Bisphosphonates and breast carcinoma: present and future

Bisphosphonates are analogues of endogenous pyrophosphates in which a carbon atom replaces the central atom of oxygen. Bisphosphonates are potent inhibitors of osteoclastic bone resorption and are effective in decreasing the incidence of skeletal complications in breast carcinoma patients with osteolytic bone metastases.

Zoledronate is a new, potent third-generation bisphosphonate that is 500-1000 times more potent than pamidronate. A Phase II clinical trial of 0.4, 2.0, or 4.0 mg of zoledronate as a 5-minute infusion or 90 mg of pamidronate as a 2-hour infusion recently was completed. In addition, osteoprotegerin (OPG) recently has been identified as a novel, naturally occurring protein that inhibits osteoclast formation.

A 5-minute infusion of 2.0 or 4.0 mg of zoledronate is at least as effective as 90 mg of pamidronate in preventing skeletal complications. OPG currently is entering Phase I clinical trials. Finally, tumor cells staining strongly for matrix metalloproteinases are observed in osteolytic pathologic bone fractures secondary to metastatic carcinoma. In many of these lesions frequent tumor cells are observed and osteoclasts are rare.

Bisphosphonate treatment can decrease skeletal events in patients with breast carcinoma that is metastatic to bone. Current trials to improve results further are employing more potent bisphosphonates such as zoledronate and nonbisphosphate inhibitors of osteoclasts such as OPG. An osteoclast-independent phase of bone destruction also deserves further consideration.