Approval summary for zoledronic acid for treatment of multiple myeloma and cancer bone metastases.

PURPOSE: This article summarizes data submitted to the United States Food and Drug Administration for marketing approval of zoledronic acid (Zol; Novartis Pharmaceuticals, East Hanover, NJ), a bisphosphonate drug for treating patients with bone metastases. Experimental Design: We review the chemistry, toxicology, pharmacology, and clinical study results submitted to support the supplemental New Drug Application for Zol for treatment of patients with bone metastases. Four- and 8-mg Zol doses were selected for Phase III trials based on bone resorption markers and clinical efficacy parameters. Patients with bone metastases were randomized in three Phase III studies (prostate cancer, solid tumors, and multiple myeloma or breast cancer) to receive 4 or 8 mg of Zol or to a control arm. The control was a placebo in the prostate cancer study and the other solid tumor study and was 90 mg of pamidronate (Pam) in the study of breast cancer and multiple myeloma. Studies were amended twice because of renal toxicity, initially to increase Zol infusion time from 5 to 15 min and later to decrease the dose in the Zol 8-mg arm to 4 mg. The efficacy end point was skeletal-related events (SREs), a composite end point consisting of pathologic fracture, radiation therapy to bone, changes in antineoplastic therapy for bone pain (prostate cancer only), surgery to bone, or spinal cord compression. This end point was analyzed either as the proportion of patients with SRE or time to first SRE. The breast cancer and myeloma study used a noninferiority statistical analysis methods to determine efficacy. RESULTS: In prostate cancer, both the proportions analysis and time-to-SRE analysis showed significantly less bone morbidity on Zol (4 mg) than placebo, but no significant difference between Zol (8 mg) and placebo in either analysis. In the solid tumor study, the time to SRE analysis but not the proportions analysis showed significantly less skeletal morbidity on Zol (4 mg) than placebo, and Zol (8 mg) was significantly better than placebo in both analyses. The breast cancer and myeloma study demonstrated noninferiority of Zol compared with Pam, with Zol retaining at least 49.3% of the Pam treatment effect previously demonstrated in placebo-controlled trials. Zol was approved on February 22, 2002, by the United States Food and Drug Administration for the "treatment of patients with multiple myeloma and documented bone metastases from solid tumors, in conjunction with standard antineoplastic therapy. Prostate cancer should have progressed after treatment with at least one hormonal therapy." The recommended dose and schedule is 4 mg of Zol infused over 15 min every 3-4 weeks. Increased Zol doses and shorter infusions are not recommended because of potential renal toxicity.     

Efficacy and safety of intravenous bisphosphonates for patients with breast cancer metastatic to bone: a review of randomized, double-blind, phase III trials

Intravenous bisphosphonates are the preferred treatment to prevent skeletal complications for patients with breast cancer and bone metastases. Pamidronate, a single-nitrogen bisphosphonate, was the early standard of care for such patients based on 2 large, placebo-controlled trials involving 754 patients. Zoledronic acid, a new-generation bisphosphonate containing 2 nitrogens, was evaluated in 1130 patients with breast cancer in a large, randomized, comparative, phase III trial with pamidronate. At 25 months, zoledronic acid (4 mg) significantly reduced the overall risk of developing a skeletal-related event (SRE) by an additional 20% versus 90 mg pamidronate by multiple-event analysis. Furthermore, zoledronic acid was at least as effective as pamidronate in reducing the proportion of patients with > or = 1 SRE and in delaying the onset of SREs. Moreover, a retrospective subset analysis of 352 patients with > or = 1 osteolytic lesion proved zoledronic acid more effective than pamidronate in reducing the risk and delaying the onset of SREs. Intravenous ibandronate (6 mg via 1-2-hour infusion) was evaluated in a placebo-controlled, phase III trial of 466 patients and was significantly more effective than placebo in reducing the number of 12-week treatment periods in which an SRE occurred. The safety profiles among all intravenous bisphosphonates were similar; patients treated with intravenous bisphosphonates reported notably less bone pain but a higher incidence of mild to moderate transient infusion-related adverse events (eg, nausea, vomiting, myalgia, and anorexia) compared with placebo. In summary, intravenous bisphosphonates are effective for the treatment of bone metastases in patients with breast cancer and have similar safety profiles, but the shorter infusion time and greater efficacy of zoledronic acid in reducing overall skeletal morbidity provide advantages over other available agents.     

双膦酸盐联合化疗治疗多发性骨髓瘤骨并发症的临床观察

 目的　比较唑来膦酸联合化疗及伊班膦酸联合化疗预防和治疗多发性骨髓瘤（MM）骨并发症的效果及其安全性。方法　选择2005年3月至2008年3月中山大学附属第一医院治疗的MM患者77例,按照用药情况分为唑来膦酸联合化疗组24例,伊班膦酸联合化疗组26例,单纯化疗组27例。结果　唑来膦酸联合化疗组、伊班膦酸联合化疗组和单纯化疗组患者发生1次骨相关事件（SRE）的比例分别为25.0 ％、26.9 ％、48.1 ％（P＝0.145）。唑来膦酸联合化疗组、伊班膦酸联合化疗组发生脊柱压缩性骨折（VCF）的比例分别为4.2 ％和7.7 ％,少于单纯化疗组的14.8 ％（P＝0.115）。三组的中位首次发生SRE时间（T-SRE）分别为7.5、6.5和4.5个月（P＜0.001）。唑来膦酸联合化疗组止痛有效率为66.7 ％,伊班膦酸联合化疗组有效率为69.2 ％,单纯化疗组为29.6 %,差异有统计学意义（P＝0.028）。唑来膦酸联合化疗组治疗后的血钙水平低于伊班膦酸联合化疗组（P＝0.016）,降至正常水平所需时间也较伊班膦酸联合化疗组短（P＝0.04）。唑来膦酸联合化疗组和伊班膦酸联合化疗组的不良反应发生率低,两组不良反应发生率差异无统计学意义（P＞0.05）。结论　应用双膦酸盐可减少MM患者SRE的发生率和VCF。唑来膦酸在减少VCF发生率、减轻骨痛上与伊班膦酸类似,优于单纯化疗组;唑来膦酸在降低血钙水平方面优于伊班膦酸。唑来膦酸临床应用不良反应少,患者均可耐受。     

双膦酸盐联合化疗治疗多发性骨髓瘤骨并发症的临床观察

目的 比较唑来膦酸联合化疗及伊班膦酸联合化疗预防和治疗多发性骨髓瘤(MM)骨并发症的效果及其安全性.方法 选择2005年3月至2008年3月中山大学附属第一医院治疗的MM患者77例,按照用药情况分为唑来膦酸联合化疗组24例,伊班膦酸联合化疗组26例.单纯化疗组27例.结果唑来膦酸联合化疗组、伊班膦酸联合化疗组和单纯化疗组患者发生1次骨相关事件(SRE)的比例分别为25.0%、26.9%、48.1%(P=0.145).唑来膦酸联合化疗组、伊班膦酸联合化疗组发生脊柱压缩性骨折(VCF)的比例分别为4.2%和7.7%,少于单纯化疗组的14.8%(P=0.115).三组的中位首次发生SRE时间(T-SRE)分别为7.5、6.5和4.5个月(P＜0.001).唑来瞵酸联合化疗组止痛有效率为66.7%,伊班膦酸联合化疗组有效率为69.2%,单纯化疗组为29.6%,差异有统计学意义(P=0.028).唑来膦酸联合化疗组治疗后的血钙水平低于伊班膦酸联合化疗组(P=0.016),降至正常水平所需时间也较伊班膦酸联合化疗组短(P=0.04).唑来膦酸联合化疗组和伊班瞵酸联合化疗组的不良反应发牛率低,两组不良反应发生率差异无统计学意义(P＞0.05).结论 应用双瞵酸盐可减少MM患者SRE的发生率和VCF.唑来膦酸在减少VCF发生率、减轻骨痛上与伊班膦酸类似,优于单纯化疗组;唑来膦酸在降低血钙水平方面优于伊班膦酸.唑来膦酸临床应用不良反应少.患者均可耐受.     

Long-term efficacy and safety of zoledronic acid compared with pamidronate disodium in the treatment of skeletal complications in patients with advanced multiple myeloma or breast carcinoma: a randomized, double-blind, multicenter, comparative trial

BACKGROUND: The goal of the current study was to compare the long-term (25-month) safety and efficacy of zoledronic acid with pamidronate in patients with bone lesions secondary to advanced breast carcinoma or multiple myeloma. METHODS: Patients (n = 1648) were randomized to receive 4 mg or 8 mg (reduced to 4 mg) zoledronic acid as a 15-minute infusion or to receive 90 mg pamidronate as a 2-hour infusion every 3-4 weeks for 24 months. The primary endpoint was the proportion of patients with at least 1 skeletal-related event (SRE), defined as pathologic fracture, spinal cord compression, radiation therapy, or surgery to bone. Secondary analyses included time to first SRE, skeletal morbidity rate, and multiple-event analysis. Hypercalcemia of malignancy (HCM) was included as an SRE in some secondary analyses. RESULTS: After 25 months of follow-up, zoledronic acid reduced the overall proportion of patients with an SRE and reduced the skeletal morbidity rate similar to pamidronate. Compared with pamidronate, zoledronic acid (4 mg) reduced the overall risk of developing skeletal complications (including HCM) by an additional 16% (P = 0.030). In patients with breast carcinoma, zoledronic acid (4 mg) was significantly more effective than pamidronate, reducing the risk of SREs by an additional 20% (P = 0.025) compared with pamidronate and by an additional 30% in patients receiving hormonal therapy (P = 0.009). Zoledronic acid (4 mg) and pamidronate were tolerated equally well. The most common adverse events included bone pain, nausea, and fatigue. CONCLUSIONS: Long-term follow-up data confirm that zoledronic acid was more effective than pamidronate in reducing the risk of skeletal complications in patients with bone metastases from breast carcinoma and was of similar efficacy in patients with multiple myeloma.     

A phase II trial evaluating the palliative benefit of second-line oral ibandronate in breast cancer patients with either a skeletal related event (SRE) or progressive bone metastases (BM) despite standard bisphosphonate (BP) therapy

Background Despite bisphosphonate treatment, most patients with metastatic breast cancer will have either progressive bone metastases or skeletal related events (SREs). We evaluated the impact of second-line ibandronate on pain control and markers of bone turnover in these patients. Methods Patients with either an SRE or bony progression while on clodronate or intravenous (IV) pamidronate were switched to oral ibandronate 50 mg daily for 12 weeks. Pain scores and urinary N-telopeptide were evaluated weekly for 4 weeks and at weeks 8 and 12. There was no change in systemic anti-cancer treatment in the month before or after commencing study treatment. Palliative response was defined as a ≥ two-unit reduction in the worst pain score. Patient preferences between IV and oral bisphosphonate therapy were assessed. Results Thirty women completed the study. By week 12, patients experienced a significant improvement in pain control (OR = 0.41; P = 0.028) with 12 of 26 (46.2%) evaluable patients achieving a palliative response. Of the 23 patients who had received first-line IV pamidronate, 20 of 23 (87.0%) preferred oral therapy. Conclusion Patients with either progressive bone metastases or SREs while on clodronate or pamidronate may experience significant pain palliation with a switch to a more potent bisphosphonate. If confirmed by randomized trials, clinicians can start moving away from the paradigm whereby patients remain on a single bisphosphonate regimen throughout the course of their disease.     

Efficacy of ibandronate for the treatment of skeletal events in patients with metastatic breast cancer

Patients with breast carcinoma often develop bone metastases that carry a high risk of complications. A randomized, placebo-controlled trial was conducted to evaluate the efficacy and safety of ibandronate in patients with metastatic bone disease following breast cancer. The primary efficacy end point of the study was the proportion of patients who developed skeletal-related events (SREs, defined as pathologic fracture, spinal cord compression, radiation therapy to bone, change in anti-neoplastic therapy and surgery to bone). Secondary end points included time to first skeletal event, skeletal morbidity rate (events/year) and time to progression of bone lesions. In 150 patients (148♀/2♂) with breast carcinoma and bone metastases, treatment with intravenous ibandronate 6 mg over 15 min every 4 weeks for 24 months significantly reduced the proportion of patients who experienced an SRE compared with placebo (36% vs. 48%; P  = 0.027). Time to first SRE was also delayed significantly (median 457 vs. 304 days; P  = 0.007). Multiple event analysis showed that ibandronate reduced the risk of developing an SRE by 32% (hazard ratio = 0.69; 95% confidence interval 0.42–0.79; P  = 0.003). In general, ibandronate was well tolerated with very rare grade 3 or 4 toxicity. In this study, ibandronate was shown to be significantly more effective than placebo as a treatment for metastatic bone disease from breast cancer using multiple end points.     

Clinical benefit of zoledronic acid in patients with lung cancer and other solid tumors: analysis based on history of skeletal complications

The results of a retrospective exploratory analysis of a phase III trial of zoledronic acid in patients with bone metastases secondary to lung cancer or other solid tumors are reported herein to assess the risk of skeletal-related events (SREs) and the efficacy of 4 mg zoledronic acid compared with placebo. The study is based on patient SRE history before study entry. Patients were stratified based on SRE history (eg, pathologic fracture, spinal cord compression, radiation therapy or surgery to bone, or hypercalcemia) before study entry, and SRE incidence over 21 months was analyzed. Of 507 patients randomized to 4 mg zoledronic acid or placebo, 131 completed the 9-month core phase and 69 entered the 12-month extension phase. Before study entry, 347 of 503 patients who were evaluable for efficacy (69%) experienced >/= 1 SRE; these patients had a higher risk of developing an SRE on study than patients with no prior SRE (odds ratio, 1.41). Among patients with an SRE before study entry, zoledronic acid reduced the risk of SREs by 31% (P = 0.009), reduced the mean skeletal morbidity rate (1.96 vs. 2.81 SREs per year for placebo; P = 0.030), and prolonged the median time to first SRE by nearly 4 months (215 days vs. 106 days for placebo; P = 0.011). Among patients with no SRE before study entry (n = 156), zoledronic acid reduced the risk of SREs by 23% (P = 0.308), reduced the mean skeletal morbidity rate (1.34 vs. 2.53 SREs per year for placebo; P = 0.332), and prolonged the median time to first SRE by 2.5 months (P = 0.534). This exploratory analysis demonstrates that patients with a history of SREs are at high risk for subsequent SREs, but zoledronic acid reduces skeletal morbidity regardless of SRE history.     

Zoledronic acid and survival in breast cancer patients with bone metastases and elevated markers of osteoclast activity

OBJECTIVE: Most breast cancer patients with bone metastases will receive bisphosphonate treatment. This post hoc analysis investigated whether early normalization of urinary N-telopeptide of type I collagen (NTX) levels during bisphosphonate therapy correlates with a long-term reduction in skeletal-related event (SRE) risk and mortality in patients with breast cancer. METHODS: This was a retrospective subset analysis of a phase III randomized trial comparing i.v. zoledronic acid with pamidronate treatment in patients with bone metastases from breast cancer or multiple myeloma. Patients with breast cancer who had NTX assessments at baseline and at months 1 and 3 (n = 342) were classified as normal (NTX < 64 nmol/mmol creatinine) or elevated (NTX > or = 64 nmol/mmol creatinine). The relative risk for an SRE or death was estimated with Cox regression models. RESULTS: Among the 328 evaluable patients treated with zoledronic acid, 196 patients (59.7%) had elevated baseline NTX, with 149 of those patients (76.0%) having normalized NTX levels and 31 patients (15.8%) having persistently elevated NTX levels at 3 months. The normalized NTX group had significantly lower risks for a first SRE, a first fracture or surgery to bone, or death than the group that had persistently elevated NTX levels. CONCLUSIONS: These results suggest that early normalization of elevated baseline NTX while receiving zoledronic acid is associated with longer event-free and overall survival times compared with persistently elevated NTX. Further analyses in cancer patients with elevated marker levels are warranted to confirm the implications of these findings.     

The cost of treatment of skeletal-related events in patients with bone metastases from lung cancer

PURPOSE: Patients with bone metastases from lung cancer often experience skeletal-related events (SREs) including pathological fracture, spinal cord compression, hypercalcemia or pain requiring surgery, radiotherapy or opioid analgesics. These complications result in impaired mobility and reduced quality of life and have a significant negative impact on survival. The economic consequences of SREs in patients with lung cancer have not been examined. METHODS: We conducted a retrospective analysis using a large US health insurance claims database to estimate the incidence and costs of treatment of SREs in patients with bone metastases of lung cancer treated in a naturalistic setting. Study subjects had >/=2 encounters with a diagnosis of primary lung cancer and >/=2 encounters with a diagnosis of metastases to bone. SREs were identified based on the occurrence on or after the date of first diagnosis of bone metastases, of (1) >/=1 encounter with a diagnosis of pathological fracture, spinal cord compression or hypercalcemia, (2) >/=1 bone surgery or radiotherapy procedure, or (3) the initiation of opioid analgesic therapy. Survival and costs of SRE-related care in patients with SREs were estimated using Kaplan-Meier methods. RESULTS: We identified 534 patients with lung cancer and bone metastases, including 295 (55%) with >/=1 SRE. Radiotherapy (68%) and fracture (35%) were the most common SREs. Median survival after the first identified SRE was 4.1 months (95% confidence interval: 3.6-5.5 months). The estimated lifetime SRE-related cost per patient was USD 11,979 (95% confidence interval: USD 10,193-13,766). Radiotherapy accounted for the greatest proportion of cost (61%) by SRE type. CONCLUSION: The economic burden of SREs in patients with bone metastases of lung cancer is substantial. Intravenous bisphosphonates, such as zoledronic acid, which have been shown to prevent these events, may reduce these costs.     

Denosumab for the prevention of skeletal complications in metastatic castration-resistant prostate cancer: comparison of skeletal-related events and symptomatic skeletal events

In this analysis of a phase III trial in patients with castration-resistant prostate cancer and bone metastases, treatment with denosumab reduced the risk of skeletal complications vs zoledronic acid regardless of whether the end point was defined as SSE or SRE. Both SSEs and SREs were associated with development of moderate/severe pain among patients with no/mild pain at baseline.BackgroundIn a phase III trial in patients with castration-resistant prostate cancer (CRPC) and bone metastases, denosumab was superior to zoledronic acid in reducing skeletal-related events (SREs; radiation to bone, pathologic fracture, surgery to bone, or spinal cord compression). This study reassessed the efficacy of denosumab using symptomatic skeletal events (SSEs) as a prespecified exploratory end point.Patients and methodsPatients with CRPC, no previous bisphosphonate exposure, and radiographic evidence of bone metastasis were randomized to subcutaneous denosumab 120 mg plus i.v. placebo every 4 weeks (Q4W), or i.v. zoledronic acid 4 mg plus subcutaneous placebo Q4W during the blinded treatment phase. SSEs were defined as radiation to bone, symptomatic pathologic fracture, surgery to bone, or symptomatic spinal cord compression. The relationship between SSE or SRE and time to moderate/severe pain was assessed using the Brief Pain Inventory Short Form.ResultsTreatment with denosumab significantly reduced the risk of developing first SSE [HR, 0.78; 95% confidence interval (CI) 0.66–0.93; P = 0.005] and first and subsequent SSEs (rate ratio, 0.78; 95% CI 0.65–0.92; P = 0.004) compared with zoledronic acid. The treatment differences in the number of patients with SSEs or SREs were similar (n = 48 and n = 45, respectively). Among patients with no/mild pain at baseline, both SSEs and SREs were associated with moderate/severe pain development (P < 0.0001). Fewer patients had skeletal complications, particularly fractures, when defined as SSE versus SRE.ConclusionIn patients with CRPC and bone metastases, denosumab reduced the risk of skeletal complications versus zoledronic acid regardless of whether the end point was defined as SSE or SRE.     

Efficacy and safety of zoledronic acid in patients with breast cancer metastatic to bone: a multicenter clinical trial

PURPOSE: This study evaluated the efficacy and safety of zoledronic acid in breast cancer patients with newly diagnosed bone metastases. MATERIALS AND METHODS: Patients diagnosed with bone metastases < or = 6 weeks prior to first visit were enrolled. Zoledronic acid (4 mg) was administered via a 15-minute infusion every 3 or 4 weeks for 12 infusions. Skeletal-related events (SREs) were defined as pathologic bone fractures, spinal cord compression, surgery to bone, radiation therapy to bone, and hypercalcemia of malignancy. Primary efficacy end points were the proportion of patients with at least one SRE and the time to first SRE. Secondary end points included pain, analgesic use, and quality of life. RESULTS: Among 312 patients enrolled, 30% experienced at least one SRE during the 12-month study, and 22% experienced only one SRE. The median time to first SRE was not reached in the intent-to-treat population. Mean pain and analgesic scores declined from baseline, and quality-of-life scores remained stable to study end. The most frequently reported adverse events, regardless of relationship to study drug, were pyrexia (22%) and bone pain (10%). Serum creatinine levels did not significantly increase from baseline throughout the study. CONCLUSIONS: Breast cancer patients with newly diagnosed bone metastases who were treated with zoledronic acid had a low incidence of SREs compared with patients who received placebo in randomized phase III trials, and pain was decreased from baseline. This study demonstrated the favorable risk:benefit ratio of zoledronic acid for the prevention of skeletal complications.     

Optimizing skeletal‐related events prevention in patients with advanced prostate cancer

In patients with metastatic castration‐resistant prostate cancer (mCRPC), bone is a dominant site of metastasis. Bone metastases often lead to skeletal‐related events (SREs), which include pain, spinal cord compression and fractures. The treatment of bone metastases in men with mCRPC aims to improve SRE‐free survival, quality of life and clinical outcomes. Effective treatment options include antiresorptive bone‐targeted agents such as zoledronic acid and denosumab, and radium‐223, a bone‐targeting radiopharmaceutical. Although overseas and local guidelines have widely recommended using either zoledronic acid or denosumab for the prevention of SREs in men with mCRPC and associated bone metastases, current evidence suggests that denosumab is superior to zoledronic acid in terms of longer SRE‐free time and fewer total SREs observed in patients.     

Combined analysis of two multicenter, randomized, placebo-controlled studies of pamidronate disodium for the palliation of bone pain in men with metastatic prostate cancer.

PURPOSE: Bone metastases occur in approximately 80% of patients with advanced prostate cancer. Pain is common in these patients. The purpose of this study was to evaluate the effect of an intravenous bisphosphonate, pamidronate disodium, on pain control in metastatic prostate cancer patients. PATIENTS AND METHODS: Two multicenter, double-blind, randomized, placebo-controlled trials were conducted in patients with bone pain due to metastatic prostate cancer, with disease progression after first-line hormonal therapy. Intravenous pamidronate disodium (90 mg) or placebo was administered every 3 weeks for 27 weeks. Efficacy was measured via self-reported pain score (Brief Pain Inventory), analgesic use, the proportion of patients with a skeletal-related event (SRE; defined as pathologic fracture, radiation or surgery to bone, spinal cord compression, or hypercalcemia), and a pilot quantitative measurement of mobility. Laboratory evaluations included serum prostate-specific antigen, interleukin-6, bone alkaline phosphatase, and urinary bone resorption markers. RESULTS: Results of the two trials were pooled. There were no sustained significant differences between the pamidronate and placebo groups in self-reported pain measurements, analgesic use, proportion of patients with an SRE, or mobility at week 9 or 27. Urinary bone resorption markers were suppressed in the pamidronate group compared with placebo. CONCLUSION: Pamidronate disodium failed to demonstrate a significant overall treatment benefit compared with placebo in palliation of bone pain or reduction of SREs. Evaluation of more potent bisphosphonates in patients with prostate cancer is warranted.     

Prevention and Treatment of Myeloma Bone Disease

Osteolytic bone disease is the most common complication of multiple myeloma, resulting in skeletal-related events (SREs) that cause significant morbidity. Bone destruction in myeloma is due to an increased activity of osteoclasts coupled with suppressed bone formation by osteoblasts. Currently, bisphosphonates are the mainstay of the treatment of myeloma bone disease. Zoledronic acid and pamidronate have shown similar efficacy in reducing SREs in a randomized study in the conventional chemotherapy era. However, in a recent study (the Myeloma-IX trial of the UK Medical Research Council, MRC), zoledronic acid was found to be superior to clodronate in reducing SREs, but also it produced a survival advantage of approximately 10?months in patients with bone disease at baseline. During recent years, novel agents targeting bone have been used in myeloma. This review focuses on the established therapy of myeloma bone disease and also on recent advances in treatment that take advantage of the better understanding of the pathophysiology of bone disease.     

Prognostic factors for skeletal complications from metastatic bone disease in breast cancer

Skeletal morbidity is common in patients with bone metastases from breast cancer (BC) and can undermine patients’ functional independence and quality of life. Previously defined prognostic factors may not reflect current treatment standards and the use of antiresorptive therapies. We report a comprehensive multivariate analysis of potential prognostic factors for skeletal-related events (SREs) using data from a phase III, randomized study of zoledronic acid in patients with bone metastases from BC. The trial evaluated the number and timing of SREs (pathologic fracture, palliative radiotherapy to bone, surgery to bone to treat or prevent a fracture, and spinal cord compression) and assessed variables for prognostic significance in univariate and multivariate Cox-regression analyses. Continuous variables were categorized with predefined cutpoints. All associations with P < 0.05 were considered significant. A total of 444 zoledronic acid-treated patients with assessments of biochemical markers of bone metabolism and complete baseline variable data were included. Significant baseline prognostic factors for occurrence of a first SRE by multivariate analyses included age, pain score, prior history of an SRE, predominant lesion type, elevated bone-specific alkaline phosphatase, and lactate dehydrogenase. Prior fracture was found to be prognostic in a reduced multivariate analysis of time to first fracture, but not for time to first palliative radiotherapy. In conclusion, this model identified several prognostic factors that may be useful in routine clinical care. Validation of these factors in a separate dataset and generation of a prognostic risk score are recommended next steps.     

Spotlight on Zoledronic Acid in the Management of Bone Metastases and Hypercalcemia of Malignancy

Zoledronic acid (Zometa®) is an effective inhibitor of osteoclast-mediated bone resorption. Zoledronic acid demonstrated efficacy in the reduction of skeletal-related events (SREs) in patients with multiple myeloma or bone metastases secondary to breast cancer, prostate cancer or other solid tumors, or hypercalcemia of malignancy. Zoledronic acid was effective in patients with multiple myeloma or metastatic breast cancer with osteolytic or mixed bone lesions. The proportion of patients who experienced an SRE was similar during 12 months of treatment with zoledronic acid 4mg or pamidronic acid 90mg, but significantly fewer patients receiving zoledronic acid required radiotherapy to bone. Furthermore, in patients with breast cancer and osteolytic lesions, median time to a first SRE was more than 4 months longer with zoledronic acid than with pamidronic acid. In the multiple event analysis in a 12-month extension study (total study duration was 25 months) in patients with breast cancer, zoledronic acid was superior to pamidronic acid, with an 18% reduction in the risk of experiencing an SRE. Both drugs were associated with a slight reduction in pain. Zoledronic acid 4mg, compared with placebo, significantly reduced the proportion of patients with prostate cancer bone metastases experiencing an SRE, particularly pathological fractures, after 15 months’ treatment. The drug also significantly delayed the onset of skeletal complications compared with placebo in patients with prostate cancer or other solid tumors including non-small cell lung cancer. When administered as a single 15-minute intravenous infusion, zoledronic acid 4mg was significantly more effective than pamidronic acid administered as a 2-hour infusion in the treatment of severe hypercalcemia of malignancy, as assessed by complete responses measuring normalized serum calcium concentrations at day 10 after a single dose. Furthermore, zoledronic acid normalized serum calcium concentrations significantly faster than pamidronic acid, and the duration of response and median time to relapse were approximately twice as long in zoledronic acid recipients than in pamidronic acid recipients. Zoledronic acid is well tolerated and has a similar tolerability profile to pamidronic acid. The most commonly reported adverse events included flu-like symptoms (fever, arthralgias, myalgias, and bone pain), fatigue, gastrointestinal reactions, anemia, weakness, dyspnea, and edema. Conclusion: In conjunction with antitumor therapy, zoledronic acid should be considered for routine use to reduce skeletal complications in patients with advanced malignancies involving bone. In patients with hypercalcemia of malignancy, zoledronic acid is expected to become the treatment of choice.     

A multicenter,retrospective epidemiologic survey of the clinical features and management of bone metastatic disease in China

Background: Bone metastases are common in patients with advanced cancer. Bisphosphonates (BPs) could prevent or delay the development of skeleton-related events (SREs). The present study aimed to identify the clinical features of and treatment strategies for Chinese patients with bone metastases. Methods: Consecutive cancer patients who had bone metastases and received BP treatment were enrolled. A ques-tionnaire was developed to collect the patients’clinical data, as well as information on the diagnosis and manage-ment of bone metastases. Physicians’awareness of the guidelines and knowledge of the application of BP were also assessed. Results: A total of 3223 patients with lung cancer (36.5%), breast cancer (30.9%), prostate cancer (8.5%), and gas-trointestinal cancer (5.7%) were included in this study. The sites of bone metastases were the thoracic spine (56.0 %), lumbar spine (47.1%), ribs (32.6%), and pelvis (23.2%). The SRE frequency was the highest in patients with multiple myeloma (36.6%), followed by those with lung cancer (25.9%), breast cancer (20.2%), prostate cancer (18.2%), and gas-trointestinal cancer (17.3%). Irradiation to the bone was the most frequent SRE (58% in lung cancer patients, 45% in breast cancer patients, and 48% in prostate cancer patients). Our survey also showed that 45.5% of patients received BP within 3 months after their diagnosis of bone metastases, whereas the remaining 54.5% of patients did not receive BP treatment until at least 3 months after their diagnosis of bone metastases. The SRE frequency in the former group was significantly lower than that in the latter group (4.0% vs. 42.3%, P < 0.05). In patients with more than 6 months of continuous BP treatment, the mean time to the first SRE was significantly longer than that in patients with less than 6 months of continuous BP treatment (7.2 vs. 3.4 months, P < 0.05). In addition, 12.2% of the physicians were not aware of the efcacy of BP in preventing and delaying SRE. Only half (52.3%) of the physicians agreed that the BP treatment should persist for at least 6 months unless it was intolerable. Conclusions: Our study suggested that prompt and persistent BP treatment was associated with a reduced risk of SREs. However, our survey also revealed that the proper application of BP was not as common as expected in China.     

Continuing benefit of zoledronic acid in preventing skeletal complications in patients with bone metastases

PURPOSE: We previously reported the efficacy of zoledronic acid 4 mg versus placebo (every 3 weeks for 24 months) for the prevention of skeletal-related events (SREs) in men with advanced prostate cancer and bone metastases. We conducted several retrospective exploratory analyses to determine whether zoledronic acid has continuing efficacy during long-term treatment. PATIENTS AND METHODS: This report included analysis of the occurrence of SREs during the extension phase only (months 16-24), analysis of skeletal complications excluding the first SRE at 15 months (core phase), and stratified analysis of patients by history of SREs before study entry. RESULTS: Patients (N=422) were randomized to receive zoledronic acid 4 mg or placebo. For the 132 patients who entered the extension phase, zoledronic acid significantly delayed the onset of first SRE (P=.009) and decreased the risk of developing an SRE by 53% compared with placebo (P=.022). Among all 422 patients, zoledronic acid significantly reduced the incidence of a second on-study SRE (P=.017) and significantly delayed the median time to second SRE compared with placebo (P=.006) at 15 months. Among 144 patients (34%) with a history of SREs before study entry, zoledronic acid significantly reduced the skeletal morbidity rate by 65% (P=.036) and reduced the overall risk of developing an SRE by 40% (P=.028) compared with placebo at 24 months. CONCLUSION: This analysis confirms our previously reported results and suggests that long-term treatment with zoledronic acid provides continuing clinical benefit in patients with advanced prostate cancer, even after the occurrence of SREs.     

双膦酸盐类药物治疗骨髓瘤骨病的临床研究

 目的 总结双膦酸盐类药物对我国多发性骨髓瘤患者骨病的疗效及其意义。方法 采用历史同期对照研究分析1995年2月至2007年12月205例多发性骨髓瘤患者,比较应用双膦酸盐类药物组（简称用药组）和未用双膦酸盐类药物组（简称未用药组）患者骨骼事件的发生率,骨病改善的程度,并分析此类药物的应用对预后的影响。结果 骨骼事件发生率用药组低于未用药组[38.9%(35/90)比54.8%(63/115)]（P＜0.01）,用药组发生第一次骨事件时间及发生第一次病理性骨折的时间均明显长于未用药组[（34.7±3.2）个月比（27.5±3.2）个月,（47.2±3.6）个月比（42.7±5.0）个月]（均P＜0.05）。分层分析上述时间,MP/M2及VAD/DVD为主的方案组中用药组发生第一次骨骼事件的时间均明显长于未用药组[（59.4±5.6）个月比（30.1±4.0）个月,（29.0±4.0）个月比（22.4±4.7）个月]（P=0.024,P=0.043）。治疗6周期后不同治疗组评价骨髓瘤骨病（MBD）的治疗反应,用药组有效+显效者比例明显高于未用药组[80.0%（64/80）比48.7%（37/76）]（P<0.001）;高钙血症治疗的有效率分别为100%（70/70）、98.3%（59/60）,二者差异无统计学意义（P=0.278）。治疗6周期后用药组骨痛缓解有效+显效者的比例及ECOG评分≤2分者比例均显著高于未用药组[83.9%（73/87）比63.2%（55/87）（P=0.001）;80.0%（68/85）比53.5%（46/86）]（P=0.001;P＜0.001）。治疗6周期后,用药组骨髓浆细胞比例明显低于未用药组[（10.5±6.5）%比（19.2±3.5）%]（P=0.025）,而其他反映肿瘤负荷的指标差异无明显统计学（均P 0.05）。90例用药组中双膦酸盐类药物不良反应轻微,常见不良反应包括胃肠道反应3例（3.3%）、发热1例（1.1%）、皮疹2例（2.2%）。应用双膦酸盐不影响总体生存时间[（39.4±4.2）个月比（36.2±2.9）个月]（P=0.580）。结论 双膦酸盐可有效降低骨骼事件的发生率,延长第一次骨骼事件及病理性骨折的发生时间。双膦酸盐可明显改善MBD治疗反应、ECOG评分,缓解骨骼疼痛,从而提高生存质量。双膦酸盐的应用不能延长患者的总体生存时间。