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Zoledronic acid (Zometa)

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Latest Research Publications

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Latest Research Publications

Garcia JR, Pérez C, Bassa P, et al.
18F-FDG PET/CT in the Staging and Management of Breast Cancer: Value in Disease Outcome and Planning Therapy.
Clin Nucl Med. 2017; 42(3):191-192 [PubMed] Related Publications
In hormone receptor-positive locally advanced breast cancer, endocrine therapy becomes an integral part of the therapeutic strategy. There are now significant numbers of available hormonal directed compounds, including selective aromatase and mTOR inhibitors, which allow an important therapeutic advance in these patients. Sequential F-FDG PET/CT studies provided essential information regarding response to different treatments, including targeted therapies, and adverse therapeutic effects that helped to better define the right moment to implement each therapeutic approach.

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.

Grávalos C, Rodríguez C, Sabino A, et al.
SEOM Clinical Guideline for bone metastases from solid tumours (2016).
Clin Transl Oncol. 2016; 18(12):1243-1253 [PubMed] Article available free on PMC after 03/07/2017 Related Publications
Bone metastases are common in many advanced solid tumours, being breast, prostate, thyroid, lung, and renal cancer the most prevalent. Bone metastases can produce skeletal-related events (SREs), defined as pathological fracture, spinal cord compression, need of bone irradiation or need of bone surgery, and hypercalcaemia. Patients with bone metastases experience pain, functional impairment and have a negative impact on their quality of life. Several imaging techniques are available for diagnosis of this disease. Bone-targeted therapies include zoledronic acid, a potent biphosfonate, and denosumab, an anti-RANKL monoclonal antibody. Both reduce the risk and/or delay the development of SREs in several types of tumours. Radium 233, an alpha-particle emitter, increases overall survival in patients with bone metastases from resistant castration prostate cancer. Multidisciplinary approach is essential and bone surgery and radiotherapy should be integrated in the treatment of bone metastases when necessary. This SEOM Guideline reviews bone metastases pathogenesis, clinical presentations, lab tests, imaging techniques for diagnosis and response assessment, bone-targeted agents, and local therapies, as radiation and surgery, and establishes recommendations for the management of patients with metastases to bone.

Fragkoulis C, Gkialas I, Papadopoulos G, Ntoumas K
Current therapeutic options targeting bone metastasis in metastatic castration resistant prostate cancer.
J BUON. 2016 Jul-Aug; 21(4):787-791 [PubMed] Related Publications
Prostate cancer is a major public health problem worldwide, still remaining the most common cancer among elder males in both Europe and USA, being responsible for approximately 30,000 deaths in USA in 2014. Nowadays, after decades of basic research, novel treatment options have emerged focusing on men suffering from metastatic castration-resistant prostate cancer improving overall survival. It is also estimated that more than 90% of such patients develop bone metastasis, resulting in a significant increase in morbidity and mortality. The purpose of this review was to discuss the treatment options targeting bone metastasis in castration-resistant prostate cancer patients by examining the available literature focusing primarily in the role of zoledronic acid, denosumab and radium 223.

Pressey JG, Adams J, Harkins L, et al.
In vivo expansion and activation of γδ T cells as immunotherapy for refractory neuroblastoma: A phase 1 study.
Medicine (Baltimore). 2016; 95(39):e4909 [PubMed] Article available free on PMC after 03/07/2017 Related Publications
INTRODUCTION: CD3+ γδ+ T cells comprise 2% to 5% of circulating T cells with Vγ9Vδ2+ cells the dominant circulating subtype. Vγ9Vδ2+ cells recognize non-peptide phosphoantigens and stress-associated NKG2D ligands expressed on malignant cells. Strategies that incorporate the tumoricidal properties of γδ T cells represent a promising immunotherapeutic strategy for treatment of solid malignancies including neuroblastoma (NB). In this prospective, non-randomized Phase I trial, we assessed whether circulating Vγ9Vδ2+ cells could be safely expanded using intravenous ZOL (Zoledronate [Zometa]) and subcutaneous Interleukin-2 (IL-2) in patients with refractory NB.
METHODS: Patients 2 to 21 years of age with refractory neuroblastoma with no known curative therapeutic options received ZOL on day 1, and IL-2 on days 1 to 5 and 15 to 19 of each 28-day cycle (n = 4). Lymphocyte immunophenotyping was assessed weekly. Immunophenotyping studies from the treatment group were compared with healthy pediatric controls (n = 16; range, 5y-15y) and of untreated NB disease controls (n = 9; range, 4m-18y).
RESULTS: Treatment was well tolerated with no unexpected grade 3 and 4 toxicities. Lymphocyte subset counts did not differ significantly between volunteers and disease controls with the exception of γδ+ T cell counts that were significantly higher in healthy volunteers (212 + 93 vs. 89 + 42, P = 0.05). Study patients showed increases in circulating γδ+ T cell count (3-10 fold) after the first week, increasing into the range seen in healthy volunteers (125 + 37, P = 0.1940). Interestingly, all ZOL + IL-2 treated patients showed significant increases in CD3+CD4+CD27CD127 T cells that rose weekly in 2 patients throughout the 4 weeks of observation (maximum 41% and 24% of total CD3+CD4+ T cells, respectively).
CONCLUSIONS: In summary, combined ZOL and IL-2 is well tolerated and restored γδ+ T cell counts to the normal range with a moderate expansion of Natural Killer cells. Progressive increases in circulating CD4+ T cells with a regulatory phenotype cells may offset beneficial effects of this therapy.

Hepp P, Andergassen U, Jäger B, et al.
Association of CA27.29 and Circulating Tumor Cells Before and at Different Times After Adjuvant Chemotherapy in Patients with Early-stage Breast Cancer - The SUCCESS Trial.
Anticancer Res. 2016; 36(9):4771-6 [PubMed] Related Publications
BACKGROUND: Evidence for the prognostic value of circulating tumor cells (CTCs) in early-stage breast cancer is swiftly increasing. An alternative approach for identifying patients at risk for recurrence is based on the detection of the mucin-1 (MUC1)-based tumor marker CA27.29. Here we report the association of these two prognostic markers before and immediately after chemotherapy (CHT), as well as after 2 and 5 years of follow-up.
PATIENTS AND METHODS: The SUCCESS trial compared fluorouracil, epirubicin and cyclophosphamide followed by docetaxel vs. FEC followed by docetaxel plus gemcitabine, and 2 vs. 5 years of treatment with zoledronic acid in 3,754 patients with node-positive or high-risk node-negative early-stage breast cancer. CA27.29 was measured with the ST AIA-PACK CA27.29 reagent (Tosoh Bioscience, Belgium). The cutoff for CA27.29 positivity was >31 U/ml. CTCs were assessed with the CellSearch System (Veridex, USA). The cutoff for CTC positivity was ≥1 CTC/15 ml whole blood. The relationship between CTC positivity and CA27.29 positivity was assessed based on Chi-square statistics and Cramer's V, which varies from 0 (no association between the variables) to 1 (complete association). Samples for CA27.29 and CTC determinations during follow-up were only drawn from patients that had no relapse.
RESULTS: Both CA27.29 and CTC data were available for 1,981, 1,602, 1,159 and 707 patients before, immediately after and at 2 and 5 years after CHT, respectively. Positivity rates for CTC were 21.3%, 22.8%, 18.6% and 8.5%, respectively. CA27.29 was positive in 7.9%, 21.0%, 2.8%and 7.5%, respectively. Positivity for both CA27.29 and CTC was found in 2.4%, 4.2%, 0.7% and 1.8% of patients, respectively. The association between CA27.29 and CTC was significant but weak before CHT (p=0.0015; Cramer's V=0.063) and 5 years after CHT (p<0.001; Cramer's V=0.164), and not significant immediately after CHT (p=0.162; Cramer's V=0.035) and 2 years after (p=0.349; Cramer's V=0.028).
CONCLUSION: We showed that CTC and CA27.29 positivity were significantly, but only weakly associated before CHT and 5 years after CHT, while no significant association was found immediately or 2 years after CHT during the course of early-stage breast cancer. It, therefore, seems reasonable to further evaluate the prognostic value of CTCs and CA27.29 as a combined prognostic test of two potentially independent markers that might provide complementary prognostic information.

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.

Turner B, Ali S, Pati J, et al.
Retrospective Audit: Does Prior Assessment by Oral and Maxillofacial Surgeons Reduce the Risk of Osteonecrosis of The Jaw in Patients Receiving Bone-Targeted Therapies for Metastatic Cancers to the Skeleton?--Part II.
Urol Nurs. 2016 May-Jun; 36(3):117-22, 132 [PubMed] Related Publications
Men who receive bone-targeted therapy for metastatic prostate cancer are at increased risk of osteonecrosis of the jaw (ONJ). Development of ONJ has been associated with the administration of bone-targeted therapies in association with other risk factors. ONJ can be distressing for a patient because it can cause pain, risk of jaw fracture, body image disturbance, difficultly eating, and difficulty maintaining good oral hygiene. The aim of this article is to report results of an audit of prior assessment by oral and maxillofacial surgeons (OMFS) before initiation of bone-targeted therapies and whether it may reduce the risk of ONJ in patients receiving bone-targeted therapies for advanced cancers.

Turner B, Drudge-Coates L, Ali S, et al.
Osteonecrosis of the Jaw in Patients Receiving Bone-Targeted Therapies: An Overview--Part I.
Urol Nurs. 2016 May-Jun; 36(3):111-6, 154 [PubMed] Related Publications
Urologic patients receiving bone-targeted therapies are at risk of developing osteonecrosis of the jaw (ONJ). ONJ has historically been associated with bisphosphonate therapy. More recently, RANK-Ligand inhibitors (denosumab) have also been used to reduce the risk of skeletal-related events in patients who have advanced cancers with bone metastases. More than 65% of men with metastatic prostate cancer and nearly 75% of women with metastatic breast cancer are affected by bone metastases. The literature has described ONJ associated with bisphosphonate therapy as bisphosphonate-related osteonecrosis of the jaw (BRONJ). However, with evidence also linking the use of RANK-Ligand inhibitors with osteonecrosis of the jaw, we advocate use of the term "anti-bone resorption therapy-related osteonecrosis of the jaw" (ABRT-ONJ). The term "medication-related osteonecrosis of the jaw" (MRONJ) is now becoming more widespread. There is not a universally accepted definition of ABRT-ONJ, which may have hindered recognition and reporting of the condition. In Part I of this article, a review of current knowledge around the etiology of ABRT-ONJ and incidence data are provided. In Part II, we provide an audit of ONJ in a nurse consultant-led bone support clinic. In the article, we refer to zoledronic acid because this is the bisphosphonate of choice for use in men with prostate cancer in the United Kingdom.

Yamasaki M, Yuasa T, Uehara S, et al.
Improvement of renal function by changing the bone-modifying agent from zoledronic acid to denosumab.
Int J Clin Oncol. 2016; 21(6):1191-1195 [PubMed] Article available free on PMC after 03/07/2017 Related Publications
BACKGROUND: In order to help in selecting the optimum bone-modifying agent (BMA; zoledronic acid or denosumab), we investigated the impact of the BMA on the renal function of patients with bone metastases.
MATERIALS AND METHODS: The present study consisted of 118 patients who were treated with denosumab for bone metastases secondary to prostate cancer, renal cell cancer, and urothelial cancer at our hospital between 2012 and 2015. The clinical course of the renal function of these patients, treated with zoledronic acid or denosumab, was retrospectively evaluated.
RESULTS: Of the 118 patients who were treated with denosumab during the study period, 57 (48 %) had previously been administered zoledronic acid and 61 (52 %) had received denosumab as the first-line BMA. The reasons for changing from zoledronic acid to denosumab were increased creatinine serum level (26 patients, 46 %), patient preference (16 patients, 28 %), difficulty with venous infusion (10 patients, 17 %), and other reasons (5 patients, 9 %). The median level of creatinine clearance in the patients who changed from zoledronic acid to denosumab due to increased serum creatinine level was 59.9 ml/min before administration of zoledronic acid, 40.9 ml/min at the beginning of denosumab treatment, 47.5 ml/min at 3 months after administration of denosumab, and 52.0 ml/min at the last follow-up. There were significant differences.
CONCLUSIONS: For the first time, we demonstrated that the renal function of some patients, which had deteriorated following zoledronic acid administration, successfully improved after changing to denosumab.

Amirifard N, Sadeghi E
Breast Cancer in Men: a Report from the Department of Radiation Oncology in Kermanshah Province, Iran.
Asian Pac J Cancer Prev. 2016; 17(5):2593-6 [PubMed] Related Publications
BACKGROUND: Male breast cancer (MBC) is a rare disease that accounts for less than 1% of all cancers in men and less than 1% of all diagnosed breast cancers. In this study, we retrospectively evaluated the clinicopathological features, treatment options and overall survival in Kurdish MBC cases.
MATERIALS AND METHODS: Seventeen MBC were referred to Department of Radiation Oncology in Imam Reza Hospital, Kermanshah, Iran, between 2010 and 2016. Immunohistochemical analysis was performed for ER, PR and Her2 biomarkers and FISH for those with Her2 2+. Median follow-up period was 30 months (2-65 months). We excluded from the study patients who did not have follow-up after initial diagnosis. Treatment methods were chemotherapy, radiotherapy, hormonal therapy, target therapy and palliative care. Survival was estimated by the Kaplan Meier method (Prism 5).
RESULTS: The mean age at diagnosis was 49.2 ± 17 years (range, 24-85 years). Grade II was the most grade in MBC (65%). Fourteen patients (82%) had invasive ductal carcinoma, one (6%) had ductal carcinoma in situ and 2 (12%) had invasive papillary. ER, PR and Her2 were significantly positive in 14/17, 8/17 and 2/17 cases, respectively. The treatment included modified radical mastectomy for most patients. Chemotherapy with TAC and CEF regimens was delivered to 15/17 cases. Tamoxifen therapy was delivered to 14/17 cases. Three stage IV patients received Avestin and two with Her2 3+ were given Trastuzumab (Herceptin). Patients received adjuvant radiotherapy following surgery and chemotherapy. The site of metastasis was the bone in 2 cases, lung in 1 case and liver in 1 case. Zoledronic acid (Zometa) was prescribed for patients with bone metastasis. Five-year overall survival rate was 64%.
CONCLUSIONS: MBC is rare. Thus, we need larger studies are in collaboration with several research centers in the field of breast cancer. ER positive, grade II of invasive ductal carcinoma, stage II and right side happened more with MBC. Overall survival is similar to other studies.

Kitagawa J, Shibata Y, Matsumoto T, et al.
Efficacy and safety of denosumab in multiple myeloma.
Rinsho Ketsueki. 2016; 57(5):592-6 [PubMed] Related Publications
We analyzed 11 patients with multiple myeloma (MM) treated using denosumab in our institute. The median age was 69 years (range, 54-76 years), and 7 patients were male. Seven patients had presented with newly diagnosed MM. Four patients were initially treated with zoledronic acid, which was then later switched to denosumab. The median number of injections was 15 (range, 1-27). No patients developed skeletal-related events (SRE) during denosumab treatment. Hypocalcemia was defined as serum calcium levels below the baseline in all patients. To prevent hypocalcemia, 8 patients were administered oral calcium. The first course of denosumab injections in 9 patients resulted in more marked decreases in serum calcium concentrations than subsequent courses. Two patients discontinued denosumab after osteonecrosis of the jaw (ONJ) was suspected, but squamous cell carcinoma was later identified in one of these cases. Denosumab might be effective and safe for preventing SRE. Cautionary measurement of serum calcium concentrations and prophylactic supplementation with oral calcium are warranted to avoid hypocalcemia after the first denosumab injection. The possibility of ONJ also merits attention. The clinical diagnosis of ONJ should be considered based on performing appropriate histological analyses.

Yamaguchi Y, Katata Y, Okawaki M, et al.
A Prospective Observational Study of Adoptive Immunotherapy for Cancer Using Zoledronate-Activated Killer (ZAK) Cells - An Analysis for Patients with Incurable Pancreatic Cancer.
Anticancer Res. 2016; 36(5):2307-13 [PubMed] Related Publications
BACKGROUND/AIM: Adoptive immunotherapy (AIT) using autologous zoledronate-activated killer (ZAK) cells has been performed for developing a novel modality of cancer treatment. In this study, data series from incurable pancreatic cancer were analyzed.
PATIENTS AND METHODS: Patients were treated with AIT using intravenous administration of ZAK cells every 3 to 4 weeks in combination with standard chemotherapy and possible clinical benefits were examined.
RESULTS: Seventy-five patients were treated. A median overall survival (OS) time of 6.7 months was achieved for all patients and 13.1 months for those treated 5 times or more, that increased to 14.6 and 18.3 months, respectively, when the previous treatment period of chemotherapy alone was included in the analysis. The disease control rate was 58.5 %. Multivariate regression analysis showed a significant positive correlation between the survival and baseline value of lymphocyte percentage in white blood cell counts (p=0.031).
CONCLUSION: The data suggest that AIT using ZAK cells in combination with chemotherapy is safe and feasible and may be effective in prolonging survival for patients with incurable pancreatic cancer. The lymphocyte percentage at baseline may be a good biomarker for predicting the survival benefit of ZAK cell AIT.

Feng C, Liu X, Li X, et al.
Zoledronic acid increases the antitumor effect of gefitinib treatment for non-small cell lung cancer with EGFR mutations.
Oncol Rep. 2016; 35(6):3460-70 [PubMed] Related Publications
Non-small cell lung cancer (NSCLC) patients with epithelial growth factor receptor (EGFR) mutations and bone metastases are often concurrently administered tyrosine kinase inhibitors (TKIs) and bisphosphonates. Yet, the effects and mechanisms of these agents are unclear. In the present study, we aimed to ascertain whether zoledronic acid (ZA) increases the antitumor effects of gefitinib treatment on NSCLC with EGFR mutations and the related mechanisms of action. The effects of ZA and gefitinib on NSCLC tumor cells with EGFR mutations (HCC827, HCC827 GR and H1975) in regards to proliferation, apoptosis, cell cycle and signaling pathways were detected. ZA increased the antitumor effects of gefitinib on NSCLC with EGFR activating mutations and TKI resistance in vitro. Gefitinib caused cell cycle arrest in the G0/G1 phase, ZA induced S phase accumulation and the effect of the combined treatment was neutralization. Combined treatment obviously inhibited STAT3 and/or p‑STAT3 protein expression compared with treatment with each single drug in vitro and in vivo, and it also significantly inhibited TKI resistance NSCLC tumor growth in vivo. In conclusion, ZA increased the antitumor effects of gefitinib on NSCLC with EGFR activating mutations and TKI resistance by regulating the cell cycle, inducing caspase-3 expression and inhibiting STAT3 expression.

Turner B, Ali S, Drudge-Coates L, et al.
Skeletal Health Part 2: Development of a Nurse Practitioner Bone Support Clinic for Urologic Patients.
Urol Nurs. 2016 Jan-Feb; 36(1):22-6 [PubMed] Related Publications
Part 1 of this article highlighted the potential negative effects of cancer on the skeleton and provided an overview of available treatment options. Part 2 presents a nurse practitioner-led Bone Support Clinic, which was developed for patients with cancer-induced bone disease and cancer therapy-induced bone loss. This clinic, started in 2011 in a university medical center urology/oncology outpatient center in London, England, United Kingdom, has been a collaborative effort among a multidisciplinary team of doctors, nurse practitioners and nurses. Patients have responded positively to the improved continuity of care, and we have been able to assess and treat impending skeletal-related events in a more timely manner The needs of our patient population and problems with the existing service are reviewed, and the importance of a multidisciplinary approach to these problems is discussed. Initiation of a nurse practitioner-led Bone Support Clinic and the impact of timely response to the effects of cancer and cancer therapies on the skeletal system are outlined and offered as a model.

Nishimukai A, Higuchi T, Ozawa H, et al.
Different patterns of change in bone turnover markers during treatment with bone-modifying agents for breast cancer patients with bone metastases.
Breast Cancer. 2017; 24(2):245-253 [PubMed] Related Publications
BACKGROUND: Bone-modifying agents are effective for treatment of breast cancer patients with bone metastases. Since their action is mediated through suppression of the osteoclast function, their efficacy can be determined by monitoring bone turnover markers. However, the clinical significance of these markers is yet to be compared.
METHODS: For this study, 52 breast cancer patients with bone metastases treated with zoledronic acid (n = 36) or denosumab (n = 22) were enrolled (6 patients were treated sequentially with both agents). Serum tartrate-resistant acid phosphatase-5b (TRACP-5b), pyridinoline cross-linked carboxyterminal telopeptide of type I collagen (1CTP), N-terminal cross-linking telopeptides of type I collagen (NTX) and bone-specific alkaline phosphatase (BAP) were measured at pretreatment and 1, 3 and 6 months after treatment.
RESULTS: Serum TRACP-5b (p < 0.0001), NTX (p = 0.0007) and BAP (p = 0.0032) decreased significantly after treatment. The baseline median value of TRACP-5b (457.5 mU/dL, range 173-1630 mU/dL) decreased to 137 mU/dL (91-795 mU/dL) 1 month after treatment. Reduction in serum NTX and BAP was greatest after 3 and 6 months, respectively. TRACP-5b, NTX and BAP were above normal levels at baseline in 62.5, 25 and 35.3 % of patients, respectively, and nearly 80 % of these patients attained normal levels during the treatment.
CONCLUSIONS: Although bone-modifying agents reduced the baseline levels of TRACP-5b, NTX and BAP significantly, the reduction patterns differed. TRACP-5b appears to affect levels most quickly and sensitively, possibly due to its direct link to the number and activity of osteoclasts. These findings suggest that the efficacy of TRACP-5b is clinically significant when considering which bone-modifying agents to use for breast cancer patients with bone metastases.

Fragni M, Bonini SA, Stabile A, et al.
Inhibition of Survivin Is Associated with Zoledronic Acid-induced Apoptosis of Prostate Cancer Cells.
Anticancer Res. 2016; 36(3):913-20 [PubMed] Related Publications
BACKGROUND/AIM: Evidence suggests that zoledronic acid (ZA) exerts direct antitumor effects on cancer cells but the underlying mechanisms of these actions are unknown. This study investigated the possible involvement of survivin in the antiproliferative effects of ZA in prostate cancer.
MATERIALS AND METHODS: 3-(4,5-dimethyl-2-thiazol)-2,5-diphenyl-2H-tetrazolium bromide (MTT) dye reduction assay was used to assess cell viability and acridine orange/ethidium bromide double staining to analyze cell death. Human Apoptosis Array evaluated the expression of apoptosis-related proteins. Survivin protein was measured by western blot technique and miR-203 levels were quantified by quantitative real-time polymerase chain reaction.
RESULTS: ZA induced inhibition of cell proliferation and apoptosis activation, with down-regulation of survivin protein. A negative regulation at gene expression level may be hypothesized because we observed a significant decrease of survivin mRNA level and an increase of miR-203 expression after ZA exposure.
CONCLUSION: This study provides evidence that ZA may directly inhibit cancer cell proliferation, identifying survivin as one of its downstream targets.

Tanaka R, Yonemori K, Hirakawa A, et al.
Risk Factors for Developing Skeletal-Related Events in Breast Cancer Patients With Bone Metastases Undergoing Treatment With Bone-Modifying Agents.
Oncologist. 2016; 21(4):508-13 [PubMed] Article available free on PMC after 01/04/2017 Related Publications
BACKGROUND: Bone-modifying agents (BMAs) reduce the incidence of skeletal-related events (SREs) and are thus recommended for breast cancer patients with bone metastases. However, the risk factors for SREs during BMA treatment are not well-understood. This study evaluated the number and timing of SREs from case studies to identify these factors.
METHODS: The medical records of 534 women with breast cancer who developed bone metastases between 1999 and 2011 were reviewed. SREs were defined as a pathologic fracture, spinal cord compression, or the need for bone irradiation or surgery. Multiple variables were assessed and were analyzed by using the Cox proportional hazard analyses and the Andersen and Gill method.
RESULTS: Multivariate analyses for both the time to the first SRE and the primary and subsequent SRE frequency demonstrated that significant baseline risk factors included luminal B type disease, a history of palliative radiation therapy, BMA treatment within 2 years, and elevated serum calcium levels at the time of the initial BMA dose. Additionally, for the time to the first SRE and for the primary and subsequent SRE frequency, the presence of extraskeletal metastases and BMA administration initiation ≥6 months after the detection of bone metastases were also significant risk factors, respectively.
CONCLUSION: In breast cancer patients with bone metastases, more vigilant observation should be considered for patients with the identified risk factors. To reduce the risk for SRE, BMAs should be administered within 6 months of bone metastases diagnosis and before palliative radiation therapy.
IMPLICATIONS FOR PRACTICE: Retrospectively, risk factors were identified for skeletal-related events (SREs) in breast cancer patients with bone metastasis who were treated with bone-modifying agents (BMAs). For the time to the first SRE and for the SRE frequency, presence of extraskeletal metastases and BMA initiation ≥6 months after the detection of bone metastases were risk factors, respectively. Luminal B type disease, a history of palliative radiation therapy, BMA treatment within 2 years, and elevated serum calcium levels at initial BMA dose were risk factors for both first SRE and SRE frequency. More vigilant observation should be considered for patients with these risk factors.

Göbel A, Thiele S, Browne AJ, et al.
Combined inhibition of the mevalonate pathway with statins and zoledronic acid potentiates their anti-tumor effects in human breast cancer cells.
Cancer Lett. 2016; 375(1):162-71 [PubMed] Related Publications
Amino-bisphosphonates are antiresorptive drugs for the treatment of osteolytic bone metastases, which are frequently caused by breast and other solid tumors. Like statins, amino-bisphosphonates inhibit the mevalonate pathway. Direct anti-tumor effects of amino-bisphosphonates and statins have been proposed, although high concentrations are required to achieve these effects. Here, we demonstrate that the treatment of different human breast cancer cell lines (MDA-MB-231, MDA-Bone, and MDA-Met) by combined inhibition of the mevalonate pathway using statins and zoledronic acid at the same time significantly reduces the concentrations required to achieve a meaningful anti-tumor effect over a single agent approach (50% reduction of cell vitality and 4-fold increase of apoptosis; p < 0.05). The effects were mediated by suppressed protein geranylation that caused an accumulation of GTP-bound RhoA and CDC42. Importantly, the knockdown of both proteins prior to mevalonate pathway inhibition reduced apoptosis by up to 65% (p < 0.01), indicating the accumulation of the GTP-bound GTPases as the mediator of apoptosis. Our results point to effective anti-tumor effects in breast cancer by the combination of statins and zoledronic acid and warrant further validation in preclinical settings.

Zlatev HP, Auriola S, Mönkkönen J, Määttä JA
Uptake of free, calcium-bound and liposomal encapsulated nitrogen containing bisphosphonates by breast cancer cells.
Eur J Pharm Sci. 2016; 86:58-66 [PubMed] Related Publications
PURPOSE: We have examined the uptake routes by which breast cancer cells internalize different formulations of nitrogen containing bisphosphonates (N-BPs).
METHODS: Cell viability was assessed with the tetrazolium colorimetric test (MTT assay) after treatment with different N-BP formulations in the presence or absence of inhibitors for different endocytosis mechanisms. Intracellular formation of isopentenyl pyrophosphate (IPP) and triphosphoric acid 1-adenosin-5'-yl ester 3-(3-methylbut-3-enyl) ester (ApppI), were quantified with mass spectrometry (ES-LTQ-MS) as surrogate markers for N-BP efficacy. Direct quantification intracellular [(14)C]-labeled zoledronic acid was done with liquid scintillation counting.
RESULTS: The main uptake route for all the different formulations of nitrogen containing bisphosphonates was shown to be dynamin dependent endocytosis, which was significantly enhanced with calcium. This uptake mechanism was mostly caveolin and clathrin independent in MCF7 cells, but more clathrin dependent in T47D cells. Liposome encapsulation of the drug shifted the uptake mechanism to be more dependent on caveolin in both the cell lines. The cytotoxicity of N-BPs and the concentrations of formed intracellular ApppI and IPP were significantly increased by calcium chelation and liposome encapsulation, the latter being the most potent formulation.
CONCLUSION: Nitrogen containing bisphosphonates require active endocytosis for cellular uptake and in the breast cancer cells the mechanism is uniformly dynamin dependent for all the formulations tested. This differs e.g. from the previous observations on macrophages, which mostly utilize macropinocytosis. Liposomal formulation was found to prolong the duration of the drug effect in cells.

Sugai S, Yoshikawa T, Iwama T, et al.
Hepatocellular carcinoma cell sensitivity to Vγ9Vδ2 T lymphocyte-mediated killing is increased by zoledronate.
Int J Oncol. 2016; 48(5):1794-804 [PubMed] Article available free on PMC after 01/04/2017 Related Publications
The limited efficacy of vaccines in hepatocellular carcinoma (HCC), due to the low frequency of tumor-infiltrating cytotoxic T lymphocytes (CTLs), indicates the importance of innate immune surveillance, which assists acquired immunity by directly recognizing and eliminating HCC. Innate Vγ9Vδ2 T cells have major histocompatibility complex-unrestricted antitumor activity and are activated by phosphoantigens, which are upregulated in cancer cells by the nitrogen-containing bisphosphonate, zoledronate (Zol). A better understanding of HCC susceptibility to Zol and downstream γδ T cell-mediated killing is essential to optimize γδ T cell-mediated immunotherapy. This study systematically examined the interactions between γδ T cells and Zol-treated HCC cell lines (HepG2, HLE, HLF, HuH-1, JHH5, JHH7, and Li-7) in vitro. All HCC cell lines expressed the DNAX accessory molecule-1 ligands, poliovirus receptor, and Nectin-2, and γδ T cell-mediated killing of these cells was significantly enhanced by Zol. Small interfering RNA-mediated knockdown of these ligands did not affect the susceptibility to γδ T cell lysis. This killing activity was partly inhibited by mevastatin, an inhibitor of the mevalonate pathway, and markedly reduced by a monoclonal antibody to γ- and δ-chain T cell receptor, indicating that this is crucial for Zol-induced HCC killing. In addition, Zol-treated HCC cell lines triggered γδ T cell proliferation and induced production of Th1 and Th2, but not Th17, cytokines. The Zol concentration that enhanced HCC cell susceptibility to γδ T cell killing was lower than that required to directly inhibit HCC proliferation. Thus, γδ T cells may be important effector cells in the presence of Zol, especially where there are insufficient number of cancer antigen-specific CTLs to eliminate HCC. Our in vitro data support the proposal that Zol-treatment, combined with adaptive γδ T cell immunotherapy, may provide a feasible and effective approach for treatment of HCC.

Mohamed M
Two diagnoses from bone marrow biopsy: multiple myeloma and Paget's disease of bone.
BMJ Case Rep. 2016; 2016 [PubMed] Related Publications
Multiple myeloma and Paget's disease of bone show certain similarities such as increased osteoclastic activity and predilection to the axial skeleton. However, pathological and radiological changes of the bones are distinctive between multiple myeloma and Paget's disease of bone. This case report describes a patient who had a concomitant diagnosis of multiple myeloma and Paget's disease evidenced from bone marrow biopsy. Such a co-existence is rare, with only a few cases reported so far.

Vignani F, Bertaglia V, Buttigliero C, et al.
Skeletal metastases and impact of anticancer and bone-targeted agents in patients with castration-resistant prostate cancer.
Cancer Treat Rev. 2016; 44:61-73 [PubMed] Related Publications
Incidence of bone metastases is very high in advanced prostate cancer patients. Bone metastases likely have a significant impact on functional status and quality of life, not only related to pain, but also to the relevant risk of skeletal-related events. A better understanding of mechanisms associated with bone metastatic disease secondary to prostate cancer and more specifically to the cross-talk between tumor cells and bone microenvironment in metastatic progression represented the background for the development of new effective bone-targeted therapies. Furthermore, a better knowledge of biological mechanisms driving disease progression led to significant advances in the treatment of castration-resistant prostate cancer, with the development and approval of new effective drugs. Aim of this review is to outline the physiopathology of bone metastases in prostate cancer and summarize the main results of clinical trials conducted with different drugs to control morbidity induced by skeletal metastases and bone disease progression. For each agent, therapeutic effect on bone metastases has been measured in terms of pain control and/or incidence of skeletal-related events, usually defined as a composite endpoint, including the need for local treatment (radiation therapy or surgery), spinal cord compression, pathological bone fractures. In details, data obtained with chemotherapy (mitoxantrone, docetaxel, cabazitaxel), new generation hormonal agents (abiraterone, enzalutamide), radium-223, bone-targeted agents (zoledronic acid, denosumab) and with several experimental agents (cabozantinib, dasatinib, anti-endothelin and other agents) in patients with castration-resistant prostate cancer are reviewed.

Fragni M, Bonini SA, Bettinsoli P, et al.
The miR-21/PTEN/Akt signaling pathway is involved in the anti-tumoral effects of zoledronic acid in human breast cancer cell lines.
Naunyn Schmiedebergs Arch Pharmacol. 2016; 389(5):529-38 [PubMed] Related Publications
Preclinical data indicate a direct anti-tumor effect of zoledronic acid (ZA) outside the skeleton, but its molecular mechanism is still not completely clarified. The aim of this study was to investigate the anti-cancer effects of ZA in human breast cancer cell lines, suggesting that they may in part be mediated via the miR-21/PTEN/Akt signaling pathway. The effect of ZA on cell viability was measured by MTT assay, and cell death induction was analyzed using either a double AO/EtBr staining and M30 ELISA assay. A Proteome Profiler Human Apoptosis Array was executed to evaluate the molecular basis of ZA-induced apoptosis. Cell cycle analysis was executed by flow cytometry. The effect of ZA on miR-21 expression was quantified by qRT-PCR, and the amount of PTEN protein and its targets were analyzed by Western blot. ZA inhibited cell growth in a concentration- and time-dependent manner, through the activation of cell death pathways and arrest of cell cycle progression. ZA downregulated the expression of miR-21, resulting in dephosphorilation of Akt and Bad and in a significant increase of p21 and p27 proteins expression. These results were observed also in MDA-MB-231 cells, commonly used as an experimental model of bone metastasis of breast cancer. This study revealed, for the first time, an involvement of the miR-21/PTEN/Akt signaling pathway in the mechanism of ZA anti-cancer actions in breast cancer cells. We would like to underline that this pathway is present both in the hormone responsive BC cell line (MCF-7) as well as in a triple negative cell line (MDA-MB-231). Taken together these results reinforce the use of ZA in clinical practice, suggesting the role of miR-21 as a possible mediator of its therapeutic efficacy.

Yang H, Qiu L, Zhang L, et al.
Platinum-zoledronate complex blocks gastric cancer cell proliferation by inducing cell cycle arrest and apoptosis.
Tumour Biol. 2016; 37(8):10981-92 [PubMed] Related Publications
A series of novel dinuclear platinum complexes based on the bisphosphonate ligands have been synthesized and characterized in our recent study. For the purpose of discovering the pharmacology and action mechanisms of this kind of compounds, the most potent compound [Pt(en)]2ZL was selected for systematic investigation. In the present study, the inhibition effect on the human gastric cancer cell lines SGC7901 and action mechanism of [Pt(en)]2ZL were investigated. The traditional 3-[4,5-dimethyl-2-thiazolyl]-2,5-diphenyl-2-tetrazolium bromide (MTT) assay and colony formation assay were carried out to study the effect of [Pt(en)]2ZL on the cell viability and proliferation capacity, respectively. The senescence-associated β-galactosidase staining and immunofluorescence staining were also performed to assess the cell senescence and microtubule polymerization. Fluorescence staining and flow cytometry (FCM) were used to monitor the cell cycle distribution and apoptosis, and Western blot analysis was applied to examine the expression of several apoptosis-related proteins. The results demonstrated that [Pt(en)]2ZL exhibited remarkable cytotoxicity and anti-proliferative effects on the SGC7901 cells in a dose- and time-dependent manner, and it also induced cell senescence and abnormal microtubule assembly. The cell apoptosis and cell cycle arrest induced by [Pt(en)]2ZL were also observed with the fluorescence staining and FCM. The expressions of cell cycle regulators (p53, p21, cyclin D1, cyclin E, and cyclin-dependent kinase (CDK)2) and apoptosis-related proteins (Bcl-2, Bax, caspase-3, poly ADP ribose polymerase (PARP), and survivin) were regulated by the treatment of [Pt(en)]2ZL, resulting in the cell cycle arrest and apoptosis. Therefore, [Pt(en)]2ZL exerted anti-tumor effect on the gastric cancer via inducing cell cycle arrest at G1/S phase and apoptosis.

Kus T, Aktas G, Kalender ME, et al.
Complete response of a recurrent-metastatic liposarcoma with dedifferentiated histological features following the administration of trabectedin and review of literature.
J Cancer Res Ther. 2015 Oct-Dec; 11(4):974-6 [PubMed] Related Publications
The present case report defines a rare case of a liposarcoma with bone metastasis resulting in a complete remission (CR) following trabectedin treatment. The patient was referred with abdominal swelling and pain. A retroperitoneal mass was detected and described as dedifferentiated liposarcoma (DDLS). The mass was surgically removed and consequently adjuvant chemotherapy was administered. Three months after the completion of chemotherapy, patient presented with bone metastasis in thoracic and lumbar vertebrae. Vertebroplasty and radiotherapy (RT) was performed. After these therapies, bone pain persisted and bone scintigraphy showed increased activity in L4, T11, and T12 vertebrae. Zoledronic acid was added to trabectedin treatment. CR has been detected on bone scintigraphy and positron emission tomography-computed tomography (PET-CT) after 18 weeks. Previous cases about liposarcoma treated with trabectedin were mostly about the myxoid/round cell type (former name, currently known as myxoid liposarcoma (MLS)) and mostly reported partial responses. In this study, trabectedin was used for the treatment of a metastatic retroperitoneal DDLS and a CR was achieved.

Qiao H, Wang TY, Yu ZF, et al.
Structural simulation of adenosine phosphate via plumbagin and zoledronic acid competitively targets JNK/Erk to synergistically attenuate osteoclastogenesis in a breast cancer model.
Cell Death Dis. 2016; 7:e2094 [PubMed] Article available free on PMC after 01/04/2017 Related Publications
The treatment of breast cancer-induced osteolysis remains a challenge in clinical settings. Here, we explored the effect and mechanism of combined treatment with zoledronic acid (ZA) and plumbagin (PL), a widely investigated component derived from Plumbago zeylanica, against breast cancer-induced osteoclastogenesis. We found that the combined treatment with PL and ZA suppressed cell viability of precursor osteoclasts and synergistically inhibited MDA-MB-231-induced osteoclast formation (combination index=0.28) with the abrogation of recombinant mouse receptor activator of nuclear factor-κB ligand (RANKL)-induced activation of NF-κB/MAPK (nuclear factor-κB/mitogen-activated protein kinase) pathways. Molecular docking suggested a putative binding area within c-Jun N-terminal kinase/extracellular signal-regulated kinase (JNK/Erk) protease active sites through the structural mimicking of adenosine phosphate (ANP) by the spatial combination of PL with ZA. A homogeneous time-resolved fluorescence assay further illustrated the direct competitiveness of the dual drugs against ANP docking to phosphorylated JNK/Erk, contributing to the inhibited downstream expression of c-Jun/c-Fos/NFATc-1 (nuclear factor of activated T cells, cytoplasmic, calcineurin-dependent 1). Then, in vivo testing demonstrated that the combined administration of PL and ZA attenuated breast cancer growth in the bone microenvironment. Additionally, these molecules prevented the destruction of proximal tibia, with significant reduction of tartrate-resistant acid phosphatase (TRAcP)-positive osteoclast cells and potentiation of apoptotic cancer cells, to a greater extent when combined than when the drugs were applied independently. Altogether, the combination treatment with PL and ZA could significantly and synergistically suppress osteoclastogenesis and inhibit tumorigenesis both in vitro and in vivo by simulating the spatial structure of ANP to inhibit competitively phosphorylation of c-Jun N-terminal kinase/extracellular signal-regulated kinase (JNK/Erk).

Kinoshita Y, Arai M, Ito N, et al.
High serum ALP level is associated with increased risk of denosumab-related hypocalcemia in patients with bone metastases from solid tumors.
Endocr J. 2016; 63(5):479-84 [PubMed] Related Publications
Metastatic bone disease is one of the most common complications of advanced cancers. Pathological fractures, spinal cord compression, and radiotherapy or surgery to the bone are collectively called skeletal-related events (SREs), which cause severe pain, increase hospitalization rates, and impair the quality of life (QOL) of patients with bone metastases. The receptor activator of nuclear factor-kB ligand (RANKL)/RANK pathway is critical in the progression of bone metastases. Previous studies have demonstrated that an anti-RANKL antibody (denosumab) was superior to zoledronic acid in prolonging time to first SRE in patients with bone metastases from prostate and breast cancers. However, severe hypocalcemic events occur more frequently after treatment with denosumab compared with zoledronic acid. In this study, 368 administrations of denosumab in 219 patients with metastatic bone disease from solid tumors were analyzed to clarify the risk factors for developing hypocalcemia. The results showed that grade 2/3 hypocalcemia was observed in 10.4% of the total number of denosumab administrations. Patients with higher baseline serum ALP, higher performance status (PS), or gastric cancer were at higher risk for developing hypocalcemia. The cut-off value for ALP to predict denosumab-related hypocalcemia was 587 U/L with a sensitivity of 0.77 and a specificity of 0.81. Close monitoring of serum calcium, especially after the first treatment with denosumab, is strongly recommended in these patients.

Yoshiyama A, Morii T, Ohtsuka K, et al.
Development of Stemness in Cancer Cell Lines Resistant to the Anticancer Effects of Zoledronic Acid.
Anticancer Res. 2016; 36(2):625-31 [PubMed] Related Publications
BACKGROUND: Drug resistance is closely related to cancer cell stemness, that is acquired along with resistance to various anticancer agents. However, this has not been investigated as a potential mechanism underlying cancer cell resistance to zoledronate, that is used to suppress bone metastasis.
MATERIALS AND METHODS: Zoledronate-resistant A549 lung cancer and MG63 osteosarcoma cell lines were established by repeated treatment with sub-lethal concentrations of zoledronate. Expression levels of the stem cell marker NANOG, cMYC, octamer-binding transcription factor 4, and sex-determining region Y-box 2 were evaluated and sphere formation was compared between parental and resistant cell lines. Tumourigenicity was assessed in vivo.
RESULTS: Stem cell marker expression was up-regulated and sphere formation was enhanced in resistant compared to parental cells and showed greater tumour formation capacity in mice.
CONCLUSION: Repeated treatment of malignant tumour cell lines with zoledronate, induces the development of drug resistance and stemness.

Cheng HL, Lin CW, Yang JS, et al.
Zoledronate blocks geranylgeranylation not farnesylation to suppress human osteosarcoma U2OS cells metastasis by EMT via Rho A activation and FAK-inhibited JNK and p38 pathways.
Oncotarget. 2016; 7(9):9742-58 [PubMed] Article available free on PMC after 01/04/2017 Related Publications
Zoledronate is a standard treatment for preventing skeletal complications of osteoporosis and some types of cancer associated with bone metastases, but we little know whether the effect of zoledronate on metastasis of osteosarcoma. Here, we investigated the inhibitory effects of zoledronate on cell viability, motility, migration and invasion of 4 osteosarcoma cell lines (Saos2, MG-63, HOS and U2OS) by affecting cell morphology, epithelial-mesenchymal transition (EMT) and cytoskeletal organization as well as induction of E-cadherin and reduction of N-cadherin with activation of transcription factors Slug and Twist, especially in U2OS cells. Zoledronate decreased JNK and p38 phosphorylation and upper streams of focal adhesion kinase (FAK) and Src to suppress the motility, invasiveness and migration of U2OS cells. In addition to zoledronate-inhibited Rho A and Cdc42 membrane translocation and GTPγS activities, the anti-metastatic effects in U2OS cells including inhibition of adhesion were reversed by geranylgeraniol, but not farnesol. In conclusion, Zoledronate blocks geranylgeranylation not farnesylation to suppress human osteosarcoma U2OS cell-matrix and cell-cell interactions, migration potential, the invasive activity, and the adhesive ability by EMT via Rho A activation and FAK-inhibited JNK and p38 pathways.

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