI Interference (P = .06). Median PFS was 7.5 months (95% CI, 3.4-11.2) on everolimus plus zoledronic acid and 5.4 months (95% CI, 3.2-6.3) on everolimus (P = .009). Median time to first SRE was 9.6 months (95% CI, 4.3-15.5) on everolimus plus zoledronic acid and 5.2 months (95% CI, 1.6-8.2) on everolimus (P = .03).
CONCLUSION: In this RCC population, the addition of zoledronic acid to everolimus significantly reduced bone resorption markers and may prolong tumor control.

Okegawa T, Higaki M, Matsumoto T, et al.
Zoledronic acid improves clinical outcomes in patients with bone metastatic hormone-naïve prostate cancer in a multicenter clinical trial.
Anticancer Res. 2014; 34(8):4415-20 [PubMed] Related Publications
AIM: To assess whether zoledronic acid (ZOL) adds to the effect of combined androgen blockade (CAB) in patients with hormone-naive bone metastatic prostate cancer.
PATIENTS AND METHODS: Patients were treated with either a combination of CAB (luteinizing hormone-releasing hormone agonist and bicalutamide) and ZOL (CAB-Z group) or CAB-alone (historical control patients, CAB-C group). ZOL was injected intravenously at 4 mg every 4 weeks. One hundred and five and 100 patients among 205 enrolled patients were assigned to the CAB-Z group and CAB-C group, respectively. The time to prostate-specific antigen (PSA) failure in patients in the CAB-Z group was compared to that in the CAB-C group. The primary end-point of the study was the time-to-PSA failure.
RESULTS: PSA and serum N-telopeptide of type I collagen (NTx) levels were examined before treatment and every 3 months after treatment. PSA failure occurred in 42 (40.0%) patients in the CAB-Z group and 48 (48.0%) patients in the CAB-C group. The biochemical recurrence-free rate was significantly lower in patients in the CAB-C group (p=0.004, by log-rank test). The categorical biopsy Gleason score pre-treatment serum NTx and treatment with ZOL were shown to be independent predictors of PSA failure-free survival time (p=0.040, p=0.005 and p=0.026, respectively).
CONCLUSION: ZOL given with CAB as initial treatment delays the time-to-PSA failure in patients with hormone-naive bone metastatic prostate cancer.

Li F, Wang W, Li L, et al.
An effective therapy to painful bone metastases: cryoablation combined with zoledronic acid.
Pathol Oncol Res. 2014; 20(4):885-91 [PubMed] Related Publications
Approximately half or more of patients diagnosed with late malignant tumors may suffer from metastatic bone pain, effective palliation of pain becomes an important part of comprehensive therapy for malignant tumors. In this study, we examined the efficacy and safety of the combined regimen of cryoablation and zoledronic acid in patients of bone metastatic pain. A total of 84 subjects were randomly divided into three groups, and underwent treatments of cryoablation plus zoledronic acid, cryoablation alone, zoledronic acid alone between June 2009 and March 2012. Patients responses had been assessed for a total of 6 months by using the Brief Pain Inventory (BPI)-Short Form. The results showed that the mean response of worst and average pain significantly dropped at week 2 (all P < 0.05) in group with cryoablation treatment but at week 4 (all P < 0.05) in group with zoledronic acid treatment. While between week 16 and week 24, zoledronic acid treatments showed more durable response to worst and average pain compared to cryoablation (all P < 0.05). Cryoablation plus zoledronic acid regimen showed significant drop in worst and average pain between week 1 and week 4 compared to zoledronic acid alone (all P < 0.05) and more durable effect on bone metastatic pain between week 12 and week 24 than cryoablation alone (all P < 0.05). Additionally, no serious adverse effects and complication were observed by this combination use. In conclusion, cryoablation combined with zoledronic acid was safe and effective regimen and showed its superiority of fast response and durable effect on painful bone metastases.

Addison CL, Bouganim N, Hilton J, et al.
A phase II, multicentre trial evaluating the efficacy of de-escalated bisphosphonate therapy in metastatic breast cancer patients at low-risk of skeletal-related events.
Breast Cancer Res Treat. 2014; 144(3):615-24 [PubMed] Article available free on PMC after 03/07/2017 Related Publications
The optimal frequency of intravenous (IV) bisphosphonate administration is unclear. We thus performed a study evaluating the effects of switching from 3-4 to 12 weekly therapy in patients with biochemically defined low-risk bone metastases. Patients with serum C-telopeptide (CTx) levels ≤600 ng/L after ≥3 months of 3-4 weekly IV pamidronate were switched to 12 weekly therapy for 48 weeks. Primary endpoint was the proportion of patients maintaining CTx levels in the lower-risk range. All endpoints (serum CTx and bone-specific alkaline phosphatase (BSAP), skeletal-related events (SREs) and self-reported pain) were measured at baseline, 6, 12, 24, 36 and 48 weeks. Treatment failure was defined as biochemical failure (CTx > 600 ng/L) or a SRE. Exploratory biomarkers including; serum TGF-β, activin-A, bone sialoprotein (BSP), procollagen type 1 N-terminal propeptide and urinary N-telopeptide (NTx) were assessed at baseline as predictors for failure to complete treatment. Seventy-one patients accrued and 43 (61 %) completed 48 weeks of de-escalated therapy. Reasons for failure to complete treatment included; biochemical failure (CTx > 600 ng/L) (n = 10, 14.1 %), on-study SRE (n = 9, 12.7 %), disease progression (n = 7, 9.9 % including death from disease [n = 1, 1.4 %]) or patient choice (n = 2, 2.8 %). Elevated baseline levels of CTx, BSAP, NTx and BSP were associated with treatment failure. The majority of patients in this biochemically defined low-risk population could switch from 3-4 weekly to 12 weekly bisphosphonate therapy with no effect on CTx levels or SREs during the 48 week study. Larger trials are required to assess the roles of biomarkers as predictors of adequacy of de-escalated therapy.

Wirth M, Tammela T, Cicalese V, et al.
Prevention of bone metastases in patients with high-risk nonmetastatic prostate cancer treated with zoledronic acid: efficacy and safety results of the Zometa European Study (ZEUS).
Eur Urol. 2015; 67(3):482-91 [PubMed] Related Publications
BACKGROUND: Patients with high-risk localised prostate cancer (PCa) are at risk of developing bone metastases (BMs). Zoledronic acid (ZA) significantly reduces the incidence of skeletal complications in castration-resistant metastatic PCa versus placebo.
OBJECTIVE: To investigate ZA for the prevention of BMs in high-risk localised PCa.
DESIGN, SETTING, AND PARTICIPANTS: Randomised open-label multinational study with patients having at least one of the following: prostate-specific antigen ≥20 ng/ml, node-positive disease, or Gleason score 8-10.
INTERVENTION: Standard PCa therapy alone or combined with 4mg ZA intravenously every 3 mo for ≤4 yr.
OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: BMs were assessed using locally evaluated bone-imaging procedures (BIPs), with subsequent blinded central review. Patients with BMs, time to BMs, overall survival, and adverse events were compared between treatment groups.
RESULTS AND LIMITATIONS: A total of 1393 of 1433 randomised patients were used for intention-to-treat (ITT) efficacy analyses, with 1040 patients with BIP-BM outcome status at 4±0.5 yr. The local urologist/radiologist diagnosed BIP-BMs in 88 of 515 patients (17.1%) in the ZA group and 89 of 525 patients (17.0%) in the control group (chi-square test: p=0.95), with a difference between proportions of 0.1% (95% confidence interval [CI], -4.4 to 4.7) in favour of the control group. In the ITT population (n=1393), the Kaplan-Meier estimated proportion of BMs after a median follow-up of 4.8 yr was 14.7% in the ZA group versus 13.2% in the control group (log-rank: p=0.65). Low hot spot numbers on bone scans were confirmed as metastases with additional imaging. Central reviews of BIPs were possible only on a subset of patients.
CONCLUSIONS: ZA administered every 3 mo was demonstrated to be ineffective for the prevention of BMs in high-risk localised PCa patients at 4 yr.
PATIENT SUMMARY: Zoledronic acid administered every 3 mo was demonstrated to be ineffective for the prevention of bone metastases in high-risk nonmetastatic PCa patients at 4 yr.
TRIAL REGISTRATION: The ZEUS trial is registered in the Dutch trial register www.trialregister.nl and the ISRCTN register at http://www.controlled-trials.com/ISRCTN66626762.

Smith MR, Halabi S, Ryan CJ, et al.
Randomized controlled trial of early zoledronic acid in men with castration-sensitive prostate cancer and bone metastases: results of CALGB 90202 (alliance).
J Clin Oncol. 2014; 32(11):1143-50 [PubMed] Article available free on PMC after 03/07/2017 Related Publications
PURPOSE: Zoledronic acid decreases the risk for skeletal-related events (SREs) in men with castration-resistant prostate cancer and bone metastases but its role earlier in the natural history of the disease is unknown. This phase III study evaluated the efficacy and safety of earlier treatment with zoledronic acid in men with castration-sensitive metastatic prostate cancer.
PATIENTS AND METHODS: Men with castration-sensitive prostate cancer and bone metastases whose androgen-deprivation therapy was initiated within 6 months of study entry were randomly assigned in a blinded 1:1 ratio to receive zoledronic acid (4 mg intravenously every 4 weeks) or a placebo. After their disease progressed to castration-resistant status, all patients received open-label treatment with zoledronic acid. The primary end point was time to first SRE, defined as radiation to bone, clinical fracture, spinal cord compression, surgery to bone, or death as a result of prostate cancer. Target accrual was 680 patients. Primary analysis was planned after 470 SREs. The study was discontinued prematurely (645 patients; 299 SREs) after the corporate supporter withdrew study drug supply.
RESULTS: Early zoledronic acid was not associated with increased time to first SRE. The median time to first SRE was 31.9 months in the zoledronic acid group (95% CI, 24.2 to 40.3) and 29.8 months in the placebo group (95% CI, 25.3 to 37.2; hazard ratio, 0.97; 95% CI, 0 to 1.17; one-sided stratified log-rank P = .39). Overall survival was similar between the groups (hazard ratio, 0.88; 95% CI, 0.70 to 1.12; P = .29). Rates of adverse events were similar between the groups.
CONCLUSION: In men with castration-sensitive prostate cancer and bone metastases, early treatment with zoledronic acid was not associated with lower risk for SREs.

Chiang PH, Wang HC, Lai YL, et al.
Zoledronic acid treatment for cancerous bone metastases: a phase IV study in Taiwan.
J Cancer Res Ther. 2013 Oct-Dec; 9(4):653-9 [PubMed] Related Publications
AIM OF STUDY: To investigate the features, adverse effects, bone marker changes in patients with breast cancer, prostate cancer, and multiple myeloma with bone metastases under Zometa® therapy.
MATERIALS AND METHODS: This post-marketing study included 414 Taiwanese patients with bone metastases secondary to breast cancer, prostate cancer, or multiple myeloma who received Zometa® for 48 weeks. The patients' characteristics, medication and adverse events were recorded, meanwhile changes in four serum bone metabolic markers and pain reduction were assessed every three months for one year.
RESULTS: A total of 3,711 doses of Zometa® were infused, accounting for 294.5 patient-years. Adverse events occurred in 9.4% of patients, with bone pain, insomnia, constipation, and pyrexia as the most frequently reported. There was no osteonecrosis of the jaw. The incidence of skeletal-related events decreased significantly from 44.9% to 18.8%. Serum NTx, BAP, and TRACP5b steadily decreased to nadir at six months, but serum OPG was persistently elevated until the end of one year. The average decrease in pain score was 14.1, 14.3, and 16.7 for prostate cancer, breast cancer, and multiple myeloma patients, respectively.
CONCLUSION: Zometa® can be safely administered in Taiwanese patients with bone metastases secondary to breast cancer, prostate cancer, and multiple myeloma. There are concomitant decreases in skeletal-related events and bone pain.

Foroni C, Milan M, Strina C, et al.
Pure anti-tumor effect of zoledronic acid in naïve bone-only metastatic and locally advanced breast cancer: proof from the "biological window therapy".
Breast Cancer Res Treat. 2014; 144(1):113-21 [PubMed] Related Publications
The study investigated the anti-tumour effect of zoledronic acid (ZA) administered alone in a biological window therapy in naïve bone-only metastatic and locally advanced breast cancer (LABC) patients. 33 patients with LABC (Group 1) and 20 patients with a first diagnosis of bone metastasis only (Group 2) received 4 mg single dose of ZA, 14 days (biological window) before starting any treatment. In Group 1, Ki67, CD34, p53/bcl-2 and caspase 3 expression along with the adenosine triphosphate (ATP) levels and RNA disruption index were evaluated as markers of tumor growth in tumour specimens obtained before and after ZA administration (basal, day 14). In Group 2, the total enumeration of circulating tumour cells (CTCs), and of M30+ve CTCs along with the soluble marker of cell death (M30/M65) were carried-out as markers of tumor dissemination at baseline, at 48 h and day 14th. In Group 1, there was a significant reduction in Ki67, CD34, bcl-2 expression after 14 days ZA based-treatment (p = 0.0032; p = 0.0001, p < 0.00001 respectively). ZA showed a significant increase of RNA disruption (p < 0.0076). In Group 2, we observed a significant reduction of CTCs number after 48 h (p = 0.0012), followed by a significant rebound at 14 days (p = 0.012). The apoptotic CTCs/M30+ve and M65 levels significantly increased under treatment (p = 0.018 and p = 0.039 respectively) after drug administration when compared to the baseline. These results are the first prospective in vivo data showing the direct pure anti-tumour effect (either on the tumour cell or on CTCs) of ZA.

Barrett-Lee P, Casbard A, Abraham J, et al.
Oral ibandronic acid versus intravenous zoledronic acid in treatment of bone metastases from breast cancer: a randomised, open label, non-inferiority phase 3 trial.
Lancet Oncol. 2014; 15(1):114-22 [PubMed] Related Publications
BACKGROUND: Bisphosphonates are routinely used in the treatment of metastatic bone disease from breast cancer to reduce pain and bone destruction. Zoledronic acid given by intravenous infusion has been widely used, but places a substantial logistical burden on both patient and hospital. As a result, the use of oral ibandronic acid has increased, despite the absence of comparative data. In the ZICE trial, we compared oral ibandronic acid with intravenous zoledronic acid for the treatment of metastatic breast cancer to bone.
METHODS: This phase 3, open-label, parallel group active-controlled, multicentre, randomised, non-inferiority phase 3 study was done in 99 UK hospitals. Eligibility criteria included at least one radiologically confirmed bone metastasis from a histologically confirmed breast cancer. Patients with ECOG performance status 0 to 2 and clinical decision to treat with bisphosphonates within 3 months of randomisation were randomly assigned to receive 96 weeks of treatment with either intravenous zoledronic acid at 4 mg every 3-4 weeks or oral ibandronic acid 50 mg daily. Randomisation (1:1) was done via a central computerised system within stratified block sizes of four. Randomisation was stratified on whether patients had current or planned treatment with chemotherapy; current or planned treatment with hormone therapy; and whether they had a previous skeletal-related event within the last 3 months or had planned radiotherapy treatment to the bone or planned orthopaedic surgery due to bone metastases. The primary non-inferiority endpoint was the frequency and timing of skeletal-related events over 96 weeks, analysed using a per-protocol analysis. All active (non-withdrawn) patients have now reached the 96-week timepoint and the trial is now in long-term follow-up. The trial is registered with ClinicalTrials.gov, number NCT00326820.
FINDINGS: Between Jan 13, 2006, and Oct 4, 2010, 705 patients were randomly assigned to receive ibandronic acid and 699 to receive zoledronic acid; three patients withdrew immediately after randomisation. The per-protocol analysis included 654 patients in the ibandronic acid group and 672 in the zoledronic acid group. Annual rates of skeletal-related events were 0·499 (95% CI 0·454-0·549) with ibandronic acid and 0·435 (0·393-0·480) with zoledronic acid; the rate ratio for skeletal-related events was 1·148 (95% CI 0·967-1·362). The upper CI was greater than the margin of non-inferiority of 1·08; therefore, we could not reject the null hypothesis that ibandronic acid was inferior to zoledronic acid. More patients in the zoledronic acid group had renal toxic effects than in the ibandronic acid group (226 [32%] of 697 vs 172 [24%] of 704) but rates of osteonecrosis of the jaw were low in both groups (nine [1%] of 697 vs five [<1%] of 704). The most common grade 3 or 4 adverse events were fatigue (97 [14%] of 697 patients allocated zoledronic acid vs 98 [14%] of 704 allocated ibandronic acid), increased bone pain (91 [corrected] [13%] vs 85 [corrected] [12%]), joint pain (41 [corrected] [6%] vs 38 [5%]), infection (31 [5%] vs 23 [corrected] [3%]), and nausea or vomiting (38 [5%] vs 41 [6%]).
INTERPRETATION: Our results suggest that zoledronic acid is preferable to ibandronic acid in preventing skeletal-related events caused by bone metastases. However, both drugs have acceptable side-effect profiles and the oral formulation is more convenient, and could still be considered if the patient has a strong preference or if difficulties occur with intravenous infusions.
FUNDING: Roche Products Ltd (educational grant), supported by National Institute for Health Research Cancer Network, following endorsement by Cancer Research UK (CRUKE/04/022).

Søe K, Delaissé JM, Jakobsen EH, et al.
Dosing related effects of zoledronic acid on bone markers and creatinine clearance in patients with multiple myeloma and metastatic breast cancer.
Acta Oncol. 2014; 53(4):547-56 [PubMed] Related Publications
UNLABELLED: Zoledronic acid (Zol) is frequently used for the treatment of bone disease in patients with multiple myeloma and breast cancer with metastasis to bone. Therefore, there is also an interest in finding the optimal dosing regimen to optimize effects, minimize side effects and reduce costs. In our phase II clinical trial we investigated the effect of Zol treatment on the serum levels of the bone markers collagen type 1 cross-linked C-telopeptide (CTX) and bone specific alkaline phosphatase (bALP) as well as on creatinine clearance (kidney function) in response to dosing and duration of treatment for each individual patient.
METHODS: We enrolled 30 multiple myeloma (MM) and 30 breast cancer (BC) patients whereof 10 of each had never received bisphosphonate and 20 had received at least six prior Zol treatments.
RESULTS: We found that Zol treatment strongly reduced CTX (Spearman's correlation, rs = -0.59, p = 0.0007) and bALP (Spearman's correlation, rs = -0.51, p = 0.0042) in MM patients while only CTX (Spearman's correlation, rs = -0.42, p = 0.024) was significantly affected in BC patients. Multiple linear regression analyses done on the entire cohort showed that the average time between each dose of Zol had the strongest impact on CTX (p < 0.001) and bALP (p = 0.011) levels while the total accumulated number of Zol infusions had a less pronounced effect on CTX levels (p = 0.015). In contrast, multiple linear regression analysis showed that the total number of Zol infusions had a strong negative impact on kidney function (p = 0.014) while the average time between each dose of Zol had no significant impact.
CONCLUSION: Thus, if MM and BC patients are not treated regularly every month with Zol bone turnover is not fully suppressed, while prolonged treatment with zoledronic acid compromises kidney function. We believe that these data significantly contribute to the knowledge needed to find the optimal Zol treatment schedule.

Henry D, Vadhan-Raj S, Hirsh V, et al.
Delaying skeletal-related events in a randomized phase 3 study of denosumab versus zoledronic acid in patients with advanced cancer: an analysis of data from patients with solid tumors.
Support Care Cancer. 2014; 22(3):679-87 [PubMed] Related Publications
PURPOSE: Bone complications of metastatic disease, including skeletal-related events (SREs), impair patients' functioning and quality of life. In a randomized, phase 3 trial of 1,776 patients with metastases from solid tumors (except breast or prostate) or multiple myeloma, denosumab was non-inferior to zoledronic acid (ZA) in delaying or preventing SREs. This ad hoc analysis reports outcomes in the subgroup of 1,597 patients with solid tumors, excluding patients with multiple myeloma.
METHODS: Patients received monthly subcutaneous denosumab 120 mg or intravenous ZA 4 mg, adjusted for creatinine clearance, with calcium and vitamin D supplementation recommended. Endpoints included times to first on-study SRE, first-and-subsequent SREs, and pain worsening.
RESULTS: Denosumab significantly delayed time to first on-study SRE compared with ZA (HR, 0.81; 95 % CI, 0.68-0.96) and time to first-and-subsequent SREs (RR, 0.85; 95 % CI, 0.72-1.00). Denosumab also significantly delayed time to development of moderate or severe pain (HR, 0.81; 95 % CI, 0.66-1.00), pain worsening (HR, 0.83; 95 % CI, 0.71-0.97), and worsening pain interference in patients with no/mild baseline pain (HR, 0.77; 95 % CI, 0.61-0.96). Adverse event rates were 96 % in both groups. Grade 3 or 4 hypocalcemia, mostly without clinical sequelae, was more frequent in denosumab-treated patients (denosumab 4 %, ZA 2 %). Osteonecrosis of the jaw occurred infrequently (denosumab 0.8 %, ZA 1.1 %).
CONCLUSIONS: Denosumab was more effective in delaying or preventing SREs in patients with bone metastases from solid tumors and also prevented pain progression compared to ZA in this ad hoc analysis.

Nelson A, Fenlon D, Morris J, et al.
QUALZICE: a QUALitative exploration of the experiences of the participants from the ZICE clinical trial (metastatic breast cancer) receiving intravenous or oral bisphosphonates.
Trials. 2013; 14:325 [PubMed] Article available free on PMC after 03/07/2017 Related Publications
BACKGROUND: This qualitative sub-study aimed to explore the experiences of participants on the National Cancer Research Institute ZICE clinical trial, a randomised trial assessing two types of bisphosphonate treatment in breast cancer patients with bone metastases. Participants in the clinical trial were randomly allocated to receive either zoledronate, delivered by an intravenous (IV) infusion at clinic, or oral ibandronate, taken at home.
METHODS: Qualitative research interviews were conducted with participant groups organised by treatment and location. Interviews covered experiences and understanding of bisphosphonate treatment, the experience of the delivery mechanisms (IV or oral), side effects and benefits, and quality of life issues. The analytic framework was interpretative phenomenological analysis.
RESULTS: This paper reports on one of four superordinate themes: participants' experience of the ZICE trial, which explores the participants' experiences with clinical trial-related processes. Results show that participants were generally satisfied with their randomised treatment, although most participants had an initial preference for oral bisphosphonates. Some difficulties were reported from participants for both interventions: needle phobia, poor veins, difficulty with swallowing and gastric side effects, but pain control was improved with both modes of delivery. However, the infused bisphosphonate was reported to lose effectiveness after three weeks for some participants, whereas the oral bisphosphonate was reported to give consistent pain control. Geographical location and distance to travel made little difference to convenience of access to clinic as the reported lengths of travel time were similar due to traffic congestion in the urban areas. Most participants understood the trial processes, such as randomisation, and information about bisphosphonates but some participants showed little understanding of certain aspects of the trial. Some participants reported difficulties in accessing dental treatment due to their dentist's perceptions of bisphosphonate treatment.
CONCLUSIONS: In trials of medicinal products, especially when testing for non-inferiority, participants' preferences and idiosyncrasies in relation to treatments should not be assumed. This study has shown that in a trial context, participants' views can usefully add to the main trial outcomes and they should be taken into account when prescribing in the real world.
TRIAL REGISTRATION: ISRCTN13914201. Main ZICE MREC: 05/MRE09/57. CRUK E/04/022.

Ueno S, Mizokami A, Fukagai T, et al.
Efficacy of combined androgen blockade with zoledronic acid treatment in prostate cancer with bone metastasis: the ZABTON-PC (zoledronic acid/androgen blockade trial on prostate cancer) study.
Anticancer Res. 2013; 33(9):3837-44 [PubMed] Related Publications
AIM: Zoledronic acid (ZA) reduces the risk of skeletal-related events (SREs) in castration-resistant prostate cancer (CRPC) with bone metastasis and improves quality of life. It remains unclear when clinicians should initiate ZA treatment.
PATIENTS AND METHODS: Hormone-naïve patients were randomized to a combined androgen blockade (CAB) group or CAB with ZA group (CAB-ZA) based on Gleason score (GS) or extent of disease. The primary end-point of the study was progression-free survival (PFS) and the secondary end-point was incidence of SREs and bone pain.
RESULTS: Thirty-one and 29 patients among 60 enrolled patients were assigned to the CAB group and the CAB-ZA group, respectively. There was no significant difference in PFS between the two groups. Subgroup analyses revealed better PFS in the CAB-ZA group with GS ≥8 (p=0.021). Moreover, incidence of SREs, including bone pain, was lower in the CAB-ZA group (p=0.019).
CONCLUSION: CAB-ZA treatment was found to improve PFS for patients with prostate cancer with high GS. CAB-ZA treatment could be recommended for treatment of patients with prostate cancer.

von Moos R, Body JJ, Egerdie B, et al.
Pain and health-related quality of life in patients with advanced solid tumours and bone metastases: integrated results from three randomized, double-blind studies of denosumab and zoledronic acid.
Support Care Cancer. 2013; 21(12):3497-507 [PubMed] Related Publications
PURPOSE: This analysis evaluated patient-reported outcomes and analgesic use in patients with bone metastases from solid tumours across three comparative studies of denosumab and zoledronic acid.
METHODS: Pooled data were analysed from three identically designed double-blind phase III studies comparing subcutaneous denosumab 120 mg with intravenous zoledronic acid 4 mg monthly in patients with bone metastases from breast cancer (n = 2,046), castration-resistant prostate cancer (n = 1,901) or other solid tumours (n = 1,597). Pain severity, pain interference, health-related quality of life and analgesic use were quantified.
RESULTS: At baseline, approximately half of patients had no/mild pain (53 % [1,386/2,620] denosumab; 50 % [1,297/2,578] zoledronic acid). Denosumab delayed onset of moderate/severe pain by 1.8 months (median, 6.5 vs 4.7 months; hazard ratio, 0.83; 95 % CI, 0.76-0.92; p < 0.001; 17 % risk reduction) and clinically meaningful increases in overall pain interference by 2.6 months (median, 10.3 vs 7.7 months; hazard ratio, 0.83; 95 % CI, 0.75-0.92; p < 0.001; 17 % risk reduction) compared with zoledronic acid. Strong opioid use and worsening of health-related quality of life were less common with denosumab.
CONCLUSIONS: Across three large studies of patients with advanced solid tumours and bone metastases, denosumab prevented progression of pain severity and pain interference more effectively than zoledronic acid.

Van den Wyngaert T, Delforge M, Doyen C, et al.
Prospective observational study of treatment pattern, effectiveness and safety of zoledronic acid therapy beyond 24 months in patients with multiple myeloma or bone metastases from solid tumors.
Support Care Cancer. 2013; 21(12):3483-90 [PubMed] Related Publications
PURPOSE: To study the treatment patterns, effectiveness and safety of zoledronic acid (ZOL) beyond 2 years of therapy, given the paucity of data on long-term treatment in daily clinical practice.
METHODS: Patients with multiple myeloma (MM) or solid tumor bone metastases (STM) and at least 24 months of regular q3-4w ZOL therapy were followed prospectively for an additional 18 months beyond the 24 months required for study entry. End-points included ZOL exposure, incidence of skeletal related events (SRE), and safety.
RESULTS: In all, 298 evaluable patients were enrolled. The mean continuation rate of ZOL was 90.6%. Exposure to ZOL decreased with time in all patients, but was lower (50.0% vs. 67.6%; p<0.001) and with higher discontinuation rates (incidence rate ratio [IRR]=1.95; p=0.002) in MM compared to the STM group. ZOL suppressed the rate of SREs similarly during the study as compared to before inclusion (0.12 vs. 0.13 events per person-year; p=0.7). At 18 months, 84.5% remained SRE-free. In STM patients, persistent ZOL therapy was associated with lower SRE risk (hazard ratio [HR]=0.42; p=0.01), but not in MM. Renal deterioration occurred in 3.7% and osteonecrosis of the jaw (ONJ) developed in 6.0%, with dental trauma increasing ONJ risk (HR=4.67; p=0.002).
CONCLUSIONS: Beyond 2 years of therapy, treatment patterns of ZOL were heterogeneous and SRE rates were low. The safety profile of ZOL was acceptable, and interrupting ZOL in patients with solid tumors was associated with a higher risk of SREs.

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