Bisphosphonates in oncology: physiopathologic bases and clinical activity

Osteoclastic activation is the ultimate way of bone resorption in neoplasia, induced by the combined effects of tumor-secreted humoral factors (especially parathyroid hormone-related peptides) and osteoclastic-osteoblastic interaction. Bisphosphonates inhibit the osteoclast activity and reduce bone resorption and are a valuable supportive measure for bone disease of neoplasms. Experimental models also suggest an activity of bisphosphonates against cancer cells. Controlled studies, especially in advanced breast cancer and multiple myeloma, indicate different effectiveness against the distinct skeletal-related events. Intravenous clodronate and, especially, pamidronate and zoledronate are the first-choice drugs for hypercalcemia, and they play a significant role in reducing metastatic bone pain. Their prolonged use delays, without hampering, the progression of bone disease, including the appearance of osteolysis and the occurrence of pathologic fractures. This effect is probably more valuable when bisphosphonates are administered early in the course of the disease. The evidence that adjuvant bisphosphonates improve survival needs to be confirmed in ongoing studies. Although poorly absorbed by the gastrointestinal tract, oral bisphosphonates are effective in preventing and treating cancer-induced osteoporosis in long-living patients with operable breast cancer. At present, there is little hope that newer bisphosphonates are more effective than those currently used.