Robert E Coleman

..Additionally, these drugs may modify the course of bone destruction via inhibitory effects on the 'vicious cycle' of growth factor and cytokine signalling between tumour and bone cells within the bone marrow microenvironment...

..Here, we have critically reviewed the increasing evidence to support a disease-modifying effect of bone-targeted treatment and discussed the impact on clinical management...

....

..Results from ongoing clinical trials evaluating such potential applications of bone markers are awaited...

..Ongoing research is aimed at trying to define the optimum route, dose, schedule and type of bisphosphonate...

....

..Because many patients with cancer die before trial completion, there is a need for survival-adjusted methods to accurately assess the effects of treatment on skeletal morbidity...

..ZOL in the adjuvant setting is well tolerated, and can be safely administered in addition to adjuvant therapy including chemotherapy. The adverse events were consistent with the known safety profile of ZOL, with a low incidence of ONJ...

....

..Knowing that joint symptoms can be managed in most patients may encourage patient-physician communication and treatment compliance...

..Biochemical markers of bone turnover and tumor markers are being characterized and may provide useful tools to identify high-risk patients who may especially benefit from bisphosphonate therapy...

..Therefore, patients with early-stage disease may benefit from early bisphosphonate therapy, before bone metastasis develops, and investigations are ongoing to determine the clinical utility of bisphosphonates in this setting...

....

....

..Our improved understanding of prognostic and predictive factors may enable delivery of a more personalized treatment for the individual patient and a more cost-effective use of health care resources...

..In this conclusion, we summarise data from leading studies relating to the search for useful markers of bone resorption and bone formation in MBD...

..Bone markers are also being evaluated as a possible guide to optimize treatment of bone complications. In the reports included in this supplement, experts at the frontiers of bone marker research offer insights on their progress...

..The high frequency of stomatitis seen with 6 weekly treatment makes this the less preferred of the two schedules tested...

..The incidence, clinical importance and prevention strategies to minimise the impact of this problem on patients requiring bisphosphonates is discussed...

..Biochemical markers of bone metabolism may meet an unmet need for useful, noninvasive, and sensitive surrogate information for following patients' skeletal health...

..In comparison to most other cancer treatments, adverse events related to bisphosphonate therapy are generally mild and infrequent; thus, the benefits of treatment within licensed indications will almost always outweigh the risks...

..Ongoing clinical trials in patients with solid tumors will provide further insight into the potential of ZOL to prevent distant metastases and improve survival...

..Zoledronic acid is a widely used intravenous bisphosphonate that reduces this skeletal morbidity in both benign and malignant conditions...

..With the switch strategy used in IES, the on treatment adverse bone effects of exemestane are reversed. Ongoing monitoring of BMD is therefore not routinely required...

....

..This article, which is the third of four articles covering key topics in cancer thrombosis, focuses on treatment and secondary prevention of VTE in cancer patients...

..We report a retrospective evaluation comparing pathological response in the primary tumour between treatment groups...

..In addition, they are increasingly used to prevent cancer treatment-induced bone loss and show promise in the adjuvant setting to prevent metastasis from breast cancer...

..We conducted a study to determine whether treatment with zoledronic acid, in addition to standard adjuvant therapy, would improve disease outcomes in such patients...

..The results of ongoing large metastasis prevention trials are however, required before routine use of adjuvant bisphosphonates can be recommended...

..Summarize current knowledge, critical gaps in knowledge, and recommendations to advance the field of metastatic bone cancer...

..Additionally, cancer treatments may have adverse effects on bone health. Therefore, a clear rationale exists for bone-targeted therapies to prevent skeletal complications and potentially modify the underlying disease...

....

..Preclinical data suggest that bisphosphonates have antitumour effects. Bisphosphonates may also be of use in the adjuvant setting...

....

..These trials provide an opportunity for investigating the correlation between bone metabolism and clinical outcome during bisphosphonate therapy...

..On the basis of these results, zoledronic acid has rapidly become the new international standard of care for patients with bone metastases from breast cancer...

..Thus other strategies to protect bone are needed. This article discusses various treatments that attempt to offset this bone loss--mainly the protective effects of several bisphosphonates...

..The third case history illustrates the benefits of rapid pain relief from an intensive, high-dose regimen of intravenous ibandronate in metastatic prostate cancer...

..Biochemical markers of bone resorption have been identified that can augment the imaging techniques used to diagnose bone metastases and assess response to bisphosphonate therapy...

..It may be possible to replace the current oral regimens for prevention of bone loss with a single annual infusion of the highly potent bisphosphonate zoledronic acid...

..N-telopeptide levels were more consistent prognostic indicators than bone-specific alkaline phosphatase for all tumor types, reflecting the key role of osteolysis in the development of skeletal complications...

..Our data are the first to show the specific molecular pathways by which sequential treatment with doxorubicin and zoledronic acid induce tumor cell apoptosis and inhibit proliferation in an in vivo model of breast tumor growth in bone...

..The ARIBON trial is a double-blind, randomized, placebo-controlled study designed to evaluate the impact of bisphosphonate treatment on bone mineral density (BMD) in women taking anastrozole...

..Combination treatment with doxorubicin followed by zoledronic acid inhibits development and progression of spontaneously occurring mammary tumours...

..Our data are the first to show a sustained antitumor effect in vivo following a limited course of sequential administration of doxorubicin followed by zoledronic acid...

..For 10 microM zoledronic acid, pre- or post-doxorubicin also reduces invasion, but for this combination inhibition of cell growth may contribute to the reduction in invasion observed...

....

..We investigated the effects of clinically achievable doses of doxorubicin (Dox) and Zol, given alone, in sequence, and in combination, on the growth of established breast tumors in vivo...

..We also give an overview of the use of bisphosphonates in the treatment of breast cancer, including examples of key clinical trials. The potential side effects and future clinical applications of bisphosphonates will be outlined...

..Whilst POCDs appear to record higher values than laboratory assays, the correlation between devices is good and with further research the NTX categories could be modified to accommodate this variation...

..It is therefore important to understand the effects of long-term aromatase inhibitor therapy on BMD...

..Radiological imaging and biochemical analyses may help our understanding of AIA and these are discussed...

..This is the first study to report the proangiogenic effects of OPG in vitro, as well as correlating expression of OPG by tumour endothelial cells with clinicopathological data in human tumours...

..This study assesses the extent of bone loss due to previous chemotherapy in men...

..We have therefore investigated the antitumor effects of clinically relevant doses of these drugs in a mouse model of breast cancer bone metastasis...

..With potent bisphosphonates, such as zoledronic acid, it may be possible to maintain efficacy with relatively infrequent administration...

..This review will focus on emerging evidence of the anticancer activities of bisphosphonates and possible underlying mechanisms of action...

..Several placebo-controlled trials using oral clodronate, oral risedronate, intravenous pamidronate and intravenous zoledronic acid have all now demonstrated benefits in reducing the loss in bone mineral density...

..Evidence for effects on different processes and cell types involved in cancer development and progression is discussed, and the main outstanding issues identified...

..These findings may have relevance for the clinical setting, particularly breast cancer patients receiving these drugs in the adjuvant setting...

..However, recent data suggest that bisphosphonate use in breast cancer may provide more than just supportive care and modify the course of the disease by disrupting the metastatic process...

..This is the first report showing a specific effect of zoledronic acid on a protein involved in the regulation of chromosome segregation, identifying Cenp-F as a potential new molecular target for NBPs in tumour cells...

..To review retrospectively the causes of death in unselected patients with gestational trophoblastic neoplasia (GTN)...

..This review discusses the preclinical evidence for the potential use of BPs and cytotoxic drugs for inhibiting tumor cell invasion, a key process in cancer progression...

....

..The results from trials involving protease inhibitors in clinical development will also be briefly discussed...

....

..Adjuvant studies of zoledronic acid in patients with breast cancer are in development and should further clarify the role of zoledronic acid in the prevention of bone metastases...

..The authors investigated the relationship between androgen levels, QOL, self-esteem, fatigue, and sexual function in young male cancer survivors compared with control subjects...

..To our knowledge these results are the first to demonstrate that OPG can act as an endocrine survival factor for breast cancer cells, as well as reporting the expression patterns of OPG in a large cohort of human breast tumours...

..Our experience suggests that, in selected patients, this approach might be a useful form of salvage therapy...

....

..Strategies for the identification and management of treatment-induced bone loss are currently being defined...

..To compare health-related quality of life (HRQOL) in patients with metastatic breast cancer receiving the combination of doxorubicin and paclitaxel (AT) or doxorubicin and cyclophosphamide (AC) as first-line chemotherapy treatment...

..Changes were comparable to those with pamidronate. AMGN-0007 was well tolerated...

..The potential cardiotoxicity of the doxorubicin-paclitaxel regimen, when paclitaxel is given shortly after the end of the anthracycline infusion, is an issue of concern, as suggested by small single institution Phase II studies...

..Future clinical trials should be designed to prospectively evaluate the prognostic role of reduction of betaCTX and VEGF in response to ZOL to predict clinical and skeletal outcome...

..The aim of this review is to improve our understanding of bone markers as a clinical tool for the management of malignant bone disease in patients with MM...

....

..Management recommendations have been summarised in two algorithms, one for women experiencing a premature menopause and the other for postmenopausal women requiring adjuvant aromatase inhibitor therapy...

..For patients with bone metastases, high N-telopeptide of type I collagen (NTX) levels correlate with increased risks of skeletal-related events and death. However, the relation between NTX decreases and clinical benefits is unclear...

..Zoledronic acid (ZOL) reduces SRE risk and NTX levels...

..This study evaluated an immediate or delayed strategy of bone protection therapy with zoledronic acid...

..There were no significant cost differences between patients receiving zoledronic acid and those receiving pamidronate...

..04). CONCLUSIONS: Exemestane therapy after two to three years of tamoxifen therapy significantly improved disease-free survival as compared with the standard five years of tamoxifen treatment...

..CONCLUSIONS: These findings demonstrate that 1 mCi/kg 153Sm-lexidronam is both safe and effective for the palliation of painful bone metastases in patients with hormone-refractory prostate cancer...

..CONCLUSION In contrast to the positive results reported for sequential docetaxel after AC as primary chemotherapy of breast cancer, our data do not suggest a benefit for simultaneous AD over AC...

..Denosumab (AMG 162), a fully human monoclonal antibody to RANKL, was developed to treat patients with skeletal diseases...

..Treatment with zoledronic acid (Zol) was compared with a dose of 90 mg of pamidronate (Pam) in breast carcinoma (BC) patients with at least 1 osteolytic lesion based on data from a Phase III, randomized trial...

..The goal of the current study was to compare the long-term (25-month) safety and efficacy of zoledronic acid with pamidronate in patients with bone lesions secondary to advanced breast carcinoma or multiple myeloma...

..Use of hybrid linkers to target hCTM01 or other antibodies to EOC may warrant further investigation...

..The conclusions reached during the 2-day meeting are summarized in this article and presented in more detail in the individual articles and accompanying discussion sessions that comprise the conference proceedings...