Management Of Skeletal Complications Research Articles

A phase II, single-arm study of denosumab in multiple myeloma patients with renal insufficiency.

8520 Background: Bone destruction is a devastating consequence of multiple myeloma (MM). An unmet medical need exists for the management of skeletal complications in MM patients with renal insufficiency. Despite the effectiveness of intravenous bisphosphonates, their use is limited in situations where renal dysfunction is present. Denosumab is a fully human monoclonal IgG2 antibody to RANKL that has been shown to be non-inferior to zoledronic acid for SRE rates in MM (Raje, et al. Lancet Oncol). More importantly, it does not have the same renal toxicity as the bisphosphonates. We hypothesize that denosumab can be safely and effectively administered in MM patients with renal insufficiency to improve bone health. This may fill a gap in clinical care for bone-directed therapy in this patient population. Methods: This multi-center study will include forty adult patients with newly diagnosed or relapsed MM with a creatinine clearance of less than 30 mL/min (NCT02833610). All patients will receive a subcutaneous injection of denosumab 120 mg Q4W for a total of 12 cycles. In addition, it is required that all subjects receive daily vitamin D and calcium supplementation at standard doses (at least 2000 mg calcium citrate and1000 IU of vitamin D), unless documented hypercalcemia develops on study. The primary objective is to assess the effect of denosumab 120 mg Q4W on serum c-terminal telopeptide (sCTX). Secondary objectives include evaluation of safety and tolerability of denosumab in patients with renal insufficiency, incidence of hypocalcemia, effect on bone mineral density, effect on urinary n-terminal telopeptide, and proportion of patients who have a documented skeletal-related event. Results: At the time of this analysis, a total of 20 out of a planned 40 patients have been enrolled, including 9 women, 11 men. Of those treated, 8 patients have completed the planned 12 cycles of therapy. Hypocalcemia was observed in 7 (35%) patients. Four patients (20%) experienced grade 3 hypocalcemia, 3 (15%) grade 2 or less. Two patients developed osteonecrosis of the jaw, one (5%) grade 1 and one (5%) grade 4 event. Data for the analysis of the primary endpoint of sCTX levels will be presented. Conclusions: Investigation of denosumab in MM patients with renal insufficiency defined as a creatinine clearance less than 30 mL/min is ongoing. Early data support that denosumab can be safely administered in this population. However, incidence of hypocalcemia despite aggressive prophylactic calcium dosing underscores the importance of the trial to inform safe practice in this more fragile population. Clinical trial information: NCT02833610 .

Skeletal complications in congenital insensitivity to pain with anhidrosis: a case series of 14 patients and review of articles published in Japanese

Background Congenital insensitivity to pain with anhidrosis (CIPA) is a rare disorder with various skeletal complications; thus, a compilation of data on affected patients could provide a valuable resource for the management of this disease. The aim of this study was to ascertain and report the frequency, location, age of onset, cause, and management of skeletal complications in Japanese patients with CIPA.Methods The medical records of 14 CIPA patients in our institute and information on 77 patients reported in Japanese articles were analyzed. Data regarding skeletal-system complications, including location, symptom, major cause and management of fractures, joint dislocations, infections, and Charcot joints, were extracted.Results Fractures occurred in 59/91 patients (65 %), 91 % of them in the lower limbs. Joint dislocations occurred in 27/91 patients (30 %), 91 % of them in the hip joint. Bone and joint infections occurred in 22 patients (24 %) and Charcot joints in 26 patients (29 %); 62 % of infections and 87 % of Charcot joints developed in the lower limbs. Most fractures occurred from 1 to 7 years of age; there was no apparent relationship between age and other complications. The major known causes of bone disorders were minor trauma such as short falls; however, most were of unknown cause. Conservative therapy was used more frequently than surgery to manage fractures, dislocations, and Charcot joints.Conclusions These data show that most CIPA patients have skeletal complications, most of which occur in the lower limbs. Fractures are frequent between 1 and 7 years of age, whereas other bone disorders have no apparent age relationship. The major known causes of bone disorders were minor trauma such as short falls. Conservative therapy was more frequently used to manage fractures, dislocations, and Charcot joints.

Abstract IA02: Tumor plasticity and reactive stroma in breast cancer metastasis

Abstract Metastasis represents the most devastating stage of cancer progression. The multi-step cascade of cancer metastasis is driven by both intrinsic changes of cancer cell properties, as well as the stromal reaction to tumor cells. Epithelial-mesenchymal transition (EMT) is a complex process that is associated with dramatic changes in cell adhesion, polarity, and migratory properties, and is intimately associated both with cell fate transitions during embryonic development and with the acquisition of invasive properties during early steps of cancer metastasis. We found that the transcription factor Elf5, a key regulator of alveologenesis in the mammary gland, regulates EMT in both mammary gland development and metastasis. This specific role for Elf5 in suppressing EMT and metastasis was uncovered via analyses of Elf5 conditional knockout animals, various in vitro and in vivo models of EMT and metastasis, an MMTV-neu transgenic model of mammary gland tumor progression, and clinical breast cancer samples. Furthermore, we demonstrate that this role of Elf5 is mediated by the direct transcriptional repression of Snail2/Slug, a master regulator of mammary stem cells and a known inducer of EMT. These findings establish a broad molecular function of Elf5 that extends from being a key cell lineage regulator during normal mammary gland development to serving as a suppressor of EMT and metastasis in breast cancer. The growth of disseminated tumor cells at distant organs represents a critical final stage of metastasis development. Bone metastasis is a frequent occurrence in breast cancer, affecting more than 70% of late stage cancer patients. Increasing evidence suggest that the development of bone metastasis relies on the positive feedbacks from stromal components of the bone microenvironment. Using in vivo imaging technology, we showed that TGFβ is released from bone matrix upon bone destruction, and signals to breast cancer to further enhance their malignancy in developing bone metastasis. We furthered identified Jagged1 as a TGFβ target genes in tumor cells that engaged bone stromal cells through the activation of Notch signaling to provide a positive feedback to promote tumor growth and to activate osteoclast differentiation. More recently, we identified osteoclast-derived miRNAs as biomarkers and therapeutic targets of osteolytic bone metastasis. Importantly, pharmaceutical inhibitors against TGFβ and Notch signaling pathways and miRNAs blocking osteoclast differentiation significantly reduce the development of bone metastasis, suggesting novel avenues for clinical management of skeletal complications of breast cancer. Citation Format: Yibin Kang. Tumor plasticity and reactive stroma in breast cancer metastasis. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Breast Cancer Research: Genetics, Biology, and Clinical Applications; Oct 3-6, 2013; San Diego, CA. Philadelphia (PA): AACR; Mol Cancer Res 2013;11(10 Suppl):Abstract nr IA02.

Abstract BS1-2: Reactive Stroma as Therapeutic Targets in Breast Cancer Bone Metastasis

Abstract Metastasis represents the most devastating stage of cancer progression. Bone metastasis is a frequent occurrence in breast cancer, affecting more than 70% of late stage cancer patients. Discovering bone metastasis genes that are clinically relevant and functionally important are critical for the development of novel therapeutics for high-risk breast cancer patients. We apply a multidisciplinary approach to analyze the molecular basis of breast cancer bone metastasis, combining functional genomics tools with animal models and clinical analysis of cancer metastasis. Candidate bone metastasis genes were identified from gene expression profiling of highly bone metastatic cells derived after in vivo selection in animal models. Functional characterization of these genes revealed their novel role in mediating tumor-stromal interactions essential for the formation of osteolytic bone metastasis. We discovered a novel metalloprotease-initiated, EGFR-dependent paracrine signaling cascade among tumor cells, osteoblasts and osteoclasts that promotes the maturation of bone-degrading osteoclasts and formation of osteolytic lesions. Using in vivo imaging technology, we showed that TGFbis released from bone matrix upon bone destruction, and signals to breast cancer to further enhance their malignancy in developing bone metastasis. We furthered identified Jagged1 as a TGFb target genes in tumor cells that engaged bone stromal cells through the activation of Notch signaling to provide a positive feedback to promote tumor growth and to activate osteoclast differentiation. More recently, we identified osteoclast-derived miRNAs as biomarkers and therapeutic targets of osteolytic bone metastasis. Importantly, pharmaceutical inhibitors against EGFR, TGFb and Notch signaling pathways and miRNAs blocking osteoclast differentiation significantly reduce the development of bone metastasis, suggesting novel avenues for clinical management of skeletal complications of breast cancer. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr BS1-2.

Role of denosumab in the management of skeletal complications in patients with bone metastases from solid tumors

Skeletal-related events (SREs) including pain, fractures, and hypercalcemia are a major source of morbidity for cancer patients with bone metastases. The receptor activator of NF-κB ligand (RANKL) is a key mediator of osteoclast formation and activity in normal bone physiology as well as cancer-induced bone resorption. The first commercially available drug that specifically targets and inhibits the RANKL pathway is denosumab, a fully human monoclonal antibody that binds and neutralizes RANKL, thereby inhibiting osteoclast function. In this review, we summarize the major studies leading to the US Food and Drug Administration-approval of denosumab for the prevention of SREs in patients with bone metastases from solid tumors. Further, we discuss the role of denosumab in the prevention and treatment of SREs and bone loss in cancer patients. As a monoclonal antibody, denosumab has several advantages over bisphosphonates, including improved efficacy, better tolerability, and the convenience of administration by subcutaneous injection. In addition, as denosumab has no known renal toxicity, it may be the preferred choice over bisphosphonates in patients with baseline renal insufficiency or receiving nephrotoxic therapies. However, other toxicities, including osteonecrosis of the jaw and hypocalcemia, appear to be class effects of agents that potently inhibit osteoclast activity and are associated with both denosumab and bisphosphonate use. The data presented highlight the differences associated with intravenous bisphosphonate and denosumab use as well as confirm the essential role bone-modifying agents play in maintaining the quality of life for patients with bone metastases.

Encounter of cancer cells with bone. Management of bone metastasis arising from prostate cancer

Bone metastases and skeletal complications are major causes of morbidity in prostate cancer patients. Despite an osteoblastic appearance of bone metastases on imaging studies, patients have high osteoclast activity. Current evidence indicates that newer-generation nitrogen-containing bisphosphonates, particularly zoledronic acid, are potent inhibitors of bone resorption via suppression of osteoclast activity. Indeed, zoledronic acid has been reported to significantly decrease the risk of skeletal complications in men with castration-resistant prostate cancer and bone metastases. Additionally, an increased understanding of the pathogenesis of bone metastasis has resulted in the development of several bone-targeted therapies, including a monoclonal antibody targeting the receptor activator of nuclear factor-κB ligand. In this paper, the current state and the future of bone metastases management from prostate cancer are outlined.

Denosumab to Prevent Disease and Treatment-Related Skeletal Complications in Men with Prostate Cancer: Emerging Evidence

Denosumab to Prevent Disease and Treatment-Related Skeletal Complications in Men with Prostate Cancer: Emerging Evidence

Are Fractures Secondary to LHRH Agonist Therapy in Prostate Cancer a Significant Problem?

Are Fractures Secondary to LHRH Agonist Therapy in Prostate Cancer a Significant Problem?

Bone turnover markers as predictive tools for skeletal complications in men with metastatic prostate cancer treated with zoledronic acid

Bone turnover markers are helpful to diagnose bone metastases. The aim of this study was to evaluate the usefulness of these markers in prostate cancer patients with bone metastases before and during the treatment with zoledronic acid as predictive and monitoring tools of skeletal-related events (SRE). One hundred seventeen prostate cancer patients with bone metastases and treated with zoledronic acid (4 mg every 4 weeks) were examined. Fifty-six patients were with and 61 patients without SRE during a 60-week study. Total and bone-specific alkaline phosphatase, and amino-terminal procollagen propeptides of type-I-collagen (PINP), cross-linked N-terminal (NTx), cross-linked C-terminal telopeptides of type-I-collagen (ICTP), and C-terminal telopeptides of type-I-collagen as well as prostate-specific antigen (PSA) were measured before and 12, 24, 36, 48, and 60 weeks after starting treatment. Higher baseline concentrations were observed in the SRE group. The bone markers except for ICTP and tALP decreased to 20-80% of the baseline values at week 12 after the drug administration showing a generally higher decline in the non-SRE group except for NTx. At all time points during treatment higher and increasing concentrations of bone markers were observed in the SRE group compared with non-SRE group. Cox regression models with clinical data and bone markers showed the baseline NTx concentration as predictor of SREs. During the study, percentage changes of PINP and ICTP were most indicative for SREs. Bone markers are useful tools to predict and diagnose SRE in prostate cancer patients with bone metastases under receiving zoledronic acid therapy.

Osteoclast-targeted therapy for metastatic prostate cancer

Bone metastases and skeletal complications are major causes of morbidity in men with prostate cancer. Despite the osteoblastic appearance of bone metastases on imaging studies, patients with bone metastases have elevated markers of bone resorption, indicative of high osteoclast activity. Indeed, increased osteoclast activity is independently associated with higher risk of subsequent skeletal complications. Therapies aimed at reducing osteoclast activity would theoretically diminish disease-related skeletal complications, bone metastases and treatment-related fractures. Phase III clinical trials to address the role of osteoclast-targeted therapy in metastatic prostate cancer are reviewed here. Zoledronic acid, a potent bisphosphonate, significantly decreased the risk of skeletal complications in men with androgen-independent prostate cancer and bone metastases. Ongoing studies will evaluate the use of bisphosphonates or denosumab, a monoclonal antibody that inhibits the receptor activator of nuclear factor-κB ligand signaling in the prevention of bone metastases or skeletal complications. Additional studies are needed to determine the optimal timing, schedule and duration of bisphosphonate treatment in men with bone metastases. The results of these trials in the near future may herald further evolution in the targeting of osteoclasts and optimal supportive care in men with prostate cancer.

Predictors of Skeletal Complications in Men with Hormone-Refractory Metastatic Prostate Cancer

Skeletal complications are a major cause of morbidity in men with hormone-refractory metastatic prostate cancer. These analyses were designed to identify the variables associated with a greater risk of skeletal complications. The 643 subjects in this report were participants in a randomized placebo-controlled trial to evaluate the effects of zoledronic acid on the incidence of skeletal-related events. All subjects had bone metastases and disease progression despite medical or surgical castration. The relationships between the baseline covariates and the time to the first skeletal-related event were assessed by Cox proportional hazard analyses. The serum bone-specific alkaline phosphatase (BAP) and urinary N-telopeptide level was assessed as a representative specific marker of osteoblastic and osteoclastic activity, respectively. The other covariates included in the model were age, cancer duration, Eastern Cooperative Oncology Group performance status, analgesic use, and prostate-specific antigen, hemoglobin, and lactate dehydrogenase levels. Elevated BAP levels were consistently associated with a greater risk of adverse skeletal outcomes. Elevated BAP was significantly associated with a shorter time to the first skeletal-related event on multivariate analyses of the entire study population (relative risk 1.84, 95% confidence interval 1.40 to 2.43; P <0.001) and in subset analyses of the placebo and zoledronic acid groups. Elevated BAP levels were also consistently associated with adverse skeletal outcomes on multivariate analyses of the time to radiotherapy and pathologic fracture, the most common types of skeletal-related events in the study population. No other baseline variable was consistently associated with the risk of adverse skeletal outcomes. The results of our study have shown that elevated serum BAP levels are associated with a greater risk of adverse skeletal outcomes in men with hormone-refractory prostate cancer and bone metastases.

Bisphosphonates for Treatment and Prevention of Bone Metastases

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

Osteoclast-targeted therapy for prostate cancer.

Skeletal complications are a major cause of morbidity in men with metastatic prostate cancer. Bone metastases cause pain, fractures, spinal-cord compression, and ineffective hematopoiesis. Men without bone metastases are also at risk for skeletal complications. Androgen deprivation therapy (ADT), the mainstay of treatment for metastatic prostate cancer and a routine part of the management for many men with nonmetastatic prostate cancer, decreases bone mineral density, and increases fracture risk. Pathological osteoclast activation plays a central role in both disease and treatment-related skeletal morbidity. Bisphosphonates, potent inhibitors of osteoclast activity, are now an important part of the management for many men with prostate cancer. Zoledronic acid, a potent intravenous bisphosphonate, decreases the risk of skeletal complications in men with hormone-refractory prostate cancer and bone metastases. Zoledronic acid and pamidronate preserve bone mineral density in men receiving ADT for nonmetastatic prostate cancer. Ongoing clinical trials will evaluate the role of osteoclast-targeted therapy in other settings including prevention of treatment-related fractures, prevention of bone metastases in men with high-risk nonmetastatic prostate cancer, and prevention of skeletal complications in men with hormone-sensitive metastatic disease.

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.

Continuing benefit of zoledronic acid for the prevention of skeletal complications in men with advanced prostate cancer

4575 Background: We previously reported the efficacy and safety of 4 mg zoledronic acid (Zol) at 15 months compared with placebo in patients with bone metastases from prostate cancer (Saad et al. J Natl Cancer Inst. 2002;94:1458–1468). We report here the results of an exploratory analysis of the 15- to 24-month extension phase of this study to evaluate the benefit of Zol treatment beyond 15 months.Methods: Data were collected during months 15 to 24 for patients who chose to enter the 9-month extension phase. Endpoints included the percentage of patients with a skeletal-related event (SRE), time to first SRE, skeletal morbidity rate (SMR), and multiple event analysis using the method of Andersen and Gill. Results: Of 422 patients randomized to the 4-mg or placebo treatment arms, 147 completed the 15-month core phase, and 133 elected to enter the extension phase. Among these patients, multiple event analysis revealed a 53% reduction in the risk of developing an SRE for patients treated with 4 mg Zol compared with placebo (risk ratio = 0.467; 95% CI = 0.243, 0.897; P = .022). Additionally, only 19% of patients treated with 4 mg Zol had an SRE during the extension phase versus 38% of patients treated with placebo (P = .017). Time to first SRE was significantly extended in the 4–mg Zol group compared with placebo (P = .036), and mean SMR was reduced approximately 2-fold (0.42 for 4 mg Zol versus 0.88 for placebo; P = .016). Conclusions: This exploratory analysis suggests that long-term treatment with Zol provides significant and ongoing clinical benefit in patients with bone metastases from advanced prostate cancer. Considering that patients who have an SRE are also at higher risk for a subsequent SRE, this analysis suggests that patients should continue on bisphosphonate therapy even after they have an SRE. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Novartis Pharmaceuticals Corp. Novartis Pharmaceuticals Corp.

Continuing benefit of zoledronic acid for the prevention of skeletal complications in men with advanced prostate cancer

4575 Background: We previously reported the efficacy and safety of 4 mg zoledronic acid (Zol) at 15 months compared with placebo in patients with bone metastases from prostate cancer (Saad et al. J Natl Cancer Inst. 2002;94:1458–1468). We report here the results of an exploratory analysis of the 15- to 24-month extension phase of this study to evaluate the benefit of Zol treatment beyond 15 months.Methods: Data were collected during months 15 to 24 for patients who chose to enter the 9-month extension phase. Endpoints included the percentage of patients with a skeletal-related event (SRE), time to first SRE, skeletal morbidity rate (SMR), and multiple event analysis using the method of Andersen and Gill. Results: Of 422 patients randomized to the 4-mg or placebo treatment arms, 147 completed the 15-month core phase, and 133 elected to enter the extension phase. Among these patients, multiple event analysis revealed a 53% reduction in the risk of developing an SRE for patients treated with 4 mg Zol compared with placebo (risk ratio = 0.467; 95% CI = 0.243, 0.897; P = .022). Additionally, only 19% of patients treated with 4 mg Zol had an SRE during the extension phase versus 38% of patients treated with placebo (P = .017). Time to first SRE was significantly extended in the 4–mg Zol group compared with placebo (P = .036), and mean SMR was reduced approximately 2-fold (0.42 for 4 mg Zol versus 0.88 for placebo; P = .016). Conclusions: This exploratory analysis suggests that long-term treatment with Zol provides significant and ongoing clinical benefit in patients with bone metastases from advanced prostate cancer. Considering that patients who have an SRE are also at higher risk for a subsequent SRE, this analysis suggests that patients should continue on bisphosphonate therapy even after they have an SRE. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Novartis Pharmaceuticals Corp. Novartis Pharmaceuticals Corp.

Association between androgen deprivation therapy and fracture risk: A population-based cohort study in men with non-metastatic prostate cancer

4507 Background: Androgen deprivation therapy with a gonadotropin-releasing hormone (GnRH) agonist decreases bone mineral density in men with prostate cancer. Small retrospective studies have suggested that GnRH agonists increase fracture risk. We conducted a population-based cohort study to better characterize the association between GnRH agonist treatment and clinical fractures. Methods: Using 1991–2001 medical claims data from a 5% national random sample of Medicare beneficiaries, we identified a study group (N=3887) of men with non-metastatic prostate cancer who initiated GnRH agonist treatment in 1992–94. A comparison group (N=7,774) of men with non-metastatic prostate cancer who did not receive GnRH agonist treatment during the study period was randomly matched on a 1:2 ratio based on age, race and Charlson co-morbidity index. We analyzed their inpatient, outpatient, and physician claims to identify clinical fractures between 1994–2001. Results: One third of the men who received GnRH agonist treatment experienced one or more fractures. When adjusted for survival, the fracture incidence rates during the final year of the analysis were 83% for the study group versus 56% for control group. Men in the study group were significantly more likely to develop fractures over the study period than men in control group (hazard ratio 1.4; 95% CI 1.16–1.70; P<0.001). Longer-term (>3 years) treatment with a GnRH agonist was associated with a marked increase in fracture risk compared to shorter term use (< 1year) (hazard ratio 1.5; 95% CI 1.17–1.93; P<0.001). Conclusion: Non-metastatic prostate cancer patients receiving GnRH agonist treatment were 40% more likely to develop a clinical fracture over the study period relative to those not receiving this treatment. Long-term treatment is associated with higher fracture risk. These results highlight the importance of diagnosis and management of skeletal complications in this population. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Novartis Pharmaceutical Corp. Novartis Oncology Novartis Oncology

Association between androgen deprivation therapy and fracture risk: A population-based cohort study in men with non-metastatic prostate cancer

4507 Background: Androgen deprivation therapy with a gonadotropin-releasing hormone (GnRH) agonist decreases bone mineral density in men with prostate cancer. Small retrospective studies have suggested that GnRH agonists increase fracture risk. We conducted a population-based cohort study to better characterize the association between GnRH agonist treatment and clinical fractures. Methods: Using 1991–2001 medical claims data from a 5% national random sample of Medicare beneficiaries, we identified a study group (N=3887) of men with non-metastatic prostate cancer who initiated GnRH agonist treatment in 1992–94. A comparison group (N=7,774) of men with non-metastatic prostate cancer who did not receive GnRH agonist treatment during the study period was randomly matched on a 1:2 ratio based on age, race and Charlson co-morbidity index. We analyzed their inpatient, outpatient, and physician claims to identify clinical fractures between 1994–2001. Results: One third of the men who received GnRH agonist treatment experienced one or more fractures. When adjusted for survival, the fracture incidence rates during the final year of the analysis were 83% for the study group versus 56% for control group. Men in the study group were significantly more likely to develop fractures over the study period than men in control group (hazard ratio 1.4; 95% CI 1.16–1.70; P<0.001). Longer-term (>3 years) treatment with a GnRH agonist was associated with a marked increase in fracture risk compared to shorter term use (< 1year) (hazard ratio 1.5; 95% CI 1.17–1.93; P<0.001). Conclusion: Non-metastatic prostate cancer patients receiving GnRH agonist treatment were 40% more likely to develop a clinical fracture over the study period relative to those not receiving this treatment. Long-term treatment is associated with higher fracture risk. These results highlight the importance of diagnosis and management of skeletal complications in this population. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Novartis Pharmaceutical Corp. Novartis Oncology Novartis Oncology

COST-EFFECTIVENESS OF ZOLEDRONIC ACID FOR THE PREVENTION OF SKELETAL COMPLICATIONS IN PATIENTS WITH PROSTATE CANCER

We estimated the cost-effectiveness of zoledronic acid vs placebo for decreasing skeletal complications in men with prostate cancer. We performed a cost-effectiveness analysis alongside a multinational clinical trial of zoledronic acid. Cost estimation was based on prospectively collected resource use data for 85.3% of enrolled patients. Cost-effectiveness ratios were based on within-trial data on clinical outcomes, quality of life and study medication cost. Patients receiving zoledronic acid experienced fewer hospital days during a mean followup of 9 months (average 5.6 vs 8.0 days; p = 0.1910). Mean direct costs excluding study medication were US dollars 5365 for patients receiving zoledronic acid and US dollars 5689 for patients receiving placebo, a difference of US dollars 324 (95% CI US dollars 1781 to US dollars 1146). The global average cost of zoledronic acid plus its administration during the trial was US dollars 5677 (US dollars 450 per dose). The nominal cost per skeletal complication avoided was US dollars 112300 (95% CI US dollars 6900 to US dollars 48700) and the cost per additional patient free of skeletal complications was US dollars 51400 (95% CI US dollars 26900 to US dollars 243700). Nominal within-trial cost per quality adjusted life-year was US dollars 159200, which varied widely in sensitivity analyses. The nominal base case estimate of the cost per quality adjusted life-year for zoledronic acid in the prevention of skeletal complications of prostate cancer is consistent with that of bisphosphonates in breast cancer. However, the cost-effectiveness ratios for bisphosphonates are higher than commonly cited thresholds for conferring cost-effectiveness.

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.