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.
- Coleman RE. Metastatic bone disease: clinical features, pathophysiology and treatment strategies. Cancer Treat Rev 2001;27:165-76.
- Diel IJ, Solomayer EF, Bastert G. Treatment of metastatic bone disease in breast cancer: bisphosphonates. Clin Breast Cancer 2000;1:43-51.
- Lipton A, Theriault RL, Hortobagyi GN, et al. Pamidronate prevents skeletal complications and is effective palliative treatment in women with breast carcinoma and osteolytic bone metastases: long term follow-up of two randomized, placebo-controlled trials. Cancer 2000;88:1082-90.
- Rogers MJ, Watts DJ, Russell RG. Overview of bisphosphonates. Cancer 1997;80 Suppl:1652-60.
- Body JJ, Mancini I. Bisphosphonates for cancer patients: why, how and when? Support Care Cancer 2002;10:399-407.
- Russell RG, Rogers MJ. Bisphosphonates: from the laboratory to the clinic and back again. Bone 1999;25:97-106.
- Paterson AH, Powles TJ, Kanis JA, et al. Double-blind controlled trial of oral clodronate in patients with bone metastases from breast cancer. J Clin Oncol 1993;11:59-65.
- Hortobagyi GN, Theriault RL, Lipton A, et al. Long-term prevention of skeletal complications of metastatic breast cancer with pamidronate. Protocol 19 Aredia Breast Cancer Study Group. J Clin Oncol 1998;16:2038-44.
- Theriault RL, Lipton A, Hortobagyi GN, et al. Pamidronate reduces skeletal morbidity in women with advanced breast cancer and lytic bone lesions: a randomized, placebo-controlled trial. J Clin Oncol 1999;17:846-54.
- Pavlakis N, Stockler M. Bisphosphonates for breast cancer. Cochrane Database Syst Rev 2002:1 (CD003474).
- Small EJ, Smith MR, Seaman JJ, et al. Combined analysis of two multicenter, randomized, placebo-controlled studies of pamidronate disodium for the palliation of bone pain in men with metastatic prostate cancer. J Clin Oncol 2003;21:4277-84.
- Rosen LS, Gordon D, Kaminski M, et al. Long-term efficacy and safety of zoledronic acid compared with pamidronate disodium in the treatment of skeletal complications in patients with advanced multiple myeloma or breast carcinoma: a randomized, double-blind, multicenter, comparative trial. Cancer 2003;98:1735-44.
- Saad F, Gleason DM, Murray R, et al. A randomized, placebo-controlled trial of zoledronic acid in patients with hormone-refractory metastatic prostate carcinoma. J Natl Cancer Inst 2002;94:1458-68.
- Rosen LS, Gordon D, Tchekmedyian S, et al. Zoledronic acid versus placebo in the treatment of skeletal metastases in patients with lung cancer and other solid tumors: a phase III, double-blind, randomized trial – the Zoledronic Acid Lung Cancer and Other Solid Tumors Study Group. J Clin Oncol 2003;21:3150-7.
- Tripathy D, Body JJ, Diel I, et al. For the Bondronat Study Group. Oral daily ibandronate: efficacy in reducing skeletal complications in patients with metastatic bone disease from breast cancer. Proc ASCO 2003;22:46 (Abstract 185).
- Body JJ, Diel IJ, Lichinitser MR, et al. Intravenous ibandronate reduces the incidence of skeletal complications in patients with breast cancer and bone metastases. Ann Oncol 2003;14:1399-405.
- Heidenreich A, Ohlmann C, Olbert P, et al High-dose ibandronate is effective and well tolerated in the treatment of pain and hypercalcaemia due to prostate cancer. Eur J Cancer 2003;1 Suppl 5:S270 (Abstract 897).
- Mancini I, Duman JC, Toth C, et al. Short-term treatment with the bisphosphonate ibandronate for opioid resistant metastatic bone pain. Bone 2002;30 Suppl 3:51 (Abstract B56).
- Chang JT, Green L, Beitz J. Renal failure with the use of zoledronic acid. N Engl J Med 2003;349:1676-9.
- Johnson KB, Gable P, Kaime EM, Luiken G, Castillos T, Hu J. Significant deterioration in renal function with the new bisphosphonate, zoledronic acid. Proc ASCO 2003;22:738 (Abstract 2968).
- Stein SH, Davidson R, Tweed A, et al. Renal dysfunction with IV bisphosphonates in patients with metastatic breast cancer. Proc ASCO 2003;22:46 (Abstract 2997).
- Markowitz GS, Fine PL, Stack JI, et al. Toxic acute tubular necrosis following treatment with zoledronate (Zometa). Kidney Int 2003;64:281-9.
- Pfister T, Atzpodien E, Bauss F. The renal effects of minimally nephrotoxic doses of ibandronate and zoledronate following single and intermittent intravenous administration in rats. Toxicology 2003;191:159-67.
- Diel I, Bell R, Tripathy D, Body JJ, Bergström B. Renal safety of oral and intravenous ibandronate in metastatic bone disease: phase III clinical trial results. Support Care Cancer 2003;11:415 (Abstract A-106).
- Bondronat product label. Basel, Switzerland: F Hoffmann-La Roche Ltd, 2003.
- DesHarnais-Castel L, Bajwa K, Markle JP, et al. A microcosting analysis of zoledronic acid and pamidronate therapy in patients with metastatic bone disease. Support Care Cancer 2001;9:545-51.
- Powles T, Paterson S, Kanis JA, et al. Randomized, placebo-controlled trial of clodronate in patients with primary operable breast cancer. J Clin Oncol 2002;20:3219-24.
- Cramer JA. Obtaining optimal compliance with drug therapy. Manag Care 2003;12 Suppl 10:9-11.
- Diel I, Pecherstorfer M, Body JJ, et al. Safety and tolerability of oral ibandronate therapy in patients with metastatic bone disease. Eur J Cancer 2003;1 Suppl 5:S135 (Abstract 443).
European Organisation for Research and Treatment of Cancer
European Society for Medical Oncology
Federation of European Cancer Societies
The Zometa International Site