Comparison of the effects of intravenous pamidronate and oral clodronate on symptoms and bone resorption in patients with metastatic bone disease

Annals oj Oncology 12: 1433-1438, 2001. © 2001 Khmer Academic Publishers. Primed in the Netherlands. Original article Comparison of the effects of intravenous pamidronate and oral clodronate on symptoms and bone resorption in patients with metastatic bone disease S.P. Jagdev,1 O.P. Purohit,1 S. Heatley,1 C. Herling2 & R. E. Coleman1 1 Yorkshire Cancer Research Department oj Clinical Oncology. Cancer Research Centre. Weston Park Hospital, Sheffield. UK: Osteometer Biotech, Herlev, Denmark 2 Summary Background: There is considerable debate as to the optimum schedule of bisphosphonate treatment in advanced malignancy. Short term studies using symptomatic response and biochemical markers of bone resorption may provide useful insight into differences between agents. Patients and methods: Fifty-one patients with metastatic bone disease were randomly allocated to either oral clodronate 1600 mg daily (group 1), intravenous clodronate followed by the same schedule of oral clodronate (group 2), or intravenous pamidronate 90 mg monthly (group 3). No radiotherapy was delivered or other systemic anticancer treatments were allowed except for long term endocrine therapy. Bone resorption was assessed by measurement of urinary collagen crosslinks. At each visit a pain score was recorded. Introduction Bone metastases are a frequent cause of morbidity from advanced cancer. Commonly occurring malignancies, such as breast, prostate and lung cancers, metastasise to bone causing considerable problems such as bone pain, loss of mobility, pathological fractures, hypercalcaemia and spinal cord compression. The bisphosphonates are a class of agents that are now established in the management of metastatic bone disease for the relief of bone pain and the prevention of skeletal-related events. They are potent inhibitors of osteoclast-mediated bone resorption [1] and have become the treatment of choice for hypercalcaemia of malignancy [2]. In addition, randomised controlled trials in patients with advanced breast cancer and multiple myeloma have demonstrated that the long-term use of bisphosphonates reduces the number and rate of skeletal complications and improves quality of life [3-7]. The palliation of bone pain is an important aspect in the management of metastatic bone disease. Randomised controlled studies have suggested that intravenous bisphosphonate treatment can provide symptomatic relief [8-10]. An improvement in analgesic use and pain scale scores has been demonstrated with intravenous clodronate treatment in patients with bone metastases Results: Symptomatic response was more frequent in the pamidronate group than in patients receiving clodronate. Nine of sixteen patients experienced a sustained improvement in pain score in the pamidronate-treated group, in contrast to only 4 of 16 and 2 of 11 patients in groups 1 and 2, respectively. There was a significant improvement in pain scores in the pamidronate arm compared with the clodronale treated patients after both three months of treatment (P < 0.01) and at the last measurement (P <0.05). Biochemical changes correlated with changes in the pain score (P - 0.01). Conclusion: Intravenous pamidronate appears to be more effective than oral clodronate in both controlling symptoms and suppressing bone resorption. Key words: bisphosphonates. bone pain, clodronate. collagen crosslinks, pamidronate from a range of tumours [10, 11]. Studies using intravenous pamidronate have also consistently shown beneficial effects in around one half of patients treated [8, 11]. In contrast, the benefits of oral bisphosphonate therapy appear to be variable. The use of either oral etidronate [12, 13] or oral pamidronate [14, 15] has not been shown to have any significant impact on bone pain or skeletal events. Studies with oral clodronate have shown beneficial effects on the development [16] and progression of bone metastases [17], and the ability in some circumstances to prevent skeletal-related events [5,6], but the acute effects on bone pain have been disappointing [18]. The American Society of Clinical Oncolgy (ASCO) guidelines strongly advocate the use of intravenous pamidronate in favour of oral alternatives [19] but elsewhere in the world, especially where oral clodronate is available, there is considerable disagreement on the choice of bisphosphonate and the optimum route of administration. Trials using skeletal related events as the primary endpoint need to be large to provide statistical power and only one preliminary report of a comparison of oral vs. intravenous bisphosphonates has been published [20] However, small trials evaluating pain and biochemical markers may provide a useful indication of relative efficacy. Recent data suggest that normalisation of bone resorption is required for clinical benefit, indi- 1434 Table I Patient characteristics Oral clodronate (n = 18) Arm II IV + oral clodronate (n = 15) Arm III IV pamidronale (n = 18) 63 46 -79 58.5 38-72 66.5 38-78 9 9 5 10 7 II 9 (50%) 6 (33%) 1 (6%) 0 0 2(11%) (1 parotid. 1 melanoma) 5 (33%) 3 (20%) 0 3 (20%) 1 (7%) 3 (20%) (1 unknown primary. 1 cervix. 1 Ewings's sarcoma) 8 (44%) 7 (39%,) 0 2(11%) 0 1 (6%) (1 unknown primary) 2 7 9 1 6 8 0 13 5 6 1-12 8 1-12 8 4-12 2631 188-51820 857 404-12558 1469 231-6767 246 19-849 76 50-850 120 21-346 Arm 1 Age (years) Median Range Sex Male Female Tumour type Breast Prostate Renal Lung Thyroid Other Performance status ECOGO ECOG 1 ECOG2 Clinical score Median Range Crosslaps(U/l) Median Range NTX (nmol/mmol creatinine) Median Range Patients characteristics and baseline evaluation eating that biochemical monitoring may be a surrogate marker for response [21, 22]. The aims of this study were to compare the efficacy of two schedules of clodronate with intravenous pamidronate using pain scores and urinary markers of bone resorption as endpoints. Patients and methods Patient eligibility Patients with histologically proven malignancy and radiographic evidence of widespread, multiple, symptomatic bone metastases were enrolled into the study between July 1997 and June 1999. Patients with lytic. sclerotic and mixed bone lesions were included. The participants were required to have a minimum age of 18 years and to have an Eastern Co-operative Oncology Group (ECOG) performance status of 0-3. All endocrine treatments commenced more than six months prior lo entry in to the study were continued but no other systemic treatment was allowed. Patients requiring urgent systemic treatment, for example due to progressive extraskeletal disease, were not included in the study. Treatment with bisphosphonates or with other drugs known to influence bone metabolism, such as systemic corticosteroids, within the previous three months excluded the patient from the study. Patients with hypercalcaemia (adjusted calcium > 2 6 mmol/l) were also not suitable for the trial. All patients provided written informed consent and the study was approved by t (...truncated)