Osteoporosis is a common disease that weakens the structure of bones with age. Although current treatments for osteoporosis work quite well in stopping bone loss, they lack the ability to promote bone growth and cannot be taken orally. A newly discovered small molecule shows promise on both fronts. The finding could open pathways for specific and effective new treatments with minimal side effects, according to this preliminary evidence.
Scientists recently established that a hormone receptor called relaxin family peptide receptor 2 (RXFP2) is important for healthy bone formation and maintenance. A collaborative group of scientists led by Alexander Agoulnik, a geneticist at Florida International University, and Juan Marugan, a pharmaceutical scientist at the National Institutes of Health (NIH), hypothesized that increasing RXFP2 activity could increase bone formation in conditions like osteoporosis.
“What you want to do is more than prevent elimination of bone. You want to promote the differentiation of new bone, which is what is really impaired,” said Marugan.
The team screened more than 80,000 potential compounds to find ones that bind to RXFP2 and enhance its function, otherwise known as an agonist. To see whether the top four agonists they identified affected bone density, they treated human bone-forming cells with three different doses of each compound. One compound, called 6641, stood out from the rest by dramatically enhancing bone mineralization, a sign of bone strength. It led to 3.5 times more mineralization compared to the control.
Further experiments in a specific type of female mice with low bone density revealed that compound 6641 increased bone formation with no obvious side effects. They also demonstrated that 6641 was effective when taken orally.
“The discovery and optimization of a small-molecule RXFP2 agonist is an important first step towards any future therapeutic development,” said Michelle Halls, a pharmaceutical scientist at Monash University, who was not involved in the study.
The team plans to follow up on this study by testing mouse models of osteoporosis to see what dose of the treatment they need and for how long. They also plan to look at other possible side effects that may not have shown up in this preliminary study.
“This initial data seems promising, but we have a long way to go in terms of evaluating other models, dose response, and toxicity. But even if you have all that together, eventually you need to convince somebody to adopt the patent and move into clinical development,” said Marugan. “That is really difficult.”
Still, the team plans to continue investigating the efficacy and safety of the potential treatment and, hopefully, help patients in the future.
The molecule could also help treat other bone disorders, said Marugan. “We definitely want to go beyond just osteoporosis. There are good treatments right now, but they have limitations. But for rare disorders, there’s pretty much nothing.”
Esteban-Lopez, M., Wilson, K.J., Myhr, C. et al. Discovery of small molecule agonists of the Relaxin Family Peptide Receptor 2. Commun Biol 5, 1183 (2022).