Oral daily ibandronate: an effective and convenient therapy for skeletal complications in metastatic breast cancer

Bisphosphonate therapy reduces the relative risk of skeletal-related events in metastatic bone disease and is widely used in the long-term management of this condition. The efficacy of oral ibandronate, a third-generation high potency aminobisphosphonate, has been evaluated in patients with bone metastases from breast cancer. In a phase III trial (MF 4434), daily treatment with ibandronate 50 mg over 96 weeks significantly reduced the number of 12-week periods with new bone complications (the skeletal morbidity period rate [SMPR]) compared with placebo (P=0.037). These results were supported by a protocol-specified pooled analysis of this trial and another study of identical design (MF 4414), which demonstrated that overall SMPR and SMPR for bone radiotherapy were significantly reduced versus placebo (P=0.004). The pooled analysis also revealed that oral ibandronate rapidly reduced and maintained bone pain below baseline over 2 years of treatment (P=0.001 versus placebo) and significantly improved patient quality of life (P=0.03). Oral ibandronate is therefore an effective bisphosphonate for the management of metastatic bone disease, and offers a convenient alternative to intravenous (i.v.) bisphosphonate therapy.     

Intravenous ibandronate reduces the incidence of skeletal complications in patients with breast cancer and bone metastases.

BACKGROUND: This phase III study compared the efficacy of the new potent bisphosphonate, ibandronate, with placebo as intravenous (i.v.) therapy in metastatic bone disease due to breast cancer. PATIENTS AND METHODS: A total of 466 patients were randomised to receive placebo (n = 158), or 2 mg (n = 154) or 6 mg (n = 154) ibandronate every 3-4 weeks for up to 2 years. The primary efficacy parameter was the number of 12-week periods with new bone complications, expressed as the skeletal morbidity period rate (SMPR). Bone pain, analgesic use and safety were evaluated monthly. Results SMPR was lower in both ibandronate groups compared with the placebo group; the difference was statistically significant for the ibandronate 6 mg group (P = 0.004 versus placebo). Consistent with the SMPR, ibandronate 6 mg significantly reduced the number of new bone events (by 38%) and increased time to first new bone event. Patients on ibandronate 6 mg also experienced decreased bone pain scores and analgesic use. Treatment with ibandronate was well tolerated. CONCLUSIONS: These results indicate that 6 mg i.v. ibandronate is effective and safe in the treatment of bone metastases from breast cancer.     

Oral ibandronate reduces the risk of skeletal complications in breast cancer patients with metastatic bone disease: results from two randomised, placebo-controlled phase III studies

Although intravenous (i.v.) bisphosphonates are the standard of care for metastatic bone disease, they are less than ideal for many patients due to infusion-related adverse events (AEs), an increased risk of renal toxicity and the inconvenience of regular hospital visits. The use of oral bisphosphonate therapy is limited by concerns over efficacy and gastrointestinal (GI) side effects. There remains a clinical need for an oral bisphosphonate that offers equivalent efficacy to i.v. bisphosphonates, good tolerability and dosing convenience. Oral ibandronate, a highly potent, third-generation aminobisphosphonate, has been evaluated in phase III clinical trials of patients with bone metastases from breast cancer. In two pooled phase III studies, patients with breast cancer and bone metastases were randomised to receive oral ibandronate 50 mg (n=287) or placebo (n=277) once daily for up to 96 weeks. The primary end point was the skeletal morbidity period rate (SMPR), defined as the number of 12-week periods with new skeletal complications. Multivariate Poisson's regression analysis was used to assess the relative risk of skeletal-related events in each treatment group during the study period. Oral ibandronate 50 mg significantly reduced the mean SMPR compared with placebo (0.95 vs 1.18, P=0.004). There was a significant reduction in the mean number of events requiring radiotherapy (0.73 vs 0.98, P<0.001) and events requiring surgery (0.47 vs 0.53, P=0.037). Poisson's regression analysis confirmed that oral ibandronate significantly reduced the risk of a skeletal event compared with placebo (hazard ratio 0.62, 95% CI=0.48, 0.79; P=0.0001). The incidence of mild treatment-related upper GI AEs was slightly higher in the oral ibandronate 50 mg group compared with placebo, but very few serious drug-related AEs were reported. Oral ibandronate 50 mg is an effective, well-tolerated and convenient treatment for the prevention of skeletal complications of metastatic bone disease.     

Oral ibandronate for the treatment of metastatic bone disease in breast cancer: efficacy and safety results from a randomized, double-blind, placebo-controlled trial.

BACKGROUND: We report the first results of a randomized trial assessing a new oral aminobisphosphonate, ibandronate, in patients with bone metastases from breast cancer. PATIENTS AND METHODS: Patients (n = 435) received placebo, or oral ibandronate 20 mg or 50 mg once-daily for 96 weeks. The primary efficacy measure was the number of 12-week periods with new bone complications [skeletal morbidity period rate (SMPR)]. Multivariate Poisson regression analysis assessed the relative risk reduction of skeletal-related events. Secondary efficacy analyses included bone pain and analgesic use. Adverse events were monitored. RESULTS: SMPR was significantly reduced with oral ibandronate [placebo 1.2, 20 mg group 0.97 (P = 0.024), 50 mg group 0.98 (P = 0.037)]. Ibandronate 50 mg significantly reduced the need for radiotherapy (P = 0.005 versus placebo). The relative risk of skeletal events was reduced by 38% (20 mg dose) and 39% (50 mg dose) versus placebo (P = 0.009 and P = 0.005). The tolerability profile of ibandronate was similar to placebo. CONCLUSIONS: Oral ibandronate is an effective and well-tolerated treatment for metastatic bone disease. The 50 mg dose is being further evaluated in clinical trials, and this dose was recently approved in the European Union for the prevention of skeletal events in patients with breast cancer and bone metastases.     

伊班膦酸钠治疗恶性肿瘤骨转移临床评价

蔓伊班膦酸钠为三代含氮双磷酸盐，已被临床应用于治疗恶性肿瘤骨转移及继发的骨相关事件。伊班膦酸钠同时具有口服和静脉两种剂型，临床试验证实二者均能有效降低骨相关事件的发生率、减轻骨转移所致骨痛的程度、改善骨转移病人的生活质量。在安全性评价方面，伊班膦酸钠具有突出的肾脏安全性，即使采用负荷剂量仍然表现出良好的耐受性。本篇综述主要介绍伊班膦酸钠在治疗骨转移瘤方面的有效性和安全性。     

Improved quality of life after long-term treatment with the bisphosphonate ibandronate in patients with metastatic bone disease due to breast cancer

Bone metastases occur in most women with advanced breast cancer and can lead to considerable morbidity and a rapid deterioration in the patient's quality of life. It was the aim of the present study to assess changes in quality of life and bone pain due to intravenous (i.v.) ibandronate, a potent third-generation bisphosphonate. In a phase III randomised, double-blind, placebo-controlled trial in patients with bone metastases due to breast cancer, 466 women were randomised to receive placebo, 2 mg ibandronate or 6 mg ibandronate for up to 96 weeks. Treatment was administered i.v. at 3- or 4-weekly intervals. Clinical endpoints included the incidence of adverse events, quality of life (assessed using the European Organisation for the Research and Treatment of Cancer (EORTC) Quality of Life Scale - Core 30 questionnaire (QLQ-C30)), and bone pain (assessed on a 5-point scale from 0=none to 4=intolerable). Ibandronate was generally well tolerated. Compared with baseline measurements, the bone pain score was increased at the last assessment in both the placebo and 2 mg ibandronate groups, but was significantly reduced in the patients receiving 6 mg ibandronate (-0.28+/-1.11, P < 0.001). A significant improvement in quality of life was demonstrated for patients treated with ibandronate (P < 0.05) for all global health status. Overall, at the last assessment, the 6 mg ibandronate group showed significantly better functioning compared with placebo (P = 0.004), and had significantly better scores on the domains of physical, emotional, and social functioning, and in global health status (P < 0.05). Significant improvements in the symptoms of fatigue and pain were also observed in the 6 mg ibandronate group. I.v. ibandronate treatment leads to significant improvements in quality of life, and is an effective and well-tolerated palliative treatment in patients with bone metastases due to breast cancer.     

Efficacy and safety of ibandronate in the treatment of opioid-resistant bone pain associated with metastatic bone disease: a pilot study.

PURPOSE: Bone metastases are associated with severe and sometimes intractable pain, compromising patient quality of life (QOL). This open-label pilot study investigated the effects of short-term intensive treatment with intravenous (i.v.) ibandronate on opioid-resistant bone pain in patients with skeletal metastases. PATIENTS AND METHODS: Eighteen patients with advanced tumors and metastatic bone disease received nonstandard treatment with 4 mg of ibandronate administered i.v. (2-hour infusion) for 4 consecutive days (16-mg total dose). Baseline opioid analgesic use was equivalent to 400 mg/d of morphine. Patients were assessed for 6 weeks or until death. Changes from baseline were determined for bone pain, opioid consumption, patient functioning, QOL, performance status, and biochemical markers of calcium metabolism and bone turnover. Renal function was assessed by serum urea and creatinine measurement. RESULTS: Short-term, intensive ibandronate treatment significantly reduced bone pain scores within 7 days (P <.001). Pain reductions were sustained over the study period. Ibandronate significantly improved QOL, patient functioning, and performance status (P <.05). Mean values of the urinary cross-links pyridinoline and deoxypyridinoline tended to increase after day 21, returning close to baseline values by day 42. There was no correlation between the change in crosslinks values and the change in pain scores after ibandronate treatment. Ibandronate was well tolerated, with no evidence of renal toxicity. CONCLUSION: Nonstandard, intensive treatment with i.v. ibandronate seems to have a marked analgesic effect in patients with opioid-resistant bone pain from metastatic bone disease. Further investigation is warranted.     

Bisphosphonates for metastatic bone disease: a therapeutic rationale

Metastatic bone disease is a common clinical occurrence in patients with advanced malignancy. Bisphosphonates target the underlying pathophysiology of skeletal metastases by inhibiting the activity of osteoclasts reducing bone turnover. By effectively reducing skeletal complications and improving patient quality of life, mobility and functioning, bisphosphonates have become a standard of care in this indication. Currently, most patients with metastatic bone disease are managed with intravenous (i.v.) bisphosphonates infused every 3–4 weeks. This requires regular hospital treatment and close patient monitoring for renal adverse events. Although daily oral bisphosphonate therapy is available as an alternative to i.v. dosing, its clinical utility is compromised by unpleasant gastrointestinal side effects and dosing inconvenience. The third-generation bisphosphonate ibandronate has been formulated as an i.v. and an oral therapy for the management of metastatic bone disease. Clinical trial data demonstrated that ibandronate reduces the risk of skeletal complications, relieves bone pain, improves quality of life and is well tolerated in patients with bone metastases from breast cancer. The availability of ibandronate will widen bisphosphonate treatment options for metastatic bone 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 in patients with metastatic bone disease: results of a phase 3 study of denosumab versus zoledronic acid

BackgroundPatients with metastatic bone disease are living longer in the metastatic stage due to improvements in cancer therapy, making strategies to prevent the aggravation of bone disease and its complications, such as skeletal-related events (SREs) and pain, increasingly important.Patients and resultsIn this phase 3 trial in patients with advanced cancer (excluding breast and prostate cancer) or multiple myeloma, denosumab reduced the risk of radiation to bone by 22% relative to zoledronic acid (P = 0.026), prevented worsening of pain and pain interference (2-point increase in Brief Pain Inventory score; P < 0.05 versus zoledronic acid), and reduced the frequency of a shift from no/weak opioid analgesic use to strong opioids (P < 0.05 versus zoledronic acid at months 3–5). Denosumab delayed the time to moderate-to-severe pain compared with zoledronic acid in patients with mild or no pain at the baseline (P = 0.04), supporting early treatment. Health-related quality-of-life scores were similar in both groups. The number needed to treat to avoid one SRE for denosumab was 3 patient-years versus placebo and 10 patient-years versus zoledronic acid.ConclusionThe use of denosumab was associated with better prevention of the complications of metastatic bone disease secondary to solid tumors or multiple myeloma versus zoledronic acid.     

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.     

Ibandronate: efficacy in the treatment of metastatic bone disease

Ibandronate is a bisphosphonate treatment for metastatic bone disease. In Phase III trials in breast cancer patients, intravenous and oral formulations of ibandronate lowered the incidence of skeletal-related events, reduced metastatic bone pain scores throughout 2 years of treatment, and had significant positive effects on patient quality of life, demonstrating its efficacy in this condition. Recent pilot studies in other primary cancers suggest that a loading dose of ibandronate may relieve severe or opioid-resistant metastatic bone pain. In safety analyses, ibandronate was well tolerated with a safety profile comparable to placebo. Ibandronate therefore represents a treatment choice with documented efficacy and safety in metastatic bone disease from breast cancer.     

Efficacy of ibandronate in metastatic bone disease: review of clinical data

Metastatic bone disease affects many cancer patients and has a significant disease burden because of complications such as pathologic fractures and severe pain, which affect patient mobility and quality of life. Bisphosphonates are the current standard of care for treating metastatic bone disease. Available agents have shown varying degrees of efficacy in clinical trials, and treatment potential can be limited by efficacy, tolerance, or toxicity issues. Ibandronate (Bondronat); F. Hoffman-La Roche Ltd., Basel, Switzerland, http://www.roche.com) is a highly potent, single-nitrogen bisphosphonate that is available in i.v. and oral formulations. In phase III trials in breast cancer patients, both formulations reduced the incidence of skeletal complications associated with metastatic bone disease and had significant and sustained effects on bone pain and patient quality of life. Open-label studies of loading-dose ibandronate administered over consecutive days suggest it also may be useful for relieving severe or opioid-resistant metastatic bone pain. New trials have been designed or are in progress that may extend the clinical indications of ibandronate for patients with metastatic bone disease.     

Renal safety of ibandronate

Despite their efficacy in treating complications associated with metastatic bone disease, there are concerns about the potential nephrotoxicity of certain i.v. bisphosphonates for the long-term management of cancer patients. Clinical data suggest, however, that i.v. ibandronate (Bondronat); F. Hoffman-La Roche Ltd., Basel, Switzerland, http://www.roche.com), unlike other bisphosphonates, has a renal safety profile comparable with that of placebo. In a 2-year, phase III study of patients with breast cancer metastatic to bone, the incidence of adverse renal events in patients treated with 6 mg i.v. ibandronate was low and comparable with that of placebo (4% versus 4.5% with placebo). Two-year assessments of time to serum creatinine increase also demonstrated renal safety comparable with that of placebo (patients with creatinine increase: 6% versus 12% with placebo). Long-term (4-year) renal safety of ibandronate was demonstrated in a 2-year extension of the trial. Phase II, open-label studies show that intensive ibandronate dosing does not compromise renal safety in patients with metastatic bone pain from a variety of tumor types. In addition, i.v. ibandronate is well tolerated, with no evidence of renal toxicity in multiple myeloma and urologic cancer patients with existing renal impairment. The potential nephrotoxicity of some bisphosphonates has prompted additional renal safety precautions in product labeling for these agents. The precautions are not, however, contained in the label for ibandronate, which may thus simplify patient management.     

Zoledronic acid significantly reduces pathologic fractures in patients with advanced-stage prostate cancer metastatic to bone

The skeletal complications of metastatic bone disease secondary to advanced prostate cancer result in significant morbidity. In particular, pathologic fractures often require clinical intervention and are independent predictors of mortality in men with advanced prostate cancer. Before the introduction of zoledronic acid, bisphosphonates had been shown to provide pain palliation in patients with prostate cancer and bone metastases but were not efficacious in preventing skeletal complications. Zoledronic acid is the first bisphosphonate to show efficacy in reducing skeletal complications associated with the predominantly osteoblastic bone lesions characteristic of prostate cancer. In a large phase III randomized trial, zoledronic acid 4 mg every 3 weeks for 15 months significantly reduced the percentage of men who experienced a skeletal complication and reduced the incidence of pathologic fractures. Additionally, zoledronic acid 4 mg significantly decreased the annual incidence of skeletal complications, including fractures, and provided better control of bone pain compared with placebo. Adverse events with zoledronic acid were primarily limited to the flu-like, acute-phase symptoms previously reported with intravenous bisphosphonates, namely fever, myalgia, nausea, and anemia. These adverse events were mild to moderate and easily managed with supportive care. Zoledronic acid is the first and only bisphosphonate shown to reduce skeletal morbidity, including fractures, in patients with advanced prostate cancer and bone metastases.     

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.     

Pharmacokinetic and clinical equivalence of oral and intravenous ibandronate for metastatic bone disease

While monthly infusions of intravenous (i.v.) bisphosphonates effectively reduce skeletal complications of metastatic bone disease, regular hospital visits are inconvenient for patients and may reduce their quality of life. Daily oral bisphosphonate therapy would allow long-term patient management in the community setting. However, the use of oral bisphosphonate therapy (e.g. oral clodronate) is limited in clinical practice, due to its relatively low efficacy in comparison with i.v. agents, poor gastrointestinal tolerability, and a large tablet size that is difficult for patients to administer. Ibandronate is a highly potent, third-generation aminobisphosphonate that has been developed in an oral formulation with a small, easy-to-swallow tablet and convenient once-daily dosing. Pharmacokinetic evaluations of oral ibandronate have shown a linear dose-dependent increase in plasma concentrations that is non-saturable, and is proportional to its effect on bone-resorption markers. This ensures predictability of response to a given oral dose of ibandronate, reducing safety concerns. Bioavailability analysis suggests that oral ibandronate (50 mg) taken once daily, 30 min before food, provides comparable bone-surface exposure to i.v. ibandronate (6 mg) infused every 3–4 weeks i.e. the two formulations are dose-equivalent. The clinical equivalence of oral ibandronate (50 mg) and i.v. ibandronate (6 mg) is indicated by comparable reductions in the relative risk of skeletal events in phase III trials of patients with bone metastases from breast cancer.     

Effects of long-term intravenous ibandronate therapy on skeletal-related events, survival, and bone resorption markers in patients with advanced multiple myeloma.

PURPOSE: Bisphosphonates have been found to reduce the incidence of skeletal-related events (SREs) in patients with multiple myeloma. This is the first double-blind, randomized, placebo-controlled study to assess the efficacy of ibandronate, a third-generation amino-bisphosphonate, in preventing SREs in advanced-stage multiple myeloma patients. PATIENTS AND METHODS: Patients with multiple myeloma stage II or III were randomly assigned to receive either ibandronate 2 mg or placebo as a monthly intravenous (IV) bolus injection for 12 to 24 months in addition to conventional chemotherapy. SREs such as peripheral pathologic or vertebral fractures, hypercalcemia, severe bone pain, and bone radiotherapy or surgery were analyzed. Bone-turnover markers were also studied. Finally, post hoc analyses of bone morbidity and survival were performed. RESULTS: Ninety-nine patients per treatment group were assessable for efficacy analysis. The occurrence of SRE per patient year and the time to first SRE were not significantly different between the two treatment groups. In overall evaluation, no differences were found between the treatment groups regarding bone pain, analgesic drug use, quality of life, and median survival (33.1 v 28.2 months, respectively). Explorative post hoc analyses revealed that ibandronate patients with strongly suppressed bone-turnover markers (> or = 30% and > or = 50% mean reduction of serum osteocalcin and urinary C-terminal telopeptides) developed significantly less bone morbidity. Ibandronate was tolerated well during as many as 25 therapy cycles. CONCLUSION: Monthly injections of ibandronate 2 mg IV neither reduced bone morbidity nor prolonged survival in the overall population of stage II/III multiple myeloma patients.     

Procollagen type I N-propeptide is a predictor of skeletal morbidity in patients with malignant osteolytic bone disease on bisphosphonates

Background

There is an urgent need for individualized treatment of malignant bone disease (MBD), as the clinical benefit from bone-targeted therapies is moderate. We assessed the predictive value of the bone formation marker procollagen type I N-propeptide (PINP) for skeletal morbidity in patients with MBD receiving pamidronate.

Methods

Seventy patients with advanced MBD were randomized to receive pamidronate 60?mg (n?=?35) or 90?mg (n?=?35) every 3?weeks for six cycles in a double-blind study. PINP was analyzed at baseline and before each administration of pamidronate, using a validated ELISA. Serum PINP concentrations were compared with pain response (visual analog scale VAS, composite pain score) and skeletal morbidity (skeletal-related events, SRE) using Student??s T-test, Wilcoxon rank-sum and log-rank test, respectively.

Results

Patients with ??20% pain reduction in the VAS had lower baseline PINP concentrations when compared to patients with <20% VAS response (P?<?0.0001). A high baseline serum PINP concentration (highest tertile versus lower two tertiles) was significantly associated with a shorter duration of pain response (P?<?0.0001) and a shorter time interval to first SRE (P?<?0.008). Sensitivity of a low baseline PINP serum concentration for freedom from SRE at 1?year from randomization was 75% (15 out of 20 patients), while specificity was 82% (27 out of 33 patients).

Conclusions

Serum PINP has been shown to be a significant predictor for skeletal morbidity in patients with MBD on pamidronate treatment. Prospective validation of PINP in patients with MBD to assess the prognosis or individualize bone-targeted treatment is justified.     

Oral ibandronate is as active as intravenous zoledronic acid for reducing bone turnover markers in women with breast cancer and bone metastases.

BACKGROUND: Phase III study comparing the effect of oral ibandronate and intravenous zoledronic acid on bone markers. PATIENTS AND METHODS: Breast cancer patients with bone metastases received ibandronate 50 mg/day (n = 137) or zoledronic acid 4 mg every 4 weeks (n = 138) for 12 weeks. The primary end point was mean percentage change in serum levels of cross-linked C-terminal telopeptide of type I collagen (S-CTX) at week 12. Urinary CTX (U-CTX), bone alkaline phosphatase (ALP), amino-terminal procollagen propeptide of type I collagen (PINP) and osteocalcin (OC) were also measured and bone pain and safety assessed. RESULTS: Both bisphosphonates significantly reduced S-CTX (mean ibandronate 76% +/- 29 (SD) versus mean zoledronic acid 73% +/- 47; P < 0.001 for both versus baseline) and U-CTX (ibandronate 78% +/- 50 versus zoledronic acid 86% +/- 17; P < 0.001). The difference in S-CTX between treatments was 0.6% (confidence interval -1.7% to 3.0%), which was within the prespecified noninferiority margin. Bone ALP, PINP and OC decreased by 26%-47% compared with baseline with both bisphosphonates. Compared with zoledronic acid, ibandronate patients reported fewer adverse events overall (65.0% versus 75.9%), and on days 1-3 (8.0% versus 47.5%), including less pyrexia (overall incidence 0% versus 16.8%) and bone pain (5.8% versus 12.4%). CONCLUSIONS: Oral ibandronate was well tolerated and statistically noninferior to zoledronic acid for percentage change in the bone resorption marker, S-CTX.