Abstracts of 2nd Scientific Meeting on Bone Disease in Multiple Myeloma
Bisphosphonates into the future
Professor Robert Coleman: Cancer Research Centre, YCR Dept. of Clinical Oncology, Weston Park Hospital, Sheffield, UK
Metastatic bone disease develops as a result of the many interactions between tumour cells and bone cells. This leads to disruption of normal bone metabolism, with the increased osteoclast activity seen in most if not all tumour types providing a rational target for treatment. External beam radiotherapy and systemic endocrine and cytotoxic treatments are the mainstay of treatment in advanced cancers. However, it is now clear that the bisphosphonates provide an additional treatment strategy, which reduces both the symptoms and complications of bone involvement[1]. At present clodronate, usually given orally, and infusions of pamidronate are the two most widely used bisphosphonates in oncology. However, only a small percentage (>5%) of an oral dose of clodronate is absorbed, and for some patients the size and number of capsules required limits compliance, while infusions of pamidronate are time consuming and place additional demands on already overworked intravenous therapy units. The development of more potent bisphosphonates could be expected to simplify treatment and possibly improve the therapeutic effectiveness of bisphosphonate therapy.
Zoledronic acid, a third-generation aminobisphosphonate with a heterocyclic imidazole side chain, is the most potent of the bisphosphonates currently in clinical development. After extensive pre-clinical testing, and because of its high therapeutic ratio in animal models of benign and malignant bone disorders, this compound was selected for evaluation in clinical trials. In the pre-clinical studies, zoledronic acid effectively inhibited bone resorption in vitro and in vivo in microgram quantities which were well tolerated and had little or no undesirable effect on bone mineralization. Long-term studies in ovariectomized rats and monkeys demonstrated increases in bone mineral density, with preservation of bone strength and normal bone architecture[2,3]. Based on these findings, clinical trials in patients with hypercalcaemia of malignancy (HCM), bone metastases, Paget's disease of bone, and osteoporosis were initiated.
A phase I study in thirty patients with hypercalcaemia indicated dose levels as low as 0.02mg/kg (1-2mg total dose) were effective in achieving normocalcaemia[4] and a randomised comparison with pamidronate in hypercalcaemia has now been completed. This has shown more rapid and complete control of hypercalcaemia with zoledronate at doses of 4-8mg (Figure 1)[5].
In normocalcaemic patients receiving zoledronate, a dose dependent reduction in deoxypyridinoline, a specific marker of bone resorption was identified. These biochemical responses were at least as large as those previously reported after infusions of pamidronate 90mg, and pain relief was impressive, particularly at the highest dose of 8mg[6]. Recently, a randomised double-blind, dose finding phase II study of zoledronate has been completed for the treatment of osteolytic metastases from breast cancer and multiple myeloma which defined a dose of 4-8mg of zoledronate as appropriate for phase III evaluation across the spectrum of metastatic bone disease[7].
Three large multicenter, phase III trials in treatment of bone metastases are now completed with zoledronic acid. One goal of these trials is to determine whether zoledronic acid can further improve management of patients with bone metastases, since approximately 50% of patients in the pamidronate trials still developed skeletal complications on bisphosphonate treatment. Protocol 010 is a randomized, double-blind, comparative study of 4/8 mg zoledronic acid and 90 mg pamidronate every 3-4 weeks for a total of 13 months in the treatment of osteolytic lesions in patients with multiple myeloma and breast cancer patients. SREs are the primary efficacy variable, but progression of bone disease (radiological assessment) and biochemical markers of bone resorption will also be monitored. Over 1600 patients have been enrolled in this trial. The phase III programme in bone metastases also evaluates the efficacy and safety of zoledronic acid in patients with cancers other than multiple myeloma and breast cancer (Protocols 011 and 039). Study results for all three trials, which remain blinded, are anticipated in 2001.
Figure 1: Complete response rates (normalized corrected serum calcium) by Day 10 for 4 mg zoledronic acid, 8 mg zoledronic acid, and 90 mg pamidronate - pooled analysis. Adapted from reference [5].
![Figure 1: Complete response rates (normalized corrected serum calcium) by Day 10 for 4 mg zoledronic acid, 8 mg zoledronic acid, and 90 mg pamidronate - pooled analysis. Adapted from reference [5].](images/coleman.gif)
Ibandronate is another highly potent amino-bisphosphonate, which is licensed in Europe for the treatment of hypercalcaemia of malignancy, and in clinical development for both the treatment of metastatic bone disease, and the prevention and treatment of osteoporosis. Bisphosphonates are known to show dose-dependent inhibition of retinoid-induced hypercalcaemia in the thyro-parathyroidectomized rat, and in this model ibandronate was found to be about 2, 10, 50 and 500 times more potent than risedronate, alendronate, pamidronate and clodronate respectively[8]. The intravenous route was 100 times more effective than oral administration, reflecting the typical poor absorption of bisphosphonates. However with such a potent agent, it is anticipated that sufficient amounts of oral ibandronate would be absorbed to inhibit effectively the accelerated bone resorption associated with metastatic bone disease.
Preliminary analysis of a phase III placebo-controlled trial of monthly infusions in breast cancer has shown a significant reduction in skeletal related morbidity with ibandronate 6mg[9]. Lower doses appear largely ineffective in both breast cancer and multiple myeloma.
Originally an oral capsule was developed but this resulted in an unacceptably high incidence of gastro-intestinal adverse event[10]. As a result new formulations were developed including a film-coated tablet which, in animal models, exhibited the same effects on bone resorption as the original capsule. This has been shown to produce a dose dependent reduction, at doses that are generally well tolerated, in both urinary calcium and collagen crosslink excretion[11]. Further development of this oral formulation is anticipated.
References
1 Body JJ, Bartl R, Burckhardt P, Delmas PD et al. Current use of bisphosphonates in oncology. International Bone and Cancer Study Group. J Clin Oncol 16: 3890-3899, 1998.
2 Green JR, Hornby SB, Evans GP, et al: Effect of 1-year treatment with zoledronate (CGP 42446) on bone mineral density, bone mechanical properties, and biochemical markers in the ovariectomized rat. J Bone Miner Res, Abstract M631, 1996 [Medline abstract not available]
3 Binkley N, Kimmel D, Bruner J, et al: Zoledronate prevents the development of absolute osteopenia following ovariectomy in adult rhesus monkeys. J Bone Miner Res 13(11):1775-1782, 1998.
4 Body JJ, Lortholary A, Romieu G, Vigneron AM, Ford J. A dose-finding study of zoledronate in hypercalcaemic cancer patients. J Bone Miner Res 14: 1557-1661, 1999.
5 Major P, Lortholary A, Hon J, Abdi E et al. Zoledronic acid is superior to pamidronate in the treatment of tumour-induced hypercalcaemia: a pooled analysis. J Clin Oncol 2001 19(2): 558-67.
6 Berenson JR, Lipton A, Rosen LS et al. Phase I clinical study of a new bisphosphonate, zoledronate (CGP-42446), inpatients with osteolytic bone metastases. Blood 88: (Suppl 1) 586a, 1998 [Medline abstract not available].
7 Berenson JR, Rosen LS, Howell A, Porter L, Coleman RE et al. Zoledronic acid reduces skeletal related events in patients with osteolytic metastases. Cancer 2001 91(7): 1191-200.
8 Muhlbauer RC, Bauss F, Schenk R, Janner M, Bosies E, Strein K, Fleish H. BM21.0955, a potent new bisphosphonate to inhibit bone resorption. J Bone Miner Res 6: 1003-1011, 1991.
9 Body JJ, Lichinitser MR, Diehl I E et al. Double-blind placebo controlled trial of ibandronate in breast cancer metastatic to bone. Proceedings ASCO 18: 575a, 1999 [Medline abstract not available].
10 Bauss F, Muhlbauer RC. Ibandronate, monosodium salt, monohydrate. Drugs of the Future 19: 13-16, 1994 [Medline abstract not available].
11. Coleman RE, Purohit OP, Black C et al Double-blind, randomised, placebo-controlled study of oral ibandronate in patients with metastatic bone disease. Ann. Oncol 10: 311-316, 1999.