Bisphosphonates and Cancer

Abstract

Bisphosphonates form a family of drugs characterized pharmacologically by their ability to inhibit bone resorption and pharmacokinetically by similar intestinal absorption, skeletal distribution, and renal elimination. Two groups of bisphosphonates exist chemically, non-amino-bisphosphates and amino-bisphosphonates. The amino-bisphosphonates have greater antiresorptive capabilities and represent a newer generation of bisphosphonates. The primary mechanism of action of bisphosphonates is inhibition of osteoclastic activity. Non-amino-bisphosphonates are incorporated into the energy pathways of the osteoclast, resulting in disrupted cellular energy metabolism leading to apoptosis. Amino-bisphosphonates exert their effect on osteoclasts via their inhibition of the mevalonate pathways, resulting in disruption of intracellular signaling and induction of apoptosis. Bisphosphonates also inhibit cancer cell proliferation, induce apoptosis in in vitro cultures, inhibit angiogenesis, inhibit matrix metalloproteinase, have effects on cytokine and growth factors, and are immunomodulatory. Clinical applications in oncology could include therapy for hypercalcemia of malignancy, inhibition of bone metastasis, and therapy for bone pain. Although bisphosphonates are regarded as metabolically inert in the body, adverse effects do occur and include esophagitis, gastritis, suppression of bone repair, and allergic reactions. Little is published on the effects of bisphosphonates in dogs with cancer. Further research into the role of bisphosphonates in veterinary oncology is needed to identify clinical efficacy and safety of these potentially beneficial drugs.