Randomized trial of marker-directed versus standard schedule zoledronic acid for bone metastases from breast cancer.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 511-511 ◽  
Author(s):  
Robert Edward Coleman ◽  
Jonathan Wright ◽  
Stephen Houston ◽  
Rajiv Agrawal ◽  
Om Pra-Kash Purohit ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Zoledronic Acid ◽  
Bone Metastases ◽  
Type I Collagen ◽  
Treatment Strategies ◽  
Median Number ◽  
Osteonecrosis Of The Jaw ◽  
Treatment Schedule ◽  
Type I ◽  
Skeletal Related Events

511 Background: Zoledronic acid (ZOL) reduces skeletal morbidity associated with metastatic bone disease by 30-50%. Current recommendations are for indefinite administration of intravenous 3-4 weekly (w) ZOL 4mg. Over recent years it has become clear that the risk of skeletal morbidity is related to the rate of bone resorption. We have compared a marker directed schedule of ZOL (M-ZOL), using measurements of urinary n-telopeptide of type I collagen (NTX), to a standard treatment schedule (S-ZOL) in patients with bone metastases from breast cancer. Methods: The primary endpoint was skeletal related events (SRE). A non-inferiority study was designed with 80% power and (one-sided) 5% alpha to demonstrate that M-ZOL retained 67% of the efficacy of S-ZOL. This required 1500 patients, assuming a SRE rate of 0.7/year. Following minimisation for known prognostic factors, patients were randomised to receive S-ZOL 3-4 w or M-ZOL (15-16w; 8-9 w or 3-4w if NTX levels were <50, 50-100, >100 nmol/mmol creatinine respectively), with the schedule adjusted according to NTX measured every 16 weeks. The study duration was 24 months. Results: Due to lower than expected recruitment, the study closed in 2009 following recruitment of 289 patients. 90% of patients had received >4 cycles of ZOL or pamidronate prior to randomisation. The median number of ZOL infusions administered to S-ZOL patients was >2x that received on M-ZOL. 46 (32%) S-ZOL and 55 (38%) M-ZOL patients experienced an SRE. The numbers of SRE were 94 and 138 in the S-ZOL and M-ZOL arms, with the excess in SRE being largely due to more patients on M-ZOL experiencing ≥2 SRE. Multivariate analysis adjusting for key minimisation factors and baseline NTX for all SRE showed a hazard ratio for M-ZOL vs. S-ZOL of 1.41 (90%CI 0.98-2.02, p=.12). NTX levels were significantly higher at all time points in the M-ZOL treated patients. Osteonecrosis of the jaw was uncommon with 3 cases with S-ZOL and 1 with M-ZOL. Conclusions: The study is underpowered to demonstrate non-inferiority in SRE outcome between the treatment strategies. However, the results suggest that the adjustment of ZOL schedule based on NTX values alone may represent sub-optimal management.

Normalization of bone markers and improved survival during zoledronic acid therapy

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 9013-9013 ◽  
Author(s):  
A. Lipton ◽  
R. Cook ◽  
R. E. Coleman ◽  
P. Major ◽  
E. Terpos ◽  
...  
Keyword(s):  
Zoledronic Acid ◽  
Bone Metastases ◽  
Lower Risk ◽  
Type I Collagen ◽  
Continuous Variable ◽  
Type I ◽  
Acid Therapy ◽  
Relative Risks ◽  
Skeletal Related Events ◽  
Tumor Types

9013 Background: In patients (pts) with bone metastases, elevated N-telopeptide of type I collagen (NTX) levels correlate with increased relative risks (RR) of skeletal-related events (SREs), disease progression, and death (Brown et al. J Natl Cancer Inst. 2005;97:59–69; Coleman et al. J Clin Oncol. 2005;23:4925–4935). Therefore, we conducted an exploratory analysis of 3 large, randomized, controlled trials to investigate whether reductions in NTX levels by treatment with zoledronic acid (ZOL) correspond with decreased risks of SREs and death. Methods: Urinary NTX was measured at baseline and at 3 months in pts with bone metastases from breast (BC; n = 379), prostate (PC; n = 314), or lung cancer and other solid tumors (LC/OST; n = 204) who received ZOL for up to 24 months. Pts were stratified by baseline NTX levels (normal, < 64 nmol/mmol creatinine; elevated, = 64 nmol/mmol creatinine). Results: Approximately 50% of pts had elevated baseline NTX, and NTX normalization occurred within 3 months of ZOL treatment in 81% of pts with BC or LC/OST and in 70% of PC pts. For all tumor types, NTX normalization in response to ZOL correlated with reduced risk of first SRE and death compared with pts whose NTX did not normalize ( Table ). Further analyses using NTX level as a continuous variable revealed that, for all tumor types, any reduction in NTX levels correlated with lower risk of first SRE and death regardless of baseline NTX level. Conclusions: Pts whose NTX normalized on ZOL at 3 months had a lower risk of first SRE and death compared with pts whose elevated baseline NTX did not normalize. Regardless of baseline NTX level, a reduction in NTX over 3 months (absolute and % change) provided a continuum of SRE risk reduction and survival benefit. No significant financial relationships to disclose. [Table: see text]

Bone modifying agents for patients with bone metastases from breast cancer managed in routine practice setting: Treatment patterns and outcome

2019 ◽  
Vol 26 (4) ◽  
pp. 906-911
Author(s):  
Jamal Zekri ◽  
Kamel Farag ◽  
Osama Yousof ◽  
Yazeed Zabani ◽  
Wael Mohamed ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Overall Survival ◽  
Zoledronic Acid ◽  
Bone Metastases ◽  
Treatment Patterns ◽  
Routine Practice ◽  
Related Event ◽  
Modifying Agent ◽  
Skeletal Related Events ◽  
Skeletal Related Event

Introduction Bone metastases are common in patients with breast cancer and can lead to pain and skeletal-related events. Bone modifying agents are licensed to be used for these patients. We report the treatment patterns and outcome of zoledronic acid and denosumab in routine practice. Methodology Women with bone metastases from breast cancer who have started denosumab or zoledronic acid between 2011 and 2016 were eligible. Those with history of bone modifying agent use prior to diagnosis of bone metastases or with switching treatment between zoledronic acid and denosumab were excluded. Details of patients, tumors, bone modifying agent treatment, selected bone modifying agent toxicity, time to skeletal-related event development, and overall survival were collected retrospectively. Results In total, 163 women were eligible and included in this analysis. Number of skeletal-related events prior to starting bone modifying agents was 0, 1, 2, and 3 in 91 (55.8%), 53 (32.5%), 13 (8%), and 6 (3.7%), respectively. Zoledronic acid was started for 107 (65.6%) and denosumab for 56 (34.4%) patients. The proportion of patients receiving denosumab increased from 23.1 to 54.3% in years 2011 and 2016, respectively. Dose delay, reduction, and discontinuation due to toxicity were reported more frequently in patients receiving zoledronic acid. Denosumab delayed time to first on-treatment skeletal-related event compared with zoledronic acid (hazard ratio, 0.64; 95% CI, 0.41–0.98; log rank P = 0.044). There was no significant difference in median survival (zoledronic acid: 62 and denosumab: 58 months; log rank P = 0.956). Conclusion Denosumab is superior to zoledronic acid in reducing risk of skeletal-related events and in tolerance profile. However, overall survival is similar with both treatments. Our findings mirror those reported in scrutinized environment of landmark clinical trials.

Bisphosphonate-induced osteonecrosis of the jaw: Incidence and risk factors in patients with breast cancer and gynecological malignancies

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 1113-1113
Author(s):  
V. Beck ◽  
E. Solomayer ◽  
M. Krimmel ◽  
C. Reinert ◽  
T. Fehm
Keyword(s):  
Breast Cancer ◽  
Risk Factors ◽  
Zoledronic Acid ◽  
Bone Metastases ◽  
Osteonecrosis Of The Jaw ◽  
Bisphosphonate Therapy ◽  
Gynecological Malignancies ◽  
Dental Procedures ◽  
The Mean ◽  
Number Of Treatment

1113 Background: Bisphosphonates are potent inhibitors of osteoclast-mediated bone resorption. They are successfully used in conditions of increased bone turnover such as osteoporosis or bone metastases. Since 2003 multiple cases of bisphosphonate-induced osteonecrosis of the jaw (ONJ) were reported. Our purpose was to describe the incidence and risk factors of ONJ in patients with breast cancer or gynecological malignancies. Patients and Methods: ONJ was assessed retrospectively for all patients with breast cancer or gynecological malignancies treated with bisphosphonates at the Department of Gynecology and Obstetrics, University Hospital Tuebingen during April 1999 until May 2006. Results: 10 of 310 (3%) patients with breast cancer or gynecological malignancies developed ONJ while receiving bisphosphonate therapy. All patients with ONJ were treated for bone metastases. Except one all patients with ONJ had a history of recent dental procedures. All patients had received zoledronic acid as part of their bisphosphonate regimen. In 4 of 10 patients this was the only bisphosphonate given. The remaining 6 patients had received at least one of the other bisphosphonates (alendronate, ibandronate, clodronate or pamidronate) before or after zoledronic acid therapy during their course of disease. Time of exposure to bisphosphonates and the number of treatment cycles were significant risk factors for the development of ONJ (p<0.001). In patients diagnosed with ONJ the mean number of treatment cycles was 27 ±18 cycles (median: 21 cycles, range 6–62 cycles) and the mean duration of bisphosphonate therapy was 29 ±20 months (median: 22 months, range 1–67 months). In contrast, the mean number of treatment cycles in patients without manifestation of ONJ was 11 ±12 cycles (median: 6 cycles, range 1–90 cycles). The mean duration of therapy was 12 months (median: 7 months, range 1–81 months). Conclusion: Osteonecrosis of the jaw is regarded a major side effect of bisphosphonate therapy. Length of exposure to bisphosphonates and the number of treatment cycles seem to be the most important risk factors for the development of ONJ. In addition, recent dental procedures favours the development of an ONJ. No significant financial relationships to disclose.

Osteonecrosis of the jaw (ONJ) in radium 223 (Ra223)-treated metastatic castration-resistant prostate cancer (mCRPC) patients (pts) with exposure to zoledronic acid and/or denosumab.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 5575-5575
Author(s):  
Yen Thi Kim Hong Cao ◽  
Janson Trieu ◽  
Vanessa Rojas ◽  
Michael Elias ◽  
Michael J. Anderson ◽  
...  
Keyword(s):  
Zoledronic Acid ◽  
Bone Metastases ◽  
Data Entry ◽  
Sequential Therapy ◽  
Median Number ◽  
Osteonecrosis Of The Jaw ◽  
Sequential Treatment ◽  
Castration Resistant Prostate Cancer ◽  
Radium 223 ◽  
Sequential Group

5575 Background: Bone health agents (BHA) including denosumab, a monoclonal antibody, and Zoledronic acid (ZA), a bisphosphonate, are recommended for men with CRPC and bone metastases to prevent skeletal-related complications. ONJ occurs in about 5% of patients (pts) on BHA. The incidence of ONJ in pts treated with Ra223 and BHA remains unknown, particularly in those who receive sequential treatment of BHAs. Here we describe the rate of ONJ in a real-world setting in mCRPC pts treated with Ra223 in 3 groups: 1) denosumab alone, 2) ZA alone, and 3) sequential ZA /denosumab or vice versa. Methods: A retrospective analysis of a cohort of mCRPC pts with bone metastases who received Ra223. Follow-up was until date of death or last data entry. Chart inclusion criteria included patients who received Ra223 between November 2010 to August 2018 with documentations of data points. Results: A total of 177 pts received Ra223 between 11/2010 and 8/2018. Median age 73 at 1st Ra223 (range 40-93); Median PSA 15.8- at 1st Ra223 (range 0.1-1952); Demographics-AA-10, C-130, Asian-9, unspecified-28; Median Alk Phos 95 at 1st Ra233 (range 25-1515). 93 % (164/177) received BHA. Of the 164 who received BHA, 45% (73/164) received denosumab only, 37% (61/164) received ZA only, and 18% (30/164) received sequential treatment. ONJ developed in 9.7% (16/164) of all patients on BHA. Denosumab alone caused ONJ in 7 of 73 pts (9.6%). ZA alone caused ONJ in 6 of 61 pts (9.8%). ONJ occurred in 3 of 30 pts (10%) in the sequential group. The median number of doses of BHA before development of ONJ was 10 with denosumab, 20 with ZA, and 19.5 (denosumab) and 22 (ZA) in the sequential group. Conclusions: In patients treated with Ra223 and a BHA, the rate of ONJ is 9.7%. The rate of ONJ was similar in groups treated with denosumab alone, ZA alone, and sequential treatment of ZA and denosumab However, ONJ developed more quickly in patients on denosumab. We conclude that the risk of ONJ is increased in patients treated with Ra223 and BHA. ZA or sequential therapy appears to delay time to onset of ONJ compared to denosumab. Clinicians should be mindful of the toxic synergy between Ra223 and BHA. ZA may be the preferred BHA partner with Ra223.

Osteonecrosis of the jaw associated with intravenous bisphosphonate therapy—A single institution experience

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 18553-18553 ◽  
Author(s):  
E. M. Wallace ◽  
K. I. Quintyne ◽  
B. M. Cantwell ◽  
P. M. Calvert ◽  
G. D. Leonard
Keyword(s):  
Breast Cancer ◽  
Metastatic Breast Cancer ◽  
Zoledronic Acid ◽  
Metastatic Breast ◽  
Median Number ◽  
Osteonecrosis Of The Jaw ◽  
Bisphosphonate Therapy ◽  
Unknown Primary ◽  
Dental Procedures ◽  
Increased Risk

18553 Background: Osteonecrosis of the jaw (ONJ) is a debilitating disease that has been associated with cancer therapy. Recently a link between ONJ and chronic intravenous (IV) bisphosphonates has been suggested. We assessed the incidence of ONJ and its risk factors in patients treated with IV bishosphonates at our institution. Methods: All patients with a cancer diagnosis treated at our institution with at least four cycles of either IV Zoledronic Acid, Pamidronate, or a combination of both, from 2000–2005 were evaluated using outpatient records. Patients with ONJ were identified and their characteristics were compared to all patients receiving bisphosphonate therapy. Results: One hundred and twenty-one patients were evaluated, 36 Male and 85 Female. Median age- 62 (Range 34–85). Seventy-six had metastatic Breast cancer, 25 Prostate, 7 Lung, 3 Colorectal, 3 Renal, 2 unknown primary, 1 each of Penile, Bladder, Seminoma, Lymphoma and Melanoma. Forty patients received Pamidronate infusions alone, 51 Zoledronic Acid alone and 30 a combination of the two. The median number of Pamidronate infusions was 8 (Range 4–10), Zoledronic infusions 10.7 (Range 4–32), and a combination of pamidronate and zoledronic acid was 12 (Range 5–66). Three patients developed ONJ. All 3 patients were female, had a median age of 62 (range 52–74) and had metastatic breast cancer. The median number of bisphosphonate infusions prior to the development of ONJ was 35 (Range 18–47). All patients had chest wall radiotherapy and 1 had chemotherapy and steroids. No patients had dental procedures or prolonged antibacterial therapy. Conclusions: ONJ is a complication associated with IV Bisphosphonate therapy. Our study suggests that female sex, zoledronic acid, and prolonged administration of bisphosphonates, may confer an increased risk for the development of ONJ. Further prospective studies with adequate power are needed to clarify what patients are most at risk for developing ONJ and what measures are needed to prevent its occurrence. No significant financial relationships to disclose.

Cross-linked type I collagen C- and N-telopeptides in women with bone metastases from breast cancer

2001 ◽  
Vol 264 (4) ◽  
pp. 186-190 ◽  
Author(s):  
U. Ulrich ◽  
K. Rhiem ◽  
J. Schmolling ◽  
C. Flaskamp ◽  
I. Paffenholz ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Bone Metastases ◽  
Type I Collagen ◽  
Type I ◽  
C And N

Denosumab Compared With Zoledronic Acid for the Treatment of Bone Metastases in Patients With Advanced Breast Cancer: A Randomized, Double-Blind Study

2010 ◽  
Vol 28 (35) ◽  
pp. 5132-5139 ◽  
Author(s):  
Alison T. Stopeck ◽  
Allan Lipton ◽  
Jean-Jacques Body ◽  
Guenther G. Steger ◽  
Katia Tonkin ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Zoledronic Acid ◽  
Bone Metastases ◽  
Human Monoclonal Antibody ◽  
Randomized Study ◽  
Pathologic Fracture ◽  
Cord Compression ◽  
Osteonecrosis Of The Jaw ◽  
Double Blind Study ◽  
Double Blind

Purpose This randomized study compared denosumab, a fully human monoclonal antibody against receptor activator of nuclear factor κ B (RANK) ligand, with zoledronic acid in delaying or preventing skeletal-related events (SREs) in patients with breast cancer with bone metastases. Patients and Methods Patients were randomly assigned to receive either subcutaneous denosumab 120 mg and intravenous placebo (n = 1,026) or intravenous zoledronic acid 4 mg adjusted for creatinine clearance and subcutaneous placebo (n = 1,020) every 4 weeks. All patients were strongly recommended to take daily calcium and vitamin D supplements. The primary end point was time to first on-study SRE (defined as pathologic fracture, radiation or surgery to bone, or spinal cord compression). Results Denosumab was superior to zoledronic acid in delaying time to first on-study SRE (hazard ratio, 0.82; 95% CI, 0.71 to 0.95; P = .01 superiority) and time to first and subsequent (multiple) on-study SREs (rate ratio, 0.77; 95% CI, 0.66 to 0.89; P = .001). Reduction in bone turnover markers was greater with denosumab. Overall survival, disease progression, and rates of adverse events (AEs) and serious AEs were similar between groups. An excess of renal AEs and acute-phase reactions occurred with zoledronic acid; hypocalcemia occurred more frequently with denosumab. Osteonecrosis of the jaw occurred infrequently (2.0%, denosumab; 1.4%, zoledronic acid; P = .39). Conclusion Denosumab was superior to zoledronic acid in delaying or preventing SREs in patients with breast cancer metastatic to bone and was generally well tolerated. With the convenience of a subcutaneous injection and no requirement for renal monitoring, denosumab represents a potential treatment option for patients with bone metastases.

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