The role of adjuvant clodronate therapy for prevention of bone metastasis in breast cancer

Bisphosphonates are effective against increased bone resorption because they inhibit osteoclast activity. The use of these drugs is well established for the treatment of metastatic breast and other cancers; they reduce skeletal complications, hypercalcemia, bone pain, and metastatic progression and they can improve the overall survival and quality of life. Preclinical observations and early clinical data indicate that early bisphosphonate treatment reduces the incidence and the extent of newly developed metastases in breast cancer. There is considerable interest in determining whether bisphosphonate treatment is to prevent the incidence of bone metastases and associated complications. To date three randomized, controlled clinical trials have examined the effect of long-term use of clodronate (1600 mg/d po.) on the incidence of bone metastases, other metastases, the survival of patients, and the side effects of the study drug as well. All the trials have observed significant reduction of the occurrence of bone metastases, although this reduction was significant only during the medication period. One of the trials mentioned have shown an unexpected reduction in non-osseous metastases, and two of them have revealed significant improvements in the death rates. These promising results need further evaluation by large clinical trials with longer treatment periods to establish the clinical role of adjuvant bisphosphonate treatment of primary breast cancer.     

靶向治疗乳腺癌骨转移的研究进展

本文对双磷酸盐、狄诺塞麦、Sagopilone等特异性靶向药物在乳腺癌骨转移靶向治疗中的作用机制、临床应用、临床疗效等方面的相关研究进展情况进行了简要阐述。双磷酸盐在抑制骨转移和非骨转移中发挥作用,狄诺塞麦可能成为双磷酸盐的合理替代物,尤其在双磷酸盐治疗效果不佳的病人中,而新型抗癌药物Sagopilone、骨唾液酸蛋白抑制剂亦可通过多种机制参与乳腺癌转移过程,具有抑制骨转移的巨大潜力。     

Clodronat therapy of hypercalcaemia associated with male breast cancer

OBJECTIVES: The aim of this study is to survey the treatment of bone metastases and hypercalcaemia. MATERIALS AND METHODS: A case of male breast cancer is presented here by the authors. The applied clodronat therapy was beneficial. RESULTS: The diagnostic difficulties of such rare, unusually localised, metastasizing male breast cancer are discussed with the survey of Hungarian and world literature. CONCLUSION: The bisphosphonates - beside treating the hypercalcaemia caused by bone metastasis - provide a better quality of life.     

Clinical usefulness of bisphosphonates in oncology: treatment of bone metastases, antitumoral activity and effect on bone resorption markers

The present article overviews the role of bisphosphonates for the treatment and prevention of bone metastases and their antiangiogenic effects and antitumoral activity. The skeleton is a frequent and clinically relevant site of metastasis in cancer patients. The major events related to bone metastases include bone pain, bone loss, hypercalcemia, spinal cord compression, and fractures. On the basis of their radiographic features, bone metastases are classified as osteoblastic, osteoclastic, or mixed. The primary goals of treatment of bone metastases are reduction of the risk of pathological fractures and other skeletal-related events, and pain control. Bisphosphonates are used to prevent pathological fractures by inhibition of osteoclasts. Recent studies suggest that bisphosphonates have some direct antitumoral activity, mainly mediated through the blockade of angiogenic pathways. Further clinical studies are needed to determine the optimal treatment duration, timing and schedule of bisphosphonates, assess their role as adjuvant therapy for the prevention of bone metastases, and establish their antiangiogenic activity in association with standard cytotoxic and hormonal drugs for treatment of patients with advanced disease.     

Systematic review of role of bisphosphonates on skeletal morbidity in metastatic cancer

Objective To review the evidence for the use of bisphosphonates to reduce skeletal morbidity in cancer patients with bone metastases.Data sources Electronic databases, scanning reference lists, and consultation with experts and pharmaceutical companies. Foreign language papers were included.Study selection Included trials were randomised controlled trials of patients with malignant disease and bone metastases who were treated with oral or intravenous bisphosphonate compared with another bisphosphonate, placebo, or standard care. All trials measured at least one outcome of skeletal morbidity.Results 95 articles were identified; 30 studies fulfilled inclusion criteria. In studies that lasted ≥ 6 months, compared with placebo bisphosphonates significantly reduced the odds ratio for fractures (vertebral 0.69, 95% confidence interval 0.57 to 0.84, P < 0.0001; non-vertebral 0.65, 0.54 to 0.79, P < 0.0001; combined 0.65, 0.55 to 0.78, P < 0.0001), radiotherapy (0.67, 0.57 to 0.79, P < 0.0001), and hypercalcaemia (0.54, 0.36 to 0.81, P = 0.003) but not for orthopaedic surgery (0.70, 0.46 to 1.05, P = 0.086) or spinal cord compression (0.71, 0.47 to 1.08, P = 0.113). The reduction in orthopaedic surgery was significant in studies that lasted over a year (0.59, 0.39 to 0.88, P = 0.009). Use of bisphosphonates significantly increased time to first skeletal related event but did not increase survival. Subanalyses showed that most evidence supports use of intravenous aminobisphosphonates.Conclusions In people with metastatic bone disease bisphosphonates significantly decrease skeletal morbidity, except for spinal cord compression and increased time to first skeletal related event. Treatment should start when bone metastases are diagnosed and continue until it is no longer clinically relevant.     

Modulation of tumour-induced bone resorption by bisphosphonates.

Tumour cells produce systemic or local factors which can stimulate osteoclast development and activity leading to increased bone resorption. The clinical consequences are bone pain, fractures and hypercalcaemia. Inhibitors of osteoclast-mediated bone resorption, such as the bisphosphonates, are now the treatment of choice for tumour-induced hypercalcaemia. Recent evidence indicates that these compounds, especially the newer ones, reduce skeletal morbidity in patients with metastatic bone disease and improve their quality of life. Better understanding of the mechanisms underlying tumour-induced bone resorption and development of more potent and less toxic bisphosphonates will lead to improved management of patients with malignant diseases involving the skeleton.     

Metabolic effects of single-dose pamidronate administration in prostate cancer patients with bone metastases

BACKGROUND: Increased osteolysis usually accompanies sclerotic bone metastases from prostate cancer. This provides a rationale for the use of bisphosphonates to treat bone pain and prevent skeletal complications. METHODS: The fasting urinary levels of calcium, hydroxyproline (OHPRO), pyridinolines (PYD), deoxypyridinolines (DPYD), collagen cross-linked N-telopeptide (NTX) and the serum values of calcium, total alkaline phosphatase and relevant bone isoenzyme, bone gla protein (BGP), carboxy-telopeptide of type I collagen (ICTP) and parathyroid hormone (PTH) were determined at baseline and on the 15th, 30th, 60th and 90th days after single-dose (90 mg) pamidronate administration in 35 consecutive prostate cancer patients with bone metastases. These biochemical indices and serum interleukin 6 (IL-6) were also measured after four days in the last consecutive 17 cases. RESULTS: PYD, DPYD and NTX showed a significant decrease lasting four weeks (p<0.01, <0.01 and <0.001, respectively). OHPRO and ICTP did not change significantly. The NTX decline was greater than that of PYD and DPYD (maximum percent decrease: -71.3, -23.1 and -28.2, respectively). Bone formation markers and serum calcium did not change significantly. Serum PTH showed a rapid initial increase followed by a slow decrease (p<0.001). DPYD and NTX patterns did not correlate with changes in bone pain. As observed in the last 17 cases, the maximum osteolysis inhibition after pamidronate occurred on the fourth day after drug infusion. Serum IL-6 levels showed a short-lived decrease preceded by a transient rise on the fourth day. CONCLUSIONS: Pamidronate is able to induce a decrease in bone resorption without significantly influencing bone formation. The maximum decrease in bone resorption occurs very early. NTX is the most sensitive bone resorption marker in bisphosphonate therapy monitoring. Changes in IL-6 but not bone resorption markers may be useful in the prediction of symptomatic response.     

Managing Bone Health in Breast Cancer

ObjectiveOsteoporosis is a common condition that can be caused or exacerbated by estrogen deficiency.MethodsThis narrative review will discuss optimizing bone health in the setting of adjuvant endocrine treatments for hormone receptor–positive breast cancer and the current use of antiresorptive agents as adjuvant therapy and as bone modifying agents.ResultsAdjuvant endocrine treatments for hormone receptor–positive breast cancer (tamoxifen and aromatase inhibitors) affect bone health. The exact effect depends on the agent used and the menopausal state of the woman. Antiresorptive medications for osteoporosis, bisphosphonates and denosumab, lower the risk of bone loss from aromatase inhibitors. Use of bisphosphonates as adjuvant treatment in breast cancer, regardless of hormone receptor status, is increasing because of benefits seen to cancer relapse and survival.ConclusionOptimizing bone health in women with breast cancer during and after cancer treatment is informed by an understanding of breast cancer treatment and its skeletal effect.     

Serum levels of tartrate-resistant acid phosphatase-5b in breast cancer patients treated with pamidronate

A novel immunoassay specific for the osteoclast-produced TRAP isoform 5b has been developed recently. By means of this assay we studied the usefulness of serum TRAP-5b in monitoring the response to palliative treatment with pamidronate in breast cancer patients with bone metastases. We correlated serum TRAP-5b levels with pain intensity and intake of analgesics to assess the possible utility of the marker in identifying patients who could benefit from pamidronate treatment. Twenty-eight advanced breast cancer patients with bone metastases entered the study. Patients were treated according to the following schedule: two two-week cycles of 60 mg/week pamidronate IV, with a three-week interval in between (six infusions over seven weeks), followed by one infusion every three weeks for a total of 24 infusions over a treatment period of 61 weeks. Blood samples were taken before the start of treatment and before each infusion during two treatment cycles. To measure serum TRAP levels we employed the new immunoassay kit BoneTRAP produced by Suomen Bioanalytiikka Oy (SBA), Oulu, Finland. In order to assess the usefulness of this marker in evaluating the response to pamidronate treatment we divided patients into two groups (group A, worsened; group B, improved) with respect to pain trend and analgesic intake. Our results did not show any statistically significant difference in baseline serum TRAP levels in the two groups. However, one week after the first pamidronate infusion TRAP-5b serum levels decreased by 39% and 18% in groups A and B, respectively (p=0.01); these levels persisted throughout the treatment period. In conclusion, a decrease in TRAP-5b serum levels may reflect the pharmacological activity of pamidronate and seems to predict pain relief and a reduction in analgesic consumption.     

Managing bone loss and bone metastases in prostate cancer patients: a focus on bisphosphonate therapy

Androgen deprivation therapy (ADT) and bone metastases are the most important risk factors for developing skeletal complications (eg, bone loss, pathologic fractures) in prostate cancer (PC) patients with locally advanced and metastatic disease. Bisphosphonates, which inhibit excessive osteoclast activity caused by ADT and bone metastases, have proven to be safe and effective in preventing skeletal complications and presently are the standard of care in patients with metastatic disease. Bisphosphonates should be considered for use in all PC patients with locally advanced disease initiating ADT for an intended duration of at least 1 year, especially those with a low baseline bone mineral density.     

Osteoblasts suppress high bone turnover caused by osteolytic breast cancer in-vitro

The skeleton is the most common site of breast cancer metastasis, which can occur in up to 85% of patients during their lifetime. The morbidity associated with bone metastases in patients with breast cancer includes pathological fractures, bone pain, hypercalcaemia, and spinal cord compression. When breast cancer metastasizes to bone, the balance of bone resorption (mediated by osteoclasts) and bone formation (mediated by osteoblasts) favors bone resorption, which leads to net bone destruction (i.e., osteolysis). Anti-resorptive agents such as bisphosphonates are commonly used to treat bone resorption in osteoporosis or osteolytic cancer patients. However, bisphosphonates by themselves are unable to rebuild lost bone tissue, and can cause severe side effects. In this study, we developed a bovine bone explant culture system and have observed that murine osteoblasts can modulate the activity of osteotropic human breast cancer cells on this substrate. Using markers of bone metabolism, we observe diminished bone turnover in organ culture following the addition of exogenous osteoblasts. The data presented in this study supports further investigation into the use of cytotherapies to limit breast cancer mediated osteolysis.     

乳腺癌双膦酸盐辅助治疗临床研究进展

乳腺癌是女性发病率和死亡率最高的恶性肿瘤,复发和远处转移仍是导致患者死亡的首位原因,而双膦酸盐作为一种骨质吸收抑制剂,能够抑制破骨细胞介导的骨质吸收,在多种实体肿瘤骨转移及多发性骨髓瘤等恶性疾病所致的骨相关事件治疗中起重要作用。近年来大量体外、体内实验表明双膦酸盐还具有抑制肿瘤细胞生长、粘附、播散和侵润,降低肿瘤细胞膜稳定性、促进肿瘤细胞凋亡等直接抗肿瘤作用以及抑制肿瘤血管生成、激活免疫细胞对肿瘤细胞的杀伤等间接抗肿瘤作用,基于这些基础研究结果已经开展了一系列针对双膦酸盐辅助治疗乳腺癌的临床试验研究,本文就近年相关临床试验研究进展做简要综述。     

Angiostatin inhibits bone metastasis formation in nude mice through a direct anti-osteoclastic activity

Bone is a very common metastatic site for breast cancer. In bone metastasis, there is a vicious circle wherein bone-residing metastatic cells stimulate osteoclast-mediated bone resorption, and bone-derived growth factors released from resorbed bone promote tumor growth. The contribution of tumor angiogenesis in the growth of bone metastases is, however, unknown. By using an experimental model of bone metastasis caused by MDA-MB-231/B02 breast cancer cells that quite closely mimics the conditions likely to occur in naturally arising metastatic human breast cancers, we demonstrate here that when MDA-MB-231/B02 cells were engineered to produce at the bone metastatic site an angiogenesis inhibitor, angiostatin, there was a marked inhibition in the extent of skeletal lesions. Inhibition of skeletal lesions came with a pronounced reduction in tumor burden in bone. However, although angiostatin produced by MDA-MB-231/B02 cells was effective at inhibiting in vitro endothelial cell proliferation and in vivo angiogenesis in a Matrigel implant model, we have shown that it inhibited cancer-induced bone destruction through a direct inhibition of osteoclast activity and generation. Overall, these results indicate that, besides its well known anti-angiogenic activity, angiostatin must also be considered as a very effective inhibitor of bone resorption, broadening its potential clinical use in cancer therapy.     

乳腺癌双膦酸盐辅助治疗临床研究进展

乳腺癌是女性发病率和死亡率最高的恶性肿瘤,复发和远处转移仍是导致患者死亡的首位原因,而双膦酸盐作为一种骨质吸收抑制剂,能够抑制破骨细胞介导的骨质吸收,在多种实体肿瘤骨转移及多发性骨髓瘤等恶性疾病所致的骨相关事件治疗中起重要作用。近年来大量体外、体内实验表明双膦酸盐还具有抑制肿瘤细胞生长、粘附、播散和侵润,降低肿瘤细胞膜稳定性、促进肿瘤细胞凋亡等直接抗肿瘤作用以及抑制肿瘤血管生成、激活免疫细胞对肿瘤细胞的杀伤等间接抗肿瘤作用,基于这些基础研究结果已经开展了一系列针对双膦酸盐辅助治疗乳腺癌的,陆床试验研究,本文就近年相关临床试验研究进展做简要综述。     

Denosumab

Denosumab is an anti-receptor activator of nuclear factor (NF)-kappaB (RANK) ligand human monoclonal antibody studied as a treatment for postmenopausal osteoporosis (PMO) and bone destruction due to rheumatoid arthritis (RA) or metastatic cancers. As of February 2009, the candidate was undergoing US Food and Drug Administration review, and might be approved by October 2009. Late phase clinical trials demonstrated that denosumab possesses a similar safety profile to bisphosphonates and that it can be either equally or more effective than bisphosphonates at preventing bone loss due to PMO, RA or cancer treatment and metastases.Key Words: monoclonal antibody, RANKL, bone loss, osteoporosis, breast cancer, rheumatoid arthritis     

Breast cancer at bone metastatic sites: recent discoveries and treatment targets

Breast carcinoma is the most common cancer of women. Bones are often involved with breast carcinoma metastases with the resulting morbidity and reduced quality of life. Breast cancer cells arriving at bone tissues mount supportive microenvironment by recruiting and modulating the activity of several host tissue cell types including the specialized bone cells osteoblasts and osteoclasts. Pathologically activated osteoclasts produce osteolytic lesions associated with bone pain, pathological fractures, cord compression and other complications of metastatic breast carcinoma at bone. Over the last decade there has been enormous growth of knowledge in the field of osteoclasts biology both in the physiological state and in the tumor microenvironment. This knowledge allowed the development and implementation of several targeted therapeutics that expanded the armamentarium of the oncologists dealing with the metastases-associated osteolytic disease. While the interactions of cancer cells with resident bone cells at the established metastatic gross lesions are well-studied, the preclinical events that underlie the progression of disseminated tumor cells into micrometastases and then into clinically-overt macrometastases are just starting to be uncovered. In this review, we discuss the established information and the most recent discoveries in the pathogenesis of osteolytic metastases of breast cancer, as well as the corresponding investigational drugs that have been introduced into clinical development.     

Intractable pain with breast cancer.

This study examines retrospectively the cause, clinical features, natural history and results of treatment of intractable pain associated with breast cancer in 210 patients. The three chief types of pain were that due to skeletal metastases or brachial plexus neuropathy and pain of psychogenic origin. Onset at the time of cancer diagnosis characterized the psychogenic pain, whereas pain from metastases first occurred after a median latency of 3.7 years. Treatment was custom-tailored to the specific patient and pain problem, with several factors taken into account. The onset of intractable pain due to metastatic disease indicated a short survival (median, 9 months).     

Tests for multivariate recurrent events in the presence of a terminal event

In studies involving diseases associated with high rates of mortality, trials are frequently conducted to evaluate the effects of therapeutic interventions on recurrent event processes terminated by death. In this setting, cumulative mean functions form a natural basis for inference for questions of a health economic nature, and Ghosh and Lin (2000) recently proposed a relevant class of test statistics. Trials of patients with cancer metastatic to bone, however, involve multiple types of skeletal complications, each of which may be repeatedly experienced by patients over their lifetime. Traditionally the distinction between the various types of events is ignored and univariate analyses are conducted based on a composite recurrent event. However, when the events have different impacts on patients' quality of life, or when they incur different costs, it can be important to gain insight into the relative frequency of the specific types of events and treatment effects thereon. This may be achieved by conducting separate marginal analyses with each analysis focusing on one type of recurrent event. Global inferences regarding treatment benefit can then be achieved by carrying out multiplicity adjusted marginal tests, more formal multiple testing procedures, or by constructing global test statistics. We describe methods for testing for differences in mean functions between treatment groups which accommodate the fact that each particular event process is ultimately terminated by death. The methods are illustrated by application to a motivating study designed to examine the effect of bisphosphonate therapy on the incidence of skeletal complications among patients with breast cancer metastatic to bone. We find that there is a consistent trend towards a reduction in the cumulative mean for all four types of skeletal complications with bisphosphonate therapy; there is a significant reduction in the need for radiation therapy for the treatment of bone. The global test suggests that bisphosphonate therapy significantly reduces the overall number of skeletal complications.