Management of Metastatic Bone Disease and Hypercalcemia of Malignancy

Thirty years of research have established bisphosphonates as the most effective agents for the inhibition of osteoclast-mediated bone resorption, and they play an important role in the management of malignant bone disease. Bisphosphonates have been systematically improved through chemical engineering, and the newest nitrogen-containing compounds, including zoledronic acid and ibandronate, are 1000-fold more potent than first-generation compounds. Consequently, they can be administered at low molar doses via short intravenous infusions without compromising renal safety. Bisphosphonates have a variety of metabolic effects on osteoclasts. Nitrogen-containing bisphosphonates inhibit protein prenylation via the mevalonate pathway, thereby inhibiting osteoclast activation and inducing apoptosis. Preclinical studies suggest that bisphosphonates also have direct and indirect antitumor activity. In animal models, bisphosphonates reduced skeletal tumor burden and bone metastases. Currently, intravenous bisphosphonates are the standard therapy for hypercalcemia of malignancy, and they have become an integral part of the treatment of bone metastases in conjunction with standard antineoplastic agents. Intravenous bisphosphonates quickly normalize serum calcium, reduce skeletal complications, and palliate bone pain in patients with bone metastases. Intravenous pamidronate (90mg via 2-hour infusion every 3–4 weeks) has, until recently, been the international standard for the treatment of osteolytic bone lesions from breast cancer or multiple myeloma. However, 4mg zoledronic acid (via 15-minute infusion) is quickly becoming the new standard based on evidence that it is as safe and effective as 90mg pamidronate in patients with breast cancer and multiple myeloma and significantly more effective for hypercalcemia of malignancy. Consequently, the American Society of Clinical Oncology guidelines for breast cancer and multiple myeloma recommend pamidronate or zoledronic acid for patients with radiographic evidence of osteolytic bone destruction. Moreover, 4mg zoledronic acid is the only bisphosphonate that has demonstrated significant clinical benefit in patients with other solid tumors, including lung cancer, and prostate cancer patients with primarily osteoblastic bone metastases. Bisphosphonates also may have activity in the adjuvant setting to prevent or delay the development of bone metastases. Studies with oral clodronate in early breast cancer have provided clinical evidence that bone metastases can be inhibited, and the studies are ongoing with more potent bisphosphonates. Bisphosphonates have also been shown to prevent cancer treatment-induced bone loss. These and other studies continue to redefine the role of bisphosphonates in the treatment of malignant bone disease and the management of bone health in cancer patients.     

Bisphosphonates: from preclinical evidence to survival data in the oncologic setting

Bisphosphonate therapy has become a standard of therapy for patients with malignant bone disease. In vivo pre-clinical data suggest that bisphosphonates may exert an antitumor effect and preliminary clinical data show promising activity on metastatic disease in cancer patients. This review will describe the pre-clinical evidence of action of bisphosphonates on osteoclasts and tumor cells, in both in vitro and animal models. In addition, the effects of principal bisphosphonates on skeletal disease progression in patients with cancers in different sites, including breast cancer, prostate cancer and non-small cell lung cancer will be reported. The preliminary clinical data from retrospective trials on the effect of bisphosphonates on survival will be described and the ongoing adjuvant phase III trial will be analyzed. This review will describe the preliminary clinical evidences from prospective studies on the effect of zoledronic acid treatment on the prevention of bone metastases.     

Anti-tumour activity of zoledronic acid

Bisphosphonates are proven to be effective in the treatment of benign or malignant skeletal diseases characterized by enhanced osteoclastic bone resorption. Nitrogen-containing bisphosphonates (N-BPs) have also been demonstrated to exhibit direct anti-tumour effects. They not only inhibit proliferation and induce apoptosis in cultured cancer cells, but additionally interfere with adhesion of cancer cells to the bone matrix and inhibit cell migration and invasion. These effects are potentiated when N-BPs are combined with anticancer drugs like taxoids, doxorubicin or imatinib. Zoledronic acid is a highly potent N-BP that has been particularly well investigated, preclinically and in clinical practice. Growing preclinical evidence shows that zoledronic acid also exhibits direct anti-tumour activity. The overall effects on tumour cells appear to be mediated via diverse pathways, such as apoptosis, angiostasis, cell-cell-interactions and immunomodulation. The current insights and fronts of ongoing research are reviewed. Higher doses of zoledronic acid or more frequent applications than currently approved may be required to achieve clinically meaningful anti-tumour effects. The future challenge is to focus on optimizing dosing regimens and drug combinations to maximize the anti-tumour potential of zoledronic acid and to take advantage of the observed synergy with standard neoplastic agents.     

Antitumor effects and anticancer applications of bisphosphonates

Bisphosphonates are firmly entrenched in the treatment of metastatic bone disease secondary to several tumor types, including breast cancer, prostate cancer, and myeloma. More recently, an emerging body of preclinical and clinical evidence indicates that bisphosphonates might also exhibit antitumor activity. This expanded role for bisphosphonates in the adjuvant setting might have profound clinical implications in many cancer types, particularly in the context of prevention of bone metastasis. Increased understanding of the mechanistic basis of the antitumor effects indicates that these might occur via direct mechanisms such as induction of apoptosis and inhibition of tumor cell adhesion and invasion, as well as indirect mechanisms such as inhibition of angiogenesis. There is also considerable evidence to suggest that nitrogen-containing bisphosphonates might exert additive or synergistic interactions with standard cytotoxic agents. However, mature clinical data with bisphosphonates are limited and, thus far, provide conflicting evidence regarding the antitumor role of bisphosphonates, but have mostly been conducted with first-generation bisphosphonates such as clodronate that are not as effective as next-generation bisphosphonates. Several large randomized clinical trials are ongoing with the next-generation bisphosphonate zoledronic acid to prospectively confirm an antitumor role for bisphosphonates in various tumor types. This review assesses the current body of preclinical and clinical evidence in favor of an antitumor effect of bisphosphonates in different cancer types.     

Adjuvant bisphosphonates in endocrine-responsive breast cancer: what is their place in therapy?

Recent advances in the treatment of early breast cancer have improved clinical outcomes and prolonged survival, especially in women with endocrine-responsive disease. However, cancer therapies including cytotoxic chemotherapy, ovarian suppression, and aromatase inhibitors can drastically reduce circulating estrogen, increasing bone loss and fracture risk. Because most women with early breast cancer will live for many years, it is important to protect bone health during cancer therapy. Several recent clinical trials combining adjuvant endocrine therapy with bisphosphonates have demonstrated efficacy for preventing cancer treatment-induced bone loss in pre- and postmenopausal women with early breast cancer. The largest body of evidence supporting the use of adjuvant bisphosphonates comes from studies with zoledronic acid; however, studies with risedronate, ibandronate, and denosumab (a biologic agent) have also demonstrated efficacy for preventing bone loss. Adding zoledronic acid to endocrine therapy prevents bone loss and improves bone mineral density (BMD). In addition, preclinical studies suggest that bisphosphonates have direct and indirect antitumor activity, such as inducing tumor cell apoptosis, reducing tumor cell adhesion and invasion, reducing angiogenesis, activating immune responses, and synergy with chemotherapy agents, among others. Clinical trials have demonstrated significantly improved disease-free survival in patients receiving adjuvant endocrine therapy plus zoledronic acid compared with endocrine therapy alone. Ongoing studies will further define the role of adjuvant bisphosphonates in maintaining bone health and improving clinical outcomes. The available evidence suggests that pre- and postmenopausal patients may receive clinical benefit from including bisphosphonates as part of their adjuvant treatment regimen for endocrine-responsive early breast cancer.     

Bisphosphonates in the Adjuvant Treatment of Breast Cancer

Bisphosphonates, as potent inhibitors of osteoclast-mediated bone resorption, significantly reduce the risk of skeletal complications in metastatic bone disease and also prevent cancer treatment-induced bone loss (CTIBL). However, more recently, there has been increasing data indicating that bisphosphonates exhibit anti-tumour activity, possibly via both indirect and direct effects, and can potentially modify the metastatic disease process providing more than just supportive care. The evidence from previous studies of an anti-tumour effect of bisphosphonates was inconclusive, with conflicting evidence from adjuvant oral clodronate trials. However, more recent trials using zoledronic acid have shown benefits in terms of disease-free and overall survival outcomes in certain subgroups, most evidently in older premenopausal women with hormone-sensitive disease treated with ovarian suppression, and in women in established menopause at trial entry. In the adjuvant setting, the use of bisphosphonates has also been focused on the prevention and treatment of CTIBL and recent guidelines have defined treatment strategies for CTIBL. The role of bisphosphonates in CTIBL in early breast cancer is well defined. There have been mixed results from large adjuvant metastasis-prevention studies of bisphosphonates, but there are strong signals from large subgroups analyses of randomised phase III trials suggesting significant anti-tumour beneficial effects in specific patient populations.     

Bisphosphonates: preclinical review

Bisphosphonates effectively inhibit osteoclast-mediated bone resorption and are integral in the treatment of benign and malignant bone diseases. The evolution of bisphosphonates over the past 30 years has led to the development of nitrogen-containing bisphosphonates (N-BPs), which have a mechanism of action different from that of the nonnitrogen-containing bisphosphonates. Studies conducted over the past decade have elucidated the mechanism of action and pharmacologic properties of the N-BPs. N-BPs exert their effects on osteoclasts and tumor cells by inhibiting a key enzyme in the mevalonate pathway, farnesyl diphosphate synthase, thus preventing protein prenylation and activation of intracellular signaling proteins such as Ras. Recent evidence suggests that N-BPs also induce production of a unique adenosine triphosphate analogue (Apppi) that can directly induce apoptosis. Our increased understanding of the pharmacologic effects of bisphosphonates is shedding light on the mechanisms by which they exert antitumor effects. As a result of their biochemical effects on protein prenylation, N-BPs induce caspase-dependent apoptosis, inhibit matrix metalloproteinase activity, and downregulate alpha(v)beta(3) and alpha(v)beta(5) integrins. In addition, zoledronic acid (Zometa; Novartis Pharmaceuticals Corp.; East Hanover, NJ and Basel, Switzerland) exerts synergistic antitumor activity when combined with other anticancer agents. Zoledronic acid also inhibits tumor cell adhesion to the extracellular matrix and invasion through Matrigel trade mark and has antiangiogenic activity. A growing body of evidence from animal models demonstrates that zoledronic acid and other bisphosphonates can reduce skeletal tumor burden and prevent metastasis to bone. Further studies are needed to fully elucidate these biochemical mechanisms and to determine if the antitumor potential of bisphosphonates translates to the clinical setting.     

Should bisphosphonates be utilized in the adjuvant setting for breast cancer?

Adjuvant therapies for early breast cancer are associated with substantial decreases in bone mineral density. Bisphosphonates are antiresorptive agents that have an established role in preventing skeletal morbidity in patients with bone metastases and in the treatment of osteoporosis. Recently, several trials have demonstrated the efficacy of bone-directed agents for prevention of cancer treatment-induced bone loss in both premenopausal and postmenopausal women with early stage breast cancer. Moreover, it is now becoming evident that bisphosphonates may also exert anticancer effects in the adjuvant setting. For example, long-term follow-up of a study in patients with bone marrow micrometastases from breast cancer revealed overall survival benefits for clodronate versus placebo, and an ongoing large trial may provide further insights. Addition of twice-yearly zoledronic acid to standard adjuvant endocrine therapy significantly improved disease-free survival and decreased disease recurrence compared with standard therapy alone in 3 clinical trials involving nearly 3,500 patients with stage I-IIIA breast cancer, and monthly zoledronic acid during neoadjuvant therapy decreased residual tumor volume and improved pathologic response in patients with stage II/III breast cancer. Overall, a large and growing body of evidence suggests the potential adjuvant benefits of bisphosphonates in early breast cancer.     

The bisphosphonate, zoledronic acid, induces apoptosis of breast cancer cells: evidence for synergy with paclitaxel

Bisphosphonates are well established in the management of breast-cancer-induced bone disease. Recent studies have suggested that these compounds are effective in preventing the development of bone metastases. However, it is unclear whether this reflects an indirect effect via an inhibition of bone resorption or a direct anti-tumour effect. The breast cancer cell lines, MCF-7 and MDA-MB-231 cells were treated with increasing concentrations of the bisphosphonate, zoledronic acid, for varying time periods, in the presence or absence of paclitaxel. The effects of zoledronic acid were determined by assessing cell number and rate of apoptosis by evaluating changes in nuclear morphology and using a fluorescence nick translation assay. Zoledronic acid caused a dose- and time-dependent decrease in cell number (P< 0.001) and a concomitant increase in tumour cell apoptosis (P< 0.005). Short-term exposure to zoledronic acid was sufficient to cause a significant reduction in cell number and increase in apoptosis (P< 0.05). These effects could be prevented by incubation with geranyl geraniol, suggesting that zoledronic acid-induced apoptosis is mediated by inhibiting the mevalonate pathway. Treatment with zoledronic acid and clinically achievable concentrations of paclitaxel resulted in a 4-5-fold increase in tumour cell apoptosis (P< 0.02). Isobologram analysis revealed synergistic effects on tumour cell number and apoptosis when zoledronic acid and paclitaxel were combined. Short-term treatment with zoledronic acid, which closely resembles the clinical setting, has a clear anti-tumour effect on breast cancer cells. Importantly, the commonly used anti-neoplastic agent, paclitaxel, potentiates the anti-tumour effects of zoledronic acid. These data suggest that, in addition to inhibiting bone resorption, zoledronic acid has a direct anti-tumour activity on breast cancer cells in vitro.     

New research findings on zoledronic acid: survival, pain, and anti-tumour effects

OBJECTIVES: To summarize the current evidence for clinical, anti-tumour, and survival benefits from zoledronic acid in patients with genitourinary cancers. METHODS: Studies were identified through MEDLINE searches, review of bibliographies of relevant articles, and review of abstracts from scientific meetings. RESULTS: Among patients with bone metastases from prostate cancer or renal cell carcinoma, zoledronic acid significantly delayed the onset and reduced the incidence of skeletal complications compared with placebo. Zoledronic acid is also the only bisphosphonate that has demonstrated a trend toward improved survival and delayed progression of bone lesions in patients with urologic malignancies. Furthermore, zoledronic acid reduced the incidence of pathologic fracture, a skeletal-related event known to be associated with reduced survival. Bisphosphonates have also demonstrated significant palliative benefits, and preclinical evidence indicates that bisphosphonates may have direct anti-tumour effects. CONCLUSIONS: Zoledronic acid is the only bisphosphonate that has demonstrated statistically significant, long-term clinical benefits through the prevention and delay of skeletal-related events in patients with metastatic prostate cancer or renal cell carcinoma.     

唑来膦酸在乳腺癌中抗肿瘤作用的研究进展

唑来膦酸(ZOL)是第三代双膦酸盐类药物的典型代表,在已上市的双膦酸盐类药物中应用最广泛、综合疗效最好,现已作为乳腺癌骨转移的常规治疗药物.多项临床前研究及临床研究已证实,唑来膦酸对肿瘤细胞有直接或间接的抑制作用,联合其他辅助治疗(化疗和内分泌治疗)可发挥协同作用,对改善乳腺癌患者术后生存、抑制复发及转移具有重要作用,本文就上述研究进展作一综述.     

Anti-tumour activity of bisphosphonates in preclinical models of breast cancer

There is increasing evidence of anti-tumour effects of bisphosphonates from pre-clinical studies, supporting a role for these drugs beyond their traditional use in treatment of cancer-induced bone disease. A range of model systems have been used to investigate the effects of different bisphosphonates on tumour growth, both in bone and at peripheral sites. Most of these studies conclude that bisphosphonates cause a reduction in tumour burden, but that early intervention and the use of high and/or repeated dosing is required. Successful eradication of cancer may only be achievable by targeting the tumour cells directly whilst also modifying the tumour microenvironment. In line with this, bisphosphonates are demonstrated to be particularly effective at reducing breast tumour growth when used in combination with agents that directly target cancer cells. Recent studies have shown that the effects of bisphosphonates on breast tumours are not limited to bone, and that prolonged anti-tumour effects may be achieved following their inclusion in combination therapy. This has opened the field to a new strand of bisphosphonate research, focussed on elucidating their effects on cells and components of the local, regional and distal tumour microenvironment. This review highlights the recent developments in relation to proposed anti-tumour effects of bisphosphonates reported from in vitro and in vivo models, and summarises the data from key breast cancer studies. Evidence for effects on different processes and cell types involved in cancer development and progression is discussed, and the main outstanding issues identified.     

The role of bisphosphonates in the management of advanced cancer with a focus on non-small-cell lung cancer. Part 1: Mechanisms of action, role of biomarkers and preclinical applications

With recent advances in cancer management, patients with metastatic bone disease are likely to have a prolonged clinical course, with skeletal-related events such as pain, hypercalcemia, pathologic fractures, spinal cord and nerve compression. Bisphosphonate use has resulted in the reduction of skeletal-related complications for a number of tumors including breast, prostate and myeloma, and improvements in the quality of life for patients. There is now evidence that newer, highly potent, nitrogen-containing bisphosphonates reduce skeletal complications in patients with bone metastases from other solid tumors (including lung cancer). The early identification of patients at high risk for developing bone metastases may help curtail a complex and costly clinical problem--skeletal-related events. In this article, we review the different mechanisms of bisphosphonates and the potential role of newer-generation bisphosphonates, such as zoledronic acid, in the management of advanced, metastatic bone disease. We include a review of mechanistic studies and preclinical data. Additionally, the utility of evolving concepts such as bone markers and imaging of bone metastases are discussed.     

唑来膦酸抗肿瘤作用研究

双膦酸盐的抗骨吸收机制研究比较明确,已成为治疗恶性肿瘤骨转移的标准药物.越来越多的体内外临床前实验表明,包括唑来膦酸在内的双膦酸盐能通过抑制肿瘤细胞的增殖、黏附、侵袭以及血管牛成、调节免疫等发挥其抗肿瘤作用,与放化疗联合有增效作用.     

Skeletal complications of prostate cancer: pathophysiology and therapeutic potential of bisphosphonates

Patients with prostate cancer are at risk for skeletal complications resulting from treatment-induced bone loss and for bone metastases. The therapeutic potential of zoledronic acid for the treatment of prostate cancer has been demonstrated in both preclinical and clinical studies. In patients receiving androgen-deprivation therapy, zoledronic acid increases bone mineral density, and, in patients with bone metastases, it reduces the incidence of skeletal complications. Preclinical studies have also demonstrated the antitumor potential of bisphosphonates. Specifically, zoledronic acid inhibits proliferation and induces apoptosis of human prostate cancer cell lines in vitro and has enhanced antitumor activity when combined with taxanes. Animal models have further shown that bisphosphonates decrease tumor-induced osteolysis and reduce skeletal tumor burden. In a model of prostate cancer, zoledronic acid significantly inhibited growth of both osteolytic and osteoblastic tumors and reduced circulating levels of prostate-specific antigen. These studies suggest that zoledronic acid has the potential to inhibit bone metastasis and bone lesion progression in patients with prostate cancer.     

Implications of bone metastases and the benefits of bone-targeted therapy

Several cancers, including those originating in the breast, prostate, and lung, exhibit a propensity to metastasize to bone, resulting in debilitating skeletal complications. These sequelae, such as intractable pain, pathologic fractures, spinal compression, and hypercalcemia, greatly erode the patients' quality of life. Bisphosphonates, a class of antiresorptive drugs, are now the mainstay of the treatment of skeletal-related events in myeloma bone disease and many solid cancers with bone metastases. Current evidence indicates that newer-generation nitrogen-containing bisphosphonates, particularly zoledronic acid, are potent inhibitors of bone resorption. In addition, increased understanding of the pathogenesis of bone metastasis has resulted in the development of several bone-targeted therapies including a monoclonal antibody targeting the receptor activator of nuclear factor (NF)-κB ligand (RANKL). In this review, clinical evidence regarding the efficacy and safety of currently available bone-targeted therapies including bisphosphonates and anti-RANKL monoclonal antibody in the treatment of bone metastasis due to breast cancer, prostate cancer, lung cancer, and multiple myeloma bone disease will be summarized.     

Zoledronic acid: past, present and future roles in cancer treatment

Bisphosphonates are widely used to stabilize the bone and prevent devastating skeletal complications in patients with malignant bone disease from breast cancer or multiple myeloma. Bisphosphonates work by inhibiting osteoclast-mediated bone resorption and have also demonstrated antitumor activity in preclinical models. Of the available bisphosphonates, intravenous zoledronic acid has demonstrated the broadest clinical activity and is approved for the treatment of bone metastases from any solid tumor in many countries throughout the world. Clinical trials in breast and prostate cancer are also investigating zoledronic acid for the prevention of bone metastasis and bone loss associated with hormonal therapy. Due to its unique pharmacologic profile, zoledronic acid has activity in a variety of clinical settings at low doses and with infrequent intravenous dosing.     

唑来膦酸治疗乳腺癌及其骨转移的研究进展

唑来膦酸是第三代含氮双膦酸盐类药物的典型代表,在已上市的双膦酸盐类药物中其综合疗效最好,不仅可以通过抑制甲羟戊酸途径直接作用于破骨细胞,也可直接或间接对肿瘤细胞产生抑制作用.乳腺癌属于易发生骨转移的一类恶性肿瘤,大量研究表明唑来膦酸对乳腺癌骨转移具有一定的疗效,可缓解骨痛,目前其已被纳入乳腺癌骨转移的临床常规治疗中,同时唑来膦酸在辅助性内分泌治疗乳腺癌时亦发挥重要的作用.本文就唑来膦酸对乳腺癌骨转移治疗方面的相关研究进展做一综述.     

Bisphosphonates as anticancer therapy for early breast cancer

Bisphosphonates (BPs) are approved for preventing the skeletal-related events associated with malignant bone disease. Several studies indicate that they may also prevent cancer therapy-induced bone loss. Multiple preclinical and early clinical studies provide evidence of the anticancer activity of BPs, including an inhibition of tumor cell proliferation and survival, a reduction of angiogenesis, and a stimulation of innate anticancer immunity. In addition to their evident single-agent activity, BPs may also act synergistically with other antineoplastic agents. Translational studies corroborate the effects of bisphosphonates on angiogenesis and innate immunity. Moreover, many of these anticancer effects occur at clinically relevant drug concentrations. Indeed, clinical data suggest that in addition to being well-tolerated and efficacious in maintaining bone health, BPs including clodronate, pamidronate, and zoledronic acid also improve cancer-related outcomes such as tumor response, disease-free survival, and overall survival in patients with breast cancer. Among the BPs, zoledronic acid is the most extensively studied in the adjuvant and neoadjuvant settings and has accumulated the most data pointing to anticancer activity, although a survival benefit has not been documented. Future studies are necessary to elucidate the anticancer activity of BPs. Other aspects of BP therapy that require further study include the optimization of dosing regimens for single agents and combinations in various clinical settings and the identification of prognostic factors that predict treatment outcomes. This review summarizes the preclinical and clinical evidence of anticancer activity of BPs, with a focus on zoledronic acid.     

唑来膦酸在早期乳腺癌中的抗肿瘤研究进展

早期乳腺癌在接受辅助治疗（化疗和内分泌治疗）时均会对患者骨密度造成不良影响,加速骨丢失。第三代双磷酸盐—唑来膦酸其作用机制是抑制破骨细胞介导的骨质重吸收,主要用于恶性肿瘤骨转移引起的高钙血症。唑来膦酸-弗隆辅助协同试验（ZO-FAST）显示唑来膦酸在早期乳腺癌辅助内分泌治疗同时使用不仅可有效防止骨质丢失,还具有明显降低肿瘤复发的作用。奥地利乳腺癌和结直肠癌研究小组-12（ABCSG-12）试验结果同样表明唑来膦酸在联合内分泌治疗时可显著降低患者的疾病进展风险和死亡风险。除此之外,临床前实验和临床试验也证实唑来膦酸联合化疗也具有协同的抗肿瘤作用。唑来膦酸联合新辅助化疗降低复发（AZURE试验）,对于绝经5年以上和年龄>60岁的人群,辅助化疗加唑来膦酸显著减低疾病进展和死亡风险。在ABCSG-12试验中同样发现对于年龄>40岁的患者,唑来膦酸可明显降低复发风险,而年龄≤40岁患者却未在唑来膦酸的治疗中获益。这些结果表明唑来膦酸在雌激素低水平（自然的或治疗后结果）的早期乳腺癌患者中易于发挥抗肿瘤作用。目前对于唑来膦酸的最佳剂量和持续时间尚有待于进一步的研究确认,相信随着相关临床试验结果的公布可以提供更充足的证据来支持唑来膦酸在早期乳腺癌的使用。