Treatment Of Metastatic Bone Disease Research Articles

Bone Targeted Therapies for Bone Metastasis in Breast Cancer.

Cancer metastasis to the bone develops commonly in patients with various malignancies, and is a major cause of morbidity and diminished quality of life in many affected patients. Emerging treatments for metastatic bone disease have arisen from advances in our understanding of the unique cellular and molecular mechanisms that contribute to the bone metastasis. The tendency of cancer cells to metastasize to bone is probably the end result of many factors including vascular pathways, the highly vascular nature of the bone marrow (which increases the probability that cancer cells will be deposited in bone marrow capillaries), and molecular characteristics of the cancer cells that allow them to adapt to the bone marrow microenvironment. The goals of treating osseous metastases are manifold. Proper treatment can lead to significant improvements in pain control and function, and maintain skeletal integrity. The treatment plan requires a multidisciplinary approach. Widespread metastatic disease necessitates systemic therapy, while a localized problem is best managed with surgery, external beam radiotherapy, or both. Patients with bone metastasis can have prolonged survival, and proper management can have a significant impact on their quality of life. We will review the factors in this article that are promising molecular bone-targeted therapies or will be likely targets for future therapeutic intervention to restore bone remodeling and suppress tumor growth.

Contemporary Management of Metastatic Bone Disease

Metastatic bone disease has a significant effect on a patient's mortality and health-related quality of life. An aging US population and improved survival rates of patients with cancer have led to an increase in the incidence of symptomatic bony metastatic lesions that may require orthopaedic care. Skeletal-related events in neoplastic disease include pain, pathologic fracture, hypercalcemia, and neural compression, including spinal cord compression. The clinical evaluation and diagnostic study of a patient with a skeletal lesion of unknown etiology should be approached carefully. In patients with widespread metastatic disease, the treatment of a skeletal-related event may be limited to stabilization of the pathologic fracture or local disease control. The treatment of metastatic bone disease is guided by the nature of the skeletal-related event, the responsiveness of the lesion to adjuvant care, and the overall condition and survival expectations of the patient. Impending pathologic fractures are often more easily treated, with less morbidity and easier recovery for patients, than completed fractures. Quality of life is the most important outcome measure in these patients. When surgery is indicated, the approach, choice of fixation, and use of adjuvant should allow for immediate and unrestricted weight bearing. Because metastatic lesions to the skeleton have a limited capacity for spontaneous healing, surgical fixation should be durable for the life expectancy of the patient. In the epiphyseal region of long bones, replacement arthroplasty is generally preferred over internal fixation. Metaphyseal and diaphyseal regions can generally be addressed with intramedullary nailing or plate fixation with adjuvant. The specific treatment of acetabular lesions is dictated by the anatomy and the degree of bone loss. Spinal stability and neural compromise are important considerations in choosing a strategy for managing spine tumors. Effective surgical approaches to metastatic disease of the spine may include vertebral augmentation or open decompression and realignment of the spinal column with internal fixation. Radiation therapy is an important adjunctive modality in the treatment of metastatic bone disease. Medical management consists of symptom control, cytotoxic chemotherapy, and targeted therapy. Emerging technologies, including radiofrequency ablation, cementoplasty, and advances in intraoperative imaging and navigation, show promise in the treatment of metastatic bone disease.

Improving diagnosis of early bisphosphonate-related osteonecrosis of the jaws: schneiderian membrane thickening in a case-control study

Background and objetives: Bisphosphonates are antiresorptive drug fully accepted for the treatment of metastatic bone disease, osteoporosis and other bone diseases. In 2003, Marx published 36 patients with exposed bone of the jaws induced by bisphosphonates. Although Bisphosphonate-related Osteonecrosis of he Jaws’s (BONJ) diagnostic criteria proposed by the American Association of Oral and Maxillofacial Surgeons (AAOMS) excludes the use of imaging studies, is plenty accepted that imaging tests play a key role not only for the diagnosis itself, but also to define the extention of the affected bone. Methods: An observational case-control study was designed including patients diagnosed and treated by BONJ in the University Central Hospitall during 96 months. All cases showed the diagnostic criteria of the AAOMS. Control subjects included were healthy people who had never received bisphosphonates and belonged to the same geographic area and hospital than cases. Results: Seventy cases were identified, but only 32 cases included studies with Computed Tomography (CT). By gender, 10 patients were men and 22 women, with a mean age of 69.2 years. In 20 patients (62.5%) intravenously zoledronic acid was administred. The average time of bisphosphonate administration was 17.9 months. Mandibulatr involvement was found in 19 patients and stage IIwas themost common degree of the disease (18 cases). Schneiderian membrane thickening was objectified in 20 maxillary sinuses of 18 patients (56.3%) by CT and thirteen of these patients (40.6%)presented theSchneiderianmembrane thickening without underlying bone exposure. In control subjects, Schneiderian membrane thickening of the mucosa was recognizable only 6 different subjects (18.8%). Conclusions: In our study, the thickening of the Schneiderian membrane is significantly more frequent in cases. The presence of this sign may be an early sign of involvement of BONJ and should be taken into consideration in further studies.

Radiopharmaceuticals for Bone Metastasis Therapy and Beyond: A Voyage from the Past to the Present and a Look to the Future

Bone cancer can be divided into primary and secondary (metastatic) bone cancer. Osteosarcoma is the most common type of primary bone cancer, but still is a rare cancer. The development of bone metastases is a common event for the cancer patient and the main cause of treatment failure and death, being chronic pain syndrome the most important complication. There are currently several therapeutic modalities for the treatment of metastatic bone disease, including radiation therapy. Treatment with radionuclides (β- and α-particle emitters and Auger electron cascades) is a safe and effective tool of medicine. There is a great deal of interest in diphosphonic acids in nuclear medicine as ligands for radiometals in bone-seeking diagnostic and therapeutic agents. Several radiopharmaceuticals have been designed with the phosphonates as ligands. A recent approach to develop an effective radiopharmaceutical for therapy of bone cancer was the design of a water-soluble polymer that would exploit the disrupted vasculature in tumors according to the enhanced permeability and retention effect. To enhance the effect of radionuclide therapy on the cancer cells, new strategies have recently been investigated, such as the combined radionuclide and chemotherapy, high-dose radionuclide therapy, and repeated radionuclide therapy.

Time to Put an End to the “One Size Fits All” Approach to Bisphosphonate Use in Patients with Metastatic Breast Cancer?

Bisphosphonates emerged as an effective treatment for metastatic bone disease in the mid-1990s, and in a relatively short time, they have become an integral component in the palliative care of a range of common malignancies that spread to bone[...].

Bisphosphonate therapy in children

Bisphosphonates are analogues of pyrophosphates that bind to bone and inhibit osteoclast resorption of bone and promote osteoclast apoptosis. They are used widely in adults for treatment of metastatic bone disease and osteoporosis. The off-label use of bisphosphonates in children is expanding to treat low bone mass and osteoporotic disorders like osteogenesis imperfecta and cerebral palsy-related osteopenia, as well as localized bone disorders like fibrous dysplasia. The effects of these drugs on the growing skeleton are still incompletely understood, and they should be used with care. Overall, when administered with close monitoring, they have been shown to be beneficial in treating a number of childhood low bone mass states and bone diseases. Bisphosphonates also offer particular promise in treating Legg-Calve-Perthes disease and avascular necrosis of the hip in young people.

Antitumor effects of zoledronic acid in combination with histone deacetylase inhibitor valproic acid.

e15158 Background: The established utilisation of bisphosphonates is the treatment of metastatic bone disease derived from several tumor types including prostate (PCa) and breast cancer. However, recently preclinical as well as clinical evidence support anti-tumor activities of these drugs in their own right. To probe into the molecular basis of such observations we treated PCa bone metastasis derived cell lines (VCaP, PC-3) and breast cancer cells (MCF-7) with zoledronic acid (ZA) and ZA in combination with valproic acid (VPA). HDAC-Inhibitor VPA according to our previous findings rectifies aberrant androgen receptor signalling and thus, implies an anti-androgen element in these treatments. Methods: PCa cells (VCaP, PC-3) and breast cancer cells (MCF-7) were treated with ZA (Zometa, Novartis) at 0, 5, 25 or 100µM or same ZA concentrations in combination with VPA (5mM). Tumor cell viability and proliferation were analysed by AlamarBlue- and BrdU-tests. Gene expression and PSA secretion was quantitated by real time RT-PCR and was further assessed with ELISA-kits, respectively. Results: In all cell types ZA has no impact on tumor cell viability or proliferation of its own exceeding the effects of VPA alone. Likewise, PSA secretion in VCaP cells is not further diminished in the combined ZA/VPA treatments. However, among a marked impact on cancer relevant gene expression protective elements such as vitamin D- and β-estrogen-receptor are up-regulated by ZA alone and in excess by the combined treatment. Other genes associated with protective features such as IGFBP-3, SOCS-3 and Se-BP-3 are up-regulated only by the ZA/VPA combination. Conclusions: We present molecular evidence for anti-tumor effects of zoledronic acid. Our data suggest the necessity of a concomitant anti-androgen treatment for maximal benefit. The genes addressed by such treatments are more associated with cancer prevention than immediate androgen signalling targets. Therefore, the main anti-tumor potential of ZA may emerge from an early onset of combined therapies to prevent bone metastases.

Potential Anticancer Properties of Bisphosphonates: Insights From Preclinical Studies

Bone is a common site of metastasis from advanced cancers, and metastasis to bone accounts for the majority of distant recurrences from breast and prostate cancers. Bone metastases are characterized by increased rates of bone turnover. Bisphosphonates are extensively used in the treatment of metastatic bone disease to reduce the rates of osteolysis and the risk of skeletal-related events. In addition, bisphosphonates have demonstrated direct and indirect anticancer potential in preclinical studies. These activities include induction of apoptosis, inhibition of invasion, synergistic cytotoxicity with chemotherapy agents, antiangiogenic properties, and modulation of immunologic activity against transformed cells. Notably, these activities of bisphosphonates are not limited to the bone microenvironment; indeed some effects are mediated on the cancer cells themselves. These preclinical data provide the rationale for the underlying potential clinical benefits from bisphosphonates (e.g., prevention of metastasis to bone and other sites in the early breast cancer setting and delayed disease progression in malignancies involving colonization of bone [e.g., multiple myeloma]). This review article summarizes the preclinical anticancer activities of bisphosphonates in various cancer types and evaluates their potential contributions to the recently demonstrated clinical effects.

Bisphosphonate-Related Osteonecrosis of the Jaws. A Severe Side Effect of Bisphosphonate Therapy

Bisphosphonates (BP) are potent inhibitors of bone resorption used mainly in the treatment of metastatic bone disease and osteoporosis. By inhibiting bone resorption, they prevent complications as pathological fracture, pain, tumor-induced hypercalcemia. Even though patient's benefit of BP therapy is huge, various side effects may develop. Bisphosphonate-related osteonecrosis of the jaws (BRONJ) is among the most serious ones. Oncologic patients receiving high doses of BP intravenously are at high risk of BRONJ development. BPs impair bone turnover leading to compromised bone healing which may result in the exposure of necrotic bone in the oral cavity frequently following tooth extraction or trauma of the oral mucosa. Frank bone exposure may be complicated by secondary infection leading to osteomyelitis development with various symptoms and radiological findings. In the management of BRONJ, conservative therapy aiming to reduce the symptoms plays the main role. In patients with extensive bone involvement resective surgery may lead to complete recovery, provided that the procedure is correctly indicated. Since the treatment of BRONJ is difficult, prevention is the main goal. Therefore in high risk patients dental preventive measures should be taken prior to bisphosphonate administration. This requires adequate communication between the prescribing physician, the patient and the dentist.

Src inhibitors in the treatment of metastatic bone disease: rationale and clinical data

Src is a nonreceptor tyrosine kinase essential for the activation of osteoclasts, the cells that degrade bone. Src also regulates normal cell functions, cancer cell growth and metastasis to organs, including bone where tumor cells induce bone destruction by osteoclasts. Src inhibitors prevent bone destruction and tumor cell growth in animal models of metastatic bone disease, and some are being investigated in clinical trials, particularly in patients with prostate cancer, which has high bone metastatic potential. Here, we review how Src regulates osteoclast formation, activation and survival and the results of preclinical and clinical trials of Src inhibitors, which show some promise in inhibiting the effects of tumor cells on the skeleton.

Economic Evaluation of Clodronate and Zoledronate in Patients Diagnosed With Metastatic Bone Disease From the Perspective of Public and Third Party Payors in Brazil

Background Metastatic bone disease (MBD) is responsible for >99% of malignant tumors that affect the bone. MBD patients have increased risk of skeletal complications that are often dramatic and result in loss of function or disability, leading to rapid deterioration of quality of life. Bisphosphonates have become the standard therapy for the treatment and prevention of skeletal-related events (SREs). Objective The objective of this study was to evaluate the cost-effectiveness of zoledronate and clodronate in the prevention of SREs in patients with MBD. Methods A pharmacoeconomic analysis was performed for a hypothetical cohort of patients with MBD to compare the costs and consequences of the use of clodronate and zoledronate for treatment and prevention of SREs in MBD in Brazil. The model was constructed using decision analysis techniques. Costs were described in 5 categories—drugs, physician visits, hospitalizations, surgical/medical care, and laboratory tests—and were reported in 2008 Brazilian reais (1 BRL = 0.54 US dollar). Quality-adjusted life years gained was considered as an outcome. Sensitivity analyses tested model robustness. Results The total cost of treatment of MBD in Brazil for a 5-year time-horizon was R$46,313 with clodronate and R$50,319 with zoledronate. The estimated number of quality-adjusted life years was 2.00 and 1.90 for clodronate and zoledronate, respectively. Cost-effectiveness ranking was unchanged when model time-horizon was changed to 1 or 10 years. Univariate analysis revealed the incidence of osteonecrosis as a sensitive parameter in the model. Multivariate analysis confirmed base-case results, in which >60% of model iterations favored clodronate over zoledronate. Conclusion The present pharmacoeconomic evaluation, under the premises presented, found that clodronate was dominant over zoledronate from both the public and the private health care perspectives in Brazil.

Evidence for orthopaedic surgery in the treatment of metastatic bone disease of the extremities: A review article

Background: The decision to offer orthopaedic surgery to patients with metastatic bone disease is often difficult and requires an understanding of the underlying disease, the patient’s needs or wishes, the expected outcomes and the principles of surgery. Aim: We aimed to look at the literature to support the role of orthopaedic surgery for skeletal metastasis in improving key outcomes such as pain, quality of life and physical functioning. Design: Review article. Data sources: The ‘Dialog Datastar’ database was used to access Medline and other resources from 1951 to December 2009 using keywords ‘Metasta$’ AND ‘Bone or Skeletal’ AND ‘Results Or Outcome Or Surg$ Or Management’. Results: The majority of the studies that have looked at these key outcomes are limited by their design and their use of non-validated outcome measures. This study has detailed the measures to assess outcome, predict survival, predict fracture and how to arrive at key decisions, such as when to operate and when not to operate on these patients. Conclusion: Timely and appropriate surgical intervention reliably alleviates pain and improves quality of life and can be undertaken with few complications in most patients. Although most procedures can be undertaken by non-specialists, consultation with other members of the multidisciplinary team is mandatory, and in complex cases, referral to a specialist orthopaedic oncology centre can be helpful.

OPG/RANKL/RANK Pathway as a Therapeutic Target in Cancer

Bone metastases play an important role in the morbidity and mortality of patients with malignant disease. Despite therapeutic advances in the treatment of solid organ malignancy such as lung cancer, less development on metastasis interventions has been forthcoming. More recent research has focused on molecular pathway manipulation in the prevention and treatment of metastatic bone disease and associated complications such as bone pain and hypercalcemia. The osteoprotegerin/receptor activator of nuclear factor-кβ ligand/receptor activator of nuclear factor-кβ pathway, which is physiologically involved in bone turnover, has been of considerable interest, and recent promising data have been revealed. In this study, we describe this molecular pathway in terms of its natural physiological function, manipulation for therapeutic benefit, and recent clinical trial results.

Under usage of zoledronic acid in non-small cell lung cancer patients with metastatic bone disease – a short communication

Background and aim The use of zoledronic acid (ZA) is now recommended for patients with NSCLC and metastatic bone disease (MBD). We thus examined the rates of ZA administration in NSCLC looking specifically at the use of this drug with systemic chemotherapy (ZCt) and comparing overall survival between patients who had ZCt from diagnosis to those who had chemotherapy (Ct) alone. Method In this retrospective audit, we analysed the data of 114 consecutive patients with stage IV NSCLC and MBD at presentation. Forty-three of these patients had received zoledronic acid and chemotherapy (ZCt) and 71 had received chemotherapy alone (Ct). Results Forty-three (37.7%, 43/114) of NSCLC patients diagnosed with MBD received ZA with their first chemotherapy (ZCt). Patients on ZCt, after adjustment for the planned prognostic factors (sites of disease, histology and PS), had better overall survival (OS), with a median of 34 weeks, compared to those who received chemotherapy alone, who had a median of 19 weeks ( p = 0.03), HR = 0.60 (95%CI: 0.38–0.96). After adjusting for prognostic factors (sex, age. single versus doublet chemotherapy), ZCt patients still maintained a trend to better OS ( p = 0.06) HR 0.63 (95%CI: 0.39–1.02) 34 versus 21 weeks. Conclusions The percentage of patients with MBD treated with ZA at first chemotherapy (37.7%) is low. The addition of ZA increased OS in NSCLC patients with MBD in this audit. More formal policies and dedicated trials on the treatment of MBD in NSCLC patients need to be put in place.

Abstract LB-159: Bisphosphonates are internalised by myeloid derived suppressor cells (MDSCs) in vivo in a mouse model of breast cancer

Abstract Zoledronic acid (Zometa; ZOL), a nitrogen-containing bisphosphonate (N-BP), has become the standard treatment for metastatic bone disease due to its ability to inhibit osteoclast-mediated resorption. The molecular target of ZOL in osteoclasts is FPP synthase, an enzyme of the mevalonate pathway. Inhibition of this enzyme prevents the synthesis of isoprenoid lipids necessary for the prenylation of small GTPases such as Rho, Rac and Rap, thereby causing the accumulation of the unprenylated form of these proteins and fundamentally affecting cell function and survival. ZOL and other N-BPs have anti-tumour effects in some preclinical models of skeletal and non-skeletal tumours, and, more recently, have tantalising effects on patient survival in some clinical trials. However, the exact mechanisms responsible for these anti-tumour effects in vivo are still unknown, and the extent to which N-BPs are internalised by cells other than osteoclasts (such as immune cells) is unclear. We have sought to address this question in the 4T1 murine breast cancer model using a novel, fluorescently-labeled N-BP (AF647-RIS). 24 hours after a subcutaneous injection, using flow cytometry we have demonstrated for the first time the cellular uptake of this N-BP by Gr1+CD11b+ myeloid-derived suppressor cells (MDSCs), as well as by CD14+F4/80+ monocytes/macrophages (TAMs) in mammary tumours, whole blood, liver, spleen and bone marrow. Uptake of N-BP was not detectable in the tumour cells or other cell types. Furthermore, 7 days after a single injection of a clinically relevant dose of ZOL into tumour-bearing mice, we detected a significant reduction in MDSC number in the spleen. It remains unknown whether ZOL affects protein prenylation in MDSCs or TAMs in vivo. Currently available methods to detect changes in protein prenylation, using western blotting to detect unprenylated small GTPases, are too insensitive to detect subtle effects of N-BPs on prenylation in cells in vivo. Importantly, we have now optimised a new, highly sensitive enzyme-based approach to detect the accumulation of unprenylated proteins in cell and tissue extracts from N-BP-treated animals. Additional studies are now in the very final stages to determine conclusively whether a clinically-relevant dose of ZOL inhibits protein prenylation in MDSCs and TAMs in 4T1 mice. In summary, we provide the first conclusive evidence that N-BPs can be internalized in vivo by MDSC and other myeloid cells such as TAMs. Given the important role of these cells in the progression of tumour growth and metastasis, our studies will finally clarify the mechanism underlying the preclinical, and potentially clinical, anti-tumour activity of these agents. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr LB-159. doi:10.1158/1538-7445.AM2011-LB-159

Treatment of Metastatic Bone Lesions in the Upper Extremity: Indications for Surgery

Pathological fractures caused by metastatic malignant disease have been the subject of increasing interest in recent years. This article describes our experience with the treatment of metastatic bone disease of the upper extremity and our attempt to clarify the indications for different surgical procedures. Of 53 patients with metastatic lesions to the upper extremity, 20 who had been surgically treated were analyzed retrospectively. These comprised 13 men and 7 women with a mean patient age of 62 years. The most common primary tumors to metastasize were lung and liver, with the humerus involved in 12 cases and the scapula and forearm in 4 cases each. Four patients with scapula and forearm involvement underwent tumor resection due to uncontrollable tumor size, while 3 were successfully treated by selective arterial embolization. Three metastases to the humeral head were reconstructed with endoprosthesis, but functional restriction was noted. Five cases with metastases to the humeral shaft were treated with tumor curettage, internal fixation using intramedullary nailing, adjuvant cryosurgery, and cementing. This achieved good results for pain relief and functional restoration with minimal complications. Two metastases to the humeral condyle were unable to be stabilized with plate and locking screws. Metastatic lesions to the scapula and forearm are commonly treated nonsurgically, but some patients with uncontrollable tumor mass require surgical resection. Endoprosthetic replacement is recommended if the lesion involves the humeral head or condyle. Most patients with the humeral shaft lesion are likely to benefit from tumor curettage, intramedullary nailing with locking screw, and cementing.

Evolving Role of Bone Biomarkers in Castration-Resistant Prostate Cancer

The preferential metastasis of prostate cancer cells to bone disrupts the process of bone remodeling and results in lesions that cause significant pain and patient morbidity. Although prostate-specific antigen (PSA) is an established biomarker in prostate cancer, it provides only limited information relating to bone metastases and the treatment of metastatic bone disease with bisphosphonates or novel noncytotoxic targeted or biological agents that may provide clinical benefits without affecting PSA levels. As bone metastases develop, factors derived from bone metabolism are released into blood and urine, including N- and C-terminal peptide fragments of type 1 collagen and bone-specific alkaline phosphatase, which represent potentially useful biomarkers for monitoring metastatic bone disease. A number of clinical trials have investigated these bone biomarkers with respect to their diagnostic, prognostic, and predictive values. Results suggest that higher levels of bone biomarkers are associated with an increased risk of skeletal-related events and/or death. As a result of these findings, bone biomarkers are now being increasingly used as study end points, particularly in studies investigating novel agents with putative bone effects. Data from prospective clinical trials are needed to validate the use of bone biomarkers and to confirm that marker levels provide additional information beyond traditional methods of response evaluation for patients with metastatic prostate cancer.

Targeted Therapy Options for Treatment of Bone Metastases; Beyond Bisphosphonates

Cancer is a major leading cause of death in the western world (following heart diseases). It poses an enormous burden on patients and society with a major impact on healthcare and economy. Once cancers have spread to the skeleton, treatment options are predominantly limited to palliation, treatment of hypercalcemia and prevention of pathological fractures. Despite the elaborate efforts of modern medicine to improve treatment, novel therapies for the treatment of solid tumors in patients with advanced disease, including metastatic bone disease, have generally failed to improve patient overall survival. Despite initial beneficial responses on metastatic tumor burden this is frequently followed by re-growth of therapy resistant, malignant metastatic bone lesions. Cancer relapse in bone coincides with devastating consequences and causes considerable morbidity. Bisphosphonates represent the current gold standard in bone metastasis therapies. Because of the progress made in our understanding of the pathogenesis of skeletal metastasis using preclinical models, newer and more efficacious compounds and therapies have been developed that are being evaluated (or will soon be) in clinical trails. In this chapter, we discuss novel therapeutic targets and strategies for the treatment of metastatic bone disease. Future, successful treatment of skeletal metastasis will rely on targeting critical molecular mediators/processes in both metastasis-initiating subpopulations of osteotropic cancers ("the seed") together with their supportive, cellular and extra-cellular surrounding bone/bone marrow stroma ("the soil").

Future directions of bone-targeted therapy for metastatic breast cancer

Bone is the most common metastatic site for breast cancer, and bone metastases can cause pain as well as risk of pathological fractures. Emerging treatments for metastatic bone disease have arisen from advances in our understanding of the unique cellular and molecular mechanisms that contribute to bone metastasis. The interaction between tumor cells and the bone microenvironment results in a 'vicious cycle' that increases both bone destruction and tumor burden. The tumor secretes factors, such as parathyroid hormone-related peptide, that stimulate osteoclastogenesis. Similarly, the bone stroma produces growth factors, such as transforming growth factor β, that promote tumor growth in bone. Therapeutic targeting of these microenvironmental factors is under intensive investigation. Other attractive therapeutic targets include signaling molecules, such as receptor activator of nuclear factor κB ligand, Src kinase, and cathepsin K, all of which regulate osteoclast function, and chemokine receptor 4, which is involved in the homing of tumor cells to bone. In this Review, we describe the progress and future directions of novel bone-targeted therapies that may reduce or prevent destructive bone metastasis from breast cancer. Novel modalities for predicting and monitoring treatment response will also be described.

Serum follistatin in patients with prostate cancer metastatic to the bone

The clinical significance of circulating follistatin (FLST), an inhibitor of the multifunctional cytokine activin A (Act A), was investigated in patients with prostate cancer (PCa). The serum concentrations of this molecule were determined by an enzyme-linked immunosorbent assay (ELISA) in PCa patients with (M+) or without (M0) bone metastases, in patients with benign prostate hyperplasia (BPH) and in healthy subjects (HS). The effectiveness of FLST in detecting PCa patients with skeletal metastases was determined by the receiver operating characteristic (ROC) curve analysis. Serum FLST was significantly higher in PCa patients than in BPH patients (P=0.001) or HS (P=0.011). Conversely, in BPH patients, FLST levels resulted lower than in HS (P=0.025). In cancer patients the serum concentrations of FLST significantly correlated with the presence of bone metastases (P=0.0005) or increased PSA levels (P=0.04). Interestingly, significant differences in the ratio between FLST and Act A serum concentrations (FLST/Act A) were observed between HS and BPH patients (P=0.001) or PCa patients (P=0.0005). Finally, ROC curve analysis, highlighted a sound diagnostic performance of FLST in detecting M+patients (P=0.0001). However, the diagnostic effectiveness of FLST did not result significantly superior to that of Act A or PSA. These findings suggest that FLST may be regarded as a potential, molecular target in the treatment of metastatic bone disease while its clinical role as soluble marker in the clinical management of PCa patients with bone metastases needs to be better defined.