Efficacy and Safety of Intravenous Bisphosphonates in Patients with Bone Metastases Caused by Metastatic Breast Cancer Solid tumors frequently metastasize to bone. This results in debilitating skeletal complications such as intracta-ble bone pain, pathologic fractures, spinal cord compression, and hypercalcemia. Patients frequently require palliative radiation therapy or orthopedic surgery. Bisphosphonates have been shown to delay the incidence and decrease the frequency of skeletal-related events. Zoledronic acid is the only bisphosphonate that has provided benefits for patients with bone metastases secondary to a broad range of solid tumors. Among patients with metastatic breast or prostate cancer, zoledronic acid has demonstrated significant reductions in pain and skeletal morbidity compared with placebo. Zoledronic acid has also shown significant reductions in skeletal morbidity in patients with lung cancer or other solid tumors compared with placebo. Zoledronic acid is generally well tolerated. Flu-like symptoms which are manageable with standard treatment can occur. Renal monitoring is recommended, with dose reductions for patients with renal dysfunction. Osteonecrosis has been reported in patients receiving bisphosphonates and might be avoidable with appropriate dental care. Clinical Breast Cancer, Vol. 7, Suppl. 1, S14-S20, 2007 Key words: Bone mineral density, Multiple myeloma, Radiation therapy, Skeletal-related events
primarily palliative in nature and include radiation therapy According to American Cancer Society estimates, breast (RT), surgery, analgesics, and bisphosphonates. In addition cancer will be diagnosed in 180,510 patients in 2007 and to reducing skeletal complications with bisphosphonate 40,910 patients will die of the disease.1 Approximately 10% therapy, some preclinical evidence suggests potential antitu- of newly diagnosed patients with breast cancer present with locally advanced and/or metastatic disease, and 20%-85% of patients (depending upon initial stage, tumor biology, and Bisphosphonates: Structure and
treatment strategy) diagnosed with early-stage breast can- Mechanism of Action
cer will develop recurrent and/or metastatic disease.2 Bone Various bisphosphonates have been investigated for bone metastases occur in 70% of patients with metastatic breast metastases including clodronate, pamidronate, risedronate, cancer (MBC), and the median survival, after an initial diag- ibandronate, and zoledronic acid. Pamidronate was approved nosis of bone metastases, is 2 years.3,4 in 1996 by the US Food and Drug Administration (FDA) for Bone metastases are associated with severe skeletal com- treatment of bone metastases resulting from multiple myelo- plications that include hypercalcemia, pathologic fractures, ma (MM) and breast cancer, and for hypercalcemia of malig- spinal cord compression, and pain and result in consider- nancy, and Paget’s disease of bone.6 Approved earlier for able morbidity, affecting patient mobility and quality of hypercalcemia of malignancy, zoledronic acid was approved life. Traditional treatments for skeletal complications are in 2002 in the United States for treatment of bone metas-tases caused by MM and solid tumors including MBC, pros- Division of Hematology/Oncology, Department of Medicine, Milton S. Hershey Medical Center, Hershey, PA tate cancer, lung cancer, renal cancer, and colorectal cancer among others, after the benefits were noted.7 Ibandronate Submitted: Oct 31, 2006; Revised: Jun 29, 2007; Accepted: Jul 5, 2007 and clodronate are approved in Europe and Canada for treat- Address for correspondence: Allan Lipton, MD, Milton S. Hershey ment of bone metastases in patients with breast cancer.
Medical Center, PO Box 850 H-46, 500 University Dr, Hershey, PA 17033-0850 Bisphosphonates are stable analogs of pyrophosphonate Fax: 717-531-5076; e-mail: [email protected] that bind to hydroxyapatite on bone and get internalized by Dr Lipton has received research support from Novartis Oncology, Proctor & Gamble, and Pfi zer. He has also served as a paid consultant or been on the Advisory Board of Novartis Oncology, Amgen, Merck, and Monogram Bioscience and been a member of the Speaker’s Bureau for Novartis Oncology and Amgen.
This article includes discussion of investigational and/or unlabeled use of drugs, including clodronate, denosumab, ibandronate, and zoledronic acid for bone metastasis arising from breast cancer; adjuvant clodronate for early-stage breast cancer; zoledronic acid for bone loss reduction from estrogen depletion therapy; and the combination of pamidronate and zoledronic acid for bone metastases arising from multiple myeloma, breast cancer, prostate cancer, or thyroid cancer.
S14 Clinical Breast Cancer Supplement July 2007
osteoclasts, inducing apoptosis in these cells, resulting in a decrease in tumor-induced bone resorption. Bisphosphonates, such as zoledronic acid, with an alkylamine group at the bridging carbon atom between 2 phosphate atoms, are more potent than other phosphonate moi- eties. N-bisphosphonates inhibit the enzyme Relative In Vivo
farnesyl diphosphate synthase in the meval- onate pathway.8 The products downstream of farnesyl diphosphate synthase in the meva- geranyl moieties that are important for the prenylation of signaling molecules, including clinical model systems, N-bisphosphonates reportedly inhibit angiogenesis, cell adhe- sion, and matrix metalloproteinases, and might work synergistically with cytotoxic agents.9-12 Preclinical studies have also com- pared various bisphosphonates on inhibition of farnesyl diphosphate synthase pathway. Inhibition by zoledronic acid was 104-105 times superior to the clodronate group compared with placebo.16 However, the the non–N-bisphosphonates, clodronate and etidronate, 200 incidence of RT was higher in the clodronate group compared times higher than the tertiary amine–containing risedro- with the control group (P = 0.069). No effect was noted on nate, and 10 times higher than the primary amine–contain- progression of bone disease or survival. Clodronate treatment– related side effects leading to treatment discontinuation were nausea and diarrhea. Another study in 137 evaluable patients reported significantly delayed median time to first SRE (244 Efficacy of Bisphosphonates
days versus 180 days for placebo; P = 0.05) with significant in Bone Metastases from Metastatic
reductions in pain intensity (P = 0.01) and analgesics (P = Breast Cancer
0.02) after treatment with oral clodronate (1600 mg per day for Data on Clodronate
up to 12 months) versus placebo.17 There were no significant A double-blind, placebo-controlled trial of oral clo- differences in adverse events between treatment arms.
dronate 1600 mg daily in 173 patients demonstrated significant reduction in the combined rate of all morbid Phase III Trials of Pamidronate
skeletal-related events (SREs) after treatment with clodro- in Breast Cancer
nate versus placebo (218.6 vs. 304.8 per 100 patient-years; The efficacy and safety of pamidronate were established for P < 0.001).14 Treatment with clodronate led to significant bone metastases in breast cancer based on the results from reduction in the total number of hypercalcemic episodes (28 2 large, randomized, multicenter phase III studies with 380 vs. 52; P < 0.01), number of terminal hypercalcemic episodes patients and 372 patients, respectively.18,19 These pivotal phase (7 vs. 17; P < 0.05), incidence of vertebral fractures (84 vs. III studies enrolled patients with stage IV breast cancer who 124 per 100 patient-years; P < 0.025), and rate of vertebral had ≥ 1 predominant osteolytic lesion of ≥ 1 cm in diameter. deformity (168 vs. 252 per 100 patient-years; P < 0.001). Of Treatment consisted of pamidronate 90 mg or placebo admin- note, no significant survival differences between the 2 treat- istered over 2 hours every 4 weeks. The primary endpoint was ment groups were noted. The statistical analysis for this trial proportion of patients who developed an SRE, defined as patho- was criticized for overestimation of treatment effects based logic fracture, spinal cord compression, bone surgery, radiation on the use of events per person per year.15 to treat bone pain, or hypertrophic cardiomyopathy. Two other placebo-controlled trials of clodronate were Both trials separately reported significantly longer median conducted. One trial with 100 evaluable patients, who were time to first SRE (13.1 months vs. 7 months, P = 0.005; 10.4 randomized to receive oral clodronate 800 mg twice daily for months vs. 6.9 months, P = 0.049; Table 2)18-20 and lower 2 years versus placebo, noted a reduction in the number of proportion of patients with skeletal complications (43% vs. SREs (defined as hypertrophic cardiomyopathy, fractures, or 56%, P = 0.008; 56% vs. 67%, P = 0.027) in patients treated RT) after treatment with clodronate (14 of 48 patients vs. with pamidronate compared with placebo. Significant reduc- 21 of 51 patients) coupled with a significantly delayed time tion in bone pain was also reported in the pamidronate group to first SRE (P = 0.015) and fewer fractures (P = 0.023) in Clinical Breast Cancer Supplement July 2007 S15
Intravenous Bisphosphonates in Bone Metastases Caused by MBC Table 2 Placebo-Controlled Phase III Trials of Pamidronate
Table 3 Phase III Trial of Zoledronic Acid Versus Pamidronate
Pamidronate 90 mg vs. Placebo
Zoledronic Acid 4 mg (n = 190)
Pamidronate 90 mg (n = 162)
13.1 Months vs. 7 months; P = 0.005 10.4 Months vs. 6.9 months; P = 0.049 12.7 Months vs. 7 months; P < 0.001 Reduction in Risk of Skeletal Events (HRs)† 2.4 vs. 3.7 SREs/year; P < 0.001 *An additional 176 patients were in the zoledronic acid 8-mg/4-mg group, with 51% having q 1 SRE.
A combined analysis of both trials (N = 752) at 2 years of †Favors zoledronic acid over pamidronate.
follow-up demonstrated that treatment with pamidronate 12-month extension phase (n = 279; 139 patients receiving significantly reduced the mean skeletal morbidity rate (2.4 zoledronic acid 4 mg, 140 receiving pamidronate 90 mg).22 SREs per year vs. 3.7 SREs per year; P < 0.001) and propor- During months 13-25, zoledronic acid further reduced the tion of patients with ≥ 1 SRE (51% vs. 64%; P < 0.001) than percentage of patients with an SRE (20% vs. 29%; P = 0.072), placebo.20 Treatment with pamidronate delayed the onset of and prolonged the time to first SRE (397 days vs. 224 days; SRE by 5.7 months compared with placebo in the patient pop- P = 0.067) compared with pamidronate. The overall reduc- ulation (median time to SRE 12.7 vs. 7 months; P < 0.001). tion in risk of skeletal complications favored zoledronic acid The overall survival (OS) did not differ significantly between over the entire 25-month study (hazard ratio [HR], 0.799; treatment groups in either trial. Pain scores were superior in P = 0.025) and during the 12-month extension phase (HR, patients treated with pamidronate compared with placebo.
0.591; P = 0.026). In addition, zoledronic acid significantly Phase III Trial of Zoledronic Acid Versus
delayed the time to second SRE (P = 0.035) and reduced the Pamidronate in Breast Cancer
risk of developing subsequent SREs (HR, 0.69; P = 0.045).
Zoledronic acid is approved by the FDA for the treatment of bone metastases secondary to breast cancer. In a large phase III Bisphosphonate Therapy for
trial, zoledronic acid was compared directly with pamidronate Early-Stage Breast Cancer
in 1130 patients who had bone metastases caused by breast Adjuvant Studies
cancer.21 Patients were randomized to receive zoledronic acid, Previously, 3 prospective phase III trials investigated the 4 mg or 8 mg as a 15-minute infusion, or pamidronate 90 mg use of clodronate in adjuvant setting with conflicting results. as a 2-hour infusion every 3-4 weeks for 12 months. The pro- Diel and colleagues randomized 302 patients with T1-4 and portion of SREs was similar between arms when all patients N0-2 primary breast cancer to receive treatment with oral were analyzed. However, among the subset of patients with clodronate 1600 mg daily for 2 years and standard follow-up ≥ 1 osteolytic lesion (n = 528) at a median follow-up of 13 with no bisphosphonate therapy.23,24 At a median follow- months, the proportion of patients with SREs was lower in up of 36 months, treatment with clodronate demonstrated the group treated with zoledronic acid (4 mg) than those significantly lower incidence of distant metastasis (13% vs. treated with pamidronate (90 mg; 48% vs. 58%; P = 0.058; 29%; P < 0.001), bone metastasis (8% vs. 17%; P = 0.003), Table 3).21,22 The time to first SRE was significantly prolonged visceral metastasis (8% vs. 19%; P = 0.003), and number of in the zoledronic acid group compared with the pamidronate bony metastases per patient (3.1 vs. 6.3; P = 0.004) compared group (median, 310 days vs. 174 days; P = 0.013). Multiple- with standard follow-up. Of note, patients in the clodronate event analysis demonstrated a 30% greater reduction in the group had a significantly prolonged metastasis-free survival risk of developing SREs with zoledronic acid in the osteolytic (P < 0.001) and OS (P = 0.001).23 The updated data at a subset over that achieved with pamidronate (P = 0.01) and a median follow-up of 53 months in 288 patients demonstrated 20% greater reduction in the risk of developing SREs for all reduction in bone metastases (14% vs. 24%; P = 0.044), a patients with breast cancer (P = 0.037). An extension of this trend toward reduction in visceral metastases (17% vs. 26%; trial was conducted, in which patients who had completed the P = 0.091) coupled with a significantly prolonged OS (91% initial 13-month core phase (n = 454) could elect to enter the vs. 77%; P = 0.002) over control arm.24 S16 Clinical Breast Cancer Supplement July 2007
Table 4 Effect of Prophylactic Zoledronic Acid on Bone Mineral
Table 5 American Society of Clinical Oncology Guidelines for the
Use of Bisphosphonates in Metastatic Breast Cancer31 Zoledronic
Patients demonstrating radiographic evidence of bone metastasis Bone Mineral
P Value
should be initiated on pamidronate 90 mg I.V. over 2 hours Density in LS
or zoledronic acid 4 mg I.V. over 15 minutes every 3-4 weeks.
Patients with an abnormal bone scan and abnormal computed tomography or magnetic resonance imaging showing bone destruction, but normal radiographs, can be started on bisphosphonates.
Patients with only an abnormal bone scan without evidence of bone destruction on radiographs, computed tomography, or magnetic resonance imaging, or those with bone pain only should not be initiated Powles and colleagues randomized 1069 patients with Creatinine levels in patients receiving bisphosphonates should be monitored.
operable breast cancer to receive treatment with clodronate Use of < 2 hours of infusions for pamidronate 1600 mg daily or placebo for 2 years.25 At a median follow-up and <15 minutes for zoledronic acid should be discouraged.
of 5.6 years, patients receiving clodronate had a significant reduction in the occurrence of bone metastases (51 patients vs. 73 patients; HR, 0.692; P = 0.043). This difference in ZO-FAST (Zometa®/Femara® Adjuvant Synergy Trials) favor of clodronate was also observed during the 2-year assessing the impact of zoledronic acid on aromatase inhibi- treatment period (19 patients vs. 35 patients; HR, 0.546; tor–associated bone loss in 1667 postmenopausal women P = 0.031. A significant reduction in mortality was noted in supports the first-line administration of zoledronic acid the clodronate arm over the placebo arm (all patients, HR, versus delayed administration.28 Patients who received 0.768; P = 0.048; stage II/III disease, HR, 0.743; P = 0.041).
first-line zoledronic acid reported a mean bone mineral Saarto and colleagues randomly assigned 299 patients density (BMD) increase compared with mean BMD decline with node-positive breast cancer to receive treatment in the delayed treatment group in the lumbar spine (LS) with clodronate 1600 mg daily or placebo for 3 years.26 All and the hip after 6 months (P < 0.0001 for both sites) and patients received adjuvant therapy depending upon their after 12 months (P < 0.0001 for both sites). In addition, a menopausal status and were followed up for 5 years. The significantly higher percentage of patients experienced a results from this trial were strikingly different from the 2 BMD decrease in the LS of ≥ 8% from baseline at 6 months previous trials and demonstrated significantly worse dis- (P < 0.0001) and at 12 months (P < 0.0001). Results from ease-free survival (56% vs. 71%; P = 0.007) and OS (70% a 24-month analysis of 602 women in the Z-FAST indi- vs. 83%; P = 0.009) in patients treated with clodronate than cated that patients who were given zoledronic acid first- placebo. No significant difference in the occurrence of bone line experienced a 3.06% increase in BMD in the LS and a metastases was noted between the 2 treatment arms (26% 1.37% increase in hip, compared with a decrease of 2.89% vs. 18%; P > 0.05); however, incidence of nonosseous metas- and 3.24%, respectively, in the delayed group (P = 0.001; tases (43% vs. 25%; P = 0.0007) was significantly higher in Table 4).29,30 Similar results were noted in the ABCSG the clodronate arm. The survival data remained statistically (Austrian Breast Cancer Study Group) trial 012, which significant in the multivariate analysis after adjustment for evaluated the effectiveness of zoledronic acid in prevent- prognostic factors such as lymph nodes, tumor size, and hor- ing bone loss in 401 premenopausal women treated with mone receptor status was made. Ten-year follow-up results tamoxifen/goserelin or anastrozole/goserelin.30 At 3-year were consistent, suggesting an increased frequency of metas- follow-up, BMD of the LS was stabilized in patients treated tases to sites other than bone (50% vs. 36%; P = 0.005) on with prophylactic zoledronic acid compared with those who the clodronate arm and lower 10-year disease-free survival did not receive treatment (mean, 14.4%; relative T score, (45% vs. 58%; P = 0.01).27 No significant difference in OS 1.4% standard deviation; P < 0.0001; Table 4). Updated American Society
Studies on Chemotherapy
of Clinical Oncology Guidelines
Treatment–Induced Bone Loss
Patients with early-stage disease are treated with agents on the Use of Bisphosphonates in
like aromatase inhibitors for complete estrogen suppression, Metastatic Breast Cancer
and estrogen depletion results in accelerated bone loss. Updated American Society of Clinical Oncology guidelines This chemotherapy treatment–induced bone loss on the role of bisphosphonates in breast cancer published was addressed in 2 recent trials to study the effects in 2003 indicated a lack of evidence to support the effi- of bisphosphonate therapy in preventing chemotherapy cacy of any one bisphosphonate over the other based on the treatment–induced bone loss in patients with early-stage sample size of 1130 patients in the phase III trial comparing breast cancer. An integrated 12-month analysis of Z-FAST/ zoledronic acid and pamidronate that was chosen to show Clinical Breast Cancer Supplement July 2007 S17
Intravenous Bisphosphonates in Bone Metastases Caused by MBC the equivalence and not the superiority of zoledronic acid bisphosphonates.33 These observations led to the modifica- over pamidronate.31 The recommendations continue to tion in the package inserts for US-approved bisphosphonates advise the use of either US FDA-approved bisphosphonate, (pamidronate and zoledronic acid) advising physicians that pamidronate 90 mg administered intravenously (I.V.) over patients receiving bisphosphonates should avoid invasive 2 hours or zoledronic acid 4 mg I.V. given over 15 minutes every 3-4 weeks, in patients demonstrating radiographic Van Poznak and colleagues reported an analysis of osteo- evidence of bone metastasis (Table 5).31 Patients with an necrosis of jaw specifically in patients with MBC who had abnormal bone scan and an abnormal computed tomography received I.V. bisphosphonates and were treated at Dental or magnetic resonance imaging showing bone destruction, Services of Memorial Sloan Kettering Cancer Center between but normal radiographs, can be started on bisphospho- January 2000 and September 2003.36 Of 934 patients whose nates. Patients with only an abnormal bone scan without charts were reviewed, 64 met the criteria for analysis (MBC, the evidence of bone destruction on radiographs, computed I.V. bisphosphonate, and dental service). Of 64 patients, 6 tomography scans, or magnetic resonance imaging, or those developed osteonecrosis (2 with osteonecrosis of the max- with bone pain only should not be initiated on bisphospho- illa, and 4 with osteonecrosis of the mandible). None of the nate therapy. The American Society of Clinical Oncology patients reported osteonecrosis at both sites. Two patients guidelines reiterated the need to monitor creatinine levels developed spontaneous osteonecrosis, and 4 had osteonecro- in patients receiving bisphosphonates and discouraged the sis after a tooth extraction. Four patients had comorbid dis- use of < 2 hours of infusions for pamidronate and < 15 ease. Management and treatment of osteonecrosis resulted minutes for zoledronic acid. The questions on optimal drug in resolution of osteonecrosis in 1 patient, no change in 1, dosing, route of delivery, duration of therapy, and timing of and progression in 3 patients. One patient died. drug initiation still remain unanswered.
Recently, a retrospective analysis from the University of Texas M. D. Anderson Cancer Center (MDACC) was Safety of Bisphosphonates
undertaken to identify the risk factors and estimate the Renal Toxicity of Intravenous Bisphosphonates
frequency of osteonecrosis of jaw in 4019 patients treated Bisphosphonate therapy is associated with a risk of renal with I.V. bisphosphonates at MDACC from 1996 to 2004 and toxicity, especially at higher doses, or at shorter infusion 6 patients diagnosed with osteonecrosis of jaw at the MDACC durations, resulting in high serum peak levels. In clinical Dental Clinic.37 The preliminary analysis in 4000 patients trials evaluating zoledronic acid, 8-mg treatment arms were included malignancies such as breast cancer (n = 1340), MM discontinued, and the infusion time was increased from 5 min- (n = 550), and lung cancer (n = 380). Common indications utes to 15 minutes, because of renal toxicity. Based on these for bisphosphonate therapy were presence of bone metasta- observations, the modifications in package inserts for both ses (60%), hypercalcemia (25%), MM (14%), and osteoporosis US-approved bisphosphonates for bone metastases require (7%). Thirty-four patients (18 with breast cancer, 14 with testing of patients for renal sufficiency before dosing.6,7 MM, 1 with prostate cancer, and 1 with thyroid cancer) with Renal toxicity of another I.V. bisphosphonate, ibandronate, osteonecrosis of jaw were identified. Bisphosphonate treat- was recently investigated by Bell and colleagues in the phase ments received were pamidronate in 6 patients, zoledronic III trial of ibandronate 2 mg or 6 mg I.V. vs. placebo every 3-4 acid in 10 patients, and a combination of both in 15 patients. weeks in patients with MBC for a total of 4 years.32 After the The mean cumulative doses for pamidronate in MM and initial phase of 2 years, 62 patients elected to continue iban- breast cancer were 2182 mg and 2745 mg, respectively. The dronate treatment at 6 mg I.V. every 3-4 weeks for an addi- respective mean cumulative doses for zoledronic acid were tional 2-year extension phase. Patients receiving ibandronate 61 mg and 62 mg. Of note, total doses of either bisphospho- had a 20% reduction in skeletal morbidity period rate com- nate received were significantly higher in patients who had pared with placebo (1.19 vs. 1.48 periods with events/patient experienced osteonecrosis of jaw than those who did not year; P = 0.004). There was no evidence of renal toxicity in (P < 0.0001). Patients with osteonecrosis of jaw had a longer the first 2 years of the study, and the renal safety profile dur- duration of disease and longer follow-up than non–osteone- ing the 2-year extension period was similar to placebo. crosis of jaw patients (P < 0.0001). Univariate and multi-variate analyses suggested factors such as dental extractions, Is Osteonecrosis of the Jaw a Reality?
presence of estrogen receptor–positive tumors, and bisphos- Risk factors previously identified for osteonecrosis of jaw phonate therapy with pamidronate and/or zoledronic acid were RT, chemotherapy, concomitant steroids, and presence as significant factors associated with osteonecrosis of jaw of comorbid conditions including sinus or dental infections. in patients with breast cancer, whereas dental extractions, The use of I.V. bisphosphonates was the common element periodontal disease, and osteoporosis were significant factors in an increased incidence of osteonecrosis of jaw at 3 dif- in patients with MM. Fifteen patients were followed up for ferent institutions.33-35 Ruggiero and colleagues reviewed > 6 months after treatment with aggressive oral hygiene, 56 patients with osteonecrosis of jaw at Long Island Jewish oral rinses, debridement of necrotic bone and antibiotics; 1 Medical Center, New Hyde Park, NY, and noted that none of patient recovered, 1 showed improvement, 4 were stable, and the patients had received RT; however, all had received I.V. S18 Clinical Breast Cancer Supplement July 2007
Figure 1 Phase III Trial of Ibandronate Versus Zoledronic Acid
Figure 2 Phase III Trial of Zoledronic Acid at 2 Doses Versus
in Metastatic Breast Cancer with Bone Metastases: Placebo in Metastatic Breast Cancer with Bone Abbreviations: CNS = central nervous system; ECOG = Eastern Cooperative Oncology Group; PS = performance status All these studies collectively indicate the need for good Figure 3 Phase IV Trial of Zoledronic Acid at 2 Doses in
oral hygiene coupled with pretherapy dental examination Metastatic Breast Cancer with Bone Metastases: as the most effective way to reduce osteonecrosis of jaw in Ongoing Trials of Bisphosphonates
in Metastatic Breast Cancer
Several larger phase III/IV trials have been initiated to compare 2 bisphosphonates head-to-head for treatment of bone metastases or to assess the best dosage of a bisphospho- therapy every 3-4 weeks for 9-12 infusions nate for optimal patient benefit. A randomized phase III trial of ibandronate versus zoledronic acid is currently recruiting patients with newly diagnosed bone metastases secondary to breast cancer in the United Kingdom (Figure 1).38 Eligible patients will have MBC and newly diagnosed bone metas- Abbreviations: ECOG = Eastern Cooperative Oncology Group; PS = performance status tases within the past 3 months. No brain metastases are allowed. The primary endpoint is efficacy in terms of reduc-ing frequency and timing of SREs. The secondary endpoints tive is annual overall skeletal morbidity rate. The secondary are median time to first SRE, percentage of patients experi- objectives are proportion of patients experiencing SREs, time encing SRE, number of occult vertebral fractures present in to first SRE, annual incidence of any SRE, bone pain, and patients, pain and analgesics score, and quality of life, among analgesic scores. This study will accrue 420 patients. others. The target accrual is 1400 patients.
A US-based phase III study of zoledronic acid will evaluate Novel Inhibitors for Bone Metastases
2 doses of zoledronic acid (every 3 months vs. every 4 weeks) Various other inhibitors targeting the osteoclastic and/or versus placebo in patients with documented bone metastases osteoblastic activity of bone including receptor activator caused by breast cancer (Figure 2).39 Eligible patients should of nuclear factor–κB ligand, src, and cathepsin K are cur- have previously been treated with zoledronic acid for 10-12 rently under investigation for treatment of bone metastases months. The expected enrollment is 1650 patients. The pri- in advanced cancers. We reported the results on denosumab, mary endpoint is time to first SRE. The secondary endpoint a fully human monoclonal antibody to receptor activator of is assessment of continued treatment with zoledronic acid.
nuclear factor–κB ligand, in women with histologically or cyto- A prospective, open-label, phase IV Italian study is currently logically confirmed breast cancer with radiographic evidence accruing patients with MBC and bone metastases to compare of bone metastases.41 No previous therapy with bisphospho- 2 doses of zoledronic acid (every 3 months vs. every 4 weeks) nates was allowed. The primary endpoint of change in urinary beyond 1 year of treatment (Figure 3).40 Eligible patients N-telopeptide level from baseline to week 13 (range, –63% will have histologically confirmed stage IV disease with ≥ 1 to –82% vs. –79%), and secondary endpoint of incidence of radiologically confirmed bone metastasis. They are required first SRE (9% vs. 16%) were comparable after treatment to have previous treatment with zoledronic acid every 3-4 with denosumab and I.V. bisphosphonates. Grade 3/4 adverse weeks for 9-12 infusions for ≤ 15 months. The primary objec- events were similar after respective treatments (28% vs. 33%). Clinical Breast Cancer Supplement July 2007 S19
Intravenous Bisphosphonates in Bone Metastases Caused by MBC No acute phase reactions or injection site reactions were noted Aredia Breast Cancer Study Group. J Clin Oncol 1999; 17:846-854.
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21. Rosen LS, Gordon DH, Dugan W Jr, et al. Zoledronic acid is supe- We have come a long way since the early developmental rior to pamidronate for the treatment of bone metastases in breast carcinoma patients with at least one osteolytic lesion. Cancer 2004; drugs for the treatment of bone metastases in breast cancer. Results from large, ongoing, formal phase III/IV trials will 22. Lipton A, Chen Y. Continuing benefit of zoledronic acid for the pre- vention of skeletal complications in breast cancer patients with bone further assess the long-term efficacy and safety of bisphos- metastases. Breast Cancer Res Treat 2006; 100:S62 (Abstract #1070).
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S20 Clinical Breast Cancer Supplement July 2007

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ARTIKEL HOMEOPATHIE MAGAZINE (OKTOBER 2010) Het is 1992 als bij Mieke Roerig de diagnose MS wordt gesteld. Acht jaar lang verplaatst zij zich met een scootmobiel. Als ze via haar man in aanraking komt met klassiek homeopaat Ton Jansen verandert haar leven. Vanaf het vierde bezoek aan Jansen´s praktijk kan ze weer zonder hulpmiddelen lopen. Ton Jansen, vader van vijf kinderen, is 23 jaar klass

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