Pathophysiology of bone metastases: how this knowledge may lead to therapeutic intervention

Bone metastases are common in many advanced cancers and are a clinically relevant source of skeletal morbidity. The bone mineral matrix contains numerous growth factors that are released during normal bone remodeling, providing a fertile microenvironment for tumor cell colonization and proliferation. Tumor cells then release a variety of growth factors that promote bone resorption and increase the risk of skeletal complications. Bisphosphonates are potent inhibitors of osteoclast activity that have demonstrated efficacy in the treatment of bone metastases. Bisphosphonates bind avidly to the bone matrix, are released during bone resorption, and are subsequently internalized by osteoclasts, where they interfere with biochemical pathways and induce osteoclast apoptosis. Bisphosphonates also antagonize osteoclastogenesis and promote the differentiation of osteoblasts. As a result, bisphosphonates inhibit tumor-induced osteolysis and reduce skeletal morbidity. Furthermore, preclinical studies suggest that bisphosphonates possess antitumor activity and can inhibit proliferation and induce apoptosis of tumor cell lines. In addition, zoledronic acid, a new-generation bisphosphonate, appears to inhibit tumor cell invasion of the extracellular matrix. These data suggest that zoledronic acid and other bisphosphonates may play a role in the reduction of skeletal tumor burden and the prevention of bone metastasis.     

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 for treatment and prevention of bone metastases.

Bone metastases are a major cause of morbidity for men with prostate cancer. Complications of bone metastases include pain, fractures, and spinal cord compression. Although they appear osteoblastic by radiographic imaging, most bone metastases are characterized by excess osteoclast number and activity. In addition, pathologic osteoclast activation is associated with increased risk of skeletal complications. Zoledronic acid, a potent inhibitor of osteoclast activity, differentiation, and survival, decreases the risk of skeletal complications in men with androgen-independent prostate cancer and bone metastases. Other bisphosphonates, including pamidronate and clodronate, seem to be ineffective in this setting. The reduction in risk of skeletal complications with zoledronic acid must be weighed against potential adverse effects. Additional studies are needed to determine the optimal timing, schedule, and duration of treatment in men with bone metastases as well as the potential role of bisphosphonates in other settings including the prevention of bone metastases.     

Prevention of bone metastases from breast cancer by adjuvant bisphosphonate therapy

There is increasing evidence regarding the importance of osteoclast activation in the pathogenesis of bone metastases. Cancer cells produce osteoclast-activating factors which play an important role in the development of bone metastases. Bisphosphonates are drugs that inhibit bone turnover by decreasing bone resorption. In patients with bone metastases from breast cancer, the effectiveness of bisphosphonate is well established for reducing skeletal complications, such as bone pain, pathological fracture, bone surgery and hypercalcemia. Recent attention has focused on a possible preventive effect on bisphosphonates of bone metastases. Animal models have supported the prevention of bone metastasis by bishosphonate therapy, but three major adjuvant clinical trials of the oral bisphosphonate clodronate have yielded conflicting results. However, our preliminary trial of intravenous bisphosphonate with pamidronate showed effective inhibition of bone metastases. Use of bisphosphonates as adjuvant therapy is still investigational yet promising. Several more randomized trials are underway to further investigate adjuvant therapy with bisphosphonates.     

Bisphosphonates in breast cancer

Bisphosphonates are osteoclast inhibitors, currently being used in oncology to prevent or delay bone morbidity in cancer. Oral and intravenous formulations of bisphosphonates have been found to be efficacious in preventing skeletal‐related events such as bone pain, pathologic fractures, spinal cord compression and hypercalcemia of malignancy, in patients with bone metastatic breast cancer. Bisphosphonates are also used to prevent bone loss associated with anti‐estrogen therapy using aromatase inhibitors. In addition to its role in preventing bone resorption, several pre‐clinical studies have noted an anti‐tumor role as well. Recent research effort has particularly focused on investigating an adjuvant role for bisphosphonates in early breast cancer. Recently, few randomized trials have found a beneficial effect for adjuvant use of the aminobisphosphonate, zoledronate, in older patients who are post‐menopausal. This review article will summarize the various clinical studies investigating the role of bisphosphonates in breast cancer.     

Bisphosphonates: biological response modifiers in breast cancer

Bone recurrence constitutes one third of initial sites of relapse and one half of distant sites of relapse at 10 years from diagnosis of breast cancer. Bone pain, fracture (including vertebral fracture resulting from increased bone resorption following chemotherapy-induced menopause), and hypercalcemia are components of skeletal morbidity. The pathophysiology of malignant osteopathy occurs because of the secretion of substances (such as parathyroid hormone-related peptide), by the malignant cell, which stimulate osteoclast function; this in turn feeds further growth, which causes a vicious cycle. Interruption of this cycle by bisphosphonates may inhibit the growth of malignant cells. Bisphosphonates are drugs that inhibit bone turnover by decreasing bone resorption. Side effects of bisphosphonates include upper gastrointestinal symptoms (in oral nitrogen-containing bisphosphonates) and diarrhea (in oral non-nitrogen-containing bisphosphonates) and an acute phase-like reaction with intravenous (I.V.) pamidronate. Bisphosphonates have different molecular mechanisms of action: Nitrogen-containing bisphosphonates (eg, pamidronate and alendronate) inhibit the mevalonate-signaling pathway while the non-nitrogen-containing drugs (eg, clodronate) incorporate into adenosine triphosphate analogues. There is in vitro evidence that these drugs also possess anticancer properties. In hypercalcemia patients, treatment with pamidronate and zoledronate produce prompt and efficient normocalcemia. Intravenous pamidronate and zoledronate, oral clodronate, and ibandronate reduce skeletal complications in patients with bone metastases; I.V. pamidronate and clodronate are useful for bone pain relief. Three adjuvant bisphosphonate trials are discussed herein: 2 small open-label studies giving conflicting results and a large placebo-controlled trial of oral clodronate. This latter trial shows a reduction in the incidence of skeletal metastases (while the patients are on therapy) and an improved survival at 5 years.     

The Role of Adjuvant Therapy with Bisphosphonates in Cancer

An understanding of the pathophysiology of bone metastases requires a knowledge of normal and abnormal bone remodeling. This knowledge is helpful in understanding mechanisms of action of bone active agents such as bisphosphonates. When malignant cells infiltrate bone spaces, the balance of bone formation and bone resorption is disrupted: bone remodeling and turnover become abnormal. The consequent ‘vicious cycle’ plays a central role in the progressive destruction of bone and the progression of bone metastases. This cycle in breast cancer is beginning to be understood and involves the secretion by malignant cells of substances such as parathyroid hormone related protein (PTHrP) which leads to an increase in focal and generalized bone resorption resulting in the release of breakdown products such as transforming growth factor beta which in turn stimulates the further growth of malignant cells. Study of the intricacies of this ‘vicious cycle’ has thrown some light on potential opportunities for the therapy of bone metastases. However, physiological mechanisms resulting in bone pain are poorly understood. Clinical aspects of bone metastases in breast cancer, prostate cancer, and myeloma, together with what is known about their individual pathophysiology are discussed in this review. Biochemical markers of bone resorption and formation are now available for study and early research suggests that skeletal events in patients with malignant bone disease as well as the treatment of these events may correlate with levels of serum and urine markers of bone turnover. Bisphosphonates fall into two broad classes: nitrogen containing and non-nitrogen containing compounds. Each grouping has differing biochemical modes of action, but the end action is an inhibitory effect on osteoclast activity. Trials of bisphosphonates in hypercalcemia of malignancy and bone pain as a result of metastatic disease are discussed as well as trials which have shown that these agents can prevent the common skeletal complications of fracture, bone pain, and hypercalcemia in some patients with carcinoma of the breast, myeloma and possibly prostate cancer. Their role in the adjuvant therapy of operable breast cancer is currently being explored in a large American based study, the National Surgical Adjuvant Breast and Bowel Project (NSABP) B-34. It would appear from the largest of the pioneer trials that it is possible to prevent and delay the onset of bone metastases with subsequent improved survival in patients with operable breast cancer. Bisphosphonates are recommended for the treatment of malignant hypercalcemia, bone pain, and the prevention of skeletal complications. Trials of bisphosphonsates in the adjuvant treatment of breast cancer for prevention of bone mestastases are showing encouraging results.     

Bisphosphonates and bone metastases: current status and future directions

Since bone metastases in advanced cancer are common and frequently lead to skeletal-related morbid complications, their treatment remains a major challenge in cancer therapy. Bisphosphonates not only significantly decreased the odds ratios for fracture, need for radiotherapy, and incidence of hypercalcemia, but also had proven ability in the preservation of the 3D microstructure of bone that is responsible for bone stability. Bisphosphonates are well tolerated and have a very low incidence of serious side effects. Consequently, bisphosphonates have become the standard of care for the treatment of malignant bone disease. Benefits of bisphosphonate treatment appears to be more pronounced with longer treatment, indicating that they should be continued until no longer clinically relevant. As this advice has substantial implications on resources, it is essential that the use of bisphosphonates is evidence based.     

Bisphosphonates and bone metastases: current status and future directions

Since bone metastases in advanced cancer are common and frequently lead to skeletal-related morbid complications, their treatment remains a major challenge in cancer therapy. Bisphosphonates not only significantly decreased the odds ratios for fracture, need for radiotherapy, and incidence of hypercalcemia, but also had proven ability in the preservation of the 3D microstructure of bone that is responsible for bone stability. Bisphosphonates are well tolerated and have a very low incidence of serious side effects. Consequently, bisphosphonates have become the standard of care for the treatment of malignant bone disease. Benefits of bisphosphonate treatment appears to be more pronounced with longer treatment, indicating that they should be continued until no longer clinically relevant. As this advice has substantial implications on resources, it is essential that the use of bisphosphonates is evidence based.     

The role of bisphosphonates in the treatment of prostate cancer: recommendations from an expert panel

In this study, we provide consensus guidelines for the use of bisphosphonates in men with prostate cancer. To this end, an expert panel composed of urologists, medical oncologists, radiation oncologists, and endocrinologists met to review current clinical evidence for the use of bisphosphonates in patients with different stages of prostate cancer to derive consensus recommendations. Physicians should be proactive in monitoring bone loss in patients receiving long-term androgen-deprivation therapy for prostate cancer. Further study is needed before recommending the routine use of bisphosphonates in men with nonmetastatic prostate cancer. However, if a patient has clinically significant bone loss, use of a bisphosphonate to prevent further compromise of bone integrity should be strongly considered, regardless of hormonal and metastatic status. Bone scans are the preferred method for the identification of bone metastases. In patients with hormonerefractory prostate cancer and bone metastases, zoledronic acid is the only bisphosphonate indicated for the prevention of skeletal complications. In conclusion, patients with prostate cancer are at high risk for skeletal morbidity. Bisphosphonates have been shown to prevent cancer treatment-induced bone loss in men receiving androgen-deprivation therapy as well as skeletal complications in men with bone metastases. However, further study of the use of bisphosphonates across the clinical spectrum of prostate cancer is needed.     

Metastatic Bone Disease

The cancer patient with skeletal metastases now has a much improved range of treatment options with major advances in bone-specific drug therapy as well as radiotherapy and radiopharmaceuticals, orthopaedic surgery, and systemic anticancer therapy with cytotoxic and endocrine agents. Recent advances in the understanding of bone remodeling mechanisms and the interdependence of cancer cells and bone have been closely associated with development of the bisphosphonate drugs and newer agents such as osteoprotegerin (OPG). The bisphosphonates are potent inhibitors of osteoclast mediated bone resorption and appear to function either by induction of apoptosis in mature osteoclasts or by inhibition of formation of osteoclasts from progenitor cells. Bisphosphonates are the treatment of choice in tumor-induced hypercalcemia. Bisphosphonates have a clear role in reducing bone pain and skeletal complications, such as pathological fracture and are being evaluated in the prevention of bone metastases. Until recently, intravenous (IV) pamidronate has been the drug most commonly prescribed for oncological indications and oral clodronate has also been widely used in some countries outside the US. However, newer and more potent drugs, such as zoledronate, are increasingly having a major impact on routine therapy. Three of the largest ever bisphosphonate trials, using zoledronate in metastatic bone disease have recently been completed. In a breast and multiple myeloma trial in 1648 patients, zoledronate (4mg IV) was shown to be equivalent to pamidronate (90mg IV) in reducing skeletal events and was more convenient to administer. In trials in prostate cancer and a wide range of other solid tumor types affecting bone, both the number of patients with skeletal-related events and the rate of bone complications were reduced. The indications for bisphosphonates are, therefore, no longer constrained by tumor type. The assessment of response to therapy is a vital part of management of metastatic bone disease. Plain radiographs and the isotope bone scan remain widely used but have many limitations. Newer imaging techniques such as computerized tomography, magnetic resonance imaging, and positron emission tomography may be useful in selected situations. Recent research suggests that measurement of tumor markers and bone-specific markers will play an increasingly important role in assessment of response. In particular, bone resorption markers measuring collagen breakdown have potential as rapid, convenient, and inexpensive measures of response, with suppression of bone resorption into the normal range being an important aim of bone-specific treatments.     

Treatment of breast cancer with bone metastasis: bisphosphonate treatment — current and future

There are a variety of treatments for patients with bone metastases from breast cancer. These include bisphosphonates, antitumor endocrine and cytotoxic systemic therapies, radiotherapy to the metastatic site, radionucleotides, and conservative treatment (analgesics). The optimal combination treatment for bone metastases is not clear. Bisphosphonates are effective for reducing skeletal complications such as bone pain, pathological fracture, bone surgery, and hypercalcemia. Bisphosphonates are recommended as the gold standard therapy for breast cancer with bone metastases. Treatment guidelines tend to recommend starting a bisphosphonate at the time of diagnosis of bone metastases. Animal models have supported the prevention of bone metastasis by bisphosphonate therapy, but three major adjuvant clinical trials of the oral bisphosphonate clodronate have yielded conflicting results. However, our preliminary trial of an intravenous bisphosphonate, pamidronate, showed effective inhibition of bone metastases. The use of bisphosphonates, especially zoledronic acid, as adjuvant therapy is promising, but it is still investigational.     

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.     

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.     

The role of bisphosphonates in the management of metastatic prostate cancer

Most men with advanced prostate cancer have primarily skeletal metastases, which are responsible for most of the morbidity and mortality of prostate cancer. Although bone lesions are osteoblastic in radiographic appearance, recent evidence has demonstrated that anti-osteoclast therapy with bisphosphonates reduces skeletal-related complications in hormone-refractory prostate cancer. This observation may be explained by the demonstration that osteoclast activity is greatly upregulated even in osteoblastic metastases. Furthermore, androgen deprivation therapy, the mainstay of treatment for advanced prostate cancer, leads to increased bone resorption and reduces bone mineral density. These effects can be ameliorated, and potentially completely prevented, by coadministration of bisphosphonates. These findings may point to a role for bisphosphonates in men with prostate cancer even prior to the development of skeletal metastases. Determination of whether such early therapy ultimately results in delayed time to skeletal progression or in improved survival will require large randomized studies.     

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.     

Bone complications in multiple myeloma

Multiple myeloma is the malignant proliferation of plasma cells involving more than 10% of the bone marrow. The bone complications associated with multiple myeloma include bone pain, pathologic fractures, hypercalcemia of malignancy and cord compressions. The principal pathophysiology of bone disease in multiple myeloma is a shift in the balance of bone remodeling toward bone resorption. In recent years, bisphosphonates have become an important treatment for the bone complications of multiple myeloma. Potent inhibitors of osteoclast activity, bisphosphonates interfere with biochemical pathways and induce osteoclast apoptosis. Bisphosphonates also antagonize osteoclastogenesis and promote differentiation of osteoblasts, as well as inhibiting other aspects of osteoclast homeostasis and metabolism. Several studies have evaluated treatment with bisphosphonates in patients with multiple myeloma, and have demonstrated the efficacy of clodronate (Bonefos; Anthra Pharmaceuticals; Princeton, NJ; www.bonefos.com), pamidronate (Aredia; Novartis Pharmaceuticals Corp; East Hanover, NJ; www.pamidronate.com) and zoledronic acid (Zometa; Novartis Pharmaceuticals Corp; East Hanover, NJ; www.us.zometa.com) in reduction of pain, reduction of SREs and survival. Moreover, recent data suggest direct and indirect antimyeloma activity of pamidronate and zoledronic acid.     

Bisphosphonates in breast cancer.

Breast cancer is the leading type of cancer among women, and bone metastases are common in patients with breast cancer, affecting more than half of all patients with advanced disease. Bisphosphonates are the current standard of care for preventing skeletal complications associated with bone metastases. Clinical trials investigating the benefit of bisphosphonate therapy have used a composite end point defined as a skeletal-related event (SRE) or bone event, which typically includes pathologic fracture, spinal cord compression, radiation or surgery to bone, and hypercalcaemia of malignancy. Bisphosphonates significantly reduced the incidence of these events. Zoledronic acid, pamidronate, clodronate and ibandronate have demonstrated efficacy compared with placebo. Zoledronic acid has also been compared with another active bisphosphonate (i.e. pamidronate) and shown by multiple event analysis to be significantly more effective at reducing the risk of SREs. Bisphosphonates effectively reduce and prevent skeletal complications in patients with bone metastases from breast cancer. Preclinical data suggest that bisphosphonates have antitumour effects. Bisphosphonates may also be of use in the adjuvant setting.     

Prostate cancer metastases to bone: pathophysiology, pain management, and the promise of targeted therapy

Bone metastases are a significant cause of pain and morbidity in prostate cancer, especially if they lead to complications such as pathological fractures and spinal cord compression. Palliation of pain can be achieved with radiation, radioisotopes, hormone therapy, chemotherapy, and bisphosphonates. Bisphosphonates also reduce the risk of skeletal complications. Studies with animal models and advances in understanding the molecular basis for bone metastases have yielded new targets for therapy. Some of the promising therapeutic trials are reviewed in this paper.     

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.