Understanding the Higher Risk of Bone Fractures Among People With Diabetes

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Researchers in a project involving three universities have identified a molecule that could be a major factor in the higher risk of bone fractures among people with diabetes.

Type 1 diabetes is generally linked to lower-than-average bone density, but bone density tends to be higher in people with Type 2 diabetes. The puzzling thing has been that both groups are more prone to bone fracture.

The study, published in late May in the journal Nature Communications, attempted to zero in on the cause of bone fracture among people with Type 2 diabetes by extracting bone marrow from hyperglycemic mice and healthy mice. It was conducted by researchers at New York University’s College of Dentistry, Stanford University and Dalian Medical University in China.

“The team ran a systematic analysis of hyperglycemia’s effects on bone metabolism using bone marrow samples from diabetic and healthy mice,” explains a report by the California Institute for Regenerative Medicine, which helped fund the research. “They found that the levels of succinate, a key molecule involved in energy production, are over 20 times higher in the diabetic mice. It turns out that succinate also acts as a stimulator of bone breakdown.”

Our bodies continually break down and absorb old bone and form new bone tissue. The study appears to show that the high levels of succinate keep the body from maintaining the right balance of breakdown and bone formation; researchers also found that the hyperglycemic mice had considerable lower levels of spongy yet strong bone mass, called trabecular bone.

Succinate wasn’t the only molecule in the metabolic pathways of bone-marrow cells to be examined. The researchers identified 142 metabolites whose levels were significantly different in the hyperglycemic mice than in the healthy ones. Of those, the mice with diabetes had increased levels of 126 metabolites and reduced levels of 16. But the one that stood out was succinate, with a 240-fold increase among hyperglycemic mice.

“The results are important because diabetics have a significantly higher fracture risk and their healing process is always delayed,” the study’s senior investigator, Xin Li, said in a statement. Li is a professor of basic science and craniofacial biology at NYU. “In our study, the hyperglycemic mice had increased bone resorption [the breakdown and absorption of old bone], which outpaced the formation of new bone. This has implications for bone protection as well as for the treatment of diabetes-associated collateral bone damage.”

Succinate was the first metabolite in the energy pathway, and the steeply increased concentration overwhelmed the energy pathways, the researchers said.

“The bottom line is that the high level of succinate combined with the finding of more fragile bone points to a new target to protect bone,” the study’s lead author, Yuqi Guo, said in a statement. Guo is an associate research scientist at the NYU College of Dentistry.

If these findings are confirmed, finding ways to regulate succinate levels could provide promising treatments for reducing bone fractures, though it’s worth noting that diabetes treatments that have been found successful for mice sometimes don’t work with humans.

Major funding for the research was provided by a grant from the National Institutes of Health as well as CIRM and various Chinese agencies, as well as from NYU.

Earlier this year, Stanford researchers also published a paper showing that activating bone stem cells helped repair fractures in diabetic mice. Their study, published in January in the journal Science Translational Medicine, found that applying a protein to the site of the fracture promoted the expression of key signaling proteins.

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