Osteoporosis Drugs Work, but How?

Study Shows Fosamax Is Effective but May Not Work the Way Experts Believed

Reviewed by Brunilda Nazario, MD on January 02, 2009
From the WebMD Archives

Dec. 31, 2008 -- Millions of people with osteoporosis take bisphosphonates like the drug Fosamax to make their bones stronger. The drugs work well, but a new study shows that they probably don't work in the way experts have thought.

It has been widely believed that bisphosphonates work by targeting and impairing the action of cells known as osteoclasts -- and reducing their number. These cells break down bone in a process known as bone resorption.

But in the new study, many postmenopausal women who took Fosamax showed increases in osteoclast numbers compared to women who took a placebo.

The longer the women were on the drug, the more osteoclasts they tended to have. And many also showed evidence of giant and detached osteoclasts, which have not been previously recognized, researcher Robert Weinstein, MD, of the University of Arkansas for Medical Sciences, tells WebMD.

The study appears in the Jan. 1, 2009, issue of the New England Journal of Medicine.

"The bisphosphonates do work. They are a mainstay of osteoporosis treatment," he says. "But it is clear that they don't work the way we thought they did."

Fosamax vs. Placebo

Weinstein and colleagues from the University of Arkansas and the Central Arkansas Veterans Healthcare System examined 51 bone biopsy specimens obtained following a three-year trial designed to determine the effectiveness of Fosamax for improving bone health.

Some of the women in the study took Fosamax and others took placebo.

The bone biopsies revealed a 260% increase in osteoclasts among women who took 10 milligrams of the bisphosphonate daily for three years, compared to women in the placebo group.

Roughly a third of the osteoclasts were giant and detached, and these giant cells were still present a year after the women stopped taking the drug.

While the cells appeared dysfunctional, Weinstein points out that this may not be the case in women who take osteoporosis drugs for many years.

"We don't really know the long-term consequences of building up a large army of these giant cells," he says. "It appears that they do no direct damage, but we can't say this for sure."

And since most clinicians aren't aware of the link between bisphosphonate use and the giant cells, they may mistake them for some other bone disorder, leading to unnecessary testing and even treatment, he adds.

Higher Doses, More Giant Cells

The number of abnormal osteoclasts was much greater in women taking the highest doses of Fosamax than in those taking lower doses, but some women taking higher doses of the drug showed no evidence of the giant cells.

This finding shows that not everyone responds to bisphosphonates in the same way, says Julie Glowacki, PhD, who directs the Skeletal Biology Lab at Boston's Brigham and Women's Hospital.

"This study will cause us to ask new questions about how these drugs work," Glowacki tells WebMD. "The fact that they saw this in some women but not in others is really interesting."

In an editorial examining the study, Glowacki wrote that more research is needed to understand how bisphosphonates inhibit bone resorption.

In a statement issued Tuesday, a spokesman for Fosamax manufacturer Merck & Co. noted that the new research shows the drug to be effective for the treatment of osteoporosis.

"The research by Weinstein et al. support Merck's findings that [Fosamax] 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," the statement notes.

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Weinstein, R.S. New England Journal of Medicine, Jan. 1, 2009; vol 360: pp 53-62.

Robert S. Weinstein, MD, professor of medicine; director, Bone Morphology Laboratory, University of Arkansas for Medical Sciences, Little Rock.

Julie Glowacki, PhD, professor of orthopaedic surgery and oral-maxillofacial surgery, Brigham and Women's Hospital, Boston.

Ronald Rogers, spokesman, Merck & Co.

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