Protein insight could cut osteoporosis therapy side effects

New research may open up new and potentially more effective osteoporosis treatments.

The researchers have identified a new way to maintain bone health while reducing bone resorption.

Osteoporosis is the most common age-related bone disease worldwide. It’s estimated that one in three women and one in five men aged over 50 suffer from osteoporotic bone fractures.

In aging populations, the incidence of hip fractures increases dramatically, resulting in a high risk of morbidity and mortality. As such, osteoporosis is an immediate and significant health concern in Singapore and worldwide.

Researchers used genetic analysis to discover a connection between a small protein, chemokine CXCL9, and the important part it plays in maintaining healthy bones. They also identified two inhibitors as promising drug targets for osteoporosis.

Small protein with big effects

Osteoporosis is caused by excessive activity of bone resorbing cells, called “osteoclasts,” and reduced activity of bone-forming cells, called “osteoblasts.” In healthy individuals, a balanced activity of these two cell types allows constant bone turnover to maintain healthy and strong bones.

With osteoporosis, however, disproportionate bone resorption leads to low bone mineral density and consequently weak and fracture-prone bones.

The researchers showed that the small protein, chemokine CXCL9, plays a role in osteoporosis when it is released from osteoblasts located on the surface of the bone matrix. Under osteoporotic conditions, CXCL9 diffuses towards reservoirs that hold osteoclast precursors. These osteoclast precursors produce a receptor, CXCR3, on their cell surface. Upon activation by CXCL9, the osteoclast precursors mobilize and migrate long distances in a highly directed fashion towards the bone matrix, where they start resorbing bone.

Both CXCL9 and its receptor CXCR3 have long been known to modulate the migration of immune cells to inflammation sites, for example in psoriasis and rheumatoid arthritis. Their role in osteoporosis and recruitment of bone cells, however, is unknown. The small-molecule inhibitors AMG-487 and NBI-74330 were known to block CXCR3 activity but have had little success in earlier clinical tests for the treatment of psoriasis.

The researchers showed that these inhibitors are highly effective in blocking osteoclast recruitment and protecting bone from osteoporotic effects.

New osteoporosis therapies?

Most current osteoporosis therapies include the use of bisphosphonates, which block osteoclast activity and thus prevent excessive bone resorption. However, prolonged treatment with these drugs eliminates the necessary bone turnover leading to increased fracture risk and other unwanted side effects. Therefore, there is an urgent need to develop new strategies that overcome the limitations of current treatments.

“Based on our studies, both AMG-487 and NBI-74330 lowered the number of formed osteoclasts by more than 50% when administered at the efficient dosage. While these two inhibitors have been tested in preclinical and clinical trials, they have not been used as targets for osteoporosis. We propose that the two small-molecule antagonists can be used to modulate or adjust excessive osteoclast numbers in osteoporosis patients in a dose-dependent fashion,” says Christoph Winkler, an associate professor in the biological sciences department at the National University of Singapore.

“Our new strategy has major advantages as excessive bone resorption can be prevented in a targeted manner but normal bone turn-over will still continue,” he says. “This offers potential to avoid increased fracture risks in osteoporosis patients and to maintain healthy bone for improved quality of life.”

The research appears in the Proceedings of the National Academy of Sciences.

Additional researchers are from the National University of Singapore, the Genome Institute Singapore, and the University of Wuerzburg.

Source: National University of Singapore

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