Results from a Phase 2 Trial of Senolytic Therapy Dasatinib and Quercetin for Osteoporosis

Senescent cells accumulate with age to cause disruption to tissue structure and function throughout the body. So far the only senolytic therapy demonstrated in clinical trials to clear senescent cells in humans as well as it does in mice is the dasatinib and quercetin combination. In general, senolytic therapies have produced very impressive results in mice, but the few clinical research groups presently running human studies are still in the process of figuring out dosing and optimal use cases for the various first generation small molecule senolytics, such as dasatinib and quercetin, and perhaps fisetin.

Initial results from a Mayo Clinic phase 2 study in older women with osteoporosis covered by today's research material are actually quite positive, despite the failure to produce a significant difference when considering the whole treatment group. Only those women with a larger burden of senescent cells responded well to the therapy, showing reduced markers of underlying processes of osteoporosis. They did respond, however, including improvement in bone mineral density. This is a good demonstration of the point that a better clinical means of assessment of the burden of cellular senescence is very much needed. Given simple robust and cost-effective assays, the widespread off-label use of the low-cost treatment of dasatinib and quercetin would arrive that much more rapidly.

Interestingly, this clinical trial does include a fisetin treated arm, but the researchers do not discuss that here. The Mayo Clinic has been conducting other human trials of fisetin as a senolytic treatment for various age-related conditions, and this absence of information is also the case there as well. Fisetin performed well in early studies in mice, but did not do well in the Interventions Testing Program study - for reasons that may have had more to do with the study design rather than the properties of fisetin. It is somewhat frustrating that the Mayo Clinic is choosing not to present their human study data on fisetin.

Drugs that kill "zombie" cells may benefit some older women, but not all

In the 20-week, phase 2 randomized controlled trial, 60 healthy women past menopause intermittently received a senolytic combination composed of FDA-approved dasatinib and quercetin, a natural product found in some foods. It is the first randomized controlled trial of intermittent senolytic treatment in healthy aging women, and the investigators used bone metabolism as a marker for efficacy. Subjects received 100mg dasatinib plus 1000mg quercetin taken orally daily for three consecutive days on an intermittent schedule repeated every 28 days over 20 weeks, resulting in five total three-day dosing periods throughout the entire intervention.

Researchers found that this combination, known as D+Q, had beneficial effects on bone formation but did not reduce bone resorption or the breakdown and removal of bone tissue. Furthermore, D+Q mainly benefited people with evidence of a high number of senescent cells. This group had more robust increases in bone formation, decreases in bone resorption, and an increase in bone mineral density at the wrist. "Our findings argue against what many people are already doing - using commercial products like quercetin or related compounds like fisetin that may show some senolytic properties. They're using them as anti-aging agents without knowing if they have high enough senescent cell numbers to benefit, or what dose or dosing regimen is needed to be effective yet safe."

Effects of intermittent senolytic therapy on bone metabolism in postmenopausal women: a phase 2 randomized controlled trial

Preclinical evidence demonstrates that senescent cells accumulate with aging and that senolytics delay multiple age-related morbidities, including bone loss. Thus, we conducted a phase 2 randomized controlled trial of intermittent administration of the senolytic combination dasatinib plus quercetin (D + Q) in postmenopausal women (n = 60 participants). The primary endpoint, percentage changes at 20 weeks in the bone resorption marker C-terminal telopeptide of type 1 collagen (CTx), did not differ between groups. The secondary endpoint, percentage changes in the bone formation marker procollagen type 1 N-terminal propeptide (P1NP), increased significantly (relative to control) in the D + Q group at both 2 weeks and 4 weeks, but was not different from control at 20 weeks. No serious adverse events were observed.

In exploratory analyses, the skeletal response to D + Q was driven principally by women with a high senescent cell burden (highest tertile for T cell p16 mRNA levels) in which D + Q concomitantly increased P1NP and reduced CTx at 2 weeks, and increased radius bone mineral density at 20 weeks. Thus, intermittent D + Q treatment did not reduce bone resorption in the overall group of postmenopausal women. However, our exploratory analyses indicate that further studies are needed testing the hypothesis that the underlying senescent cell burden may dictate the clinical response to senolytics.

Comments

I am the senior author of the Mayo study described above. To be clear, there is no attempt to "hide" the fisetin data. As stated in the paper, the original study design did include a fisetin arm. However, this study was conducted in part during the Covid pandemic, so due to problems with recruitment and increasing costs, we had to reduce to 2 arms and make a choice between continuing the dasatinib+quercetin or fisetin arms. We chose to continue the dasatinib+quercetin arm as our previous study in mice had demonstrated beneficial effects on bone using this combination (Nat Med 23:1072, 2017), and we have no data in mice on whether fisetin has beneficial effects on bone. As such, the number of participants in the fisetin arm was too small to provide any meaningful information.

Posted by: Sundeep Khosla at July 3rd, 2024 2:46 PM

@Sundeep Khosla: the additional information is appreciated. Hopefully we'll see human data on fisetin as a senolytic coming out of the Mayo Clinic at some point in the future.

Posted by: Reason at July 3rd, 2024 6:27 PM

I'm sorry if this is a naive question but how does one go about testing for the amount of senescent cells in one's body? Is this a test anyone can ask a doctor to order?

Posted by: Christopher Neck at July 6th, 2024 7:53 PM

Not a naive question at all. Unfortunately, there is currently not a simple blood test to determine senescent cell burden. In this study, a specific type of blood cell (T cell) was harvested and special techniques used to measure markers of senescence in these cells. This is not available outside the research setting. So more work is needed to establish tests like this for clinical use.

Posted by: Sundeep Khosla at July 7th, 2024 10:33 AM
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