Description

At the recent Cancer Associated Bone Disease (CIBD) conference in Davos, Switzerland, the delegates were treated to an intensive update in all aspects of the management of patients with skeletal metastases, and also the assessment and treatment of accelerated bone loss from cancer therapies. Inevitably, much of the focus was on pharmacological intervention, for which the bisphosphonates have been in the forefront for the last ten years.
Bisphosphonates are potent inhibitors of bone resorption and their use in the treatment of metastatic bone disease is now well established with intravenous (IV) pamidronate, IV zoledronate or oral clodronate used widely in the many countries including the UK. Treatment is usually initiated in patients with bone metastases to reduce pain and bone destruction, and continues until clinical deterioration makes continued use inappropriate. However, prolonged IV bisphosphonate use places considerable burdens upon both patient and hospital and oral clodronate can be associated with side effects such as nausea, vomiting and diarrhoea leading to a minority of patients failing to tolerate oral clodronate therapy and having to revert to an IV bisphosphonate preparation.
Ibandronic acid (ibandronate) is a new potent third generation aminobisphosphonate with both oral and IV formulations tested in phase 3 studies in metastatic breast cancer patients. In the oral studies, ibandronate was compared with placebo and was shown to be well tolerated and effective. The incidence of bone events was significantly reduced with oral ibandronate, and similar to that achieved with the 6mg IV every four weeks regimen. Pharmacokinetic studies confirmed similar bioactivity of the oral preparation in a dose of 50mg daily compared to the 6mg IV administration and both preparations reduced mean bone pain scores compared to placebo, with the maximal effect occurring at about eight to ten weeks, and maintained over two years. Oral ibandronate is now going to be compared to IV zoledronate in the UK in a CTAAC/NCRN approved randomised trial of one thousand four hundred patients with newly diagnosed bone metastases from breast cancer (ZICE Trial). The primary endpoint of this trial is to demonstrate non-inferiority of oral ibandronate versus zoledronate IV with respect to efficacy as assessed using the frequency and timing of skeletal related events over two years (multiple event analysis).
However, we also learnt at this excellent conference that researches are discovering the molecular signals between tumour cells and bone cells that lead to activation and consequent increased and disordered bone metabolism. At the present time, bisphosphonates are thought to act at the level of the activated osteoclast, but newer generations of antibodies and drugs are being developed which are capable with interfering with earlier stages of the process. One molecule, involved in osteoclast regulation is the ligand for Receptor Activator of NF-kappa B (RANK ligand) which is produced by osteoblasts. An antibody inhibitor of this pathway has shown promise in phase II trials in cancer patients with bone metastases.</p>
This is a rapidly advancing field, with the potential for more effective, less toxic agents to be produced in the distressing clinical problem which causes so much suffering for our patients.