Researchers have uncovered a new cause for osteoporosis in the body’s so-called senescent cells. By targeting these cells with anti-aging drugs, the findings could change therapeutic approaches for the treatment of age-related bone loss.
The National Osteoporosis Foundation (NOF) report that in the United States, 10 million people live with osteoporosis, which is a condition wherein bones become brittle and break. Another 44 million U.S. individuals are thought to have low bone density.
Additionally, the NOF caution that approximately half of all people in the country aged 50 and above “are at risk of breaking a bone and should be concerned about bone health.”
Researchers from the Mayo Clinic in Rochester, MN, have uncovered a new cause for osteoporosis in mice. The first author of the study is Joshua N. Farr, of the Robert and Arlene Kogod Center on Aging and Division of Endocrinology at the Mayo Clinic College of Medicine, and the findings are published in the journal Nature Medicine.
The body’s so-called senescent cells are those involved in the normal process of aging and in diseases related to aging. For the new research, Farr and colleagues designed several mouse models wherein the mice had bone loss and were aged between 20 and 22 months – the equivalent of being over 70 years old in human years.
The researchers targeted these cells in a variety of ways. They “switched off” the genes for these cells, and they eradicated them using so-called senolytic drugs, which are meant to “kill off” senescent cells.
Finally, they used a drug that inhibits the activity of a type of enzyme called Janus kinase enzymes to block the production of a pro-inflammatory substance secreted by senescent cells.
Dr. Sundeep Khosla, director of the Aging Bone and Muscle program at Mayo Clinic’s Robert and Arlene Kogod Center on Aging, explains the results of the study, saying, “The effects of all three approaches on aging bone were strikingly similar.”
“They all enhanced bone mass and strength by reducing bone resorption but maintaining or increasing bone formation, which is fundamentally different from all current osteoporosis drugs.”
Some of these approaches were also tested in young mice aged around 12 months. Genetically killing off senescent cells and inhibiting them with senolytic drugs did not have any beneficial effect on the bones of young mice, which further strengthens the causal link between senescent cells and age-related osteoporosis.
The senolytic drugs used were dasatinib and quercetin, and they were administered in combination once per month.
Co-corresponding study author Dr. James Kirkland, Ph.D., director of the Kogod Center on Aging, further explains the results. He says, “Even though this senolytic drug combination was only present in the mice for a couple of hours, it eliminated senescent cells and had a long-lasting effect.”
“This is another piece of the mounting evidence that senolytic drugs are targeting basic aging processes and could have widespread application in treating multiple chronic diseases,” he adds.
The authors also explain the benefits of administering this drug combination only intermittently – that is, at clearly set monthly intervals – compared with currently available osteoporosis medication, which needs to be taken daily and can have serious side effects.
Current medication for osteoporosis, the authors explain, has a significant negative effect in that it decreases bone resorption, which, in turn, decreases bone formation. Bone resorption refers to the process whereby bone is naturally removed throughout one’s lifetime, while new bone forms.
The senolytic drugs used intermittently in this study lowered bone resorption but preserved bone formation and even sometimes increased it.
“While we know from previous work that the accumulation of senescent cells causes tissue dysfunction, the role of cell senescence in osteoporosis up to this point has been unclear,” Dr. Khosla says.
“The novelty of this work for the bone field lies in the fact that, rather than targeting a bone-specific pathway, as is the case for all current treatments for osteoporosis, we targeted a fundamental aging process that has the potential to improve not only bone mass, but also alleviate other age-related conditions as a group.”
Dr. Sundeep Khosla
“We need to continue to pursue these potential interventions that target fundamental aging mechanisms as, hopefully, an eventual way to reduce the burden of fractures and other conditions, such as cardiovascular dysfunction, diabetes, and frailty,” he concludes.