Bisphosphonate use in metastatic breast cancer

Skeletal metastatic disease affects more than 70% of patients with breast cancer. These patients frequently demonstrate a prolonged survival with high morbidity. Hypercalcemia, bone pain, and fracture with potential neurologic compromise represent the major morbidity of skeletal metastases. The management of skeletal metastases in breast cancer revolves around the consequences of bone destruction. The lytic destruction of bone is a result of increased osteoclastic activity, prompting the use of bisphosphonates, which reduce osteoclastic activity and inhibit bone resorption. Their use has become the first line of therapy in hypercalcemia of malignancy. Studies with oral clodronate demonstrate efficacy in palliation of bone pain, reduction in analgesic use and of skeletal-related events, and reduction of hypercalcemia. Pamidronate is a second-generation aminobisphosphonate with a potent inhibition of osteoclastic activity and superior results, which can be demonstrated with IV rather than oral administration. This review intended to highlight the current published data on IV pamidronate use in patients with advanced skeletal metastases. Included are large, multi-institutional, prospective, randomized, blinded and nonblinded, controlled trials carried out through the Aredia Multinational Cooperative Group, and a well-designed, nonblinded, controlled trial with uniform crossover from a single institution. The studies are complementary, and each highlights questions and directions of study that are either currently under investigation or still require the development of well-designed studies. Protocol 19 of the Aredia Breast Cancer Study Group produced a large database to establish the safety and efficacy of long-term IV pamidronate use, expanding the treatment and follow-up of the original study patients over 2 years. Significantly fewer skeletal complications were noted in the pamidronate group, which was maintained for the 2 years of study. The treatment was given in conjunction with IV cytotoxic therapy and, consequently, the pamidronate-specific benefit may be partially obscured by the palliative effects of cytotoxic therapy. The trial by Conte is similarly affected with the use of concomitant chemotherapy. Significant data were accrued, however, to reflect both the efficacy and safety of this therapeutic regimen. The use of a blinded controlled trial has been criticized in this population of patients, and the Conte trial overcame this issue by using a nonblind controlled design and subsequent blinded extramural review.The data supporting prolonged PD allow speculation on the use of bisphosphonates to prevent further disease formation or prevent skeletal metastases in an adjunctive setting. The adjuvant use of bisphosphonates in the prevention of skeletal metastases is currently in a trial development phase with consideration of the use of more potent, third-generation IV bisphosphonates or oral clodronate. The issue of length of treatment is unclear, with data suggesting that a protective effect is lost after therapy is discontinued. Long-term use would favor an oral and more cost-effective and quality-of-life-effective route of administration.Evidence for dose responsiveness prompted the use of higher-dose, single-agent, and prolonged therapy. The trial by Coleman et al reflects these study modifications and further advances our knowledge of the metabolic response of bisphosphonates charted with the clinical and qualitative subjective response to treatment. This study helps to elucidate a population of patients with bone metastases, which are more likely to respond, and a method of clinically monitoring response to treatment through the more cost-effective and reproducible ELISAs of bone metabolism. Although higher doses of IV pamidronate were not more effective in obtaining greater rates of subjective response, ELISAs did demonstrate effective bone resorptive activity. A decrease in the incremental change in subjective scoring was seen over time despite objective evidence of bone resorption. Consequently, this prompts the question of whether a third-generation bisphosphonate—such as zoledronate, with a potency that has been demonstrated to be greater than 100 times that of second-generation bisphosphonates—could affect an improved or sustained, subjective clinical benefit. Studies might also be designed to elucidate and overcome mechanisms of bisphosphonate resistance. The development and utilization of agents to affect non-osteoclastic-mediated mechanisms of bone destruction could lead to a greater subjective response when used in conjunction or independently of bisphosphonates. Certainly the results of these studies highlight the multifactorial process associated with subjective and clinical skeletal-related events. The long-term survival of patients with skeletal metastases and the associated morbidity underscore the crucial, beneficial, palliative effects of the bisphosphonates in breast cancer. The potential for long-term use in both the metastatic and adjunctive settings should prompt the addition of formal cost-benefit analyses to future prospective study designs.