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Journal ArticleDOI: 10.1016/J.BONE.2021.115907

The use of bisphosphonates to treat skeletal complications in solid tumours

04 Mar 2021-Bone (Elsevier)-Vol. 147, pp 115907-115907
Abstract: The skeleton is the most common site of secondary disease in breast cancer and prostate cancer, with up to 80% of patients with advanced disease developing bone metastases (BM). The proportion is also substantial in advanced lung cancer (20%–40%). Because of the high prevalence of cancers of the breast, prostate and lung, these cancers account for more than 80% of cases of metastatic bone disease occurring in solid tumours. Metastatic bone disease is associated with greatly increased bone resorption by osteoclasts, leading to moderate to severe pain and other skeletal complications, with major impact on quality of life (QoL). Skeletal Related Events (SREs) have been defined as: pathological long bone or vertebral fractures; spinal cord compression; need for radiation for pain relief or to prevent fracture/spinal cord compression, need for surgery to bone and hypercalcaemia. More recently, Symptomatic Skeletal Events (SSEs) have been defined to monitor QoL. Although there are currently no curative treatments for metastatic bone disease, patients with breast or prostate cancer and BM are now surviving for several years and sometimes longer, and prevention of SREs is the key aim to optimization of QoL. Since their discovery 50 years ago and their introduction more than 30 years ago into the field of metastatic bone disease, a range of oral and intravenous bisphosphonate drugs have made a major contribution to prevention of SREs. Large trials have clearly demonstrated the clinical value of different bisphosphonate-based drugs (including the oral drugs ibandronate and clodronate and intravenous agents such as zoledronate and pamidronate), in treatment of hypercalcaemia of malignancy and the reduction of SREs and SSEs in a range of cancers. Despite the success of denosumab in reducing osteolysis, bisphosphonates also remain mainstay drugs for treatment of metastatic bone disease. Recognizing the 50th Anniversary of the discovery of bisphosphonates, this review focuses on their continuing value in BM treatment and their future potential, for example in providing a bone-targeting vehicle for cytotoxic drugs.

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Topics: Bone metastasis (64%), Bone disease (62%), Denosumab (60%) ... show more
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Open accessJournal ArticleDOI: 10.3390/CELLS10061377
02 Jun 2021-Cells
Abstract: Despite the remarkable advances in the diagnosis and treatment of breast cancer patients, the presence or development of metastasis remains an incurable condition. Bone is one of the most frequent sites of distant dissemination and negatively impacts on patient's survival and overall frailty. The interplay between tumor cells and the bone microenvironment induces bone destruction and tumor progression. To date, the clinical management of bone metastatic breast cancer encompasses anti-tumor systemic therapies along with bone-targeting agents, aimed at slowing bone resorption to reduce the risk of skeletal-related events. However, their effect on patients' survival remains controversial. Unraveling the biology that governs the interplay between breast neoplastic cells and bone tissue would provide means for the development of new therapeutic agents. This article outlines the state-of-the art in the characterization and targeting the bone metastasis in breast cancer, focusing on the major clinical and translational studies on this clinically relevant topic.

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Topics: Bone metastasis (69%), Breast cancer (63%), Metastatic breast cancer (62%) ... show more

1 Citations


Open accessJournal ArticleDOI: 10.32388/MQ2IYG
Vittorio Fusco, Marco Cabras1, Alessio Gambino1, Massimo Di Maio1  +15 moreInstitutions (1)
Abstract: Survival of cancer and myeloma patients after diagnosis of bone lesions is largely variable. Appropriate medical therapy together with antiresorptive treatment (bisphosphonates or denosumab) can obtain prolonged survival with adequate quality of life. Osteonecrosis of Jaws (ONJ) is not rare in patients with bone metastatic cancer and myeloma patients, occurring mostly after prolonged antiresorptive treatment. Expected survival can influence the choice of antiresorptive treatment, the perception of ONJ risk, and even the ONJ management. We reviewed survival data after start of antiresorptive treatment of 509 ONJ patients registered in a cancer network database (Rete Oncologica Piemonte-Valle d’Aosta, North-Western Italy). Main characteristics: 196 males, 313 females; median age: 68 (39-89) years. Underlying disease: breast cancer: 42.9%; myeloma: 25.3%; prostate cancer: 17.2%; lung cancer: 6.7%; renal cancer: 2.5%; other cancer types: 4.3%. Main antiresorptive treatment: zoledronic acid: 79.4%; denosumab: 5.3%; other drugs/sequences: 15.3%. Actuarial median survival (range) after the start of antiresorptive treatment was 66.0 (95% CI 57-77) months for breast cancer patients, 77.3 (95% CI 61.9-86.8) months for myeloma patients, 47.3. (95% CI 37.8-51.9) months for prostate cancer patients, 29.4 (95% CI 20.4-40.1) months for lung cancer patients, 39.4 (95% CI 20-107.3) months for renal cancer patients, 82.4 (95% CI 51.9-150.9) months for other cancer patients. Two-, three- and four-year actuarial survival rates were respectively 91.7%%, 80.2%, 67.4% for breast cancer patients, 91.4%, 83.7%, 68.9% for myeloma patients, 78.4%, 61.2%, 41.9% for prostate cancer patients; 55.8%, 32.3%, 23.5% for lung cancer patients; 61.5%, 53.8%, 46.1% for renal cancer patients; 81.8%, 77.3%, 68.1% for others cancer types. Our data support careful evaluation of short and long-term actuarial ONJ risk (versus short-term absolute risk) in the choice of antiresorptive treatment duration for bone metastatic cancer and myeloma patients. Furthermore, exclusion of jawbone surgery due to expected short survival in most of ONJ patients seems not warranted.

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Topics: Cancer (59%), Breast cancer (57%), Zoledronic acid (54%) ... show more

1 Citations


Open accessJournal ArticleDOI: 10.3389/FENDO.2021.763846
Abstract: The skeleton is a common site for cancer metastases with the bone microenvironment providing the appropriate conditions for cancer cell colonization. Once in bone, cancer cells effectively manipulate their microenvironment to support their growth and survival. Despite previous efforts to improve treatment modalities, skeletal metastases remain with poor prognoses. This warrants an improved understanding of the mechanisms leading to bone metastasis that will aid development of effective treatments. Macrophages in the tumor microenvironment are termed tumor associated macrophages (TAMs) and their crosstalk with cancer cells is critical in regulating tumorigenicity in multiple cancers. In bone metastases, this crosstalk is also being increasingly implicated but the specific signaling pathways remain incompletely understood. Here, we summarize the reported functions, interactions, and signaling of macrophages with cancer cells during the metastatic cascade to bone. Specifically, we review and discuss how these specific interactions impact macrophages and their profiles to promote tumor development. We also discuss the potential of targeting this crosstalk to inhibit disease progression. Finally, we identify the remaining knowledge gaps that will need to be addressed in order to fully consider therapeutic targeting to improve clinical outcomes in cancer patients.

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Topics: Bone metastasis (61%), Tumor microenvironment (57%), Myeloid-derived Suppressor Cell (57%) ... show more

Journal ArticleDOI: 10.1016/J.TCB.2021.08.001
Sarah K. Deasy1, Neta Erez1Institutions (1)
Abstract: Modification of the extracellular matrix (ECM) is a critical aspect of developing a metastasis-supportive organ niche. Recent work investigating ECM changes that facilitate metastasis has revealed ways in which different metastatic organ niches are similar as well as the distinct characteristics that make them unique. In this review, we present recent findings regarding how ECM modifications support metastasis in four frequent metastatic sites: the lung, liver, bone, and brain. We discuss ways in which these modifications are shared between metastatic organs as well as features specific to each location. We also discuss areas of technical innovation that could be advantageous to future research and areas of inquiry that merit further investigation.

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Open accessJournal ArticleDOI: 10.3389/FENDO.2021.705499
Shu-Ting Lin1, Yi-Zhong Li1, Xiao-Qi Sun1, Qian-Qian Chen1  +3 moreInstitutions (1)
Abstract: Breast cancer and osteoporosis are common diseases that affect the survival and quality of life in postmenopausal women. Women with breast cancer are more likely to develop osteoporosis than women without breast cancer due to certain factors that can affect both diseases simultaneously. For instance, estrogen and the receptor activator of nuclear factor-κB ligand (RANKL) play important roles in the occurrence and development of these two diseases. Moreover, chemotherapy and hormone therapy administered to breast cancer patients also increase the incidence of osteoporosis, and in recent years, neuropeptide Y (NPY) has also been found to impact breast cancer and osteoporosis.Y1 and Y5 receptors are highly expressed in breast cancer, and Y1 and Y2 receptors affect osteogenic response, thus potentially highlighting a potential new direction for treatment strategies. In this paper, the relationship between breast cancer and osteoporosis, the influence of NPY on both diseases, and the recent progress in the research and treatment of these diseases are reviewed.

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Topics: Breast cancer (69%), Osteoporosis (52%)
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Journal ArticleDOI: 10.1016/S0140-6736(88)90741-6
Pekka Saikku1, Pekka Saikku2, Kimmo Mattila1, Kimmo Mattila2  +12 moreInstitutions (2)
29 Oct 1988-The Lancet
Abstract: Paired sera from 40 male patients with acute myocardial infarction (AMI), 30 male patients with chronic coronary heart disease (CCHD), and 41 controls, matched for sex, age, time, and locality were investigated for antibodies to a novel type of Chlamydia sp, TWAR, and to chlamydial lipopolysaccharide (LPS) group antigen. 27 patients with AMI (68%), and 15 (50%) patients with CCHD had raised IgG (greater than or equal to 128) and/or IgA (greater than or equal to 32) titres in the microimmunofluorescence test with chlamydia TWAR. Both frequencies were significantly higher than in the controls (7, 17%). 26 (68%) of 38 patients with AMI also showed a significant seroconversion in enzyme immunoassay with LPS antigen; this response was absent in all patients with CCHD and all but 1 of the controls. Chronic chlamydial infection could be a factor in the pathogenesis of cardiovascular diseases.

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Topics: Myocardial infarction (51%), Seroconversion (50%)

1,966 Citations


Journal ArticleDOI: 10.1016/J.JOMS.2014.04.031
Abstract: Strategies for management of patients with, or at risk for, medication-related osteonecrosis of the jaw (MRONJ) were set forth in the American Association of Oral and Maxillofacial Surgeons (AAOMS) position papers in 2007 and 2009. The position papers were developed by a special committee appointed by the board and composed of clinicians with extensive experience in caring for these patients and basic science researchers. The knowledge base and experience in addressing MRONJ has expanded, necessitating modifications and refinements to the previous position paper. This special committee met in September 2013 to appraise the current literature and revise the guidelines as indicated to reflect current knowledge in this field. This update contains revisions to diagnosis, staging, and management strategies and highlights current research status. The AAOMS considers it vitally important that this information be disseminated to other relevant health care professionals and organizations.

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1,860 Citations


Open accessJournal ArticleDOI: 10.1158/1078-0432.CCR-06-0931
Robert E. Coleman1Institutions (1)
Abstract: The skeleton is the most common organ to be affected by metastatic cancer and the site of disease that produces the greatest morbidity. Skeletal morbidity includes pain that requires radiotherapy, hypercalcemia, pathologic fracture, and spinal cord or nerve root compression. From randomized trials in advanced cancer, it can be seen that one of these major skeletal events occurs on average every 3 to 6 months. Additionally, metastatic disease may remain confined to the skeleton with the decline in quality of life and eventual death almost entirely due to skeletal complications and their treatment. The prognosis of metastatic bone disease is dependent on the primary site, with breast and prostate cancers associated with a survival measured in years compared with lung cancer, where the average survival is only a matter of months. Additionally, the presence of extraosseous disease and the extent and tempo of the bone disease are powerful predictors of outcome. The latter is best estimated by measurement of bone-specific markers, and recent studies have shown a strong correlation between the rate of bone resorption and clinical outcome, both in terms of skeletal morbidity and progression of the underlying disease or death. 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.

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Topics: Bone disease (60%), Pathologic fracture (57%), Cancer (53%) ... show more

1,731 Citations


Open accessJournal ArticleDOI: 10.1016/S0140-6736(10)62344-6
05 Mar 2011-The Lancet
Abstract: Summary Background Bone metastases are a major burden in men with advanced prostate cancer. We compared denosumab, a human monoclonal antibody against RANKL, with zoledronic acid for prevention of skeletal-related events in men with bone metastases from castration-resistant prostate cancer. Methods In this phase 3 study, men with castration-resistant prostate cancer and no previous exposure to intravenous bisphosphonate were enrolled from 342 centres in 39 countries. An interactive voice response system was used to assign patients (1:1 ratio), according to a computer-generated randomisation sequence, to receive 120 mg subcutaneous denosumab plus intravenous placebo, or 4 mg intravenous zoledronic acid plus subcutaneous placebo, every 4 weeks until the primary analysis cutoff date. Randomisation was stratified by previous skeletal-related event, prostate-specific antigen concentration, and chemotherapy for prostate cancer within 6 weeks before randomisation. Supplemental calcium and vitamin D were strongly recommended. Patients, study staff, and investigators were masked to treatment assignment. The primary endpoint was time to first on-study skeletal-related event (pathological fracture, radiation therapy, surgery to bone, or spinal cord compression), and was assessed for non-inferiority. The same outcome was further assessed for superiority as a secondary endpoint. Efficacy analysis was by intention to treat. This study is registered with ClinicalTrials.gov, number NCT00321620, and has been completed. Findings 1904 patients were randomised, of whom 950 assigned to denosumab and 951 assigned to receive zoledronic acid were eligible for the efficacy analysis. Median duration on study at primary analysis cutoff date was 12·2 months (IQR 5·9–18·5) for patients on denosumab and 11·2 months (IQR 5·6–17·4) for those on zoledronic acid. Median time to first on-study skeletal-related event was 20·7 months (95% CI 18·8–24·9) with denosumab compared with 17·1 months (15·0–19·4) with zoledronic acid (hazard ratio 0·82, 95% CI 0·71–0·95; p=0·0002 for non-inferiority; p=0·008 for superiority). Adverse events were recorded in 916 patients (97%) on denosumab and 918 patients (97%) on zoledronic acid, and serious adverse events were recorded in 594 patients (63%) on denosumab and 568 patients (60%) on zoledronic acid. More events of hypocalcaemia occurred in the denosumab group (121 [13%]) than in the zoledronic acid group (55 [6%]; p vs 12 [1%]; p=0·09). Interpretation Denosumab was better than zoledronic acid for prevention of skeletal-related events, and potentially represents a novel treatment option in men with bone metastases from castration-resistant prostate cancer. Funding Amgen.

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Topics: Denosumab (66%), Zoledronic acid (61%), Bone metastasis (50%)

1,606 Citations


Open accessJournal ArticleDOI: 10.1093/JNCI/94.19.1458
Abstract: Background: Bone metastases are a common cause of morbidity in patients with prostate carcinoma. We studied the effect of a new bisphosphonate, zoledronic acid, which blocks bone destruction, on skeletal complications in prostate cancer patients with bone metastases. Methods: Patients with hormone-refractory prostate cancer and a history of bone metastases were randomly assigned to a double-blind treatment regimen of intravenous zoledronic acid at 4 mg (N = 214), zoledronic acid at 8 mg (subsequently reduced to 4 mg; 8/4) (N = 221), or placebo (N = 208) every 3 weeks for 15 months. Proportions of patients with skeletal-related events, time to the first skeletal-related event, skeletal morbidity rate, pain and analgesic scores, disease progression, and safety were assessed. All statistical tests were two-sided. Results: Approximately 38% of patients who received zoledronic acid at 4 mg, 28% who received zoledronic acid at 8/4 mg, and 31% who received placebo completed the study. A greater proportion of patients who received placebo had skeletal-related events than those who received zoledronic acid at 4 mg (44.2% versus 33.2%; difference = –11.0%, 95% confidence interval [CI] = –20.3% to –1.8%; P = .021) or those who received zoledronic acid at 8/4 mg (38.5%; difference versus placebo = –5.8%, 95% CI = –15.1% to 3.6%; P = .222). Median time to first skeletalrelated event was 321 days for patients who received placebo, was not reached for patients who received zoledronic acid at 4 mg ( P= .011 versus placebo), and was 363 days for those who received zoledronic acid at 8/4 mg ( P= .491 versus placebo). Compared with urinary markers in patients who received placebo, urinary markers of bone resorption were statistically significantly decreased in patients who received zoledronic acid at either dose (P = .001). Pain and analgesic scores increased more in patients who received placebo than in patients who received zoledronic acid, but there were no differences in disease progression, performance status, or quality-of-life scores among the groups. Zoledronic acid at 4 mg given as a 15-minute infusion was well tolerated, but the 8-mg dose was associated with renal function deterioration. Conclusion: Zoledronic acid at 4 mg reduced skeletalrelated events in prostate cancer patients with bone metastases. [J Natl Cancer Inst 2002;94:1458–68]

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Topics: Zoledronic acid (60%), Placebo (51%), Placebo-controlled study (50%)

1,566 Citations