Optimising treatment of bone metastases by Aredia™ and Zometa™

Metastatic bone disease develops as a result of the many interactions between tumour cells and bone cells. This leads to disruption of normal bone metabolism, with the increased osteoclast activity seen in most, if not all, tumor types providing a rational target for treatment. The clinical course of metastatic bone disease in multiple myeloma, breast and prostate cancers is relatively long, with patients experiencing sequential skeletal complications over a period of several years. These include bone pain, fractures, hypercalcaemia, and spinal cord compression, all of which may profoundly impair a patient's quality of life. External beam radiotherapy and systemic endocrine and cytotoxic treatments are the mainstay of treatment in advanced cancers. However, it is now clear that the bisphosphonates provide an additional treatment strategy, which reduces both the symptoms and complications of bone involvement. Pamidronate (Aredia(TM)) is the most widely evaluated bisphosphonate and is recommended for most patients with multiple myeloma or breast cancer with bone metastases. Current research aims include the evaluation of new potent bisphosphonates such as zoledronic acid (Zometa(TM)). It is hoped that this compound is not only more convenient and easier to administer but also more effective in inhibiting skeletal morbidity. Zometa may also have some direct anticancer activity. Preclinical studies with Zometa have demonstrated its potential in malignant bone disease. Clinical studies in treatment of hypercalcemia of malignancy have been completed, as have Phase I and II trials in patients with cancer and pre-existing bone metastases. Three randomized, double-blind, controlled Phase III trials are now ongoing to establish the efficacy and safety of Zometa in treatment of bone metastases in patients with osteolytic and osteoblastic lesions. Additionally, new specific molecules such as osteoprotogerin have been developed that are based on our improved understanding of the cellular signalling mechanisms involved in cancer induced bone disease. These potent molecules are now entering clinical trials. Ongoing research is aimed at trying to define the optimum route, dose, schedule and type of bisphosphonate in metastatic bone disease and their use in the prevention and treatment of osteoporosis in cancer patients. In vitro suggestions of direct anti-cancer activity and some promising clinical data in early breast cancer have resulted in considerable interest in the possible adjuvant use of bisphosphonates to inhibit the development of bone metastases.     

Metastatic bone disease: clinical features, pathophysiology and treatment strategies.

Metastatic bone disease develops as a result of the many interactions between tumour cells and bone cells. This leads to disruption of normal bone metabolism, with the increased osteoclast activity seen in most, if not all, tumour types providing a rational target for treatment. The clinical course of metastatic bone disease in multiple myeloma, breast and prostate cancers is relatively long, with patients experiencing sequential skeletal complications over a period of several years. These include bone pain, fractures, hypercalcaemia and spinal cord compression, all of which may profoundly impair a patient's quality of life.External beam radiotherapy and systemic endocrine and cytotoxic treatments are the mainstay of treatment in advanced cancers. However, it is now clear that the bisphosphonates provide an additional treatment strategy, which reduces both the symptoms and complications of bone involvement. Ongoing research is aimed at trying to define the optimum route, dose, schedule and type of bisphosphonate in metastatic bone disease and in the prevention and treatment of osteoporosis in cancer patients. In vitro suggestions of direct anticancer activity and some promising clinical data in early breast cancer have resulted in considerable interest in the possible adjuvant use of bisphosphonates to inhibit the development of bone metastases.     

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.     

Direct and indirect anticancer activity of bisphosphonates: a brief review of published literature

The bone marrow microenvironment provides a site for cancer cells to evade systemic anticancer therapy. Dormant tumor micrometastases are believed to be the source of disease persistence and relapse; however, the exact characteristics of cancer stem cells vs. cancer cells with limited metastatic potential have yet to be elucidated. Bisphosphonates inhibit osteoclast-mediated bone resorption, are approved for treating malignant bone disease from advanced cancers, and have shown efficacy for preventing cancer treatment-induced bone loss. Altering the bone marrow microenvironment to make it less conducive to cancer cell survival is now emerging as an important means to prevent cancer recurrence. This review aims to distill the diverse literature and provide a brief overview of the numerous preclinical and early clinical studies of bisphosphonates demonstrating a variety of direct and indirect anticancer activities that affect both the tumor cell (the "seed") and surrounding microenvironment (the "soil"). Recently, zoledronic acid was found to improve disease-free survival and overall survival in some adjuvant breast cancer settings and prolonged survival in patients with multiple myeloma and other advanced cancers. In the prostate cancer setting, antiresorptive therapy was reported to delay the development of overt bone metastases. Ongoing studies will provide further insight regarding the anticancer potential of bisphosphonates and other antiresorptive agents.     

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.     

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.     

Bisphosphonates in Breast Cancer: From Metastasis to Prevention

Bisphosphonate compounds have efficacy for the prevention and treatment of osteoporosis as they reduce the risk of fractures due to bone fragility by one third to one half. Likewise, bisphosphonates are important supportive therapies for the management of bone integrity in patients with bone metastases from breast cancer as, in this setting, they reduce the risk of skeletal-related events by one third. Bone is a common, and often the first, site of involvement from advanced breast cancer. It is thought that bisphosphonates may slow the progression of metastatic breast cancer by altering communication between tumor cells and the bone microenvironment. Although bisphosphonates have not been shown to alter overall survival in metastatic breast cancer, preclinical and clinical data suggest that bisphosphonate therapy may have a role as an anticancer strategy. Proposed general mechanisms to explain this putative antitumor activity include effects on the bone microenvironment, immune response modulation, inhibition of angiogenesis, inhibition of proliferation, and induction of apoptosis. The optimization of bisphosphonate use is being investigated. This article discusses the clinical and basic scientific data surrounding zoledronic acid, which is the most potent nitrogen-containing bisphosphonate used in patients with breast cancer.     

Effects of bone-targeted agents on cancer progression and mortality

Bone-targeted treatments with bisphosphonates and denosumab, which reduce bone resorption, are known to reduce the risk of skeletal complications and prevent treatment-induced bone loss in patients with malignant bone disease. Additionally, these drugs may modify the course of bone destruction via inhibitory effects on the "vicious cycle" of growth factor and cytokine signaling between tumor and bone cells within the bone marrow microenvironment. Effects of the drugs on the stem cell niche, direct effects on the cancer cells, and immune modulation may also contribute. In early-stage (stages I, II, and III) breast cancer, treatment with the bisphosphonate zoledronic acid has shown improvements in disease-free and overall survival. Improved survival was particularly notable in women with established menopause at diagnosis and in premenopausal women with endocrine-responsive disease who received treatment with goserelin, which suppresses ovarian function by inhibiting the production of ovarian hormones. Additionally, in castrate-resistant prostate cancer, treatment with denosumab delays the development of bone metastases. These results strongly support the adjuvant use of bone-targeted treatments but suggest that reproductive hormones are an important treatment modifier to take into account. In advanced-stage (stage IV, ie, metastatic) cancers, survival benefits have been observed in patients with multiple myeloma and in patients with other solid tumors with rapid rates of bone destruction who received treatment with zoledronic acid. 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.     

Bisphosphonates, pain and quality of life in metastatic breast cancer patients: a literature review

Bisphosphonates constitute the standard treatment for cancer hypercalcemia and prevention of complications of metastatic bone disease. Various clinical endpoints have been used to evaluate the impact of bisphosphonates on bone metastases. This literature review is focused on the analgesic effect of bisphosphonates and their impact on quality of life (QoL) in patients with bone metastases from breast cancer. Twenty-five randomized trials studying bisphosphonates with pain and/or QoL as primary or secondary endpoints were considered. These studies were analyzed with following criterias : study type, primary cancer, drug scheduling, number of patients included, associated specific treatment, primary and secondary endpoints, pain assessment, and QoL assessment. The results are in favor of an efficacy of bisphosphonates in bone pain, even when not always statistically significant and with an important variability in assessment criterias and tools. QoL assessment with validated, reliable scales (EORTC QLQ-C30, Rotterdam Symptom Checklist...) has been performed in 9 studies. The use of bisphosphonates with systemic and radiation therapy increases QoL or reduces QoL deterioration. Despite some methodological limitations, these studies indicate a beneficial effect on bone pain, and an improvement in the QoL of patients with metastatic bone disease of breast cancer. Because of a lack of systemic data, reliable analysis of the results is difficult. Several questions remain open about which bisphosphonates and route of administration to choose, and the variable effects on different primaries.     

Bisphosphonates in cancer therapy

Bisphosphonates inhibit osteoclast-mediated bone resorption in metastatic bone disease. A wealth of preclinical data have begun to shed light on the complex mechanisms by which bisphosphonates inhibit bone resorption and interfere with the formation and growth of bone metastases. Nitrogen-containing bisphosphonates inhibit the mevalonate pathway, which results in the inhibition of osteoclast function and the induction of apoptosis in osteoclasts and tumor cells alike. There is now extensive evidence that bisphosphonates have cytostatic activity against tumor cell lines and inhibit tumor cell adhesion and invasion of the extracellular matrix. These data are supported by a growing body of evidence from animal models demonstrating that bisphosphonates can reduce skeletal tumor burden. However, it remains unclear whether this reduction reflects a direct antitumor effect or an indirect effect via osteoclast inhibition and alteration of the bone microenvironment. Further preclinical studies are needed to elucidate these biochemical mechanisms fully; ultimately, well-controlled clinical trials will be required to investigate whether the antitumor potential of bisphosphonates translates into a significant clinical benefit for patients with cancer.     

Approaches to managing bone metastases from breast cancer: the role of bisphosphonates

Conventional management of metastatic bone disease involves local and systemic therapies in various combinations, along with symptomatic management to provide optimal care. In recent years, it has become clear that adding bisphosphonates to these treatments reduces the incidence and severity of skeletal complications. Bisphosphonates can also relieve metastatic bone pain and improve quality of life, although the extent to which they have demonstrated these effects may differ between agents. While bisphosphonates are the standard of care for the treatment of bone metastases, clinical trials are investigating additional indications for these agents, including the use of intensive dosing regimens for the relief of severe or opioid-resistant metastatic bone pain and adjuvant treatment for the prevention of bone metastases and cancer treatment-induced bone loss. Current and future indications demand effective, well-tolerated and convenient bisphosphonates, and the benefits of different drugs must be balanced against their limitations. The cost-effectiveness of bisphosphonate treatment is also a consideration, given the high economic burden of metastatic bone disease from breast cancer.     

Biology of bone metastases: causes and consequences

Breast cancer is a highly osteotropic neoplasm, and as many as 75% of patients with metastatic disease will have involvement of the bony skeleton. On radiologic examination, these metastases are predominantly osteolytic but can be osteoblastic or mixed. The mechanisms by which metastases are formed are complex, involving many steps that include angiogenesis, invasion, and proliferation in the bone microenvironment. Tumor cells in the bone microenvironment produce a large number of cytokines that stimulate osteoclastic activity. Increased osteoclastic activity, in turn, leads to production of a variety of lymphokines and growth factors that can increase tumor cell proliferation. Thus, a cytokine network is established, which results in an imbalance of the processes of bone formation and bone resorption. As tumor burden in bone increases, osteoclast-mediated bone resorption is accelerated, resulting in loss of bone strength, fractures, pain, and other morbidities. Tumor cells metastatic to bone can also secrete growth factors, leading to increased osteoblastic activity. Osteoblasts lay down an excess of new bone that is structurally weak. There is considerable crosstalk between osteoclasts, osteoblasts, macrophages, and other cellular elements within the bone environment. The increasing understanding of the biology of bone metastases has opened the door to improved management of this important clinical problem. Current treatment strategies include approaches to reduce tumor burden and developing treatments that directly inhibit osteoclast function. The bisphosphonates are a class of drugs that inhibit osteoclast recruitment and function. Several highly potent bisphosphonates are now available for clinical use and represent an important adjunct in the management of bone metastases from breast cancer, multiple myeloma, and several other types of malignancies. Some newer therapeutic approaches include agents designed to inhibit the osteoclast-osteoblast signaling interactions or alter processes of adhesion and invasion.     

Ibandronate: its pharmacology and clinical efficacy in the management of tumor-induced hypercalcemia and metastatic bone disease

It is well accepted that tumor cells in the bone, especially from breast cancer, prostate cancer and multiple myeloma, can stimulate osteoclast formation and activity. Bisphosphonates are potent inhibitors of osteoclast-mediated normal and pathologic bone resorption. Besides their apoptotic and antiproliferative activity on osteoclasts, bisphosphonates can also exert similar effects on macrophages and tumor cells. Currently, it is unknown if this effect can be translated into clinical practice with regard to an effective adjuvant therapeutic regimen for high-risk patients with systemic recurrences following primary treatment of a given cancer. There are several new aspects that might extend the clinical use of ibandronate, a bisphosphate, in oncology: prevention of hypogonadal osteoporosis in men, palliative management of painful osseous metastases and adjuvant therapy of high-risk prostate cancer patients. Safety and tolerability are excellent for the oral and intravenous formulations, and ibandronate can even be safely applied in pre-existing renal insufficiency. The purpose of this review is to critically reflect the pharmacology and clinical efficacy of ibandronate in the management of tumor-induced hypercalcemia, osteoporosis and metastatic bone disease.     

The use of bisphosphonates in cancer patients

Skeletal-related events resulting from bone metastases or osteoporosis can significantly contribute to morbidity and mortality in cancer patients. Expert opinion on the effectiveness of bisphosphonates in this setting is evolving. Here we review current evidence on the risks and benefits of bisphosphonate therapy for a wide variety of cancers, as well as clinical management of its adverse effects. A MEDLINE search of English-language literature (1966 through May 2006) was conducted using the terms bisphosphonate, cancer, multiple myeloma, malignancy, and randomized controlled clinical studies. Studies were selected based on clinical pertinence, with an emphasis on phase III clinical trials. We reviewed bibliographies for other relevant articles. Accumulating evidence reveals that bisphosphonate therapy has a significant effect in preventing skeletal complications in multiple myeloma, breast cancers, and prostate cancer, and in reducing skeletal complications in other metastatic bone malignancies. Emerging data indicate that bisphosphonates are useful for preventing bone loss resulting from cancer or its therapy. The efficacy of bisphosphonates for early-stage breast cancers remains controversial. Significant risks of bisphosphonate therapy include nephrotoxicity, electrolyte abnormalities, and osteonecrosis of the jaw. Bisphosphonate therapy has a clear role in the management of skeletal metastases associated with a variety of cancers. However, significant side effects require ongoing monitoring and treatment.     

The role of bisphosphonates as adjuvant therapy for breast cancer

Bone is the most common site of distant recurrence in breast cancer. The development of skeletal metastases involves complex interactions between the cancer cells and the bone microenvironment. The presence of tumor in bone is associated with activation of osteoclasts, resulting in excessive bone resorption. Bisphosphonates are potent inhibitors of osteoclastic bone resorption with proven efficacy in reducing tumor-associated skeletal complications. Several studies have investigated the adjuvant, or preventive, use of these drugs in breast cancer. Laboratory experiments have shown that the development of bone metastases can be inhibited by bisphosphonates. Three randomized clinical trials of bisphosphonates in nonmetastatic breast cancer patients have yielded conflicting results with respect to development of osseous and visceral metastases and survival. Defining the potential role of these agents in adjuvant breast cancer treatment requires further investigation in randomized, large-scale, multicenter clinical trials. The data available to date provide a strong impetus for continued clinical and laboratory work with bisphosphonates in breast cancer.     

Ibandronate: its pharmacology and clinical efficacy in the management of tumor-induced hypercalcemia and metastatic bone disease

It is well accepted that tumor cells in the bone, especially from breast cancer, prostate cancer and multiple myeloma, can stimulate osteoclast formation and activity. Bisphosphonates are potent inhibitors of osteoclast-mediated normal and pathologic bone resorption. Besides their apoptotic and antiproliferative activity on osteoclasts, bisphosphonates can also exert similar effects on macrophages and tumor cells. Currently, it is unknown if this effect can be translated into clinical practice with regard to an effective adjuvant therapeutic regimen for high-risk patients with systemic recurrences following primary treatment of a given cancer. There are several new aspects that might extend the clinical use of ibandronate, a bisphosphate, in oncology: prevention of hypogonadal osteoporosis in men, palliative management of painful osseous metastases and adjuvant therapy of high-risk prostate cancer patients. Safety and tolerability are excellent for the oral and intravenous formulations, and ibandronate can even be safely applied in pre-existing renal insufficiency. The purpose of this review is to critically reflect the pharmacology and clinical efficacy of ibandronate in the management of tumor-induced hypercalcemia, osteoporosis and metastatic bone disease.     

Exploring the anti-tumour activity of bisphosphonates in early breast cancer

Bisphosphonates are potent inhibitors of osteoclast-mediated bone resorption and are firmly established in the management of breast cancer patients with metastatic skeletal disease. There are extensive data that bisphosphonates, particularly nitrogen-containing bisphosphonates such as zoledronic acid, exhibit anti-tumour activity potentially via both indirect and direct mechanisms in vitro. In vivo studies using animal models of breast cancer induced bone disease have shown that bisphosphonates exert anti-tumour effects via inhibiting osteolysis and reducing skeletal tumour burden. Furthermore, pre-clinical studies have demonstrated synergistic anti-tumour effects between chemotherapy agents commonly used in breast cancer treatment and nitrogen-containing bisphosphonates. This, coupled with emerging evidence from pre-clinical in vivo studies suggesting that bisphosphonates may have additional anti-tumour activity outside of the bone microenvironment, could be of significant importance in the clinical management of breast cancer. The evidence in favour of an anti-tumour effect of bisphosphonates in the clinical setting is inconclusive however, with conflicting evidence from several trials. This review focuses on the anti-tumour activity of bisphosphonates in breast cancer, with particular focus on zoledronic acid. The pre-clinical evidence for anti-tumour activity will be reviewed, followed by the synergistic effects with anti-cancer agents. Finally, the clinical relevance and strategies for the evaluation of anti-tumour activity in breast cancer will be discussed. We are currently exploring the potential synergistic anti-tumour effects of the sequential treatment of neoadjuvant chemotherapy followed by zoledronic acid in a randomised phase II study evaluating biological endpoints including apoptosis, proliferation and angiogenesis in patients with breast cancer.     

Potential use of bisphosphonates in the prevention of metastases in early-stage breast cancer

Great strides have been made over the past 20 years in the treatment of breast cancer, and despite increasing incidence, the number of deaths has fallen sharply since the late 1980s. The advent of new therapies including taxanes and aromatase inhibitors and recent, exciting results that announced trastuzumab in the adjuvant treatment for patients with HER2-positive tumors should decrease the number of deaths even further. However, although most patients present with disease that appears to be localized to the breast, a significant proportion of women will eventually develop metastatic breast cancer. Therefore, the detection and treatment of micrometastatic disease represents perhaps the most important remaining challenge in breast cancer management. Bone is the most frequent site of distant relapse, accounting for approximately 40% of all first recurrences. In addition to the well-recognized release of bone cell-activating factors from the tumor, it is now appreciated that release of bone-derived growth factors and cytokines from bone can attract cancer cells to the bone surface and facilitate their growth and proliferation. Bisphosphonates are potent inhibitors of bone osteolysis; therefore, their use in early-stage cancer could be an adjuvant therapeutic strategy of potential importance. Bisphosphonates might also have direct effects on tumor cells in the bone marrow microenvironment. Clinical trial results with the early bisphosphonate clodronate have proven inconclusive, but the results of recently completed large adjuvant clinical trials with this compound and more potent second-generation and third-generation bisphosphonates are eagerly awaited.     

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.     

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.