Prevention Of Skeletal-related Events Research Articles

Targeting RANKL in breast cancer: bone metastasis and beyond

In breast cancer, RANK ligand (RANKL) appears to play an important role in the process of chemotaxis between circulating tumor cells and the bone microenvironment, which enables RANK-expressing breast cancer cells to migrate into the bone. Mounting clinical evidence has further demonstrated that the anti-RANKL monoclonal antibody; denosumab is the most effective approach in the prevention of skeletal-related events. On the other hand, inhibiting RANKL in preclinical models, not only reduced breast cancer formation but also decreased the development of lung metastases, suggesting RANKL as a novel target for breast cancer chemoprevention. In addition, recent data have pointed to a potential role of RANKL in the biology of breast cancer arising at a young age. Hence, RANKL emerges as a key molecule, not only in the field of breast cancer bone metastasis but also in the biology of breast cancer as a whole.

Bone-Targeted Therapies in Metastatic Castration-Resistant Prostate Cancer: Evolving Paradigms

Majority of patients with metastatic castrate resistant prostate cancer (mCRPC) develop bone metastases which results in significant morbidity and mortality as a result of skeletal-related events (SREs). Several bone-targeted agents are either in clinical use or in development for prevention of SREs. Bisphosphonates were the first class of drugs investigated for prevention of SREs and zoledronic acid is the only bisphosphonate that is FDA-approved for this indication. Another bone-targeted agent is denosumab which is a fully humanized monoclonal antibody that binds to the RANK-L thereby inhibiting RANK-L mediated bone resorption. While several radiopharmaceuticals were approved for pain palliation in mCRPC including strontium and samarium, alpharadin is the first radiopharmaceutical to show significant overall survival benefit. Contemporary therapeutic options including enzalutamide and abiraterone have effects on pain palliation and SREs as well. Other novel bone-targeted agents are currently in development, including the receptor tyrosine kinase inhibitors cabozantinib and dasatinib. Emerging therapeutics in mCRPC has resulted in great strides in preventing one of the most significant sources of complications of bone metastases.

Abstract OT2-3-03: Denosumab versus placebo as adjuvant treatment for women with early-stage breast cancer at high risk of disease recurrence (D-CARE): An international, randomized, double-blind, placebo-controlled phase 3 clinical trial

Abstract Bone represents approximately 40% of all first recurrences in women with early-stage breast cancer and is a common site of distant recurrence. In preclinical studies, RANKL inhibition significantly delays skeletal tumor formation, reduces skeletal tumor burden, and prolongs survival of tumor-bearing mice. Denosumab is approved for the prevention of skeletal-related events (SREs) in patients with established bone metastases from solid tumors. Purpose: The D-CARE trial is designed to assess if denosumab treatment prolongs bone metastasis-free survival (BMFS) and disease-free survival (DFS) in the adjuvant breast cancer setting. The primary endpoint of this event-driven trial is BMFS. Secondary endpoints include DFS and overall survival. Additional endpoints are safety, breast density, incidence of SREs (following the development of bone metastasis) patient reported outcomes, and biomarkers. Methods: In this international, randomized, double-blind, and placebo controlled phase 3 trial, approximately 4,500 women with stage II or III breast cancer, at high risk for recurrence and with known hormone and HER-2 receptor status, are eligible. High risk is defined as biopsy evidence of breast cancer in regional lymph nodes, tumor size > 5 cm, (T3), or locally advanced disease (T4). Standard-of-care adjuvant or neoadjuvant chemo-, endocrine, or HER-2 targeted therapy, alone or in combination, must be planned. Patients with a prior history of breast cancer (except ductal carcinoma in situ or lobular carcinoma in situ) or distant metastasis, oral bisphosphonate (BP) use within 1 year of randomization, or any intravenous BP use, are not eligible. Patients are randomized 1:1 to receive denosumab 120 mg or placebo subcutaneously monthly for 6 months, then every 3 months for a total of 5 years of treatment. Supplemental vitamin D (≥ 400 IU) and calcium (≥ 500 mg) will be administered. The trial, sponsored by Amgen Inc. and registered with the ClinicalTrials.gov identifier NCT01077154, began enrolling patients in June 2010 and is expected to complete enrollment in late 2012. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr OT2-3-03.

Avances en la prevención y el tratamiento de las metástasis óseas en cáncer de próstata. Papel de la inhibición de RANK/RANKL

BackgroundBone metastases are a common complication of prostate cancer, so treatment and prevention are essential to slow the progression of the disease and the occurrence of skeletal related events (SREs), which have devastating consequences for the quality of life of patients. Evidence acquisitionWe reviewed the literature based on analysis of clinical trials developed in the prevention and treatment of bone metastases and in the new strategies in place with association of new therapeutic targets. Summary of evidenceBone metastases are characterized by increased bone turnover and altered balance between osteogenesis and osteolysis, with activation of the RANK and its ligand (RANKL). In patients with metastatic prostate cancer, bisphosphonates have been the bone-targeted agents most commonly used to date. Zoledronic acid has demonstrated efficacy in the reduction and delay of SREs in patients with bone metastases. Denosumab, a RANKL inhibitor, has been demonstrated to be superior to zoledronic acid in the prevention of SREs in castration-resistant prostate cancer (CRPC). Both agents are being considered, along with other new bone-targeted agents, for the prevention of bone metastases in patients with nonmetastatic CRPC, where denosumab has already demonstrated superiority over placebo. ConclusionsDenosumab and zoledronic acid prevent SREs in patients with prostate cancer and bone metastases. Denosumab also has a potential role in delaying bone metastases in nonmetastatic patients. Advances in the treatment of CRPC include an increasing focus on prevention of the progression of bone disease.

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.

NICE guidance on denosumab for prevention of skeletal-related events in adults with bone metastases from solid tumours

NICE guidance on denosumab for prevention of skeletal-related events in adults with bone metastases from solid tumours

SY8-4 - Treatment of Bone Metastases

ABSTRACT Bone metastases occur frequently in cancer patients and can lead to skeletal-related events (SREs) such as pathological fracture, spinal cord compression, radiation to bone, and surgery to bone. To prevent SREs in patients with bone metastases, bisphosphonates such as zoledronic acid have been used for many years. In January 2012, denosumab, a fully human monoclonal antibody to RANK ligand, was also approved in Japan for the prevention of SREs. Three pivotal phase 3 trials showed that denosumab was non-inferior to zoledronic acid in reducing the risk of SREs in patients with bone metastases from solid tumors. In patients with breast or prostate cancer, significant superiority of denosumab to zoledronic acid was also shown. I will discuss how we should manage bone metastases and related complications and how we should use bisphosphonates or denosumab to prevent SREs and to improve or maintain quality of life in patients with bone metastases.

Superiority of denosumab to zoledronic acid for prevention of skeletal-related events: A combined analysis of 3 pivotal, randomised, phase 3 trials

BackgroundPatients with bone metastases from advanced cancer often experience skeletal-related events (SRE), which cause substantial pain and morbidity. Denosumab, a fully human monoclonal antibody that inhibits RANK Ligand (RANKL), is a novel bone-targeted agent with a distinct mechanism of action relative to the bisphosphonate zoledronic acid, for prevention of SRE. This pre-planned analysis evaluates the efficacy and safety of denosumab versus zoledronic acid across three pivotal studies. MethodsPatient-level data from three identically designed, randomised, double-blind, active-controlled, phase 3 trials of patients with breast cancer, prostate cancer, other solid tumours or multiple myeloma were combined. End-points included time to first SRE, time to first and subsequent (multiple) SRE, adverse events, time to disease progression and overall survival. FindingsDenosumab was superior to zoledronic acid in delaying time to first on-study SRE by a median 8.21months, reducing the risk of a first SRE by 17% (hazard ratio, 0.83 [95% confidence interval (CI): 0.76–0.90]; P<0.001). Efficacy was demonstrated for first and multiple events and across patient subgroups (prior SRE status; age). Disease progression and overall survival were similar between the treatments. In contrast to zoledronic acid, denosumab did not require monitoring or dose modification/withholding based on renal status, and was not associated with acute-phase reactions. Hypocalcaemia was more common for denosumab. Osteonecrosis of the jaw occurred at a similar rate (P=0.13). ConclusionDenosumab was superior to zoledronic acid in preventing SRE with favourable safety and convenience in patients with bone metastases from advanced cancer.

Review of current literature and implications of RANKL inhibitors for oral health care providers

Bisphosphonates (BPs) were the first class of drugs commonly used to prevent skeletal-related events (SRE) in patients with osteoporosis, multiple myeloma (MM), or solid tumors with metastases to bone. A new alternative class of agents, receptor activator of nuclear factor kappa-B ligand (RANKL) inhibitors, are now available for use in these indications and have the potential to replace intravenous BPs. This paper presents a review of the current literature on denosumab and its association with osteonecrosis of the jaw (ONJ). Denosumab is a RANKL inhibitor that has recently been approved for the prevention of SRE for the same indications as BPs except for MM. Although the overall frequency of denosumab-related ONJ may be similar or higher than estimates of the occurrence rate of bisphosphonate-related ONJ, evidence continues to support appropriate planning and preventive care can reduce the likelihood of adverse effects, including osteonecrosis.

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.

The development of denosumab for the treatment of diseases of bone loss and cancer‐induced bone destruction

Denosumab is a fully human monoclonal antibody against RANK ligand (RANKL), an essential cytokine for the formation, function, and survival of osteoclasts. The role of excessive RANKL as a contributor to conditions characterized by bone loss or bone destruction has been well studied. With its novel mechanism of action, denosumab offers a significant advance in the treatment of postmenopausal osteoporosis; bone loss associated with hormone ablation therapy in women with breast cancer and men with prostate cancer; and the prevention of skeletal-related events in patients with bone metastases from solid tumors by offering clinical benefit to these patients in need.

Denosumab for the treatment of cancer therapy-induced bone loss and prevention of skeletal-related events in patients with solid tumors

Development of bone metastasis is common among patients with advanced cancer. Improvements in chemotherapeutic agents have allowed these patients to live longer with metastatic-stage disease. Thus, treatments to prevent skeletal complications of metastatic bone disease, such as skeletal-related events and pain, are increasingly important. As the skeletal damage with bone metastases is largely caused by increased osteoclast activity, antiresorptive agents (denosumab or bisphosphonates) are recommended for use in these patients. Denosumab, a fully human monoclonal antibody to RANKL, a key mediator of osteoclast activity, was shown to be superior to zoledronic acid for the prevention of skeletal-related events in patients with solid tumors and bone metastases. In addition, denosumab is the only agent currently approved for the treatment of bone loss in patients with breast or prostate cancer receiving hormone-ablation therapy. Denosumab is also being evaluated in several other indications, including adjuvant treatment of breast cancer and giant cell tumor of the bone.

SEOM guidelines for the treatment of bone metastases from solid tumours

Bone metastases are a common and distressing effect of cancer, being a major cause of morbidity in many patients with advanced stage cancer, in particular in breast and prostate cancer. Patients with bone metastases can experience complications known as skeletal-related events (SREs) which may cause significant debilitation and have a negative impact on quality of life and functional independence. The current recommended systemic treatment for the prevention of SREs is based on the use of bisphosphonates: ibandronate, pamidronate and zoledronic acid- the most potent one- are approved in advanced breast cancer with bone metastases, whereas only zoledronic acid is indicated in advanced prostate cancer with bone metastases. The 2011 ASCO guidelines on breast cancer, recommend initiating bisphosphonate treatment only for patients with evidence of bone destruction due to bone metastases. Denosumab, a fully human antibody that specifically targets the RANK-L, has been demonstrated in two phase III studies to be superior to zoledronic acid in preventing or delaying SREs in breast and prostate cancer and non-inferior in other solid tumours and mieloma; it's convenient subcutaneous administration and the fact that does not require dose adjustment in cases of renal impairment, make this agent an attractive new therapeutic option in patients with bone metastases. Finally, in a phase III study against placebo, denosumab significantly increased the median metastasis-free survival in high risk non-metastatic prostate cancer, arising the potential role of these bone-modifying agents in preventing or delaying the development of bone metastases.

Denosumab: Delay of bone metastasis in men with nonmetastatic castrate-resistant prostate cancer.

In a large multicenter phase 3 randomized controlled trial published in Lancet , Smith and colleagues highlight a potential new indication for denosumab for patients with hormone refractory prostate cancer (1). Already approved for prevention of skeletal-related events in the setting of bone metastases in solid tumors (Xgeva) and prevention of androgen deprivation therapy (ADT) induced bone loss (Prolia), the authors theorized that denosumab administered prior to bone metastasis might stabilize the bone microenvironment thus delaying time to first bone metastasis. Men with castrate-resistant nonmetastatic prostate cancer treated with denosumab showed improved bone-metastasis-free survival and delayed time to first bone metastasis compared to those dosed with placebo.

Lifetime cost-effectiveness of denosumab versus zoledronic for prevention of skeletal-related events (SREs) in patients (pts) with castrate-resistant prostate cancer (CRPC) and bone metastases (BM): United States managed care perspective.

e15172 Background: Denosumab (Dmab) is superior to zoledronic acid (ZA) for prevention of SREs in pts with CRPC and BM. As Dmab is not cleared renally, it can be used in pts regardless of renal status or concomitant use of nephrotoxic drugs. Previous economic analyses were limited as the analyses were based on short duration-trial based perspectives and/or did not account for disutility associated with IV vs SC administration of ZA and Dmab, respectively. These analyses assess the lifetime cost-effectiveness of Dmab vs ZA in pts with CRPC and BM from a US managed care perspective, with extensive scenario and sensitivity analyses. Methods: A lifetime Markov model was developed, with efficacy of Dmab vs ZA in SRE prevention from a head-to-head phase 3 trial; clinical practice SRE rate in ZA pts from a large commercial claims database analysis; SRE and mode of administration (IV vs SC) quality adjusted life-year (QALY) decrements estimated using the time trade-off method; and SRE costs estimated from a nationally representative commercial claims database. Drug, drug administration, and renal monitoring costs were also included. Costs and QALYs were discounted at 3% per year. Scenario analyses (including adverse events, drug discontinuation, etc), one-way and multivariate probabilistic sensitivity analyses were conducted. Results: Dmab reduced the number of SREs and increased pts’ QALY vs ZA. In the base case and the scenario analyses, cost per QALY gained was below $50,000, which is commonly considered good value. Cost per SRE avoided was below $9,000. In one-way sensitivity analyses, drug costs and SRE rate were the most influential variables. Probabilistic sensitivity analyses showed the probabilities of Dmab being cost-effective vs ZA were 0.83, 0.94, and 0.98 with willingness-to-pay of $100,000, $150,000 and $200,000 per QALY gained, respectively. Conclusions: Dmab is a cost-effective treatment option in preventing SREs in pts with CRPC and BM compared with ZA from a US managed care perspective. The overall value of Denosumab is based on superior efficacy and more efficient administration.

Health state preferences associated with subcutaneous injections and intravenous infusions for treatment of bone metastases.

e16528 Background: Although cost utility models are often used to estimate the value of treatments for metastatic cancer, limited information is available on the utility of common treatment modalities. Bisphosphonate treatment for bone metastases (BM) is frequently administered via intravenous (IV) infusion, while a recently approved treatment to prevent skeletal-related events (SREs) of BM is administered as a subcutaneous (SC) injection. This study estimated the impact of these treatment modalities on health state (HS) preference. Methods: Participants from the UK general population completed time trade-off interviews to assess the utility of HS vignettes. Respondents first rated a HS representing cancer with BM. Subsequent HSs added descriptions of treatment modalities (ie, injection or infusion) to this basic HS. To represent a range of possible treatment experiences, the two treatment modalities were presented with and without chemotherapy (chemotx), and infusion characteristics were varied by duration (30 minutes or 2 hours) and renal monitoring. Results: A total of 121 participants completed the interviews (47.9% male, 76.9% white). Cancer with BM had a mean utility of 0.40 on a standard utility scale (1 = full health; 0 = death). Adding an injection resulted in a mean utility decrease (ie, disutility) of -0.004. The 30 minute and 2 hour infusions had mean disutilities of -0.02 and -0.04, respectively. Mean disutility of the 30 minute infusion was greater with renal monitoring (-0.05 with same-day blood draw; -0.07 with blood draw 2 days prior). Chemotx was associated with substantial disutility (-0.17). For the HS of BM with chemotx, the mean disutilities of injection, 30 minute infusion, and 2 hour infusion, were -0.02, -0.03, and -0.04, respectively. Disutility associated with injection was significantly smaller than the disutility of both the 30 minute and 2 hour infusions (p &lt; 0.05), regardless of chemotx status. Conclusions: Respondents perceived an inconvenience with each type of BM treatment, but injections were preferred over infusions. The resulting utilities may be used in cost utility models examining the value of treatments for the prevention of SREs in patients with BM.

Baseline covariates impacting overall survival (OS) in a phase III study of men with bone metastases from castration-resistant prostate cancer.

4642 Background: Prognostic models of OS in men with metastatic castrate-resistant prostate cancer (M+CRPC), have been limited. Here we present an analysis of baseline covariates associated with OS from an international phase 3 study that demonstrated superiority of denosumab over zoledronic acid for prevention of skeletal-related events (SRE) in this population (Fizazi et al., Lancet 2011;377:813-822). Methods: Patients had confirmed bone metastases (BM) from CRPC (a rising PSA despite castrate testosterone levels) and no prior bone anti-resorptive therapy. Proportional hazards modeling with various selection strategies was used to assess the prognostic significance of baseline covariates in multivariate analyses. Study-specified factors (previous SRE [Y vs N], PSA level [&lt;10 vs ≥10 ng /mL]) and additional variables (Cook et al., Clin Cancer Res 2006;12:3361-3367; Halabi et al., J Clin Oncol 2003;21:1232-1237; Halabi et al., J Clin Oncol 2008;26:2544-2549) were explored. As no difference in OS was observed between treatment arms, analyses were performed using the pooled overall patient population. Results: Analyses included all randomized subjects with available baseline covariate data (n=1745). At the primary analysis date (median study duration 12.2 months), OS was 51%. Various selection strategies produced consistent results. In multivariate analysis, bone-specific alkaline phosphatase (BAP) ≥146 μg/L (p&lt;0.0001) and corrected urinary N-telopeptide (uNTx) &gt;50 nmol/mmol (p=0.0008) were associated with shorter OS, as were prior SRE (p=0.0002), PSA ≥10 ng /mL (p&lt;0.0001), visceral metastases (p=0.0002), greater time from either diagnosis to first BM or first BM to randomization (p&lt;0.0001 for both), ECOG performance status 2 vs. 0/1 (p=0.017), BPI-SF pain score &gt;4 (p&lt;0.0001), age (p=0.008), alkaline phosphatase &gt;143 U/L (p&lt;0.0001), and hemoglobin ≤128 g/L (p&lt;0.0001). Conclusions: Besides known factors previously associated with OS in men with CRPC (Halabi et al., 2003), we show that bone-associated covariates (pain, prior SRE, BAP, and uNTx) are also important and independent prognostic factors for OS.

Denosumab versus placebo as adjuvant treatment for women with early-stage breast cancer who are at high risk of disease recurrence (D-CARE): An international, randomized, double-blind, placebo-controlled phase III clinical trial.

TPS670 Background: Bone is a common site of distant recurrence in women with early-stage breast cancer, and represents approximately 40% of all first recurrences. Tumor cells in bone release growth factors and cytokines that stimulate osteoclast-mediated bone resorption through the RANK ligand (RANKL) pathway. In preclinical studies, RANKL inhibition significantly delays skeletal tumor formation, reduces skeletal tumor burden, and prolongs survival of tumor-bearing mice. Denosumab is a fully human monoclonal antibody that binds to RANKL with high affinity and specificity. It is approved for the prevention of skeletal-related events in patients with established bone metastases from a variety of solid tumors. The purpose of the D-CARE trial is to evaluate the ability of denosumab to prolong bone metastasis-free survival (BMFS) and disease-free survival (DFS) in the adjuvant breast cancer setting. Methods: Approximately 4,500 women with stage II or III breast cancer, at high risk for recurrence and with known hormone and HER-2 receptor status, are eligible. Standard-of-care adjuvant or neoadjuvant chemo-, endocrine, or HER-2 targeted therapy, alone or in combination must be planned. Exclusion criteria include: a prior history of breast cancer (except DCIS or LCIS) or distant metastasis, oral bisphosphonate (BP) use within 1 year of randomization or any intravenous BP use. Patients are randomized 1:1 to receive denosumab 120 mg or placebo subcutaneously monthly for 6 months, then every 3 months for a total of 5 years of treatment. All patients receive vitamin D (≥ 400 IU) and calcium (≥ 500 mg) supplements. Primary endpoint of this event-driven trial is BMFS. Secondary endpoints include DFS and overall survival. Safety, quality of life assessments, breast density, and biomarkers are additional endpoints. The trial, sponsored by Amgen Inc. and registered with the ClinicalTrials.gov identifier NCT01077154, began enrolling patients in June 2010 and is expected to complete in October 2016. Paul Goss and Dianne Finkelstein supported in part by the Avon Foundation New York.

Pharmacoeconomics of Bisphosphonates for Skeletal-Related Event Prevention in Metastatic Non-Breast Solid Tumours

Bisphosphonates reduce the risk of skeletal-related events (SREs; i.e. spinal cord compression, pathological fracture, radiation or surgery to the bone, and hypercalcaemia) in patients with metastatic cancer. A number of analyses have been conducted to assess the cost effectiveness of bisphosphonates in patients with bone metastases secondary to breast cancer, but few in other solid tumours. This is a review of cost-effectiveness analyses in patients with non-breast solid tumours and bone metastases. A literature search was conducted to identify cost-effectiveness analyses reporting the cost per QALY gained of bisphosphonates in patients with metastatic bone disease secondary to non-breast solid tumours. Four analyses met inclusion criteria. These included two in prostate cancer (one of which used a global perspective but expressed results in $US, and the other reported from a multiple country perspective: France, Germany, Portugal and the Netherlands). The remaining analyses were in lung cancer (in the UK, France, Germany, Portugal and the Netherlands), and renal cell carcinoma (in the UK, France and Germany). In each analysis, the cost effectiveness of zoledronic acid versus placebo was analysed. Zoledronic acid was found to be cost effective in all European countries across all three indications but not in the sole global prostate cancer analysis. Across countries and indications, assumptions regarding patient survival, drug cost and baseline utility (i.e. patient utility with metastatic disease but without an SRE) were the most robust drivers of modelled estimates. Assumptions of SRE-related costs were most often the second strongest cost driver. Further review indicated that particular attention should be paid to the inclusion or exclusion of nonsignificant survival benefits, whether health state utilities were elicited from community or patient samples or author assumptions, delineation between symptomatic and asymptomatic SREs, and the methods with which SRE disutility was modelled over time. While the field of cost-effectiveness analysis in solid tumours other than breast cancer is still evolving, outcomes will likely continue to be driven by drug cost and assumptions regarding treatment benefits. Although considerations such as adverse events and administration costs are important, they were not found to influence cost-effectiveness estimates greatly. As zoledronic acid will lose patent protection in 2013 and subsequently be greatly reduced in price, it is likely that the field of cost effectiveness will change with regard to SRE-limiting agents. Meanwhile, research should be conducted to improve our understanding of the impact on quality of life and medical costs of preventing SREs.