© 1998 by Oxford University Press
In a recent article in The New England Journal of Medicine, researchers found that a member of a class of drugs known for their ability to help stop bone destruction also reduced the incidence and the number of new bony and visceral (soft tissue) metastases in breast cancer patients at high risk for distant disease.
The drug, oral clodronate, which is not yet available in the United States, is a bisphosphonate -- a class of drugs used to treat bone diseases including bone cancer. The surprise finding that clodronate was somehow involved with reducing metastases to soft tissue is raising numerous questions about this and other bisphosphonates.
Although bisphosphonates were first synthesized in the 1860s, information regarding their biological characteristics did not occur until the late 1960s. Twenty years later, these compounds were developed into drugs to treat bone diseases.
It took so long because "the methods to measure the effect [of bisphosphonates] on osteoporosis were not there early on," said Herbert Fleisch, M.D., at the University of Bern, Switzerland.
Bisphosphonates, analogues of simple phosphates, are now used to treat osteoporosis, Paget's disease, hypercalcemia, and bone metastases where bone is being broken down at a faster rate than it is being formed.
Bisphosphonates were developed by changing the structure of the simple phosphates, which also changed how they worked. For example, the amount of drug taken up by the bone varies depending on the type of bisphosphonate used. Newer compounds provide greater uptake by the bone and minimize gastrointestinal absorption. Also, until recently, said Gabriel Hortobagyi, M.D., at the University of Texas M. D. Anderson Cancer Center, Houston, there were no good animal models for bone metastases.
On the Horizon
Researchers generally agreed that the NEJM study needs to be confirmed and that more research is needed to answer important questions about clodronate and other bisphosphonates.
While some researchers argue that bisphosphonates should be given to breast cancer patients with no evidence of bone metastases, others, such as Fleisch, believe it is best to await more data. Studies are now under way to assess the differences between the various types of bisphosphonates. Newer forms of these compounds are, for example, 1,000 to 10,000 times more potent than first generation bisphosphonates, such as clodronate. The critical question remains, however, whether these compounds can be used interchangeably.
Not all bisphosphonates are created equal. Even small changes in chemical structure alter the drug's effect. "Many people are aware that clodronate has some effects different than other bisphosphonates," said Toshiyuki Yoneda, Ph.D., professor of medicine at the University of Texas Health Science Center, San Antonio.
The finding of decreased incidence of visceral tissue metastases in the NEJM study may have been an artifact of the patient population or the result of combining clodronate with cytotoxic drugs, according to Ingo J. Diel, M.D., at the University of Heidelberg, Germany, and the study's principal investigator.
"We don't know if clodronate would have a similar effect by itself," Diel said. "Maybe this effect was seen only in a subgroup of high risk patients with minimal residual disease."
Hortobagyi explained the finding somewhat differently -- in what he terms molecular addresses. "The cell has a key and the target tissue has a keyhole, and unless, the two meet, there will be no metastases," he said. "If a fraction of patients initially only had a capacity to metastasize to bone, then theoretically, you can make metastatic cells homeless by interfering with osteoclast (bone cells responsible for bone destruction) activity. For as long as the cancer cells have the bone address, you can then prevent the occurrence of secondary metastases."
Not only do bisphosphonates improve bone lesions, said Gregory R. Mundy, M.D., at the University of Texas, San Antonio, but they also decrease the number of tumor cells that are in bone, and "we guess they do that by changing the bone environment and making the bone a less hospitable place for the cancer cells to grow."
The majority of breast cancer patients in whom cancer has spread beyond its primary origin experience metastases to bone. For these patients, a loss in bone, also known as resorption, creates severe pain due to the fragility of bone and increases the number of fractures. Research into treating bone metastases and its related consequences has increased as a result of the development and application of bisphosphonates, including clodronate.
"Increased survival in patients, however," said Mundy, "isn't clear yet but may be very likely."
"All of this is extremely exciting work," added V. Craig Jordan, Ph.D., director of the Lynn Sage Breast Cancer Research Program at the Robert H. Lurie Cancer Center, Chicago. "It [clodronate] is a good example of translational research in which there has been lots of suspicions in model systems, but now we're getting the first flood of information."
-- Mary Derrane
Bisphosphonates: Lingering Questions About Their Use
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