Geriatrics

The administration of IV ketamine over the course of 2 months can improve treatment resistant depression (TRD) and executive function in older adults, findings from a new pilot study suggest.

Results showed nearly 50% of participants responded to ketamine and 25% achieved complete remission from TRD, as measured by scores on the Montgomery-Asberg Depression Rating Scale (MADRS).

“Our pilot study suggests that IV ketamine is well-tolerated, safe, and associated with improvement in late-life TRD,” co-investigator Marie Anne Gebara, MD, assistant professor of psychiatry at the University of Pittsburgh, told this news organization.

Dr. Gebara pointed out the treatment “may not be appropriate for all patients with TRD,” such as those with a history of psychotic symptoms or uncontrolled hypertension; but “it appears to be a promising option.”

The findings were published online in the American Journal of Geriatric Psychiatry.
 

Lack of data in seniors

Although ketamine has been shown in prior research to rapidly reduce suicidal ideation in adults, there has been a lack of data on its efficacy and safety in older adults, the current investigators note.

“Almost 50% of older adults suffering from depression have TRD, which is a leading cause of disability, excess mortality from suicide, and dementia,” Dr. Gebara said.

She added that after two failed trials of antidepressants, “older adults have few evidence-based choices: aripiprazole or bupropion augmentation, transcranial magnetic stimulation, or electroconvulsive therapy. Novel treatments with rapid benefit are needed as long-term outcomes are poor and recurrence rates are high.”

Dr. Gebara and colleagues at five sites (Columbia University, New York State Psychiatric Institute, University of Toronto, University of Pittsburgh, and Washington University in St. Louis) each enrolled five participants aged 60 and older into the pilot study between October 2020 and November 2021, for a total of 25 participants (mean age, 71 years).

Each participant was recruited from patient registries or referred by behavioral health or primary care providers and diagnosed with TRD, which was defined as an episode of major depressive disorder without psychotic features that persisted despite two or more trials of antidepressants including at least one evidence-based second-line treatment.

Participants had to take an oral antidepressant dosage for at least 1 month prior to the start of the IV ketamine infusions, and continue their antidepressant for the length of the trial.

They received IV ketamine twice weekly for 4 weeks. The dosage was weight-dependent.

At the end of the 4 weeks, participants who achieved a MADRS total score of less than 10 or had a 30% or greater reduction from their baseline MADRS score entered another 4-week phase of the trial. This phase consisted of once-weekly administration of IV ketamine.
 

Larger plans

Results showed 15 of the 25 participants (60%) experienced a 30% or higher reduction in MADRS scores in the first phase of the study. The mean change in MADRS total score from the beginning to the end of the first phase was a decrease of 9.4 points (P < .01).

At the end of the continuation phase, half (48%) met criteria for response and 27% met criteria for remission.

After ketamine administration, the researchers also found an improvement in Fluid Cognition Composite Score (Cohen’s d value = .61), indicating a medium to large effect size, and in three measures of executive function.

Overall, adverse events were rare and did not keep patients from participating in the study, the investigators note. Five of the 25 participants reported infusion-induced hypertension that was transient.

Study limitations cited include the small sample size and the absence of randomization and placebo control or comparison treatment.

“We were very pleased with these findings because they establish the safety of this novel intervention in older adults,” Dr. Gebara said.

“After establishing safety and tolerability, we can plan for larger, randomized controlled trials that will allow us to determine the effectiveness of IV ketamine for older adults with TRD,” she added.
 

Multiple mechanisms

In a comment, Gerard Sanacora, MD, PhD, professor of psychiatry at Yale University and director of the Yale Depression Research Program, New Haven, Conn., noted multiple mechanisms likely contribute to the antidepressant effects of ketamine.

Dr. Sanacora has independently researched the effects of ketamine but was not involved with the current study.

“Much of the work to date has focused on the drug’s proximal effects on the glutamatergic neurotransmitter system and the resulting enhancement of adaptive neuroplasticity in several brain regions,” he said.

“However, there is also evidence to suggest other neurotransmitter systems and possibly even neuroinflammatory regulators are also contributing to the effect,” Dr. Sanacora added.

He noted that these mechanisms are also likely amplified by the “hope, optimism, expectations, and improved medical management overall that are known to be associated with treatments that require close monitoring and follow-up with health care providers.”

Dr. Gebara noted that “internal/department funds at each site” were used to support the study. She also reported receiving support from Otsuka US. Disclosures for the other investigators are listed in the original article. Dr. Sanacora has reported having “no major direct conflicts” with the study.

A version of this article first appeared on Medscape.com.

The administration of IV ketamine over the course of 2 months can improve treatment resistant depression (TRD) and executive function in older adults, findings from a new pilot study suggest.

Results showed nearly 50% of participants responded to ketamine and 25% achieved complete remission from TRD, as measured by scores on the Montgomery-Asberg Depression Rating Scale (MADRS).

“Our pilot study suggests that IV ketamine is well-tolerated, safe, and associated with improvement in late-life TRD,” co-investigator Marie Anne Gebara, MD, assistant professor of psychiatry at the University of Pittsburgh, told this news organization.

Dr. Gebara pointed out the treatment “may not be appropriate for all patients with TRD,” such as those with a history of psychotic symptoms or uncontrolled hypertension; but “it appears to be a promising option.”

The findings were published online in the American Journal of Geriatric Psychiatry.
 

Lack of data in seniors

Although ketamine has been shown in prior research to rapidly reduce suicidal ideation in adults, there has been a lack of data on its efficacy and safety in older adults, the current investigators note.

“Almost 50% of older adults suffering from depression have TRD, which is a leading cause of disability, excess mortality from suicide, and dementia,” Dr. Gebara said.

She added that after two failed trials of antidepressants, “older adults have few evidence-based choices: aripiprazole or bupropion augmentation, transcranial magnetic stimulation, or electroconvulsive therapy. Novel treatments with rapid benefit are needed as long-term outcomes are poor and recurrence rates are high.”

Dr. Gebara and colleagues at five sites (Columbia University, New York State Psychiatric Institute, University of Toronto, University of Pittsburgh, and Washington University in St. Louis) each enrolled five participants aged 60 and older into the pilot study between October 2020 and November 2021, for a total of 25 participants (mean age, 71 years).

Each participant was recruited from patient registries or referred by behavioral health or primary care providers and diagnosed with TRD, which was defined as an episode of major depressive disorder without psychotic features that persisted despite two or more trials of antidepressants including at least one evidence-based second-line treatment.

Participants had to take an oral antidepressant dosage for at least 1 month prior to the start of the IV ketamine infusions, and continue their antidepressant for the length of the trial.

They received IV ketamine twice weekly for 4 weeks. The dosage was weight-dependent.

At the end of the 4 weeks, participants who achieved a MADRS total score of less than 10 or had a 30% or greater reduction from their baseline MADRS score entered another 4-week phase of the trial. This phase consisted of once-weekly administration of IV ketamine.
 

Larger plans

Results showed 15 of the 25 participants (60%) experienced a 30% or higher reduction in MADRS scores in the first phase of the study. The mean change in MADRS total score from the beginning to the end of the first phase was a decrease of 9.4 points (P < .01).

At the end of the continuation phase, half (48%) met criteria for response and 27% met criteria for remission.

After ketamine administration, the researchers also found an improvement in Fluid Cognition Composite Score (Cohen’s d value = .61), indicating a medium to large effect size, and in three measures of executive function.

Overall, adverse events were rare and did not keep patients from participating in the study, the investigators note. Five of the 25 participants reported infusion-induced hypertension that was transient.

Study limitations cited include the small sample size and the absence of randomization and placebo control or comparison treatment.

“We were very pleased with these findings because they establish the safety of this novel intervention in older adults,” Dr. Gebara said.

“After establishing safety and tolerability, we can plan for larger, randomized controlled trials that will allow us to determine the effectiveness of IV ketamine for older adults with TRD,” she added.
 

Multiple mechanisms

In a comment, Gerard Sanacora, MD, PhD, professor of psychiatry at Yale University and director of the Yale Depression Research Program, New Haven, Conn., noted multiple mechanisms likely contribute to the antidepressant effects of ketamine.

Dr. Sanacora has independently researched the effects of ketamine but was not involved with the current study.

“Much of the work to date has focused on the drug’s proximal effects on the glutamatergic neurotransmitter system and the resulting enhancement of adaptive neuroplasticity in several brain regions,” he said.

“However, there is also evidence to suggest other neurotransmitter systems and possibly even neuroinflammatory regulators are also contributing to the effect,” Dr. Sanacora added.

He noted that these mechanisms are also likely amplified by the “hope, optimism, expectations, and improved medical management overall that are known to be associated with treatments that require close monitoring and follow-up with health care providers.”

Dr. Gebara noted that “internal/department funds at each site” were used to support the study. She also reported receiving support from Otsuka US. Disclosures for the other investigators are listed in the original article. Dr. Sanacora has reported having “no major direct conflicts” with the study.

A version of this article first appeared on Medscape.com.

The administration of IV ketamine over the course of 2 months can improve treatment resistant depression (TRD) and executive function in older adults, findings from a new pilot study suggest.

Results showed nearly 50% of participants responded to ketamine and 25% achieved complete remission from TRD, as measured by scores on the Montgomery-Asberg Depression Rating Scale (MADRS).

“Our pilot study suggests that IV ketamine is well-tolerated, safe, and associated with improvement in late-life TRD,” co-investigator Marie Anne Gebara, MD, assistant professor of psychiatry at the University of Pittsburgh, told this news organization.

Dr. Gebara pointed out the treatment “may not be appropriate for all patients with TRD,” such as those with a history of psychotic symptoms or uncontrolled hypertension; but “it appears to be a promising option.”

The findings were published online in the American Journal of Geriatric Psychiatry.
 

Lack of data in seniors

Although ketamine has been shown in prior research to rapidly reduce suicidal ideation in adults, there has been a lack of data on its efficacy and safety in older adults, the current investigators note.

“Almost 50% of older adults suffering from depression have TRD, which is a leading cause of disability, excess mortality from suicide, and dementia,” Dr. Gebara said.

She added that after two failed trials of antidepressants, “older adults have few evidence-based choices: aripiprazole or bupropion augmentation, transcranial magnetic stimulation, or electroconvulsive therapy. Novel treatments with rapid benefit are needed as long-term outcomes are poor and recurrence rates are high.”

Dr. Gebara and colleagues at five sites (Columbia University, New York State Psychiatric Institute, University of Toronto, University of Pittsburgh, and Washington University in St. Louis) each enrolled five participants aged 60 and older into the pilot study between October 2020 and November 2021, for a total of 25 participants (mean age, 71 years).

Each participant was recruited from patient registries or referred by behavioral health or primary care providers and diagnosed with TRD, which was defined as an episode of major depressive disorder without psychotic features that persisted despite two or more trials of antidepressants including at least one evidence-based second-line treatment.

Participants had to take an oral antidepressant dosage for at least 1 month prior to the start of the IV ketamine infusions, and continue their antidepressant for the length of the trial.

They received IV ketamine twice weekly for 4 weeks. The dosage was weight-dependent.

At the end of the 4 weeks, participants who achieved a MADRS total score of less than 10 or had a 30% or greater reduction from their baseline MADRS score entered another 4-week phase of the trial. This phase consisted of once-weekly administration of IV ketamine.
 

Larger plans

Results showed 15 of the 25 participants (60%) experienced a 30% or higher reduction in MADRS scores in the first phase of the study. The mean change in MADRS total score from the beginning to the end of the first phase was a decrease of 9.4 points (P < .01).

At the end of the continuation phase, half (48%) met criteria for response and 27% met criteria for remission.

After ketamine administration, the researchers also found an improvement in Fluid Cognition Composite Score (Cohen’s d value = .61), indicating a medium to large effect size, and in three measures of executive function.

Overall, adverse events were rare and did not keep patients from participating in the study, the investigators note. Five of the 25 participants reported infusion-induced hypertension that was transient.

Study limitations cited include the small sample size and the absence of randomization and placebo control or comparison treatment.

“We were very pleased with these findings because they establish the safety of this novel intervention in older adults,” Dr. Gebara said.

“After establishing safety and tolerability, we can plan for larger, randomized controlled trials that will allow us to determine the effectiveness of IV ketamine for older adults with TRD,” she added.
 

Multiple mechanisms

In a comment, Gerard Sanacora, MD, PhD, professor of psychiatry at Yale University and director of the Yale Depression Research Program, New Haven, Conn., noted multiple mechanisms likely contribute to the antidepressant effects of ketamine.

Dr. Sanacora has independently researched the effects of ketamine but was not involved with the current study.

“Much of the work to date has focused on the drug’s proximal effects on the glutamatergic neurotransmitter system and the resulting enhancement of adaptive neuroplasticity in several brain regions,” he said.

“However, there is also evidence to suggest other neurotransmitter systems and possibly even neuroinflammatory regulators are also contributing to the effect,” Dr. Sanacora added.

He noted that these mechanisms are also likely amplified by the “hope, optimism, expectations, and improved medical management overall that are known to be associated with treatments that require close monitoring and follow-up with health care providers.”

Dr. Gebara noted that “internal/department funds at each site” were used to support the study. She also reported receiving support from Otsuka US. Disclosures for the other investigators are listed in the original article. Dr. Sanacora has reported having “no major direct conflicts” with the study.

A version of this article first appeared on Medscape.com.

The standard nonsurgical treatment for pelvic organ prolapse does not appear to work as well as surgery to correct the problem, Dutch researchers have found. 

Pelvic organ prolapse is an uncomfortable condition, causing a troublesome vaginal bulge, often accompanied by urinary, bowel, or sexual dysfunction. Between 3% and 6% of women develop symptomatic prolapse, with the highest incidence in women aged 60-69 years – a fast-growing demographic.

Although many women choose surgical treatment, the American College of Obstetricians and Gynecologists recommends that women be offered a vaginal pessary as a noninvasive alternative, despite inconsistent data from observational studies on their effectiveness.

Lisa van der Vaart, MD, a doctoral student in ob.gyn. at the University of Amsterdam and the lead author of the new study, published in JAMA, said that differences in outcome measures, small sample size, and lack of long-term follow-up have bedeviled previous comparisons of the two techniques.

“We thought it was very important to perform a randomized control trial on this subject to improve counseling to women who suffer from symptomatic pelvic organ prolapse,” Dr. van der Vaart said.

She and her colleagues conducted a noninferiority randomized clinical trial that recruited 1,605 women with stage II or higher prolapse who were referred to specialty care at 21 hospitals in the Netherlands between 2015 and 2019. Of the 440 women who agreed to participate in the trial, 218 received a pessary, a device inserted into the vagina that provides support to tissues displaced by prolapse, and 222 underwent surgery.

The primary outcome was subjective improvement using a standardized questionnaire at 24 months; women were asked to rank their symptoms on a seven-point scale, and subjective improvement was defined as a response of much better or very much better.

“We saw a substantial amount of improvement in both groups,” Dr. van der Vaart said in an interview.

After 24 months of follow-up, outcome data were available for 173 women in the pessary group and 162 in the surgery group. For this intention-to treat population, 76.3% in the pessary group and 81.5% in the surgery group reported improvement.

Results were similar for the smaller group of participants who completed the study per protocol, without crossing over to a treatment to which they had not been allocated.

However, neither the intention-to-treat nor per-protocol analysis met the prespecified criteria for noninferiority, suggesting that use of a vaginal pessary is not equivalent to surgery.

The study also found differences in adverse events. Among women randomly assigned to surgery, 9% suffered a postoperative urinary tract infection, and 5.4% underwent additional therapy, such as pessary or repeat operation.

But use of a pessary also had downsides. The most common adverse event was discomfort (42.7%), and by 24 months, 60% of the participants in the pessary group had discontinued use.

Dr. van der Vaart said that she was surprised by the high number of women assigned to the pessary group who later elected to undergo surgery. “Women should be told that their chance of crossing over to a surgical intervention is quite high – more than 50% do eventually end up having surgery.”

Cheryl Iglesia, MD, director of the National Center for Advanced Pelvic Surgery at MedStar Health and professor of obstetrics and gynecology and urology at Georgetown University, both in Washington, was also struck by the high crossover rate. “We’ve had the same pessaries probably for the last 100 years,” she said. “We need to get better.”

Dr. Iglesia welcomed new approaches to making vaginal pessaries that are custom designed for each woman’s unique anatomy using 3D printing and pointed to promising initial clinical trials of disposable pessaries. With the aging of the population and demand for treatment of prolapse increasing, she cited a need for better nonsurgical alternatives: “We have a work-force issue and may not have enough adequately trained urogynecologists to meet the demand for prolapse repairs as our population ages.”

The study was funded by a grant from ZonMW, a Dutch governmental health care organization. Dr. van der Vaart reported grants from ZonMW during the conduct of the study.

A version of this article first appeared on Medscape.com.

The standard nonsurgical treatment for pelvic organ prolapse does not appear to work as well as surgery to correct the problem, Dutch researchers have found. 

Pelvic organ prolapse is an uncomfortable condition, causing a troublesome vaginal bulge, often accompanied by urinary, bowel, or sexual dysfunction. Between 3% and 6% of women develop symptomatic prolapse, with the highest incidence in women aged 60-69 years – a fast-growing demographic.

Although many women choose surgical treatment, the American College of Obstetricians and Gynecologists recommends that women be offered a vaginal pessary as a noninvasive alternative, despite inconsistent data from observational studies on their effectiveness.

Lisa van der Vaart, MD, a doctoral student in ob.gyn. at the University of Amsterdam and the lead author of the new study, published in JAMA, said that differences in outcome measures, small sample size, and lack of long-term follow-up have bedeviled previous comparisons of the two techniques.

“We thought it was very important to perform a randomized control trial on this subject to improve counseling to women who suffer from symptomatic pelvic organ prolapse,” Dr. van der Vaart said.

She and her colleagues conducted a noninferiority randomized clinical trial that recruited 1,605 women with stage II or higher prolapse who were referred to specialty care at 21 hospitals in the Netherlands between 2015 and 2019. Of the 440 women who agreed to participate in the trial, 218 received a pessary, a device inserted into the vagina that provides support to tissues displaced by prolapse, and 222 underwent surgery.

The primary outcome was subjective improvement using a standardized questionnaire at 24 months; women were asked to rank their symptoms on a seven-point scale, and subjective improvement was defined as a response of much better or very much better.

“We saw a substantial amount of improvement in both groups,” Dr. van der Vaart said in an interview.

After 24 months of follow-up, outcome data were available for 173 women in the pessary group and 162 in the surgery group. For this intention-to treat population, 76.3% in the pessary group and 81.5% in the surgery group reported improvement.

Results were similar for the smaller group of participants who completed the study per protocol, without crossing over to a treatment to which they had not been allocated.

However, neither the intention-to-treat nor per-protocol analysis met the prespecified criteria for noninferiority, suggesting that use of a vaginal pessary is not equivalent to surgery.

The study also found differences in adverse events. Among women randomly assigned to surgery, 9% suffered a postoperative urinary tract infection, and 5.4% underwent additional therapy, such as pessary or repeat operation.

But use of a pessary also had downsides. The most common adverse event was discomfort (42.7%), and by 24 months, 60% of the participants in the pessary group had discontinued use.

Dr. van der Vaart said that she was surprised by the high number of women assigned to the pessary group who later elected to undergo surgery. “Women should be told that their chance of crossing over to a surgical intervention is quite high – more than 50% do eventually end up having surgery.”

Cheryl Iglesia, MD, director of the National Center for Advanced Pelvic Surgery at MedStar Health and professor of obstetrics and gynecology and urology at Georgetown University, both in Washington, was also struck by the high crossover rate. “We’ve had the same pessaries probably for the last 100 years,” she said. “We need to get better.”

Dr. Iglesia welcomed new approaches to making vaginal pessaries that are custom designed for each woman’s unique anatomy using 3D printing and pointed to promising initial clinical trials of disposable pessaries. With the aging of the population and demand for treatment of prolapse increasing, she cited a need for better nonsurgical alternatives: “We have a work-force issue and may not have enough adequately trained urogynecologists to meet the demand for prolapse repairs as our population ages.”

The study was funded by a grant from ZonMW, a Dutch governmental health care organization. Dr. van der Vaart reported grants from ZonMW during the conduct of the study.

A version of this article first appeared on Medscape.com.

The standard nonsurgical treatment for pelvic organ prolapse does not appear to work as well as surgery to correct the problem, Dutch researchers have found. 

Pelvic organ prolapse is an uncomfortable condition, causing a troublesome vaginal bulge, often accompanied by urinary, bowel, or sexual dysfunction. Between 3% and 6% of women develop symptomatic prolapse, with the highest incidence in women aged 60-69 years – a fast-growing demographic.

Although many women choose surgical treatment, the American College of Obstetricians and Gynecologists recommends that women be offered a vaginal pessary as a noninvasive alternative, despite inconsistent data from observational studies on their effectiveness.

Lisa van der Vaart, MD, a doctoral student in ob.gyn. at the University of Amsterdam and the lead author of the new study, published in JAMA, said that differences in outcome measures, small sample size, and lack of long-term follow-up have bedeviled previous comparisons of the two techniques.

“We thought it was very important to perform a randomized control trial on this subject to improve counseling to women who suffer from symptomatic pelvic organ prolapse,” Dr. van der Vaart said.

She and her colleagues conducted a noninferiority randomized clinical trial that recruited 1,605 women with stage II or higher prolapse who were referred to specialty care at 21 hospitals in the Netherlands between 2015 and 2019. Of the 440 women who agreed to participate in the trial, 218 received a pessary, a device inserted into the vagina that provides support to tissues displaced by prolapse, and 222 underwent surgery.

The primary outcome was subjective improvement using a standardized questionnaire at 24 months; women were asked to rank their symptoms on a seven-point scale, and subjective improvement was defined as a response of much better or very much better.

“We saw a substantial amount of improvement in both groups,” Dr. van der Vaart said in an interview.

After 24 months of follow-up, outcome data were available for 173 women in the pessary group and 162 in the surgery group. For this intention-to treat population, 76.3% in the pessary group and 81.5% in the surgery group reported improvement.

Results were similar for the smaller group of participants who completed the study per protocol, without crossing over to a treatment to which they had not been allocated.

However, neither the intention-to-treat nor per-protocol analysis met the prespecified criteria for noninferiority, suggesting that use of a vaginal pessary is not equivalent to surgery.

The study also found differences in adverse events. Among women randomly assigned to surgery, 9% suffered a postoperative urinary tract infection, and 5.4% underwent additional therapy, such as pessary or repeat operation.

But use of a pessary also had downsides. The most common adverse event was discomfort (42.7%), and by 24 months, 60% of the participants in the pessary group had discontinued use.

Dr. van der Vaart said that she was surprised by the high number of women assigned to the pessary group who later elected to undergo surgery. “Women should be told that their chance of crossing over to a surgical intervention is quite high – more than 50% do eventually end up having surgery.”

Cheryl Iglesia, MD, director of the National Center for Advanced Pelvic Surgery at MedStar Health and professor of obstetrics and gynecology and urology at Georgetown University, both in Washington, was also struck by the high crossover rate. “We’ve had the same pessaries probably for the last 100 years,” she said. “We need to get better.”

Dr. Iglesia welcomed new approaches to making vaginal pessaries that are custom designed for each woman’s unique anatomy using 3D printing and pointed to promising initial clinical trials of disposable pessaries. With the aging of the population and demand for treatment of prolapse increasing, she cited a need for better nonsurgical alternatives: “We have a work-force issue and may not have enough adequately trained urogynecologists to meet the demand for prolapse repairs as our population ages.”

The study was funded by a grant from ZonMW, a Dutch governmental health care organization. Dr. van der Vaart reported grants from ZonMW during the conduct of the study.

A version of this article first appeared on Medscape.com.

The American College of Physicians has updated their guideline for pharmacotherapy to reduce fracture risk in adults with primary osteoporosis or osteopenia (low bone mass) based on a systematic review of the evidence.

This is the first update for 5 years since the previous guidance was published in 2017.

It strongly recommends initial therapy with bisphosphonates for postmenopausal women with osteoporosis, as well as men with osteoporosis, among other recommendations.

However, the author of an accompanying editorial, Susan M. Ott, MD, says: “The decision to start a bisphosphonate is actually not that easy.”

She also queries some of the other recommendations in the guidance.

Her editorial, along with the guideline by Amir Qaseem, MD, PhD, MPH, and colleagues, and systematic review by Chelsea Ayers, MPH, and colleagues, were published in the Annals of Internal Medicine.

Ryan D. Mire, MD, MACP, president of the ACP, gave a brief overview of the new guidance in a video.
 

Systematic review

The ACP commissioned a review of the evidence because it says new data have emerged on the efficacy of newer medications for osteoporosis and low bone mass, as well as treatment comparisons, and treatment in men.

The review authors identified 34 randomized controlled trials (in 100 publications) and 36 observational studies, which evaluated the following pharmacologic interventions:

• Antiresorptive drugs: four bisphosphonates (alendronate, ibandronate, risedronate, zoledronate) and a RANK ligand inhibitor (denosumab).
• Anabolic drugs: an analog of human parathyroid hormone (PTH)–related protein (abaloparatide), recombinant human PTH (teriparatide), and a sclerostin inhibitor (romosozumab).
• Estrogen agonists: selective estrogen receptor modulators (bazedoxifene, raloxifene).

The authors focused on effectiveness and harms of active drugs compared with placebo or bisphosphonates.
 

Major changes from 2017 guidelines, some questions

“Though there are many nuanced changes in this [2023 guideline] version, perhaps the major change is the explicit hierarchy of pharmacologic recommendations: bisphosphonates first, then denosumab,” Thomas G. Cooney, MD, senior author of the clinical guideline, explained in an interview.

“Bisphosphonates had the most favorable balance among benefits, harms, patient values and preferences, and cost among the examined drugs in postmenopausal females with primary osteoporosis,” Dr. Cooney, professor of medicine, Oregon Health & Science University, Portland, noted, as is stated in the guideline.

“Denosumab also had a favorable long-term net benefit, but bisphosphonates are much cheaper than other pharmacologic treatments and available in generic formulations,” the document states.

The new guideline suggests use of denosumab as second-line pharmacotherapy in adults who have contraindications to or experience adverse effects with bisphosphonates.

The choice among bisphosphonates (alendronate, risedronate, zoledronic acid) would be based on a patient-centered discussion between physician and patient, addressing costs (often related to insurance), delivery-mode preferences (oral versus intravenous), and “values,” which includes the patient’s priorities, concerns, and expectations regarding their health care, Dr. Cooney explained.

Another update in the new guideline is, “We also clarify the specific, albeit more limited, role of sclerostin inhibitors and recombinant PTH ‘to reduce the risk of fractures only in females with primary osteoporosis with very high-risk of fracture’,” Dr. Cooney noted.

In addition, the guideline now states, “treatment to reduce the risk of fractures in males rather than limiting it to ‘vertebral fracture’ in men,” as in the 2017 guideline.

It also explicitly includes denosumab as second-line therapy for men, Dr. Cooney noted, but as in 2017, the strength of evidence in men remains low.

“Finally, we also clarified that in females over the age of 65 with low bone mass or osteopenia that an individualized approach be taken to treatment (similar to last guideline), but if treatment is initiated, that a bisphosphonate be used (new content),” he said.

The use of estrogen, treatment duration, drug discontinuation, and serial bone mineral density monitoring were not addressed in this guideline, but will likely be evaluated within 2 to 3 years.
 

‘Osteoporosis treatment: Not easy’ – editorial

In her editorial, Dr. Ott writes: “The data about bisphosphonates may seem overwhelmingly positive, leading to strong recommendations for their use to treat osteoporosis, but the decision to start a bisphosphonate is actually not that easy.”

“A strong recommendation should be given only when future studies are unlikely to change it,” continues Dr. Ott, professor of medicine, University of Washington, Seattle.

“Yet, data already suggest that, in patients with serious osteoporosis, treatment should start with anabolic medications because previous treatment with either bisphosphonates or denosumab will prevent the anabolic response of newer medications.”

“Starting with bisphosphonate will change the bone so it will not respond to the newer medicines, and then a patient will lose the chance for getting the best improvement,” Dr. Ott clarified in an email to this news organization.

But, in fact, the new guidance does suggest that, to reduce the risk of fractures in females with primary osteoporosis at very high risk of fracture, one should consider use of the sclerostin inhibitor romosozumab (moderate-certainty evidence) or recombinant human parathyroid hormone (teriparatide) (low-certainty evidence) followed by a bisphosphonate (conditional recommendation).

Dr. Ott said: “If the [fracture] risk is high, then we should start with an anabolic medication for 1-2 years. If the risk is medium, then use a bisphosphonate for up to 5 years, and then stop and monitor the patient for signs that the medicine is wearing off,” based on blood and urine tests.
 

‘We need medicines that will stop bone aging’

Osteopenia is defined by an arbitrary bone density measurement, Dr. Ott explained. “About half of women over 65 will have osteopenia, and by age 85 there are hardly any ‘normal’ women left.”

“We need medicines that will stop bone aging, which might sound impossible, but we should still try,” she continued.

“In the meantime, while waiting on new discoveries,” Dr. Ott said, “I would not use bisphosphonates in patients who did not already have a fracture or whose bone density T-score was better than –2.5 because, in the major study, alendronate did not prevent fractures in this group.”

Many people are worried about bisphosphonates because of problems with the jaw or femur. These are real, but they are very rare during the first 5 years of treatment, Dr. Ott noted. Then the risk starts to rise, up to more than 1 in 1,000 after 8 years. So people can get the benefits of these drugs with very low risk for 5 years.

“An immediate [guideline] update is necessary to address the severity of bone loss and the high risk for vertebral fractures after discontinuation of denosumab,” Dr. Ott urged.

“I don’t agree with using denosumab for osteoporosis as a second-line treatment,” she said. “I would use it only in patients who have cancer or unusually high bone resorption. You have to get a dose strictly every 6 months, and if you need to stop, it is recommended to treat with bisphosphonates. Denosumab is a poor choice for somebody who does not want to take a bisphosphonate. Many patients and even too many doctors do not realize how serious it can be to skip a dose.”

“I also think that men could be treated with anabolic medications,” Dr. Ott said. “Clinical trials show they respond the same as women. Many men have osteoporosis as a consequence of low testosterone, and then they can usually be treated with testosterone. Osteoporosis in men is a serious problem that is too often ignored – almost reverse discrimination.”

It is also unfortunate that the review and recommendations do not address estrogen, one of the most effective medications to prevent osteoporotic fractures, according to Dr. Ott.
 

Clinical considerations in addition to drug types

The new guideline also advises:

• Clinicians treating adults with osteoporosis should encourage adherence to recommended treatments and healthy lifestyle habits, including exercise, and counseling to evaluate and prevent falls.
• All adults with osteopenia or osteoporosis should have adequate calcium and vitamin D intake, as part of fracture prevention.
• Clinicians should assess baseline fracture risk based on bone density, fracture history, fracture risk factors, and response to prior osteoporosis treatments.
• Current evidence suggests that more than 3-5 years of bisphosphonate therapy reduces risk for new vertebral but not other fractures; however, it also increases risk for long-term harms. Therefore, clinicians should consider stopping bisphosphonate treatment after 5 years unless the patient has a strong indication for treatment continuation.
• The decision for a bisphosphonate holiday (temporary discontinuation) and its duration should be based on baseline fracture risk, medication half-life in bone, and benefits and harms.
• Women treated with an anabolic agent who discontinue it should be offered an antiresorptive agent to preserve gains and because of serious risk for rebound and multiple vertebral fractures.
• Adults older than 65 years with osteoporosis may be at increased risk for falls or other adverse events because of drug interactions.
• Transgender persons have variable risk for low bone mass.

The review and guideline were funded by the ACP. Dr. Ott has reported no relevant disclosures. Relevant financial disclosures for other authors are listed with the guideline and review.

A version of this article first appeared on Medscape.com.

The American College of Physicians has updated their guideline for pharmacotherapy to reduce fracture risk in adults with primary osteoporosis or osteopenia (low bone mass) based on a systematic review of the evidence.

This is the first update for 5 years since the previous guidance was published in 2017.

It strongly recommends initial therapy with bisphosphonates for postmenopausal women with osteoporosis, as well as men with osteoporosis, among other recommendations.

However, the author of an accompanying editorial, Susan M. Ott, MD, says: “The decision to start a bisphosphonate is actually not that easy.”

She also queries some of the other recommendations in the guidance.

Her editorial, along with the guideline by Amir Qaseem, MD, PhD, MPH, and colleagues, and systematic review by Chelsea Ayers, MPH, and colleagues, were published in the Annals of Internal Medicine.

Ryan D. Mire, MD, MACP, president of the ACP, gave a brief overview of the new guidance in a video.
 

Systematic review

The ACP commissioned a review of the evidence because it says new data have emerged on the efficacy of newer medications for osteoporosis and low bone mass, as well as treatment comparisons, and treatment in men.

The review authors identified 34 randomized controlled trials (in 100 publications) and 36 observational studies, which evaluated the following pharmacologic interventions:

• Antiresorptive drugs: four bisphosphonates (alendronate, ibandronate, risedronate, zoledronate) and a RANK ligand inhibitor (denosumab).
• Anabolic drugs: an analog of human parathyroid hormone (PTH)–related protein (abaloparatide), recombinant human PTH (teriparatide), and a sclerostin inhibitor (romosozumab).
• Estrogen agonists: selective estrogen receptor modulators (bazedoxifene, raloxifene).

The authors focused on effectiveness and harms of active drugs compared with placebo or bisphosphonates.
 

Major changes from 2017 guidelines, some questions

“Though there are many nuanced changes in this [2023 guideline] version, perhaps the major change is the explicit hierarchy of pharmacologic recommendations: bisphosphonates first, then denosumab,” Thomas G. Cooney, MD, senior author of the clinical guideline, explained in an interview.

“Bisphosphonates had the most favorable balance among benefits, harms, patient values and preferences, and cost among the examined drugs in postmenopausal females with primary osteoporosis,” Dr. Cooney, professor of medicine, Oregon Health & Science University, Portland, noted, as is stated in the guideline.

“Denosumab also had a favorable long-term net benefit, but bisphosphonates are much cheaper than other pharmacologic treatments and available in generic formulations,” the document states.

The new guideline suggests use of denosumab as second-line pharmacotherapy in adults who have contraindications to or experience adverse effects with bisphosphonates.

The choice among bisphosphonates (alendronate, risedronate, zoledronic acid) would be based on a patient-centered discussion between physician and patient, addressing costs (often related to insurance), delivery-mode preferences (oral versus intravenous), and “values,” which includes the patient’s priorities, concerns, and expectations regarding their health care, Dr. Cooney explained.

Another update in the new guideline is, “We also clarify the specific, albeit more limited, role of sclerostin inhibitors and recombinant PTH ‘to reduce the risk of fractures only in females with primary osteoporosis with very high-risk of fracture’,” Dr. Cooney noted.

In addition, the guideline now states, “treatment to reduce the risk of fractures in males rather than limiting it to ‘vertebral fracture’ in men,” as in the 2017 guideline.

It also explicitly includes denosumab as second-line therapy for men, Dr. Cooney noted, but as in 2017, the strength of evidence in men remains low.

“Finally, we also clarified that in females over the age of 65 with low bone mass or osteopenia that an individualized approach be taken to treatment (similar to last guideline), but if treatment is initiated, that a bisphosphonate be used (new content),” he said.

The use of estrogen, treatment duration, drug discontinuation, and serial bone mineral density monitoring were not addressed in this guideline, but will likely be evaluated within 2 to 3 years.
 

‘Osteoporosis treatment: Not easy’ – editorial

In her editorial, Dr. Ott writes: “The data about bisphosphonates may seem overwhelmingly positive, leading to strong recommendations for their use to treat osteoporosis, but the decision to start a bisphosphonate is actually not that easy.”

“A strong recommendation should be given only when future studies are unlikely to change it,” continues Dr. Ott, professor of medicine, University of Washington, Seattle.

“Yet, data already suggest that, in patients with serious osteoporosis, treatment should start with anabolic medications because previous treatment with either bisphosphonates or denosumab will prevent the anabolic response of newer medications.”

“Starting with bisphosphonate will change the bone so it will not respond to the newer medicines, and then a patient will lose the chance for getting the best improvement,” Dr. Ott clarified in an email to this news organization.

But, in fact, the new guidance does suggest that, to reduce the risk of fractures in females with primary osteoporosis at very high risk of fracture, one should consider use of the sclerostin inhibitor romosozumab (moderate-certainty evidence) or recombinant human parathyroid hormone (teriparatide) (low-certainty evidence) followed by a bisphosphonate (conditional recommendation).

Dr. Ott said: “If the [fracture] risk is high, then we should start with an anabolic medication for 1-2 years. If the risk is medium, then use a bisphosphonate for up to 5 years, and then stop and monitor the patient for signs that the medicine is wearing off,” based on blood and urine tests.
 

‘We need medicines that will stop bone aging’

Osteopenia is defined by an arbitrary bone density measurement, Dr. Ott explained. “About half of women over 65 will have osteopenia, and by age 85 there are hardly any ‘normal’ women left.”

“We need medicines that will stop bone aging, which might sound impossible, but we should still try,” she continued.

“In the meantime, while waiting on new discoveries,” Dr. Ott said, “I would not use bisphosphonates in patients who did not already have a fracture or whose bone density T-score was better than –2.5 because, in the major study, alendronate did not prevent fractures in this group.”

Many people are worried about bisphosphonates because of problems with the jaw or femur. These are real, but they are very rare during the first 5 years of treatment, Dr. Ott noted. Then the risk starts to rise, up to more than 1 in 1,000 after 8 years. So people can get the benefits of these drugs with very low risk for 5 years.

“An immediate [guideline] update is necessary to address the severity of bone loss and the high risk for vertebral fractures after discontinuation of denosumab,” Dr. Ott urged.

“I don’t agree with using denosumab for osteoporosis as a second-line treatment,” she said. “I would use it only in patients who have cancer or unusually high bone resorption. You have to get a dose strictly every 6 months, and if you need to stop, it is recommended to treat with bisphosphonates. Denosumab is a poor choice for somebody who does not want to take a bisphosphonate. Many patients and even too many doctors do not realize how serious it can be to skip a dose.”

“I also think that men could be treated with anabolic medications,” Dr. Ott said. “Clinical trials show they respond the same as women. Many men have osteoporosis as a consequence of low testosterone, and then they can usually be treated with testosterone. Osteoporosis in men is a serious problem that is too often ignored – almost reverse discrimination.”

It is also unfortunate that the review and recommendations do not address estrogen, one of the most effective medications to prevent osteoporotic fractures, according to Dr. Ott.
 

Clinical considerations in addition to drug types

The new guideline also advises:

• Clinicians treating adults with osteoporosis should encourage adherence to recommended treatments and healthy lifestyle habits, including exercise, and counseling to evaluate and prevent falls.
• All adults with osteopenia or osteoporosis should have adequate calcium and vitamin D intake, as part of fracture prevention.
• Clinicians should assess baseline fracture risk based on bone density, fracture history, fracture risk factors, and response to prior osteoporosis treatments.
• Current evidence suggests that more than 3-5 years of bisphosphonate therapy reduces risk for new vertebral but not other fractures; however, it also increases risk for long-term harms. Therefore, clinicians should consider stopping bisphosphonate treatment after 5 years unless the patient has a strong indication for treatment continuation.
• The decision for a bisphosphonate holiday (temporary discontinuation) and its duration should be based on baseline fracture risk, medication half-life in bone, and benefits and harms.
• Women treated with an anabolic agent who discontinue it should be offered an antiresorptive agent to preserve gains and because of serious risk for rebound and multiple vertebral fractures.
• Adults older than 65 years with osteoporosis may be at increased risk for falls or other adverse events because of drug interactions.
• Transgender persons have variable risk for low bone mass.

The review and guideline were funded by the ACP. Dr. Ott has reported no relevant disclosures. Relevant financial disclosures for other authors are listed with the guideline and review.

A version of this article first appeared on Medscape.com.

The American College of Physicians has updated their guideline for pharmacotherapy to reduce fracture risk in adults with primary osteoporosis or osteopenia (low bone mass) based on a systematic review of the evidence.

This is the first update for 5 years since the previous guidance was published in 2017.

It strongly recommends initial therapy with bisphosphonates for postmenopausal women with osteoporosis, as well as men with osteoporosis, among other recommendations.

However, the author of an accompanying editorial, Susan M. Ott, MD, says: “The decision to start a bisphosphonate is actually not that easy.”

She also queries some of the other recommendations in the guidance.

Her editorial, along with the guideline by Amir Qaseem, MD, PhD, MPH, and colleagues, and systematic review by Chelsea Ayers, MPH, and colleagues, were published in the Annals of Internal Medicine.

Ryan D. Mire, MD, MACP, president of the ACP, gave a brief overview of the new guidance in a video.
 

Systematic review

The ACP commissioned a review of the evidence because it says new data have emerged on the efficacy of newer medications for osteoporosis and low bone mass, as well as treatment comparisons, and treatment in men.

The review authors identified 34 randomized controlled trials (in 100 publications) and 36 observational studies, which evaluated the following pharmacologic interventions:

• Antiresorptive drugs: four bisphosphonates (alendronate, ibandronate, risedronate, zoledronate) and a RANK ligand inhibitor (denosumab).
• Anabolic drugs: an analog of human parathyroid hormone (PTH)–related protein (abaloparatide), recombinant human PTH (teriparatide), and a sclerostin inhibitor (romosozumab).
• Estrogen agonists: selective estrogen receptor modulators (bazedoxifene, raloxifene).

The authors focused on effectiveness and harms of active drugs compared with placebo or bisphosphonates.
 

Major changes from 2017 guidelines, some questions

“Though there are many nuanced changes in this [2023 guideline] version, perhaps the major change is the explicit hierarchy of pharmacologic recommendations: bisphosphonates first, then denosumab,” Thomas G. Cooney, MD, senior author of the clinical guideline, explained in an interview.

“Bisphosphonates had the most favorable balance among benefits, harms, patient values and preferences, and cost among the examined drugs in postmenopausal females with primary osteoporosis,” Dr. Cooney, professor of medicine, Oregon Health & Science University, Portland, noted, as is stated in the guideline.

“Denosumab also had a favorable long-term net benefit, but bisphosphonates are much cheaper than other pharmacologic treatments and available in generic formulations,” the document states.

The new guideline suggests use of denosumab as second-line pharmacotherapy in adults who have contraindications to or experience adverse effects with bisphosphonates.

The choice among bisphosphonates (alendronate, risedronate, zoledronic acid) would be based on a patient-centered discussion between physician and patient, addressing costs (often related to insurance), delivery-mode preferences (oral versus intravenous), and “values,” which includes the patient’s priorities, concerns, and expectations regarding their health care, Dr. Cooney explained.

Another update in the new guideline is, “We also clarify the specific, albeit more limited, role of sclerostin inhibitors and recombinant PTH ‘to reduce the risk of fractures only in females with primary osteoporosis with very high-risk of fracture’,” Dr. Cooney noted.

In addition, the guideline now states, “treatment to reduce the risk of fractures in males rather than limiting it to ‘vertebral fracture’ in men,” as in the 2017 guideline.

It also explicitly includes denosumab as second-line therapy for men, Dr. Cooney noted, but as in 2017, the strength of evidence in men remains low.

“Finally, we also clarified that in females over the age of 65 with low bone mass or osteopenia that an individualized approach be taken to treatment (similar to last guideline), but if treatment is initiated, that a bisphosphonate be used (new content),” he said.

The use of estrogen, treatment duration, drug discontinuation, and serial bone mineral density monitoring were not addressed in this guideline, but will likely be evaluated within 2 to 3 years.
 

‘Osteoporosis treatment: Not easy’ – editorial

In her editorial, Dr. Ott writes: “The data about bisphosphonates may seem overwhelmingly positive, leading to strong recommendations for their use to treat osteoporosis, but the decision to start a bisphosphonate is actually not that easy.”

“A strong recommendation should be given only when future studies are unlikely to change it,” continues Dr. Ott, professor of medicine, University of Washington, Seattle.

“Yet, data already suggest that, in patients with serious osteoporosis, treatment should start with anabolic medications because previous treatment with either bisphosphonates or denosumab will prevent the anabolic response of newer medications.”

“Starting with bisphosphonate will change the bone so it will not respond to the newer medicines, and then a patient will lose the chance for getting the best improvement,” Dr. Ott clarified in an email to this news organization.

But, in fact, the new guidance does suggest that, to reduce the risk of fractures in females with primary osteoporosis at very high risk of fracture, one should consider use of the sclerostin inhibitor romosozumab (moderate-certainty evidence) or recombinant human parathyroid hormone (teriparatide) (low-certainty evidence) followed by a bisphosphonate (conditional recommendation).

Dr. Ott said: “If the [fracture] risk is high, then we should start with an anabolic medication for 1-2 years. If the risk is medium, then use a bisphosphonate for up to 5 years, and then stop and monitor the patient for signs that the medicine is wearing off,” based on blood and urine tests.
 

‘We need medicines that will stop bone aging’

Osteopenia is defined by an arbitrary bone density measurement, Dr. Ott explained. “About half of women over 65 will have osteopenia, and by age 85 there are hardly any ‘normal’ women left.”

“We need medicines that will stop bone aging, which might sound impossible, but we should still try,” she continued.

“In the meantime, while waiting on new discoveries,” Dr. Ott said, “I would not use bisphosphonates in patients who did not already have a fracture or whose bone density T-score was better than –2.5 because, in the major study, alendronate did not prevent fractures in this group.”

Many people are worried about bisphosphonates because of problems with the jaw or femur. These are real, but they are very rare during the first 5 years of treatment, Dr. Ott noted. Then the risk starts to rise, up to more than 1 in 1,000 after 8 years. So people can get the benefits of these drugs with very low risk for 5 years.

“An immediate [guideline] update is necessary to address the severity of bone loss and the high risk for vertebral fractures after discontinuation of denosumab,” Dr. Ott urged.

“I don’t agree with using denosumab for osteoporosis as a second-line treatment,” she said. “I would use it only in patients who have cancer or unusually high bone resorption. You have to get a dose strictly every 6 months, and if you need to stop, it is recommended to treat with bisphosphonates. Denosumab is a poor choice for somebody who does not want to take a bisphosphonate. Many patients and even too many doctors do not realize how serious it can be to skip a dose.”

“I also think that men could be treated with anabolic medications,” Dr. Ott said. “Clinical trials show they respond the same as women. Many men have osteoporosis as a consequence of low testosterone, and then they can usually be treated with testosterone. Osteoporosis in men is a serious problem that is too often ignored – almost reverse discrimination.”

It is also unfortunate that the review and recommendations do not address estrogen, one of the most effective medications to prevent osteoporotic fractures, according to Dr. Ott.
 

Clinical considerations in addition to drug types

The new guideline also advises:

• Clinicians treating adults with osteoporosis should encourage adherence to recommended treatments and healthy lifestyle habits, including exercise, and counseling to evaluate and prevent falls.
• All adults with osteopenia or osteoporosis should have adequate calcium and vitamin D intake, as part of fracture prevention.
• Clinicians should assess baseline fracture risk based on bone density, fracture history, fracture risk factors, and response to prior osteoporosis treatments.
• Current evidence suggests that more than 3-5 years of bisphosphonate therapy reduces risk for new vertebral but not other fractures; however, it also increases risk for long-term harms. Therefore, clinicians should consider stopping bisphosphonate treatment after 5 years unless the patient has a strong indication for treatment continuation.
• The decision for a bisphosphonate holiday (temporary discontinuation) and its duration should be based on baseline fracture risk, medication half-life in bone, and benefits and harms.
• Women treated with an anabolic agent who discontinue it should be offered an antiresorptive agent to preserve gains and because of serious risk for rebound and multiple vertebral fractures.
• Adults older than 65 years with osteoporosis may be at increased risk for falls or other adverse events because of drug interactions.
• Transgender persons have variable risk for low bone mass.

The review and guideline were funded by the ACP. Dr. Ott has reported no relevant disclosures. Relevant financial disclosures for other authors are listed with the guideline and review.

A version of this article first appeared on Medscape.com.

Taking more steps per day is associated with a progressively lower risk of cardiovascular disease (CVD) among older adults – and the benefits accrue at well below the widely promoted threshold of 10,000 steps per day, new research shows.

Among adults aged 60 and older, those who took roughly 6,000 to 9,000 steps per day had a 40% to 50% lower risk of CVD, compared with peers logging just 2,000 steps per day.

“We hope this study will contribute evidence to future public health and clinical guidance on how many steps we need for health,” Amanda Paluch, PhD, with University of Massachusetts Amherst, told this news organization.

Getting in more steps per day can lower an individual’s risk for heart disease – but it’s not an “all or nothing” situation, Dr. Paluch said.

“The heart health benefits begin at lower than 10,000 steps per day. So, for the many adults that may find 10,000 steps a bit out of reach, it is important to promote that even small increases in steps can be beneficial for health,” Dr. Paluch said.

The study was published online in Circulation.
 

Attainable step goals

As part of the Steps for Health Collaborative, Dr. Paluch and colleagues examined the dose-response relationship between steps per day and CVD in a meta-analysis of eight prospective studies involving 20,152 adults (mean age 63, 52% women).

Steps were measured in each study using one of five different commercially available step-measuring devices. Adults aged 60 years and older took a median of 4,323 steps per day (interquartile range, 2,760-6,924), while younger adults walked a bit more (median 6,911 daily steps; IQR, 4,783-9,794).

During follow-up lasting an average of 6.2 years, a total of 1,523 CVD events were reported.

In the final adjusted model, for older adults, compared with those in quartile 1 who got the fewest steps per day (median 1,811), the risk of CVD was 20% lower in those in quartile 2, who got a median of 3,823 steps per day (hazard ratio, 0.80; 95% confidence interval, 0.69-0.93).

CVD risk was 38% lower in older adults in quartile 3 who got a median of 5,520 steps per day (HR, 0.62; 95% CI, 0.52-0.74) and 49% lower in those in quartile 4 who walked the most (a median of 9,259 steps per day; HR, 0.51; 95% CI, 0.41-0.63).

Restricting the analysis to individuals without known CVD at baseline showed similar results.

Among six studies that excluded adults with a history of CVD at baseline, compared with the lowest quartile, the HR for incident CVD events was 0.74 (95% CI, 0.60-0.91) in the second quartile, 0.60 (95% CI, 0.47-0.77) in the third quartile, and 0.55 (95% CI, 0.40-0.76) in the fourth quartile.

Despite the inverse association of steps with CVD in older adults, there was no association in younger adults. The researchers caution, however, that CVD is a disease of aging, and the follow-up period in these studies may not have been long enough to capture CVD incidence in younger adults.

Stepping rate (pace or cadence) was not associated with CVD risk beyond that of total steps per day. However, only four of the eight studies reported data on stepping rate, so this finding should be viewed as preliminary, Dr. Paluch and colleagues say.
 

Start small and go from there

Dr. Paluch said the take-home message from this study and numerous others is simple.

“Move more and sit less! Being physically active, by getting in your steps, is an important part of keeping your heart healthy,” she said in an interview.

For adults who are currently inactive, Dr. Paluch suggests finding small ways to get in a few more steps per day. “It does not need to be drastic changes. Consider a brief 5- to 10-minute walking break at lunch, taking the stairs, or playing a game of hide and seek with the grandchildren,” Dr. Paluch advised.

“For adults starting at 3,000 steps a day, set a goal of 4,000, and then 5,000. Each improvement can lead to better heart health,” Dr. Paluch said. “And for those who are already active, keep it up, as there are benefits with higher volumes of steps per day as well.”

Support for this research was provided by the Intergovernmental Personnel Act Agreement through the Centers for Disease Control and Prevention. The authors have reported no relevant financial relationships.

A version of this article first appeared on Medscape.com.

Taking more steps per day is associated with a progressively lower risk of cardiovascular disease (CVD) among older adults – and the benefits accrue at well below the widely promoted threshold of 10,000 steps per day, new research shows.

Among adults aged 60 and older, those who took roughly 6,000 to 9,000 steps per day had a 40% to 50% lower risk of CVD, compared with peers logging just 2,000 steps per day.

“We hope this study will contribute evidence to future public health and clinical guidance on how many steps we need for health,” Amanda Paluch, PhD, with University of Massachusetts Amherst, told this news organization.

Getting in more steps per day can lower an individual’s risk for heart disease – but it’s not an “all or nothing” situation, Dr. Paluch said.

“The heart health benefits begin at lower than 10,000 steps per day. So, for the many adults that may find 10,000 steps a bit out of reach, it is important to promote that even small increases in steps can be beneficial for health,” Dr. Paluch said.

The study was published online in Circulation.
 

Attainable step goals

As part of the Steps for Health Collaborative, Dr. Paluch and colleagues examined the dose-response relationship between steps per day and CVD in a meta-analysis of eight prospective studies involving 20,152 adults (mean age 63, 52% women).

Steps were measured in each study using one of five different commercially available step-measuring devices. Adults aged 60 years and older took a median of 4,323 steps per day (interquartile range, 2,760-6,924), while younger adults walked a bit more (median 6,911 daily steps; IQR, 4,783-9,794).

During follow-up lasting an average of 6.2 years, a total of 1,523 CVD events were reported.

In the final adjusted model, for older adults, compared with those in quartile 1 who got the fewest steps per day (median 1,811), the risk of CVD was 20% lower in those in quartile 2, who got a median of 3,823 steps per day (hazard ratio, 0.80; 95% confidence interval, 0.69-0.93).

CVD risk was 38% lower in older adults in quartile 3 who got a median of 5,520 steps per day (HR, 0.62; 95% CI, 0.52-0.74) and 49% lower in those in quartile 4 who walked the most (a median of 9,259 steps per day; HR, 0.51; 95% CI, 0.41-0.63).

Restricting the analysis to individuals without known CVD at baseline showed similar results.

Among six studies that excluded adults with a history of CVD at baseline, compared with the lowest quartile, the HR for incident CVD events was 0.74 (95% CI, 0.60-0.91) in the second quartile, 0.60 (95% CI, 0.47-0.77) in the third quartile, and 0.55 (95% CI, 0.40-0.76) in the fourth quartile.

Despite the inverse association of steps with CVD in older adults, there was no association in younger adults. The researchers caution, however, that CVD is a disease of aging, and the follow-up period in these studies may not have been long enough to capture CVD incidence in younger adults.

Stepping rate (pace or cadence) was not associated with CVD risk beyond that of total steps per day. However, only four of the eight studies reported data on stepping rate, so this finding should be viewed as preliminary, Dr. Paluch and colleagues say.
 

Start small and go from there

Dr. Paluch said the take-home message from this study and numerous others is simple.

“Move more and sit less! Being physically active, by getting in your steps, is an important part of keeping your heart healthy,” she said in an interview.

For adults who are currently inactive, Dr. Paluch suggests finding small ways to get in a few more steps per day. “It does not need to be drastic changes. Consider a brief 5- to 10-minute walking break at lunch, taking the stairs, or playing a game of hide and seek with the grandchildren,” Dr. Paluch advised.

“For adults starting at 3,000 steps a day, set a goal of 4,000, and then 5,000. Each improvement can lead to better heart health,” Dr. Paluch said. “And for those who are already active, keep it up, as there are benefits with higher volumes of steps per day as well.”

Support for this research was provided by the Intergovernmental Personnel Act Agreement through the Centers for Disease Control and Prevention. The authors have reported no relevant financial relationships.

A version of this article first appeared on Medscape.com.

Taking more steps per day is associated with a progressively lower risk of cardiovascular disease (CVD) among older adults – and the benefits accrue at well below the widely promoted threshold of 10,000 steps per day, new research shows.

Among adults aged 60 and older, those who took roughly 6,000 to 9,000 steps per day had a 40% to 50% lower risk of CVD, compared with peers logging just 2,000 steps per day.

“We hope this study will contribute evidence to future public health and clinical guidance on how many steps we need for health,” Amanda Paluch, PhD, with University of Massachusetts Amherst, told this news organization.

Getting in more steps per day can lower an individual’s risk for heart disease – but it’s not an “all or nothing” situation, Dr. Paluch said.

“The heart health benefits begin at lower than 10,000 steps per day. So, for the many adults that may find 10,000 steps a bit out of reach, it is important to promote that even small increases in steps can be beneficial for health,” Dr. Paluch said.

The study was published online in Circulation.
 

Attainable step goals

As part of the Steps for Health Collaborative, Dr. Paluch and colleagues examined the dose-response relationship between steps per day and CVD in a meta-analysis of eight prospective studies involving 20,152 adults (mean age 63, 52% women).

Steps were measured in each study using one of five different commercially available step-measuring devices. Adults aged 60 years and older took a median of 4,323 steps per day (interquartile range, 2,760-6,924), while younger adults walked a bit more (median 6,911 daily steps; IQR, 4,783-9,794).

During follow-up lasting an average of 6.2 years, a total of 1,523 CVD events were reported.

In the final adjusted model, for older adults, compared with those in quartile 1 who got the fewest steps per day (median 1,811), the risk of CVD was 20% lower in those in quartile 2, who got a median of 3,823 steps per day (hazard ratio, 0.80; 95% confidence interval, 0.69-0.93).

CVD risk was 38% lower in older adults in quartile 3 who got a median of 5,520 steps per day (HR, 0.62; 95% CI, 0.52-0.74) and 49% lower in those in quartile 4 who walked the most (a median of 9,259 steps per day; HR, 0.51; 95% CI, 0.41-0.63).

Restricting the analysis to individuals without known CVD at baseline showed similar results.

Among six studies that excluded adults with a history of CVD at baseline, compared with the lowest quartile, the HR for incident CVD events was 0.74 (95% CI, 0.60-0.91) in the second quartile, 0.60 (95% CI, 0.47-0.77) in the third quartile, and 0.55 (95% CI, 0.40-0.76) in the fourth quartile.

Despite the inverse association of steps with CVD in older adults, there was no association in younger adults. The researchers caution, however, that CVD is a disease of aging, and the follow-up period in these studies may not have been long enough to capture CVD incidence in younger adults.

Stepping rate (pace or cadence) was not associated with CVD risk beyond that of total steps per day. However, only four of the eight studies reported data on stepping rate, so this finding should be viewed as preliminary, Dr. Paluch and colleagues say.
 

Start small and go from there

Dr. Paluch said the take-home message from this study and numerous others is simple.

“Move more and sit less! Being physically active, by getting in your steps, is an important part of keeping your heart healthy,” she said in an interview.

For adults who are currently inactive, Dr. Paluch suggests finding small ways to get in a few more steps per day. “It does not need to be drastic changes. Consider a brief 5- to 10-minute walking break at lunch, taking the stairs, or playing a game of hide and seek with the grandchildren,” Dr. Paluch advised.

“For adults starting at 3,000 steps a day, set a goal of 4,000, and then 5,000. Each improvement can lead to better heart health,” Dr. Paluch said. “And for those who are already active, keep it up, as there are benefits with higher volumes of steps per day as well.”

Support for this research was provided by the Intergovernmental Personnel Act Agreement through the Centers for Disease Control and Prevention. The authors have reported no relevant financial relationships.

A version of this article first appeared on Medscape.com.

The Alzheimer’s Association has filed a formal request with the Centers for Medicare & Medicaid Services that it provide full and unrestricted coverage for Alzheimer’s disease (AD) treatments approved by the U.S. Food and Drug Administration.

In a letter addressed to CMS administrator Chiquita Brooks-LaSure, MPP, the association has asked the agency to remove the requirements for “coverage with evidence development” in its national coverage determination for FDA-approved anti-amyloid monoclonal antibodies.

The CMS coverage restrictions for anti-amyloid drugs were finalized in April on the basis of data available at the time.

Since then, new data from the CLARITY AD trial “clearly demonstrate a meaningful clinical benefit” from the investigational anti-amyloid agent lecanemab (Eisai/Biogen), Robert Egge, chief public policy officer for the Alzheimer’s Association, told this news organization.

The CLARITY AD results were published in the New England Journal of Medicine. Lecanemab is currently under accelerated review at the FDA.

The Alzheimer’s Association’s letter to the CMS includes a joint statement signed by more than 200 AD researchers and experts. All agree that the lecanemab results represent “significant new evidence” that necessitates reconsidering the restrictions on anti-amyloid agents.

“CMS has said it would look at new evidence, and now that evidence is here. We believe CMS recognizes this evidence for lecanemab is stronger than that for many treatments Medicare routinely covers,” Mr. Egge said.
 

‘No time to waste’

“With the timing of accelerated approvals for both lecanemab and donanemab in the next few months, the Alzheimer’s Association wants to ensure, if approved, that patients can access these treatments,” Mr. Egge noted.

“Because revisions to National Coverage Determinations can be a lengthy process, CMS needs to act quickly to minimize delays. People living with Alzheimer’s disease don’t have time to waste,” he added.

The Alzheimer’s Association estimates that every day, more than 2,000 individuals aged 65 or older may transition from mild dementia due to AD to a more advanced stage of the disease in which they may no longer be eligible for lecanemab and the other anti-amyloid agents currently being tested.

“Each day matters when it comes to slowing the progression of this disease,” Joanne Pike, DrPH, president and incoming chief executive officer for the Alzheimer’s Association, noted in a news release.

“The current CMS policy to severely limit access to these treatments eliminates people’s options, is resulting in continued irreversible disease progression, and contributes to greater health inequities. That’s not acceptable,” Dr. Pike said.

A version of this article first appeared on Medscape.com.

The Alzheimer’s Association has filed a formal request with the Centers for Medicare & Medicaid Services that it provide full and unrestricted coverage for Alzheimer’s disease (AD) treatments approved by the U.S. Food and Drug Administration.

In a letter addressed to CMS administrator Chiquita Brooks-LaSure, MPP, the association has asked the agency to remove the requirements for “coverage with evidence development” in its national coverage determination for FDA-approved anti-amyloid monoclonal antibodies.

The CMS coverage restrictions for anti-amyloid drugs were finalized in April on the basis of data available at the time.

Since then, new data from the CLARITY AD trial “clearly demonstrate a meaningful clinical benefit” from the investigational anti-amyloid agent lecanemab (Eisai/Biogen), Robert Egge, chief public policy officer for the Alzheimer’s Association, told this news organization.

The CLARITY AD results were published in the New England Journal of Medicine. Lecanemab is currently under accelerated review at the FDA.

The Alzheimer’s Association’s letter to the CMS includes a joint statement signed by more than 200 AD researchers and experts. All agree that the lecanemab results represent “significant new evidence” that necessitates reconsidering the restrictions on anti-amyloid agents.

“CMS has said it would look at new evidence, and now that evidence is here. We believe CMS recognizes this evidence for lecanemab is stronger than that for many treatments Medicare routinely covers,” Mr. Egge said.
 

‘No time to waste’

“With the timing of accelerated approvals for both lecanemab and donanemab in the next few months, the Alzheimer’s Association wants to ensure, if approved, that patients can access these treatments,” Mr. Egge noted.

“Because revisions to National Coverage Determinations can be a lengthy process, CMS needs to act quickly to minimize delays. People living with Alzheimer’s disease don’t have time to waste,” he added.

The Alzheimer’s Association estimates that every day, more than 2,000 individuals aged 65 or older may transition from mild dementia due to AD to a more advanced stage of the disease in which they may no longer be eligible for lecanemab and the other anti-amyloid agents currently being tested.

“Each day matters when it comes to slowing the progression of this disease,” Joanne Pike, DrPH, president and incoming chief executive officer for the Alzheimer’s Association, noted in a news release.

“The current CMS policy to severely limit access to these treatments eliminates people’s options, is resulting in continued irreversible disease progression, and contributes to greater health inequities. That’s not acceptable,” Dr. Pike said.

A version of this article first appeared on Medscape.com.

The Alzheimer’s Association has filed a formal request with the Centers for Medicare & Medicaid Services that it provide full and unrestricted coverage for Alzheimer’s disease (AD) treatments approved by the U.S. Food and Drug Administration.

In a letter addressed to CMS administrator Chiquita Brooks-LaSure, MPP, the association has asked the agency to remove the requirements for “coverage with evidence development” in its national coverage determination for FDA-approved anti-amyloid monoclonal antibodies.

The CMS coverage restrictions for anti-amyloid drugs were finalized in April on the basis of data available at the time.

Since then, new data from the CLARITY AD trial “clearly demonstrate a meaningful clinical benefit” from the investigational anti-amyloid agent lecanemab (Eisai/Biogen), Robert Egge, chief public policy officer for the Alzheimer’s Association, told this news organization.

The CLARITY AD results were published in the New England Journal of Medicine. Lecanemab is currently under accelerated review at the FDA.

The Alzheimer’s Association’s letter to the CMS includes a joint statement signed by more than 200 AD researchers and experts. All agree that the lecanemab results represent “significant new evidence” that necessitates reconsidering the restrictions on anti-amyloid agents.

“CMS has said it would look at new evidence, and now that evidence is here. We believe CMS recognizes this evidence for lecanemab is stronger than that for many treatments Medicare routinely covers,” Mr. Egge said.
 

‘No time to waste’

“With the timing of accelerated approvals for both lecanemab and donanemab in the next few months, the Alzheimer’s Association wants to ensure, if approved, that patients can access these treatments,” Mr. Egge noted.

“Because revisions to National Coverage Determinations can be a lengthy process, CMS needs to act quickly to minimize delays. People living with Alzheimer’s disease don’t have time to waste,” he added.

The Alzheimer’s Association estimates that every day, more than 2,000 individuals aged 65 or older may transition from mild dementia due to AD to a more advanced stage of the disease in which they may no longer be eligible for lecanemab and the other anti-amyloid agents currently being tested.

“Each day matters when it comes to slowing the progression of this disease,” Joanne Pike, DrPH, president and incoming chief executive officer for the Alzheimer’s Association, noted in a news release.

“The current CMS policy to severely limit access to these treatments eliminates people’s options, is resulting in continued irreversible disease progression, and contributes to greater health inequities. That’s not acceptable,” Dr. Pike said.

A version of this article first appeared on Medscape.com.

Weak handgrip in older adults is linked to a higher risk for depression – while a stronger handgrip may have protective benefits, new research suggests.
 

In a study of more than 115,000 adults, there was a significant association between stronger handgrip, up to 40 kg in men and 27 kg in women, and lower depression risk.

Investigators add that there was a “dose-response” association between physical strength and risk for depression.

“Being physically strong may serve as a preventive factor for depression in older adults, but this is limited to a maximum specific threshold for men and women,” Ruben Lopez-Bueno, PhD, of the department of physical medicine and nursing, University of Zaragoza, Spain, and colleagues write.

The findings were published online in the British Journal of Psychiatry.
 

Easy, fast, reliable

Depression is a major public health problem, and studies “aimed at examining preventive factors to tackle the increase in depression are required,” the investigators write.

They add that a “growing body of research” is examining the link between depression and muscle strength, with handgrip as an estimator, in healthy middle-aged and older adults.

Handgrip strength is an “easy-to-use, fast and reliable indicator of both sarcopenia (age-related loss of muscle mass) and dynapenia (age-related loss of muscle strength), both of which have been associated with depression,” the researchers note.

It is plausible that there is a “regulatory role of skeletal muscle on brain function affecting this condition,” they add.

They note that exercise seems to play a “key role” because it can improve muscle strength as well as muscle mass, downregulate systemic inflammation, and improve neuroplasticity, neuroendocrine, and oxidative stress responses.

Previous studies have relied either on cross-sectional or prospective cohort models and have focused mostly on a specific country, “not accounting for time-varying changes of both handgrip strength and relevant covariables.”

Moreover, previous evidence has been mixed regarding the “extent to which handgrip strength levels may associate with lower risk of depression, with study results ranging from weak to strong associations,” the investigators write.

So “higher-quality research with representative samples from different countries is required to better clarify the strength of such an association and to confirm directionality,” they add.
 

SHARE data

To fill this gap, the researchers turned to data from waves 1, 2, 4, 5, 6, and 7 of the Survey of Health, Ageing and Retirement in Europe (SHARE). This encompassed 115,601 individuals aged 50 years and older (mean age, 64.3 years; 54.3% women) residing in European countries and Israel (24 countries total).

Data from wave 3 were not used because handgrip measures were not used in that wave. In the other waves, a handheld dynamometer was used to measure handgrip strength.

The participants were divided into tertiles of handgrip strength, with the “first third” being the lowest tertile of strength and the “final third” representing the highest strength.

All participants were followed for a median of 7.3 years (792,459 person-years), during which 26.1% experienced a risk for depression, as reflected by scores on the EURO-D 12-item scale.

The investigators set the time scale as the months from study entry until either a first depression onset or the end of follow-up.

Covariates that the researchers accounted for included gender, age, education, country, body mass index, physical inactivity, smoking, alcohol consumption, whether living with a partner, wave of inclusion, chronic diseases, consumption of prescribed drugs, and fruit and vegetable consumption.

The researchers used two models: the first adjusted for gender and age at time of the interview, and the second adjusted for all confounders.

In the model that was adjusted only for gender and age, greater handgrip strength was associated with a significantly reduced risk for depression among participants in the second, third, and the final third in comparison with the first third (hazard ratio, 0.65; 95% confidence interval, 0.63-0.68; and HR, 0.50; 95% CI, 0.48-0.53, respectively).

The associations remained consistent in the fully adjusted model, although risk for depression was slightly attenuated in the second and final thirds compared with the first third (HR, 0.76; 95% CI, 0.71-0.81; and HR, 0.64; 95% CI, 0.59-0.69, respectively).

When the researchers conducted analyses using restricted cubic spline modeling, they found a significant association for each kilogram increase of handgrip strength and depression, up to 40 kg in men and 27 kg in women (HR, 1.39; 95% CI, 1.08-1.71; and HR, 1.28; 95% CI, 1.05-1.55, respectively).

There was no greater reduction in depression risk in those with handgrip strength above those values.
 

Potential depression screen

The investigators suggest several explanations for their findings. For example, handgrip strength has “been used as an overall indicator of health status, including sarcopenia,” they write.

Adults with sarcopenia have been found to be at greater risk for depression because of reduced muscle strength, since neurotrophins are produced by skeletal muscle, among other tissues, and are associated with improvement in mood.

From a psychological point of view, “being physically strong may lead to a sensation of psychological wellbeing,” the researchers write.

Moreover, being physically active “across the lifespan also promotes structural and functional changes in the brain, benefiting cognitive functioning and reducing the risk of neurodegeneration,” they write.

This can be important because aging adults with cognitive impairments can also experience neuromuscular impairments that “presumably will contribute to becoming weaker,” they note.

Overall, the findings “warrant strength training programmes aimed at older adults to reduce depression risk,” the investigators write. Clinicians “may consider using the observed handgrip strength thresholds to screen for potential depression risk in older adults,” they add.
 

Protective factor?

Commenting for this news organization, Julian Mutz, PhD, postdoctoral research associate at the Social, Genetic and Developmental Psychiatry Centre, King’s College, London, said the study “provides further evidence that physical strength may be a protective factor against depression in older adults.”

This confirms a “plethora of cross-sectional and longitudinal studies,” including one recently conducted by Dr. Mutz’s group.

The design of the current study “allowed the authors to address a number of key limitations of previous studies, for example, by including repeated measurements of grip strength and adjustment for potential confounding factors over time,” said Dr. Mutz, who was not involved with the research.

Additionally, “an important contribution of this study is that the authors show that higher grip strength is only associated with a lower risk of depression up to a specific threshold,” he noted.

“The clinical implication of this finding is that only individuals with grip strength below this threshold are at a higher risk of depression. These individuals especially may benefit from interventions aimed at increasing physical strength,” Dr. Mutz said.

The SHARE data collection has been funded by the European Commission and by DG Employment, Social Affairs and Inclusion. Additional funding was obtained from the German Ministry of Education and Research, the Max Planck Society for the Advancement of Science, and the U.S. National Institute on Aging. Dr. Lopez-Bueno is supported by the European Union – Next Generation EU. The other investigators and Dr. Mutz have reported no relevant financial relationships.

A version of this article first appeared on Medscape.com.

Weak handgrip in older adults is linked to a higher risk for depression – while a stronger handgrip may have protective benefits, new research suggests.
 

In a study of more than 115,000 adults, there was a significant association between stronger handgrip, up to 40 kg in men and 27 kg in women, and lower depression risk.

Investigators add that there was a “dose-response” association between physical strength and risk for depression.

“Being physically strong may serve as a preventive factor for depression in older adults, but this is limited to a maximum specific threshold for men and women,” Ruben Lopez-Bueno, PhD, of the department of physical medicine and nursing, University of Zaragoza, Spain, and colleagues write.

The findings were published online in the British Journal of Psychiatry.
 

Easy, fast, reliable

Depression is a major public health problem, and studies “aimed at examining preventive factors to tackle the increase in depression are required,” the investigators write.

They add that a “growing body of research” is examining the link between depression and muscle strength, with handgrip as an estimator, in healthy middle-aged and older adults.

Handgrip strength is an “easy-to-use, fast and reliable indicator of both sarcopenia (age-related loss of muscle mass) and dynapenia (age-related loss of muscle strength), both of which have been associated with depression,” the researchers note.

It is plausible that there is a “regulatory role of skeletal muscle on brain function affecting this condition,” they add.

They note that exercise seems to play a “key role” because it can improve muscle strength as well as muscle mass, downregulate systemic inflammation, and improve neuroplasticity, neuroendocrine, and oxidative stress responses.

Previous studies have relied either on cross-sectional or prospective cohort models and have focused mostly on a specific country, “not accounting for time-varying changes of both handgrip strength and relevant covariables.”

Moreover, previous evidence has been mixed regarding the “extent to which handgrip strength levels may associate with lower risk of depression, with study results ranging from weak to strong associations,” the investigators write.

So “higher-quality research with representative samples from different countries is required to better clarify the strength of such an association and to confirm directionality,” they add.
 

SHARE data

To fill this gap, the researchers turned to data from waves 1, 2, 4, 5, 6, and 7 of the Survey of Health, Ageing and Retirement in Europe (SHARE). This encompassed 115,601 individuals aged 50 years and older (mean age, 64.3 years; 54.3% women) residing in European countries and Israel (24 countries total).

Data from wave 3 were not used because handgrip measures were not used in that wave. In the other waves, a handheld dynamometer was used to measure handgrip strength.

The participants were divided into tertiles of handgrip strength, with the “first third” being the lowest tertile of strength and the “final third” representing the highest strength.

All participants were followed for a median of 7.3 years (792,459 person-years), during which 26.1% experienced a risk for depression, as reflected by scores on the EURO-D 12-item scale.

The investigators set the time scale as the months from study entry until either a first depression onset or the end of follow-up.

Covariates that the researchers accounted for included gender, age, education, country, body mass index, physical inactivity, smoking, alcohol consumption, whether living with a partner, wave of inclusion, chronic diseases, consumption of prescribed drugs, and fruit and vegetable consumption.

The researchers used two models: the first adjusted for gender and age at time of the interview, and the second adjusted for all confounders.

In the model that was adjusted only for gender and age, greater handgrip strength was associated with a significantly reduced risk for depression among participants in the second, third, and the final third in comparison with the first third (hazard ratio, 0.65; 95% confidence interval, 0.63-0.68; and HR, 0.50; 95% CI, 0.48-0.53, respectively).

The associations remained consistent in the fully adjusted model, although risk for depression was slightly attenuated in the second and final thirds compared with the first third (HR, 0.76; 95% CI, 0.71-0.81; and HR, 0.64; 95% CI, 0.59-0.69, respectively).

When the researchers conducted analyses using restricted cubic spline modeling, they found a significant association for each kilogram increase of handgrip strength and depression, up to 40 kg in men and 27 kg in women (HR, 1.39; 95% CI, 1.08-1.71; and HR, 1.28; 95% CI, 1.05-1.55, respectively).

There was no greater reduction in depression risk in those with handgrip strength above those values.
 

Potential depression screen

The investigators suggest several explanations for their findings. For example, handgrip strength has “been used as an overall indicator of health status, including sarcopenia,” they write.

Adults with sarcopenia have been found to be at greater risk for depression because of reduced muscle strength, since neurotrophins are produced by skeletal muscle, among other tissues, and are associated with improvement in mood.

From a psychological point of view, “being physically strong may lead to a sensation of psychological wellbeing,” the researchers write.

Moreover, being physically active “across the lifespan also promotes structural and functional changes in the brain, benefiting cognitive functioning and reducing the risk of neurodegeneration,” they write.

This can be important because aging adults with cognitive impairments can also experience neuromuscular impairments that “presumably will contribute to becoming weaker,” they note.

Overall, the findings “warrant strength training programmes aimed at older adults to reduce depression risk,” the investigators write. Clinicians “may consider using the observed handgrip strength thresholds to screen for potential depression risk in older adults,” they add.
 

Protective factor?

Commenting for this news organization, Julian Mutz, PhD, postdoctoral research associate at the Social, Genetic and Developmental Psychiatry Centre, King’s College, London, said the study “provides further evidence that physical strength may be a protective factor against depression in older adults.”

This confirms a “plethora of cross-sectional and longitudinal studies,” including one recently conducted by Dr. Mutz’s group.

The design of the current study “allowed the authors to address a number of key limitations of previous studies, for example, by including repeated measurements of grip strength and adjustment for potential confounding factors over time,” said Dr. Mutz, who was not involved with the research.

Additionally, “an important contribution of this study is that the authors show that higher grip strength is only associated with a lower risk of depression up to a specific threshold,” he noted.

“The clinical implication of this finding is that only individuals with grip strength below this threshold are at a higher risk of depression. These individuals especially may benefit from interventions aimed at increasing physical strength,” Dr. Mutz said.

The SHARE data collection has been funded by the European Commission and by DG Employment, Social Affairs and Inclusion. Additional funding was obtained from the German Ministry of Education and Research, the Max Planck Society for the Advancement of Science, and the U.S. National Institute on Aging. Dr. Lopez-Bueno is supported by the European Union – Next Generation EU. The other investigators and Dr. Mutz have reported no relevant financial relationships.

A version of this article first appeared on Medscape.com.

Weak handgrip in older adults is linked to a higher risk for depression – while a stronger handgrip may have protective benefits, new research suggests.
 

In a study of more than 115,000 adults, there was a significant association between stronger handgrip, up to 40 kg in men and 27 kg in women, and lower depression risk.

Investigators add that there was a “dose-response” association between physical strength and risk for depression.

“Being physically strong may serve as a preventive factor for depression in older adults, but this is limited to a maximum specific threshold for men and women,” Ruben Lopez-Bueno, PhD, of the department of physical medicine and nursing, University of Zaragoza, Spain, and colleagues write.

The findings were published online in the British Journal of Psychiatry.
 

Easy, fast, reliable

Depression is a major public health problem, and studies “aimed at examining preventive factors to tackle the increase in depression are required,” the investigators write.

They add that a “growing body of research” is examining the link between depression and muscle strength, with handgrip as an estimator, in healthy middle-aged and older adults.

Handgrip strength is an “easy-to-use, fast and reliable indicator of both sarcopenia (age-related loss of muscle mass) and dynapenia (age-related loss of muscle strength), both of which have been associated with depression,” the researchers note.

It is plausible that there is a “regulatory role of skeletal muscle on brain function affecting this condition,” they add.

They note that exercise seems to play a “key role” because it can improve muscle strength as well as muscle mass, downregulate systemic inflammation, and improve neuroplasticity, neuroendocrine, and oxidative stress responses.

Previous studies have relied either on cross-sectional or prospective cohort models and have focused mostly on a specific country, “not accounting for time-varying changes of both handgrip strength and relevant covariables.”

Moreover, previous evidence has been mixed regarding the “extent to which handgrip strength levels may associate with lower risk of depression, with study results ranging from weak to strong associations,” the investigators write.

So “higher-quality research with representative samples from different countries is required to better clarify the strength of such an association and to confirm directionality,” they add.
 

SHARE data

To fill this gap, the researchers turned to data from waves 1, 2, 4, 5, 6, and 7 of the Survey of Health, Ageing and Retirement in Europe (SHARE). This encompassed 115,601 individuals aged 50 years and older (mean age, 64.3 years; 54.3% women) residing in European countries and Israel (24 countries total).

Data from wave 3 were not used because handgrip measures were not used in that wave. In the other waves, a handheld dynamometer was used to measure handgrip strength.

The participants were divided into tertiles of handgrip strength, with the “first third” being the lowest tertile of strength and the “final third” representing the highest strength.

All participants were followed for a median of 7.3 years (792,459 person-years), during which 26.1% experienced a risk for depression, as reflected by scores on the EURO-D 12-item scale.

The investigators set the time scale as the months from study entry until either a first depression onset or the end of follow-up.

Covariates that the researchers accounted for included gender, age, education, country, body mass index, physical inactivity, smoking, alcohol consumption, whether living with a partner, wave of inclusion, chronic diseases, consumption of prescribed drugs, and fruit and vegetable consumption.

The researchers used two models: the first adjusted for gender and age at time of the interview, and the second adjusted for all confounders.

In the model that was adjusted only for gender and age, greater handgrip strength was associated with a significantly reduced risk for depression among participants in the second, third, and the final third in comparison with the first third (hazard ratio, 0.65; 95% confidence interval, 0.63-0.68; and HR, 0.50; 95% CI, 0.48-0.53, respectively).

The associations remained consistent in the fully adjusted model, although risk for depression was slightly attenuated in the second and final thirds compared with the first third (HR, 0.76; 95% CI, 0.71-0.81; and HR, 0.64; 95% CI, 0.59-0.69, respectively).

When the researchers conducted analyses using restricted cubic spline modeling, they found a significant association for each kilogram increase of handgrip strength and depression, up to 40 kg in men and 27 kg in women (HR, 1.39; 95% CI, 1.08-1.71; and HR, 1.28; 95% CI, 1.05-1.55, respectively).

There was no greater reduction in depression risk in those with handgrip strength above those values.
 

Potential depression screen

The investigators suggest several explanations for their findings. For example, handgrip strength has “been used as an overall indicator of health status, including sarcopenia,” they write.

Adults with sarcopenia have been found to be at greater risk for depression because of reduced muscle strength, since neurotrophins are produced by skeletal muscle, among other tissues, and are associated with improvement in mood.

From a psychological point of view, “being physically strong may lead to a sensation of psychological wellbeing,” the researchers write.

Moreover, being physically active “across the lifespan also promotes structural and functional changes in the brain, benefiting cognitive functioning and reducing the risk of neurodegeneration,” they write.

This can be important because aging adults with cognitive impairments can also experience neuromuscular impairments that “presumably will contribute to becoming weaker,” they note.

Overall, the findings “warrant strength training programmes aimed at older adults to reduce depression risk,” the investigators write. Clinicians “may consider using the observed handgrip strength thresholds to screen for potential depression risk in older adults,” they add.
 

Protective factor?

Commenting for this news organization, Julian Mutz, PhD, postdoctoral research associate at the Social, Genetic and Developmental Psychiatry Centre, King’s College, London, said the study “provides further evidence that physical strength may be a protective factor against depression in older adults.”

This confirms a “plethora of cross-sectional and longitudinal studies,” including one recently conducted by Dr. Mutz’s group.

The design of the current study “allowed the authors to address a number of key limitations of previous studies, for example, by including repeated measurements of grip strength and adjustment for potential confounding factors over time,” said Dr. Mutz, who was not involved with the research.

Additionally, “an important contribution of this study is that the authors show that higher grip strength is only associated with a lower risk of depression up to a specific threshold,” he noted.

“The clinical implication of this finding is that only individuals with grip strength below this threshold are at a higher risk of depression. These individuals especially may benefit from interventions aimed at increasing physical strength,” Dr. Mutz said.

The SHARE data collection has been funded by the European Commission and by DG Employment, Social Affairs and Inclusion. Additional funding was obtained from the German Ministry of Education and Research, the Max Planck Society for the Advancement of Science, and the U.S. National Institute on Aging. Dr. Lopez-Bueno is supported by the European Union – Next Generation EU. The other investigators and Dr. Mutz have reported no relevant financial relationships.

A version of this article first appeared on Medscape.com.

Corticosteroid (CS) injections may worsen progression of knee osteoarthritis as seen on radiography and whole-knee MRI. Injecting hyaluronic acid (HA) instead, or managing the condition without injections, may better preserve knee structure and cartilage, according to results of two related studies presented at the annual meeting of the Radiological Society of North America.

The findings come nonrandomized, observational cohort studies, leading knee OA experts to call for further study in randomized trial settings. In the meantime, shared decision-making between patients and clinicians is advised on the use of these injections.

For knee OA, most patients seek a noninvasive treatment for symptomatic relief. “At least 10% of these patients undergo local treatment with injectable corticosteroids or hyaluronic acid,” the lead author of one of the studies, Upasana Upadhyay Bharadwaj, MD, research fellow in musculoskeletal radiology at the University of California, San Francisco, said in a video press release.

Researchers in both studies used data and images from the Osteoarthritis Initiative (OAI), a multicenter, longitudinal, observational study of 4,796 U.S. patients aged 45-79 years with knee OA. Participants were enrolled from February 2004 to May 2006.

The OAI maintains a natural history database of information regarding participants’ clinical evaluation data, x-rays, MRI scans, and a biospecimen repository. Data are available to researchers worldwide.
 

Two studies draw similar conclusions

In one study, Dr. Bharadwaj and colleagues found that HA injections appeared to show decreased knee OA progression in bone marrow lesions.

They investigated 8 patients who received one CS injection, 12 who received one HA injection, and 40 control persons who received neither treatment. Participants were propensity-score matched by age, sex, body mass index (BMI), Kellgren-Lawrence (KL) grade, Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC), and Physical Activity Scale for the Elderly (PASE).

The researchers semiquantitatively graded three Tesla MRI scans that had been obtained at baseline, 2 years before the injection, and 2 years after the injection, using whole-organ MRI score (WORMS) for the meniscus, bone marrow lesions, cartilage, joint effusion, and ligaments.

They quantified OA progression using the difference in WORMS between baseline and 2-year follow-up, and they used linear regression models, adjusted for age, sex, BMI, KL grade, WOMAC, and PASE, to identify the link between type of injection and progression of WORMS.

At 2 years, the authors found a significant association between CS injection and postinjection progression of WORMS over 2 years for the knee overall, the lateral meniscus, lateral cartilage, and medial cartilage. There was no significant link between HA injection and postinjection progression of WORMS or between either injection type and progression of pain, as quantified by WOMAC. There was also no significant difference in progression of WORMS over the 2 years prior to injection for CS and HA injections.

“Corticosteroid injections must be administered with caution with respect to long-term effects on osteoarthritis,” Dr. Bharadwaj advised. “Hyaluronic acid injections, on the other hand, may slow down progression of knee osteoarthritis and alleviate long-term effects while offering similar symptomatic relief to corticosteroid injections. Overall, they are perhaps a safer alternative when looking at medium- and long-term disease course of knee osteoarthritis.”

In the second study, lead author Azad Darbandi, MS, a fourth-year medical student at Chicago Medical School, North Chicago, and colleagues found that patients who received CS injections experienced significantly more medial joint space narrowing.

They identified 210 knees with imaging at baseline and at 48 months that received CS injections, and 59 that received HA injections; 6,827 knees served as controls. The investigators matched 50 patients per group on the basis of confounding factors, which included age, sex, BMI, comorbidities, surgery, and semiquantitative imaging outcomes at baseline. They performed ANCOVA testing using 48-month semiquantitative imaging outcomes as dependent variables and confounding variables as covariates.

The researchers analyzed joint space narrowing, KL grade, and tibia/femur medial/lateral compartment osteophyte formation and sclerosis.

At 4 years, the average KL grade in the CS group was 2.79, it was 2.11 in the HA group,;and it was 2.37 in the control group. Intergroup comparisons showed significant differences in KL grade between CS and HA groups and between CS and control groups. Medial compartment joint space narrowing was 1.56 in the CS group, 1.11 in the HA group, and 1.18 in controls. There was a significant difference between the CS and control groups. Other dependent variables were not significant.

“These preliminary results suggest that corticosteroid injections accelerated the radiographic progression of osteoarthritis, specifically medial joint space narrowing and Kellgren-Lawrence grading, whereas hyaluronic acid injections did not,” Mr. Darbandi said in an interview.

“OA radiographic progression does not always correlate with clinical progression, and further research is needed,” he added.

Proper matching of patients at baseline for confounding factors is a strength of the study, Mr. Darbandi said, while the retrospective study design is a weakness.
 

Experts share their perspectives on the preliminary results

Michael M. Kheir, MD, assistant professor of orthopedic surgery at the University of Michigan Health System, who was not involved in the studies, said he would like to see further related research.

“Perhaps steroid injections are not as benign as they once seemed,” he added. “They should be reserved for patients who already have significant arthritis and are seeking temporary relief prior to surgical reconstruction with a joint replacement, or for patients with recalcitrant pain after having already tried HA injections.”

William A. Jiranek, MD, professor and orthopedic surgeon at Duke Health in Morrisville, N.C., who also was not involved in the studies, was not surprised by the findings.

“It is important to do these studies to learn that steroid injections do not come with zero cost,” he said.

“I am pretty sure that a percentage of these patients had no cartilage loss at all,” he added. “We need to understand which OA phenotypes are not at risk of progressive cartilage loss from steroid injections.”

Annunziato (Ned) Amendola, MD, professor and sports medicine orthopedic surgeon at Duke Health in Durham, N.C., who was also not involved in the studies, said he would like to know how injection effectiveness and activity level are related.

“If the injections were effective at relieving pain, and the patients were more active, that may have predisposed to more joint wear,” he said. “It’s like tires that last longer if you don’t abuse them.”
 

Shared decision-making and further research recommended

Amanda E. Nelson, MD, associate professor of medicine in the division of rheumatology, allergy, and immunology at the University of North Carolina at Chapel Hill, said: “The lack of randomization introduces potential biases around why certain therapies (CS injection, HA injection, or neither) were selected over others (such as disease severity, preference, comorbid conditions, other contraindications, etc), thus making interpretation of the findings challenging.

“The causal relationship remains in question, and questions around the efficacy of intra-articular HA in particular, and the ideal settings for intra-articular therapy in general, persist,” noted Dr. Nelson, who was also not involved in the studies. “Thus, shared decision-making between patients and their providers is essential when considering these options.”

C. Kent Kwoh, MD, professor of medicine and medical imaging at the University of Arizona and director of the University of Arizona Arthritis Center, both in Tucson, said in an interview that these types of studies are important because CS injections are common treatments for knee OA, they are recommended in treatment guidelines, and other good options are lacking.

But he pointed out that the results of these two studies need to be interpreted with caution and should not be used to decide the course of treatment.

“These data are hypothesis generating. They suggest association, but they do not show causation,” said Dr. Kwoh, who was also not involved in the studies. “Both studies are secondary analyses of data collected from the OAI, which was not specifically designed to answer the questions these studies are posing.

“The OAI was not a treatment study, and participants were seen only once a year or so. They may have had joint injections anytime from only days to around 1 year before their visit, and their levels of activity or pain just prior to or just after their joint injections were not reported,” Dr. Kwoh explained.

The reasons why patients did or did not receive a specific joint injection – including their socioeconomic status, race, access to insurance, and other confounding factors – were not assessed and may have affected the results, he added.

The fact that both studies used the same data and came to the same conclusions gives the conclusions some strength, he said, but “the gold standard to understanding causation would be a randomized, controlled trial.”

Mr. Darbandi’s research received grant support from Boeing, His c-authors, as well as all experts not involved in the studies, reported no relevant financial relationshiips. Dr. Bharadwaj did not provide conflict-of-interest and funding details. Dr. Kwoh reported membership on panels that have developed guidelines for the management of knee OA.

A version of this article first appeared on Medscape.com.

Corticosteroid (CS) injections may worsen progression of knee osteoarthritis as seen on radiography and whole-knee MRI. Injecting hyaluronic acid (HA) instead, or managing the condition without injections, may better preserve knee structure and cartilage, according to results of two related studies presented at the annual meeting of the Radiological Society of North America.

The findings come nonrandomized, observational cohort studies, leading knee OA experts to call for further study in randomized trial settings. In the meantime, shared decision-making between patients and clinicians is advised on the use of these injections.

For knee OA, most patients seek a noninvasive treatment for symptomatic relief. “At least 10% of these patients undergo local treatment with injectable corticosteroids or hyaluronic acid,” the lead author of one of the studies, Upasana Upadhyay Bharadwaj, MD, research fellow in musculoskeletal radiology at the University of California, San Francisco, said in a video press release.

Researchers in both studies used data and images from the Osteoarthritis Initiative (OAI), a multicenter, longitudinal, observational study of 4,796 U.S. patients aged 45-79 years with knee OA. Participants were enrolled from February 2004 to May 2006.

The OAI maintains a natural history database of information regarding participants’ clinical evaluation data, x-rays, MRI scans, and a biospecimen repository. Data are available to researchers worldwide.
 

Two studies draw similar conclusions

In one study, Dr. Bharadwaj and colleagues found that HA injections appeared to show decreased knee OA progression in bone marrow lesions.

They investigated 8 patients who received one CS injection, 12 who received one HA injection, and 40 control persons who received neither treatment. Participants were propensity-score matched by age, sex, body mass index (BMI), Kellgren-Lawrence (KL) grade, Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC), and Physical Activity Scale for the Elderly (PASE).

The researchers semiquantitatively graded three Tesla MRI scans that had been obtained at baseline, 2 years before the injection, and 2 years after the injection, using whole-organ MRI score (WORMS) for the meniscus, bone marrow lesions, cartilage, joint effusion, and ligaments.

They quantified OA progression using the difference in WORMS between baseline and 2-year follow-up, and they used linear regression models, adjusted for age, sex, BMI, KL grade, WOMAC, and PASE, to identify the link between type of injection and progression of WORMS.

At 2 years, the authors found a significant association between CS injection and postinjection progression of WORMS over 2 years for the knee overall, the lateral meniscus, lateral cartilage, and medial cartilage. There was no significant link between HA injection and postinjection progression of WORMS or between either injection type and progression of pain, as quantified by WOMAC. There was also no significant difference in progression of WORMS over the 2 years prior to injection for CS and HA injections.

“Corticosteroid injections must be administered with caution with respect to long-term effects on osteoarthritis,” Dr. Bharadwaj advised. “Hyaluronic acid injections, on the other hand, may slow down progression of knee osteoarthritis and alleviate long-term effects while offering similar symptomatic relief to corticosteroid injections. Overall, they are perhaps a safer alternative when looking at medium- and long-term disease course of knee osteoarthritis.”

In the second study, lead author Azad Darbandi, MS, a fourth-year medical student at Chicago Medical School, North Chicago, and colleagues found that patients who received CS injections experienced significantly more medial joint space narrowing.

They identified 210 knees with imaging at baseline and at 48 months that received CS injections, and 59 that received HA injections; 6,827 knees served as controls. The investigators matched 50 patients per group on the basis of confounding factors, which included age, sex, BMI, comorbidities, surgery, and semiquantitative imaging outcomes at baseline. They performed ANCOVA testing using 48-month semiquantitative imaging outcomes as dependent variables and confounding variables as covariates.

The researchers analyzed joint space narrowing, KL grade, and tibia/femur medial/lateral compartment osteophyte formation and sclerosis.

At 4 years, the average KL grade in the CS group was 2.79, it was 2.11 in the HA group,;and it was 2.37 in the control group. Intergroup comparisons showed significant differences in KL grade between CS and HA groups and between CS and control groups. Medial compartment joint space narrowing was 1.56 in the CS group, 1.11 in the HA group, and 1.18 in controls. There was a significant difference between the CS and control groups. Other dependent variables were not significant.

“These preliminary results suggest that corticosteroid injections accelerated the radiographic progression of osteoarthritis, specifically medial joint space narrowing and Kellgren-Lawrence grading, whereas hyaluronic acid injections did not,” Mr. Darbandi said in an interview.

“OA radiographic progression does not always correlate with clinical progression, and further research is needed,” he added.

Proper matching of patients at baseline for confounding factors is a strength of the study, Mr. Darbandi said, while the retrospective study design is a weakness.
 

Experts share their perspectives on the preliminary results

Michael M. Kheir, MD, assistant professor of orthopedic surgery at the University of Michigan Health System, who was not involved in the studies, said he would like to see further related research.

“Perhaps steroid injections are not as benign as they once seemed,” he added. “They should be reserved for patients who already have significant arthritis and are seeking temporary relief prior to surgical reconstruction with a joint replacement, or for patients with recalcitrant pain after having already tried HA injections.”

William A. Jiranek, MD, professor and orthopedic surgeon at Duke Health in Morrisville, N.C., who also was not involved in the studies, was not surprised by the findings.

“It is important to do these studies to learn that steroid injections do not come with zero cost,” he said.

“I am pretty sure that a percentage of these patients had no cartilage loss at all,” he added. “We need to understand which OA phenotypes are not at risk of progressive cartilage loss from steroid injections.”

Annunziato (Ned) Amendola, MD, professor and sports medicine orthopedic surgeon at Duke Health in Durham, N.C., who was also not involved in the studies, said he would like to know how injection effectiveness and activity level are related.

“If the injections were effective at relieving pain, and the patients were more active, that may have predisposed to more joint wear,” he said. “It’s like tires that last longer if you don’t abuse them.”
 

Shared decision-making and further research recommended

Amanda E. Nelson, MD, associate professor of medicine in the division of rheumatology, allergy, and immunology at the University of North Carolina at Chapel Hill, said: “The lack of randomization introduces potential biases around why certain therapies (CS injection, HA injection, or neither) were selected over others (such as disease severity, preference, comorbid conditions, other contraindications, etc), thus making interpretation of the findings challenging.

“The causal relationship remains in question, and questions around the efficacy of intra-articular HA in particular, and the ideal settings for intra-articular therapy in general, persist,” noted Dr. Nelson, who was also not involved in the studies. “Thus, shared decision-making between patients and their providers is essential when considering these options.”

C. Kent Kwoh, MD, professor of medicine and medical imaging at the University of Arizona and director of the University of Arizona Arthritis Center, both in Tucson, said in an interview that these types of studies are important because CS injections are common treatments for knee OA, they are recommended in treatment guidelines, and other good options are lacking.

But he pointed out that the results of these two studies need to be interpreted with caution and should not be used to decide the course of treatment.

“These data are hypothesis generating. They suggest association, but they do not show causation,” said Dr. Kwoh, who was also not involved in the studies. “Both studies are secondary analyses of data collected from the OAI, which was not specifically designed to answer the questions these studies are posing.

“The OAI was not a treatment study, and participants were seen only once a year or so. They may have had joint injections anytime from only days to around 1 year before their visit, and their levels of activity or pain just prior to or just after their joint injections were not reported,” Dr. Kwoh explained.

The reasons why patients did or did not receive a specific joint injection – including their socioeconomic status, race, access to insurance, and other confounding factors – were not assessed and may have affected the results, he added.

The fact that both studies used the same data and came to the same conclusions gives the conclusions some strength, he said, but “the gold standard to understanding causation would be a randomized, controlled trial.”

Mr. Darbandi’s research received grant support from Boeing, His c-authors, as well as all experts not involved in the studies, reported no relevant financial relationshiips. Dr. Bharadwaj did not provide conflict-of-interest and funding details. Dr. Kwoh reported membership on panels that have developed guidelines for the management of knee OA.

A version of this article first appeared on Medscape.com.

Corticosteroid (CS) injections may worsen progression of knee osteoarthritis as seen on radiography and whole-knee MRI. Injecting hyaluronic acid (HA) instead, or managing the condition without injections, may better preserve knee structure and cartilage, according to results of two related studies presented at the annual meeting of the Radiological Society of North America.

The findings come nonrandomized, observational cohort studies, leading knee OA experts to call for further study in randomized trial settings. In the meantime, shared decision-making between patients and clinicians is advised on the use of these injections.

For knee OA, most patients seek a noninvasive treatment for symptomatic relief. “At least 10% of these patients undergo local treatment with injectable corticosteroids or hyaluronic acid,” the lead author of one of the studies, Upasana Upadhyay Bharadwaj, MD, research fellow in musculoskeletal radiology at the University of California, San Francisco, said in a video press release.

Researchers in both studies used data and images from the Osteoarthritis Initiative (OAI), a multicenter, longitudinal, observational study of 4,796 U.S. patients aged 45-79 years with knee OA. Participants were enrolled from February 2004 to May 2006.

The OAI maintains a natural history database of information regarding participants’ clinical evaluation data, x-rays, MRI scans, and a biospecimen repository. Data are available to researchers worldwide.
 

Two studies draw similar conclusions

In one study, Dr. Bharadwaj and colleagues found that HA injections appeared to show decreased knee OA progression in bone marrow lesions.

They investigated 8 patients who received one CS injection, 12 who received one HA injection, and 40 control persons who received neither treatment. Participants were propensity-score matched by age, sex, body mass index (BMI), Kellgren-Lawrence (KL) grade, Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC), and Physical Activity Scale for the Elderly (PASE).

The researchers semiquantitatively graded three Tesla MRI scans that had been obtained at baseline, 2 years before the injection, and 2 years after the injection, using whole-organ MRI score (WORMS) for the meniscus, bone marrow lesions, cartilage, joint effusion, and ligaments.

They quantified OA progression using the difference in WORMS between baseline and 2-year follow-up, and they used linear regression models, adjusted for age, sex, BMI, KL grade, WOMAC, and PASE, to identify the link between type of injection and progression of WORMS.

At 2 years, the authors found a significant association between CS injection and postinjection progression of WORMS over 2 years for the knee overall, the lateral meniscus, lateral cartilage, and medial cartilage. There was no significant link between HA injection and postinjection progression of WORMS or between either injection type and progression of pain, as quantified by WOMAC. There was also no significant difference in progression of WORMS over the 2 years prior to injection for CS and HA injections.

“Corticosteroid injections must be administered with caution with respect to long-term effects on osteoarthritis,” Dr. Bharadwaj advised. “Hyaluronic acid injections, on the other hand, may slow down progression of knee osteoarthritis and alleviate long-term effects while offering similar symptomatic relief to corticosteroid injections. Overall, they are perhaps a safer alternative when looking at medium- and long-term disease course of knee osteoarthritis.”

In the second study, lead author Azad Darbandi, MS, a fourth-year medical student at Chicago Medical School, North Chicago, and colleagues found that patients who received CS injections experienced significantly more medial joint space narrowing.

They identified 210 knees with imaging at baseline and at 48 months that received CS injections, and 59 that received HA injections; 6,827 knees served as controls. The investigators matched 50 patients per group on the basis of confounding factors, which included age, sex, BMI, comorbidities, surgery, and semiquantitative imaging outcomes at baseline. They performed ANCOVA testing using 48-month semiquantitative imaging outcomes as dependent variables and confounding variables as covariates.

The researchers analyzed joint space narrowing, KL grade, and tibia/femur medial/lateral compartment osteophyte formation and sclerosis.

At 4 years, the average KL grade in the CS group was 2.79, it was 2.11 in the HA group,;and it was 2.37 in the control group. Intergroup comparisons showed significant differences in KL grade between CS and HA groups and between CS and control groups. Medial compartment joint space narrowing was 1.56 in the CS group, 1.11 in the HA group, and 1.18 in controls. There was a significant difference between the CS and control groups. Other dependent variables were not significant.

“These preliminary results suggest that corticosteroid injections accelerated the radiographic progression of osteoarthritis, specifically medial joint space narrowing and Kellgren-Lawrence grading, whereas hyaluronic acid injections did not,” Mr. Darbandi said in an interview.

“OA radiographic progression does not always correlate with clinical progression, and further research is needed,” he added.

Proper matching of patients at baseline for confounding factors is a strength of the study, Mr. Darbandi said, while the retrospective study design is a weakness.
 

Experts share their perspectives on the preliminary results

Michael M. Kheir, MD, assistant professor of orthopedic surgery at the University of Michigan Health System, who was not involved in the studies, said he would like to see further related research.

“Perhaps steroid injections are not as benign as they once seemed,” he added. “They should be reserved for patients who already have significant arthritis and are seeking temporary relief prior to surgical reconstruction with a joint replacement, or for patients with recalcitrant pain after having already tried HA injections.”

William A. Jiranek, MD, professor and orthopedic surgeon at Duke Health in Morrisville, N.C., who also was not involved in the studies, was not surprised by the findings.

“It is important to do these studies to learn that steroid injections do not come with zero cost,” he said.

“I am pretty sure that a percentage of these patients had no cartilage loss at all,” he added. “We need to understand which OA phenotypes are not at risk of progressive cartilage loss from steroid injections.”

Annunziato (Ned) Amendola, MD, professor and sports medicine orthopedic surgeon at Duke Health in Durham, N.C., who was also not involved in the studies, said he would like to know how injection effectiveness and activity level are related.

“If the injections were effective at relieving pain, and the patients were more active, that may have predisposed to more joint wear,” he said. “It’s like tires that last longer if you don’t abuse them.”
 

Shared decision-making and further research recommended

Amanda E. Nelson, MD, associate professor of medicine in the division of rheumatology, allergy, and immunology at the University of North Carolina at Chapel Hill, said: “The lack of randomization introduces potential biases around why certain therapies (CS injection, HA injection, or neither) were selected over others (such as disease severity, preference, comorbid conditions, other contraindications, etc), thus making interpretation of the findings challenging.

“The causal relationship remains in question, and questions around the efficacy of intra-articular HA in particular, and the ideal settings for intra-articular therapy in general, persist,” noted Dr. Nelson, who was also not involved in the studies. “Thus, shared decision-making between patients and their providers is essential when considering these options.”

C. Kent Kwoh, MD, professor of medicine and medical imaging at the University of Arizona and director of the University of Arizona Arthritis Center, both in Tucson, said in an interview that these types of studies are important because CS injections are common treatments for knee OA, they are recommended in treatment guidelines, and other good options are lacking.

But he pointed out that the results of these two studies need to be interpreted with caution and should not be used to decide the course of treatment.

“These data are hypothesis generating. They suggest association, but they do not show causation,” said Dr. Kwoh, who was also not involved in the studies. “Both studies are secondary analyses of data collected from the OAI, which was not specifically designed to answer the questions these studies are posing.

“The OAI was not a treatment study, and participants were seen only once a year or so. They may have had joint injections anytime from only days to around 1 year before their visit, and their levels of activity or pain just prior to or just after their joint injections were not reported,” Dr. Kwoh explained.

The reasons why patients did or did not receive a specific joint injection – including their socioeconomic status, race, access to insurance, and other confounding factors – were not assessed and may have affected the results, he added.

The fact that both studies used the same data and came to the same conclusions gives the conclusions some strength, he said, but “the gold standard to understanding causation would be a randomized, controlled trial.”

Mr. Darbandi’s research received grant support from Boeing, His c-authors, as well as all experts not involved in the studies, reported no relevant financial relationshiips. Dr. Bharadwaj did not provide conflict-of-interest and funding details. Dr. Kwoh reported membership on panels that have developed guidelines for the management of knee OA.

A version of this article first appeared on Medscape.com.

For many years, it has been believed that the aging process is inevitable and that age-related diseases cannot be prevented or reversed. For example, the U.S. Food and Drug Administration does not recognize aging as an indication for drug approval because there are no markers to determine whether possible treatments have a significant impact on the hallmarks of aging.

The field of geroscience aims to find ways to change this by delaying the onset of age-related diseases or by extending the life span. On May 19, 2021, experts in geroscience met virtually at a symposium of the New York Academy of Sciences. Presentations and discussions with experts in the field showed that remarkable advances have been made in understanding the mechanisms underlying biological aging. Those mechanisms contribute to the vulnerability of older adults. The presentations focused on identifying biomarkers of aging and on the search for interventions to prevent and treat age-related diseases.

Perspectives from this meeting were published in a report.
 

An abridged glossary

• Senescent cells: These are old cells with irreversibly damaged DNA; they strongly resist apoptosis. Thus, they are not eliminated and continue to secrete pathogenic proinflammatory molecules.
• Senolytics: This is a class of compounds that promote the removal of senescent cells from the body.
• Autophagy: This is a process that promotes protein degradation, which is attenuated with aging and that impedes the aggregation of proteins harmful to cell function, particularly those of the central nervous system.
• Proteostasis: This is the dynamic regulation of protein homeostasis.
• Epigenetics: This is the field of biology that studies phenotype changes that are not caused by changes in DNA sequencing and that continue to affect cellular division.
• Metabolome: This refers to small molecules that make up the building blocks of all organismal features, from cell membranes to metabolic cycles to genes and proteins.
• Translational research: This involves applying primary research results to clinical research and vice versa.

Possible research topics

Senescence not only occurs with age but also drives aging. At the meeting, evidence was provided that senescent cells may exacerbate the clinical course of older adults in cases of infections (for example, COVID-19) as they lead to cytokine storms.

Experiments on old mice that have undergone genetic modification of senescent cells or the administration of “senolytic cocktails” composed of dasatinib plus quercetin protected the animals from the effects of viral infections. This finding corroborates the idea that factors involved in biological aging increase vulnerability and could be modified through treatment.

Alzheimer’s disease is an example of the effects of cellular senescence. Senescent cells develop a senescence-associated secretory phenotype that can be toxic to neighboring healthy cells and can allow senescence to propagate within tissues. This effect makes Alzheimer’s disease an essential focal point when studying the use of senolytics. In addition, agents that stimulate autophagy may be of interest for treating degenerative diseases.
 

Assessing therapeutic effects

It may be possible to assess the therapeutic effects of drug candidates using the following biomarkers.

• Growth hormone and type 1 insulin-like growth factor (IGF-1): Older adults are often prescribed growth hormone. However, recent data suggest that doing so is not advantageous to this patient population, because it antagonizes proteostasis and other cell maintenance mechanisms in older age. Experimental studies and studies conducted on centenarians suggest that low growth hormone and IGF-1 levels contribute to longevity and may be therapeutic biomarkers.
• Epigenetics: DNA methylation is a method that offers an “epigenetic clock” to compare biological age with chronologic age. Higher epigenetic age was associated with increased mortality risk, breast cancer, and nonalcoholic fatty liver disease. Therefore, it could also be a therapeutic biomarker.
• Metabolomics: Studying metabolomes facilitates the identification of the link between genetic polymorphisms and longevity, as most polymorphisms explain less than 0.5% of longevity variations.
• New translational strategy: It is common practice to treat each age-related disease individually. An alternative strategy would be to target the hallmarks of biological aging to prevent these diseases from developing. The rate of biological aging correlates with the speed of damage accumulation at the macromolecular, organelle, and cellular levels. It also affects the capacity of the body to repair this damage. The assessment of biomarkers would make possibile research into the effects of short- and long-term treatments that minimize damage and enhance resilience related to diseases common with aging.

New translational research

The report highlights two translational research models: the in-depth study of centenarians and the analysis of how immune aging makes older adults vulnerable to COVID-19. The impact of impaired immunity on aging became particularly evident during the pandemic. However, to home in on immunity as a therapeutic target and to better understand immune resilience, the specific nature of immune and biological deficits still need to be defined.

Metformin is among the therapeutic agents under investigation in cutting-edge clinical research. Its effect on aging will be studied in the Targeting Aging with Metformin (TAME) clinical trial. This trial is the first to study aging outcomes. The goal is to create a regulatory framework that future therapies can follow to achieve FDA approval.

There are three promising therapeutic platforms among the cutting-edge research studies. The first aims to produce adenosine triphosphate, levels of which decline dramatically with aging. The second aims to promote autophagy to remove cellular waste to treat neurodegenerative diseases. The third reprograms the epigenome to a younger state.

Research on mitochondrial dysfunction is relevant because it is highly involved in age-related diseases. Mitochondrial-derived peptides could potentially serve as biomarkers of mitochondrial function in aging studies and become promising therapeutic targets in age-related diseases. One of these peptides, humanin, has been demonstrated to exert protective effects on the heart, brain, and liver. Researchers observed that mitochondrial proteins are age-dependent and are suppressed by growth hormone and IGF-1. They also found that humanin levels are correlated with endothelial function. Data from animal studies have shown that sustained humanin levels are positively linked to longevity; these findings are mirrored in data from centenarians and their offspring, who have higher levels of humanin.

The formation of a Translational Geroscience Network composed of several scientists from various institutions should accelerate the application of this understanding. Despite the ongoing investigational and clinical studies, senolytics should not be regarded as extending life span or treating certain conditions, because their full safety profiles have not yet been elucidated.
 

Conclusion

Geroscience faces challenges in dealing with age-related problems. It is hoped that these challenges will be overcome through investigational and clinical studies on the mechanisms involved in aging. In-depth study of the interactions of underlying mechanisms of aging are needed to answer the following questions:

• Is there a hierarchical relationship among these mechanisms?
• Are there organ or cell-type differences in the interactions among these mechanisms?
• Is it possible to achieve a synergistic effect through combined interventions targeting several of the processes that drive aging?

It is complicated, but researchers are starting to see the light at the end of the tunnel.

This article was translated from the Medscape Portuguese edition and a version appeared on Medscape.com.

For many years, it has been believed that the aging process is inevitable and that age-related diseases cannot be prevented or reversed. For example, the U.S. Food and Drug Administration does not recognize aging as an indication for drug approval because there are no markers to determine whether possible treatments have a significant impact on the hallmarks of aging.

The field of geroscience aims to find ways to change this by delaying the onset of age-related diseases or by extending the life span. On May 19, 2021, experts in geroscience met virtually at a symposium of the New York Academy of Sciences. Presentations and discussions with experts in the field showed that remarkable advances have been made in understanding the mechanisms underlying biological aging. Those mechanisms contribute to the vulnerability of older adults. The presentations focused on identifying biomarkers of aging and on the search for interventions to prevent and treat age-related diseases.

Perspectives from this meeting were published in a report.
 

An abridged glossary

• Senescent cells: These are old cells with irreversibly damaged DNA; they strongly resist apoptosis. Thus, they are not eliminated and continue to secrete pathogenic proinflammatory molecules.
• Senolytics: This is a class of compounds that promote the removal of senescent cells from the body.
• Autophagy: This is a process that promotes protein degradation, which is attenuated with aging and that impedes the aggregation of proteins harmful to cell function, particularly those of the central nervous system.
• Proteostasis: This is the dynamic regulation of protein homeostasis.
• Epigenetics: This is the field of biology that studies phenotype changes that are not caused by changes in DNA sequencing and that continue to affect cellular division.
• Metabolome: This refers to small molecules that make up the building blocks of all organismal features, from cell membranes to metabolic cycles to genes and proteins.
• Translational research: This involves applying primary research results to clinical research and vice versa.

Possible research topics

Senescence not only occurs with age but also drives aging. At the meeting, evidence was provided that senescent cells may exacerbate the clinical course of older adults in cases of infections (for example, COVID-19) as they lead to cytokine storms.

Experiments on old mice that have undergone genetic modification of senescent cells or the administration of “senolytic cocktails” composed of dasatinib plus quercetin protected the animals from the effects of viral infections. This finding corroborates the idea that factors involved in biological aging increase vulnerability and could be modified through treatment.

Alzheimer’s disease is an example of the effects of cellular senescence. Senescent cells develop a senescence-associated secretory phenotype that can be toxic to neighboring healthy cells and can allow senescence to propagate within tissues. This effect makes Alzheimer’s disease an essential focal point when studying the use of senolytics. In addition, agents that stimulate autophagy may be of interest for treating degenerative diseases.
 

Assessing therapeutic effects

It may be possible to assess the therapeutic effects of drug candidates using the following biomarkers.

• Growth hormone and type 1 insulin-like growth factor (IGF-1): Older adults are often prescribed growth hormone. However, recent data suggest that doing so is not advantageous to this patient population, because it antagonizes proteostasis and other cell maintenance mechanisms in older age. Experimental studies and studies conducted on centenarians suggest that low growth hormone and IGF-1 levels contribute to longevity and may be therapeutic biomarkers.
• Epigenetics: DNA methylation is a method that offers an “epigenetic clock” to compare biological age with chronologic age. Higher epigenetic age was associated with increased mortality risk, breast cancer, and nonalcoholic fatty liver disease. Therefore, it could also be a therapeutic biomarker.
• Metabolomics: Studying metabolomes facilitates the identification of the link between genetic polymorphisms and longevity, as most polymorphisms explain less than 0.5% of longevity variations.
• New translational strategy: It is common practice to treat each age-related disease individually. An alternative strategy would be to target the hallmarks of biological aging to prevent these diseases from developing. The rate of biological aging correlates with the speed of damage accumulation at the macromolecular, organelle, and cellular levels. It also affects the capacity of the body to repair this damage. The assessment of biomarkers would make possibile research into the effects of short- and long-term treatments that minimize damage and enhance resilience related to diseases common with aging.

New translational research

The report highlights two translational research models: the in-depth study of centenarians and the analysis of how immune aging makes older adults vulnerable to COVID-19. The impact of impaired immunity on aging became particularly evident during the pandemic. However, to home in on immunity as a therapeutic target and to better understand immune resilience, the specific nature of immune and biological deficits still need to be defined.

Metformin is among the therapeutic agents under investigation in cutting-edge clinical research. Its effect on aging will be studied in the Targeting Aging with Metformin (TAME) clinical trial. This trial is the first to study aging outcomes. The goal is to create a regulatory framework that future therapies can follow to achieve FDA approval.

There are three promising therapeutic platforms among the cutting-edge research studies. The first aims to produce adenosine triphosphate, levels of which decline dramatically with aging. The second aims to promote autophagy to remove cellular waste to treat neurodegenerative diseases. The third reprograms the epigenome to a younger state.

Research on mitochondrial dysfunction is relevant because it is highly involved in age-related diseases. Mitochondrial-derived peptides could potentially serve as biomarkers of mitochondrial function in aging studies and become promising therapeutic targets in age-related diseases. One of these peptides, humanin, has been demonstrated to exert protective effects on the heart, brain, and liver. Researchers observed that mitochondrial proteins are age-dependent and are suppressed by growth hormone and IGF-1. They also found that humanin levels are correlated with endothelial function. Data from animal studies have shown that sustained humanin levels are positively linked to longevity; these findings are mirrored in data from centenarians and their offspring, who have higher levels of humanin.

The formation of a Translational Geroscience Network composed of several scientists from various institutions should accelerate the application of this understanding. Despite the ongoing investigational and clinical studies, senolytics should not be regarded as extending life span or treating certain conditions, because their full safety profiles have not yet been elucidated.
 

Conclusion

Geroscience faces challenges in dealing with age-related problems. It is hoped that these challenges will be overcome through investigational and clinical studies on the mechanisms involved in aging. In-depth study of the interactions of underlying mechanisms of aging are needed to answer the following questions:

• Is there a hierarchical relationship among these mechanisms?
• Are there organ or cell-type differences in the interactions among these mechanisms?
• Is it possible to achieve a synergistic effect through combined interventions targeting several of the processes that drive aging?

It is complicated, but researchers are starting to see the light at the end of the tunnel.

This article was translated from the Medscape Portuguese edition and a version appeared on Medscape.com.

For many years, it has been believed that the aging process is inevitable and that age-related diseases cannot be prevented or reversed. For example, the U.S. Food and Drug Administration does not recognize aging as an indication for drug approval because there are no markers to determine whether possible treatments have a significant impact on the hallmarks of aging.

The field of geroscience aims to find ways to change this by delaying the onset of age-related diseases or by extending the life span. On May 19, 2021, experts in geroscience met virtually at a symposium of the New York Academy of Sciences. Presentations and discussions with experts in the field showed that remarkable advances have been made in understanding the mechanisms underlying biological aging. Those mechanisms contribute to the vulnerability of older adults. The presentations focused on identifying biomarkers of aging and on the search for interventions to prevent and treat age-related diseases.

Perspectives from this meeting were published in a report.
 

An abridged glossary

• Senescent cells: These are old cells with irreversibly damaged DNA; they strongly resist apoptosis. Thus, they are not eliminated and continue to secrete pathogenic proinflammatory molecules.
• Senolytics: This is a class of compounds that promote the removal of senescent cells from the body.
• Autophagy: This is a process that promotes protein degradation, which is attenuated with aging and that impedes the aggregation of proteins harmful to cell function, particularly those of the central nervous system.
• Proteostasis: This is the dynamic regulation of protein homeostasis.
• Epigenetics: This is the field of biology that studies phenotype changes that are not caused by changes in DNA sequencing and that continue to affect cellular division.
• Metabolome: This refers to small molecules that make up the building blocks of all organismal features, from cell membranes to metabolic cycles to genes and proteins.
• Translational research: This involves applying primary research results to clinical research and vice versa.

Possible research topics

Senescence not only occurs with age but also drives aging. At the meeting, evidence was provided that senescent cells may exacerbate the clinical course of older adults in cases of infections (for example, COVID-19) as they lead to cytokine storms.

Experiments on old mice that have undergone genetic modification of senescent cells or the administration of “senolytic cocktails” composed of dasatinib plus quercetin protected the animals from the effects of viral infections. This finding corroborates the idea that factors involved in biological aging increase vulnerability and could be modified through treatment.

Alzheimer’s disease is an example of the effects of cellular senescence. Senescent cells develop a senescence-associated secretory phenotype that can be toxic to neighboring healthy cells and can allow senescence to propagate within tissues. This effect makes Alzheimer’s disease an essential focal point when studying the use of senolytics. In addition, agents that stimulate autophagy may be of interest for treating degenerative diseases.
 

Assessing therapeutic effects

It may be possible to assess the therapeutic effects of drug candidates using the following biomarkers.

• Growth hormone and type 1 insulin-like growth factor (IGF-1): Older adults are often prescribed growth hormone. However, recent data suggest that doing so is not advantageous to this patient population, because it antagonizes proteostasis and other cell maintenance mechanisms in older age. Experimental studies and studies conducted on centenarians suggest that low growth hormone and IGF-1 levels contribute to longevity and may be therapeutic biomarkers.
• Epigenetics: DNA methylation is a method that offers an “epigenetic clock” to compare biological age with chronologic age. Higher epigenetic age was associated with increased mortality risk, breast cancer, and nonalcoholic fatty liver disease. Therefore, it could also be a therapeutic biomarker.
• Metabolomics: Studying metabolomes facilitates the identification of the link between genetic polymorphisms and longevity, as most polymorphisms explain less than 0.5% of longevity variations.
• New translational strategy: It is common practice to treat each age-related disease individually. An alternative strategy would be to target the hallmarks of biological aging to prevent these diseases from developing. The rate of biological aging correlates with the speed of damage accumulation at the macromolecular, organelle, and cellular levels. It also affects the capacity of the body to repair this damage. The assessment of biomarkers would make possibile research into the effects of short- and long-term treatments that minimize damage and enhance resilience related to diseases common with aging.

New translational research

The report highlights two translational research models: the in-depth study of centenarians and the analysis of how immune aging makes older adults vulnerable to COVID-19. The impact of impaired immunity on aging became particularly evident during the pandemic. However, to home in on immunity as a therapeutic target and to better understand immune resilience, the specific nature of immune and biological deficits still need to be defined.

Metformin is among the therapeutic agents under investigation in cutting-edge clinical research. Its effect on aging will be studied in the Targeting Aging with Metformin (TAME) clinical trial. This trial is the first to study aging outcomes. The goal is to create a regulatory framework that future therapies can follow to achieve FDA approval.

There are three promising therapeutic platforms among the cutting-edge research studies. The first aims to produce adenosine triphosphate, levels of which decline dramatically with aging. The second aims to promote autophagy to remove cellular waste to treat neurodegenerative diseases. The third reprograms the epigenome to a younger state.

Research on mitochondrial dysfunction is relevant because it is highly involved in age-related diseases. Mitochondrial-derived peptides could potentially serve as biomarkers of mitochondrial function in aging studies and become promising therapeutic targets in age-related diseases. One of these peptides, humanin, has been demonstrated to exert protective effects on the heart, brain, and liver. Researchers observed that mitochondrial proteins are age-dependent and are suppressed by growth hormone and IGF-1. They also found that humanin levels are correlated with endothelial function. Data from animal studies have shown that sustained humanin levels are positively linked to longevity; these findings are mirrored in data from centenarians and their offspring, who have higher levels of humanin.

The formation of a Translational Geroscience Network composed of several scientists from various institutions should accelerate the application of this understanding. Despite the ongoing investigational and clinical studies, senolytics should not be regarded as extending life span or treating certain conditions, because their full safety profiles have not yet been elucidated.
 

Conclusion

Geroscience faces challenges in dealing with age-related problems. It is hoped that these challenges will be overcome through investigational and clinical studies on the mechanisms involved in aging. In-depth study of the interactions of underlying mechanisms of aging are needed to answer the following questions:

• Is there a hierarchical relationship among these mechanisms?
• Are there organ or cell-type differences in the interactions among these mechanisms?
• Is it possible to achieve a synergistic effect through combined interventions targeting several of the processes that drive aging?

It is complicated, but researchers are starting to see the light at the end of the tunnel.

This article was translated from the Medscape Portuguese edition and a version appeared on Medscape.com.

SAN FRANCISCO – In a widely anticipated report, researchers reported that a phase 3 study showed statistically significant improvements in patients with agitation related to Alzheimer’s disease (AD) who took the atypical antipsychotic brexpiprazole (Rexulti).

Members of a panel of dementia specialists here at the 15th Clinical Trials on Alzheimer’s Disease (CTAD) conference said that the results were encouraging. But they also noted that the available data make it difficult to understand the impact of the drug on the day-to-day life on patients.

“I’d like to be able to translate that into something else to understand the risk benefit calculus,” said neurologist and neuroscientist Alireza Atri, MD, PhD, of Banner Sun Health Research Institute in Phoenix. “How does it affect the patients themselves, their quality of life, and the family members and their burden?”

Currently, there’s no Food and Drug Administration–approved treatment for agitation in AD.

In 2015, the FDA approved brexpiprazole, an oral medication, as a treatment for schizophrenia and an adjunctive treatment for major depressive disorder (MDD). It is an expensive drug with an average retail price per GoodRx of $1,582 per month, and no generic is available.

Researchers released the results of a trio of phase 3 clinical trials at CTAD that examined various doses of brexpiprazole. The results of the first two trials had been released earlier in 2018.
 

Three trials

All trials were multicenter, 12-week, randomized, double-blind and placebo-controlled.

Study participants were aged 55-90 years, had probable AD diagnoses, and had agitation per various scales. The average age in the groups was 74 years, 56.0%-61.7% were women, and 94.3%-98.1% were White.

The first trial examined two fixed doses (1 mg/d, n = 137; and 2 mg/d, n = 140) or placebo (n = 136). “The study initially included a 0.5 mg/day arm,” the researchers reported, “which was removed in a protocol amendment, and patients randomized to that arm were not included in efficacy analyses.”

The second trial looked at a flexible dose (0.5-2 mg/d, n = 133) or placebo (n = 137).

In a CTAD presentation, Nanco Hefting of Lundbeck, a codeveloper of the drug, said that the researchers learned from the first two trials that 2 mg/d might be an appropriate dose, and the FDA recommended they also examine 3 mg/day. As a result, the third trial examined two fixed doses (2 mg/d, n = 75; 3 mg/d, n = 153; or placebo, n = 117).

In the third trial, both the placebo and drug groups improved per a measurement of agitation; those in the drug group improved somewhat more.

The mean change in baseline on the Cohen-Mansfield Agitation Inventory scale – the primary endpoint – was –5.32 for the 2-mg/d and 3-mg/d groups vs. placebo (P = .0026); the score in the placebo group fell by about 18 and by about 22 in the drug group.

The key secondary endpoint was an improvement from baseline to week 12 in the Clinical Global Impression–Severity (CGI-S) score related to agitation. Compared with the placebo group, this score was –0.27 in the drug group (P = .0078). Both scores hovered around –1.0.

Safety data show the percentage of treatment-emergent events ranged from 45.9% in the placebo group to 49.0%-56.8% for brexpiprazole in the three trials. The percentage of these events leading to discontinuation was 6.3% among those receiving the drug and 3.4% in the placebo group.

University of Exeter dementia researcher Clive Ballard, MD, MB ChB, one of the panelists who discussed the research after the CTAD presentation, praised the trials as “well-conducted” and said that he was pleased that subjects in institutions were included. “It’s not an easy environment to do trials in. They should be really commended for doing for doing that.”

But he echoed fellow panelist Dr. Atri by noting that more data are needed to understand how well the drug works. “I would like to see the effect sizes and a little bit more detail to understand the clinical meaningfulness of that level of benefit.”

What’s next? A spokeswoman for Otsuka, a codeveloper of brexpiprazole, said that it hopes to hear in 2023 about a supplemental new drug application that was filed in November 2022.

Otsuka and Lundbeck funded the research. Mr. Hefting is an employee of Lundbeck, and several other authors work for Lundbeck or Otsuka. The single non-employee author reports various disclosures. Disclosures for Dr. Atri and Dr. Ballard were not provided.
 

A version of this article first appeared on Medscape.com.

SAN FRANCISCO – In a widely anticipated report, researchers reported that a phase 3 study showed statistically significant improvements in patients with agitation related to Alzheimer’s disease (AD) who took the atypical antipsychotic brexpiprazole (Rexulti).

Members of a panel of dementia specialists here at the 15th Clinical Trials on Alzheimer’s Disease (CTAD) conference said that the results were encouraging. But they also noted that the available data make it difficult to understand the impact of the drug on the day-to-day life on patients.

“I’d like to be able to translate that into something else to understand the risk benefit calculus,” said neurologist and neuroscientist Alireza Atri, MD, PhD, of Banner Sun Health Research Institute in Phoenix. “How does it affect the patients themselves, their quality of life, and the family members and their burden?”

Currently, there’s no Food and Drug Administration–approved treatment for agitation in AD.

In 2015, the FDA approved brexpiprazole, an oral medication, as a treatment for schizophrenia and an adjunctive treatment for major depressive disorder (MDD). It is an expensive drug with an average retail price per GoodRx of $1,582 per month, and no generic is available.

Researchers released the results of a trio of phase 3 clinical trials at CTAD that examined various doses of brexpiprazole. The results of the first two trials had been released earlier in 2018.
 

Three trials

All trials were multicenter, 12-week, randomized, double-blind and placebo-controlled.

Study participants were aged 55-90 years, had probable AD diagnoses, and had agitation per various scales. The average age in the groups was 74 years, 56.0%-61.7% were women, and 94.3%-98.1% were White.

The first trial examined two fixed doses (1 mg/d, n = 137; and 2 mg/d, n = 140) or placebo (n = 136). “The study initially included a 0.5 mg/day arm,” the researchers reported, “which was removed in a protocol amendment, and patients randomized to that arm were not included in efficacy analyses.”

The second trial looked at a flexible dose (0.5-2 mg/d, n = 133) or placebo (n = 137).

In a CTAD presentation, Nanco Hefting of Lundbeck, a codeveloper of the drug, said that the researchers learned from the first two trials that 2 mg/d might be an appropriate dose, and the FDA recommended they also examine 3 mg/day. As a result, the third trial examined two fixed doses (2 mg/d, n = 75; 3 mg/d, n = 153; or placebo, n = 117).

In the third trial, both the placebo and drug groups improved per a measurement of agitation; those in the drug group improved somewhat more.

The mean change in baseline on the Cohen-Mansfield Agitation Inventory scale – the primary endpoint – was –5.32 for the 2-mg/d and 3-mg/d groups vs. placebo (P = .0026); the score in the placebo group fell by about 18 and by about 22 in the drug group.

The key secondary endpoint was an improvement from baseline to week 12 in the Clinical Global Impression–Severity (CGI-S) score related to agitation. Compared with the placebo group, this score was –0.27 in the drug group (P = .0078). Both scores hovered around –1.0.

Safety data show the percentage of treatment-emergent events ranged from 45.9% in the placebo group to 49.0%-56.8% for brexpiprazole in the three trials. The percentage of these events leading to discontinuation was 6.3% among those receiving the drug and 3.4% in the placebo group.

University of Exeter dementia researcher Clive Ballard, MD, MB ChB, one of the panelists who discussed the research after the CTAD presentation, praised the trials as “well-conducted” and said that he was pleased that subjects in institutions were included. “It’s not an easy environment to do trials in. They should be really commended for doing for doing that.”

But he echoed fellow panelist Dr. Atri by noting that more data are needed to understand how well the drug works. “I would like to see the effect sizes and a little bit more detail to understand the clinical meaningfulness of that level of benefit.”

What’s next? A spokeswoman for Otsuka, a codeveloper of brexpiprazole, said that it hopes to hear in 2023 about a supplemental new drug application that was filed in November 2022.

Otsuka and Lundbeck funded the research. Mr. Hefting is an employee of Lundbeck, and several other authors work for Lundbeck or Otsuka. The single non-employee author reports various disclosures. Disclosures for Dr. Atri and Dr. Ballard were not provided.
 

A version of this article first appeared on Medscape.com.

SAN FRANCISCO – In a widely anticipated report, researchers reported that a phase 3 study showed statistically significant improvements in patients with agitation related to Alzheimer’s disease (AD) who took the atypical antipsychotic brexpiprazole (Rexulti).

Members of a panel of dementia specialists here at the 15th Clinical Trials on Alzheimer’s Disease (CTAD) conference said that the results were encouraging. But they also noted that the available data make it difficult to understand the impact of the drug on the day-to-day life on patients.

“I’d like to be able to translate that into something else to understand the risk benefit calculus,” said neurologist and neuroscientist Alireza Atri, MD, PhD, of Banner Sun Health Research Institute in Phoenix. “How does it affect the patients themselves, their quality of life, and the family members and their burden?”

Currently, there’s no Food and Drug Administration–approved treatment for agitation in AD.

In 2015, the FDA approved brexpiprazole, an oral medication, as a treatment for schizophrenia and an adjunctive treatment for major depressive disorder (MDD). It is an expensive drug with an average retail price per GoodRx of $1,582 per month, and no generic is available.

Researchers released the results of a trio of phase 3 clinical trials at CTAD that examined various doses of brexpiprazole. The results of the first two trials had been released earlier in 2018.
 

Three trials

All trials were multicenter, 12-week, randomized, double-blind and placebo-controlled.

Study participants were aged 55-90 years, had probable AD diagnoses, and had agitation per various scales. The average age in the groups was 74 years, 56.0%-61.7% were women, and 94.3%-98.1% were White.

The first trial examined two fixed doses (1 mg/d, n = 137; and 2 mg/d, n = 140) or placebo (n = 136). “The study initially included a 0.5 mg/day arm,” the researchers reported, “which was removed in a protocol amendment, and patients randomized to that arm were not included in efficacy analyses.”

The second trial looked at a flexible dose (0.5-2 mg/d, n = 133) or placebo (n = 137).

In a CTAD presentation, Nanco Hefting of Lundbeck, a codeveloper of the drug, said that the researchers learned from the first two trials that 2 mg/d might be an appropriate dose, and the FDA recommended they also examine 3 mg/day. As a result, the third trial examined two fixed doses (2 mg/d, n = 75; 3 mg/d, n = 153; or placebo, n = 117).

In the third trial, both the placebo and drug groups improved per a measurement of agitation; those in the drug group improved somewhat more.

The mean change in baseline on the Cohen-Mansfield Agitation Inventory scale – the primary endpoint – was –5.32 for the 2-mg/d and 3-mg/d groups vs. placebo (P = .0026); the score in the placebo group fell by about 18 and by about 22 in the drug group.

The key secondary endpoint was an improvement from baseline to week 12 in the Clinical Global Impression–Severity (CGI-S) score related to agitation. Compared with the placebo group, this score was –0.27 in the drug group (P = .0078). Both scores hovered around –1.0.

Safety data show the percentage of treatment-emergent events ranged from 45.9% in the placebo group to 49.0%-56.8% for brexpiprazole in the three trials. The percentage of these events leading to discontinuation was 6.3% among those receiving the drug and 3.4% in the placebo group.

University of Exeter dementia researcher Clive Ballard, MD, MB ChB, one of the panelists who discussed the research after the CTAD presentation, praised the trials as “well-conducted” and said that he was pleased that subjects in institutions were included. “It’s not an easy environment to do trials in. They should be really commended for doing for doing that.”

But he echoed fellow panelist Dr. Atri by noting that more data are needed to understand how well the drug works. “I would like to see the effect sizes and a little bit more detail to understand the clinical meaningfulness of that level of benefit.”

What’s next? A spokeswoman for Otsuka, a codeveloper of brexpiprazole, said that it hopes to hear in 2023 about a supplemental new drug application that was filed in November 2022.

Otsuka and Lundbeck funded the research. Mr. Hefting is an employee of Lundbeck, and several other authors work for Lundbeck or Otsuka. The single non-employee author reports various disclosures. Disclosures for Dr. Atri and Dr. Ballard were not provided.
 

A version of this article first appeared on Medscape.com.

The antidepressant vortioxetine (Trintellix) improved cognition, memory, and depressive symptoms in patients with comorbid major depressive disorder (MDD) and dementia.

The results of the 12-week open-label, single-group study are positive, study investigator Michael Cronquist Christensen, MPA, DrPH, a director with the Lundbeck pharmaceutical company, told this news organization before presenting the results in a poster at the 15th Clinical Trials on Alzheimer’s Disease conference.

“The study confirms earlier findings of improvement in both depressive symptoms and cognitive performance with vortioxetine in patients with depression and dementia and adds to this research that these clinical effects also extend to improvement in health-related quality of life and patients’ daily functioning,” Dr. Christensen said.

“It also demonstrates that patients with depression and comorbid dementia can be safely treated with 20 mg vortioxetine – starting dose of 5 mg for the first week and up-titration to 10 mg at day 8,” he added.

However, he reported that Lundbeck doesn’t plan to seek approval from the U.S. Food and Drug Administration for a new indication. Vortioxetine received FDA approval in 2013 to treat MDD, but 3 years later the agency rejected an expansion of its indication to include cognitive dysfunction.

“Vortioxetine is approved for MDD, but the product can be used in patients with MDD who have other diseases, including other mental illnesses,” Dr. Christensen said.

Potential neurotransmission modulator

Vortioxetine is a selective serotonin reuptake inhibitor and serotonin receptor modulator. According to Dr. Christensen, evidence suggests the drug’s receptor targets “have the potential to modulate neurotransmitter systems that are essential for regulation of cognitive function.”

The researchers recruited 83 individuals aged 55-85 with recurrent MDD that had started before the age of 55. All had MDD episodes within the previous 6 months and comorbid dementia for at least 6 months.

Of the participants, 65.9% were female. In addition, 42.7% had Alzheimer’s disease, 26.8% had mixed-type dementia, and the rest had other types of dementia.

The daily oral dose of vortioxetine started at 5 mg for up to week 1 and then was increased to 10 mg. It was then increased to 20 mg or decreased to 5 mg “based on investigator judgment and patient response.” The average daily dose was 12.3 mg.

In regard to the primary outcome, at week 12 (n = 70), scores on the Montgomery-Åsberg Depression Rating Scale (MADRS) fell by a mean of –12.4 (.78, P < .0001), which researchers deemed to be a significant reduction in severe symptoms.

“A significant and clinically meaningful effect was observed from week 1,” the researchers reported.

“As a basis for comparison, we typically see an improvement around 13-14 points during 8 weeks of antidepressant treatment in adults with MDD who do not have dementia,” Dr. Christensen added.

More than a third of patients (35.7%) saw a reduction in MADRS score by more than 50% at week 12, and 17.2% were considered to have reached MDD depression remission, defined as a MADRS score at or under 10.

For secondary outcomes, the total Digit Symbol Substitution test score grew by 0.65 (standardized effect size) by week 12, showing significant improvement (P < .0001). In addition, participants improved on some other cognitive measures, and Dr. Christensen noted that “significant improvement was also observed in the patients’ health-related quality of life and daily functioning.”

A third of patients had drug-related treatment-emergent adverse events.

Vortioxetine is one of the most expensive antidepressants: It has a list price of $444 a month, and no generic version is currently available.

Small trial, open-label design

In a comment, Claire Sexton, DPhil, senior director of scientific programs and outreach at the Alzheimer’s Association, said the study “reflects a valuable aspect of treatment research because of the close connection between depression and dementia. Depression is a known risk factor for dementia, including Alzheimer’s disease, and those who have dementia may experience depression.”

Alzheimer’s Association

She cautioned, however, that the trial was small and had an open-label design instead of the “gold standard” of a double-blinded trial with a control group.

The study was funded by Lundbeck, where Dr. Christensen is an employee. Another author is a Lundbeck employee, and a third author reported various disclosures. Dr. Sexton reported no disclosures.

A version of this article first appeared on Medscape.com.

The antidepressant vortioxetine (Trintellix) improved cognition, memory, and depressive symptoms in patients with comorbid major depressive disorder (MDD) and dementia.

The results of the 12-week open-label, single-group study are positive, study investigator Michael Cronquist Christensen, MPA, DrPH, a director with the Lundbeck pharmaceutical company, told this news organization before presenting the results in a poster at the 15th Clinical Trials on Alzheimer’s Disease conference.

“The study confirms earlier findings of improvement in both depressive symptoms and cognitive performance with vortioxetine in patients with depression and dementia and adds to this research that these clinical effects also extend to improvement in health-related quality of life and patients’ daily functioning,” Dr. Christensen said.

“It also demonstrates that patients with depression and comorbid dementia can be safely treated with 20 mg vortioxetine – starting dose of 5 mg for the first week and up-titration to 10 mg at day 8,” he added.

However, he reported that Lundbeck doesn’t plan to seek approval from the U.S. Food and Drug Administration for a new indication. Vortioxetine received FDA approval in 2013 to treat MDD, but 3 years later the agency rejected an expansion of its indication to include cognitive dysfunction.

“Vortioxetine is approved for MDD, but the product can be used in patients with MDD who have other diseases, including other mental illnesses,” Dr. Christensen said.

Potential neurotransmission modulator

Vortioxetine is a selective serotonin reuptake inhibitor and serotonin receptor modulator. According to Dr. Christensen, evidence suggests the drug’s receptor targets “have the potential to modulate neurotransmitter systems that are essential for regulation of cognitive function.”

The researchers recruited 83 individuals aged 55-85 with recurrent MDD that had started before the age of 55. All had MDD episodes within the previous 6 months and comorbid dementia for at least 6 months.

Of the participants, 65.9% were female. In addition, 42.7% had Alzheimer’s disease, 26.8% had mixed-type dementia, and the rest had other types of dementia.

The daily oral dose of vortioxetine started at 5 mg for up to week 1 and then was increased to 10 mg. It was then increased to 20 mg or decreased to 5 mg “based on investigator judgment and patient response.” The average daily dose was 12.3 mg.

In regard to the primary outcome, at week 12 (n = 70), scores on the Montgomery-Åsberg Depression Rating Scale (MADRS) fell by a mean of –12.4 (.78, P < .0001), which researchers deemed to be a significant reduction in severe symptoms.

“A significant and clinically meaningful effect was observed from week 1,” the researchers reported.

“As a basis for comparison, we typically see an improvement around 13-14 points during 8 weeks of antidepressant treatment in adults with MDD who do not have dementia,” Dr. Christensen added.

More than a third of patients (35.7%) saw a reduction in MADRS score by more than 50% at week 12, and 17.2% were considered to have reached MDD depression remission, defined as a MADRS score at or under 10.

For secondary outcomes, the total Digit Symbol Substitution test score grew by 0.65 (standardized effect size) by week 12, showing significant improvement (P < .0001). In addition, participants improved on some other cognitive measures, and Dr. Christensen noted that “significant improvement was also observed in the patients’ health-related quality of life and daily functioning.”

A third of patients had drug-related treatment-emergent adverse events.

Vortioxetine is one of the most expensive antidepressants: It has a list price of $444 a month, and no generic version is currently available.

Small trial, open-label design

In a comment, Claire Sexton, DPhil, senior director of scientific programs and outreach at the Alzheimer’s Association, said the study “reflects a valuable aspect of treatment research because of the close connection between depression and dementia. Depression is a known risk factor for dementia, including Alzheimer’s disease, and those who have dementia may experience depression.”

Alzheimer’s Association

She cautioned, however, that the trial was small and had an open-label design instead of the “gold standard” of a double-blinded trial with a control group.

The study was funded by Lundbeck, where Dr. Christensen is an employee. Another author is a Lundbeck employee, and a third author reported various disclosures. Dr. Sexton reported no disclosures.

A version of this article first appeared on Medscape.com.

The antidepressant vortioxetine (Trintellix) improved cognition, memory, and depressive symptoms in patients with comorbid major depressive disorder (MDD) and dementia.

The results of the 12-week open-label, single-group study are positive, study investigator Michael Cronquist Christensen, MPA, DrPH, a director with the Lundbeck pharmaceutical company, told this news organization before presenting the results in a poster at the 15th Clinical Trials on Alzheimer’s Disease conference.

“The study confirms earlier findings of improvement in both depressive symptoms and cognitive performance with vortioxetine in patients with depression and dementia and adds to this research that these clinical effects also extend to improvement in health-related quality of life and patients’ daily functioning,” Dr. Christensen said.

“It also demonstrates that patients with depression and comorbid dementia can be safely treated with 20 mg vortioxetine – starting dose of 5 mg for the first week and up-titration to 10 mg at day 8,” he added.

However, he reported that Lundbeck doesn’t plan to seek approval from the U.S. Food and Drug Administration for a new indication. Vortioxetine received FDA approval in 2013 to treat MDD, but 3 years later the agency rejected an expansion of its indication to include cognitive dysfunction.

“Vortioxetine is approved for MDD, but the product can be used in patients with MDD who have other diseases, including other mental illnesses,” Dr. Christensen said.

Potential neurotransmission modulator

Vortioxetine is a selective serotonin reuptake inhibitor and serotonin receptor modulator. According to Dr. Christensen, evidence suggests the drug’s receptor targets “have the potential to modulate neurotransmitter systems that are essential for regulation of cognitive function.”

The researchers recruited 83 individuals aged 55-85 with recurrent MDD that had started before the age of 55. All had MDD episodes within the previous 6 months and comorbid dementia for at least 6 months.

Of the participants, 65.9% were female. In addition, 42.7% had Alzheimer’s disease, 26.8% had mixed-type dementia, and the rest had other types of dementia.

The daily oral dose of vortioxetine started at 5 mg for up to week 1 and then was increased to 10 mg. It was then increased to 20 mg or decreased to 5 mg “based on investigator judgment and patient response.” The average daily dose was 12.3 mg.

In regard to the primary outcome, at week 12 (n = 70), scores on the Montgomery-Åsberg Depression Rating Scale (MADRS) fell by a mean of –12.4 (.78, P < .0001), which researchers deemed to be a significant reduction in severe symptoms.

“A significant and clinically meaningful effect was observed from week 1,” the researchers reported.

“As a basis for comparison, we typically see an improvement around 13-14 points during 8 weeks of antidepressant treatment in adults with MDD who do not have dementia,” Dr. Christensen added.

More than a third of patients (35.7%) saw a reduction in MADRS score by more than 50% at week 12, and 17.2% were considered to have reached MDD depression remission, defined as a MADRS score at or under 10.

For secondary outcomes, the total Digit Symbol Substitution test score grew by 0.65 (standardized effect size) by week 12, showing significant improvement (P < .0001). In addition, participants improved on some other cognitive measures, and Dr. Christensen noted that “significant improvement was also observed in the patients’ health-related quality of life and daily functioning.”

A third of patients had drug-related treatment-emergent adverse events.

Vortioxetine is one of the most expensive antidepressants: It has a list price of $444 a month, and no generic version is currently available.

Small trial, open-label design

In a comment, Claire Sexton, DPhil, senior director of scientific programs and outreach at the Alzheimer’s Association, said the study “reflects a valuable aspect of treatment research because of the close connection between depression and dementia. Depression is a known risk factor for dementia, including Alzheimer’s disease, and those who have dementia may experience depression.”

Alzheimer’s Association

She cautioned, however, that the trial was small and had an open-label design instead of the “gold standard” of a double-blinded trial with a control group.

The study was funded by Lundbeck, where Dr. Christensen is an employee. Another author is a Lundbeck employee, and a third author reported various disclosures. Dr. Sexton reported no disclosures.

A version of this article first appeared on Medscape.com.