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.

Related Stories

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.

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 ...

Recommended for you

Flow means 'go' for proper lymph system development

July 27, 2015

The lymphatic system provides a slow flow of fluid from our organs and tissues into the bloodstream. It returns fluid and proteins that leak from blood vessels, provides passage for immune and inflammatory cells from the ...

Fluorescent material reveals how cells grow

July 21, 2015

Fibre from a semiconducting polymer, developed for solar cells, is an excellent support material for the growth of new human tissue. Researchers at Linköping University have shown that the fibre glows, which makes it possible ...

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.