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Professor of Medicine
University of Texas Southwestern Medical Center
Bone metastases often occur in advanced cancer and represent a substantial disease burden. Bisphosphonates are the standard of care for the prevention of skeletal complications. Several intravenous and oral bisphosphonates, each with specific advantages and limitations, have been approved on the basis of randomised controlled trials. Effective, well-tolerated and more convenient bisphosphonates could improve patient management.
Bone metastases often occur in advanced cancer, particularly with breast and prostate tumours or multiple myeloma.(1,2) Approximately 40–50% of patients will develop one or more skeletal-related events per year.(3) Complications, which include severe bone pain and disability, pathological fractures, spinal cord compression and hypercalcaemia,(1,2) have a major impact on quality of life (Figure 1).
There is an uncoupling of normal bone resorption and formation in metastatic bone disease, driven by increased osteoclast-mediated bone turnover. As potent inhibitors of osteoclast activity,(4–6) bisphosphonates are the standard of care for the prevention of skeletal complications. They are generally used as an adjunct to chemotherapy or hormonal therapy for primary malignancy. Table 1 summarises the dosing regimens of commonly used and recently approved agents.
Efficacy of bisphosphonates
Until 2002, oral clodronate and intravenous (IV) pamidronate were most often used in clinical practice, following demonstration of their efficacy in trials of patients with bone lesions from breast cancer or multiple myeloma. (3,7–9) However, a meta-analysis of skeletal-event data from clinical studies suggested that clodronate is less effective than pamidronate,(10) and that pamidronate has more consistent benefits than clodronate on other clinical parameters, such as bone pain.(3,8)
The perceived high efficacy of pamidronate helped it to become the gold standard treatment for bone metastases from breast cancer during the 1990s, although its effectiveness in other tumour types (eg, prostate cancer) is questionable.(11)
The last couple of years have seen the approval of two highly potent aminobisphosphonates for metastatic bone disease, zoledronic acid (Zometa(®); Novartis Pharmaceuticals) and ibandronate (Bondronat(®); Roche Pharmaceuticals). Zoledronic acid is recommended for patients with bone metastases from breast prostate and lung cancer, and other solid tumours.
In phase III trials, IV zoledronic acid significantly reduced the risk of skeletal events, compared with pamidronate, in breast cancer or multiple myeloma; it also decreased the proportion of patients experiencing skeletal complications (primary endpoint) versus placebo in prostate cancer.(12,13) In a placebo-controlled trial in lung or other solid tumours, zoledronic acid had little effect on the proportion of patients with bone events, although time to first new bone event was delayed.(14) Bone pain relief of a magnitude similar to that of pamidronate was reported with zoledronic acid over one year of treatment in breast cancer and multiple myeloma.(12)
Oral and IV ibandronate received EU approval in October 2003 for the prevention of skeletal events in breast cancer and bone metastases. In phase III trials, both formulations significantly reduced skeletal events, relieved bone pain below baseline and reduced quality of life deterioration compared with placebo throughout the two-year treatment period.(15,16)
Independent studies have suggested that intensive, “loading dose” IV ibandronate therapy relieves severe metastatic bone pain from breast cancer, prostate cancer or other tumours.(17,18) The efficacy of ibandronate in metastatic bone disease from various tumour types is being further investigated by an ongoing clinical trial programme that includes comparative studies of ibandronate and zoledronic acid. The collection of these data will allow clinicians to make better informed, evidence-based prescribing decisions.
Patient management issues
As for any supportive care product, long-term tolerability is considered in the choice of a bisphosphonate. Renal safety has become a concern following reports of functional impairment with IV zoledronic acid and pamidronate, occasionally progressing to acute renal failure, renal dialysis and, rarely, death.(19–22)
Nevertheless, renal toxicity may not be a class effect of bisphosphonates. Preclinical and clinical trial data indicate that ibandronate at clinical doses does not cause renal tubular damage(23) and has a renal adverse event profile comparable to that of placebo.(24) Unlike other IV bisphosphonates, serum creatinine monitoring is not required before each infusion of ibandronate, which may be used in patients with severely compromised renal functioning, and in those receiving nephrotoxic drugs (eg, cisplatins).(25)
Convenience, resource use and costs
For patients in hospital, bisphosphonate infusions may be combined with other IV regimens, such as chemotherapy. However, for outpatients, regular hospital trips are inconvenient and greatly impact on nurse time and resources. When preparation time and patient monitoring are considered, the average duration of a hospital infusion has been estimated at approximately one hour for zoledronic acid, and almost three hours for pamidronate.(26) Although rapid infusions (as with zoledronic acid) free up infusion chair time and allow more patients to be treated, the cost of treatment remains substantial, at more than $700 (euro 560 or £400) per patient.(26)
In patients who have completed IV chemotherapy, prescribing an oral bisphosphonate with efficacy similar to that of IV bisphosphonates would eliminate the impact of infusions and patient monitoring on hospital resources. Although oral clodronate has been available for at-home dosing for many years, its lower efficacy, multiple daily doses and gastrointestinal (GI) side-effects (particularly diarrhoea) may affect clinical outcomes and compliance.(7,27,28) Oral ibandronate provides an alternative to clodronate, with similar efficacy to IV ibandronate, once-daily dosing and relatively few GI tolerability concerns.(29) However, in noncompliant patients, bisphosphonate infusions may still be preferable.
Several bisphosphonates are used to manage skeletal complications from metastatic bone disease. While their efficacy is proven, the choice of bisphosphonate should be individualised, based on convenience, tolerability and compliance. Effective, well-tolerated and more convenient bisphosphonates simplify patient management and reduce the treatment burden on hospital resources.
European Organisation for Research and Treatment of Cancer
European Society for Medical Oncology
Federation of European Cancer Societies
The Zometa International Site