A randomized trial of the effect of clodronate on skeletal morbidity in multiple myeloma

Abstract

In patients with multiple myeloma, despite a major reduction of bone pain achieved with chemotherapy, skeletal disease continues to progress. The effects of clodronate, an inhibitor of osteoclastic bone resorption, are evaluated on the natural history of skeletal disease in patients with newly diagnosed multiple myeloma. Within the framework of the VIth MRC Multiple Myeloma Trial, 536 patients (218 women, 318 men) with recently diagnosed multiple myeloma were randomized to receive either clodronate 1600 mg daily (n=264) or an outwardly identical placebo (n=272) in addition to chemotherapy. Treatment with clodronate was associated with a 50% decrease in the proportion of patients with severe hypercalcaemia (5.1% v 10.1%, P=0.06) and a similar reduction in reported non-vertebral fractures (6.8% v 13.2%, P=0.04). Fewer patients receiving clodronate sustained vertebral fractures after entry to the trial (38% v 55%, P=0.01) and patients also lost less height over 3 years compared to those receiving placebo (2.0 v 3.4 cm, P=0.01). Biochemical indices of bone turnover were significantly lower in patients receiving concomitant clodronate, both at plateau and at disease relapse. The frequencies of back pain and poor performance status were significantly lower at 24 months in clodronate than in placebo-treated patients (10.9% v 19.9%, P=0.05, and 18.3% v 30.5% P=0.03 respectively.) There was no statistically significant difference in survival between the clodronate and placebo treated patients. The study indicates that long-term oral clodronate slows the progression of skeletal disease in multiple myeloma and decreases the associated morbidity. Patients without overt skeletal disease at diagnosis were also found to benefit from clodronate, indicating that this treatment should be initiated as early in the course of the disease as possible.

Bisphosphonates: Mode of Action and Pharmacology

“…There is the important possibility that the survival of patients may be prolonged [107][108][109] in some groups of patients. Recently, osteonecrosis of the jaw 110 was identified as a potential complication of high-dose bisphosphonate therapy in malignant diseases.…”

Growth inhibition and synergistic induction of apoptosis by zoledronate and dexamethasone in human myeloma cell lines

“…8 Clinical studies have suggested that BPs may induce a reduction of the tumor burden 9 and may prolong the survival of MM patients. 10,11 We have evaluated if the combination of zoledronate (Zln), a potent antiresorptive BP, 12 and dexamethasone (Dex), which is commonly used in the treatment of MM, could strengthen the inhibition of cell growth and the induction of apoptosis in human myeloma cell lines in vitro. Here, we show that the combination of both agents results in synergistic anti-myeloma effects, providing a rationale for in vivo investigations on this therapeutical combination.…”

The bisphosphonate, zoledronic acid, induces apoptosis of breast cancer cells: evidence for synergy with paclitaxel

“…In recent years bisphosphonates have become important in the management of cancer-induced bone disease and are now well established in the management of patients with multiple myeloma and bone metastases secondary to breast cancer (Paterson et al, 1993;Berenson et al, 1996;Hortobagyi et al, 1996;Diel et al, 1998;McCloskey et al, 1998;Theriault et al, 1999). Randomized controlled trials in patients with breast cancer have demonstrated that clodronate and pamidronate reduce skeletal morbidity and improve quality of life (Paterson et al, 1993;Hortobagyi et al, 1996;Kanis et al, 1996).…”