Study: Rapid bone loss as possible side effect of anti-obesity drug now in clinical trials

February 7, 2012
UT Southwestern researchers (from left) Drs. Yihong Wan, Wei Wei and David Mangelsdorf have found in mice that a hormone used as an anti-obesity drug causes significant bone loss. Credit: UT Southwestern Medical Center

An endocrine hormone used in clinical trials as an anti-obesity and anti-diabetes drug causes significant and rapid bone loss in mice, raising concerns about its safe use, UT Southwestern Medical Center researchers have shown.

The hormone, fibroblast growth factor 21 (FGF21), promotes bone loss by enhancing the activity of a protein that stimulates but inhibits , researchers report in a study available online in .

"This hormone is a very potent regulator of bone mass," said Dr. Yihong Wan, assistant professor of pharmacology and senior author of the study. "When we oversupply FGF21 in mice, it results in substantial bone loss."

UT Southwestern scientists had been investigating this hormone's properties since its discovery in 2005 as a potential drug. Bone loss was a side effect of another class of that had been commonly used in the treatment of diabetes – activating the same protein in a manner similar to FGF21 – and leading the research team to investigate the bone effect of FGF21 in three kinds of mice.

They found that rodents fed a drug form of the hormone over a two-week period lost 78 percent of their spongy bone. Mice engineered to produce excess FGF21 had similar effects. Conversely, researchers found mice completely lacking the hormone had comparable gains in .

While the insulin-sensitizing effects of FGF21 make it a potentially powerful anti-obesity drug, that could be canceled out by risk of osteoporosis and fractures associated with , the investigators report.

"The bone effect is clear," said Dr. David Mangelsdorf, chairman of pharmacology, a Howard Hughes Medical Institute investigator at UT Southwestern and one of the study's corresponding authors. "It's a tradeoff of benefits and risks, and the key will be to design the drug in such a way to leverage the two against each other, dialing out the side effects and dialing in the positive."

In a related study online in Cell, researchers at the medical center identified how FGF21 regulates the activity of a diabetes-fighting compound in fat tissue, altering metabolism in response to starvation and resumed eating for survival-driven energy conservation.

"FGF21 helps mobilize the fat in adipose tissue back to the liver and burn it. But when the animal is refed, it stops this process and immediately turns back to restoring fat. In one case, it turns this system on, and in the other, turns it off," said Dr. Steven Kliewer, professor of molecular biology and pharmacology and senior author of the Cell paper.

UT Southwestern researchers involved in the PNAS study were Dr. Wei Wei, lead author and postdoctoral researcher in pharmacology; Dr. Paul Dutchak, postdoctoral researcher in neuroscience; Drs. Xunde Wang and Xushan Ding, postdoctoral researchers in pharmacology; Dr. Xueqian Wang, research associate in pharmacology; Angie Bookout, graduate student in internal medicine; Dr. Robert Gerard, associate professor of internal medicine; and Dr. Kliewer.

The scientists in the Cell study included Dr. Dutchak, lead author involved while a graduate student in pharmacology; Takeshi Katafuchi, instructor in ; Ms. Bookout; and Dr. Mangelsdorf.

Explore further: Antibody injection promising for diabetes and obesity

Related Stories

Antibody injection promising for diabetes and obesity

December 16, 2011

(Medical Xpress) -- Researchers at Genetech Inc. in South San Francisco, California, led by molecular biologist Junichiro Sonoda, have discovered that a single injection of antibodies into obese diabetic mice provided a marked ...

Growth hormone increases bone formation in obese women

November 29, 2011

In a new study presented today at the annual meeting of the Radiological Society of North America (RSNA), growth hormone replacement for six months was found to increase bone formation in abdominally obese women.

Recommended for you

Artificial beta cells

December 8, 2016

Researchers led by ETH Professor Martin Fussenegger at the Department of Biosystems Science and Engineering (D-BSSE) in Basel have produced artificial beta cells using a straightforward engineering approach.

Researchers question lifelong immunity to toxoplasmosis

December 8, 2016

Medical students are taught that once infected with Toxoplasma gondii—the "cat parasite"—then you're protected from reinfection for the rest of your life. This dogma should be questioned, argue researchers in an Opinion ...

Key regulator of bone development identified

December 8, 2016

Loss of a key protein leads to defects in skeletal development including reduced bone density and a shortening of the fingers and toes—a condition known as brachydactyly. The discovery was made by researchers at Penn State ...

TET proteins drive early neurogenesis

December 7, 2016

The fate of stem cells is determined by series of choices that sequentially narrow their available options until stem cells' offspring have found their station and purpose in the body. Their decisions are guided in part by ...

1 comment

Adjust slider to filter visible comments by rank

Display comments: newest first

Temple
not rated yet Feb 07, 2012
BigPharma: "New studies have shown Anorexacil works even better than predicted!"

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.