Skeletal Events In Patients Research Articles

Circulating and Imaging Biomarkers of Radium-223 Response in Metastatic Castration-Resistant Prostate Cancer.

Radium-223 improves overall survival (OS) and reduces skeletal events in patients with bone metastatic castration-resistant prostate cancer (CRPC), but relevant biomarkers are lacking. We evaluated automated bone scan index (aBSI) and circulating tumor cell (CTC) analyses as potential biomarkers of prognosis and activity. Patients with bone metastatic CRPC were enrolled on a prospective single-arm study of standard radium-223. 99mTc-MDP bone scan images at baseline, 2 months, and 6 months were quantitated using aBSI. CTCs at baseline, 1 month, and 2 months were enumerated and assessed for RNA expression of prostate cancer-specific genes using microfluidic enrichment followed by droplet digital polymerase chain reaction. The median OS was 21.3 months in 22 patients. Lower baseline aBSI and minimal change in aBSI (<+0.7) from baseline to 2 months were each associated with better OS (P = .00341 and P = .0139, respectively). The higher baseline CTC count of ≥5 CTC/7.5 mL was associated with worse OS (median, 10.1 v 32.9 months; P = .00568). CTCs declined at 2 months in four of 15 patients with detectable baseline CTCs. Among individual genes in CTCs, baseline expression of the splice variant AR-V7 was significantly associated with worse OS (hazard ratio, 5.20 [95% CI, 1.657 to 16.31]; P = .00195). Baseline detectable AR-V7, higher aBSI, and CTC count ≥5 CTC/7.5 mL continued to have a significant independent negative impact on OS after controlling for prostate-specific antigen or alkaline phosphatase. Quantitative bone scan assessment with aBSI and CTC analyses are prognostic markers in patients treated with radium-223. AR-V7 expression in CTCs is a particularly promising prognostic biomarker and warrants validation in larger cohorts.

A National Multicenter Study on overall survival in elderly metastatic castrate-resistant prostate cancer patients treated with Radium-223.

Radium-223 prolongs overall survival (OS) and delays time to the first symptomatic skeletal events in patients with symptomatic metastatic castration-resistant prostate cancer (mCRPC). There is a lack of evidence on the safety and efficacy of Radium-223 treatment in the very elderly population. Aim of this multicentre study is to analyze mCRPC patients treated with Radium-223 in terms of OS and to assess whether there are differences between young and elderly, as well as to verify efficacy and safety in patients ≥ 75years of age. 430 mCRPC patients of six Italian Centres were analyzed in this multicenter retrospective study. At baseline and after each cycle were collected clinical and diagnostic patients' parameters. The whole cohort was divided into two groups based on the age of the patients (< 75years old and ≥ 75years old). 47% of the patients were < 75years old and 53% were ≥ 75years old. The primary outcome, OS, does not show significant differences between the two subgroups if other basal parameters are considered. Considering clinical covariates in univariate models (p < 0.05) several clinical aspects have an impact on OS, except for age (p = 0.072). Age continues to have no significant impact on the OS (p = 0.274) even in multivariate models in the two groups. The toxic effects are similar in the two groups. Radium-223 prolongs survival in both younger and older patients at the same baseline condition and is a good option in the symptomatic mCRPC setting compared to other agents.

Bone Mineral Density Changes in Patients with Prostate Cancer Treated with Androgen Deprivation Therapy and External Beam Radiation Therapy: Hip and Spine Comparison

Use of androgen-deprivation therapy (ADT) in high risk prostate cancer (PrCa) improves disease outcomes but decreases bone mineral density (BMD). External beam radiation therapy (RT) has been implicated in bone loss and skeletal events in the hip/pelvis. Little is known about differential BMD changes in skeletal sites over time in men with PrCa treated with long term ADT (LT-ADT) and RT. We hypothesized that there would be a greater decrease in BMD in the hip (RT exposed) than spine (not RT exposed). A retrospective review of men with PrCa treated with LT-ADT and definitive RT was conducted to evaluate BMD changes in the hip and spine. Patients treated from 2004 to 2017 were included if they received >1yr of ADT, pelvic RT as a component of treatment, and had baseline and follow up dual-energy X-ray absorptiometry (DXA) scan(s). ADT included total androgen blockade pre/during RT followed by LHRH agonist alone. Longitudinal comparisons of BMD changes between femoral neck (FN), total hip (TH) and lumbar spine (SP) from start of ADT were performed. Bone loss on DXA was managed as clinically indicated by T-score criteria (normal, osteopenia, osteoporosis). BMD decreases of ≥0.03 g/cm2 and change in T-score criteria were considered significant. FN and TH were contoured on and dosimetry collected from RT plans. A T-test was used to compare changes between sites (with a significance level of p<0.05). The 50 patients included for analysis had a median age of 68 yrs (43-82); duration of ADT of 27.8 mos (14.6-51.3); and follow up of 4.6 yrs (1.7-14.7). Mean doses from RT plans were: right FN 21.9 Gy (9.7-40.3) and TH 20.6 Gy (11.3-34.4), left FN 21.8 Gy (1-34.4) and TH 21.6 Gy (12.6-60.1). DXA scans at yearly timepoints (+/-6mos) were reviewed: n=35 at 1 yr, n=25 at 2 yrs, and n=11 at 3 yrs. Mean BMD declines (g/cm2) at FN, TH, and SP were: -0.026 (2.9%), -0.015 (1.4%), and -0.029 (2.3%) at 1 yr; -0.026 (2.7%), -0.045 (4.2%), and -0.027 (2%) at 2 yrs; and -0.042 (4.1%), -0.047 (4.4%), and -0.096 (7.6%) at 3 yrs. Comparisons of absolute and % BMD changes showed no significant difference in bone loss in FN vs SP or TH vs SP (all p values>0.05). In subsets with decrease in BMD at any site of ≥0.03 g/cm2, there remained no pattern of greater bone loss in FN vs SP (n=45) or TH vs SP (n=48). 21 declines in T-score criteria were observed, more often in spine than hip (9 SP, 6 FN, 6 TH). Of the 9 SP, 5 declined in SP only; and 3 FN and 2 TH declined without change in SP. Pelvic RT + LT-ADT for advanced PrCa was not associated with greater BMD decrease in the FN/TH (RT exposed) versus lumbar SP (not RT exposed). These preliminary results challenge the notion that the primary influence of bone loss and potential skeletal events in patients treated with RT + LT-ADT is due to the contributions of RT when LT-ADT is used; and should be verified prospectively.

Bone metastases in biliary cancers: A multicenter retrospective survey

•Natural history of biliary cancers metastatic to bone•The role of skeletal events in patients with biliary cancer•Biliary cancer and bone metastases: role of bisphosphonates.

Re: Effect of Longer-interval Versus Standard Dosing of Zoledronic Acid on Skeletal Events in Patients with Bone Metastases

Re: Effect of Longer-interval Versus Standard Dosing of Zoledronic Acid on Skeletal Events in Patients with Bone Metastases

Can 12-instead of 4‑weekly zoledronic acid administration reduce skeletal events in patients with bone metastases?

Can 12-instead of 4‑weekly zoledronic acid administration reduce skeletal events in patients with bone metastases?

Effect of Longer-Interval vs Standard Dosing of Zoledronic Acid on Skeletal Events in Patients With Bone Metastases

Zoledronic acid, a third-generation aminobisphosphonate, reduces the incidence of skeletal-related events and pain in patients with bone metastases. The optimal dosing interval for zoledronic acid is uncertain. To determine whether zoledronic acid administered every 12 weeks is noninferior to zoledronic acid administered every 4 weeks. Randomized, open-label clinical trial conducted at 269 academic and community sites in the United States. Patients (n = 1822) with metastatic breast cancer, metastatic prostate cancer, or multiple myeloma who had at least 1 site of bone involvement were enrolled between May 2009 and April 2012; follow-up concluded in April 2014. Patients were randomized to receive zoledronic acid administered intravenously every 4 weeks (n = 911) vs every 12 weeks (n = 911) for 2 years. The primary end point was the proportion of patients having at least 1 skeletal-related event (defined as clinical fracture, spinal cord compression, radiation to bone, or surgery involving bone) within 2 years after randomization and a between-group absolute difference of 7% as the noninferiority margin. Secondary end points included the proportion of patients with at least 1 skeletal-related event by disease type, pain as assessed by the Brief Pain Inventory (range, 0-10; higher scores indicate worse pain), Eastern Cooperative Oncology Group performance status (range, 0-4; higher scores indicate worse disability), incidence of osteonecrosis of the jaw, kidney dysfunction, skeletal morbidity rate (mean number of skeletal-related events per year), and, in a subset of 553 patients, suppression of bone turnover (assessed by C-terminal telopeptide levels). Among 1822 patients who were randomized (median age, 65 years; 980 [53.8%] women; 855 with breast cancer, 689 with prostate cancer, and 278 with multiple myeloma), 795 completed the study at 2 years. A total of 260 patients (29.5%) in the zoledronic acid every 4-week dosing group and 253 patients (28.6%) in the every 12-week dosing group experienced at least 1 skeletal-related event within 2 years of randomization (risk difference of -0.3% [1-sided 95% CI, -4% to ∞]; P < .001 for noninferiority). The proportions of skeletal-related events did not differ significantly between the every 4-week dosing group vs the every 12-week dosing group for patients with breast cancer, prostate cancer, or multiple myeloma. Pain scores, performance status scores, incidence of jaw osteonecrosis, and kidney dysfunction did not differ significantly between the treatment groups. Skeletal morbidity rates were numerically identical in both groups, but bone turnover was greater (C-terminal telopeptide levels were higher) among patients who received zoledronic acid every 12 weeks. Among patients with bone metastases due to breast cancer, prostate cancer, or multiple myeloma, the use of zoledronic acid every 12 weeks compared with the standard dosing interval of every 4 weeks did not result in an increased risk of skeletal events over 2 years. This longer interval may be an acceptable treatment option. clinicaltrials.gov Identifier: NCT00869206.

Zoledronic acid in metastatic osteosarcoma: encouraging progression free survival in four consecutive patients.

BackgroundZoledronic acid (ZA) is a third-generation bisphosphonate in widespread clinical use to reduce pain and skeletal events in patients from a variety of malignancies with bone metastases. Pre-clinical studies indicate that ZA inhibits osteosarcoma through direct anti-proliferative effects, immune activation and anti-angiogenic activity.MethodsThe purpose of this study was to evaluate the antitumor efficacy of ZA at standard dose until progression in patients with stage IV osteosarcoma lacking a standard of care treatment option proven to influence survival. Researchers retrospectively reviewed medical records of all patients at our institution with high-grade osteosarcoma presumed to be incurable due to metastases progressive after primary combination chemotherapy who received single agent ZA in an effort to delay progression.ResultsIn our four-patient cohort following initiation of ZA, the median progression-free survival was 19 months, and median overall survival was 56+ months. Two of four patients have remained progression-free since starting ZA. The other two initially progressed after 18–20 months on ZA followed by metastasectomy of lung or dural metastases and further stability for over a year following resumption of ZA. After a 20-month progression-free interval on ZA alone, one patient had partial response following addition of pazopanib to ZA that likely contributed to long term disease control. The four patients experienced no significant toxicities despite protracted dosing of ZA for up to 5 years, and none have required chemotherapy since beginning ZA.ConclusionsSingle agent ZA was associated with encouraging progression-free survival in four consecutive patients with metastatic osteosarcoma. Prospective trials of single agent ZA are warranted as protracted maintenance therapy in surgically incurable osteosarcoma relapsed or refractory to first line combination chemotherapy with radiographically measurable metastases.

Targeting bone metastases in prostate cancer: improving clinical outcome

Bone metastases develop in most patients with metastatic castration-resistant prostate cancer (mCRPC). They affect the structural integrity of bone, manifesting as pain and skeletal-related events (SREs), and are the primary cause of patient disability, reduced quality of life (QOL) and death. Understanding the pathophysiology of bone metastases resulted in the development of agents that improve clinical outcome, suggesting that managing both the systemic disease and associated bone events is important. Historically, the treatment of CRPC bone metastases with early radiopharmaceuticals and external beam radiation therapy was largely supportive; however, now, zoledronic acid and denosumab are integral to the therapeutic strategy for mCRPC. These agents substantially reduce skeletal morbidity and improve patient QOL. Radium-223 dichloride is the first bone-targeting agent to show improved survival and reduced pain and symptomatic skeletal events in patients with mCRPC without visceral disease. Five other systemic agents are currently approved for use in mCRPC based on their ability to improve survival. These include the cytotoxic drugs docetaxel and cabazitaxel, the hormone-based therapies, abiraterone and enzalutamide, and the immunotherapeutic vaccine sipuleucel-T. Abiraterone and enzalutamide are able to reduce SREs and improve survival in this setting. Novel agents targeting tumour and bone cells are under clinical development.

Effect of radium-223 dichloride on symptomatic skeletal events in patients with castration-resistant prostate cancer and bone metastases: results from a phase 3, double-blind, randomised trial

Bone metastases frequently cause skeletal events in patients with metastatic castration-resistant prostate cancer. Radium-223 dichloride (radium-223) selectively targets bone metastases with high-energy, short-range α-particles. We assessed the effect of radium-223 compared with placebo in patients with castration-resistant prostate cancer and bone metastases. In this phase 3, double-blind, randomised ALSYMPCA trial, we enrolled patients who had symptomatic castration-resistant prostate cancer with two or more bone metastases and no known visceral metastases, who were receiving best standard of care, and had previously either received or were unsuitable for docetaxel. Patients were stratified by previous docetaxel use, baseline total alkaline phosphatase level, and current bisphosphonate use, then randomly assigned (2:1) to receive either six intravenous injections of radium-223 (50 kBq/kg) or matching placebo; one injection was given every 4 weeks. Randomisation was done with an interactive voice response system, taking into account trial stratification factors. Participants and investigators were masked to treatment assignment. The primary endpoint was overall survival, which has been reported previously. Here we report on time to first symptomatic skeletal event, defined as the use of external beam radiation to relieve bone pain, or occurrence of a new symptomatic pathological fracture (vertebral or non-verterbal), or occurence of spinal cord compression, or tumour-related orthopeadic surgical intervention. All events were required to be clinically apparent and were not assessed by periodic radiological review. Statistical analyses of symptomatic skeletal events were based on the intention-to-treat population. The study has been completed and is registered with ClinicalTrials.gov, number NCT00699751. Between June 12, 2008, and Feb 1, 2011, 921 patients were enrolled, of whom 614 (67%) were randomly assigned to receive radium-223 and 307 (33%) placebo. Symptomatic skeletal events occurred in 202 (33%) of 614 patients in the radium-223 group and 116 (38%) of 307 patients in the placebo group. Time to first symptomatic skeletal event was longer with radium-223 than with placebo (median 15·6 months [95% CI 13·5-18·0] vs 9·8 months [7·3-23·7]; hazard ratio [HR]=0·66, 95% CI 0·52-0·83; p=0·00037). The risks of external beam radiation therapy for bone pain (HR 0·67, 95% CI 0·53-0·85) and spinal cord compression (HR=0·52, 95% CI 0·29-0·93) were reduced with radium-233 compared with placebo. Radium-223 treatment did not seem to significantly reduce the risk of symptomatic pathological bone fracture (HR 0·62, 95% CI 0·35-1·09), or the need for tumour-related orthopaedic surgical intervention (HR 0·72, 95% CI 0·28-1·82). Radium-223 should be considered as a treatment option for patients with castration-resistant prostate cancer and symptomatic bone metastases. Algeta and Bayer HealthCare Pharmaceuticals.

869 Prevention of symptomatic skeletal events in patients with genitourinary (GU) tumours and bone metastases treated with denosumab or zoledronic acid

869 Prevention of symptomatic skeletal events in patients with genitourinary (GU) tumours and bone metastases treated with denosumab or zoledronic acid

Denosumab for the prevention of symptomatic skeletal events in patients with castration-resistant advanced prostate cancer: A comparison with skeletal-related events.

35 Background: In a randomized controlled trial of men with castration-resistant prostate cancer (CRPC) and bone metastases, denosumab was superior to zoledronic acid (ZA) for reducing skeletal-related events (SRE, defined as pathological fracture, surgery or radiation to bone [including the use of radioisotopes], or spinal cord compression) (Fizazi, et al. Lancet 2011;377:813-822.). Recently, the composite endpoint of symptomatic skeletal event (SSE, defined as symptomatic fracture, surgery or radiation to bone, or spinal cord compression) was introduced as an alternative term/clinical trial endpoint to describe skeletal morbidity. Methods: Men with CRPC, ≥ 1 bone metastasis, and no prior IV bisphosphonate use received either SC denosumab 120 mg or IV ZA 4 mg (adjusted for creatinine clearance) in a blinded fashion every 4 weeks. Oral calcium and vitamin D supplements were recommended. SSEs included pathologic fractures considered symptomatic by the investigator, spinal cord compression and surgery and radiation to bone. Results: As previously reported, fewer men who received denosumab than ZA had confirmed first SREs, and experienced multiple SREs (Table). Similarly, fewer patients in the denosumab group than the ZA group had confirmed first SSE and multiple SSEs. The median (95% CI) estimate of time to first SSE (superiority analysis) for denosumab was not reached (28.8 mo, not estimable), and for ZA it was 24.2 (20.7, 30.2) mo (HR = 0.78 (0.66, 0.93) P = 0.01). Conclusions: Denosumab reduced the risk of skeletal events in men with CRPC regardless of endpoint definition as SRE or SSE. The risk of developing SSEs was reduced by up to 22% when comparing denosumab with ZA. Clinical trial information: NCT00321620. [Table: see text]

Bone disease in multiple myeloma and precursor disease: novel diagnostic approaches and implications on clinical management

The manifestations of bone involvement in patients with multiple myeloma (MM) can have devastating clinical effects and increase mortality. Recent studies demonstrate that patients with the precursor conditions smoldering MM (SMM) and monoclonal gammopathy of undetermined significance (MGUS) show evidence of bone disease and increased risk of fractures. The understanding of the pathogenesis of bone disease in MM has expanded in recent years. The traditional skeletal survey will probably be replaced by newer and more sensitive imaging techniques, which may have a prognostic impact and change our definition of MGUS and SMM. Bisphosphonates are recommended to prevent skeletal events in patients with MM, and have also been studied in SMM and MGUS. This article summarizes the current knowledge of bone disease in plasma cell disorders, and discusses the current standard and future role of novel imaging techniques, as well as the evidence and current guidelines for bisphosphonates in MM, SMM and MGUS.

First-line treatment with zoledronic acid as compared with clodronic acid in multiple myeloma (MRC Myeloma IX): a randomised controlled trial

SummaryBackgroundBisphosphonates reduce the risk of skeletal events in patients with malignant bone disease, and zoledronic acid has shown potential anticancer effects in preclinical and clinical studies. We aimed to establish whether bisphosphonates can affect clinical outcomes in patients with multiple myeloma.MethodsPatients of age 18 years or older with newly diagnosed multiple myeloma were enrolled from 120 centres in the UK. Computer-generated randomisation sequence was used to allocate patients equally, via an automated telephone service, to receive 4 mg zoledronic acid as an infusion every 3–4 weeks or 1600 mg oral clodronic acid daily. Patients also received intensive or non-intensive induction chemotherapy. No investigators, staff, or patients were masked to treatment allocation, and bisphosphonate and maintenance therapy continued at least until disease progression. The primary endpoints were overall survival, progression-free survival, and overall response rate. We assessed between-group differences with Cox proportional hazards models for progression-free survival and overall survival, and with logistic regression models for overall response rate. Analysis was by intention to treat. This trial is registered, number ISRCTN68454111.Findings1970 patients were enrolled between May, 2003, and November, 2007, of whom 1960 were eligible for intention-to-treat analysis: 981 in the zoledronic acid group (555 on intensive chemotherapy, 426 on non-intensive chemotherapy); and 979 on clodronic acid (556 on intensive chemotherapy, 423 on non-intensive chemotherapy). The treatment cutoff was Oct 5, 2009, with patients receiving bisphosphonates for a median of 350 days (IQR 137–632) before disease progression, with a median of 3·7 years' follow-up (IQR 2·9–4·7). Zoledronic acid reduced mortality by 16% (95% CI 4–26) versus clodronic acid (hazard ratio [HR] 0·84, 95% CI 0·74–0·96; p=0·0118), and extended median overall survival by 5·5 months (50·0 months, IQR 21·0 to not reached vs 44·5 months, IQR 16·5 to not reached; p=0·04). Zoledronic acid also significantly improved progression-free survival by 12% (95% CI 2–20) versus clodronic acid (HR 0·88, 95% CI 0·80–0·98; p=0·0179), and increased median progression-free survival by 2·0 months (19·5 months, IQR 9·0–38·0 vs 17·5 months, IQR 8·5–34·0; p=0·07). Rates of complete, very good partial, or partial response did not differ significantly between the zoledronic acid and clodronic acid groups for patients receiving intensive induction chemotherapy (432 patients [78%] vs 422 [76%]; p=0·43) or non-intensive induction chemotherapy (215 [50%] vs 195 [46%]; p=0·18). Both bisphosphonates were generally well tolerated, with similar occurrence of acute renal failure and treatment-emergent serious adverse events, but zoledronic acid was associated with higher rates of confirmed osteonecrosis of the jaw (35 [4%]) than was clodronic acid (3 [<1%]).InterpretationConsistent with the potential anticancer activity of zoledronic acid, overall survival improved independently of prevention of skeletal-related events, showing that zoledronic acid has treatment benefits beyond bone health. These findings support immediate treatment with zoledronic acid in patients with newly diagnosed multiple myeloma, not only for prevention of skeletal-related events, but also for potential antimyeloma benefits.FundingMedical Research Council (London, UK), with unrestricted educational grants from Novartis, Schering Health Care, Chugai, Pharmion, Celgene, and Ortho Biotech.

Effect of pamidronate 30 mg versus 90 mg on physical function in patients with newly diagnosed multiple myeloma (Nordic Myeloma Study Group): a double-blind, randomised controlled trial

Compared with placebo, prophylactic treatment with bisphosphonates reduces risk of skeletal events in patients with multiple myeloma. However, because of toxicity associated with long-term bisphosphonate treatment, establishing the lowest effective dose is important. This study compared the effect of two doses of pamidronate on health-related quality of life and skeletal morbidity in patients with newly diagnosed multiple myeloma. This double-blind, randomised, phase 3 trial was undertaken at 37 clinics in Denmark, Norway, and Sweden. Patients with multiple myeloma who were starting antimyeloma treatment were randomly assigned in a 1:1 ratio to receive one of two doses of pamidronate (30 mg or 90 mg) given by intravenous infusion once a month for at least 3 years. Randomisation was done by use of a central, computerised minimisation system. Primary outcome was physical function after 12 months estimated by the European Organisation for Research and Treatment of Cancer (EORTC) QLQ-C30 questionnaire (scale 0-100). All patients who returned questionnaires at 12 months and were still on study treatment were included in the analysis of the primary endpoint. This study is registered with ClinicalTrials.gov, number NCT00376883. From January, 2001, until August, 2005, 504 patients were randomly assigned to pamidronate 30 mg or 90 mg (252 in each group). 157 patients in the 90 mg group and 156 in the 30 mg group were included in the primary analysis. Mean physical function at 12 months was 66 points (95% CI 62·9-70·0) in the 90 mg group and 68 points (64·6-71·4) in the 30 mg group (95% CI of difference -6·6 to 3·3; p=0·52). Median time to first skeletal-related event in patients who had such an event was 9·2 months (8·1-10·7) in the 90 mg group and 10·2 months (7·3-14·0) in the 30 mg group (p=0·63). In a retrospective analysis, eight patients in the pamidronate 90 mg group developed osteonecrosis of the jaw compared with two patients in the 30 mg group. Monthly infusion of pamidronate 30 mg should be the recommended dose for prevention of bone disease in patients with multiple myeloma. Nordic Cancer Union and Novartis Healthcare.

Evaluation of variants of the rs1934951 locus of CYP2C8 and bisphosphonate-related osteonecrosis of the jaw in castrate-resistant prostate cancer (CRPC) patients.

9076 Background: Bisphosphonates (BPs) have been shown to prevent or delay skeletal events in patients with bone metastases. The FDA has approved IV zoledronic acid for men with bone metastases fro...

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 [female symbol] / 2 [male symbol]) 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.

Bisphosphonates in oncology: evidence for the prevention of skeletal events in patients with bone metastases

Bone metastases frequently occur in patients with advanced solid tumors, particularly breast and prostate cancers, and nearly all patients with multiple myeloma have some degree of skeletal involvement. The strides made in treating these primary tumors have extended median survival times and thereby increased patient risk for skeletal-related events (SREs), including pathologic fractures, spinal cord compression, need for palliative radiation therapy or surgery to bone, and hypercalcemia. Bisphosphonates, inhibitors of osteoclastic bone resorption that were first established as treatment of osteoporosis, have been shown to prevent and/or delay SREs related to malignancy. The results of a large, randomized phase 3 study comparing zoledronic acid and pamidronate in breast cancer or multiple myeloma patients with osteolytic lesions showed that the incidence of SREs, time to first SRE, and risk of developing a SRE were similar between treatment groups. However, in patients with solid tumors (excluding breast or prostate cancer) metastatic to the bone, only zoledronic acid has demonstrated clinical efficacy. Although bone turnover marker levels, such as N-telopeptide of type I collagen, have been shown to correlate with clinical response, additional studies are needed to validate their ability to predict response to bisphosphonate therapy.

Ibandronate is effective in preventing skeletal events in patients with bone metastases from colorectal cancer

Patients with metastatic colorectal carcinoma (CRC) often develop bone metastases with a high risk of complications. Ibandronate is a novel single-nitrogen bisphosphonate that has been shown to be effective for treating bone metastases from breast cancer. A randomized, placebo-controlled trial was conducted to evaluate the efficacy and safety of ibandronate in patients with bone metastases from CRC. The primary efficacy end point was the proportion of patients with skeletal-related events (defined as pathologic fracture, spinal cord compression, radiation therapy to bone, change in antineoplastic therapy or 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 73 patients with CRC, treatment with intravenous ibandronate 6 mg administered via a 15-min infusion significantly reduced the proportion of patients with skeletal events (39% vs. 78% with placebo; P = 0.019) and prolonged the time to first event by at least 6 months (median >279 vs. 93 days with placebo; P = 0.009). Ibandronate also significantly reduced the skeletal morbidity rate (mean 2.36 vs. 3.14 with placebo; P = 0.018) and prolonged time to progression of bone lesions (214 days vs. 81 days with placebo; P = 0.018). Ibandronate was well tolerated with very rare grade 3 or 4 toxicity. Furthermore, the incidence of renal adverse events was comparable with placebo and there were no clinically relevant changes in serum creatinine. Ibandronate provided significant clinical benefits for patients with bone metastases secondary to CRC. These results indicate that ibandronate may be an effective treatment for patients with metastatic bone disease following CRC. Larger studies are required for further assessment.

Antitumor effect of zoledronic acid in previously untreated patients with multiple myeloma

Bisphophonates are the treatment of choice to prevent skeletal events in patients with multiple myeloma. Some preclinical studies suggested that bisphophonates can be useful as antitumor drugs in some malignancies. We conducted a controlled clinical trial to assess if zoledronic acid can have this clinical activity. Ninety four patients with previously untreated multiple myeloma were treated with a conventional chemotherapy program: cyclophosphamide, vincristine, melphalan, and prednisone (CVMP) and were randomized to received either zoledronic acid (4 mg, iv, every 28 d) or not (control group). The end-point of the present study was to assess improvement in outcome, measured by event-free survival (EFS) and overall survival (OS), and the second-end point was to confirm the efficacy in preventing skeletal events. In an intent-to-treat analysis, all patients were available for efficacy and toxicity. Median follow up was 49.6 mo (range: 34-72 mo). Five year actuarial curves showed that EFS was 80% in the zoledronic acid group, which was statistically different from 52% in the control group (p < 0.01). Actuarial 5 yr OS was 80% in the zoledronic acid arm, and 46% in the control group (p < 0.01). Sketeletal events were more frequent in the control group when compared to zoledronic acid. Toxicity was mild. We confirm the efficacy of zoledronic acid to prevent skeletal events, but we felt that we can demonstrate that zoledronic acid has a clinical antitumor effect measured from a increase in complete response rate and EFS and OS that were better when compared with the control group. We began a controlled clinical trial with modern treatment (including transplant procedures) in combination with zoledronic acid to define the role of zoledonic acid in this setting of patients.