Scientists not sure if finding points to potential problems; maker stands by medication
WEDNESDAY, Dec. 31 (HealthDay News) -- Women who took the osteoporosis drug Fosamax for up to three years saw an increase in their number of osteoclasts, or cells that remove old, brittle bone, a new study says.
These women also had "giant" osteoclasts -- single cells fused together -- with as many as 40 nuclei. Normally, one would see only seven or eight nuclei in one grouping, the study authors said.
At this point, it's unclear what these findings mean in the "real world."
"Seven or eight cells fused together are more efficient at dissolving calcium from the bone and remodeling," said Dr. James Liu, chairman of the department of obstetrics and gynecology at MacDonald Women's Hospital at Case Medical Center, University Hospitals in Cleveland. "[The study authors] don't know what this means beyond that. Right now, we're just learning these nuances."
Whether these findings will signal future problems is an open question, agreed study lead author Dr. Robert S. Weinstein, a staff physician at Central Arkansas Veterans Healthcare System and a professor of medicine at University of Arkansas for Medical Sciences, both in Little Rock.
"These drugs were used for two to three years in the trial, but clinicians today use them for five and 10 years, and we know these cells accumulate and are there even before the drug is stopped," he said. "It's conceivable there could be a problem at some point. Works need to be done on what is the fate of these drugs."
The findings were published in the Jan. 1 issue of the New England Journal of Medicine.
A second paper in the journal -- a letter to the editor from U.S. Food and Drug Administration epidemiologist Diane K. Wysowski -- noted an increase in the number of reports of esophageal cancer among people taking Fosamax (alendronate).
"Bone is a dynamic tissue -- it continually remodels and repairs itself," Weinstein explained. "Just like an aircraft wing after many flights gets fatigue damage and needs to be repaired, bone also bears the weight of individuals and undergoes damage and needs repair. There's a system [in which] cells remove the old pockets that are no longer at full capacity and replaces them with new bone.
"This is accomplished by two kinds of cells: armies of osteoclasts that erode cavities in the bone, then teams of osteoblasts which replace old bone with new, strong bone," he continued.
Postmenopausal osteoporosis results from an imbalance in that remodeling process. Fosamax, part of a class of drugs known as bisphosphonates, is thought to prevent that imbalance by decreasing the number of bone-eroding cells.
But, after examining 51 bone biopsy specimens from healthy postmenopausal women (40 to 59 years of age) who had participated in a three-year trial and who took different doses of Fosamax versus a placebo, the study authors found the opposite was actually true.
Women receiving the highest dose of the drug (10 milligrams) once a day had 2.6 times the number of osteoclasts, compared with women in the placebo group. The number of osteoclasts increased with the dose, the study found.
Twenty-seven percent of the osteoclasts were "mega-cells" that were still present one year after the women had stopped taking Fosamax. The study authors hypothesized that bone cells weren't dying, allowing them to fuse together in this way.
"It's like disarming the soldiers in the bone army [osteoclasts] but increasing the size of the army by more than 260 percent," Weinstein said.
"The drugs do work, no question," he said. But, he added, it's important to figure out just how they work (knowledge that often doesn't come until drugs have been in use for a while) to make sure the right people are getting them and to anticipate side effects.
Liu said: "They [the study authors] say that osteoclasts did not die at an increased rate like they did in some of the animal studies but, rather, [Fosamax] slowed down the rate of death but also reduced the functionality or efficiency at which osteoclasts worked."
The FDA letter to the editor said the agency has received reports of 23 patients taking Fosamax who have been diagnosed with cancer of the esophagus (eight died) since the drug was first approved in 1995. Thirty-one patients from Japan and Europe also were diagnosed with this cancer after taking Fosamax.
"The concern is that there is an association, not cause-and-effect," said Liu. "The FDA doesn't really have enough evidence to say it [Fosamax] does anything to stimulate cancers [but] one of the side effects of oral bisphosphonates is that they can make GERD (gastroesophageal reflux disease) worse."
The prescribing information for Fosamax, made by Merck & Co., said that people with "certain disorders of the esophagus" should not use the drug.
In a news release, Merck said that "clinical trials of Fosamax and post-marketing reports do not suggest any association between alendronate and esophageal cancer. Fosamax has been studied in controlled clinical trials involving more than 17,000 patients, contributing as much as 10 years' data with alendronate."
Addressing the bone cell research by Weinstein, the release said the study findings support Merck research that "alendronate decreases the rate of bone resorption by osteoclasts without causing rapid osteoclast death and does not change the current clinical recommendations for the use of Fosamax."
Use of bisphosphonates has been associated with other problems in the past, including an increased risk of atrial fibrillation (a type of abnormal heart rhythm), unusual fractures of the thigh bone and inflammatory eye disease.
For more on Fosamax, visit the U.S. National Library of Medicine.
SOURCES: James Liu, M.D., chairman, department of obstetrics and gynecology, MacDonald Women's Hospital, Case Medical Center, University Hospitals, Cleveland; Robert S. Weinstein, M.D., staff physician, Central Arkansas Veterans Healthcare System, and professor of medicine, University of Arkansas for Medical Sciences, both in Little Rock; Dec. 30, 2008, news release, Merck & Co.; Jan. 1, 2009, New England Journal of Medicine
All rights reserved