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Corresponding author: Address: Pennsylvania State University, Milton S. Hershey Medical Center, 500 University Drive Suite CH46, Hershey, PA 17033, USA. Tel.: +1 717 531 8678; fax: +1 717 531 5076.
Patients 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.
Methods
Patient-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.
Findings
Denosumab was superior to zoledronic acid in delaying time to first on-study SRE by a median 8.21 months, 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).
Conclusion
Denosumab was superior to zoledronic acid in preventing SRE with favourable safety and convenience in patients with bone metastases from advanced cancer.
Bone metastases are common in patients with advanced cancer, arising in 70–80% of patients with breast or prostate cancer and 30–40% of patients with lung cancer or other solid tumours.
Patients with bone metastases may experience local irreversible skeletal complications including pathologic fracture, spinal cord compression and/or radiation or surgery to bone, known collectively as skeletal-related events (SRE). SRE are indicators of poor prognosis and cause substantial pain and morbidity frequently leading to hospitalisation, poor quality of life and increased medical resource utilisation.
Payer costs for inpatient treatment of pathologic fracture, surgery to bone, and spinal cord compression among patients with multiple myeloma or bone metastasis secondary to prostate or breast cancer.
Bone metastases may also contribute to malignant hypercalcaemia. Patients with breast and prostate cancer may survive several years with bone metastases
during which time they are at risk for SRE. Indeed, long-term management of metastatic bone disease is increasingly relevant as new anticancer treatments extend the overall survival.
Over the last two decades, intravenous bisphosphonates, such as pamidronate
Pamidronate reduces skeletal morbidity in women with advanced breast cancer and lytic bone lesions: a randomized, placebo-controlled trial. Protocol 18 Aredia Breast Cancer Study Group.
Zoledronic acid versus pamidronate in the treatment of skeletal metastases in patients with breast cancer or osteolytic lesions of multiple myeloma: a phase III, double-blind, comparative trial.
Zoledronic acid versus placebo in the treatment of skeletal metastases in patients with lung cancer and other solid tumors: a phase III, double-blind, randomized trial – the Zoledronic Acid Lung Cancer and Other Solid Tumors Study Group.
were developed as effective treatments to delay or prevent SRE in patients with bone metastases, marking an important step in the improvement of palliative cancer care. Despite treatment with bisphosphonates, about 50% of patients continue to experience SRE.
Pamidronate reduces skeletal morbidity in women with advanced breast cancer and lytic bone lesions: a randomized, placebo-controlled trial. Protocol 18 Aredia Breast Cancer Study Group.
Zoledronic acid versus pamidronate in the treatment of skeletal metastases in patients with breast cancer or osteolytic lesions of multiple myeloma: a phase III, double-blind, comparative trial.
Prevalence of Renal Insufficiency in cancer patients and implications for anticancer drug management: the renal insufficiency and anticancer medications (IRMA) study.
These issues underscore the need for additional options to manage the sequelae of bone metastases.
Crucial research in bone biology revealed a key pathway regulating the process of bone remodelling. Osteoprotegerin (OPG) and OPG-ligand (also known as RANK Ligand [RANKL]) were identified as the essential mediators of osteoclast differentiation, activation and survival leading to bone resorption.
Prostate cancer cells–osteoblast interaction shifts expression of growth/survival-related genes in prostate cancer and reduces expression of osteoprotegerin in osteoblasts.
Expression of osteoprotegerin (OPG), TNF related apoptosis inducing ligand (TRAIL), and receptor activator of nuclear factor kappaB ligand (RANKL) in human breast tumours.
Expression of receptor activator of nuclear factor kappaB ligand on bone marrow plasma cells correlates with osteolytic bone disease in patients with multiple myeloma.
Prostate cancer cells–osteoblast interaction shifts expression of growth/survival-related genes in prostate cancer and reduces expression of osteoprotegerin in osteoblasts.
In a murine model of established bone metastases, inhibition of RANKL prevented osteoclast-mediated bone destruction and growth of human breast cancer cells in bone.
The successful use of RANKL inhibition to interrupt the ‘vicious cycle’ of bone destruction and tumour proliferation in animal models suggested a potential new approach for the treatment of bone metastases. Denosumab, a fully human monoclonal antibody with high affinity and specificity for human RANKL inhibited bone resorption in early studies in patients with advanced cancer,
Randomized phase II trial of denosumab in patients with bone metastases from prostate cancer, breast cancer, or other neoplasms after intravenous bisphosphonates.
Randomized phase II trial of denosumab in patients with bone metastases from prostate cancer, breast cancer, or other neoplasms after intravenous bisphosphonates.
Denosumab compared with zoledronic acid for the treatment of bone metastases in patients with advanced breast cancer: a randomized, double-blind study.
A randomised, double-blind study of denosumab versus zoledronic acid in the treatment of bone metastases in men with castration-resistant prostate cancer.
A randomized, double-blind study of denosumab versus zoledronic acid in the treatment of bone metastases in patients with advanced cancer (excluding breast and prostate cancer) or multiple myeloma.
for the prevention of SRE in metastatic bone disease.
Combined patient-level analyses offer enhanced power to a more fully evaluated safety and efficacy, particularly with respect to patient subpopulations. This planned combined analysis of the three identically designed pivotal denosumab trials in over 5700 patients with advanced cancer and bone metastases provides an unprecedented opportunity to discriminate the relative effects of the RANKL inhibitor denosumab and the bisphosphonate zoledronic acid for the prevention of SRE.
2. Methods
Patient-level data obtained from three identically designed, double-blind, double-dummy phase 3 trials were used to compare the efficacy and safety of denosumab (XGEVA®, Amgen Inc., Thousand Oaks, CA)
at a dose of 4 mg administered intravenously. The dose of zoledronic acid was adjusted for renal function (baseline creatinine clearance ⩽60 mL/min) per the zoledronic acid prescribing information.
To maintain blinding, patients randomised to denosumab received an intravenous placebo infusion, whilst patients randomised to zoledronic acid received a subcutaneous placebo injection. Both active study drugs and the corresponding placebos were administered every 4 weeks. If the serum creatinine levels increased, subsequent dosing of intravenous product was withheld until serum creatinine levels returned to within 10% of baseline values as per the zoledronic acid prescribing information.
Denosumab compared with zoledronic acid for the treatment of bone metastases in patients with advanced breast cancer: a randomized, double-blind study.
A randomised, double-blind study of denosumab versus zoledronic acid in the treatment of bone metastases in men with castration-resistant prostate cancer.
A randomized, double-blind study of denosumab versus zoledronic acid in the treatment of bone metastases in patients with advanced cancer (excluding breast and prostate cancer) or multiple myeloma.
Denosumab compared with zoledronic acid for the treatment of bone metastases in patients with advanced breast cancer: a randomized, double-blind study.
A randomised, double-blind study of denosumab versus zoledronic acid in the treatment of bone metastases in men with castration-resistant prostate cancer.
A randomized, double-blind study of denosumab versus zoledronic acid in the treatment of bone metastases in patients with advanced cancer (excluding breast and prostate cancer) or multiple myeloma.
with radiographic evidence of at least one bone metastasis or bone lesion and an Eastern Cooperative Oncology Group performance score of 0, 1 or 2. Patients with creatinine clearance <30 mL/min (per zoledronic acid prescribing information)
or who had received bisphosphonates for treatment of bone metastases were excluded. All study participants were advised to take vitamin D and calcium supplements.
The randomisation schedule was based on a computer-generated schedule prepared before the start of the trials by an individual not involved with the studies and with no access to study data. An interactive voice response system was used to equally randomise (1:1) patients to treatment groups using randomly permuted blocks, with a block size of four. Randomisation was stratified by prior SRE (yes or no) and other factors specific to the cancer type in each trial.
Denosumab compared with zoledronic acid for the treatment of bone metastases in patients with advanced breast cancer: a randomized, double-blind study.
A randomised, double-blind study of denosumab versus zoledronic acid in the treatment of bone metastases in men with castration-resistant prostate cancer.
A randomized, double-blind study of denosumab versus zoledronic acid in the treatment of bone metastases in patients with advanced cancer (excluding breast and prostate cancer) or multiple myeloma.
SRE were defined as pathological fracture, radiotherapy to bone, surgery to bone, or spinal cord compression. Active study drugs (denosumab or zoledronic acid) and the corresponding matching placebo were identical in appearance and provided in identical boxes, with each single-use vial labelled with a unique code assigned to the subject by the interactive voice response system before each dose. All patients, investigators and study sponsor personnel involved in study conduct remained blinded during the blinded treatment phase of each study.
Prespecified end-points for this analysis included time to first on-study SRE (non-inferiority and superiority testing); time to first and subsequent on-study SRE (superiority testing); time to first on-study SRE or hypercalcaemia of malignancy (defined as serum calcium of grade ⩾2 by the Common Terminology Criteria of Adverse Events version 3.0 of >11.5 mg/dL; >2.9 mmol/L; ionised calcium >1.5 mmol/L); incidence of adverse events and adverse events of special interest; time to disease progression per investigator assessment; overall survival; concentrations of bone turnover markers; and drug usage parameters. All the planned analyses were pre-specified before the results from the first SRE study to complete were unblinded. Exploratory analyses were also performed to compare the effect of denosumab versus zoledronic acid across all solid tumour types in the three phase three trials excluding multiple myeloma.
2.1 Statistical analyses
Stopping guidelines for these studies have been described.
Denosumab compared with zoledronic acid for the treatment of bone metastases in patients with advanced breast cancer: a randomized, double-blind study.
A randomised, double-blind study of denosumab versus zoledronic acid in the treatment of bone metastases in men with castration-resistant prostate cancer.
A randomized, double-blind study of denosumab versus zoledronic acid in the treatment of bone metastases in patients with advanced cancer (excluding breast and prostate cancer) or multiple myeloma.
Briefly, the primary analysis for each study was planned to occur when approximately 745 patients had experienced at least one on-study SRE. The testing of non-inferiority of denosumab to zoledronic acid was based on a synthesis approach designed to demonstrate that denosumab preserves at least 50% of the treatment effect of zoledronic acid for time to first SRE. Time to first SRE was analysed using a Cox proportional hazards model. Multiple-event analysis using the Andersen–Gill approach with the robust estimate of variance was used to evaluate the time to first and subsequent on-study SRE. The test for heterogeneity of the effect of denosumab across the four types of SRE was based on the Wei, Lin and Weissfeld model. The combined analysis was stratified by study and stratification factors within each study. Heterogeneity of the treatment effect on time to first SRE and time to first and subsequent SRE across the three studies was assessed by evaluating the treatment-by-study interaction in the Cox model and the Andersen–Gill approach, respectively. Neither interaction was significant (P > 0.4), justifying the combined analysis from three individual studies. All statistical tests were two-sided with a significance level of 0.05. No multiplicity adjustment was applied. Data were analysed by the Amgen Biostatistics Department.
2.2 Role of the funding source
The studies were sponsored by Amgen Inc. The study investigators and Amgen Inc. collaborated on protocol design and data analysis and interpretation. All authors had access to the relevant study data and participated in the drafting, reviewing and critical revision of this paper. Medical writers, supported by Amgen Inc., assisted the authors in the drafting, editing and formatting of this paper. All authors were responsible for the final decision to submit for publication.
3. Results
3.1 Patients
This combined analysis includes data from 5723 patients randomised at 705 sites worldwide to receive either denosumab (n = 2862) or zoledronic acid (n = 2861) (Fig. 1). Patients were enrolled in the studies between 27th April 2006 and 18th December 2008; the combined analysis was completed after 30th October 2009, the primary analysis cut-off date for the last study. Sixty-nine percent of the denosumab group and 70% of the zoledronic acid group withdrew before the primary analysis cut-off date; the most common reasons were death (27% versus 26%, respectively), withdrawal of consent (14% versus 15%, respectively) or disease progression (13% versus 12%, respectively). The groups were well balanced with respect to demographics and disease characteristics at baseline (Table 1).
Denosumab was superior to zoledronic acid in reducing the risk of the first on-study SRE by 17% (hazard ratio, 0.83 [95% confidence interval (CI): 0.76–0.90]; P < 0.001 for both non-inferiority and superiority tests) (Fig. 2A). The median (95% CI) time to first on-study SRE was 27.66 (24.21 to not estimable) months for denosumab versus 19.45 (18.53–21.42) months for zoledronic acid, a difference of 8.21 months.
Fig. 2aTime to first on-study skeletal-related event (SRE).
Denosumab was also superior to zoledronic acid in reducing the risk of multiple SRE by 18% (rate ratio, 0.82 [95% CI: 0.75–0.89]; P < 0.001) (Fig. 2B). In addition, denosumab significantly delayed the time to first SRE or hypercalcaemia of malignancy (26.58 months for denosumab versus 19.35 months for zoledronic acid; hazard ratio 0.83; [95% CI: 0.76–0.90]; P < 0.001). The number of patients who developed hypercalcaemia was 36 (1.3%) in the denosumab group and 53 (1.9%) in the zoledronic acid group.
Fig. 2bTime to first and subsequent on-study skeletal-related event (SRE)∗ (multiple event analysis).
Denosumab was effective in delaying all four types of SRE relative to zoledronic acid. The Wei, Lin and Weissfeld heterogeneity test showed no evidence that treatment effect differed amongst the SRE types. For pathological fracture and radiation to bone, denosumab treatment significantly delayed the time to first on-study event (Fig. 3A) and to first and subsequent on-study events (Fig. 3B).
Fig. 3aTime to first on-study skeletal-related event (SRE) by SRE type.
In exploratory analyses, we further evaluated the effect of denosumab and zoledronic acid treatment on the reduction in risk of SRE in various patient subgroups. The reduction of risk of SRE for denosumab versus zoledronic acid was consistent in patients with or without a prior SRE (Fig. 4). Denosumab also reduced the risk of the first on-study SRE relative to zoledronic acid regardless of age <65 years (hazard ratio 0.82 [95% CI: 0.73–0.93], P = 0.002) or ⩾65 years (hazard ratio 0.82 [95% CI: 0.72–0.94], P = 0.004). Results of exploratory analyses amongst patients with solid tumours showed denosumab was also better than zoledronic acid in reducing the risk of first on-study SRE and multiple on-study SRE. As observed with the overall population, the median (95% CI) time to first on-study SRE was 8.21 months longer with denosumab (27.66 months [24.84 to not estimable]) than zoledronic acid (19.45 months [18.60–21.49]).
Fig. 4Time to first on-study skeletal-related event (SRE) by previous SRE history.
There were no differences between the denosumab and zoledronic acid groups for overall disease progression (hazard ratio, 1.02 [95% CI: 0.95–1.08]; P = 0.63) or survival (hazard ratio, 0.99 [95% CI: 0.91–1.07]; P = 0.71).
Concentrations of bone turnover markers at week 13 were significantly more suppressed from baseline in the denosumab group versus the zoledronic acid group. Median bone-specific alkaline phosphatase decreased from baseline by 39% in the denosumab group versus 32% in the zoledronic acid group (P < 0.001). Median urinary N-telopeptide corrected for serum creatinine was reduced from baseline by 80% in the denosumab group versus 68% in the zoledronic acid group (P < 0.001).
3.3 Drug exposure and adjustments for renal function
The median number [Q1,Q3] of doses administered was slightly higher for the denosumab group (13 [6,20] doses) than for the zoledronic acid group (11 [5,19] doses). Cumulative exposure was 2969 patient-years for denosumab and 2852 patient-years for zoledronic acid.
Adjustments of zoledronic acid for renal function were common: 502 (18%) patients had dose adjustments at baseline due to impaired creatinine clearance. During the study, 277 (10%) patients had doses withheld because of serum creatinine increases, with a total of 1181 zoledronic acid doses withheld. Of those patients in the zoledronic acid group who had doses withheld, 143 (52%) had prostate cancer, 78 (28%) had other solid tumours or multiple myeloma and 56 (20%) had breast cancer.
3.4 Safety
Overall, the rates of adverse events were similar between treatment groups (Table 2). The most common serious adverse event reported was anaemia (5.7% of patients). There was an increased incidence of hypocalcaemia in the denosumab group; grade 3 or 4 laboratory abnormalities for hypocalcaemia were 88 (3.1%) for the denosumab group and 38 (1.3%) for the zoledronic acid group. The incidences of renal adverse events and acute-phase reactions were higher in the zoledronic acid group. Osteonecrosis of the jaw was infrequent and similar between the treatment groups (P = 0.13).
Incidence, risk factors, and outcomes of osteonecrosis of the jaw: integrated analysis from three blinded active-controlled phase III trials in cancer patients with bone metastases.
The incidence of cardiac adverse events was balanced between the denosumab and zoledronic acid groups. The incidence of new malignancies during the study was similar between the groups and no patterns were observed with respect to new malignancy type. Very few injection site reactions were reported (Table 2).
This combined analysis in over 5700 patients with advanced cancer showed that RANKL inhibition with denosumab provided superior efficacy for prevention of SRE in patients with bone metastases relative to zoledronic acid, without the additional burden of renal toxicity or acute-phase reactions. Denosumab extended the time to a first SRE by over 8 months relative to zoledronic acid and maintained superiority in preventing multiple SRE. SRE can be disabling, and lead to serious morbidities such as severe pain, decreased ambulation and mobility, urinary or faecal incontinence and hospitalisation or other treatments.
Payer costs for inpatient treatment of pathologic fracture, surgery to bone, and spinal cord compression among patients with multiple myeloma or bone metastasis secondary to prostate or breast cancer.
Cost-effectiveness of denosumab vs zoledronic acid for prevention of skeletal-related events in patients with solid tumors and bone metastases in the United States.
As expected, time to disease progression and overall survival were similar between treatment groups, as approximately 40% of patients in each group had visceral metastasis at enrolment, which likely dictated the pace of disease progression and death. As such, the use of bone-targeting agents generally would not be expected to affect progression of the underlying cancer outside the bone space.
Examination of efficacy in patient subgroups is of interest and may be facilitated by the greater numbers associated with a combined patient-level analysis. The subgroup analyses support the consistency of the treatment effect of denosumab. As SRE tend to cluster and increase in frequency with disease progression, patients who have already experienced a SRE have a greatly increased risk of subsequent events relative to those who have not. In this exploratory analysis we were able to evaluate for the first time the efficacy of denosumab in these higher-risk patients compared with lower-risk patients who have not experienced a prior SRE, showing that the effect of denosumab versus zoledronic acid was independent of prior SRE status.
This combined analysis provided an opportunity to increase the certainty around the analysis of toxicities associated with RANKL inhibition versus bisphosphonate-induced anti-resorption. The safety profile of denosumab represents an improvement over zoledronic acid as it demonstrates no effect on renal function and can be used in patients without the need to adjust doses or monitor renal status. Renal impairment affects 50–60% of patients with advanced cancer,
Prevalence of Renal Insufficiency in cancer patients and implications for anticancer drug management: the renal insufficiency and anticancer medications (IRMA) study.
and some tumour types, such as prostate cancer, lung cancer and multiple myeloma, are associated with particularly high rates of renal damage due to the nature of the disease itself and/or to the toxicities of commonly used chemotherapies or antibiotics.
Denosumab was associated with a higher incidence of hypocalcaemia, consistent with prior studies, though most cases of hypocalcaemia were asymptomatic and did not require intervention. Patients treated with denosumab or zoledronic acid are recommended to receive oral calcium supplements and vitamin D to reduce the risk for hypocalcaemia. In the three phase 3 trials combined in this analysis, serum calcium was monitored on a monthly basis, thus giving the opportunity for investigators to increase the calcium and vitamin D supplementation in case of hypocalcaemia. Notably, subcutaneous injection of denosumab is not associated with acute-phase reactions,
Randomized phase II trial of denosumab in patients with bone metastases from prostate cancer, breast cancer, or other neoplasms after intravenous bisphosphonates.
Incidence, risk factors, and outcomes of osteonecrosis of the jaw: integrated analysis from three blinded active-controlled phase III trials in cancer patients with bone metastases.
Because of the design of these studies we were unable to collect data on patient preference for either treatment, the impact of subcutaneous versus intravenous administration on patients’ quality of life, or the time required for the different modes of administration. Additionally, we were unable to evaluate denosumab in patients with a baseline creatinine clearance of <30 mL/min as zoledronic acid is not recommended for use in patients with severe renal impairment. Denosumab is not eliminated via the kidneys and therefore can be administered to patients regardless of renal status. As patients with severe renal impairment are at greater risk of hypocalcaemia due to their underlying disease,
electrolyte levels should be monitored carefully in these patients.
In conclusion, RANKL inhibition with denosumab provides a new and better option for prevention of SRE in patients with advanced cancer and bone metastases. Further applications of denosumab may ultimately address a wider range of cancer and bone-related conditions.
Author contributions
Allan Lipton, Karim Fizazi, Alison T. Stopeck, David H. Henry, Janet Brown, Denise A. Yardley, Gary E. Richardson, Salvatore Siena, Pablo Maroto, Michael Clemens, Boris Bilynskyy, Veena Charu, Philippe Beuzeboc, Michael Rader, Maria Viniegra and Fred Saad were study investigators who participated in the collection, review and interpretation of the data, drafting and critical review of the manuscript and final approval of the manuscript for publication in The European Journal of Oncology.
Chunlei Ke is a sponsor employee who participated in the development of the protocol, review and interpretation of the data, drafting and critical review of the manuscript and final approval of the manuscript for publication in The European Journal of Oncology; he also performed the statistical analysis of the data. Ada Braun is a sponsor employee who participated in the review and interpretation of the data, critical review of the manuscript and final approval of the manuscript for publication in The European Journal of Oncology. Susie Jun is a sponsor employee who participated in the development of the protocol, review and interpretation of the data, drafting and critical review of the manuscript and final approval of the manuscript for publication in The European Journal of Oncology.
Conflict of interest statement
Allan Lipton has been a member of the speakers bureau for Amgen, Novartis, Janssen, and Genentech, received research support from Amgen, Novartis, Monogram Biosciences, and the Breast Cancer Alliance, and has provided expert testimony for Novartis.
Karim Fizazi has served as a consultant for and received honoraria from Amgen and Novartis.
Alison T. Stopeck has been a consultant and served as a member of the advisory board for Amgen and Novartis.
David H. Henry has received honoraria from Amgen, OrthoBiotech, and Watson Pharmaceuticals.
Janet E. Brown has been a consultant for Amgen and received honoraria from Amgen, Novartis, and Bristol Myers Squibb.
Denise A. Yardley has no conflicts to disclose.
Gary E. Richardson has received honoraria from Amgen and research funding from Amgen and Novartis.
Salvatore Siena has served as a member of an advisory board for Amgen, AstraZeneca, Roche, Celgene, Merck-Serono, and Fresenius, and received research funding from Amgen, Roche, Wyeth, Merck-Serono, Pfizer, AstraZeneca, Celgene, Fresenius, and Schering-Plough.
Pablo Maroto has served as an investigator for Amgen and as a consultant for Amgen, Bayer, and Pfizer.
Michael Clemens has served as a consultant for Amgen and received research funding from Amgen, AstraZeneca, Novartis, Pfizer, Roche, and Sanofi-Aventis.
Boris Bilynskyy has received research funding from Amgen.
Veena Charu has served as a member of an advisory board for Amgen, Novartis, Roche, Alexion, Pfizer, Celgene and Bristol-Myers Squibb, received travel funds for advisory board meetings, and owns stock with Amgen, Merck, Pfizer, and Bristol-Myers Squibb.
Philippe Beuzeboc has served as a member of an advisory board for Amgen, Aventis, Bayer, Janssen, Novartis, and Roche, and has received payment from Roche for development of educational presentations.
Michael Rader has been a consultant for and received honoraria from Amgen.
Maria Viniegra has received research funding from Amgen.
Fred Saad has been a consultant, received research funding, and served as a member of an advisory board for Amgen and Novartis.
Chunlei Ke, Ada Braun, and Susie Jun are employees of Amgen, and have received stock or stock options.
Acknowledgements
This analysis was sponsored by Amgen Inc., Thousand Oaks, CA. Wanda J. Krall, Ph.D. (consultant funded by Amgen Inc.) and Amy K. Foreman-Wykert, Ph.D. (Amgen Inc.) assisted with manuscript drafting, editing and formatting. We thank the patients, investigators and study staff for participating in the studies comprising this analysis.
References
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Metastasis and bone loss: advancing treatment and prevention.
Payer costs for inpatient treatment of pathologic fracture, surgery to bone, and spinal cord compression among patients with multiple myeloma or bone metastasis secondary to prostate or breast cancer.
Pamidronate reduces skeletal morbidity in women with advanced breast cancer and lytic bone lesions: a randomized, placebo-controlled trial. Protocol 18 Aredia Breast Cancer Study Group.
Zoledronic acid versus pamidronate in the treatment of skeletal metastases in patients with breast cancer or osteolytic lesions of multiple myeloma: a phase III, double-blind, comparative trial.
Zoledronic acid versus placebo in the treatment of skeletal metastases in patients with lung cancer and other solid tumors: a phase III, double-blind, randomized trial – the Zoledronic Acid Lung Cancer and Other Solid Tumors Study Group.
Prevalence of Renal Insufficiency in cancer patients and implications for anticancer drug management: the renal insufficiency and anticancer medications (IRMA) study.
Prostate cancer cells–osteoblast interaction shifts expression of growth/survival-related genes in prostate cancer and reduces expression of osteoprotegerin in osteoblasts.
Expression of osteoprotegerin (OPG), TNF related apoptosis inducing ligand (TRAIL), and receptor activator of nuclear factor kappaB ligand (RANKL) in human breast tumours.
Expression of receptor activator of nuclear factor kappaB ligand on bone marrow plasma cells correlates with osteolytic bone disease in patients with multiple myeloma.
Randomized phase II trial of denosumab in patients with bone metastases from prostate cancer, breast cancer, or other neoplasms after intravenous bisphosphonates.
Denosumab compared with zoledronic acid for the treatment of bone metastases in patients with advanced breast cancer: a randomized, double-blind study.
A randomised, double-blind study of denosumab versus zoledronic acid in the treatment of bone metastases in men with castration-resistant prostate cancer.
A randomized, double-blind study of denosumab versus zoledronic acid in the treatment of bone metastases in patients with advanced cancer (excluding breast and prostate cancer) or multiple myeloma.
Incidence, risk factors, and outcomes of osteonecrosis of the jaw: integrated analysis from three blinded active-controlled phase III trials in cancer patients with bone metastases.
Cost-effectiveness of denosumab vs zoledronic acid for prevention of skeletal-related events in patients with solid tumors and bone metastases in the United States.
Trial Registration: These studies are registered with ClinicalTrials.gov with the identifiers NCT00321464, NCT00321620, and NCT00330759.
Prior Presentation: Portions of these data were previously presented at the 2010 ESMO Congress (October 8–12, 2010, Milan, Italy) and the 2011 EMCC Congress (September 23–27, 2011, Stockholm, Sweden).
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