Clinical trials with bisphosphonates

Bisphosphonates are nonbiodegradable pyrophosphate analogs that are capable of inhibiting bone resorption in vivo and in vitro. For this reason they have been used as effective therapeutic agents in several conditions characterized by increased bone turnover, including Paget's disease, hypercalcemia of malignancy, and metastatic bone disease. More recently, bisphosphonates have been proposed for the treatment and prevention of bone loss in several forms of osteoporosis. Etidronate, the first bisphosphonate to be used in clinical trials, has been found to increase vertebral bone mineral mass in osteoporotic patients. However, the gain in bone mass reaches a plateau after 1-2 years of treatment, with no further increase thereafter. No positive effect on osteoporotic fracture rate has been clearly demonstrated. Moreover, etidronate has been shown to impair bone formation and mineralization at therapeutic doses. Newer, more potent bisphosphonates selectively inhibit bone resorption without impairing bone histology and mechanical strength. Pamidronate has been shown to increase vertebral bone mass in patients with steroid-induced osteoporosis and involutional osteoporosis. In the latter group, this increase did not plateau and was found to be sustained for at least 4 years. However, pamidronate use is associated with relatively poor gastrointestinal tolerability. The use of another agent, clodronate, has been limited by the possible link with the onset of hematologic malignancies. Alendronate is another agent which in studies to date has been found to increase vertebral bone mass in postmenopausal patients. Alendronate also seems to be more potent and better tolerated than pamidronate.(ABSTRACT TRUNCATED AT 250 WORDS)