Laying the Foundation for New Approaches to Osteoporosis

By Tiffany Parnell
Monday, January 1, 2018

Recent research published in Nature Medicine found a causal link between senescent cells and osteoporosis development. This finding adds to a growing body of research supporting the use of senolytic agents in treating multiple diseases of aging.

Senescent cells no longer divide normally, but are largely resistant to cell death. These cells accumulate in aging tissues and release inflammatory, potentially disease-causing cytokines, chemokines and proteases known collectively as the senescence-associated secretory phenotype (SASP), according to an Aging Cell study.

The Nature Medicine study is not the first to point to correlations between age-related disease and senescent cells. Research published by James Kirkland, MD, PhD, Director of the Robert and Arlene Kogod Center on Aging at Mayo Clinic, for example, found a causal link between senescent cells and osteoarthritis. A separate study, published in Nature and conducted by researchers from Mayo Clinic’s Division of Cardiovascular Surgery and Departments of Pediatric and Adolescent Medicine, Biochemistry and Molecular Biology, and Immunology, found that triggering senescent cell death in genetically engineered mice lessened typical age-related deterioration of several organs, including the kidneys and heart.

A Public Health Burden

Osteoporosis decreases the strength and quality of bone, raising the risk of fracture. An estimated 10.2 million American adults age 50 and older have osteoporosis, and 43.4 million have low bone mass, according to a Journal of Bone & Mineral Research study. Conservative strategies for managing osteoporosis and low bone mass include a calcium- and vitamin D-rich diet and bone-building exercise. Two classes of medications — antiresorptive agents and anabolic drugs — are also available.

While commercially available osteoporosis drugs are effective, according to Andrew D. Bunta, MD, Associate Professor of Orthopedic Surgery at Northwestern University, potential side effects include irritation of the gastrointestinal tract, osteonecrosis of the jaw and femur fractures. These side effects are usually rare and related to long-term use or comorbid conditions, and the risk of fracture outweighs the risk of side effects. Still, Dr. Bunta, who was not involved in the Nature Medicine study, agrees there is room in the market for newer, safer drugs because of the adverse effects associated with these options.

The Connection Between Osteoporosis and Cell Senescence

For the Nature Medicine study, researchers exposed 20- to 22-month-old mice to three agents. In the first part of the study, researchers administered injections of AP20187 to INK-ATTAC mice. These genetically engineered mice have a well-validated suicide transgene within their senescent cells, and the administration of AP20187 causes the cells to self-destruct without affecting normal cells.

“These cells provided proof of concept that if you kill or reduce the burden of these senescent cells in aging mice, you could alter age-related bone loss,” says Sundeep Khosla, MD, Professor of Medicine, Mayo Clinic College of Medicine, and senior and co-corresponding author of the study.

In the second phase of the study, researchers administered a combination of dasatinib and quercetin (D+Q) — two senolytic agents that co-corresponding author Dr. Kirkland has found in previous research to destroy senescent cells without affecting healthy cells. To complete the third part of the study, researchers administered a Janus kinase inhibitor, which did not destroy the senescent cells but rather inhibited their ability to produce the SASP.

At the end of the study, the 20-month-old INK-ATTAC mice that received injections of AP20187 experienced a 50 percent increase in bone mass at the spine. The mice treated with the other approaches experienced 30 percent increases in spinal bone mass, according to Dr. Khosla. As a control, researchers also administered these three approaches to younger mice with no effect.

“The fact that [the interventions] worked in the old mice but not in young mice provides strong support that they were really targeting mechanisms related to and specific for aging,” Dr. Khosla says.

The treatment duration of the senolytic D+Q compound, which mice received monthly for four months, also has causal implications.

“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,” Dr. Kirkland said in a Mayo Clinic News Network release discussing the findings. “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.”

“Our work now establishes that cell senescence is an important mechanism that causes bone loss with aging. The fact that this is a common aging mechanism across tissues offers the possibility of a novel therapeutic approach that targets the fundamental aging mechanisms and could help affect multiple age-related comorbidities.”
— Sundeep Khosla, MD, Professor of Medicine, Mayo Clinic College of Medicine

A Fountain of Youth?

One exciting potential of this research is the ability to treat a variety of age-related comorbidities, such as osteoporosis, heart disease and frailty, with one senolytic agent that targets senescent cells instead of multiple drugs that target disease-specific pathways, according to Dr. Khosla. Moving forward at the basic science level, researchers plan to investigate which specific cell types become senescent and why senescent cells have detrimental effects on bone. On a translational level, Drs. Khosla and Kirkland are initiating early-phase trials to test the combination of D+Q in humans. Pilot studies examining new compounds that, like D+Q, eliminate senescent cells are also in development to investigate whether these compounds lower cell senescence in humans and whether they affect bone along with other tissues.

Dr. Bunta agrees that cell senescence is a worthwhile avenue of research but warns physicians not to jump to conclusions or overlook the value of current treatments.

“Would it be wonderful if we had [these] drugs? Yes,” he says. “But we have no idea how well any drug would do when measured against the anabolic agents or bisphosphonates [already on the market].”