Systematic review of role of bisphosphonates on skeletal morbidity in metastatic cancer

The Royal Marsden NHS Foundation Trust, Londinium, England, United Kingdom
BMJ (online) (Impact Factor: 17.45). 08/2003; 327(7413):469. DOI: 10.1136/bmj.327.7413.469
Source: PubMed


To review the evidence for the use of bisphosphonates to reduce skeletal morbidity in cancer patients with bone metastases.
Electronic databases, scanning reference lists, and consultation with experts and pharmaceutical companies. Foreign language papers were included.
Included trials were randomised controlled trials of patients with malignant disease and bone metastases who were treated with oral or intravenous bisphosphonate compared with another bisphosphonate, placebo, or standard care. All trials measured at least one outcome of skeletal morbidity.
95 articles were identified; 30 studies fulfilled inclusion criteria. In studies that lasted > or = 6 months, compared with placebo bisphosphonates significantly reduced the odds ratio for fractures (vertebral 0.69, 95% confidence interval 0.57 to 0.84, P < 0.0001; non-vertebral 0.65, 0.54 to 0.79, P < 0.0001; combined 0.65, 0.55 to 0.78, P < 0.0001), radiotherapy (0.67, 0.57 to 0.79, P < 0.0001), and hypercalcaemia (0.54, 0.36 to 0.81, P = 0.003) but not for orthopaedic surgery (0.70, 0.46 to 1.05, P = 0.086) or spinal cord compression (0.71, 0.47 to 1.08, P = 0.113). The reduction in orthopaedic surgery was significant in studies that lasted over a year (0.59, 0.39 to 0.88, P = 0.009). Use of bisphosphonates significantly increased time to first skeletal related event but did not increase survival. Subanalyses showed that most evidence supports use of intravenous aminobisphosphonates.
In people with metastatic bone disease bisphosphonates significantly decrease skeletal morbidity, except for spinal cord compression and increased time to first skeletal related event. Treatment should start when bone metastases are diagnosed and continue until it is no longer clinically relevant.

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Available from: Joy R Ross
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    • "Nitrogen-containing BPs (eg, pamidronate, risedronate, ibandronate, and ZOL) prevent bone resorption by inhibiting farnesyl diphosphate synthase. On the basis of systematic review and meta-analyses of published data from clinical trials of BPs,5,6 it is clear that BPs reduce SRE risks in patients with metastatic bone disease from breast cancer. Bisphosphonates also reduce bone pain. "
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    ABSTRACT: Intravenous zoledronic acid (ZOL) is an integral component for the management of patients with bone metastases, but can be associated with transient flu-like symptoms, which generally occur only with the first infusion and are typically manageable with nonprescription analgesics. A 50-year-old woman with a bone metastasis secondary to breast cancer received radiation therapy, brand-name ZOL (Zometa(®)), and letrozole. During the first 3 cycles of Zometa (4 mg every 3-4 weeks), no acute adverse events were reported. For the next 2 cycles she was switched to generic ZOL and experienced severe toxicity (nausea, vomiting, extreme weakness, and incapacitating bone pain) that required hospitalization. Toxicity differences between generic ZOL and Zometa led the patient to pay additional costs for Zometa, and subsequent Zometa infusions were without incident. This is the first case report documenting a clinically significant difference between the safety profiles of a generic formulation of ZOL and brand-name Zometa.
    Preview · Article · Oct 2012 · Clinical Medicine Insights: Case Reports
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    • "Fractures as well as spinal cord compression and the consecutive local interventions (e.g. surgery to bone, radiotherapy to bone) are summarized by the term 'skeletal-related events' (SREs) [Ross et al. 2003]. In most phase III clinical trials, reduction of SREs is chosen as the primary endpoint in order to measure the activity of drugs blocking bone resorption. "
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    ABSTRACT: Introduction: Denosumab, a fully human monoclonal antibody, targets the receptor activator of nuclear factor-kappaB (RANK) ligand, a protein essential for osteoclast differentiation, activity and survival. Loss of osteoclasts from the bone surface reduces bone turnover and bone loss in malignant and benign diseases. In breast cancer, bone metastases are frequently observed; cancer treatment-induced bone loss (CTIBL) may result as a consequence of endocrine treatment or chemotherapy. Furthermore, preclinical studies suggest a direct role of the RANK/RANK-ligand pathway in breast tumorigenesis. This paper reviews preclinical and clinical data on denosumab in breast cancer.Materials and methods: Studies were identified through the Medline database. Key search terms included: AMG-162, bisphosphonates, denosumab, RANK-ligand and zoledronic acid. Information available in abstract form only was retrieved from major oncology meetings, such as the American Society of Clinical Oncology (ASCO) annual meeting, ASCO breast meeting, European Cancer Organization, European Society of Medical Oncology and the San Antonio Breast Cancer Symposium.Results: Denosumab was consistently well tolerated throughout clinical trials, although the observed incidence of osteonecrosis of the jaw was comparable to that with bisphosphonates. Efficacy as determined by a reduction of skeletal-related events was at least equal to zoledronic acid, and superior in one phase III study conducted in patients with metastatic breast cancer. Clinical trials investigating the role of denosumab for the prevention of CTIBL and breast cancer recurrences are currently ongoing.Conclusion: In conclusion, denosumab appears to be an effective and safe treatment option in patients with bone metastases from breast cancer with the potential of also preventing CTIBL.
    Preview · Article · Sep 2011 · rapeutic Advances in Medical Oncology, The
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    • "Bisphosphonates (BPs) have become the standard treatment for malignant bone disease. BPs effectively inhibit bone resorption and have been shown to significantly reduce the incidence of skeletal complications and have analgesic effects on bone pain [5]. Methylene diphosphonate (MDP) is similar to the bisphosphonates [6]. "
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    ABSTRACT: 99mTc-MDP (technetium-99m-labeled methylene diphosphonate) has been widely used as a radiopharmaceutical for bone scintigraphy in cases of metastatic bone disease. 177Lu is presently considered as an excellent radionuclide for developing bone pain palliation agents. No study on preparing a complex of 177Lu with MDP has been reported yet. Based on these facts, it was hypothesized that a bone-seeking 177Lu–MDP (lutetium-177-labeled MDP) radiopharmaceutical could be developed as an agent for palliative radiotherapy of bone pain due to skeletal metastases. Biodistribution studies after intravenous injection of 177Lu–MDP complex in rats may yield important information to assess its potential for clinical use as a bone pain palliation agent for the treatment of bone metastases.
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