Cost-effectiveness of Oral Clodronate Compared with Oral Ibandronate, Intravenous Zoledronate or Intravenous Pamidronate in Breast Cancer Patients

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1 The Journal of International Medical Research 2008; 36: Cost-effectiveness of Oral Clodronate Compared with Oral Ibandronate, Intravenous Zoledronate or Intravenous Pamidronate in Breast Cancer Patients A PATERSON 1, E MCCLOSKEY 2, J REDZEPOVIC 3, I OTT 3 AND R GUST 3 1 Department of Oncology, Tom Baker Cancer Centre, University of Calgary, Calgary, Alberta, Canada; 2 Northern General Hospital, Sheffield, UK; 3 Institute of Pharmacy, Free University of Berlin, Berlin, Germany This study aimed to identify the effects of different bisphosphonates in reducing skeletal-related events, and to determine whether there are any differences in their cost-effectiveness, taking into account their efficacy, safety profile and administration routes. A systematic literature search of databases, such as PubMed and the Cochrane Controlled Trials Register, supplemented by the latest congress abstracts from meetings of the European Hematology Association and the American Society of Clinical Oncology was conducted up to November Important references in reviews published by peer-reviewed journals were also taken into consideration. Our base-case costeffectiveness analysis for Germany and the UK showed cost savings for oral clodronate therapy compared with other bisphosphonate therapies. In Germany, costs per patient of treatment with oral clodronate were , and less than with oral ibandronate, intravenous pamidronate and intravenous zoledronate, respectively. The UK results were similar, the costs per patient of treatment with oral clodronate being , and less than with oral ibandronate, intravenous pamidronate and intravenous zoledronate, respectively. KEY WORDS: BISPHOSPHONATES; CLODRONATE; IBANDRONATE; PAMIDRONATE; ZOLEDRONATE; BREAST CANCER; METASTATIC BONE DISEASE; CANCER TREATMENT COSTS Introduction Metastatic bone disease is a common and debilitating complication of cancer. 1 Malignant cells, often in a viciously cyclic action, stimulate osteoclast bone resorption whilst the products of this resorption lead to stimulation of further tumour growth. 2 The resulting bone destruction causes complications, such as pathologic fractures, mild, moderate and severe bone pain, impaired mobility, spinal cord compression and hypercalcaemia, leading to greater morbidity and poorer quality of life (QOL) for patients. Management of these 400

2 complications can include treatment with bisphosphonates. Bisphosphonates are a class of drug that binds to hydroxyapatite bone mineral surfaces. They are internalized by osteoclasts, resulting in the inhibition of osteoclastic activity. 3 While nitrogencontaining bisphosphonates inhibit the mevalonate pathway (the main target being farnesyl diphosphate synthase) nonnitrogen-containing bisphosphonates are incorporated into hydrolytically stable analogues of adenosine triphosphate. Both events cause an impairment of osteoclast cell function and, ultimately, lead to osteoclast apoptosis. 4 Bisphosphonates have been shown to lower the incidence and delay the onset of skeletal complications. 5 7 Furthermore, these agents play an important secondary role in the management of bone pain. 8 In patients with breast cancer, the risk of developing osteoporosis is increased due to premature ovarian failure, largely due to chemotherapy or possibly in some patients due to the effects of the breast cancer itself. Women with breast cancer have a five times higher incidence of vertebral fractures than women without breast cancer. 9 Clinical trials have shown a number of bisphosphonates, including clodronate, ibandronate, pamidronate and zoledronic acid, to be effective in patients with bone metastases arising from breast cancer. 4 The latest Cochrane Collaboration Systematic Review on the role of bisphosphonates in treating breast cancer advocates their use as a standard treatment for patients with bone metastases. 10 Although the use of bisphosphonates is associated with increased pharmaceutical acquisition costs, pharmacoeconomic studies have shown that they not only have clinical benefits and improve patients overall QOL but they also lower expenses by reducing costs incurred as a result of skeletal-related events. 8,11 13 The aim of the present study was to determine whether there are differences in the cost-effectiveness of bisphosphonates, based on their efficacy, safety profiles and differing routes of administration. Patients and methods LITERATURE SEARCH A systematic literature search was conducted of databases, such as PubMed and the Cochrane Controlled Trials Register (all years, latest issue November 2006), supplemented by the latest congress abstracts from meetings of the European Hematology Association and the American Society of Clinical Oncology ( ). Relevant references in reviews published by peer-reviewed journals were also taken into consideration. THE COST MINIMIZATION MODEL Based on data from individual clinical studies and with a paucity of large, comparative trials on bisphosphonates, we assumed that all bisphosphonates had equal efficacy in reducing skeletal-related events. The most appropriate cost minimization model was chosen based on the different safety profiles of the bisphosphonates. Other key assumptions used in the model were: (i) a mean average survival of 14.3 months for patients with metastatic breast cancer, based on a cost-effectiveness model of pamidronate versus placebo; 6,14 (ii) all metastatic breast cancer patients received intravenous (IV) chemotherapy and bisphosphonates; (iii) IV bisphosphonate therapy required hospital visits every month for infusion and monitoring, as opposed to every 3 months for the monitoring of patients receiving oral bisphosphonates (clodronate or ibandronate); 401

3 (iv) mild, moderate or severe renal impairment rates of 8% for IV pamidronate and IV zoledronate, 0.5% for oral clodronate and 1% for oral ibandronate; (v) osteonecrosis of the jaw incidence of 0.01% for clodronate, 0.5% for ibandronate, and 1% for pamidronate and zoledronate, and a probability of renal failure of 0.015% for zoledronate and pamidronate and 0.001% for ibandronate and clodronate; (vi) reduction of 29% by bisphosphonates in skeletal-related events. INPUTS INTO THE MODEL Efficacy Bisphosphonates are part of standard treatment for preventing the occurrence of skeletal-related events from metastatic bone disease. The key driver for the efficacy of bisphosphonates in our model was, therefore, the number of skeletal-related events for each treatment group identified in randomized controlled trials. Although several authors have claimed differing efficacies for various bisphosphonates based on their routes of administration, this has not been demonstrated in clinical studies (Table 1, Fig. 1). In all trials, bisphosphonates proved superior to placebo in reducing the risk of skeletal-related events (P < ; Fig. 1) and as shown by the risk ratios of < 1.0 (Table 1), the reporting of skeletal-related events and, in particular, their rate over time TABLE 1: Summary of bisphosphonate trials assessing skeletal-related events (SREs) associated with breast cancer metastatic to bone SREs/year per patient in SREs/year SRE Patients bisphosphonate per patient in reduction Main author/year (n) group placebo group (%) Risk ratio Clodronate versus placebo/ observation Paterson et al Kanis et al Kristensen et al Tubiana-Hulin et al Pamidronate versus placebo/ observation Hultborn et al Theriault et al Ibandronate versus placebo Body et al (IV) Body et al (oral) Comparison of two bisphosphonates Rosen et al (zoledronate) (pamidronate) Zoledronate versus placebo Kohno et al IV, intravenous. 402

4 Study or sub-category Bisphosphonates n/n Control n/n Odds ratio (random) 95% confidence interval Weight % Odds ratio (random) 95% confidence interval Cleton et al Paterson et al Conte et al Hultborn et al Kristensen et al Hortobagyi et al Tubiana-Hulin et al Kohno et al /81 55/90 72/ /201 14/48 194/367 42/69 35/114 63/80 70/95 263/ /203 21/51 263/384 45/68 59/ (0.24,0.98) 0.56 (0.30,1.05) 0.75 (0.49,1.16) 0.85 (0.53,1.37) 0.59 (0.26,1.36) 0.52 (0.38,0.69) 0.80 (0.40,1.60) 0.41 (0.24,0.70) Total (95% confidence interval) Total events: 620 (bisphosphonates), 947 (control). Test for heterogeneity: χ 2 = 7.11, d.f. = 7 (P = 0.42), I 2 = 1.5% Test for overall effect: Z = 5.75 (P < ) Favours treatment Favours control 0.59 (0.50,0.71) FIGURE 1: Bisphosphonates versus control for overall risk of skeletal-related events in breast cancer patients varied across the studies. According to the performed heterogeneity test (χ 2 = 7.11, degrees of freedom = 7, P = 0.42) these studies are not statistically heterogeneous in their estimate of efficacy (Fig. 1). However, only limited comparison is possible of the average number and reduction of skeletal-related events for each drug, due to differences in patient populations, time horizons and measures of efficacy (different skeletal-related events measured). Furthermore, apart from a comparative study of pamidronate and zoledronate by Rosen et al., 15 and a study comparing oral and IV clodronate, and IV pamidronate by Diel et al., 28 there are no other direct comparative studies. Quality of life In patients with bone metastases, skeletal complications negatively affect QOL and survival, and result in increased healthcare costs. Bisphosphonates have been shown in numerous clinical studies to reduce skeletal-related events significantly in patients with bone metastases from breast cancer. 5,18 20,24,25,27 Bisphosphonate therapy can provide savings in direct and indirect healthcare costs while improving QOL, as has been demonstrated in several recent economic analyses of bisphosphonates. 8,11 13 The expected healthcare costs directly attributable to pathological fracture, the most common skeletal-related event, 14 were estimated to be in Germany and in the UK. 29 The QOL improvement resulting from reduced occurrence of skeletal-related events following bisphosphonate therapy was assumed in our model to be 29% for all bisphosphonates. Safety and its effects on costs Bisphosphonates are generally well tolerated, although they are occasionally associated with adverse events. 15 All bisphosphonates can cause hypocalcaemia, regardless of their method of administration, though this is infrequently found to be a clinically symptomatic problem. The most common side-effects with oral bisphosphonates (depending on whether an aminobisphosphonate or a nonaminobisphosphonate is being used) are upper gastrointestinal, such as gastritis 30 and diarrhoea. 31 IV infusions can be associated with injection site reaction and acute systematic inflammatory reactions. 16 Renal dysfunction is a particularly problematic adverse event which may also 403

5 occur after infusion of IV bisphosphonates; however, the incidence may vary between agents, depending on renal uptake and elimination. The US Food and Drug Administration (FDA) reported that 72 patients suffered renal failure following zoledronate therapy. 32 As a result, the product labels of pamidronate and zoledronate were amended to include additional nephrotoxicity warnings. The incidence of renal impairment with IV pamidronate was 8% in the non-inferiority trial of zoledronic acid and pamidronate for patients with bone metastases from breast cancer or multiple myeloma. 33 We also assumed the same incidence of 8% for both pamidronate and zoledronate in our model. The assumed incidence of renal impairment was taken to be 1% for ibandronate and 0.5% for clodronate. Input into our model incorporated probabilities of renal failure of 0.015% for zoledronate and pamidronate, and 0.001% for ibandronate and clodronate and these values are also supported by expert clinical opinion, according to the internal Bayer Schering Pharma database. We used the following definition of renal impairment: a serum creatinine increase of 0.5 mg/dl if baseline serum creatinine was < 1.4 mg/dl; a serum creatinine increase of 1.0 mg/dl if baseline serum creatinine was 1.4 mg/dl; or a serum creatinine increase of twice the baseline value. Our cost minimization model also took into account the potential effects of osteonecrosis of the jaw on treatment-related costs. A link between bisphosphonate treatment and osteonecrosis of the jaw has been identified and described in recent years A recent report stated that 94% of published cases of osteonecrosis of the jaw were in patients with multiple myeloma and metastatic carcinoma who were receiving IV aminobisphosphonates; accordingly, these patients were at the greatest risk of osteonecrosis of the jaw. 38 The reported incidence of osteonecrosis of the jaw, which has been linked to the nitrogenous structure of some bisphosphonates, has ranged from 0.8% to 7% and may vary from country to country. 39 We assumed an incidence of 1% for pamidronate and zoledronate, and 0.5% for the newer oral agent, ibandronate, based on recently published reports. 37,38 Although only a negligible number of cases of osteonecrosis of the jaw have occurred with oral clodronate (a non-aminobisphosphonate), we assumed an incidence of 0.01% for this agent. RESOURCE USED UNIT HEALTHCARE COSTS We identified the healthcare costs for all bisphosphonate therapies over an assumed survival period of 14.3 months based on previous published cost-effectiveness studies. 6,11,14 These costs included the medical costs of skeletal-related event care for pathological fractures, personnel, supplies and medication, as well as the costs for management of adverse events caused by bisphosphonates, such as renal failure or osteonecrosis of the jaw. Our model also included non-medical healthcare costs, such as transportation to hospital and patient costs (counted as 1 h absence from work during the hospital visit, using the minimum hourly wage in each country). Drug acquisition costs were taken from the British National Formulary 40 in the UK and the Rote Liste 41 in Germany. Tables 2 5 show the unit costs of healthcare resources for the UK and Germany (up until November 2006). STATISTICAL ANALYSES Heterogeneity of the efficacy data obtained for use in this study included randomized clinical trials (Fig. 1) and was tested by using 404

6 TABLE 2: Unit costs (per patient) of healthcare resources in Germany up to November 2006 Cost driver Unit cost Source Skeletal-related event management Pathological fracture Finnern and Sykes Intravenous administration costs Personnel Physician 94.05/h (west) /h (east) Pharmacy technician 7.92/h (west) /h (east) Nurse 52.18/h (west) WSI-Tarifarchiv /h (east) Supplies Needle Gauze Alcohol swab Syringe Set of gloves Medical tape Sample tubes Disposable intravenous set ml of 5% dextrose solution Transportation costs Car rides (cost/km) 0.10 Current cost of petrol ( 1.20/l, 0.8 l/km) Taxi rides (cost/km) taxitarif.html Bus ticket (return) Munich Ambulance ride Walking 0.00 Patient s costs Minimum wage/h 7.50 mindestlohn.verdi.de Renal failure Home dialysis/year Gebührenordnung für Ärzte (GOÄ) 1 April 2005 ( ) Hospital dialysis/year Gebührenordnung für Ärzte (GOÄ) 1 April 2005 ( ) Home dialysis/session Gebührenordnung für Ärzte (GOÄ) 1 April 2005 ( ) Hospital dialysis/session Gebührenordnung für Ärzte (GOÄ) 1 April 2005 ( ) 405

7 TABLE 2 (continued): Unit costs (per patient) of healthcare resources in Germany up to November 2006 Cost driver Unit cost Source Osteonecrosis of the jaw management Physician (follow-ups every 2 3 weeks) 94.05/h (west) /h (east) Dentist 49.94/h (west) KZBV Yearbook, 2004, 45.28/h (east) Bundesagentur für Arbeit, 2005 Dental hygienist 10.71/h Zahntechniker-Innung Berlin 2004, Handwerkskammer, Hamburg 2005, Berufenet 2005 Chlorhexidine mouthwash (250 ml) Surgical removal of necrotic bone php?id=127 Amoxicillin (cost/day) Clindamycin (cost/day) TABLE 3: Medication costs in Germany up to November 2006 Cost/ 28-day Medication package Package size Dose/unit cost/unit Source Oral clodronate mg mg/day (Bonefos ) Oral ibandronate mg mg/day (Bondronat ) IV zoledronic acid mg Chemist s (4 mg/3 4 weeks) information (Zometa ) IV pamidronate (90 mg/ mg weeks) (Aredia ) rhuepo (Eprex ) x 0.5 ml 1000 IU/0.5 ml ACE inhibitors (Captopril ) mg Morphine (Kapanol ) mg Oxycodone (Oxygesic ) mg Paracetamol (paracetamol mg STADA ) IV, intravenous; rhuepo, recombinant human erythropoietin; ACE, angiotensin-converting enzyme. 406

8 TABLE 4: Unit costs (per patient) of healthcare resources in the UK up to November 2006 (exchange rate as at 24 November 2006) Cost driver Unit cost Source Skeletal-related event management Pathological fracture Finnern and Sykes Intravenous administration costs Personnel Physician ( ) Pharmacy technician ( 16.25) Nurse ( 26.60) Supplies Needle 0.07 ( 0.10) Gauze 0.04 ( 0.06) Alcohol swab 0.02 ( 0.03) Syringe 0.09 ( 0.13) Set of gloves 0.04 ( 0.04) Medical tape 0.62 ( 0.92) Sample tubes 0.05 ( 0.07) Disposable intravenous set 0.80 ( 1.18) ml of 5% dextrose solution 8.15 ( 12.04) Transportation costs Car rides (cost/km) 0.73 ( 1.08) Taxi rides (costs/km) 3.85 ( 5.70) taxi/londontariff.htm Bus ticket (return) 6.00 ( 8.86) Travel/Transport/ Ambulance rides ( 86.47) Walking 0.00 Patient s costs Minimum wage/h 5.35 ( 7.91) Renal failure Home dialysis/year ( ) TA48 Hospital dialysis/year ( ) Home dialysis/session ( 34) Hospital dialysis/session 146 ( ) Osteonecrosis of the jaw management Physician (follow-ups every ( ) weeks) uc2005/uc2005_s13.pdf Dentist ( 35.90) Dental nurse 9.61 ( 14.20) Chlorhexidine mouthwash (Chlorohex, 2.20 ( 3.25) ml) current/index.htm Surgical removal of necrotic bone ( )Smith and Cunningham Amoxicillin (generic) 1.38 ( 2.04) Mehta D Clindamycin ( 20.27) Mehta D IV, intravenous. 407

9 TABLE 5: Medication costs in the UK up to November 2006 (exchange rate as at 24 November 2006) Cost/ 28-day Medication package Package size Dose/unit cost/unit Source Oral clodronate mg Mehta mg/day (Bonefos ) ( ) Oral ibandronate mg Mehta mg/day (Bondronat ) ( ) IV zoledronic acid mg Mehta (4 mg/3 4 week) ( ) Zometa IV pamidronate (90 mg/ No 4 90 mg De Cock et al. 3 4 weeks) Aredia information ( ) rhuepo (Eprex ) x 0.5 ml 1000 IU/ 7.96 Mehta ml ( 11.76) ACE inhibitors (Captopril ) mg 1.71 Mehta ( 2.53) Morphine (MST Continus ) mg Mehta ( 32.24) Oxycodone (OxyContin ) mg Mehta ( 35.90) Paracetamol (Remedeine ) mg 5.11 Mehta ( 7.55) IV, intravenous; rhuepo, recombinant human erythropoietin; ACE, angiotensin-converting enzyme. both fixed and random models; the χ 2 statistic was calculated. RevMan 4.1 (Cochrane Collaboration, Oxford, UK) statistical software was used to perform meta-analysis. Dichotomous efficacy data were summarized using the Peto odds ratio. Risk ratios were calculated to compare bisphosphonates with placebo in reducing the risk of skeletal-related events. Metaanalysis was restricted to those trials from which suitable efficacy data could be extracted (Fig. 1). Cost data were extracted from published data and heterogeneity was assessed using a Wilcoxon s signed-rank test with the Statistical Package for the Social Sciences Software (SPSS ) version 13.0 (SPSS Inc., Chicago, IL, USA). One-way sensitivity analysis on the key assumptions regarding the incidence of osteonecrosis of the jaw and renal impairment was also undertaken to investigate how this influenced base case costs in the UK and Germany. For all analyses, a P-value of < 0.05 was considered significant. Results BASE COST ANALYSIS Tables 6 and 7 show base cost-effectiveness in Germany and the UK, respectively, simulating the results for a patient receiving bisphosphonate and IV chemotherapy for 408

10 TABLE 6: Base case cost-effectiveness (per patient) in Germany for a patient receiving bisphosphonates and IV chemotherapy for metastatic bone disease resulting from breast cancer Cost driver Oral clodronate Oral ibandronate IV zoledronate IV pamidronate Management of vertebral fracture Drug acquisition Personnel and supply Patient s costs Transportation costs Renal impairment and failure ONJ management Total cost/patient IV, intravenous; ONJ, osteonecrosis of the jaw. TABLE 7: Base case cost-effectiveness (per patient) in the UK for a patient receiving bisphosphonates and IV chemotherapy for metastatic bone disease resulting from breast cancer Cost driver Oral clodronate Oral ibandronate IV zoledronate IV pamidronate Management of vertebral fracture Drug acquisition Personnel and supply Patient s costs Transportation costs Renal impairment and failure ONJ management Total cost/patient IV, intravenous; ONJ, osteonecrosis of the jaw. metastatic bone disease resulting from breast cancer. With a survival period of 14.3 months, the model projects the total cost of treatment (including drug acquisition), renal failure, cost incurred by the patient when presenting themselves for an IV infusion (we assumed 1 h), cost of travel to the hospital and osteonecrosis of the jaw management. In Germany, the cost per patient of treatment with oral clodronate was less than with oral ibandronate, less than with IV pamidronate and less than with IV zoledronate (Table 6). The results in the UK were similar, the cost per patient of treatment with oral clodronate being less than with oral ibandronate, less than with IV pamidronate and less than with IV zoledronate (Table 7). Statistical analysis by Wilcoxon s signedrank test indicated no heterogeneity between total costs in the UK and Germany (Table 8). 409

11 TABLE 8: Test for heterogeneity of total costs for the UK and Germany using Wilcoxon s signed-rank test UK 1 UK 2 UK 3 UK 4 Germany 1 Germany 2 Germany 3 Germany 4 Oral Oral IV IV clodronate ibandronate zoledronate pamidronate Z-value Asymptotic significance (two-tailed) IV, intravenous. Variations in the rates of incidence of osteonecrosis of the jaw and renal impairment caused a negligible change in outcomes per product per country. Discussion Our model projected that total costs per patient of oral clodronate treatment are less expensive in both the UK and Germany than those of oral ibandronate, IV pamidronate or IV zoledronate. The results in each country showed no heterogeneity. The model assumed the same bisphosphonate efficacy of 29% reduction in skeletal-related events. The improvement in QOL, resulting from fewer skeletal-related events, was also assumed in our model to be equal for all bisphosphonates. There have been no convincing comparative clinical trials to demonstrate the superiority of efficacy of one bisphosphonate over another in the prevention of skeletal-related events. Comparing efficacy in trials performed in different populations of patients and over different time periods is an inaccurate technique whatever statistical methodology is applied. This also applies to comparisons of side-effects and toxicity but, in the absence of direct comparative trials, our model took into account the various safety profiles of bisphosphonates that have been published in the literature. Bisphosphonate therapy can provide significant savings in terms of direct and indirect healthcare costs and improving overall QOL, as demonstrated in several recent economic analyses. 8,11 13 We have shown that oral clodronate, when used to prevent skeletal-related events in patients with bone metastases arising from breast cancer, has a favourable cost benefit profile compared with oral ibandronate, IV zoledronate or IV pamidronate. Depending on the frequency of follow-up visits this may be greater than we have demonstrated; some patients with stable bone metastases could be followed every 6 months rather than the 3-months period that we assumed. We believe there is a role for the use of both oral and IV bisphosphonates depending on the clinical setting. Patients on chemotherapy who are attending a clinic every 3 or 4 weeks can be managed with IV clodronate, pamidronate or zoledronate; this adds little extra cost other than the increased time spent during each visit to the clinic. Patient preference and convenience has been shown to vary widely, some patients preferring oral medication with less frequent clinic visits whilst others prefer IV therapy. This has been assessed, for example, by questionnaire in metastatic colorectal carcinoma, where patients clearly showed a preference for oral tegafur uracil (UFT) over 410

12 IV 5-fluorouracil/leucovorin treatment. 43 In endocrine therapy of breast cancer, the great majority of patients preferred oral tamoxifen to intramuscular (IM) fulvestrant from the convenience perspective (Fallowfield LJ, unpublished). Generally with oral therapy the patient has more control and it gives them more time to spend with friends and family. There are also no problems with IV access and lines, resulting in fewer resources used in clinics. Nevertheless, there can be advantages to IV therapy, with better compliance and more precise dosing. There may also be fewer gastrointestinal sideeffects. In the patient with breast cancer with bone metastases, choice of bisphosphonate therapy depends on the most appropriate route of therapy for the clinical setting, as well as considerations of tolerability, sideeffects and potential toxicity. We believe that arguments citing cost savings with the use of IV bisphosphonates to the exclusion of oral medications are inaccurate and misleading. Our model was applied to the German and UK national healthcare systems and, in both countries, oral clodronate was more cost-effective than oral ibandronate, IV pamidronate or IV zoledronate. Further international analysis of the costeffectiveness of bisphosphonates using this model is warranted. From the perspectives of the UK and German national healthcare systems, the present study has shown oral clodronate to be a cost-effective treatment for breast cancer patients with bone metastasis compared with oral ibandronate, IV zoledronate and IV pamidronate. Not only does oral clodronate eliminate the costs of administration, monitoring and clinic attendance associated with bisphosphonate infusion, but long-term experience with its use over the past 20 years has also proven its favourable safety profile, which provides maximum savings in the management of adverse events. Conflicts of interest The authors had no conflicts of interest to declare in relation to this article. Received for publication 16 November 2007 Accepted subject to revision 27 November 2007 Revised accepted 28 March 2008 Copyright 2008 Field House Publishing LLP References 1 Coleman RE: Skeletal complications of malignancy. Cancer 1997; 80(suppl 8): Mundy GR: Bisphosphonates as anticancer drugs. Expert Opin Investig Drugs 1999; 8: Rogers MJ, Gordon S, Benford HL, et al: Cellular and molecular mechanisms of action of bisphosphonates. Cancer 2000; 88: Brown JE, Neville-Webbe H, Coleman RE: The role of bisphosphonates in breast and prostate cancers. Endocr Relat Cancer 2004; 11: Paterson AH, Powles TJ, Kanis JA, et al: Doubleblind controlled trial of oral clodronate in patients with bone metastases from breast cancer. J Clin Oncol 1993; 11: Hortobagyi GN, Theriault RL, Porter L, et al for the Protocol 19 Aredia Breast Cancer Study Group: Efficacy of pamidronate in reducing skeletal complications in patients with breast cancer and lytic bone metastases. N Engl J Med 1996; 335: 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: Costa L, Lipton A, Coleman RE: Role of bisphosphonates for the management of skeletal complications and bone pain from skeletal metastases. Support Cancer Ther 2006; 3: Kanis JA, Powles T, Paterson AH, et al: Clodronate decreases the frequency of skeletal metastases in women with breast cancer. Bone 1996; 19: Pavlakis N, Schmidt RL, Stockler M: Bisphosphonates for breast cancer. Cochrane Database Syst Rev 2005; CD De Cock E, Hutton J, Canney P, et al: Cost- 411

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