Purpose: The aromatase inhibitor anastrozole is a highly effective well-tolerated treatment for postmenopausal endocrine-responsive breast cancer. However, its use is associated with accelerated bone loss and an increase in fracture risk. The ARIBON trial is a double-blind, randomized, placebo-controlled study designed to evaluate the impact of bisphosphonate treatment on bone mineral density (BMD) in women taking anastrozole. Experimental Design: BMD was assessed in 131 postmenopausal, surgically treated women with early breast cancer at two U.K. centers. Of these, 50 patients had osteopenia (T score -1.0 to -2.5) at either the hip or lumbar spine. All patients were treated with anastrozole 1mg once a day and calcium and vitamin D supplementation. In addition, osteopenic patients were randomized to receive either treatment with ibandronate 150 mg orally every month or placebo. Results: After 2 years, osteopenic patients treated with ibandronate gained +2.98% (range -8.9, +19.9) and +0.60% (range -9.0, +6.9) at the lumbar spine and hip, respectively. Patients treated with placebo, however, lost -3.22% (range -16.0, +4.3) at the lumbar spine and -3.90% (range -12.3, +7.2) at the hip. The differences between the two treatment arms were statistically significant at both sites (P < 0.01). At 12 months, urinary n-telopeptide, serum c-telopeptide, and serum bone^specific alkaline phosphatase levels declined in patients receiving ibandronate (30.9%, 26.3%, and 22.8%, respectively) and increased in those taking placebo (40.3%, 34.9%, and 37.0%, respectively). Conclusions: Monthly oral ibandronate improves bone density and normalizes bone turnover in patients treated with anastrozole.

Purpose: Bisphosphonates play a central role in the management of bone loss due to a range of disorders, including metastatic bone disease, cancer treatment^induced bone loss, and postmenopausal osteoporosis. With potent bisphosphonates, such as zoledronic acid, it may be possible to maintain efficacy with relatively infrequent administration.Experimental Design: Sixty-six patients who were osteopenic at >1 year following curative cancer therapy received a single i.v. 4 mg dose of the bisphosphonate zoledronic acid. Bone mineral density (BMD) was measured using double-beam X-ray absorptiometry scan and the bone resorption marker N-telopeptide of type II collagen was determined using a chemiluminescence ELISA assay. Results: The single dose of zoledronic acid induced mean increases in bone BMD at the lumbar spine of 3.1%, 5.2%, and 5.3% and at the total hip of 2.7%, 3.5%, and 4.3% after 12, 24, and 36 months of follow-up, respectively (P < 0.001 at all time points). By 36 months, 84% of patients had achieved increase in BMD at the spine and 90% at the hip. The mean percentage decrease in the bone resorption marker N-telopeptide was f58% at 6 weeks and 42%, 33%, and 31% at 12, 24, and 36 months, respectively (P < 0.001).Conclusions: A single dose of zoledronic acid in patients with low BMD results in a sustained increase in BMD and a corresponding decrease in bone resorption.Very infrequent administration of zoledronic acid may have clinical benefits in terms of convenience, reduced toxicity, improved compliance, and cost.

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PurposeThe ARIBON trial is a double blind, randomised, placebo controlled study designed to evaluate the impact of ibandronate on bone mineral density (BMD) in women taking anastrozole for adjuvant treatment of breast cancer.Methods131 postmenopausal women with early breast cancer were recruited to the study. Of these, 13 had osteoporosis, 50 osteopenia and 68 normal BMD. Patients with osteoporosis at baseline were treated with monthly oral ibandronate 150 mg for 5 years; osteopenic patients were randomised to receive either ibandronate or placebo for two years and offered open label ibandronate depending upon the results of their 2-year BMD result.ResultsOf the 20 patients with osteopenia who were randomised to ibandronate and evaluable at the 2 year visit, 17/20 were not offered a bisphosphonate and the improvements in BMD accrued during the first 2 years were lost both at the LS (−3.21%) and TH (−5.0%). Of the 16 patients randomised to placebo 8/16 with high rates of bone loss during years 0–2 received ibandronate over the next 3 years with improvements in BMD of +5.01 and +1.19 at the LS and TH respectively. The 8 patients who were not offered a bisphosphonate experienced relatively little change in BMD throughout the 5 years of the study (LS +0.15%, TH −2.72%). BMD increased steadily in the 9/13 patients initially identified as having osteoporosis (LS +9.65%, TH +2.72%).ConclusionsMonthly oral ibandronate provides an option to clinicians considering use of a bisphosphonate to prevent bone loss during aromatase inhibitor therapy.

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Background:Brain metastases occur in up to 75% of patients with advanced melanoma. Most are treated with whole-brain radiotherapy (WBRT), with limited effectiveness. Vandetanib, an inhibitor of vascular endothelial growth factor receptor, epidermal growth factor receptor and rearranged during transfection tyrosine kinases, is a potent radiosensitiser in xenograft models. We compared WBRT with WBRT plus vandetanib in the treatment of patients with melanoma brain metastases.Methods:In this double-blind, multi-centre, phase 2 trial patients with melanoma brain metastases were randomised to receive WBRT (30 Gy in 10 fractions) plus 3 weeks of concurrent vandetanib 100 mg once daily or placebo. The primary endpoint was progression-free survival in brain (PFS brain). The main study was preceded by a safety run-in phase to confirm tolerability of the combination. A post-hoc analysis and literature review considered barriers to recruiting patients with melanoma brain metastases to clinical trials.Results:Twenty-four patients were recruited, six to the safety phase and 18 to the randomised phase. The study closed early due to poor recruitment. Median PFS brain was 3.3 months (90% confidence interval (CI): 1.6–5.6) in the vandetanib group and 2.5 months (90% CI: 0.2–4.8) in the placebo group (P=0.34). Median overall survival (OS) was 4.6 months (90% CI: 1.6–6.3) and 2.5 months (90% CI: 0.2–7.2), respectively (P=0.54). The most frequent adverse events were fatigue, alopecia, confusion and nausea. The most common barrier to study recruitment was availability of alternative treatments.Conclusions:The combination of WBRT plus vandetanib was well tolerated. Compared with WBRT alone, there was no significant improvement in PFS brain or OS, although we are unable to provide a definitive result due to poor accrual. A review of barriers to trial accrual identified several factors that affect study recruitment in this difficult disease area.

The increasing use of systemic adjuvant therapies has considerably improved the prognosis from early breast cancer. However, some of these therapies affect bone metabolism, resulting in osteoporosis. Aromatase inhibitors lower circulating oestrogen levels to almost unrecordable levels in postmenopausal women, predisposing them to bone loss with an increase in fracture risk. Ongoing clinical trials are favouring the use of the aromatase inhibitors over tamoxifen and this may advocate greater use of these drugs in the future. Strategies for the identification and management of treatment-induced bone loss are currently being defined.