Progress in the Management of Bone Metastases: One Continent at a Time?

Bone metastases are a common extension of breast, prostate, and lung cancers, multiple myeloma, malignant lymphomas, and to a lesser extent, other solid tumors. In addition to pain, bone metastases frequently cause complications such as pathologic fractures, hypercalcemia, and spinal cord compression. These complications have a major impact on quality of life, and their control requires multiple therapeutic interventions. Over the last 20 years, bisphosphonates became an integral part of the management of bone metastases. Bisphosphonates are pyrophosphate analogs with potent antiresorptive activity, based on inhibition of osteoclast activity, recruitment, and differentiation. Multiple clinical trials have demonstrated that bisphosphonates represent the treatment of choice for hypercalcemia of malignancy. Initially pamidronate, then zoledronic acid, became the standard of care for managing acute hypercalcemia. Clinical studies in patients with bone metastases also indicated that bisphosphonate therapy had analgesic effects and produced radiographically detectable sclerotic changes in osteolytic lesions. These observations, coupled with anecdotal reports of decreased skeletal complications, led to formal evaluation of bisphosphonates in the management of osteolytic bone metastases more than a decade and a half ago. Clinical trials with clodronate strongly suggested, and randomized trials with intravenous pamidronate clearly demonstrated, that bisphosphonate therapy used in association with standard anticancer interventions reduced the incidence and severity of all skeletal complications, or—as it has become customary to report— “skeletal-related events.” In addition to a dramatic reduction in the incidence of hypercalcemia, these studies also documented significant reductions in pathologic fractures, spinal cord compression, pain, analgesic requirements, and the need for radiation therapy or surgical interventions to treat or prevent fractures. These placebo-controlled randomized clinical trials were critical in establishing efficacy using a number of “soft” end points, such as changes in pain score, analgesic requirements, and even the utilization of specific therapies, such as surgery or radiation therapy. Only such carefully controlled trials could keep patient and physician bias and the placebo effect of treatment from resulting in outcome differences. The results of these trials were compelling enough to facilitate the registration of bisphosphonates as appropriate therapy for the management of osteolytic metastases in North America, Western Europe, and most of the rest of the world. Subsequent clinical trials with zoledronic acid, a more potent aminobisphosphonate, extended these observations to other tumor types and to patients with osteoblastic metastases. In patients with breast cancer and multiple myeloma, the studies compared zoledronic acid to pamidronates, which was the established standard of care. These studies demonstrated that zoledronic acid was not only more convenient to use, but was also more effective, further reducing skeletal-related events. In this issue of the Journal of Clinical Oncology, Kohno et al present the results of a prospective randomized trial of zoledronic acid in the management of bone metastases in Japanese patients. The design is identical to the original studies with pamidronate and clodronate performed more than a decade ago, and the implementation of the study was, by all appearances, impeccable. The results confirm that zoledronic acid is a potent antiresorptive agent that significantly reduces the frequency and severity of skeletal-related events in patients with bone metastases. What have we learned from this trial? We learned that the administration of zoledronic acid to Japanese women with metastatic breast cancer was safe and well tolerated, in keeping with all other studies performed to date anywhere in the world. We learned that zoledronic acid has significant activity in patients with bone metastases, as demonstrated in previous studies. JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L VOLUME 23 NUMBER 15 MAY 2