BETHESDA, MdLess than two years ago, the FDA approved Aredia (pamidronate disodium for injection) as the first agent for the treatment of osteo-lytic bone lesions in multiple myeloma patients, to be used in conjunction with standard antimyeloma chemotherapy.
James Berenson, MD, professor of medicine, UCLA School of Medicine, was principal investigator of clinical trials of the bisphosphonate, sponsored by Ciba Pharmaceuticals and Chiron Corporation, that preceded FDA approval.
For the first time, with Aredia, physicians are able to provide multiple myeloma patients with a drug that reduces the incidence of pathologic fractures, relieves bone pain and substantially preserves the quality of their lives, Dr. Berenson said at a symposium on the skeletal complications of malignancy, sponsored by the Paget Foundation and the National Cancer Institute.
Bisphosphonates: A Brief History
Malignant bone damage is caused by the activity of bone-resorbing cells (osteoclasts) stimulated by tumor cell products. Bisphosphonates are stable chemical analogues of pyrophosphate, a naturally occurring regulator of bone mineral accretion and dissolution. They function as powerful inhibitors of osteoclast function.
The first clinical use of bis-phosphonates came in the 1960s when they were employed as agents for bone scanning, based on their ability to adsorb to bone mineral. At the same time, they were shown to be effective in clinical disorders associated with increased bone resorption, at first in Pagets disease of bone and later in hypercalcemia of malignancy, myeloma, and bone metastases.
Continued testing has fueled considerable optimism regarding the effectiveness of the bis-phosphonates as adjunctive treatment for skeletal complications associated not only with multiple myeloma (see article above) but also with breast cancer, prostate cancer, and other cancers.
Pamidronate, a relatively potent aminobisphosphonate administered intravenously, has proved more effective than weaker, first-generation bisphos-phonates taken orally. Oral clodronate does reduce the development of new osteolytic lesions, Dr. Berenson said, but it does not significantly affect bone pain or the development of pathologic bone fractures.
In the pivotal trial of pamidronate, multiple myeloma patients with at least one lytic lesion were randomized to receive a monthly four-hour intravenous infusion of either pamidronate, 90 mg, or placebo for 21 cycles, in addition to chemotherapy.
Significant Decrease in Pain
Among 392 patients entered into the study, 377 were evaluated for skeletal events (pathological fracture, irradiation or surgery to bone, and spinal cord compression).
Patients who received pamidronate had significant decreases in bone pain, required less analgesia, and suffered fewer skeletal events than patients on placebo. Overall survival, however, was not significantly affected.
Dr. Berenson said that there is much to be learned about how these drugs work. Neverthess, he added, the bisphospho-nates have proved safe and relatively without side effects for most patients for whom they significantly improve quality of life.
In recent years researchers have succeeded in increasing the potency of bisphosphonates as inhibitors of bone resorption by as much as 100- to 10,000- fold, said Dr. Graham Russell, of the Department of Human Metabolism and Clinical Biochemistry, University of Sheffield Medical School, Sheffield, England.
These compounds, which include risedronate, ibandronate, and zoledro-nate, are able to suppress bone resorption in experimental animals at doses of less than 1 µg/day.
It is anticipated, Dr. Russell said, that several of these new and more potent bisphosphonates will be approved for use in the near future.