Thirty years of research have established bisphosphonates as the most effective agents for the inhibition of osteoclast-mediated bone resorption, and they play an important role in the management of malignant bone disease. Bisphosphonates have been systematically improved through chemical engineering, and the newest nitrogen-containing compounds, including zoledronic acid and ibandronate, are 1000-fold more potent than first-generation compounds. Consequently, they can be administered at low molar doses via short intravenous infusions without compromising renal safety. Bisphosphonates have a variety of metabolic effects on osteoclasts. Nitrogen-containing bisphosphonates inhibit protein prenylation via the mevalonate pathway, thereby inhibiting osteoclast activation and inducing apoptosis. Preclinical studies suggest that bisphosphonates also have direct and indirect antitumor activity. In animal models, bisphosphonates reduced skeletal tumor burden and bone metastases. Currently, intravenous bisphosphonates are the standard therapy for hypercalcemia of malignancy, and they have become an integral part of the treatment of bone metastases in conjunction with standard antineoplastic agents. Intravenous bisphosphonates quickly normalize serum calcium, reduce skeletal complications, and palliate bone pain in patients with bone metastases. Intravenous pamidronate (90mg via 2-hour infusion every 3-4 weeks) has, until recently, been the international standard for the treatment of osteolytic bone lesions from breast cancer or multiple myeloma. However, 4mg zoledronic acid (via 15-minute infusion) is quickly becoming the new standard based on evidence that it is as safe and effective as 90mg pamidronate in patients with breast cancer and multiple myeloma and significantly more effective for hypercalcemia of malignancy. Consequently, the American Society of Clinical Oncology guidelines for breast cancer and multiple myeloma recommend pamidronate or zoledronic acid for patients with radiographic evidence of osteolytic bone destruction. Moreover, 4mg zoledronic acid is the only bisphosphonate that has demonstrated significant clinical benefit in patients with other solid tumors, including lung cancer, and prostate cancer patients with primarily osteoblastic bone metastases. Bisphosphonates also may have activity in the adjuvant setting to prevent or delay the development of bone metastases. Studies with oral clodronate in early breast cancer have provided clinical evidence that bone metastases can be inhibited, and the studies are ongoing with more potent bisphosphonates. Bisphosphonates have also been shown to prevent cancer treatment-induced bone loss. These and other studies continue to redefine the role of bisphosphonates in the treatment of malignant bone disease and the management of bone health in cancer patients.
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