Anti-aging mechanism may hold key to ‘perfect’ osteoporosis treatment

A fundamental aging mechanism that drives tissue dysfunction throughout the body may serve as a novel target in the treatment of osteoporosis, suggesting an exciting new pathway for researchers in a field where a “perfect” therapy has remained elusive.

Cellular senescence, a phenomenon in which normal cells cease to divide, is becoming a buzzed-about topic as new research reveals it may be a druggable target to treat — or even prevent — multiple aging comorbidities, including osteoporosis. The research, mostly conducted with mice, but also in small human cohorts, suggests that there may be novel ways to use already available therapies to stop tissue dysfunction.

“Because there are these potential benefits with senescent cells, you want to be very careful how you target them,” Sundeep Khosla, MD, director of the Center for Clinical and Translational Science at Mayo Clinic and a leading researcher in cellular senescence, told Endocrine Today. “The approach that has been used by the Mayo Clinic group and several groups around the world is to look for specific drugs because these cells activate certain pathways that make them resistant to apoptosis, and those pathways are upregulated.”

Several drugs have now been identified, Khosla said, that selectively kill senescent cells by targeting the antiapoptotic pathways without affecting normal cells — so-called senolytic drugs.

An unmet need

There is now growing evidence that senescent cells accumulate in tissues with aging, Khosla said. The main tissue dysfunction they cause is through the senescence-associated secretory phenotype (SASP), which consists of proinflammatory cytokines and chemokines.

Sundeep Khosla

“These cells have now been shown to accumulate in multiple tissues, and there is an exploding body of literature on this,” Khosla said. “The hypothesis in the geroscience community is that if you target these cells, perhaps you can rejuvenate or prevent some of the aging-related morbidities.”

In aging, there is an accumulation of senescent osteocytes in bone, Khosla said. These cells have a high expression of multiple SASP markers, which could lead to an inhibition of bone formation and an increase in bone resorption.

Removing senescent cells might improve tissue and organ function in areas other than bone as well, potentially leading to treatments for chronic kidney disease and diabetes, LaTonya J. Hickson, MD, FASN, FACP, an associate professor of medicine at Mayo Clinic College of Medicine, told Endocrine Today.

“We are fortunate to work with a team of investigators who have devoted decades of effort to the study of senescence and inflammation in aging,” Hickson said. “Those efforts led to the discovery of drugs that selectively clear, or remove, these toxic senescent cells, which then leads to improved stem cell health and improved physical function, known as frailty.”

Fundamental aging mechanisms

Data suggest that senescent cells play a causal role in bone loss as people age, and “clearing” senescent cell burden can reduce frailty and increase the life span of mice, Khosla said. In mouse models with old mice (aged approximately 20 months) with established bone loss, 2- to 4-month treatment with senolytic interventions (clearing the senescent cells to rejuvenate tissue) or senomorphic interventions (inhibiting SASP production) improved bone mass, bone microarchitecture and bone strength in the mice, Khosla said.

LaTonya J. Hickson

The specificity of the interventions to aging was demonstrated in similar research with young mice, where no skeletal effects were observed with the same treatments, Khosla said. Additionally, by eliminating senescent cells or inhibiting SASP, cardiovascular function and insulin sensitivity in mice also improved.

‘Uncoupling’ bone resorption, formation

The cellular mechanisms that have beneficial effects of targeting senescent cells in bone differ from the current osteoporosis therapies, Khosla and colleagues wrote in a literature review published in April 2018 in The Journal of Clinical Endocrinology & Metabolism. The improvements researchers observed in trabecular bone mass and microarchitecture were associated with decreased bone resorption, but with no change in bone formation on trabecular bone surfaces — in contrast to the effects of all currently available antiresorptive drugs for osteoporosis, where a reduction in bone resorption is consistently associated with a reduction in bone formation.

“Senolytics reduce senescent cell burden, which leads to a suppression of bone resorption with either an increase (cortical bone) or maintenance (trabecular bone) in bone formation, thereby effectively ‘uncoupling’ bone resorption and formation,” the researchers wrote. “Because of this mixed antiresorptive/anabolic effect, senolytic treatment may have more sustained beneficial effects on bone as compared with conventional antiresorptive therapies, although further studies are needed to test this.”

The findings, the researchers noted, offer new promise in a field where there has been declining interest from the pharmaceutical industry to develop new osteoporosis therapies, particularly after the failure of the cathepsin K inhibitor odanacatib (Merck) due to an increase in stroke risk, and questions raised about the sclerostin inhibitor romosozumab (Evinity, Amgen) due to an observed CV signal in some studies.

Caution needed

Hickson and colleagues are now testing the safety of senolytics in individuals with diabetic kidney disease in two phase 2, pilot, randomized controlled trials. Interventions include a single-dosing regimen using a combination of dasatinib (Sprycel; Bristol-Myers Squibb, Otsuka) plus the flavonol quercetin in an open-label study with 20 adults with CKD, and a single, 2-day oral treatment with the plant polyphenol fisetin, a dietary antioxidant, in 30 adults with diabetes or CKD. The studies are expected to be completed in May 2021 and April 2022, respectively.

Primary study endpoints will examine the ability of senolytics to clear senescent cells in various tissues and improve the mesenchymal stem cell function that is often reduced in older patients with diabetes and kidney disease, Hickson said.

“Our goal is to improve the health of these stem cells so that we can give the cells back to patients in our regenerative medicine program and rejuvenate their kidneys,” Hickson said. “We believe that combining the benefits of both senolytics and stem cell therapy holds immense potential to delay the progression of kidney failure to end-stage renal disease.”

In a third Mayo Clinic pilot study, AFFIRM-LITE, researchers are testing the efficacy of fisetin in reducing frailty and markers of inflammation, insulin resistance and bone resorption in 40 older adults (aged 70-90 years) vs. placebo. That study has an estimated completion date of April 2020.

“These are only early studies with just one dosing administration,” Hickson said. “More studies will be needed to optimize the senolytic interventions and several more are underway.”

Khosla called the new discoveries exciting, but said caution is warranted.

“There is a lot of interest right now in senescence, and it is exciting, but I, personally, am not taking any of these medicines,” Khosla said. “I actually received a call from a physician who wanted to know how to take these drugs for osteoporosis. I strongly advised him not to, because we just don’t know enough. That said, this is one of the most exciting developments in the aging field in a long, long time. It opens up a whole new way of thinking about these chronic aging diseases.”– by Regina Schaffer

Disclosures: Khosla reports he has served as an unpaid consultant for Active Life Science and on the scientific advisory board for Surrozen Inc. Hickson reports no relevant financial disclosures.

A fundamental aging mechanism that drives tissue dysfunction throughout the body may serve as a novel target in the treatment of osteoporosis, suggesting an exciting new pathway for researchers in a field where a “perfect” therapy has remained elusive.

Cellular senescence, a phenomenon in which normal cells cease to divide, is becoming a buzzed-about topic as new research reveals it may be a druggable target to treat — or even prevent — multiple aging comorbidities, including osteoporosis. The research, mostly conducted with mice, but also in small human cohorts, suggests that there may be novel ways to use already available therapies to stop tissue dysfunction.

“Because there are these potential benefits with senescent cells, you want to be very careful how you target them,” Sundeep Khosla, MD, director of the Center for Clinical and Translational Science at Mayo Clinic and a leading researcher in cellular senescence, told Endocrine Today. “The approach that has been used by the Mayo Clinic group and several groups around the world is to look for specific drugs because these cells activate certain pathways that make them resistant to apoptosis, and those pathways are upregulated.”

Several drugs have now been identified, Khosla said, that selectively kill senescent cells by targeting the antiapoptotic pathways without affecting normal cells — so-called senolytic drugs.

An unmet need

There is now growing evidence that senescent cells accumulate in tissues with aging, Khosla said. The main tissue dysfunction they cause is through the senescence-associated secretory phenotype (SASP), which consists of proinflammatory cytokines and chemokines.

Sundeep Khosla

“These cells have now been shown to accumulate in multiple tissues, and there is an exploding body of literature on this,” Khosla said. “The hypothesis in the geroscience community is that if you target these cells, perhaps you can rejuvenate or prevent some of the aging-related morbidities.”

In aging, there is an accumulation of senescent osteocytes in bone, Khosla said. These cells have a high expression of multiple SASP markers, which could lead to an inhibition of bone formation and an increase in bone resorption.

Removing senescent cells might improve tissue and organ function in areas other than bone as well, potentially leading to treatments for chronic kidney disease and diabetes, LaTonya J. Hickson, MD, FASN, FACP, an associate professor of medicine at Mayo Clinic College of Medicine, told Endocrine Today.

“We are fortunate to work with a team of investigators who have devoted decades of effort to the study of senescence and inflammation in aging,” Hickson said. “Those efforts led to the discovery of drugs that selectively clear, or remove, these toxic senescent cells, which then leads to improved stem cell health and improved physical function, known as frailty.”

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Fundamental aging mechanisms

Data suggest that senescent cells play a causal role in bone loss as people age, and “clearing” senescent cell burden can reduce frailty and increase the life span of mice, Khosla said. In mouse models with old mice (aged approximately 20 months) with established bone loss, 2- to 4-month treatment with senolytic interventions (clearing the senescent cells to rejuvenate tissue) or senomorphic interventions (inhibiting SASP production) improved bone mass, bone microarchitecture and bone strength in the mice, Khosla said.

LaTonya J. Hickson

The specificity of the interventions to aging was demonstrated in similar research with young mice, where no skeletal effects were observed with the same treatments, Khosla said. Additionally, by eliminating senescent cells or inhibiting SASP, cardiovascular function and insulin sensitivity in mice also improved.

‘Uncoupling’ bone resorption, formation

The cellular mechanisms that have beneficial effects of targeting senescent cells in bone differ from the current osteoporosis therapies, Khosla and colleagues wrote in a literature review published in April 2018 in The Journal of Clinical Endocrinology & Metabolism. The improvements researchers observed in trabecular bone mass and microarchitecture were associated with decreased bone resorption, but with no change in bone formation on trabecular bone surfaces — in contrast to the effects of all currently available antiresorptive drugs for osteoporosis, where a reduction in bone resorption is consistently associated with a reduction in bone formation.

“Senolytics reduce senescent cell burden, which leads to a suppression of bone resorption with either an increase (cortical bone) or maintenance (trabecular bone) in bone formation, thereby effectively ‘uncoupling’ bone resorption and formation,” the researchers wrote. “Because of this mixed antiresorptive/anabolic effect, senolytic treatment may have more sustained beneficial effects on bone as compared with conventional antiresorptive therapies, although further studies are needed to test this.”

The findings, the researchers noted, offer new promise in a field where there has been declining interest from the pharmaceutical industry to develop new osteoporosis therapies, particularly after the failure of the cathepsin K inhibitor odanacatib (Merck) due to an increase in stroke risk, and questions raised about the sclerostin inhibitor romosozumab (Evinity, Amgen) due to an observed CV signal in some studies.

PAGE BREAK

Caution needed

Hickson and colleagues are now testing the safety of senolytics in individuals with diabetic kidney disease in two phase 2, pilot, randomized controlled trials. Interventions include a single-dosing regimen using a combination of dasatinib (Sprycel; Bristol-Myers Squibb, Otsuka) plus the flavonol quercetin in an open-label study with 20 adults with CKD, and a single, 2-day oral treatment with the plant polyphenol fisetin, a dietary antioxidant, in 30 adults with diabetes or CKD. The studies are expected to be completed in May 2021 and April 2022, respectively.

Primary study endpoints will examine the ability of senolytics to clear senescent cells in various tissues and improve the mesenchymal stem cell function that is often reduced in older patients with diabetes and kidney disease, Hickson said.

“Our goal is to improve the health of these stem cells so that we can give the cells back to patients in our regenerative medicine program and rejuvenate their kidneys,” Hickson said. “We believe that combining the benefits of both senolytics and stem cell therapy holds immense potential to delay the progression of kidney failure to end-stage renal disease.”

In a third Mayo Clinic pilot study, AFFIRM-LITE, researchers are testing the efficacy of fisetin in reducing frailty and markers of inflammation, insulin resistance and bone resorption in 40 older adults (aged 70-90 years) vs. placebo. That study has an estimated completion date of April 2020.

“These are only early studies with just one dosing administration,” Hickson said. “More studies will be needed to optimize the senolytic interventions and several more are underway.”

Khosla called the new discoveries exciting, but said caution is warranted.

“There is a lot of interest right now in senescence, and it is exciting, but I, personally, am not taking any of these medicines,” Khosla said. “I actually received a call from a physician who wanted to know how to take these drugs for osteoporosis. I strongly advised him not to, because we just don’t know enough. That said, this is one of the most exciting developments in the aging field in a long, long time. It opens up a whole new way of thinking about these chronic aging diseases.”– by Regina Schaffer

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Disclosures: Khosla reports he has served as an unpaid consultant for Active Life Science and on the scientific advisory board for Surrozen Inc. Hickson reports no relevant financial disclosures.

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