Skeletal-related Events In Men Research Articles

Impact of skeletal related events (SREs) on health-related quality of life (HRQoL) and healthcare resource utilization (HRU) in prostate cancer patients with bone metastases (BM).

e16046 Background: Advanced prostate cancer often leads to the development of BM and as a result SREs. Treatment and management of SREs, as well as the underlying disease, influences the patient’s HRQoL and HRU. We evaluated the impact of SREs on HRQoL (FACT-P) and HRU in patients with BM. Methods: Data were extracted from the Adelphi Prostate Cancer Disease-Specific Programme (DSP), a cross-sectional survey of 150 urologists and oncologists and their prostate cancer patients conducted from March to June 2012 in the US. Each specialist completed comprehensive record forms on 12 of their patients being treated for prostate cancer. Patients were invited to complete a questionnaire, which included the FACT-P HRQoL instrument. Patients were stratified by SRE experience to assess the impact of SRE on patients with BM. SRE was defined as an event of bone radiation, bone surgery, fracture, or spinal cord compression. Results: Data were collected from 1,749 prostate cancer patients, of which 941 were identified with BM; SRE status was recorded in 499 BM patients (Table). HRQoL was significantly lower in patients experiencing SREs, while the rate of consultations and likelihood of being hospitalized was significantly higher. Conclusions: SREs result in a significant economic burden on the healthcare system and negative impact on HRQoL in prostate cancer patients with BM. [Table: see text]

Management of skeletal-related events in patients with advanced prostate cancer and bone metastases: Incorporating new agents into clinical practice.

Skeletal-related events (SREs) are a common complication of bone metastases, and have serious negative consequences for patients with castrate-resistant prostate cancer (CRPC). SREs can lead to severe pain, increased risk of death, increased health care costs and reduced quality of life. Until recently, zoledronic acid has been the sole standard of care for the prevention of SREs in men with CRPC with bone metastases. Denosumab, a receptor activator of nuclear factor kappa-B ligand (RANK-L) inhibitor, has been recently approved for use in Canada for this indication, thus presenting another option for these patients. Denosumab was shown to be superior to zoledronic acid in delaying the time to first or subsequent SREs in CRPC patients with bone metastases. This review discusses current and previous trials examining agents designed to prevent SREs in men with CRPC and bone metastases. It also discusses the practical aspects of administering a bone-targeted therapy, including choosing a bone-targeted therapy, monitoring at the onset and during therapy, switching from one therapy to another, and assessing potential complications.

Management of skeletal-related events in patients with advanced prostate cancer and bone metastases: Incorporating new agents into clinical practice

Skeletal-related events (SREs) are a common complication of bone metastases, and have serious negative consequences for patients with castrate-resistant prostate cancer (CRPC). SREs can lead to severe pain, increased risk of death, increased health care costs and reduced quality of life. Until recently, zoledronic acid has been the sole standard of care for the prevention of SREs in men with CRPC with bone metastases. Denosumab, a receptor activator of nuclear factor kappa-B ligand (RANK-L) inhibitor, has been recently approved for use in Canada for this indication, thus presenting another option for these patients. Denosumab was shown to be superior to zoledronic acid in delaying the time to first or subsequent SREs in CRPC patients with bone metastases. This review discusses current and previous trials examining agents designed to prevent SREs in men with CRPC and bone metastases. It also discusses the practical aspects of administering a bone-targeted therapy, including choosing a bone-targeted therapy, monitoring at the onset and during therapy, switching from one therapy to another, and assessing potential complications.

Health-economic review of zoledronic acid for the management of skeletal-related events in bone-metastatic prostate cancer

Zoledronic acid is the only bisphosphonate approved for the prevention or delay of skeletal-related events in patients with bone metastases secondary to prostate cancer. Recently, the US FDA and the EMA approved denosumab (a fully human monoclonal antibody) to treat skeletal-related events in bone-metastatic prostate cancer. This article summarizes the cost–effectiveness literature pertaining to these two agents when used in the prevention of skeletal-related events secondary to malignancy. Zoledronic acid (and denosumab in comparison with zoledronic acid) have been found to be cost effective and cost ineffective depending on the analytical perspective and model parameters.

9 New developments in the systemic treatment of advanced prostate cancer

Most men with metastatic prostate cancer respond to initial androgen ablation but progress to have castration-resistant prostate cancer (CRPC). Signalling from the androgen receptor (AR) continues in most men with CRPC and has stimulated development of new and more potent inhibitors of androgen-dependent signalling. Randomized placebo controlled trials of abiraterone acetate, an inhibitor of CYP17:17-a-hydroxylase for men with CRPC both preand post-chemotherapy have been completed, and the latter trial shows a median 4-month improvement in overall survival (OS) with minimal toxicity. Similar trials evaluating MDV-3100, a potent antagonist of the AR, have been undertaken. The TAX 327 and SWOG 9916 clinical trials established docetaxel and prednione as preferred first-line chemotherapy for most men with symptomatic metastatic CRPC. However, only about half of the men benefit from docetaxel, and both cellular mechanisms and the tumour microenvironment are implicated in the development of resistance. Thus far agents evaluated in phase III trials in combination with docetaxel have not improved outcome: these includes the vaccine GVAX, high dose vitamin D (DN-101) and the anti-angiogenic agent bevacizumab. In contrast, cabazitaxel, a taxane that is not cross-resistant to docetaxel, improved OS in men progressing during or after treatment with docetaxel-based chemotherapy when compared to mitoxantrone and prednisone, albeit with substantial toxicity. Sipuleucil-T, an immuno-therapeutic approach where antigen-presenting cells are taken from patients with CRPC, exposed to prostate antigens ex vivo and re-infused, has also been associated with improved survival, although this is logistically difficult and the agent did not delay progression of prostate cancer. Finally bisphophonates such as zoledronic acid and denosumab, an inhibitor of rank ligand, have been shown to delay skeletal related events in men with CRPC, and their appropriate place in management will be discussed.

Contemporary management of metastatic castration-resistant prostate cancer

This review will describe the contemporary management of castration-resistant prostate cancer in the context of multiple recent advances. Two novel agents have been added to the therapeutic armamentarium including cabazitaxel and sipuleucel-T. Cabazitaxel, a novel taxane extended survival in men with progressive metastatic CRPC following conventional docetaxel-based chemotherapy. Sipuleucel-T, an autologous dendritic cell based vaccine extended survival in men with relatively asymptomatic metastatic CRPC without visceral metastasis. A third agent, abiraterone acetate, an orally administered CYP17 inhibitor, which suppresses androgen synthesis has been preliminarily reported to significantly prolong survival following prior docetaxel and approval by regulatory agencies is anticipated. Baseline and early changes in circulating tumor cells appear useful as a prognostic factor. Additionally, data demonstrated the superiority of denosumab, a RANK-ligand antagonist, compared to zoledronic acid in the prevention of skeletal related events in men with bone metastases. Cabazitaxel, sipuleucel-T and denosumab were approved in 2010 by regulatory agencies in the USA for men with metastatic CRPC, and approval of abiraterone acetate is anticipated based on the results of a phase III trial. The evaluation of circulating tumor cells assists in determining prognosis, although its utility for clinical decision-making entails validation.

Denosumab versus zoledronic acid for treatment of bone metastases in men with castration-resistant prostate cancer: a randomised, double-blind study

Bone metastases are a major burden in men with advanced prostate cancer. We compared denosumab, a human monoclonal antibody against RANKL, with zoledronic acid for prevention of skeletal-related events in men with bone metastases from castration-resistant prostate cancer. In this phase 3 study, men with castration-resistant prostate cancer and no previous exposure to intravenous bisphosphonate were enrolled from 342 centres in 39 countries. An interactive voice response system was used to assign patients (1:1 ratio), according to a computer-generated randomisation sequence, to receive 120 mg subcutaneous denosumab plus intravenous placebo, or 4 mg intravenous zoledronic acid plus subcutaneous placebo, every 4 weeks until the primary analysis cutoff date. Randomisation was stratified by previous skeletal-related event, prostate-specific antigen concentration, and chemotherapy for prostate cancer within 6 weeks before randomisation. Supplemental calcium and vitamin D were strongly recommended. Patients, study staff, and investigators were masked to treatment assignment. The primary endpoint was time to first on-study skeletal-related event (pathological fracture, radiation therapy, surgery to bone, or spinal cord compression), and was assessed for non-inferiority. The same outcome was further assessed for superiority as a secondary endpoint. Efficacy analysis was by intention to treat. This study is registered with ClinicalTrials.gov, number NCT00321620, and has been completed. 1904 patients were randomised, of whom 950 assigned to denosumab and 951 assigned to receive zoledronic acid were eligible for the efficacy analysis. Median duration on study at primary analysis cutoff date was 12·2 months (IQR 5·9-18·5) for patients on denosumab and 11·2 months (IQR 5·6-17·4) for those on zoledronic acid. Median time to first on-study skeletal-related event was 20·7 months (95% CI 18·8-24·9) with denosumab compared with 17·1 months (15·0-19·4) with zoledronic acid (hazard ratio 0·82, 95% CI 0·71-0·95; p = 0·0002 for non-inferiority; p = 0·008 for superiority). Adverse events were recorded in 916 patients (97%) on denosumab and 918 patients (97%) on zoledronic acid, and serious adverse events were recorded in 594 patients (63%) on denosumab and 568 patients (60%) on zoledronic acid. More events of hypocalcaemia occurred in the denosumab group (121 [13%]) than in the zoledronic acid group (55 [6%]; p<0·0001). Osteonecrosis of the jaw occurred infrequently (22 [2%] vs 12 [1%]; p = 0·09). Denosumab was better than zoledronic acid for prevention of skeletal-related events, and potentially represents a novel treatment option in men with bone metastases from castration-resistant prostate cancer. Amgen.

Management of castration-resistant prostate cancer: bisphosphonates and emerging therapies

Approximately 70% of patients with prostate cancer will develop bone metastases that often lead to bone pain and skeletal-related events. Several bisphosphonates have shown promising activity for palliating pain. Only zoledronic acid has significantly delayed the onset and reduced the incidence of skeletal-related events in men with castration-resistant prostate cancer. In addition, studies suggest that bisphosphonates have anticancer activity that may prevent disease progression and improve survival. Clodronate was shown to improve survival in a study of men with metastatic androgen-sensitive prostate cancer. Emerging therapies are being investigated for their ability to maintain bone health. The findings presented herein highlight the importance of bone-targeted therapies for patients with bone metastases from prostate cancer.

Understanding and Optimizing Bone Health in Breast Cancer

Bone is the preferred site of metastasis for breast cancer, and presence of skeletal lesions is associated with significant morbidity and poor prognosis. Skeletal-related effects such as pain, pathologic fractures, spinal compression, and hypercalcemia are frequent consequences of skeletal lesions of breast cancer that have debilitating effects on the patients’ quality of life. In addition to direct cancer effects on the skeleton, therapies commonly used to treat patients with breast cancer such as chemotherapy and aromatase inhibitors (AI) result in cancer therapy-induced bone loss (CTIBL) which is associated with increased risk of skeletal complications such as fractures. Bisphosphonates are a class of antiresorptive drugs that are now firmly established as the cornerstone of the management of skeletal-related events due to breast cancer. Other novel bone-targeting agents such as the anti-receptor activator of NF-κB ligand (RANKL) monoclonal antibody denosumab are also showing promising activity in the treatment of bone metastasis secondary to breast cancer. Moreover, recent provocative evidence suggests that bisphosphonates might also exhibit antitumor activity via direct and indirect mechanisms. The goal of this review is to summarize the pathophysiology of osteolytic bone lesions secondary to breast cancer, provide clinical evidence of currently available bone-targeted drugs in the treatment of bone metastasis and CTIBL, and explore the antitumor activity of current bone-targeted agents in patients with breast cancer.

Optimizing bisphosphonate therapy in patients with breast cancer on endocrine therapy

Deterioration of bone health is a major concern during progression and treatment of patients with breast cancer, especially in postmenopausal women. Disease- and treatment-associated skeletal-related events include fractures, spinal compression, bone pain, and hypercalcemia of malignancy. Bisphosphonates, which inhibit osteoclastic bone resorption, are important new agents in the management of skeletal-related events, and their impact on breast cancer-related bone metastases and on bone loss during long-term estrogen deprivation therapies such as aromatase inhibitors is reviewed. Intravenous pamidronate has become the standard bisphosphonate to reduce or delay skeletal complications of advanced breast cancer bone metastases, but the more potent agent, zoledronic acid, appears to be at least as effective. Another agent, ibandronate, is also active but has not been investigated in comparison with the other intravenous bisphosphonates. Zoledronic acid is the most convenient to administer, requiring only a short infusion. The effects of bisphosphonates on bone health in women with early breast cancer are also being investigated. A single yearly infusion of zoledronic acid has been shown to significantly increase bone mineral density in osteoporotic postmenopausal women and to reduce biochemical markers of bone turnover. The possibility of such treatment-reversing aromatase inhibitor-associated bone loss during adjuvant therapy of breast cancer is being evaluated in a trial of letrozole, with zoledronic acid added initially or after the onset of bone loss or fracture.

Skeletal Complications in Men with Prostate Cancer: Effects on Quality-of-Life Outcomes throughout the Continuum of Care

Objective: Men with prostate cancer survive for many years after diagnosis and are at risk for clinically important skeletal complications throughout the course of their disease. This review discusses the effect of skeletal complications on quality of life and treatment options available to maintain bone health throughout the continuum of care for prostate cancer. Methods: Published studies were identified through MEDLINE searches, reviewing bibliographies of relevant articles, and reviewing abstracts from scientific meetings. Results: At the time of diagnosis, many men with prostate cancer are osteopenic or osteoporotic. Subsequent androgen ablation therapy increases bone loss and the risk of fracture. The development of bone metastases further increases the risk of skeletal complications, including pathologic fractures and bone pain requiring radiation therapy. Skeletal complications result in significant morbidity and reductions in the quality of life and survival of these patients. Pathologic fractures and radiation to bone (for palliation of pain) are associated with significant declines in physical functioning and emotional well-being. Fractures can also significantly reduce overall survival. Conclusions: Skeletal complications arising from bone metastases and bone loss can adversely affect quality of life. Therefore, bisphosphonates, which maintain bone health and reduce skeletal complications in men with prostate cancer, should improve the quality of life in these patients. Zoledronic acid is effective in preventing skeletal-related events in men with advanced prostate cancer.

Zoledronic acid has long-term efficacy in reducing skeletal complications in patients with bone metastases from breast cancer

Deterioration of bone health is a major concern during progression and treatment of patients with breast cancer, especially in postmenopausal women. Disease- and treatment-associated skeletal-related events include fractures, spinal compression, bone pain, and hypercalcemia of malignancy. Bisphosphonates, which inhibit osteoclastic bone resorption, are important new agents in the management of skeletal-related events, and their impact on breast cancer-related bone metastases and on bone loss during long-term estrogen deprivation therapies such as aromatase inhibitors is reviewed. Intravenous pamidronate has become the standard bisphosphonate to reduce or delay skeletal complications of advanced breast cancer bone metastases, but the more potent agent, zoledronic acid, appears to be at least as effective. Another agent, ibandronate, is also active but has not been investigated in comparison with the other intravenous bisphosphonates. Zoledronic acid is the most convenient to administer, requiring only a short infusion. The effects of bisphosphonates on bone health in women with early breast cancer are also being investigated. A single yearly infusion of zoledronic acid has been shown to significantly increase bone mineral density in osteoporotic postmenopausal women and to reduce biochemical markers of bone turnover. The possibility of such treatment-reversing aromatase inhibitor-associated bone loss during adjuvant therapy of breast cancer is being evaluated in a trial of letrozole, with zoledronic acid added initially or after the onset of bone loss or fracture.

Bisphosphonates to Prevent Skeletal Complications in Men With Metastatic Prostate Cancer

The literature on clinical trials of bisphosphonates in men with metastatic prostate cancer is reviewed to familiarize the reader with biology of bone metastases and rationale for use of bisphosphonates. A MEDLINE review of the literature on prostate cancer and bisphosphonates was performed. In uncontrolled clinical trials bisphosphonates improved pain and analgesic scores in men with symptomatic bone metastases. In a randomized controlled trial of men with bone metastases and progressive disease after first line hormonal therapy zoledronic acid decreased the skeletal related events, a composite end point defined as fracture, surgery or radiation therapy to bone, or change in antineoplastic therapy for bone pain. Randomized controlled trials with other bisphosphonates reported no significant benefit in men with bone metastases. Problems with the study populations, drug bioavailability and potency, statistical power and end point definition may have contributed to the negative results of these other studies. Zoledronic acid decreases the risk of skeletal related events in men with bone metastases and disease progression after first line hormonal therapy. Additional clinical research is needed to evaluate the optimal timing, schedule and duration of bisphosphonate treatment in men with metastatic prostate cancer. Additional research is also necessary to determine whether bisphosphonates can prevent bone metastases in men with high risk nonmetastatic prostate cancer.

Management of Bone Loss in Men With Prostate Cancer

Bone loss is increasingly recognized as a common occurrence in men receiving androgen deprivation therapy (ADT) for prostate cancer. Skeletal metabolism and osteoporosis in men, assessment of bone mineral density (BMD), effects of ADT on BMD, management strategies and potential therapies for osteopenia or osteoporosis in men with prostate cancer are reviewed. Relevant literature is reviewed concerning bone loss and osteoporosis in men with and without prostate cancer, techniques of assessing BMD, data on bone loss and fracture risk and management strategies. The incidence of osteoporotic fractures usually increases a decade later in men than in women. ADT causes significant loss of BMD, which may hasten the development of osteoporosis. Men who are treated with hormonal therapy for an increasing prostate specific antigen and who may live for many years should have baseline BMD assessments. Osteopenia or osteoporosis should be treated to minimize the risk of osteoporotic fracture. Treatment with zoledronic acid seems appropriate since it has been shown to increase BMD in men treated with ADT and to reduce the rate of skeletal related events in men with early hormone refractory prostate cancer with metastatic disease. Monitoring BMD is warranted in men contemplating or receiving ADT but prophylactic therapy to prevent bone loss currently is not recommended. Men with evidence of significant bone loss who are receiving ADT should be treated. Zoledronic acid is a logical choice based on available data.