Penn GLP-1 study finds small increase in risk of osteoporosis and gout

John “Gabe” Horneff, an orthopedic surgeon at Pennsylvania Hospital, had noticed a peculiar trend: Some patients taking GLP-1s would come in with significant tendon injuries from relatively minor physical excursion.

For example, some suffered tears in the rotator cuff in the shoulder area while doing simple housework like vacuuming or raking leaves.

“They weren’t necessarily falling down a flight of stairs,” he said.

That anecdotal pattern of musculoskeletal injuries spurred him to conduct a study on whether using the popular weight-loss and diabetes drugs increased a person’s risk of osteoporosis and gout.

His team looked at data on almost 150,000 adults from a national database of patients with both diabetes and obesity. Half had taken GLP-1s for five years, and half hadn’t. Their outcomes were compared by looking at their medical records and accounting for factors including age, sex, race, BMI, tobacco use, and other health issues.

The rate of osteoporosis, a disease where the bones become fragile and brittle, was 3.2% in the group not taking the drug, compared to 4.1% in the GLP-1-taking group.

While notable, the difference is not cause for panic, Horneff said. The findings, which have not yet been peer-reviewed, were presented at the American Academy of Orthopaedic Surgeons annual meeting in New Orleans earlier this month.

“These are obviously helping patients a lot, but what are the things that we should be looking at?” Horneff said.

The study also found that incidence of gout, a painful form of arthritis, was 6.6% in the group not taking the drug and 7.4% in the GLP-1 group. The condition’s caused by the buildup of uric acid, which rapid weight loss can trigger, he said.

The study was observational, meaning it can only find associations. The gold standard for establishing cause-and-effect relationships is a randomized controlled trial.

The GLP-1 drugs in the study — which included semaglutide (sold as Wegovy and Ozempic), liraglutide, dulaglutide, and exenatide — have skyrocketed in popularity in recent years for weight loss and blood sugar control.

They work by mimicking a hormone the body naturally has, called GLP-1.

GLP-1 normally triggers the pancreas to release insulin, a hormone that acts like a key, unlocking the “door” to cells so that sugar can enter. Without it, sugar builds up in the blood. That’s made GLP-1 drugs popular for use in diabetes.

The drug can also reduce appetite by slowing the rate at which the stomach empties, and possibly through effects on the brain.

Attention to the side effects of these drugs has focused on gastrointestinal symptoms, but bone health is an area where research is still early — and conflicting.

For obesity medicine specialists, the study’s finding is “nothing new,” said Caroline Apovian, a professor at Harvard Medical School and co-director of the Center for Weight Management and Wellness at Brigham and Women’s Hospital.

Patients are normally counseled about the potential bone loss that can come with weight loss and urged to take preventive steps like resistance training and using vitamin D and calcium supplements.

“When you lose weight, you run the risk of bone loss,” said Apovian, who was not involved in the study.

Any form of weight loss — whether it’s caused by medication, surgery, or lifestyle changes — typically leads to bone loss, experts said. A person’s skeleton wouldn’t need to support as much weight, so it may adapt by losing bone density.

“Bone is constantly breaking itself down and rebuilding,” Horneff explained.

If a person isn’t engaging in physical activity and putting force on their bones, bone density may “waste away,” he said.

Astronauts experience an extreme example of this when they go to the International Space Station for long periods of time. When they come back to Earth, their muscles are a little bit weaker, and many show decreased bone density.

“They’re not used to the pull of gravity,” Horneff said. “There’s no force pulling on their bones.”

Horneff theorizes that taking GLP-1 drugs without also exercising could exacerbate this effect.

It’s possible the associated loss of bone density could be due to patients eating less as well, he said. GLP-1 drugs curb appetite, which can lead to decreases in intake of vitamin D and calcium important for bone health.

“I wouldn’t want my patients to think, ‘I can just take this medication, and I never have to work out. I never have to eat,’” Horneff said.

He thinks doctors should be monitoring patients’ bone health and nutrition labs to look out for risk of density loss and fractures.

The study also looked at osteomalacia, a condition where bones become softer and weaker. The rate was 0.2% in the group taking GLP-1s, compared to 0.1% in the group not taking the drug.

Elaine Yu, who directs the Bone Density Center at Massachusetts General Hospital in Boston, didn’t find this particular difference “very clinically impactful,” for the reason that the condition is often coded for incorrectly and is likely underdiagnosed in both groups. She was not involved in the study.

However, she called the osteoporosis finding “an early signal,” noting that “I don’t think it’s conclusive.”

Future research on GLP-1 medications should focus on the incidence of fractures, which bone density loss can increase risk of, she said.

Researchers should also study patients taking GLP-1s for obesity, without diabetes. The doses used for obesity are typically much higher than those used for diabetes, Yu said.

The benefits can still outweigh the potential risks.

Yu made a comparison to bariatric surgery, a weight loss method that can cause significant bone loss and increase the risk of fractures.

Despite this, she wouldn’t tell patients to avoid the surgery, which can be life-saving in some cases, she said.

She advises doctors to be proactive in monitoring the risk in GLP-1 patients, especially in postmenopausal women and men over age 50 who would already be at higher risk of bone loss due to their age. (The mean age in Horneff’s study was 59.8 years, with half being older than 61.)

“While there may be a signal that we need to pay more attention to bone [health], I don’t think this should dissuade people, necessarily, from considering these treatments,” Yu said.