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.     

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.     

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。     

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.     

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.     

Double-blind, randomised, placebo-controlled, dose-finding study of oral ibandronate in patients with metastatic bone disease

Background: Bisphosphonates are an important component of the treatment of metastatic bone disease but more potent, oral formulations are required to improve the effectiveness and convenience of treatment. An oral formulation of the new bisphosphonate, ibandronate (BM 21.0955) has recently been developed.Patients and methods: One hundred ten patients with bone metastases (77 breast, 16, prostate, 3 myeloma, 14 others) were recruited from a single institution to this double blind placebo-controlled evaluation of four oral dose levels (5, 10, 20 and 50 mg) of ibandronate. No changes in systemic anti-cancer treatment were allowed in the month before commencing treatment or during the study period. After an initial four-week tolerability phase, patients could continue on treatment for a futher three months without unblinding; patients initially allocated to placebo received ibandronate 50 mg. The primary endpoint was urinary calcium excretion (UCCR). Bone resorption was also assessed by measurement of pyridinoline (Pyr), deoxypyridinoline (Dpd), and the N-terminal (NTX) and C-terminal (Crosslaps) portions of the collagen crosslinking molecules.Results: Two patients did not receive any trial medication thus, 108 patients were evaluable for safety. Ninety-two patients were evaluable for efficacy. A dose dependent reduction was observed in both UCCR and collagen crosslink excretion. At the 50 mg dose level, the percentage reductions from baseline in UCCR, Pyr, Dpd, Crosslaps and NTX were 71%, 28%, 39% 80% and 74% respectively.One or more gastrointestinal (GI) adverse events occurring in the first month of treatment were reported by six (30%), seven (33%), nine (39%), nine (41%) and eleven (50%) patients at the placebo, 5, 10, 20 and 50 mg dose levels respectively. One patient (20 mg dose) developed radiographically confirmed oesophageal ulceration. GI tolerability may have been adversely affected by concommitant administration of non-steroidal anti-inflammatory agents. Nine (8%) patients stopped treatment within the first month due to GI intolerability but these patients were evenly distributed across the five treatment groups. There was no difference in non-GI adverse events between groups.Conclusions: Oral ibandronate has potent effects on the rate of bone resorption at doses which are generally well tolerated. Further development is appropriate to evaluate the effects of long-term administration in the prevention of metastatic bone disease and the management of established skeletal metastases.     

Safety of intravenous and oral bisphosphonates and compliance with dosing regimens

Patients with advanced cancers--particularly breast and prostate cancers--are at high risk for bone metastasis, leading to accelerated bone resorption and clinically significant skeletal morbidity. Bisphosphonates are effective inhibitors of bone resorption and reduce the risk of skeletal complications in patients with bone metastases. The standard routes of administration for bisphosphonates used in clinical practice are either oral or i.v. infusion. Oral administration of bisphosphonates is complicated by poor bioavailability (generally <5%) and poor gastrointestinal tolerability. First-generation bisphosphonates, such as clodronate (Bonefos; Anthra Pharmaceuticals; Princeton, NJ), must be administered at high oral doses (1,600-3,200 mg/day) to achieve therapeutic effects, which leads to poor tolerability and compliance with oral dosing regimens. Infusion of bisphosphonates is associated with dose- and infusion-rate-dependent effects on renal function. In particular, high bisphosphonate doses (e.g., 1,500 mg clodronate) can cause severe renal toxicity unless infused slowly over many hours. In contrast, the newer, more potent bisphosphonates effectively inhibit bone resorption at micromolar concentrations, and the small doses required can be administered via relatively short i.v. infusions without adversely affecting renal function. Zoledronic acid (Zometa; Novartis Pharmaceuticals Corp.; East Hanover, NJ) is a new generation bisphosphonate, and the recommended dose of 4 mg can be safely infused over 15 minutes. The 90-mg dose of pamidronate (Aredia; Novartis Pharmaceuticals Corp.) and the 6-mg dose of ibandronate (Bondronat; Hoffmann-La Roche Inc.; Nutley, NJ) require 1- to 4-hour infusions. Intravenous bisphosphonates require less frequent dosing (once a month) and are generally well tolerated with long-term use in patients with bone metastases. Zoledronic acid has demonstrated the broadest clinical activity in patients with bone metastases.     

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

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

Ibandronate: a well-tolerated intravenous and oral treatment for metastatic bone disease

Tolerability of drug therapies is an important factor when selecting palliative treatments for use in cancer patients. This is particularly the case when choosing long-term bisphosphonate therapy for management of skeletal metastases, because of the high disease-related morbidity burden and the toxicities associated with anticancer drugs. In a phase III trial of patients with bone metastases from breast cancer, intravenous (i.v.) ibandronate 6 mg infused every 3–4 weeks for 96 weeks has a similar safety profile to placebo, with no renal safety concerns. Pooled data from two phase III studies of oral ibandronate found that a daily 50 mg dose was well-tolerated, with few gastrointestinal side effects. These results suggest that oral and i.v. ibandronate have important safety and tolerability advantages over existing i.v. and oral bisphosphonate treatments.     

Reducing skeletal complications and bone pain with intravenous ibandronate for metastatic bone disease

Complications of metastatic bone disease substantially compromise patient independence and mobility. The goals of management include reducing the rate of skeletal complications and alleviating bone pain, to improve morbidity and patient quality of life. In a 96-week, randomised, double-blind, phase III trial, intravenous (i.v.) ibandronate 6 mg administered over 1–2 h every 3–4 weeks significantly reduced skeletal complications (assessed by the skeletal morbidity period rate [SMPR]) compared with placebo (P=0.004). Individual components of the SMPR were also significantly reduced with ibandronate (vertebral fractures, P=0.023 and need for bone radiotherapy, P=0.011 versus placebo). Ibandronate 6 mg also significantly reduced bone pain scores and maintained them below baseline over 2 years (P<0.001), an effect not reported with other bisphosphonates for metastatic bone disease. Bone pain alleviation was accompanied by significantly improved quality of life compared with placebo (P=0.004). An independent pilot study used intensive i.v. ibandronate treatment (16 mg over 4 days) to treat opioid-resistant bone pain in patients with metastatic bone disease from various tumour types. Supporting the results of the phase III clinical trial, bone pain was significantly reduced (P<0.001 versus baseline), and patients experienced significant improvement in their quality of life (P<0.05 versus baseline). The results of these studies suggest that i.v. ibandronate effectively reduces skeletal morbidity rate and provides significant bone pain and quality of life benefits that have not been demonstrated so far with other bisphosphonates.     

Bisphosphonates in breast cancer.

Breast cancer is the leading type of cancer among women, and bone metastases are common in patients with breast cancer, affecting more than half of all patients with advanced disease. Bisphosphonates are the current standard of care for preventing skeletal complications associated with bone metastases. Clinical trials investigating the benefit of bisphosphonate therapy have used a composite end point defined as a skeletal-related event (SRE) or bone event, which typically includes pathologic fracture, spinal cord compression, radiation or surgery to bone, and hypercalcaemia of malignancy. Bisphosphonates significantly reduced the incidence of these events. Zoledronic acid, pamidronate, clodronate and ibandronate have demonstrated efficacy compared with placebo. Zoledronic acid has also been compared with another active bisphosphonate (i.e. pamidronate) and shown by multiple event analysis to be significantly more effective at reducing the risk of SREs. Bisphosphonates effectively reduce and prevent skeletal complications in patients with bone metastases from breast cancer. Preclinical data suggest that bisphosphonates have antitumour effects. Bisphosphonates may also be of use in the adjuvant setting.     

Adverse effects of bisphosphonates: current issues

Four bisphosphonates are used for the treatment of metastatic bone disease: clodronate, which is available outside the United States in both intravenous and oral formulations; intravenous pamidronate; intravenous zoledronic acid; and ibandronate, which is also available in intravenous and oral forms. Since the use of bisphosphonates in patients with cancer is palliative, their impact on patients' quality of life and their adverse-effect profiles are essential considerations for effective patient management. The most common adverse effects associated with bisphosphonates are renal toxicity, acute-phase reactions, gastrointestinal (GI) toxicity, and osteonecrosis of the jaw (ONJ). The incidence of these adverse events varies significantly between bisphosphonates. Renal toxicity is a potentially life-threatening event reported in studies of zoledronic acid and, to a lesser extent, pamidronate. In contrast, the renal safety profile of intravenous ibandronate and oral bisphosphonates is similar to that of placebo. Acute-phase reactions occur only with intravenous aminobisphosphonates and may be more common with zoledronic acid. Gastrointestinal effects occur only with oral agents (clodronate and ibandronate) and may be avoided by adhering to dosing instructions. More recently, ONJ has recently emerged as a complication of bisphosphonate use. However, its true incidence is not yet known. The potential adverse effects of bisphosphonates should be considered in the context of the individual patient's characteristics and preferences when selecting a bisphosphonate for metastatic bone disease.     

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.     

Pathogenesis and bisphosphonate treatment of skeletal events and bone pain in metastatic cancer: focus on ibandronate

Bone metastases are the most common cause of pain in patients with advanced cancer, and are associated with progressive skeletal destruction, spinal problems, and hypercalcaemia. Radiotherapy, analgesia, and surgery are the accepted treatment options for chronic malignant bone pain, with a stepped approach being generally recommended. In the past decade, the bisphosphonates, which reduce bone turnover, increase bone mass, and decrease the risk of fracture, have become established as an effective treatment in patients with cancer metastasising to bone. The nitrogencontaining bisphosphonate, ibandronate, has been shown to reduce the risk of skeletal events after oral or intravenous administration in controlled clinical trials in various malignancies, and to confer significant palliation of bone pain and improvements in health-related quality of life in patients with metastatic breast cancer, in particular. Tolerability of this agent has been good, with very low frequencies of acute-phase reactions and osteonecrosis of the jaw, and no evidence of acute nephrotoxicity.     

Clinical efficacy of bisphosphonate therapy for bone metastasis from breast cancer

Bisphosphonates inhibit osteoclastic bone resorption and are being used as treatment for bone metastases from breast cancer. Intravenous bisphosphonate therapy can significantly reduce skeletal related events (SREs) when administered concurrently with chemotherapy or endocrine therapy. In addition, intravenous bisphosphonate monotherapy is also able to alleviate cancer induced bone pain, and to improve bone metastases in some patients. Oral bisphosphonates are not routinely used for the treatment of bone metastases due to their low bioavailability. However, minodronate, a bisphosphonate 100-fold more potent than pamidronate, is now in phase II clinical studies in Japan, and may alter the role of oral bisphosphonates in the treatment of bone metastasis from breast cancer. The ASCO guidelines recommend that patients with osteolytic bone metastases be treated not with bisphosphonate monotherapy, but with concurrent bisphosphonate and systemic therapy. In addition, it is also recommended that current standards of care for cancer pain, analgesics and radiotherapy, should not be replaced with bisphosphonate therapy.     

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

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

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

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

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.